Scandium triflate and secondary amine promoted AA′B 2:1 coupling and formal inverse electron demand Diels-Alder reactions of dienals

Article abstract of DOI:10.1016/j.tet.2007.11.035

Reaction prospecting studies resulted in the discovery of a Sc(OTf)₃ promoted novel AA′B 2:1 coupling of imidazolone or benzofuran substituted enals with morpholine. A related Sc(OTf)₃/morpholine promoted reaction was demonstrated for the coupling of a benzofuran substituted enal with dihydrofuran. The formation of these adducts is consistent with formal inverse electron demand Diels-Alder cycloadditions, most likely in a stepwise manner via a domino Michael-Mannich annulation process, involving iminium ion activation of the diene. A purely amine promoted formal inverse electron demand Diels-Alder cycloaddition approach was also demonstrated in the 2:1 coupling of 2,4-hexadienal with methanol. These reactions demonstrate the concepts of dual metal/amine catalysis and amine promoted formal inverse electron demand Diels-Alder cycloadditions. They differ from known examples of organocatalyzed Diels-Alder reactions, in which iminium ion activation of the dienophiles or enamine activation of the dienes occur.

Full text of DOI:10.1016/j.tet.2007.11.035

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 652e663
www.elsevier.com/locate/tet
Scandium triflate and secondary amine promoted AA0B 2:1 coupling
and formal inverse electron demand DielseAlder reactions of dienals
*
Chris D. Smith, Robert A. Batey
Department of Chemistry, 80 St. George Street, University of Toronto, Toronto, Ontario, M5S 3H6 Canada
Received 3 October 2007; received in revised form 8 November 2007; accepted 9 November 2007
Available online 17 November 2007
Abstract
Reaction prospecting studies resulted in the discovery of a Sc(OTf)3 promoted novel AA0B 2:1 coupling of imidazolone or benzofuran
substituted enals with morpholine. A related Sc(OTf)3/morpholine promoted reaction was demonstrated for the coupling of a benzofuran
substituted enal with dihydrofuran. The formation of these adducts is consistent with formal inverse electron demand DielseAlder cycloaddi-
tions, most likely in a stepwise manner via a domino MichaeleMannich annulation process, involving iminium ion activation of the diene. A
purely amine promoted formal inverse electron demand DielseAlder cycloaddition approach was also demonstrated in the 2:1 coupling of 2,4-
hexadienal with methanol. These reactions demonstrate the concepts of dual metal/amine catalysis and amine promoted formal inverse electron
demand DielseAlder cycloadditions. They differ from known examples of organocatalyzed DielseAlder reactions, in which iminium ion
activation of the dienophiles or enamine activation of the dienes occur.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Other classes of marine alkaloids are also derived through di-
merization processes involving apparent formal cycloaddi-
tions. For example, it has been suggested that the bis-indole
DielseAlder reactions have been widely employed in the
total synthesis of alkaloid natural products.1 In certain cases
synthetic strategies to these compounds are guided or inspired
by knowledge of the respective biogenetic pathways. The pyr-
roleeimidazole family of alkaloids, for example, are exclu-
sively isolated from marine sponges, mainly the Agelasidae,
Axinellidae, and Halichondridae families (Fig. 1, 1e3).2
2-Amino-4-vinylimidazoles 1, such as the metabolites oroidin,
clathrodin, and hymenidin, are believed to be the key bioge-
netic precursors. Various modes of dimerization of 1 and re-
lated compounds are possible. Al Mourabit and Potier have
also outlined a unified proposal for the biogenesis of the
pyrroleeimidazole alkaloids through the dimerization of vinyl-
ogous 2-aminoimidazole and its tautomers.3 Ageliferin 24 and
sceptrin 35 are formally derived through dimerization via for-
mal [4þ2] and [2þ2] cycloaddition of hymenidin, respectively.
NH2
N
O
NH
H
N
Y
Br
Br
NH
NH
H
N
H2N
NH
NH
N
X
N
N
H
NH2
N
H
O
hymenidin (X = H, Y = Br)
clathrodin (X = Y = H)
oroidin (X = Y = Br)
1
O
2 ageliferin
Br
NH2
Me
N
O
O
R
O
HN
N
N
N
HN
H
Me
N
H
O
NMe
H
N
HN
N
H
N
Me
N
HN
O
O
NH2
Br
4
R = H cycloaplysinopsin A
R = OH cycloaplysinopsin B
3 sceptrin
* Corresponding author. Tel./fax: þ1 416 978 5059.
E-mail address: rbatey@chem.utoronto.ca (R.A. Batey).
Figure 1. Marine sponge alkaloids.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.035

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
653
Me
N
alkaloids, cycloaplysinopsin A and B 4 can be derived through
H
N
Me
N
formal [4þ2] dimerization6 of aplysinopsin like precursors7
(Fig. 1). Particularly intriguing is the question of whether dimer-
izations to form 2 and 4 involve either concerted or stepwise for-
mal DielseAlder reactions, as well as the nature of the enzymes
presumed to be involved in these processes.8,9
a
b, c
O
O
O
OH
OH
OH
N
Me
N
Me
N
Me
O
O
O
O
5
6
8
Me
N
Me
N
The possible occurrence of pericyclic reaction mechanisms
in marine alkaloid biogenesis, raises many intriguing possibi-
lities for potential total syntheses and analog generation.
12,120-Dimethylageliferin, an analog of ageliferin, was syn-
thesized by Ohta and co-workers, using a DielseAlder cyclo-
addition of two vinyl imidazole units.4a In model studies
toward a putative biomimetic synthesis of palau’amine,10,11
the groups of both Lovely12 and Romo13 have used vinylimid-
azoles and vinyl imidazolones as dienes in DielseAlder reac-
tions. On the other hand, attempts by Mancini and co-workers
to achieve a biomimetic DielseAlder cycloaddition between
two molecules of aplysinopsin were unsuccessful under vari-
ous conditions.6b For each of these approaches, the DielseAl-
der reactions were achieved under thermal conditions (neat in
a sealed tube at 150 ꢀC and reflux in CH2Cl2 or benzene). We
were interested in the use of iminium ion or enamine activa-
tion strategies to achieve room temperature dimerizations of
oroidin-like precursors. Activation of DielseAlder reactions
via iminium ion activation of the dienophile,14 or diene activa-
tion through enamine intermediates are well precedented.15e17
As a starting point we elected to investigate the reactions of
vinyl imidazolones as a model for oroidin dimerizations. As
a result of these reaction prospecting studies,18 we report
herein the discovery of novel metal/amine triggered formal in-
verse electron demand DielseAlder type dimerization of vinyl
imidazolones in the presence of Sc(OTf)3 catalyst. Related
systems having similar reactivity are reported, as well as a
solely amine promoted formal inverse electron demand all-
carbon DielseAlder reaction.
O
OMe
d
e
O
N
Me
N
Me
9
10
H
Me
N
Me
OH
H
O
N
g
f
O
O
N
Me
N
11
12
Me
Scheme 1. Synthesis of N,N0-dimethyl imidazolone 12. Reagents and condi-
tions: (a) (MeO)2SO2, aq NaOH, reflux (67%); (b) BnBr, NEt3, DMF; (c)
DIBAL-H, CH2Cl2, ꢁ78 ꢀC (43%, two steps); (d) MnO2, 25:1 CH2Cl2/MeOH
(86%); (e) (CF3CH2O)2P(O)CH2COOMe, K2CO3, 18-crown-6, 3:1 toluene/
THF, ꢁ20 to 0 ꢀC (64%; 12:1 Z/E ); (f) DIBAL-H, CH2Cl2, ꢁ78 ꢀC (71%;
11:1 Z/E ); (g) MnO2, CH2Cl2 (81%; 3:1 Z/E ).
H
N
p-BrBn
p-BrBn
N
N
a
b
O
O
O
OH
O
OH
N
Me
N
Me
N
Me
p-BrBn
O
O
5
13
14
p-BrBn
p-BrBn
O
OMe
N
N
c
d
O
O
O
N
Me
N
Me
15
16
H
p-BrBn
p-BrBn
OH
H
O
N
N
f
e
O
O
N
Me
N
17
18
Me
2. Results and discussion
Scheme 2. Synthesis of p-bromobenzyl substituted imidazolone 18. Reagents
and conditions: (a) NaH, p-BrBnBr, DMF, 80 ꢀC (69%); (b) DIBAL-H,
CH2Cl2, ꢁ78 ꢀC (94%); (c) MnO2, CH2Cl2 (92%); (d) (CF3CH2O)2P(O)
CH2COOMe, K2CO3, 18-crown-6, 3:1 toluene/THF, ꢁ20 to 0 ꢀC (84%; 30:1
Z/E ); (e) DIBAL-H, CH2Cl2, ꢁ78 ꢀC (94%; 16:1 Z/E ); (f) MnO2, CH2Cl2
(quantitative; 13:1 Z/E ).
The synthesis of imidazolone 12 was achieved from the
known imidazolone 519 (Scheme 1). N-Methylation of 5 using
dimethylsulfate afforded the acid 6.19 Esterification of 6 as the
benzyl ester 7, followed by reduction with DIBAL-H afforded
alcohol 8 in 43% yield after purification. The lower yield
obtained for this conversion, is in part due to the high aqueous
solubility of the alcohol 8. Subsequent oxidation of 8 with
MnO2 to aldehyde 9, followed by a StilleGennari modified
HornereWadswortheEmmons olefination gave the a,b-unsat-
urated ester 10 (12:1 Z/E ) in moderate yield.20 Reduction of
10 with DIBAL-H to alcohol 11, followed by oxidation with
MnO2 gave aldehyde 12 as a 3:1 mixture of Z and E
stereoisomers.
The p-bromobenzyl substituted imidazolone 18 was
prepared using an analogous approach to that used for the
N,N0-dimethyl imidazolone 12 (Scheme 2). The StilleGennari
modified HornereWadswortheEmmons olefination gave a,b-
unsaturated methyl ester 16 (30:1 Z/E ), which on subsequent
DIBAL-H reduction and MnO2 oxidation afforded a,b-
unsaturated aldehyde 18 in high yield as a 13:1 mixture of Z
and E stereoisomers.
With aldehydes 12 and 18 in hand, the key iminium ion
promoted dimerization could be tested. We elected to use
Sc(OTf)3 as the catalyst for iminium ion formation, since it
is known to catalyze coupling reactions between heteroaro-
matic aldehydes and secondary amines,21 and is air and water
tolerant.22 Reaction of aldehyde 12 with morpholine (1 equiv)
in the presence of catalytic Sc(OTf)3 at room temperature led
to the formation of the aldehyde cycloadduct, the precursor to
alcohol 19, as evident by the ‘downfield’ singlet observed in
1
the crude H NMR spectrum. To avoid problems of aldehyde
oxidation or dimethyl acetal formation during silica gel chro-
matography (with MeOH), the crude aldehyde mixture was

654
C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
subjected to reduction with NaBH4 in MeOH, affording alco-
hol 19 in 43% yield over two steps (Scheme 3).
methylene carbons of morpholine) and 5 nitrogen atoms. In
addition, a combination of 13Ce1H (gHSQC) and long-range
13Ce1H shift correlation (CIGAR) NMR experiments allowed
us to define the structure of 19.24 In the case of dimer 19,
three-bond coupling between C-3a and 4-CH]C in the CIGAR
experiment was absent, and only a weak coupling was observed
betweenC-5and4-CH]C. This data isconsistent with thebenz-
imidazolone and the exocyclic imidazolone moieties being
nearly orthogonal, resulting in the observation of small J-coup-
lings in the CIGAR spectrum (because of a Karplus-like rela-
tionship). These two groups are presumably forced to adopt an
orthogonal conformation due to steric constraints. Furthermore,
a ROESY experiment of 19 revealed correlations between the
alkene proton 4-CH]C and two N-methyl groups, Me-N3
and Me-N30, as well as the aromatic proton H-7 with Me-N1
and 6-CH2OH.25 The structure of dimer 20 was also deduced
through a combination of high resolution EIMS, 13C and
13Ce1H shift correlation (gHSQC), and long-range 13Ce1H
shift correlation (CIGAR) NMR experiments. Extensive 2D
NMR experimentation confirmed the structural similarity with
dimer 19. Furthermore, a ROESY experiment also confirmed
that this compound was formed with the same regiochemistry
and (E )-alkene geometry. More specifically, a ROESY correla-
tion was observed between the vinylic proton (4-CH]C) and
both the methyl group (Me-N30) of the exocyclic imidazolone
group and the benzylic protons ( p-BrPhCH2-N3) of the benz-
imidazolone moiety.
The formation of 19/20 from 12/18 and morpholine are ex-
amples of AA0B 2:1 couplings,26 in which 12/18 serves two
distinct roles in the reaction. The most plausible mechanism
for the formation of these adducts is a formal DielseAlder cy-
cloaddition reaction where the precursors 12/18 act as the
source of the diene and dienophile components. DielseAlder
reactions involving molecules serving a dual role, as both di-
ene and dienophile, have been proposed in the biogenesis of
various alkaloids, such as the manzamines,27 martinelline,28
and compounds 2 and 4. A plausible mechanism for the forma-
tion of both compounds 19 and 20 is outlined in Scheme 5.
Sc(OTf)3 catalyzes the formation of an iminium ion 22 from
morpholine and the aldehyde 21. The iminium ion 22 then un-
dergoes nucleophilic attack by a second molecule of morpho-
line, to give the enamine 23. The electron-rich enamine
dienophile 23 then reacts either with the iminium ion activated
diene 22 or with the Lewis activated electron-poor diene 21, to
give 24. Finally, elimination of morpholine from 24, followed
by an oxidation reaction and iminium ion hydrolysis estab-
lishes the benzimidazolone unit and completes the formation
of the adduct 25. The key ring formation may occur through
a concerted inverse electron demand DielseAlder reaction29,30
or it may be a stepwise process. In the case of a stepwise pro-
cess, the reaction would occur through a Michael addition of
23 onto iminium ion activated 22 (or Lewis acid activated
21) followed by an intramolecular Mannich reaction. Alterna-
tive reaction partners for the ring-forming step are also possi-
ble; for example, 6p-electrocyclization of aldehyde 21 could
lead to an enol ether, which as an electron-rich dienophile
could react with 22 in the DielseAlder reaction.31
O
1)
N
H
H
OH
H
Me
N
Me
Sc(OTf)3, CH3CN
4 Å mol. sieves
7
1N
7a
3a
H
H
O
6
2
O
O
5
O
2) NaBH4, MeOH
43%, 2 steps
N
Me
3 N
Me
4
2"
H
N
12
5'
M3e"
N1'
O
4' N
19
2'
3'
Me
Scheme 3. Morpholine and Sc(OTf)3 promoted formal DielseAlder
reaction of 12.
a,b-Unsaturated imidazolone aldehyde 18 underwent ana-
logous Sc(OTf)3 catalyzed dimerization in the presence of
morpholine (1 equiv), to afford the corresponding 2:1 adduct
20; albeit, in lower yield (Scheme 4). In order to determine
the influence of the a,b-unsaturated aldehyde geometry, the
(E )-isomer of 12 (isolated after slow isomerization of the
(Z )-isomer of 12) was subjected to the Sc(OTf)3 catalyzed
conditions. Comparison of the aldehyde proton resonances in
1
the crude H NMR showed a 5.5:4:1 ratio of the cycloadduct
(i.e., the aldehyde precursor of dimer 19), unreacted (E )-iso-
mer of 12, and aldehyde 9, presumably formed via conjugate
addition of morpholine to 12 followed by a retro-Mannich re-
action. In contrast, reaction of the (Z )-isomer of aldehyde 12
resulted in a 10:0:1 ratio of 19/(E )-12/9 as determined in the
crude 1H NMR. The geometry of the a,b-unsaturated aldehyde
thus seems to play a role in the efficiency of the reaction, with
the (Z )-isomer 12 reacting more efficiently. Reaction of the
(Z )-a,b-unsaturated aldehyde under general Lewis acidic con-
ditions, but in the absence of morpholine, resulted in complete
isomerization to the (E )-isomer, without any evidence for the
formation of dimerized products or other adducts. In the ab-
sence of Sc(OTf)3, the 2:1 adducts were formed, but at a slower
rate, and incomplete consumption of the imidazolone alde-
hydes was observed.
O
Br
H
O
H
Me
N
N
H
H
O
Sc(OTf)3, CH3CN
4 Å mol. sieves
O
H
O
N
N
N
O
H
N
N
25%
H
N
O
Me
18
Me
Br
20
Br
Scheme 4. Morpholine and Sc(OTf)3 promoted formal DielseAlder
reaction of 18.
The structures of adducts 19 and 20 were determined by
a combination of NMR23 and MS experiments. 13C NMR,
1
13Ce1H shift correlation (gHSQC), and long-range He15N
shift correlation (gHMBC) NMR experiments on 19, confirmed
the presence of 20 carbon atoms (two resonances for the four

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
655
CO2Et
O
O
CHO
Me
N
Me
N
N
H
a
N
O
O
Sc(OTf)3
– OH
OH
26
O
O
O
N
R
N
R
H
O
–
27
28
HN
21
22
OH
CHO
O
O
N
b
c
d
Me
N
22
Me
N
O
O
N
O
[4+2]
29
30
O
N
R
O
O
N
N
R
O
N
O
H
N
O
N
O
H
N
N
N
31
CHO
H
RN
H
RN
23
O
24
OH
N
+ H2O
Me
Me
O
– 2 morpholine
O
O
H
N
O
O
H
32
double
elimination
O
N
O
H
H
O
H
H
Me
+ H2O
– 2 morpholine
[O]
N
25
O
O
N
R
H
N
H
N
Scheme 6. Synthesis and DielseAlder dimerization of a,b-unsaturated benzo-
furan 30. Reagents and conditions: (a) Ph3PCHCO2Et, CH2Cl2 (90%); (b)
DIBAL-H, CH2Cl2, ꢁ78 ꢀC (99%); (c) MnO2, CHCl3, 50 ꢀC (78%); (d)
morpholine (1.0 equiv), Sc(OTf)3 (10 mol %), CH3CN, 60 ꢀC (15%).
R
H
N
O
Me
Scheme 5. Proposed formal DielseAlder mechanism for the formation of the
2:1 adducts.
allylic alcohol 29. Subjection of benzofuran 30 to the Sc(OTf)3
catalyzed conditions previously described resulted in no reac-
tion at room temperature. However, heating the reaction mix-
ture to 60 ꢀC resulted in the formation of the AA0B 2:1 adduct
32, albeit in only 15% yield (Scheme 6). The low yield ob-
tained for compound 32 can be attributed to the complex mix-
ture of side-products obtained, which include aldehyde 27
obtained from a retro-Mannich reaction after conjugate addi-
tion of morpholine, and the formation of several oligomeric
by-products. The structure of 32 was deduced through a com-
bination of homonuclear and heteronuclear 2D NMR experi-
ments.23 Formation of 32 can occur through double
elimination from 31.
The results described above can be rationalized as involv-
ing dual activation by both the Lewis acid and the secondary
amine.34 However, these examples do not distinguish between
a stepwise MichaeleMannich process and a concerted Dielse
Alder process. The nature of the catalysis cannot be defini-
tively established from these examples and may be through
enamine activation of the dienophile and/or iminium ion
activation of the diene. Enamine activation of the dienophile
component seems likely given the presence of the amine in
the adducts 19, 20, and 32, but iminium ion catalysis of the di-
ene component is also possible. This type of activation is quite
unusual in the context of organocatalytic DielseAlder reactions,
where the dienophile35 is usually activated through iminium
ion catalysis or the diene through enamine activation.15e17,36
Indeed, to the best of our knowledge there are no reported
examples of organocatalyzed intermolecular inverse electron
demand DielseAlder reactions that form carbocycles.32,37
To probe for the involvement of iminium ion activation of
the diene in inverse electron demand formal DielseAlder re-
actions, an investigation of the possibility of coupling
While it is recognized that the formation of these adducts
25 occurs in low yield, this mode of dual activation for an in-
termolecular formal inverse electron demand DielseAlder re-
action is unprecedented.32 The low yields can be attributed to
the enhanced reactivity of these iminium ion activated dienals,
thus leading to several other potential reaction pathways. More
specifically, several electrophilic positions along the dienal
backbone can lead to undesired side reactions. For example,
the major side reaction observed is a retro-Mannich process,
which results in degradation of the dienal precursors to give
aldehydes 9 and 15. Moreover, intermediate 22 could undergo
1,2- and 1,4-addition reactions with enamine 23. The ambiva-
lent reactivity of these dienal precursors is largely responsible
for the diversity in the reaction pathways thus leading to mul-
tiple products. This behavior is in accord with the ambivalent
reactivity of vinylogous 2-aminoimidazoles that has been pos-
tulated in the literature.3
In view of the results obtained with the reactions of imida-
zolones 12 and 18, we then became interested in whether other
heterocycles bearing a,b-unsaturated aldehyde functionality
would undergo this unique mode of dimerization, acting as
electron-poor dienes in formal inverse electron demand
DielseAlder reactions. We elected to test this hypothesis
with the a,b-unsaturated benzofuran aldehyde 30 (Scheme
6). The preparation of 30 involved a similar approach to the
imidazolones described previously. Wittig olefination of
3-benzofuran carboxaldehyde 2733 provided exclusively the
(E )-a,b-unsaturated ester 28 in 90% yield, with none of the
(Z )-isomer detected by 1H NMR. Finally, the two-step conver-
sion to aldehyde 30 was accomplished in high yield by
DIBAL-H reduction of 28, followed by MnO2 oxidation of

656
C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
electron-poor diene substrates with other electron-rich dieno-
philes was undertaken. Accordingly, treatment of benzofuran
30 with excess 2,3-dihydrofuran 33 (3 equiv) in the presence
of L-proline (1.0 equiv) and catalytic Sc(OTf)3 (10 mol %) re-
sulted in the formation of aldehyde 35 (Scheme 7). In this case
cycloaddition was not observed in the presence of Sc(OTf)3
alone, presumably indicating iminium ion activation of diene
30 by L-proline. Cycloaddition would thus proceed via inter-
mediate 34 followed by consecutive double elimination and
hydrolysis of the iminium ion. This is similar to the mecha-
nism proposed by Bodwell for the reaction of enamines with
chromone-fused electron-deficient dienes to give 2-hydroxy-
benzophenones.38 Conversely the formation of 25, involves
a domino formal inverse electron demand DielseAlder cyclo-
addition/elimination/oxidation process (Scheme 5), similar to
that observed by Bodwell in the reactions of enamines with
coumarin-fused electron-deficient dienes.39 It is interesting
to note that attempts to achieve thermal or Lewis acid acti-
vated DielseAlder reaction of these dienes with enol ethers
were unsuccessful,39 in contrast to the reaction of 30 with 33.
activation pathway. The absence of a Lewis acid in this reac-
tion unequivocally shows amine activation by L-proline. The
most plausible mechanism involves a formal DielseAlder
cycloaddition via intermediate 43, followed by elimination
of L-proline, ring-oxidation to the aromatic ring, and iminium
ion hydrolysis.
The difficulties of determining whether DielseAlder
reactions occur through concerted or stepwise processes are
well known. The experiments outlined herein are similarly
problematic, and the reactions may occur via stepwise
MichaeleMannich, or concerted DielseAlder mechanisms.
It is perhaps more likely that the reactions occur via a stepwise
mechanism, but the more inclusive term of formal inverse
electron demand DielseAlder reaction serves to describe
both mechanisms. Stepwise mechanisms have been proposed
in other organocatalyzed DielseAlder reactions, such as for
the examples described by Hong and co-workers.41
Finally, it is instructive to consider the various dimerization
pathways that can be considered to occur through such formal
DielseAlder reactions, whether of synthetic or biogenetic or-
igin (Fig. 2). The formal DielseAlder dimerization pathways
postulated for ageliferin 2 and cycloaplysinopsin A 4 can be
considered to result from C2eC20/C5eC30 and C2eC30/
C5eC20 bond constructions, via 47 and 48, respectively. Bald-
win’s biogenetic proposal for manzamine involves C1eC20/
C4eC30 bond construction through a normal electron demand
DielseAlder reaction of intermediate 49.27 The results of
Hong and co-workers also involve a C1eC20/C4eC30 bond
construction via 50.41 Conversely, the formal inverse electron
demand DielseAlder reactions postulated in the present study
occur via C2eC10/C5eC20 bond construction,32 i.e., through
51. To the best of our knowledge this latter type of reactivity
is quite unusual, and has not been observed in any known di-
meric natural products, although related synthetic examples
have been reported by Hong and Bodwell.32,38,39
O
COOH
33
N
L-proline
10 mol% Sc(OTf)3
CH3CN-H2O
CHO
H
O
20%
O
O
H
30
34
CHO
+ H2O
- L-proline
35
double
elimination
OH
OH
Scheme 7. DielseAlder cycloaddition of 30 with 2,3-dihydrofuran.
A variation of these conditions was applied to a non-hetero-
cycle derived dienal. However, in the reaction of sorbic alde-
hyde 42 and 2,3-dihydrofuran 33, the major product isolated
did not incorporate the dienophile 33.40 Instead a 3,4-
substituted benzaldehyde 44 was isolated, arising from
a AA0B 2:1 coupling of the diene 42 and MeOH (Scheme 8).
Reaction of 42 with L-proline and Sc(OTf)3 also gave 44 in
low yield, with a considerable amount of unidentified by-
O
Me
N
O
1
Br
HN
1
3
O
3
4
H
N
2
2
4
5
HN
N
5
Me
H2N
N
H
N
4'
3'
NMe
1'
2'
2'
3'
4'
HN
HN
O
1' N
Me
5'
HN
N
1
Br
products revealed by the crude H NMR analysis. Again, in
the absence of catalytic proline dimerization did not occur,
indicating the importance of the iminium ion/enamine
5'
H
O
N
O
H2N
48
47
3
4
3
2
4
5
Y
2
NR2
NR2
1
2
3
4
NR2
N
COOH
X
1
CHO
N
N
X
L-proline
+ H2O
1'
CHO
NR2
4'
2'
(40 mol%)
– 2 L-proline
COOH
2'
3'
H
1'
Nu 5'
X
3'
N
MeOH
[O]
Me
Me
Me
Me
4'
3'
2'
X
H
4'
1'
Me
Y
16%
42
43
44
49
50
51
OMe
OMe
Figure 2. Overview of dimerization pathways and bond-connectivities in syn-
thetic and biosynthetic formal DielseAlder reactions.
Scheme 8. Methanol and L-proline promoted DielseAlder dimerization of 42.

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
657
3. Conclusions
(Spectroline, Longlife Filter) and stained with 20% phospho-
molybdic acid in ethanol, 7% (w/w) aqueous potassium per-
manganate, 2,4-dinitrophenylhydrazine (DNP), or ethanolic
As part of prospecting studies for unique reactions of
vinylogous heterocycles using amine catalysis, novel AA0B
2:1 coupling reactions of vinylogous imidazolone aldehydes
12 and 18 with morpholine have been discovered. Product for-
mation (19 and 20) can be rationalized in terms of formal
inverse electron demand DielseAlder reactions (or a domino
MichaeleMannich reaction), possibly via iminium ion activa-
tion of the diene. The plausibility of such an activation path-
way is supported by the formation of the 2:1 adducts 32 and
44, and the 1:1 adduct 35. Formation of 35 is proposed to oc-
cur via the reaction of the electron-rich dienophile dihydro-
furan with an iminium ion activated electron-poor diene
derived from 2,4-dienal 30. Adducts 32 and 44 are formed
via dimerization of 2,4-dienal precursors 30 and 42, respec-
tively, which under amine activation conditions serve as the
source of both the electron-poor diene and electron-rich dien-
ophile components. In most cases dual activation by the amine
and Lewis acid catalysts was utilized. Lewis acidic catalysis
alone did not promote coupling reactions. However, the forma-
tion of 44 was accomplished in the presence of L-proline
alone, and is therefore an example of an amine promoted for-
mal inverse electron DielseAlder reaction. In combination
these novel coupling reactions represent, to the best of our
knowledge, the first examples of amine activated intermolecu-
lar formal inverse electron DielseAlder reactions producing
carbocyclic products. These reactions demonstrate a unique
mode of reactivity, thus far unobserved in the context of amine
activation or organocatalysis. The current studies also delin-
eate problems with this approach, including the greater chal-
lenge associated with achieving carbocyclic inverse electron
demand DielseAlder reactions compared to normal electron
demand DielseAlder reactions, as well as several possible
side reactions that can occur with the omniphilic dienal sys-
tems, such as retro Aldol-like reactions. Further studies are
required to achieve high yielding reactions. Nevertheless these
studies suggest the possibility of developing organocatalytic
variants of inverse electron demand DielseAlder reactions,
a reaction class that, despite the considerable recent interest
in organocatalysis, has received limited investigation.
˚
ninhydrin. Flash columns were packed with 60 A, 230e400
mesh silica gel (Silicycle Inc.). Melting points were obtained
on a Fisher-Johns melting point apparatus and are uncorrected.
FTIR spectra were obtained on a PerkineElmer Spectrum
1000 with samples loaded as thin films on NaCl plates. Low
resolution mass spectra (LRMS) were recorded on a Bell
and Howell 21-490 spectrometer. High resolution mass spectra
(HRMS) were recorded on a AEI MS3074 spectrometer. Pro-
ton nuclear magnetic resonance spectra (1H NMR) were re-
corded at 300 MHz (Varian Mercury or Gemini), 400 MHz
(Varian Unity), or at 500 MHz (Varian Unity). Carbon nuclear
magnetic resonance spectra (13C NMR) were obtained at
50 MHz (Gemini), 75 MHz (Mercury or Gemini), or at
100 MHz (Unity). Proton chemical shifts were internally refer-
enced to TMS or to the residual proton resonance in CDCl3
(d 7.26) or DMSO-d6 (d 2.50). Carbon chemical shifts were in-
ternally referenced to TMS or to the deuterated solvent signals
in CDCl3 (d 77.23) or DMSO-d6 (d 39.52). Chemical shifts are
reported in parts per million (d) and coupling constants (J ) are
reported in hertz (Hz). The following abbreviations are used to
explain the multiplicities: s¼singlet; d¼doublet; dd¼doublet
of doublets; dt¼doublet of triplets; t¼triplet; q¼quartet;
m¼multiplet. Spectral data are provided for all new com-
pounds and for compounds that lack full characterization in
the literature.
4.1.1. 4-Hydroxymethyl-1,3-dimethyl-1,3-dihydroimidazol-
2-one (8)
To a suspension of 619 (5.00 g, 32.0 mmol) in anhydrous
DMF (80 mL) was added NEt3 (8.9 mL, 64.0 mmol) followed
by benzyl bromide (9.5 mL, 80.0 mmol) and the resultant mix-
ture was stirred overnight at room temperature. The reaction
mixture was diluted with H2O (40 mL) and brine (90 mL), and
after vigorous stirring the mixture was further diluted with
EtOAc (300 mL). The aqueous phase was separated and ex-
tracted with EtOAc (2ꢂ50 mL). The combined organic extracts
were washed with brine (4ꢂ50 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo. The crude material was sub-
jected to flash chromatography on silica gel, eluting with 3:7
hexanes/EtOAc, to afford impure 1,3-dimethyl-2-oxo-2,3-dihy-
dro-1H-imidazole-4-carboxylic acid benzyl ester (7) as a color-
less oil. To a solution of this material (8.00 g) in CH2Cl2
(170 mL) at ꢁ78 ꢀC was added a 1.0 M solution of DIBAL-H
in hexanes (80.0 mL, 80.0 mmol). After 2 h an additional por-
tion of DIBAL-H (50.0 mL, 50.0 mmol) was added, and the re-
sultant mixture was stirred for an additional 2 h. The reaction
mixture was quenched with MeOH (8 mL), the cooling bath
was removed, and a saturated solution of Rochelle’s salt
(150 mL) was added. After stirring overnight at room tempera-
ture, the aqueous phase was separated, washed with CHCl3
(2ꢂ100 mL), and concentrated in vacuo. The residual salts
were extracted with CHCl3 (3ꢂ100 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo to provide 8 (1.96 g, 43% over
two steps) as a white solid, mp 110e112 ꢀC. The alcohol was
4. Experimental section
4.1. General
Reactions were conducted under an atmosphere of nitrogen
unless otherwise stated. Solvents were distilled before use and
transferred via syringe using standard techniques: acetonitrile
(CH3CN) and dichloromethane (CH2Cl2) from calcium hy-
dride, diethyl ether (Et2O) and tetrahydrofuran (THF) from so-
dium-benzophenone ketyl and toluene from sodium. All other
solvents were obtained as ACS or anhydrous grade. Commer-
cial reagents and solutions were used as received unless other-
wise stated. Thin layer chromatography (TLC) was performed
on aluminum-backed plates of silica precoated with Alugram
SIL/G/UV254 (Silicycle Inc.), visualized with a UV254 lamp

658
C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
used without further purification. IR (thin film) 3420, 2942,
2880, 1652, 1482, 1426, 1407, 1235, 1171, 1008, 786, 744,
H in hexanes (1.9 mL, 1.9 mmol). After 3 h, the reaction mix-
ture was quenched with a saturated solution of Rochelle’s salt
(1.0 mL) and then the cooling bath was removed. After stirring
for 1.5 h at room temperature, Na2SO4 was added and the mix-
ture was filtered over Celite. The Celite pad was washed with
CH2Cl2 (50 mL) and the filtrate was concentrated in vacuo to
provide 11 (74.3 mg, 71%, 11:1 Z/E ) as a yellow oil. The al-
cohol was used without further purification. IR (thin film)
3404, 3126, 2947, 2880, 1668, 1471, 1426, 1404, 1076,
1
685 cmꢁ1; H NMR (400 MHz, CDCl3) d 6.14 (1H, s), 4.40
(2H, d, J¼5.5 Hz), 3.29 (3H, s), 3.22 (3H, s), 2.64 (1H, t,
J¼5.5 Hz); 13C NMR (75 MHz, CDCl3) d 153.9, 122.8, 109.7,
54.9, 30.4, 27.8; MS (EI) m/e (rel intensity) 143 (17), 142
(100), 141 (17), 126 (14), 125 (99); HRMS (EI) m/e calcd for
C6H10N2O2 [Mþ]: 142.0742; found: 142.0738.
1
4.1.2. 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-
carbaldehyde (9)
1031, 802, 748 cmꢁ1; H NMR (300 MHz, CDCl3) d 6.18
(1H, s), 6.09 (1H, d, J¼12.0 Hz), 5.86e5.93 (1H, m), 4.32
(1H, d, J¼1.5 Hz), 4.30 (1H, d, J¼1.5 Hz), 3.29 (3H, s),
3.22 (3H, s); 13C NMR (75 MHz, CDCl3) d 153.3, 131.3,
119.6, 116.2, 111.7, 60.0, 30.7, 27.8; MS (EI) m/e (rel inten-
sity) 169 (12), 168 (86), 139 (26), 125 (100), 112 (20), 110
(13), 94 (46); HRMS (EI) m/e calcd for C8H12N2O2 [Mþ]:
168.0899; found: 168.0901.
To a solution of 8 (1.96 g, 13.8 mmol) in CH2Cl2/MeOH
(100:4 mL) at room temperature was added activated MnO2
(10.2 g, 99.3 mmol). The resultant black suspension was
stirred overnight, filtered through Celite, and the filtrate was
concentrated in vacuo. Purification by flash chromatography
on silica gel, eluting with EtOAc, afforded aldehyde 9
(1.23 g, 86% based on recovered starting material) as a white
solid, mp 142e144 ꢀC. IR (thin film) 3154, 3084, 2792, 1698,
1662, 1579, 1466, 1407, 1318, 1286, 1181, 1060, 910, 855,
4.1.5. 3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazol-4-
yl)-propenal (12)
1
744 cmꢁ1; H NMR (300 MHz, CDCl3) d 9.27 (1H, s), 7.06
To a solution of 11 (0.182 g, 1.08 mmol) in CH2Cl2
(10 mL) at room temperature was added activated MnO2
(0.920 g, 8.99 mmol). The resultant black suspension was
stirred overnight, but incomplete consumption of the alcohol
was observed. To the black suspension was added more acti-
vated MnO2 (0.400 g, 3.91 mmol) and the reaction mixture
was stirred for an additional 3 h. The mixture was filtered
through Celite and the filtrate was concentrated in vacuo to af-
ford the aldehyde 12 (0.145 g, 81%, 3:1 Z/E ) as an orange oil.
IR (thin film) 3443, 3276, 2935, 1660, 1615, 1575, 1465,
(1H, s), 3.56 (3H, s), 3.40 (3H, s); 13C NMR (75 MHz,
CDCl3) d 177.0, 153.7, 128.2, 123.6, 31.3, 29.9; MS (EI) m/e
(rel intensity) 141 (20), 140 (100), 112 (10), 111 (32); HRMS
(EI) m/e calcd for C6H8N2O2 [Mþ]: 140.0586; found:
140.0583.
4.1.3. 3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazol-
4-yl)-acrylic acid methyl ester (10)
To a solution of 18-crown-6 (3.11 g, 11.8 mmol) in toluene
(28 mL) was added oven-dried K2CO3 (0.828 g, 5.99 mmol)
at room temperature and the resultant suspension was stirred
for 2 h. After cooling to ꢁ20 ꢀC, a solution of 9 (0.260 g,
1.86 mmol) in THF (12 mL) was added followed by
bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate
(0.651 g, 2.05 mmol). The resultant mixture was allowed to
warm to room temperature and stirred for 1.5 h. The yellow re-
action mixture was diluted with H2O (20 mL) and CHCl3
(110 mL), and the phases were separated. The organic phase
was washed with brine (2ꢂ20 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo. Purification by flash chroma-
tography on silica gel, eluting with EtOAc, afforded 10
(0.235 g, 64%, 12:1 Z/E ) as a yellow oil. IR (thin film)
3436, 3174, 2980, 2953, 1762, 1715, 1677, 1620, 1567,
1451, 1397, 1297, 1273, 1197, 1175, 1069, 943, 820, 747,
1
1398, 1287, 1161, 1131, 1064, 964, 797, 777, 742 cmꢁ1; H
NMR (300 MHz, CDCl3) d 9.81 (1H, d, J¼5.5 Hz), 9.53
(1H, d, J¼7.5 Hz), 7.48 (1H, s), 7.01 (1H, d, J¼16.0 Hz),
6.81 (1H, s), 6.79 (1H, d, J¼12.0 Hz), 6.43 (1H, dd, J¼16.0,
7.5 Hz), 6.15 (1H, dd, J¼12.0, 5.5 Hz), 3.44 (3H, s), 3.36
(3H, s), 3.35 (3H, s), 3.31 (3H, s); 13C NMR (75 MHz,
CDCl3) d 192.8, 189.2, 154.0, 153.2, 137.5, 129.8, 124.8,
123.7, 120.2, 119.7, 119.1, 118.7, 31.1, 30.9, 29.2, 27.7; MS
(EI) m/e (rel intensity) 167 (19), 166 (100), 138 (44), 137
(24), 112 (28), 109 (56); HRMS (EI) m/e calcd for
C8H10N2O2 [Mþ]: 166.0742; found: 166.0746. Slow isomeri-
zation of the 3:1 Z/E mixture to the (E )-isomer occurred
over several days. IR (thin film) 3428, 3142, 3092, 2925,
1695, 1667, 1616, 1576, 1464, 1397, 1308, 1286, 1160,
1
1130, 1063, 965, 799, 778, 742 cmꢁ1; H NMR (400 MHz,
1
653 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.08 (1H, s), 6.50
CDCl3) d 9.52 (1H, d, J¼7.5 Hz), 7.02 (1H, d, J¼16.0 Hz),
6.81 (1H, s), 6.43 (1H, dd, J¼16.0, 7.5 Hz), 3.44 (3H, s),
3.36 (3H, s); 13C NMR (100 MHz, CDCl3) d 193.0, 154.1,
137.7, 123.9, 120.4, 118.9, 31.1, 29.4; MS (EI) m/e (rel inten-
sity) 167 (12), 166 (100), 138 (51), 137 (27), 112 (36), 109
(86), 81 (70), 68 (63), 54 (77); HRMS (EI) m/e calcd for
C8H10N2O2 [Mþ]: 166.0742; found: 166.0742.
(1H, d, J¼12.5 Hz), 5.75 (1H, d, J¼12.5 Hz), 3.75 (3H, s),
3.34 (3H, s), 3.30 (3H, s); 13C NMR (50 MHz, CDCl3)
d 166.9, 153.2, 128.2, 121.4, 118.8, 113.3, 51.5, 30.9, 27.6;
MS (EI) m/e (rel intensity) 196 (55), 180 (47), 167 (14), 165
(26), 153 (37), 113 (26), 82 (56), 68 (100); HRMS (EI) m/e
calcd for C9H12N2O3 [Mþ]: 196.0848; found: 196.0855.
4.1.4. 4-(3-Hydroxypropenyl)-1,3-dimethyl-1,3-
dihydroimidazol-2-one (11)
To a solution of 10 (0.122 g, 0.622 mmol) in CH2Cl2
(7.0 mL) at ꢁ78 ꢀC was added a 1.0 M solution of DIBAL-
4.1.6. 1-(4-Bromobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-
imidazole-4-carboxylic acid 4-bromobenzyl ester (13)
To a slurry of 95% NaH (0.186 g, 7.75 mmol) in anhydrous
DMF (7.0 mL) at 0 ꢀC was added 519 (0.307 g, 2.16 mmol),

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
659
after which the ice bath was removed and the reaction mixture
was allowed to warm to room temperature. After stirring for
30 min, 4-bromobenzyl bromide (1.85 g, 7.40 mmol) was
added and the resultant mixture was heated to 80 ꢀC and
stirred overnight. The reaction mixture was diluted with water
(5 mL) and brine (10 mL), and the mixture was vigorously
stirred for 30 min. This mixture was further diluted with
EtOAc (70 mL) and the phases were separated. The combined
organic layers were washed with brine (4ꢂ15 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel, eluting with 2:1
then with 1:1 hexanes/EtOAc, gave 13 (0.71 g, 69%) as a yel-
low solid, mp 128e130 ꢀC. IR (thin film) 3447, 3106, 2942,
1719, 1690, 1588, 1489, 1460, 1395, 1351, 1240, 1169,
1577, 1489, 1467, 1422, 1405, 1339, 1163, 1070, 1012, 910,
802, 739, 717 cmꢁ1 1H NMR (400 MHz, CDCl3) d 9.23
;
(1H, s), 7.51 (2H, d, J¼8.0 Hz), 7.18 (2H, d, J¼8.0 Hz),
6.93 (1H, s), 4.84 (2H, s), 3.58 (3H, s); 13C NMR (75 MHz,
CDCl3) d 177.2, 153.4, 134.4, 132.4, 130.0, 126.5, 124.1,
122.8, 47.4, 30.0; MS (EI) m/e (rel intensity) 296 (24), 294
(25), 171 (100), 169 (99), 90 (58); HRMS (EI) m/e calcd for
C12H BrN2O2 [Mþ]: 294.0004; found: 293.9996.
79
11
4.1.9. 3-[1-(4-Bromobenzyl)-3-methyl-2-oxo-2,3-dihydro-
1H-imidazol-4-yl]-acrylic acid methyl ester (16)
To a solution of 18-crown-6 (10.8 g, 41.0 mmol) in toluene
(65 mL) was added oven-dried K2CO3 (2.80 g, 20.3 mmol) at
room temperature and the resultant suspension was stirred
for 1 h. After cooling to ꢁ20 ꢀC, a solution of 15 (1.50 g,
5.09 mmol) in THF (20 mL) was added followed by
bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate
(1.3 mL, 6.15 mmol). The resultant mixture was allowed to
warm to room temperature and was stirred for 2 h. The yellow
reaction mixture was diluted with H2O (50 mL) and EtOAc
(200 mL), and the phases were separated. The organic phase
was washed with H2O (1ꢂ50 mL) and brine (2ꢂ50 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash chromatography on silica gel, eluting with 1:1 then
1:2 hexanes/EtOAc, afforded 16 (1.51 g, 84%, 30:1 Z/E ) as
a yellow oil. IR (thin film) 3348, 3170, 2950, 1715, 1693,
1618, 1565, 1489, 1450, 1406, 1361, 1256, 1198, 1166,
1089, 1069, 1012, 800, 730 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 7.45e7.52 (4H, m), 7.24 (2H, d, J¼8.5 Hz), 7.15
(2H, d, J¼8.5 Hz), 6.97 (1H, s), 5.16 (2H, s), 4.78 (2H, s),
3.53 (3H, s); 13C NMR (75 MHz, CDCl3) d 159.3, 153.4,
135.0, 134.7, 132.3, 132.0, 130.3, 129.9, 122.8, 122.5,
119.9, 114.5, 65.6, 47.2, 29.9; MS (EI) m/e (rel intensity)
482 (27), 481 (13), 480 (44), 478 (27), 172 (12), 171 (98),
170 (13), 169 (100), 90 (35); HRMS (EI) m/e calcd for
C19H Br2N2O3 [Mþ]: 477.9528; found: 477.9532.
79
16
4.1.7. 1-(4-Bromobenzyl)-4-hydroxymethyl-3-methyl-1,3-
dihydroimidazol-2-one (14)
To a solution of 13 (4.07 g, 8.48 mmol) in CH2Cl2 (85 mL)
at ꢁ78 ꢀC was added a 1.0 M solution of DIBAL-H in hexanes
(25.4 mL, 25.4 mmol) and the resultant mixture was stirred for
3 h. The reaction mixture was quenched with MeOH (5 mL),
after which the cooling bath was removed and a saturated so-
lution of Rochelle’s salt (75 mL) was added. After stirring for
2 h at room temperature, the mixture was diluted with EtOAc
(160 mL), and the aqueous phase was separated and extracted
with CH2Cl2 (2ꢂ25 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel, eluting with
95:4:1 CH2Cl2/MeOH/NH4OH, afforded 14 (2.38 g, 94%) as
a white solid, mp 138e140 ꢀC. IR (thin film) 3420, 2928,
2860, 1661, 1488, 1470, 1407, 1160, 1070, 1012, 777,
1
1103, 1070, 1012, 818, 800, 756 cmꢁ1; H NMR (400 MHz,
CDCl3) d 8.05 (1H, s), 7.46 (2H, d, J¼8.0 Hz), 7.19 (2H, d,
J¼8.0 Hz), 6.49 (1H, d, J¼12.5 Hz), 5.76 (1H, d,
J¼12.5 Hz), 4.82 (2H, s), 3.72 (3H, s), 3.31 (3H, s); 13C
NMR (100 MHz, CDCl3) d 166.8, 152.8, 135.7, 132.1,
129.8, 128.0, 122.1, 119.8, 119.3, 114.0, 51.6, 47.2, 27.7;
MS (EI) m/e (rel intensity) 352 (45), 350 (44), 181 (24), 171
(99), 169 (100), 126 (17), 90 (29); HRMS (EI) m/e calcd for
79
15
C15H BrN2O3 [Mþ]: 350.0266; found: 350.0262.
4.1.10. 1-(4-Bromobenzyl)-4-(3-hydroxypropenyl)-3-
methyl-1,3-dihydroimidazol-2-one (17)
To a solution of 16 (1.51 g, 4.30 mmol) in CH2Cl2 (50 mL)
at ꢁ78 ꢀC was added a 1.0 M solution of DIBAL-H in hexanes
(13.0 mL, 13.0 mmol) and the resultant mixture was stirred for
2 h. The reaction mixture was quenched with MeOH (4 mL),
and then the cooling bath was removed and a saturated solu-
tion of Rochelle’s salt (50 mL) was added. After stirring for
2.5 h at room temperature, the mixture was diluted with
CH2Cl2 (50 mL), and the aqueous phase was separated and
further extracted with CH2Cl2 (2ꢂ25 mL). The combined or-
ganic extracts were dried over Na2SO4, filtered, and concen-
trated in vacuo to afford 17 (1.31 g, 94%, 16:1 Z/E ) as
a yellow solid, mp 74e76 ꢀC. IR (thin film) 3384, 2928,
2867, 1668, 1488, 1456, 1405, 1351, 1070, 1042, 1012,
743 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.46 (2H, d,
;
J¼8.5 Hz), 7.15 (2H, d, J¼8.5 Hz), 6.08 (1H, s), 4.72 (2H,
s), 4.39 (2H, d, J¼5.5 Hz), 3.34 (3H, s), 1.59 (1H, t,
J¼5.5 Hz); 13C NMR (75 MHz, CDCl3) d 153.7, 136.0,
132.0, 129.8, 123.2, 122.0, 108.3, 55.2, 46.6, 27.9; MS (EI)
m/e (rel intensity) 298 (60), 296 (67), 171 (100), 169 (99),
79
127 (21), 99 (12); HRMS (EI) m/e calcd for C12H BrN2O2
13
[Mþ]: 296.0160; found: 296.0153.
4.1.8. 1-(4-Bromobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-
imidazole-4-carbaldehyde (15)
To a solution of 14 (2.37 g, 7.99 mmol) in CH2Cl2 (80 mL)
at room temperature was added activated MnO2 (7.06 g,
69.0 mmol). The resultant black suspension was stirred over-
night, filtered through Celite, and the filtrate was concentrated
in vacuo to afford 15 (2.18 g, 92%) as a white solid, mp 105e
107 ꢀC. IR (thin film) 3419, 3095, 2942, 2819, 1702, 1659,
797 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.45 (2H, d,
;
J¼8.5 Hz), 7.14 (2H, d, J¼8.5 Hz), 6.09 (1H, s), 6.06 (1H,
d, J¼11.0 Hz), 5.84e5.93 (1H, m), 4.76 (2H, s), 4.23 (2H,
d, J¼6.5 Hz), 3.24 (3H, s); 13C NMR (75 MHz, CDCl3)
d 153.0, 135.8, 132.1, 131.9, 129.6, 122.1, 120.4, 115.8,

660
C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
110.0, 59.9, 46.8, 27.9; MS (EI) m/e (rel intensity) 324 (62),
322 (61), 171 (99), 169 (100), 153 (59), 110 (49), 98 (31),
m, H-200), 3.15e3.22 (2H, m, H-200), 3.07 (3H, s, Me-N30),
2.92 (3H, s, Me-N10), 2.42e2.48 (2H, m, H-300), 2.19e2.26
79
13
97 (19), 90 (61); HRMS (EI) m/e calcd for C14H BrN2O2
(2H, m, H-300); C NMR (75 MHz, CDCl3) d 157.1 (C-20),
15
[Mþ]: 322.0317; found: 322.0314.
155.4 (C-2), 140.5 (C-40), 134.3 (C-6), 131.0 (C-7a), 127.1
(C-3a), 122.0 (C-5), 119.5 (C-4), 104.9 (C-7), 96.1 (4-
CH]C), 77.2 (C-50), 67.2 (C-200), 65.5 (6-CH2OH), 47.6
(C-300), 30.3 (Me-N3), 29.8 (Me-N10), 27.6 (Me-N1), 27.1
(Me-N30); MS (EI) m/e (rel intensity) 401 (11), 316 (27),
315 (100), 313 (12), 125 (20), 100 (31); HRMS (EI) m/e calcd
for C20H27N5O4 [Mþ]: 401.2063; found: 401.2069.
4.1.11. 3-[1-(4-Bromobenzyl)-3-methyl-2-oxo-2,3-dihydro-
1H-imidazol-4-yl]-propenal (18)
To a solution of 17 (1.21 g, 3.74 mmol) in CH2Cl2 (40 mL)
at room temperature was added activated MnO2 (3.00 g,
29.3 mmol). The resultant black suspension was stirred over-
night, filtered through Celite, and the filtrate was concentrated
in vacuo to afford 18 (1.20 g, 100%, 13:1 Z/E ) as an orange
oil. IR (thin film) 3406, 3092, 2928, 2860, 1712, 1664,
1488, 1449, 1404, 1351, 1150, 1070, 1012, 909, 798,
4.1.13. 1-(4-Bromobenzyl)-7-[1-(4-bromobenzyl)-3-methyl-
5-morpholin-4-yl-2-oxo-imidazolidin-4-ylidenemethyl]-3-
methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-
carbaldehyde (20)
731 cmꢁ1 1H NMR (400 MHz, CDCl3) d 9.75 (1H, d,
;
J¼5.5 Hz), 7.48 (2H, d, J¼8.5 Hz), 7.36 (1H, s), 7.19 (2H,
d, J¼8.5 Hz), 6.79 (1H, d, J¼12.0 Hz), 6.15 (1H, dd,
J¼12.0, 5.5 Hz), 4.82 (2H, s), 3.33 (3H, s); 13C NMR (mixture
of E and Z isomers; 75 MHz, CDCl3) d 192.7, 189.2, 153.5,
152.8, 137.4, 135.1, 134.9, 132.1, 132.0, 130.0, 129.7,
129.6, 125.8, 124.1, 122.3, 122.2, 120.8, 119.4, 117.7,
117.1, 47.1, 47.0, 29.2, 27.8; MS (EI) m/e (rel intensity) 323
(12), 322 (26), 321 (13), 320 (24), 172 (11), 171 (96), 170
(11), 169 (100), 109 (23), 98 (12), 90 (43); HRMS (EI) m/e
To a solution of 18 (0.128 g, 0.399 mmol) in CH3CN
˚
(4.0 mL) at room temperature were added sequentially 4 A
molecular sieves (49 mg), morpholine (35.0 mL, 0.401 mmol),
and Sc(OTf)3 (21 mg, 0.043 mmol). The resultant orange mix-
ture was stirred for 6.5 h, diluted with CH2Cl2 (50 mL), and
filtered through Celite. The orange filtrate was washed with
H2O (1ꢂ10 mL) and brine (2ꢂ10 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification by flash chro-
matography on silica gel, eluting with EtOAc/hexanes (1:1
followed by 2:1), afforded 20 (35 mg, 25%) as an orange
foam. IR (thin film) 2960, 2867, 2846, 1718, 1686, 1592,
1487, 1458, 1400, 1159, 1114, 1070, 1011, 909, 797,
calcd for C14H BrN2O2 [Mþ]: 320.0160; found: 320.0150.
79
13
4.1.12. 4-(1,3-Dimethyl-5-morpholin-4-yl-2-oxo-
imidazolidin-4-ylidenemethyl)-6-hydroxymethyl-1,3-
dimethyl-1,3-dihydrobenzoimidazol-2-one (19)
To a solution of a 3:1 (Z/E ) mixture of 12 (0.116 g,
0.697 mmol) in CH3CN (7.0 mL) at room temperature were
˚
added sequentially 4 A molecular sieves (72 mg), morpholine
740 cmꢁ1 1H NMR (300 MHz, CDCl3) d 9.85 (1H, s,
;
6-CHO), 7.48 (2H, d, J¼8.5 Hz, p-BrPhCH2-N10), 7.46 (2H,
d, J¼8.5 Hz, p-BrPhCH2-N3), 7.41 (1H, s, H-5), 7.40 (1H,
s, H-7), 7.13 (2H, d, J¼8.5 Hz, p-BrPhCH2-N10), 6.97 (2H,
d, J¼8.5 Hz, p-BrPhCH2-N3), 5.52 (1H, d, J¼1.5 Hz, 4-
CH]C), 5.26 (2H, d, J¼3.5 Hz, p-BrPhCH2-N3), 4.97 (1H,
d, J¼2.0 Hz, H-50), 4.72 (1H, d, J¼15.5 Hz, p-BrPh
CH2-N10), 4.17 (1H, d, J¼15.5 Hz, p-BrPhCH2-N10), 3.54
(3H, s, Me-N1), 3.18e3.25 (2H, m, H-200), 3.06e3.14 (2H,
m, H-200), 2.88 (3H, s, Me-N30), 2.26e2.33 (2H, m, H-300),
2.07e2.16 (2H, m, H-300); 13C NMR (75 MHz, CDCl3) d 190.9
(6-CHO), 156.9 (C-20), 155.1 (C-2), 141.3 (C-40), 136.3 ( p-
BrPhCH2-N3), 135.9 ( p-BrPhCH2-N10), 132.4 ( p-BrPh
CH2-N10), 132.2 ( p-BrPhCH2-N3), 131.7 (C-3a), 131.6 (C-
7a), 130.8 (C-6), 129.9 ( p-BrPhCH2-N10), 127.6 ( p-
BrPhCH2-N3), 127.5 (C-5), 122.0 ( p-BrPhCH2-N10), 121.9
( p-BrPhCH2-N3), 119.4 (C-4), 105.8 (C-7), 95.0 (4-
CH]C), 75.3 (C-50), 67.0 (C-200), 47.7 (C-300), 45.8 ( p-BrPh
CH2-N10), 45.5 ( p-BrPhCH2-N3), 28.0 (Me-N1), 27.1 (Me-
N30); MS (EI) m/e (rel intensity) 626 (21), 625 (55), 624
(44), 623 (100), 622 (26), 621 (52), 171 (98), 170 (99), 90
(60.0 mL, 0.697 mmol), and Sc(OTf)3 (35 mg, 0.072 mmol).
The resultant orange mixture was stirred overnight and filtered
through Celite. The orange filtrate was treated with H2O
(10 mL), and the aqueous phase was separated and extracted
with CH2Cl2 (3ꢂ10 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo.
To a solution of the crude material (0.146 g) in anhydrous
MeOH (4 mL) was added NaBH4 (42.3 mg, 1.12 mmol) at
room temperature, and the resultant mixture was stirred for
8 h. The mixture was diluted with H2O (10 mL) and CH2Cl2
(20 mL), and the aqueous phase was separated and extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel, eluting with
CH2Cl2/MeOH/NH4OH (20:1:1), gave the desired product
that also contained several impurities. The impure material
(81 mg) was subjected to a second purification by flash chro-
matography on silica gel, eluting with CH2Cl2/MeOH/NH4OH
(25:1:1), to provide 19 (60 mg, 43% over two steps) as an or-
ange foam. IR (thin film) 3422, 2942, 2854, 1702, 1684, 1670,
1458, 1415, 1394, 1284, 1252, 1114, 1089, 1012, 919, 858,
(18); HRMS (EI) m/e calcd for C32H Br2N5O4 [Mþ]:
79
31
707.0743; found: 707.0730.
4.1.14. 3-Benzofuran-3-yl-acrylic acid ethyl ester (28)
To a stirred solution of 2733 (1.50 g, 10.3 mmol) in CH2Cl2
(50 mL) at room temperature was added 95% (carboethoxy-
ethylene)-triphenylphosphorane (4.14 g, 11.3 mmol). The re-
sultant yellow reaction mixture was stirred for 15 h and
concentrated in vacuo. Purification by flash chromatography
1
730 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.00 (1H, s, H-5),
6.88 (1H, s, H-7), 5.93 (1H, d, J¼1.5 Hz, 4-CH]C), 5.05
(1H, d, J¼2.0 Hz, H-50), 4.69 (2H, d, J¼4.5 Hz, 6-CH2OH),
3.58 (3H, s, Me-N3), 3.42 (3H, s, Me-N1), 3.26e3.32 (2H,

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
661
on silica gel (40þM), eluting with 100:1 then with 95:5 hex-
4.1.17. 20-Hydroxy-5-(2-morpholin-4-yl-benzofuran-3-
ylidenemethyl)-biphenyl-3-carbaldehyde (32)
To a solution of 30 (51.0 mg, 0.399 mmol) in CH3CN
(3.0 mL) at room temperature were added sequentially 4 A
molecular sieves (38 mg), morpholine (30.0 mL,
anes/EtOAc, afforded the title compound (1.99 g, 90%) as
a yellow solid, mp 71e72 ꢀC. IR (thin film) 3126, 2976,
1704, 1640, 1449, 1364, 1313, 1249, 1191, 1116, 967, 831,
˚
1
746 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.87 (1H, s), 7.85
(1H, dd, J¼7.0, 1.5 Hz), 7.79 (1H, d, J¼16.0 Hz), 7.52 (1H,
m), 7.36 (2H, m), 6.56 (1H, dd, J¼16.0, 0.5 Hz), 4.28 (2H,
q, J¼7.0 Hz), 1.36 (3H, t, J¼7.0 Hz); 13C NMR (100 MHz,
CDCl3) d 167.3, 156.3, 147.9, 134.6, 125.6, 125.0, 123.9,
121.2, 118.7, 118.1, 112.2, 60.7, 14.6; MS (EI) m/e (rel inten-
sity) 216 (100), 171 (78), 146 (37), 131 (25), 115 (85), 89 (22),
63 (28); HRMS (EI) m/e calcd for C13H12O3 [Mþ]: 216.0786;
found: 216.0791.
0.344 mmol), and Sc(OTf)3 (14.6 mg, 0.0297 mmol). The re-
sultant orange mixture was heated to 60 ꢀC and stirred for
22 h. The resultant mixture was filtered through a Celite pad
and washed with EtOAc (30 mL). The orange filtrate was
washed with H2O (1ꢂ5 mL) and brine (2ꢂ5 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (12þM), eluting with
10:1 followed by 4:1 and 2:1 hexanes/EtOAc, afforded the title
compound (9.3 mg, 15%) as an orange oil. IR (thin film) 3321,
3055, 2959, 2915, 2849, 1693, 1593, 1464, 1455, 1369, 1318,
1
4.1.15. 3-Benzofuran-3-yl-prop-2-en-1-ol (29)
1296, 1148, 1111, 1005, 909, 864, 750, 732 cmꢁ1; H NMR
To a solution of 28 (1.91 g, 8.84 mmol) in CH2Cl2 (70 mL)
at ꢁ78 ꢀC was added dropwise a 1.0 M solution of DIBAL-H
in hexanes (22 mL). After 3 h, the reaction mixture was
warmed to room temperature and quenched with 1 N HCl
(40 mL). The aqueous phase was separated and extracted
with CH2Cl2 (2ꢂ40 mL). The combined organic extracts
were washed with saturated aqueous NaHCO3 (2ꢂ30 mL),
dried over MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (40þM), eluting
with EtOAc/hexanes (1:4), afforded the title compound
(1.50 g, 99%) as a pale yellow oil. IR (thin film) 3358,
3044, 2915, 2853, 1450, 1186, 1108, 1013, 963, 856,
(400 MHz, CDCl3) d 10.10 (1H, s), 8.37 (1H, t, J¼1.5 Hz),
8.20 (1H, t, J¼1.5 Hz), 7.91 (1H, t, J¼1.5 Hz), 7.48 (1H,
dd, J¼7.5, 1.0 Hz), 7.23e7.34 (3H, m), 7.10 (1H, d,
J¼2.0 Hz), 7.05 (1H, dt, J¼7.5, 1.0 Hz), 6.99 (1H, dd, J¼
8.0, 1.0 Hz), 6.94 (1H, dt, J¼7.5, 1.0 Hz), 6.88 (1H, d,
J¼8.0 Hz), 6.02 (1H, d, J¼2.0 Hz), 5.15 (1H, s), 3.59e3.62
(4H, m), 2.90e2.93 (2H, m), 2.74e2.79 (2H, m); 13C NMR
(100 MHz, CDCl3) d 192.0 (CH), 161.3 (C), 152.4 (C),
138.6 (C), 137.72 (C), 137.71 (C), 137.2 (C), 136.1 (CH),
131.1 (CH), 130.4 (CH), 129.8 (CH), 129.7 (CH), 129.3
(CH), 126.9 (C), 126.0 (C), 121.3 (CH), 120.8 (CH), 120.7
(CH), 119.8 (CH), 116.2 (CH), 110.0 (CH), 99.7 (CH), 66.7
(CH2), 46.9 (CH2); MS (ESI) m/e (rel intensity) 415 (18),
414 (71), 375 (11), 328 (24), 327 (100); HRMS (ESI) m/e
calcd for C26H24NO4 [MþH]: 414.1692; found: 414.1699.
743 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.81 (1H, dd,
;
J¼7.5, 1.5 Hz), 7.66 (1H, s), 7.49 (1H, dd, J¼8.5, 1.5 Hz),
7.27e7.35 (2H, m), 6.70 (1H, d, J¼16.0 Hz), 6.49 (1H, dt,
J¼10.0, 5.5 Hz), 4.37 (2H, dd, J¼5.5, 4.0 Hz), 1.47 (1H, t,
J¼6.0 Hz); 13C NMR (75 MHz, CDCl3) d 156.0, 143.6,
129.6, 126.0, 124.9, 123.2, 121.0, 120.9, 118.8, 111.9, 64.2;
MS (EI) m/e (rel intensity) 174 (100), 145 (45), 131 (79),
118 (23), 115 (32); HRMS (EI) m/e calcd for C11H10O2
[Mþ]: 174.0681; found: 174.0678.
4.1.18. 20-Hydroxy-5-(2-hydroxyethyl)-biphenyl-3-
carbaldehyde (35)
To a stirred solution of L-proline (33.8 mg, 0.287 mmol),
Sc(OTf)3 (14.7 mg, 0.0290 mmol), and 30 (49.4 mg,
0.287 mmol) in CH3CN/H2O (95/5 v/v, 1.0 mL) at room tem-
perature was added 2,3-dihydrofuran (76.0 mL, 1.00 mmol).
After stirring for 24 h, the resultant mixture was washed
with H2O (2ꢂ10 mL) and brine (2ꢂ10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (12þM), eluting with 5:1
followed by 3:1 hexanes/EtOAc, afforded the title compound
(12.9 mg, 20%) as an orange oil. IR (thin film) 3347, 2951,
2879, 2734, 1686, 1597, 1459, 1386, 1291, 1266, 1224,
4.1.16. 3-Benzofuran-3-yl-propenal (30)
To a solution of 29 (1.50 g, 8.62 mmol) in CHCl3 (60 mL)
at room temperature was added in two portions activated
MnO2 (9.05 g, 88.5 mmol). The resultant black suspension
was stirred at room temperature for 4 h and heated to 50 ꢀC
for 2 h, cooled to room temperature, filtered through Celite,
and the filtrate was concentrated in vacuo to afford the title
compound (1.18 g, 78%) as a yellow crystalline solid, mp
88e90 ꢀC. IR (thin film) 3098, 3051, 1667, 1633, 1538,
1154, 1044, 755, 696 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 10.00 (1H, s), 7.85 (1H, t, J¼1.5 Hz), 7.73 (1H, t,
J¼1.5 Hz), 7.66 (1H, t, J¼1.5 Hz), 7.23e7.28 (2H, m), 7.01
(1H, td, J¼7.5, 1.0 Hz), 6.93 (1H, dd, J¼8.5, 1.0 Hz), 5.55
(1H, br s), 3.93 (2H, t, J¼6.5 Hz), 2.98 (2H, t, J¼6.5 Hz);
13C NMR (75 MHz, CDCl3) d 192.5, 152.7, 140.7, 139.0,
137.4, 136.3, 130.6, 129.8, 129.3, 129.0, 127.1, 121.4,
116.5, 63.3, 38.9; MS (EI) m/e (rel intensity) 242 (100), 211
(47), 195 (72), 181 (37), 165 (34), 152 (20), 115 (13);
HRMS (EI) m/e calcd for C15H14O3 [Mþ]: 242.0943; found:
242.0938.
1
1449, 1133, 967, 855, 821, 729 cmꢁ1; H NMR (300 MHz,
CDCl3) d 9.70 (1H, d, J¼7.5 Hz), 7.99 (1H, s), 7.84 (1H, dt,
J¼8.5, 1.0, 0.5 Hz), 7.60 (1H, d, J¼16.0 Hz), 7.56 (1H, dt, J¼
8.5, 1.0, 0.5 Hz), 7.36e7.43 (2H, m), 6.87 (1H, dd, J¼16.5,
8.0 Hz); 13C NMR (75 MHz, CDCl3) d 193.8, 156.4, 148.8,
142.3, 129.1, 126.0, 124.5, 124.3, 121.1, 118.3, 112.3; MS
(EI) m/e (rel intensity) 172 (77), 144 (33), 118 (34), 115
(100), 89 (21), 63 (22); HRMS (EI) m/e calcd for C11H8O2
[Mþ]: 172.0524; found: 172.0526.

662
C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
a thermal ring-expansion of sceptrin 3, see: Baran, P. S.; O’Malley, D. P.;
Zografos, A. L. Angew. Chem., Int. Ed. 2004, 43, 2674e2677.
10. A sequential DielseAlder cycloaddition/ring contraction biogenetic route
to palau’amine and related compounds is proposed in: Kinnel, R. B.;
Gehrken, H.-P.; Swali, R.; Skoropowski, G.; Scheuer, P. J. J. Org.
Chem. 1998, 63, 3281e3286.
4.1.19. 3-(3-Methoxybut-1-enyl)-4-methyl-benz-
aldehyde (44)
To a stirred solution of L-proline (0.159 g, 1.38 mmol) in
anhydrous MeOH (10.0 mL) at room temperature was added
42 (0.40 mL, 3.4 mmol). The resultant yellow solution was
stirred for 20 h, diluted with EtOAc (50 mL), washed with
NaHCO3 (2ꢂ10 mL) and brine (2ꢂ10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (12þM), eluting with
19:1 followed by 9:1 hexanes/EtOAc, afforded the title com-
pound (58 mg, 16%) as a yellow oil. IR (thin film) 2974,
2922, 2812, 1694, 1598, 1565, 1447, 1369, 1229, 1196,
11. The structure of palau’amine was recently reassigned. For a review,
including a discussion of the biosynthesis of the bromopyrroleeimidazole
alkaloids, see: Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew.
¨
Chem., Int. Ed. 2007, 46, 6586e6594.
12. (a) Lovely, C. J.; Du, H.; He, Y.; Rasika Dias, H. V. Org. Lett. 2004, 6,
735e738; (b) He, Y.; Chen, Y.; Wu, H.; Lovely, C. J. Org. Lett. 2003,
5, 3623e3626; (c) Lovely, C. J.; Du, H.; Rasika Dias, H. V. Heterocycles
2003, 60, 1e7; (d) Lovely, C. J.; Du, H.; Rasika Dias, H. V. Org. Lett.
2001, 3, 1319e1322.
1108, 1082, 968, 820, 758 cmꢁ1
;
1H NMR (400 MHz,
13. (a) Dransfield, P. J.; Wang, S.; Dilley, A. S.; Romo, D. Org. Lett. 2005, 7,
1679e1682; (b) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535e1538.
14. For examples of iminium ion catalysis used in the enantioselective Dielse
Alder reactions of a,b-unsaturated aldehydes and ketones, see: (a)
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243e4244; (b) Northrup, A. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 2458e2460; (c) Wilson, R. M.; Jen,
W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616e
11617; (d) Nakano, K.; Ishihara, K. J. Am. Chem. Soc. 2005, 127,
10504e10505; (e) Hayashi, Y.; Gotoh, H. Org. Lett. 2007, 9, 2859e2862.
15. For examples of enamine-catalyzed DielseAlder reactions involving in
situ-generation of 2-amino-1,3-butadienes, see: (a) Thayumanavan, R.;
Dhevalapally, B.; Sakthivel, K.; Tanaka, F.; Barbas, C. F., III. Tetrahedron
Lett. 2002, 43, 3817e3820; (b) Ramachary, D. B.; Chowdari, N. S.;
Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 6743e6746; (c) Ramachary,
D. B.; Chowdari, N. S.; Barbas, D. F., III. Angew. Chem., Int. Ed. 2003,
42, 4233e4237; (d) Ramachary, D. B.; Anebouselvy, K.; Chowdari,
N. S.; Barbas, D. F., III. J. Org. Chem. 2003, 42, 5838e5849.
16. For preformed chiral 2-amino-1,3-butadienes, see: Barluenga, J.; Aznar,
F.; Valdes, C.; Martin, A.; Garcia-Granda, S.; Martin, E. J. Am. Chem.
Soc. 1993, 15, 4403e4404.
CDCl3) d 9.98 (1H, s), 7.95 (1H, d, J¼2.0 Hz), 7.67 (1H,
dd, J¼7.5, 1.5 Hz), 7.31 (1H, d, J¼7.5 Hz), 6.75 (1H, d,
J¼16.0 Hz), 6.11 (1H, dd, J¼16.0, 7.5 Hz), 3.95 (1H, m),
3.36 (3H, s), 2.43 (3H, s), 1.36 (3H, d, J¼6.5 Hz); 13C
NMR (100 MHz, CDCl3) d 192.3, 142.9, 137.1, 135.1,
135.0, 131.2, 128.8, 127.8, 127.4, 78.1, 56.4, 21.6, 20.5; MS
(EI) m/e (rel intensity) 204 (24), 189 (53), 172 (100), 157
(31), 145 (38), 129 (89), 115 (31), 105 (30), 59 (68); HRMS
(EI) m/e calcd for C13H16O2 [Mþ]: 204.1150; found:
204.1150.
Acknowledgements
The Natural Science and Engineering Research Council
(NSERC) of Canada funded this work. C.D.S. acknowledges
receipt of an NSERC postgraduate scholarship (PGSD3). We
thank Dr. A.B. Young for mass spectrometric analysis. We
thank Prof. W. Reynolds for useful discussions, and Dr. Tim
Burrow for help in setting up 2D NMR experiments.
17. For preformed 1-amino-3-siloxy-1,3-butadienes, see: (a) Thadani, A. N.;
Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5846e5850; (b) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org.
Chem. 1999, 64, 3039e3052; (c) Kozmin, S. A.; Green, M. T.; Rawal,
V. H. J. Org. Chem. 1999, 64, 8045e8047.
References and notes
18. The term ’reaction prospecting’ is inspired by the term ’prospecting
library’, introduced by Bartlett, see: Spaller, M. R.; Burger, M. T.; Fardis,
M.; Bartlett, P. A. Curr. Opin. Chem. Biol. 1997, 1, 47e53.
1. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668e1698.
19. (a) Otter, B. A.; Falco, E. A.; Fox, J. J. J. Org. Chem. 1968, 33, 3593e
3600; (b) Hilbert, G. E. J. Am. Chem. Soc. 1932, 54, 3413e3417.
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Brown, P.; Davies, D.; O’Hanlon, P. J.; Wilson, J. M. J. Med. Chem. 1996,
39, 446e457.
21. Li, S.-W.; Batey, R. A. Chem. Commun. 2007, 3759e3761.
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1999, 15e27.
2. Hoffmann, H.; Lindel, T. Synthesis 2003, 1753e1783.
3. Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001, 2, 237e243.
4. Synthesis: (a) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.;
Nikaido, F.; Yamashita, M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377e
4380; Isolation: (b) Keifer, P. A.; Koker, M. E. S.; Schwartz, R. E.;
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ence on Antimicrobial Agents and Chemotherapy, New Orleans, Sep 28e
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525e528.
´
23. Reynolds, W. F.; Enrıquez, R. G. J. Nat. Prod. 2002, 65, 221e244.
24. Long-range heterocoupling of H-50 with C-300, C-40, and C-20 revealed that
the morpholine fragment was attached to C-50 of one of the imidazolone
units. The carbonecarbon connectivity of the benzimidazolone motif was
deduced from the following three-bond heterocouplings: C-3a with H-7,
H-5, and Me-N3; C-7a with Me-N1; C-5 with H-7 and 6-CH2OH; and
C-7 with H-5 and 6-CH2OH. (Two-bond 13Ce1H correlations involving
aromatic protons are rarely observed and, if observed, are very weak).
25. A significant ROESY correlation was observed between aromatic proton
H-5 and H-50, suggesting that H-50 is spatially oriented in the vicinity
of H-5.
5. Walker, R. P.; Faulkner, D. J.; Van Engen, D.; Clardy, J. J. Am. Chem. Soc.
1981, 103, 6772e6773.
6. (a) Iwagawa, T.; Miyazaki, M.; Okamura, H.; Nakatani, M.; Doe, M.;
Takemura, K. Tetrahedron Lett. 2003, 44, 2533e2535; (b) Mancini, I.;
Guella, G.; Zibrowius, H.; Pietra, F. Tetrahedron 2003, 59, 8757e8762.
7. (a) Kauzlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J. Tetrahedron
Lett. 1977, 18, 61e64; (b) Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F.
Helv. Chim. Acta 1988, 71, 773e781.
8. For examples of [4þ2] cycloaddition reactions catalyzed by Dielse
Alderase enzymes, see: (a) Oikawa, H. Bull. Chem. Soc. Jpn. 2005, 78,
537e554; (b) Auclair, K.; Sutherland, A.; Kennedy, J.; Witter, D. J.;
Van den Heever, J. P.; Hutchinson, C. R.; Vederas, J. C. J. Am. Chem.
Soc. 2000, 122, 11519e11520.
´
26. (a) Tejedor, D.; Garcıa-Tellado, F. Chem. Soc. Rev. 2007, 36, 484e491;
(b) Powell, D. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7569e7573.
27. In the case of manzamine biosynthesis, dimerization is believed to pro-
ceed via an intramolecular DielseAlder reaction, see: Baldwin, J. E.;
Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059e2062.
9. The biogenetic DielseAlder hypothesis for ageliferin has been questioned
by Baran and co-workers, since they accomplished its formation through

C.D. Smith, R.A. Batey / Tetrahedron 64 (2008) 652e663
663
28. (a) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J. Chem.
Commun. 1999, 651e652; (b) Powell, D. A.; Batey, R. A. Org. Lett. 2002,
4, 2913e2916.
electron demand Diels-reaction with N-methylmaleimide in 35% yield.
´
See: Bertelsen, S.; Marigo, M.; Brandes, S.; Biner, P.; Jørgensen, K. A.
J. Am. Chem. Soc. 2006, 128, 12973e12980.
29. For reviews of inverse electron demand DielseAlder reactions, see: (a)
Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. Tetrahedron 1992,
48, 9111e9171; (b) Oppolzer, W. Comprehensive Organic Synthesis;
Pergamon: New York, NY, 1991; Vol. 5, pp 315e399.
37. Organocatalytic activation of the dienophile through enamine activation has
been reported in inverse-electron demand hetero DielseAlder reactions,
see: (a) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.;
Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028e16029; (b) Juhl, K.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498e1501; (c) Wabnitz,
T. C.; Saaby, S.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 828e834.
38. The reaction of chromone-fused electron-deficient dienes 36 with enamines
is proposed to occur via 37 to give 2-hydroxybenzophenones 38. See: (a)
Bodwell, G. J.; Hawco, K. M.; da Silva, R. P. Synlett 2003, 179e182; (b)
Bodwell, G. J.; Hawco, K. M.; Satou, T. Synlett 2003, 879e881.
30. For representative examples of inverse electron demand DielseAlder
reactions, for carbocycle formations, see: (a) Hong, B.-C.; Chen, F.-L.;
Chen, S.-H.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2005, 7, 557e560; (b)
´
Bodwell, G. J.; Pi, Z. Tetrahedron Lett. 1997, 38, 309e312; (c) Marko,
´
I. E.; Evans, G. R.; Seres, P.; Chelle, I.; Janousek, Z. Pure Appl. Chem.
1996, 68, 113e122; (d) Padwa, A.; Gareau, Y.; Harrison, B.; Rodrigues,
A. J. Org. Chem. 1992, 57, 3540e3545; (e) Posner, G.; Dai, H.; Bull,
D. S.; Lee, J.-K.; Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr,
S., Jr. J. Org. Chem. 1996, 61, 671e676.
NR2
O
O
O
O
R1
COOEt
COOEt
NR2
R2
31. This mechanism cannot be excluded since the (Z )-isomer of 12 reacted
more efficiently than the corresponding (E )-isomer.
R1
Δ
R2
H
36
37
H
Me
22
O
O
N
N
6π-electrocyclization
COOEt
R1
O
- R2NH
O
R
N
O
N
R
O
N
OH
Me
R2
R
38
N
O
21
N
39. The reaction of 39 with enamines to give 41 has been proposed to occur
via a domino cycloaddition/elimination/oxidation pathway. See: Bodwell,
G. J.; Pi, Z.; Pottie, I. R. Synlett 1999, 477e479.
Me
O
RN
Me
N
N
Me
[4+2]
25
O
NR2
O
O
N
R
O
R1
COOEt
COOEt
NR2
O
O
R2
N
O
R1
Δ
R2
H
39
40
32. For an example of an organocatalyzed (50 mol % L-proline) intramole-
cular inverse electron demand DielseAlder reaction of a,b,g,d-unsaturated
aldehydes, see: Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007,
63, 2840e2850.
O
COOEt
- R2NH
- H2
O
R1
33. Synthesis of 27 from 26 was achieved via a four-step literature procedure:
alkylation of the phenol with ethyl chloroacetate, followed by hydrolysis
of the resultant ester, cyclodehydration of the acid and SeO2 oxidation of
3-methylbenzofuran. See: (a) Nielek, S.; Lesiak, T. Chem. Ber. 1982, 115,
1247e1251; (b) Zaidlewicz, M.; Chechlowska, A.; Prewysz-Kwinto, A.;
Wojtczak, A. Heterocycles 2001, 55, 569e577.
R2
41
40. Other solvents, such as THF, CH3CN, DMF, DMSO, and CHCl3, did not
result in incorporation of 33 or in formation of any other dimerized
products.
34. For reviews of organocatalysis, see: (a) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719e724; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138e5175; (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726e3748.
41. Reaction of 45 with proline gives the cycloadduct 46 in a formal Dielse
Alder manner, proposed to occur via a stepwise enamine Michael type
condensation followed by a Mannich cyclization. See: Hong, B.-C.; Wu,
M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8, 2217e2220.
35. There are numerous examples in the literature of organocatalyzed Dielse
Alder reactions using proline and imidazolone derivatives to achieve
iminium ion activation of the dienophile. See Ref. 14.
O
L-proline
H
O
AcO
AcO
68% (94% e.e.)
36. Jørgensen and co-workers have recently reported examples of diene
activation through dienamine formation, in organocatalytic g-aminations
of a,b-unsaturated aldehydes. They also reported an example of a
1-aminodiene generated from 2-(E )-pentenal participating in a normal
MeCN, 0 °C
AcO
H
45
46