Expanding the synthetic method and structural diversity potential for the intramolecular Aza Diels-Alder cyclization

Article abstract of DOI:10.1021/jo060148m

New experimental facets have been examined to expand upon the known methods for an aromatic variant of the intramolecular Aza Diels-Alder cyclization. The specific transformation under study is one that uses functionalized anilines and an aldehyde-olefin tether to provide tetrahydroquinoline cycloadducts under mild acidic conditions. Variations investigated encompass the use of N-alkylated anilines, including one with ring-constrained nitrogen, in the context of glycine, phenylalanine, and glyoxyl ester bridging elements; bridge components with structural perturbations; modified dienophile segments; and different acid catalysts. Substituted tetrahydroquinolines obtained from many of the preceding experiments were obtained in good chemical yield, generally in excess of 80%. Designed as a platform for combinatorial chemical synthesis, this reaction manifold accommodates a range of starting materials with structurally and electronically distinct characteristics. The results of this report, in combination with the discoveries from previous work in this area, enhance the ability of the intramolecular Aza Diels-Alder transformation to generate a diverse array of quinolinic structures with multiple stereogenic centers, many of which resemble lignan and arylnaphthalene-type natural products.

Full text of DOI:10.1021/jo060148m

Expanding the Synthetic Method and Structural Diversity Potential
for the Intramolecular Aza Diels-Alder Cyclization
Joseck Muhuhi and Mark R. Spaller*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
mspaller@chem.wayne.edu
ReceiVed January 23, 2006
New experimental facets have been examined to expand upon the known methods for an aromatic variant
of the intramolecular Aza Diels-Alder cyclization. The specific transformation under study is one that
uses functionalized anilines and an aldehyde-olefin tether to provide tetrahydroquinoline cycloadducts
under mild acidic conditions. Variations investigated encompass the use of N-alkylated anilines, including
one with ring-constrained nitrogen, in the context of glycine, phenylalanine, and glyoxyl ester bridging
elements; bridge components with structural perturbations; modified dienophile segments; and different
acid catalysts. Substituted tetrahydroquinolines obtained from many of the preceding experiments were
obtained in good chemical yield, generally in excess of 80%. Designed as a platform for combinatorial
chemical synthesis, this reaction manifold accommodates a range of starting materials with structurally
and electronically distinct characteristics. The results of this report, in combination with the discoveries
from previous work in this area, enhance the ability of the intramolecular Aza Diels-Alder transformation
to generate a diverse array of quinolinic structures with multiple stereogenic centers, many of which
resemble lignan and arylnaphthalene-type natural products.
Introduction
an expansive synthetic genre that includes the extensively
studied aza Diels-Alder (or imino Diels-Alder) category of
reactions.4,5 Among these, of particular note is the subclass that
involves the formation of an aromatic imine from an aniline
and aldehyde, which subsequently reacts as a 2-azadiene with
a suitable dienophile to form a tetrahydroquinoline (Figure 1A).
Since its initial disclosure,6 this type of three-component
assembly, in which the imine is either preformed or generated
in situ, has been employed to generate a range of heterocyclic
products with stereochemical and functional group variability.
As the iminium diene component is relatively electron-deficient,
this reflects an inVerse electron demand Diels-Alder transfor-
mation, which has influenced the type of components used in
the reaction. Aside from studies that have explored the use of
different diene and dienophile components, other distinct
advances from a methodology perspective have centered on
catalysis,7 especially in the realm of asymmetric induction,8 and
The design and execution of combinatorial synthetic routes
that lead to functionally, structurally, and stereochemically
diverse compound libraries are to many current practitioners
of organic synthesis what natural product and total synthesis
represented to an earlier generation of chemists. The two fields
share a common operational agenda: to devise streamlined,
high-yielding syntheses with minimal reaction and purification
steps, under defined stereochemical control, using readily
attainable starting materials, and (if possible without compro-
mising any of the preceding) with an innovative flair. Yet the
principles of combinatorial synthetic design, which are at the
core of the emerging discipline of diVersity-oriented synthesis,1
give rise to challenges distinct from those of target-oriented
synthesis, originating in large measure from the inherent forward
design nature of the former.2
One particular organic reaction class that lends itself to
combinatorial thinking is the hetero Diels-Alder cyclization,3
(4) Boger, D. L. Tetrahedron 1983, 39, 2869-2939.
(5) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57, 6099-6138.
(6) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656-670.
(7) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977-
8978.
(1) Schreiber, S. L. Science 2000, 287, 1964-1969.
(2) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr. Opin.
Chem. Biol. 1997, 1, 47-53.
(3) Tietze, L. F.; Kettschau, G. Stereosel. Heterocycl. Synth. I 1997, 189,
1-120.
(8) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357-7360.
10.1021/jo060148m CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/29/2006
J. Org. Chem. 2006, 71, 5515-5526
5515

Muhuhi and Spaller
SCHEME 1. Synthetic Route to Aza Diels-Alder
Cyclization with N-Alkylated Anilines and
4-Methoxycinnamate-Based Dienophile with Glycine Bridge
FIGURE 1. (A) Intermolecular and (B) intramolecular versions of
the aza Diels-Alder cyclization.
the use of aqueous and nontraditional reaction media, such as
ionic liquids9-11 and supercritical carbon dioxide.12,13
The intramolecular implementation of the aza Diels-Alder
using 2-azadienes has also been examined; here the added
advantages include better control over the formation of stereo-
isomers and the creation of an additional ring.14-16 This, in
conjunction with the observation that the quinolinic substructure
is present in a number of biologically active compounds,17 has
served as justification for developing combinatorial-based
syntheses around this reaction framework. An early effort that
specifically focused on such a translation developed an ap-
propriately modular route and systematically investigated the
suitability of various diene, dienophile, and intramolecular
bridging units, both in solution and on a solid-phase matrix
(Figure 1B).18,19 The chemical diversity was derived from the
anilines used to assemble the iminium diene, the cinnamic acids
used as the dienophile, and the way the two were tethered
through varied aldehyde-olefin components, which were based
on salicylaldehyde, glyoxyl ester, glyoxyl amide, and amino
acid aldehydes. The configurational diversity of the resulting
products is reminiscent of the structures of biologically active
arylnaphthalene lignan20 and heterolignan21 natural products.
Other studies exploring the combinatorial avenues possible with
the intermolecular aza Diels-Alder transformation have also
been reported.22,23
In this report, we revisit the intramolecular aza Diels-Alder
previously implemented on a combinatorial scaffold,18 with an
eye toward expanding the methodology associated with its use
while adhering to the guiding precepts of combinatorial synthetic
design.24 The modifications we chose to examine were (1) use
of secondary (N-alkylated) anilines, (2) use of various Brønsted
and Lewis acid catalysts, (3) variation of the aldehyde-alkene
bridge, and (4) a noncinnamic acid dienophile unit.
Results and Discussion
Although primary anilines were previously shown to be
efficiently incorporated into the aza Diels-Alder reaction
manifold, less investigated was the use of secondary anilines.
The application of these as input would allow for the additional
display of chemical diversity, and a convenient one at that,
considering the availability (and ease of preparation) of N-
alkylated anilines. For this investigation, the model system used
to test the ensuing chemistry was a glycine-derived aldehyde
tethered to a suitable dienophile, in this case, 4-methoxycinnamic
acid (Scheme 1). This was prepared by first carrying out a
reductive amination25 using 2,4-dimethoxybenzaldehyde and
glycine methyl ester, and the resulting secondary amine 1 was
then coupled to the 4-methoxycinnamic acid under carbodiimide
(9) Zulfiqar, F.; Kitazume, T. Green Chem. 2000, 2, 137-139.
(10) Yadav, J. S.; Reddy, B. V. S.; Reddy, J. S. S.; Rao, R. S. Tetrahedron
2003, 59, 1599-1604.
(11) Pegot, B.; Vo-Thanh, G. Synlett 2005, 1409-1412.
(12) Matsuo, J.; Tsuchiya, T.; Odashima, K.; Kobayashi, S. Chem. Lett.
2000, 178-179.
(13) Shi, M.; Cui, S. C.; Li, Q. H. Tetrahedron 2004, 60, 6163-6167.
(14) Tietze, L. F.; Utecht, J. Chem. Ber. Recl. 1992, 125, 2259-2263.
(15) Beifuss, U.; Herde, A.; Ledderhose, S. Chem. Commun. 1996, 1213-
1214.
(16) Laschat, S. Liebigs Ann. Recl. 1997, 1-11.
(17) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627-646.
(18) Spaller, M. R.; Thielemann, W. T.; Brennan, P. E.; Bartlett, P. A.
J. Comb. Chem. 2002, 4, 516-522.
(22) Tailor, J.; Hall, D. G. Org. Lett. 2000, 2, 3715-3718.
(23) Toure, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall,
D. G. Chem.-Eur. J. 2003, 9, 466-474.
(19) Spaller, M. R.; Bartlett, P. A. In 1st Lake Tahoe Symposium on
Molecular DiVersity in Drug DiscoVery; Granlibakken, CA, Nov 1996.
(20) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96.
(21) Ramos, A. C.; de Clairac, R. P. L.; Medarde, M. Heterocycles 1999,
51, 1443.
(24) Marx, M. A.; Grillot, A. L.; Louer, C. T.; Beaver, K. A.; Bartlett,
P. A. J. Am. Chem. Soc. 1997, 119, 6153-6167.
(25) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
5516 J. Org. Chem., Vol. 71, No. 15, 2006

Intramolecular Aza Diels-Alder Cyclization
TABLE 1. Tetrahydroquinoline Products from the Aza
Diels-Alder Using Variably Substituted N-Alkylated Anilines
combined
entry aniline
R1
R2
ratio 6:7
yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
-CH3
-CH3
-CH3
-H
7.0:1
4.3:1
4.6:1
8.1:1
4.2:1
2.4:1
2.0:1
5.5:1
96
95
95
91
98
89
42
91
-F
-OCH3
-H
-CH2CH3
-CH2CHdCH2 -H
-CH(CH3)2
-cyclohexyl
-Ph
-H
-H
-H
5g
5h
conditions to yield ester 2. The 2,4-dimethoxybenzyl (DMB)
group was used based on the prior finding that it serves both as
a directing element in the cyclization reaction and as an isosteric
and isoelectronic model for the corresponding resin linker when
prepared on a solid-phase matrix.18
Selective reduction of the ester moiety in 2 using lithium tri-
tert-butoxyaluminohydride furnished alcohol 3 without perturb-
ing the cinnamyl amide functionality. This was followed by a
Swern oxidation to yield the cyclization precursor aldehyde 4.
The aza Diels-Alder reaction was then performed using each
of eight different secondary anilines, representing a modest
assortment of electronic and structural diversity (Table 1). The
conditions used were quite mild, using 3 equiv of trifluoroacetic
acid (TFA) at room temperature for 30 min. In all cases, two
diastereomers were formed, although the ring fusion trans, trans
isomer 6 predominated. Whether N-methylaniline was substi-
tuted with electron-acceptor fluorine (5b) or an electron-donor
methoxy (5c), the yields of the formed tetrahydroquinoline were
quite high and comparable to unsubstituted N-methylaniline (5a),
although the stereoisomer ratios were somewhat diminished. The
remaining four entries were N-alkylated anilines possessing
larger substituents, with ethyl (5d), n-propenyl (5e), isopropyl
(5f), cyclohexyl (5g), and phenyl (5h). Yields of cycloadduct
with these anilines were also on the order of 90% or greater,
with the notable exception of the cyclohexyl aniline, which was
less than half that of the others (Table 1). The reaction with 5a
was also performed with several other solvents in addition to
acetonitrile; combined yields and the ratio of 6:7 were generally
reduced in all cases (EtOAc: 86%, 6.8:1; CH2Cl2: 71%, 4.0:1;
CHCl3: 79%, 3.0:1; CCl4: 80%, 3.5:1).
When visualizing the transition states leading to the cyclo-
adducts, the configuration obtained by way of an endo transition
state (defined based on position of the phenyl substituent of
the olefin) leads to the observed product stereochemistry (Figure
2). While the major isomers 6a-g reflect the expected pathway,
the presence of the cis, cis diastereomers 7a-g suggests that
the reaction is in fact not concerted and may constitute a
stepwise process that represents a formal aza Diels-Alder
transformation.26
The relative stereochemical disposition of the favored endo
product was confirmed by NMR analysis, in accord with the
same stereoisomer form reported previously for other products
of the intramolecular aza Diels-Alder cyclization.18 The stereo-
chemistry for the cis, cis isomer 7a was confirmed by NMR
spectroscopy; on irradiation of H2, nOe values of 5.9 and 8.4%
were observed with H1 and H3, respectively (Figure 3). In
addition, a similar enhancement of 8.1% was detected between
H2 and H3 upon irradiation of H3.
FIGURE 2. Transition states for a hypothetical concerted aza Diels-
Alder reaction leading to corresponding stereoisomeric products.
FIGURE 3. Measured nOe values for cis-fused cycloadduct 7a.
Invoking a mechanism that involves two discrete steps
(intramolecular attack of the iminium and aromatic closure onto
the benzylic cation) that are separated by a possible bond
rotation can lead to the formation of the observed tetrahydro-
quinolines (Figure 4). In forming both 6 and 7, the reaction
could be rationalized as a consequence of maximizing secondary
orbital overlap through π-stacking of the aromatic groups,
leading to the respective endo products.
After the success with this N-alkylated aniline series, a
representative entry (the N-methylaniline) was chosen to explore
the effect of other acid catalysts aside from TFA. Specifically,
we sought to determine whether the nature of the catalyst (i.e.,
Brønsted versus Lewis acid) would have a discernible impact
upon the stereoselectivity of the intramolecular cyclization with
substituted anilines. Strong Brønsted acids such as TFA have
long since been known to catalyze the intermolecular imino
Diels-Alder cyclization,27 although a variety of other acidic
catalysts have also been used, including Lewis acids such as
the lanthanide triflates28 and bismuth(III) chloride.29,30
(26) Hermitage, S.; Howard, J. A. K.; Jay, D.; Pritchard, R. G.; Probert,
M. R.; Whiting, A. Org. Biomol. Chem. 2004, 2, 2451-2460.
(27) Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855-5858.
J. Org. Chem, Vol. 71, No. 15, 2006 5517

Muhuhi and Spaller
FIGURE 4. Possible two-step pathways for the trans- and cis-4-methoxyphenyl dienophile cyclizations leading to observed stereoisomeric products.
TABLE 2. Effect of Different Acid Catalysts upon Product
Formation for the Aza Diels-Alder Cyclization with
N-Methylaniline
SCHEME 3. Aza Diels-Alder Cyclization with
N-Methylaniline and 4-Methoxycinnamate-Based Dienophile
with L-Phenylalanine Bridge
combined
entry
catalyst
TFA
TFMSA
acetic acid
p-TsOH
(L)-tartaric acid
Yb(OTf)3
BiCl3
ratio 6:7
yield (%)
1
2
3
4
5
6
7
7.0:1
6.6:1
6.0:1
5.5:1
5.8:1
6.5:1
6.3:1
96
84
87
52
89
98
86
SCHEME 2. Aza Diels-Alder Cyclization of
1,2,3,4-Tetrahydroquinoline and 4-Methoxycinnamate-Based
Dienophile with Glycine Bridge
In addition to Yb(OTf)3 and BiCl3, trifluoromethanesulfonic
acid (TFMSA), acetic acid, and tartaric acid were tested for the
reaction with 5a. The results showed that the identity of the
acid had a negligible effect on either selectivity or overall yields
(Table 2). Since the transition state would not be expected to
accommodate the acid (at least not on the nitrogen, which is
coordinately saturated after imine formation), the influence of
the catalyst is likely felt at the stage of aldehyde activation,
immediately prior to generation of the imine. One cannot rule
out partial coordination of the catalyst to the amide carbonyl,
although it seems unlikely that an energetically favorable
transition state would hold two positive charges. Despite the
lack of improvement in product isomer distribution, it was
(28) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995, 1195-
1202.
(29) Laurent-Robert, H.; Garrigues, B.; Dubac, J. Synlett 2000, 1160-
1162.
(30) Reddy, B. V. S.; Srinivas, R.; Yadav, J. S.; Ramalingam, T. Synth.
Commun. 2001, 31, 1075-1080.
5518 J. Org. Chem., Vol. 71, No. 15, 2006

Intramolecular Aza Diels-Alder Cyclization
SCHEME 4. Aza Diels-Alder Cyclization with
N-Methylaniline and Cinnamyl-Based Dienophile with
Glyoxyl Ester Bridge
SCHEME 6. Synthesis of cis-4-Methoxycinnamic Acid
SCHEME 7. Aza Diels-Alder Cyclization with
N-Methylaniline and cis-Cinnamyl-Based Dienophile with
Glycine Bridge
SCHEME 5. Synthetic Route to Aza Diels-Alder
Cyclization for N-Alkylated Anilines and
4-Methoxycinnamate-Based Dienophile with
3-Aminopropionate-Derived Bridges
we examined the consequence of moving from an unsubstituted
glycine unit to a chiral amino acid, a modification previously
shown to accommodate the aza Diels-Alder cyclization when
using primary anilines.18 An aza Diels-Alder precursor was
prepared from L-phenylalanine methyl ester in the same manner
in which precursor 4 had been prepared from glycine; namely,
via reductive amination of the amino acid ester with DMB to
yield 10, which was then coupled to 4-methoxycinnamic acid
to form ester 11, followed by reduction to alcohol 12 that was
then oxidized to aldehyde 13 using the Swern protocol. Under
essentially the same conditions as employed previously, albeit
under refluxing conditions, the Phe-based 13 did form exclu-
sively the expected trans, trans adduct 14 in 62% yield (Scheme
3), the benzyl moiety effectively controlling the facial selectivity
of the cyclization. When performed at room temperature, the
reaction delivered only 29% of 14, the remainder of the mass
balance being recovered starting material.
The cyclization was then tested with a non-amino acid bridge,
the glyoxyl ester of cinnamate, 15. The resulting tetrahydro-
quinoline 16, obtained in a 76% yield, bears a ring fusion to a
lactone instead of a lactam (and with a reversed carbonyl
orientation) as seen in the previous products (Scheme 4).
Investigating the possibility of elongating the bridging unit
was next on the agenda, specifically, modifying the amino acid
linker by adding an additional methylene within the “backbone”.
In this manner, the larger ring in the polycyclic product would
represent another degree of structural diversity, with a confor-
mational nature distinct from that of the earlier five-membered
rings. Further modifications could then be based on adding
various functional groups on such an expanded bridge. To begin,
the glycine unit was replaced with a 3-aminopropionate (“â-
alanine”) unit, and the same protocol was followed to prepare
the requisite aldehyde-alkene intermediate 22, accessed by way
of formation of ester 17, amide 18, and alcohol 20 (Scheme 5).
When subjected to the aza Diels-Alder conditions, however,
the anticipated six-membered lactam cycloadduct was not
obtained. Rather, cinnamyl amide byproduct 26 was isolated.
We rationalized that this may be due to a “retro-Michael”-type
of side reaction, in which deprotonation at the R-carbon of
aldehyde 22 results in the formation of a double bond while
expelling the amide nitrogen, thereby forming 26 and acryl-
aldehyde (the latter, though, was never isolated). The results
were the same irrespective of the choice of catalyst; trials
included using TFA, Yb(OTf)3, and BiCl3.
agreeable to see that less harsh agents, such as the acetate and
tartrate acids, could replace TFA with comparable results.
Before moving beyond the system presented in Scheme 1,
one additional aniline variation was examined, in which the
N-alkyl substitution was rigidified through inclusion in a
saturated ring. Using 1,2,3,4-tetrahydroquinoline as the aniline
moiety, we obtained cycloadducts 8 and 9 in an approximate
6:1 ratio with an overall yield of 93% (Scheme 2), a satisfying
result considering the increased complexity and constraint that
the polycyclic product possessed. The stereochemistry was
confirmed for both isomers with NMR by evaluating the
coupling constants and nOe values.
Next, a series of modifications at the bridging unit (the
segment tethering the aldehyde and olefin) were explored. First
J. Org. Chem, Vol. 71, No. 15, 2006 5519

Muhuhi and Spaller
SCHEME 8. Aza Diels-Alder Cyclization with N-Methylaniline and Furanyl-Based Dienophile with Glycine Bridge
If such an elimination reaction were to blame, we reasoned
that removal of the acidic protons by alkyl substitution should
circumvent the problem. A dimethylated analogue, 23, was
prepared in a manner commensurate with the earlier elaboration
of bridge units, except here the preparation began with the
reductive amination of 3-amino-2-dimethylpropanol with 2,4-
dimethoxyenzaldehyde to yield 19. This was followed by EDC
coupling of 19 with 4-methoxycinnamic acid to generate the
4-methoxycinnamyl amide alcohol 21, which was then oxidized
to cyclization precursor 23.
The subsequent aza Diels-Alder transformation with N-
methylaniline proved relatively sluggish and required refluxing
with Yb(OTf)3, leading to a combined yield of 77% for the
product diastereomers 24 and 25. In this case, under refluxing
conditions the TFA-mediated reaction led to crude isolates that
were much less clean than those obtained when using Yb(OTf)3.
The observed isomer ratio of 2:1 may be attributable to ring
products possessing comparable energetic stability, coupled to
a prolonged opportunity for single-bond rotation to occur before
final ring closure (this assuming that a two-step mechanism is
responsible as raised earlier). The presence of the gem-dimethyl
groups might also contribute, both in terms of sites of additional
steric contact or in conformational biasing of what might
otherwise be a very flexible alkyl bridge.
Moving on to considerations of the dienophile, we thought
to examine the consequence of using an olefin with Z stereo-
chemistry. The commercial availability of the trans-cinnamic-
type acids is far larger than that of their cis counterparts, and
therefore the former represents the more useful pool for starting
materials in a combinatorial synthesis. Nonetheless, if the cis-
based dienophiles yielded distinctly different product stereo-
isomers (or stereoisomeric distributions), then that could justify
their inclusion into a combinatorial synthesis. To make the most
direct comparison with a previously performed experiment with
a trans olefin, we prepared the cis-4-methoxycinnamic acid
(Scheme 6).
Using a variation of the Still-Gennari method,31 we hydro-
lyzed the methyl ester of the olefin, 27, to yield acid 28. A
sequence analogous to the preparation of aldehyde-olefin 4 was
followed: acid 28 was coupled to glycine-DMB amine 1 to
form ester 29 (88%), which was reduced to alcohol 30 (94%),
followed by oxidation to the cyclization precursor 31 (91%).
After application of the standard aza-Diels-Alder conditions,
31 provided a mixture of three identifiable stereoisomers
(Scheme 7). The mixture of the chromatographically inseparable
6a and 32, found in a 1:1 ratio, both maintain a trans orientation
at the ring fusion with the lactam ring. But only 32 retains the
original stereochemistry of the cis alkene, and 6a reflects, as
described previously, a possible isomerization event through a
two-step mechanism (Figure 4). The final result is also
influenced by the possibility that the cis double bond loses its
integrity when exposed to acid. This additional effect was
bolstered by the results from a test reaction in which morpholine
was added to 31 under the cyclization reaction conditions; upon
quenching and workup, the NMR spectrum indicated the
presence of two forms of the alkene.
A final adjustment to the dienophile was made by replacing
the phenyl unit with a smaller, and electronically distinct,
aromatic ring. A furan group was selected, and a sequence was
initiated that again mirrored the assembly of cyclization
precursor 4: glycine methyl ester was coupled to trans-3-(2-
furyl)acrolein to form ester 33 (97%), reduced to alcohol 34
(96%), followed by Swern oxidation to generate 35. The aza
Diels-Alder reaction provided the endo-derived tetrahydro-
quinoline 36 (92%) as the predominant product with a combined
yield of 67% (Scheme 8). While the efficiency is lower than
that of the 4-methoxycinnamate dienophile, this recovery
nevertheless represents a usable outcome and demonstrates the
feasibility of including nonphenyl moieties in the aza Diels-
Alder combinatorial synthesis.
In summary, we have demonstrated that there are chemical
aspects of the intramolecular Aza Diels-Alder that can be
modified or tuned, which enrich the combinatorial chemical
possibilities and will supplement what had earlier been dem-
onstrated with this system.18 Previously, a variety of amino acids
and electron-rich and -poor cinnamyl dienophiles and primary
anilines contributed to structural diversity; to this we can now
introduce selected variations on the dienophile and linking
bridge, as well as a range of secondary anilines that form the
diene component. Further, it is now possible to employ other
catalysts in addition to those originally investigated. Taken
together, these accumulated results will permit the use of this
transformation for the generation of chemical libraries compris-
ing a variety of structurally diverse compounds built around a
quinoline core.
Experimental Section
General procedures for preparation of the reported compounds
may be found in the Supporting Information.
(2,4-Dimethoxybenzylamino)-acetic Acid Methyl Ester (1).
2,4-Dimethoxybenzaldehyde (1.50 g, 9.0 mmol) was dissolved in
dichloroethane (100 mL); to this was added triethylamine (1.88
mL, 13.5 mmol) and glycine methyl ester (2.55 g, 13.5 mmol) and
stirred. To this solution was added, with vigorous stirring, sodium
triacetoxyborohydride (3.83 g, 18.1 mmol). The solution was stirred
under argon for 24 h, after which it was quenched with saturated
NaHCO3 (60 mL), extracted with CH2Cl2 (3 × 20 mL), and then
concentrated. Flash chromatography was performed using CH2Cl2/
1
EtOAc (1:4) to give a clear thick liquid in quantitative yield. H
NMR (500 MHz, CDCl3) δ 7.12 (d, J ) 8.0 Hz, 1H), 6.45 (d, J )
2.0 Hz, 1H), 6.42 (dd, J ) 8.0, 2.5 Hz, 1H), 4.15 (q, J ) 7.3 Hz,
2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 3.37 (s, 1H), 1.25 (t,
J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.7, 160.5,
158.9, 130.8, 120.34, 103.9, 98.7, 60.8, 55.6, 55.5, 50.3, 48.3, 14.4;
(31) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
5520 J. Org. Chem., Vol. 71, No. 15, 2006

Intramolecular Aza Diels-Alder Cyclization
IR 3340, 2996, 2949, 2833, 1736, 1613, 1578, 1497 cm-1. HRMS
calcd for C13H18O4N 238.10793 (M+), found 238.10803.
added N-methylaniline (65 µL, 0.6 mmol) and then TFA (94 µL,
1.2 mmol). The reaction mixture was stirred for 30 min, quenched
with NaHCO3 (30 mL), and extracted using CH2Cl2 (3 × 10 mL).
The combined organic layers were dried (MgSO4) and concentrated
to give a light brown film. Flash chromatographed with silica gel
using hexane/CH2Cl2/EtOAc (3:1:1) eluant to afford 159 mg (83%)
of 6a as a white solid and 22 mg (12%) of 7a as a film. mp 173.8-
{(2,4-Dimethoxybenzyl)-[3-(4-methoxyphenyl)-acroyl]amino}-
acetic Acid Methyl Ester (2). To a solution of 1 (2.00 g, 8.4 mmol)
in DMF/CH2Cl2 (21 mL, 1:3) was dissolved 4-methoxycinnamic
acid (2.23 g, 12.3 mmol). To this was added HOBt (0.162 g, 1.2
mmol) and EDCI (2.36 g, 12.3 mmol). The reaction mixture was
allowed to stir for 12 h. The organic layer was washed with 50 mL
of 0.1 M HCl solution and extracted with CH2Cl2 (3 × 20 mL).
The organic layers were combined and successively washed with
distilled water (1 × 100 mL) and saturated NaHCO3 (1 × 60 mL),
dried over MgSO4, and then concentrated. The residue was purified
by flash chromatography using CH2Cl2/EtOAc (8:1) as eluant to
afford 3.04 g (91%) as a white flaky solid. mp 94.2-95.5 °C; white
1
174.8 °C; white crystalline solid. H NMR (500 MHz, CDCl3) δ
7.18 (dd, J ) 8.5 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 1H), 7.11 (t, J )
6.0 Hz, 1H), 6.86 (d, J ) 8.5 Hz, 2H), 6.81 (d, J ) 8.5 Hz, 1H),
6.76 (d, J ) 8.0 Hz, 1H), 6.68 (t, J ) 7.5 Hz, 1H), 6.45 (d, J ) 2.0
Hz, 1H), 6.42 (dd, J ) 8.0, 2.5 Hz, 1H), 4.49 (d, J ) 14.5 Hz,
1H), 4.36 (d, J ) 15.0 Hz, 1H), 4.32 (d, J ) 12.0 Hz, 1H), 3.80 (s,
3H), 3.79 (s, 6H), 3.48 (dd, J ) 8.8, 6.5 Hz, 1H), 3.37 (ddd, J )
11.5, 9.8, 6.5 Hz, 1H), 3.22 (t, J ) 8.0 Hz, 1H), 2.92 (t, J ) 12.0
Hz, 1H), 2.76 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 172.5, 160.5,
158.6, 158.1, 148.3, 136.0, 131.03, 131.0, 130.3, 128.8, 127.3,
119.1, 117.0, 113.7, 113.4, 104.2, 98.4, 59.5, 55.3, 55.1, 50.6, 49.8,
45.1, 40.4, 36.2; IR 3061, 2996, 2932, 2874, 2827, 1695, 1613,
1503, 1462, 1362 cm-1; HRMS calcd for C28H30O4N2 was
458.22056 (M+), found 458.22002.
2-(2,4-Dimethoxybenzyl)-9-(4-methoxyphenyl)-4-methyl-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (7a). Light
yellow film. 1H NMR (500 MHz, CD2Cl2) δ 7.19 (dt, J ) 7.8, 1.5
Hz, 1H), 7.13 (dt, J ) 11.0, 2.5 Hz, 2H), 6.99 (dd, J ) 7.3, 2.0
Hz, 1H), 6.81 (dt, J ) 9.1, 2.5 Hz, 2H), 6.71 (dt, J ) 7.5, 1.5 Hz,
1H), 6.61 (d, J ) 8.0 Hz, 1H), 6.52 (d, J ) 8.0 Hz, 1H), 6.40 (d,
J ) 2.5 Hz, 1H), 6.29 (dd, J ) 8.5, 2.5 Hz, 1H), 4.42 (d, J ) 15.0
Hz, 1H), 4.40 (d, J ) 2.5 Hz, 1H), 4.16 (d, J ) 15.5 Hz, 1H), 3.95
(ddd, J ) 7.9, 5.3, 2.5 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.71 (s,
3H), 3.29 (m, 2H), 3.25 (dd, J ) 8.3, 3.0 Hz, 1H); 13C NMR (125
MHz, CD2Cl2) δ 173.1, 160.7, 158.8, 158.5, 145.9, 135.7, 129.6,
129.1, 128.3, 126.4, 118.1, 116.8, 114.0, 112.2, 104.6, 98.4, 55.7,
55.6, 55.5, 50.6, 49.9, 42.7, 40.7, 36.0; IR 3066, 2996, 2938, 2833,
1678, 1596, 1509, 1456 cm-1; HRMS calcd for C28H30O4N2 was
458.22056 (M+), found 458.22056.
1
flaky solid. H NMR (500 MHz, CDCl3) δ 7.73 (d, J ) 15.0 Hz,
1H), 7.46 (d, J ) 8.5 Hz, 2H), 7.09 (d, J ) 8.0 Hz, 1H), 6.91 (d,
J ) 14.5 Hz, 1H), 6.87 (d, J ) 8.5 Hz, 2H), 6.48 (d, J ) 2.0 Hz,
1H), 6.45 (dd, J ) 7.5 Hz, 1H), 4.66 (s, 2H), 4.15 (s, 2H), 3.82 (s,
3H), 3.80 (s, 6H), 3.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
170.0, 167.8, 160.8, 160.7, 158.3, 143.0, 129.4, 129.0, 128.0, 116.7,
114.7, 114.1, 103.9, 98.6, 55.4, 55.3, 55.2, 52.0, 47.6, 47.5, 44.8;
IR 3072, 3008, 2943, 2844, 1754, 1643, 1590, 1508, 1438 cm-1
;
HRMS calcd for C22H25O6N 399.16819 (M+), found 399.16823.
N-(2,4-Dimethoxybenzyl)-N-(2-hydroxyethyl)-3-(4-methoxy-
phenyl)-acryl Amide (3). To a solution of 2 (3.04 g, 7.6 mmol) in
50 mL of THF was added via a syringe 1 M lithium tri-tert-
butoxyaluminohydride (21.8 mL, 21.8 mmol). The mixture was
stirred for 6 h, and 60 mL of diethyl ether was added, followed by
dropwise addition of 5 mL of 10% KHSO4. The mixture was left
to stir until two separate layers formed. Vacuum filtration was used
to remove the white salt layer, which was washed with 60 mL of
EtOAc. The combined organic layers were washed with brine (40
mL), dried (MgSO4), and concentrated to give a thick light-green
slurry. The slurry was chromatographed using silica gel to afford
1
2.79 g (98%) as clear glass. H NMR (500 MHz, CDCl3) δ 7.72
(d, J ) 15.5 Hz, 1H), 7.42 (d, J ) 9.0 Hz, 2H), 7.03 (d, J ) 8.5
Hz, 1H), 6.86 (d, J ) 9.0 Hz, 2H), 6.77 (d, J ) 15.5 Hz, 1H), 6.48
(d, J ) 2.0 Hz, 1H), 6.47 (dd, J ) 9.0, 2.0 Hz, 1H), 4.62 (s, 2H),
4.12 (t, J ) 4.5 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.797 (s, 3H),
3.77 (m, 1H), 3.63 (t, J ) 4.8 Hz, 2H); 13C NMR (125 MHz, CDCl3)
169.7, 160.9, 160.6, 156.0, 143.1, 129.4, 128.2, 127.8, 116.8, 114.9,
114.1, 113.8, 104.0, 98.6, 62.4, 55.3, 55.3, 55.2, 50.4, 47.8; IR
3382, 3072, 2996, 2932, 1643, 1584, 1520, 1444 cm-1; HRMS
calcd for C21H25O5N 371.17327 (M+), found 371.17336.
2-(2,4-Dimethoxybenzyl)-7-fluoro-9-(4-methoxyphenyl)-4-meth-
yl-2,3,3a,4, 9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6b).
Prepared according to the general procedure for the cyclization.
Yield: 77%; mp 199.0-200.1 °C; white solid. 1H NMR (500 MHz,
CDCl3) δ 7.16 (d, J ) 8.5 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 1H), 6.87
(d, J ) 8.5 Hz, 2H), 6.83 (dt, J ) 8.3, 3.0 Hz, 1H), 6.73 (dd, J )
8.0, 5.0 Hz, 1H), 6.48 (ddd, J ) 9.8, 3.0, 1.0 Hz, 1H), 6.44 (d, J
) 2.0 Hz, 1H), 6.42 (dd, J ) 8.3, 2.0 Hz, 1H), 4.48 (d, J ) 14.5
Hz, 1H), 4.36 (d, J ) 15.0 Hz, 1H), 4.27 (d, J ) 12.5 Hz, 1H),
3.80 (s, 6H), 3.79 (s, 3H), 3.48 (dd, J ) 8.5, 6.0 Hz, 1H), 3.32
(ddd, J ) 9.5, 9.3, 6.5 Hz, 1H), 3.21 (t, J ) 9.3 Hz, 1H), 2.91 (t,
J ) 11.8 Hz, 1H), 2.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
172.3, 160.5, 158.5, 158.3, 157.3, 155.4, 144.7, 135.2, 131.0, 130.6,
130.6, 130.2, 117.3, 117.1, 116.9, 114.4, 114.3, 114.0, 113.9, 104.2,
98.4, 59.8, 55.3, 55.1, 50.4, 49.7, 45.3, 40.5, 36.7; IR 2996, 2938,
N-(2,4-Dimethoxybenzyl)-3-(4-methoxyphenyl)-N-(2-oxoethyl)-
acryl Amide (4). Oxalyl chloride (179 µL, 1.4 mmol) was dissolved
in 6 mL of CH2Cl2 and cooled to -78 °C. DMSO (200 µL, 2.8
mmol) dissolved in 2 mL of CH2Cl2 was added cautiously, and the
mixture was allowed to stir for 15 min, after which the alcohol
(210 mg, 0.6 mmol) was added, and the reaction was stirred for 1
h at -78 °C. Triethylamine (437 µL, 3.1 mmol) was added, and
the reaction was stirred for another 30 min and allowed to warm
to ambient temperature. The mixture was quenched with 30 mL of
saturated NH4Cl and extracted using CH2Cl2 (3 × 15 mL), washed
with brine, and dried using MgSO4. Flash chromatography was
performed using hexane/CH2Cl2/EtOAc (1:1:1) system to yield a
yellow-green thick liquid weighing 199 mg. Yield 95%. 1H NMR
(500 MHz, CDCl3) δ 9.44 (s, 1H), 7.74 (d, J ) 15.5 Hz, 1H), 7.50
(d, J ) 8.5 Hz, 2H), 7.08 (d, J ) 8.0 Hz, 1H), 6.98 (d, J ) 15.5
Hz, 1H), 6.91 (d, J ) 8.5 Hz, 2H), 6.47 (m, 2H), 4.66 (s, 2H),
4.10 (s, 2H), 3.82 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 198.5, 167.9, 160.95, 160.92, 158.3,
143.1, 129.5, 129.4, 127.8, 116.5, 114.22, 114.16, 104.1, 98.7, 56.4,
55.4, 55.33, 55.27, 55.1, 48.2; IR 3061, 2996, 2938, 2844, 1736,
1643, 1590, 1514, 1444 cm-1; HRMS calcd for C21H23O5N was
369.15678 (M+), found 369.15716.
2874, 2833, 1701, 1614, 1584, 1503, 1503, 1409, 1368 cm-1
;
HRMS calcd for C28H29O4N2F 476.21114 (M+), found 476.21135.
2-(2,4-Dimethoxybenzyl)-7-fluoro-9-(4-methoxyphenyl)-4-meth-
yl-2,3,3a,4, 9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (7b).
Prepared according to the general procedure for the cyclization.
Yield: 18%; clear film. 1H NMR (500 MHz, CD2Cl2) δ 7.13 (d, J
) 9.0 Hz, 2H), 6.88 (dt, J ) 8.9, 3.0 Hz, 1H), 6.82 (d, J ) 9.5 Hz,
2H), 6.78 (dd, J ) 8.5, 3.0 Hz, 1H), 6.56 (d, J ) 8.0 Hz, 1H), 6.53
(dd, J ) 9.3, 5.0 Hz, 1H), 6.41 (d, J ) 2.0 Hz, 1H), 6.31 (dd, J )
8.3, 3.0 Hz, 1H), 4.44 (d, J ) 15.0 Hz, 1H), 4.37 (d, J ) 3.5 Hz,
1H), 4.15 (d, J ) 14.5 Hz, 1H), 3.93 (m, 1H), 3.77 (s, 3H), 3.76
(s, 3H), 3.72 (s, 3H), 3.32 (dd, J ) 10.5, 5.5 Hz, 1H), 3.26 (m,
2H); 13C NMR (125 MHz, CD2Cl2) δ 129.7, 129.1, 116.0, 114.1,
104.5, 98.43, 55.5, 50.4, 49.8, 43.0, 40.7, 36.2, 24.4; HRMS calcd
for C28H29O4N2F 476.21114 (M+), found 476.2106.
2-(2,4-Dimethoxybenzyl)-9-(4-methoxyphenyl)-4-methyl-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6a). To a
solution of aldehyde 4 (155 mg, 0.4 mmol) in 5 mL of MeCN were
2-(2,4-Dimethoxybenzyl)-7-methoxy-9-(4-methoxyphenyl)-4-
methyl-2,3,3 a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6c).
Prepared according to the general procedure for the cyclization.
J. Org. Chem, Vol. 71, No. 15, 2006 5521

Muhuhi and Spaller
Yield: 78%; mp 178.5-179.7 °C; white solid. 1H NMR (500 MHz,
CDCl3) δ 7.17 (d, J ) 8.5 Hz, 2H), 7.11 (d, J ) 8.0 Hz, 1H), 6.85
(d, J ) 8.5 Hz, 2H), 6.77 (d, J ) 9.0 Hz, 1H), 6.71 (dd, J ) 9.0,
3.0 Hz, 1H), 6.44 (d, J ) 2.0 Hz, 1H), 6.43 (dd, J ) 8.3, 2.0 Hz,
1H), 6.34 (d, J ) 2.5 Hz, 1H), 4.48 (d, J ) 14.5 Hz, 1H), 4.35 (d,
J ) 14.5 Hz, 1H), 4.29 (d, J ) 12.0 Hz, 1H), 3.79 (s, 3H), 3.78 (s,
6H), 3.57 (s, 3H), 3.46 (dd, J ) 8.8, 6.0 Hz, 1H), 3.27 (m, 2H),
2.90 (t, J ) 11.3 Hz, 1H), 2.71 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 160.4, 158.5, 158.1, 152.7, 142.6, 135.7, 130.9,
130.2, 117.0, 116.5, 114.5, 113.7, 112.8, 104.2, 98.4, 60.1, 55.4,
55.3, 55.1, 50.7, 49.8, 45.3, 40.4, 37.0; IR 3066, 3031, 3002, 2938,
1H), 7.09 (t, J ) 7.3 Hz, 1H), 6.87 (d, J ) 8.0 Hz, 2H), 6.78 (d,
J ) 8.5 Hz, 1H), 6.73 (d, J ) 8.5 Hz, 1H), 6.64 (t, J ) 7.3 Hz,
1H), 6.44 (d, J ) 3.0 Hz, 1H), 6.43 (dd, J ) 8.3, 2.5 Hz, 1H), 5.91
(dddd, J ) 16.8, 11.8, 6.0, 4.5 Hz, 1H), 5.28 (dd, J ) 17.0, 1.5
Hz, 1H), 5.21 (d, J ) 10.0, 1.5 Hz, 1H), 4.49 (d, J ) 15.0 Hz,
1H), 4.33 (d, J ) 15.0 Hz, 1H), 4.31 (d, J ) 12.5 Hz, 1H), 4.08 (t,
J ) 2.3 Hz, 1H), 4.04 (dt, J ) 16.9, 2.3 Hz, 1H), 3.80 (s, 9H),
3.61 (m, 2H), 3.47 (dd, J ) 8.8, 6.5 Hz, 1H), 3.22 (t, J ) 9.0 Hz,
1H), 2.93 (t, J ) 11.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
172.6, 160.7, 158.4, 146.9, 136.0, 133.6, 131.4, 131.2, 130.5, 128.8,
127.5, 118.9, 117.5, 117.3, 114.0, 113.8, 104.5, 98.7, 58.2, 55.6,
55.6, 55.4, 51.5, 50.7, 49.9, 45.4, 40.8; IR 3061, 3008, 2938, 2827,
1701, 1608, 1509, 1462, 1415, 1357 cm-1; HRMS calcd for
C30H32O4N2 was 484.23621 (M+), found 484.23627.
2874, 2836, 1689, 1607, 1579, 1491, 1462, 1421, 1369 cm-1
;
HRMS calcd for C29H32O5N2 488.23112 (M+), found 488.23100.
2-(2,4-Dimethoxybenzyl)-7-methoxy-9-(4-methoxyphenyl)-4-
methyl-2,3,3 a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (7c).
Prepared according to the general procedure for the cyclization.
4-Allyl-2-(2,4-dimethoxybenzyl)-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a,-hexahydropyrrolo[3,4-b]quinolin-1-one (7e). Pre-
pared according to the general procedure for the cyclization.
1
Yield: 17%; light yellow film. H NMR (500 MHz, CD2Cl2) δ
7.16 (dd, J ) 9.5, 2.0 Hz, 2H), 6.81 (dt, J ) 9.0, 2.5 Hz, 2H), 6.76
(dd, J ) 8.8, 3.0 Hz, 1H), 6.66 (d, J ) 3.0 Hz, 1H), 6.56 (d, J )
9.0 Hz, 1H), 6.45 (d, J ) 8.5 Hz, 1H), 6.40 (d, J ) 2.5 Hz, 1H),
6.28 (dd, J ) 8.3, 2.5 Hz, 1H), 4.42 (d, J ) 15.5 Hz, 1H), 4.38 (d,
J ) 3.5 Hz, 1H), 4.14 (d, J ) 15.0 Hz, 1H), 3.95 (ddd, J ) 8.6,
5.8, 2.0 Hz, 1H), 3.76 (s, 3 H), 3.75 (s, 3H), 3.72 (s, 3H), 3.70 (s,
3H), 3.31 (dd, J ) 5.8, 3.5 Hz, 1H), 3.27 (t, J ) 5.3 Hz, 1H), 3.24
(dd, J ) 10.8, 2.5 Hz, 1H), 2.71 (s, 3H); 13C NMR (125 MHz,
CD2Cl2) δ 173.3, 160.6, 158.7, 158.5, 152.8, 139.9, 135.3, 129.4,
129.1, 128.7, 116.7, 115.4, 114.5, 113.9, 113.3, 113.2, 104.5, 98.4,
55.8, 55.7, 55.7, 55.6, 55.5, 50.8, 49.6, 43.5, 40.7, 36.2; MS calcd
for C29H32O5N2 527.3 (MK+), found 527.2.
1
Yield: 19%; light yellow film. H NMR (500 MHz, CD2Cl2) δ
7.11 (d, J ) 8.5 Hz, 2H), 6.98 (d, J ) 7.5 Hz, 1H), 6.81 (d, J )
8.5 Hz, 2H), 6.69 (t, J ) 7.5 Hz, 1H), 6.63 (d, J ) 8.0 Hz, 1H),
6.59 (d, J ) 8.0 Hz, 1H), 6.40 (d, J ) 2.5 Hz, 1H), 6.31 (dd, J )
8.8, 2.5 Hz, 1H), 5.79 (dtt, J ) 11.1, 10.5, 5.5 Hz, 1H), 5.13 (d, J
) 9.0, 1H), 5.12 (d, J ) 10.0 Hz, 1H), 4.38 (d, J ) 3.5 Hz, 1H),
4.37 (d, J ) 15.0 Hz, 1H), 4.22 (d, J ) 15.5 Hz, 1H), 3.99 (ddd,
J ) 7.3, 5.3, 2.5 Hz, 1H), 3.92 (dd, J ) 16.3, 5.0 Hz, 1H), 3.76 (s,
3H), 3.74 (s, 3H), 3.71(s, 3H), 3.68 (dd, J ) 16.5, 5.5 Hz, 1H),
3.29 (dd, J ) 10.8, 5.0 Hz, 1H), 3.26 (dd, J ) 10.0, 3.5 Hz, 1H),
3.18 (dd, J ) 8.0, 3.5 Hz, 1H); 13C NMR (125 MHz, CD2Cl2) δ
173.1, 160.7, 158.8, 158.5, 145.0, 135.8, 134.8, 129.9, 129.7, 129.2,
128.1, 126.2, 118.2, 117.2, 116.9, 114.0, 113.3, 104.6, 98.4, 55.6,
55.5, 53.7, 51.9, 51.0, 50.3, 42.2, 41.0, 40.8; IR 3061, 3002, 2932,
2827, 1684, 1608, 1509, 1444, 1340 cm-1; HRMS calcd for
C30H32O4N2 was 484.23621 (M+), found 484.23605.
2-(2,4-Dimethoxybenzyl)-4-ethyl-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a-hexahydropyrrol[3,4-b]quinolin-1-one (6d). Prepared
according to the general procedure for the cyclization. Yield 81%;
mp 166.6-167.6 °C; creamy white solid. 13H NMR (500 MHz,
CDCl3) δ 7.17 (d, J ) 8.0 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 1H), 7.08
(t, J ) 7.8 Hz, 1H), 6.85 (d, J ) 8.5 Hz, 2H), 6.79 (d, J ) 7.5 Hz,
1H), 6.73 (d, J ) 7.5 Hz, 1H), 6.62 (t, J ) 7.3 Hz, 1H), 6.45 (d,
J ) 2.0 Hz, 1H), 6.44 (dd, J ) 8.3,2.0 Hz, 1H), 4.51 (d, J ) 15.0
Hz, 1H), 4.34 (d, J ) 14.5 Hz, 1H), 4.30 (d, J ) 12.0 Hz, 1H),
3.80 (s, 3H), 3.79 (s, 6H), 3.61 (m, 2H), 3.47 (dd, J ) 8.8, 6.5 Hz,
1H), 3.22 (t, J ) 9.3 Hz, 1H), 3.09 (s, J ) 7.5 Hz, 1H), 2.89 (t, J
) 11.5 Hz, 1H), 1.09 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 160.4, 158.5, 158.1, 146.0, 135.9, 131.3, 131.0,
130.3, 128.8, 127.3, 118.3, 117.1, 113.7, 113.1, 104.2, 98.4, 56.8,
55.3, 55.1, 50.4, 49.6, 45.2, 41.9, 40.5, 9.9; IR 3066, 2967, 2926,
2868, 2838, 1695, 1602, 1509, 1462, 1369 cm-1; HRMS calcd for
C29H32O4N2 was 472.23621 (M+), found 472.23669.
2-(2,4-Dimethoxybenzyl)-4-ethyl-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a-hexahydropyrrol[3,4-b]quinolin-1-one (7d). Prepared
according to the general procedure for the cyclization. Yield: 10%;
creamy white foam. 1H NMR (500 MHz, CD2Cl2) δ 7.16 (dt, J )
7.8, 2.0 Hz, 1H), 7.12 (dt, J ) 10.0, 2.5 Hz, 2H), 6.98 (dd, J )
7.5, 1.5 Hz, 1H), 6.81 (dt, J ) 9.5, 2.5 Hz, 2H), 6.68 (d, J ) 7.5
Hz, 2H), 6.55 (d, J ) 8.5 Hz, 1H), 6.40 (d, J ) 2.0 Hz, 1H), 6.30
(dd, J ) 8.3, 3.0 Hz, 1H), 4.42 (d, J ) 15.5 Hz, 1H), 4.35 (d, J )
3.5 Hz, 1H), 4.17 (d, J ) 15.0 Hz, 1H), 3.99 (ddd, J ) 8.0, 5.5,
2.0 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.45 (dq, J )
13.7, 7.2 Hz, 1H), 3.33 (dd, J ) 10.0, 5.5 Hz, 1H), 3.21 (dd, J )
10.8, 2.5 Hz, 1H), 3.18 (dd, J ) 8.0, 3.5 Hz, 1H), 3.03 (dq, J )
14.1, 7.0 Hz, 1H), 1.11 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz,
CD2Cl2) δ 173.2, 160.6, 158.8, 158.5, 144.7, 135.7, 129.8, 129.6,
129.3, 128.2, 126.6, 117.8, 116.9, 113.9, 112.8, 104.6, 98.4, 55.7,
55.6, 55.5, 53.2, 51.2, 50.4, 42.5, 42.5, 40.7, 12.0; IR 3060, 2961,
2926, 2839, 1695, 1602, 1509, 1456 cm-1; HRMS calcd for
C29H32O4N2 was 472.23621 (M+), found 472.23603.
2-(2,4-Dimethoxybenzyl)-4-isopropyl-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6f). Pre-
pared according to the general procedure for the cyclization, but
was refluxed for 12 h and Yb(OTf)3 was used as the catalyst.
1
Yield: 63%. H NMR (400 MHz, CD2Cl2) δ 7.13 (dd, J ) 8.8,
4.0 Hz, 3H), 7.05 (t, J ) 7.4 Hz, 1H), 6.94 (d, J ) 8.0 Hz, 1H),
6.86 (d, J ) 8.8 Hz, 2H), 6.66 (d, J ) 7.6 Hz, 1H), 6.60 (t, J ) 7.4
Hz, 1 H), 6.45 (d, J ) 1.6 Hz, 1H), 6.44 (dd, J ) 11.8, 2.4 Hz,
1H), 4.48 (d, J ) 14.8 1H), 4.33 (d, J ) 14.8 Hz, 1H), 4.23 (d, J
) 12.4 Hz, 1H), 3.93 (p, J ) 6.9 Hz, 1H), 3.80 (s, 3H), 3.79 (s,
6H), 3.56 (m, 2H), 3.29 (dt, J ) 9.9, 2.4 Hz, 1H), 2.92 (t, J ) 11.6
Hz, 1H), 1.30 (d, J ) 6.4 Hz, 3H), 1.26 (d, J ) 7.6 Hz, 3H); 13C
NMR (100 MHz, CD2Cl2) δ 171.9, 160.4, 158.5, 158.1, 146.8,
135.5, 131.0, 130.9, 130.2, 129.9, 126.9, 118.3, 117.1, 115.3, 113.7,
104.2, 98.4, 56.8, 55.3, 55.3, 55.1, 51.5, 51.5, 50.3, 45.3, 40.5, 20.6,
19.8; HRMS calcd for C30H34O4N2 was 486.2519 (M+), found
486.2517.
2-(2,4-Dimethoxybenzyl)-4-isopropyl-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (7f). Pre-
pared according to the general procedure for the cyclization, but
was refluxed for 12 h and Yb(OTf)3 was used as the catalyst.
Yield: 26%. 1H NMR (500 MHz, CD2Cl2) δ 7.17 (dt, J ) 8.4, 2.0
Hz, 1H), 7.11 (dt, J ) 8.5, 2.5 Hz, 2H), 7.04 (dd, J ) 12.5, 1.5
Hz, 1H), 6.79 (dt, J ) 9.0, 2.8 Hz, 3H), 6.73 (dt, J ) 7.5, 1.0 Hz,
1H), 6.42 (d, J ) 9.0 Hz, 1H), 6.38 (d, J ) 2.5 Hz, 1H), 6.26 (dd,
J ) 8.3, 2.0 Hz, 1H), 4.45 (d, J ) 15.0 Hz, 1H), 4.30 (d, J ) 3.0
Hz, 1H), 4.19 (tt, J ) 6.5, 3.5 Hz, 1H), 4.11 (d, J ) 15.5 Hz, 1H),
3.75 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.39 (dd, J ) 10.5, 7.0 Hz,
1H), 3.36 (dd, J ) 9.8, 3.5 Hz, 1H), 3.12 (dd, J ) 10.5, 3.5 Hz,
1H), 1.15 (d, J ) 7.0 Hz, 3H), 1.08 (d, J ) 6.5 Hz, 3H); 13C NMR
(125 MHz, CD2Cl2) δ 173.8, 160.5, 158.6, 158.4, 145.9, 135.7,
131.0, 130.5, 129.8, 129.5, 129.3, 129.21, 129.16, 128.1, 118.5,
116.7, 115.1, 114.5, 113.7, 104.6, 98.4, 55.6, 55.5, 51.3, 49.4, 48.6,
43.3, 40.7, 21.5, 20.8; MS calcd for C30H34O4N2 was 487.3 (MH+),
found 487.1.
4-Allyl-2-(2,4-dimethoxybenzyl)-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a,-hexahydropyrrolo[3,4-b]quinolin-1-one (6e). Pre-
pared according to the general procedure for the cyclization.
1
Yield: 79%; mp 132.2-133.0 °C; white powder. H NMR (400
MHz, CDCl3) δ 7.17 (d, J ) 8.5 Hz, 2H), 7.12 (d, J ) 8.0 Hz,
5522 J. Org. Chem., Vol. 71, No. 15, 2006

Intramolecular Aza Diels-Alder Cyclization
4-Cyclohexyl-2-(2,4-dimethoxybenzyl)-9-(4-methoxyphenyl)-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6g). Pre-
pared according to the general procedure for the cyclization.
130.5, 129.5, 129.3, 128.8, 128.0, 122.3, 121.7, 120.5, 119.0, 116.4,
114.0, 104.7, 98.3, 55.7, 55.6, 55.4, 53.6, 52.8, 52.5, 43.3, 40.6;
IR 3066, 3036, 3006, 2924, 2837, 1687, 1614, 1593, 1515, 1493,
1455, 1385; HRMS calcd for C33H32O4N2 was 520.23621 (M+),
found 520.23665.
1
Yield: 28%. H NMR (500 MHz, CDCl3) δ 7.12 (m, 3H), 7.06
(ddd, J ) 7.8, 1.5, 1.0 Hz, 1H), 6.93 (d, J ) 8.5 Hz, 1H), 6.86 (d,
J ) 8.5 Hz, 1H), 6.63 (d, J ) 7.5 Hz, 1H), 6.58 (dt, J ) 8.5, 1.0
Hz, 1H), 6.45 (d, J ) 2.5 Hz, 1H), 6.44 (dd, J ) 8.0, 2.5 Hz, 1H),
4.49 (d, J ) 14.5 Hz, 1H), 4.30 (d, J ) 15.0 Hz, 1H), 4.21 (d, J )
12.0 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 3.67 (m, 2H), 3.51 (t, J )
12.3 Hz, 1H), 3.28 (t, J ) 8.0 Hz, 1H), 2.91 (t, J ) 11.5 Hz, 1H),
1.86 (d, J ) 12.0 Hz, 4H), 1.71 (d, J ) 13.0 Hz, 1H), 1.64 (d, J )
9.0 Hz, 1H), 1.54 (t, J ) 11.5 Hz, 1H), 1.38 (q, J ) 13.0 Hz, 1H),
1.28 (q, J ) 13.0 Hz, 1H), 1.12 (q, J ) 13.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 171.7, 160.3, 158.4, 158.1, 147.3, 135.3,
130.7, 130.7, 130.2, 130.0, 127.0, 118.1, 117.2, 115.4, 113.7, 104.2,
98.4, 61.9, 56.8, 55.3, 55.2, 55.1, 52.1, 50.2, 45.3, 40.5, 32.4, 26.8,
26.7, 25.9; IR 3057, 2993, 2932, 2850, 1697, 1610, 1502, 1480,
1450; HRMS calcd for C33H38O4N2 was 526.28316 (M+), found
526.28285.
9-(2,4-Dimethoxybenzyl)-7-(4-methoxyphenyl)-2,3,7a,9,10,
10a-hexahydro-1H,7H-9,10b-diazacyclopenta[a]phenalen-8-
one (8). Prepared according to the general procedure for the
cyclization. Yield: 80%; mp 159.6-160.8 °C; creamy white solid.
1H NMR (500 MHz, CDCl3) δ 7.19 (d, J ) 7.5 Hz, 2H), 7.12 (d,
J ) 8.0 Hz, 1H), 6.85 (m, 3H), 6.58 (d, J ) 4.5 Hz, 1H), 6.44 (d,
J ) 2.0 Hz, 1H), 6.43 (dd, J ) 8.0, 2.5 Hz, 1H), 4.50 (d, J ) 14.5
Hz, 1H), 4.33 (d, J ) 14.5 Hz, 1H), 4.30 (d, J ) 12.5 Hz, 1H),
3.79 (s, 3H), 3.79 (s, 6H), 3.45 (dd, J ) 8.5, 6.0 Hz, 1H), 3.32
(ddd, J ) 11.0, 9.8, 6.0 Hz, 1H), 3.17 (t, J ) 9.8 Hz, 1H), 3.09
(dt, J ) 10.0, 3.5 Hz, 1H), 2.91 (t, J ) 11.5 Hz, 1H), 2.90 (q, J )
11.5 Hz, 1H), 2.81 (d, J ) 5.5 Hz, 1H), 2.77 (dt, J ) 11.0, 3.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 172.7, 160.4, 158.6, 158.1,
144.5, 136.3, 131.0, 130.3, 128.9, 128.2, 127.8, 123.6, 118.9, 117.1,
113.6, 104.2, 98.4, 58.9, 55.3, 55.1, 50.5, 49.4, 46.4, 45.2, 40.4,
27.0, 22.0; IR 2990, 2926, 2845, 1707, 1619, 1584, 1509, 1450,
1351 cm-1; HRMS calcd for C30H32O4N2 was 484.23621 (M+),
found 484.23564.
4-Cyclohexyl-2-(2,4-dimethoxybenzyl)-9-4(4-methoxyphenyl)-
2,3,3a,4,9,9 a,-hexahydropyrrolo[3,4-b]quinolin-1-one (7g). Pre-
pared according to the general procedure for the cyclization.
1
Yield: 14%. H NMR (500 MHz, CD2Cl2) δ 7.17 (ddd, J ) 7.6,
7.3, 2.0 Hz, 1H), 7.13 (dd, J ) 9.0, 3.0 Hz, 2H), 7.05 (dd, J ) 7.6,
1.0 Hz, 1H), 6.79 (dt, J ) 9.3, 2.5 Hz, 2H), 6.76 (d, J ) 7.5 Hz,
1H), 6.74 (dt, J ) 7.5, 1.0 Hz, 1H), 6.38 (d, J ) 2.5 Hz, 1H), 6.35
(d, J ) 9.0 Hz, 1H), 6.24 (dd, J ) 8.3, 2.5 Hz, 1H), 4.45 (d, J )
15.0 Hz, 1H), 4.31 (d, J ) 3.0 Hz, 1H), 4.22 (ddd, J ) 10.5, 6.3,
3.5 Hz, 1H), 4.09 (d, J ) 15.0 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H),
3.71 (s, 3H), 3.40 (m, 3H), 3.11 (dd, J ) 10.0, 3.5 Hz, 1H), 1.89
(d, J ) 12.0 Hz, 1H), 1.79 (m, 1H), 1.72 (m, 1H), 1.64 (m, 1H),
1.32 (m, 5H), 1.15 (m, 1H), 0.90 (t, J ) 6.8 Hz, 1H); 13C NMR
(125 MHz, CD2Cl2) δ 174.0, 160.5, 158.6, 158.3, 145.9, 135.6,
129.8, 129.6, 129.2, 129.1, 128.1, 118.6, 116.7, 115.2, 113.6, 104.6,
98.4, 58.2, 55.6, 55.6, 55.5, 51.3, 48.8, 43.4, 40.6, 32.6, 31.3, 26.5,
26.4, 26.3; IR 3001, 2937, 1688, 1610, 1584, 1510, 1489, 1450;
HRMS calcd for C33H38O4N2 was 526.28316 (M+), found 526.2823.
2-(2,4-Dimethoxybenzyl)-9-(4-methoxyphenyl)-4-phenyl-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (6h). Pre-
pared according to the general procedure for the cyclization.
9-(2,4-Dimethoxybenzyl)-7-(4-methoxyphenyl)-2,3,7a,9,10,
10a-hexahydro-1H,7H-9,10b-diazacyclopenta[a]phenalen-8-
one (9). Prepared according to the general procedure for the
cyclization. Yield: 13%; creamy white foam. 1H NMR (500 MHz,
CD2Cl2) δ 7.11 (d, J ) 8.5 Hz, 2H), 6.84 (d, J ) 7.0 Hz, 1H),
6.82 (dd, J ) 7.0, 2.0 Hz, 2H), 6.76 (d, J ) 9.0 Hz, 1H), 6.71 (d,
J ) 7.5 Hz, 1H), 6.50 (t, J ) 7.3 Hz, 1H), 6.42 (d, J ) 2.5 Hz,
1H), 6.34 (dd, J ) 8.8, 2.5 Hz, 1H), 4.49 (d, J ) 15.0 Hz, 1H),
4.26 (d, J ) 5.0 Hz, 1H), 4.19 (d, J ) 15.5 Hz, 1H), 3.82 (ddd, J
) 7.6, 4.5, 3.0 Hz, 1H), 3.77 (s, 3 H), 3.76 (s, 3H), 3.70 (s, 3H),
3.37 (dd, J ) 11.0, 3.0 Hz, 1H), 3.35 (dd, J ) 10.3, 4.5 Hz, 1H),
3.16 (ddd, J ) 12.4, 7.3, 4.5 Hz, 1H), 3.08 (dd, J ) 7.5, 4.5 Hz,
1H), 2.77 (p, J ) 5.5 Hz, 1H), 2.66 (p, J ) 5.5 Hz, 1H), 1.85 (m,
2H); 13C NMR (125 MHz, CD2Cl2) δ 173.0, 160.8, 158.9, 158.5,
141.6, 136.2, 130.0, 129.3, 127.9, 127.6, 124.2, 122.8, 117.0, 116.7,
114.1, 104.6, 98.4, 55.7, 55.6, 55.5, 54.6, 50.6, 49.9, 47.5, 42.0,
40.7, 28.2, 22.5; IR 3002, 2933, 2842, 1688, 1619, 1593, 1506,
1459.
1
Yield: 77%; mp 175.6-177.8 °C; creamy white solid. H NMR
(500 MHz, CDCl3) δ 7.45 (t, J ) 7.75 Hz, 2H), 7.32 (dt, J ) 7.25,
1.5 Hz, 1H), 7.26 (d, J ) 7.5 Hz, 2H), 7.23 (dd, J ) 8.3, 1.5 Hz,
2H), 7.06 (d, J ) 7.5 Hz, 1H), 6.91 (m, 3H), 6.81 (d, J ) 8.0 Hz,
1H), 6.67 (dt, J ) 7.5, 1.0 Hz, 1H), 6.40 (d, J ) 2.0 Hz, 1H), 6.38
(s, 1H), 6.37 (dd, J ) 7.5, 1.0 Hz, 1H), 4.47 (d, J ) 12.5 Hz, 1H),
4.44 (d, J ) 15.0 Hz, 1H), 4.24 (d, J ) 15.0 Hz, 1H), 3.93 (dt, J
) 11.0, 8.0 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H), 3.07
(m, 3H); 13C NMR (125 MHz, CDCl3) δ 172.2, 160.3, 158.4, 158.2,
147.4, 145.1, 135.7, 131.0, 130.6, 130.3, 129.9, 128.3, 128.2, 126.9,
119.4, 117.1, 115.6, 113.7, 104.1, 98.4, 59.5, 55.3, 55.1, 50.7, 50.0,
45.2, 40.4; IR 3062, 3028, 2997, 2928, 2833, 1709, 1610, 1593,
1510, 1485; HRMS calcd for C33H32O4N2 was 520.23621 (M+),
found 520.23612.
2-(2,4-Dimethoxybenzylamino)-3-phenyl-propionic Acid Meth-
yl Ester (10). Prepared according to the general procedure for the
synthesis of amines. 1
H NMR (500 MHz, CDCl3) δ 7.27 (ddt, J )
7.0, 6.5, 1.5 Hz, 2H), 7.22 (dt, J ) 7.5, 1.3 Hz, 1H), 7.14 (d, J )
7.0 Hz, 2H), 7.03 (d, J ) 8.0 Hz, 1H), 6.38 (d, J ) 2.5 Hz, 1H),
6.37 (dd, J ) 8.3, 2.5 Hz, 1H), 3.77 (s, 3H), 3.74 (d, J ) 13.5 Hz,
1 H), 3.63 (s, 3H), 3.61 (d, J ) 13.0 Hz, 1H), 3.61 (s, 3H), 3.52
(dd, J ) 8.0, 7.0 Hz, 1H), 2.99 (dd, J ) 13.5, 6.3 Hz, 1H), 2.93
(dd, J ) 13.5, 7.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 174.8,
160.0, 158.5, 137.3, 130.3, 129.0, 128.3, 126.5, 119.9, 103.4, 98.2,
61.8, 55.2, 55.0, 51.5, 47.2, 39.5; IR 3329, 3066, 3026, 2996, 2944,
2827, 1736, 1619, 1584, 1503, 1450 cm-1; HRMS calcd for
C19H22O4N 328.15488 (M+), found 328.15465.
2-(2,4-Dimethoxybenzyl)-9-(4-methoxyphenyl)-4-phenyl-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (7h). Pre-
pared according to the general procedure for the cyclization.
Yield: 14%; light green-yellow film. 1H NMR (500 MHz, CD2Cl2)
δ 7.24 (dd, J ) 7.5, 1.5 Hz, 1H), 7.21 (dd, J ) 7.0, 2.0 Hz, 1H),
7.20 (d, J ) 7.5 Hz, 1H), 7.17 (dd, J ) 6.5, 2.0 Hz, 2H), 7.16 (dd,
J ) 9.0, 1.5 Hz, 1H), 7.02 (d, J ) 7.5 Hz, 1H), 6.98 (dt, J ) 7.5,
1.5 Hz, 1H), 6.92 (d, J ) 7.0 Hz, 1H), 6.89 (d, J ) 7.5 Hz, 2H),
6.76 (dd, J ) 6.5, 2.0 Hz, 2H), 6.37 (d, J ) 3.0 Hz, 1H), 6.26 (d,
J ) 8.5 Hz, 2H), 6.21 (dd, J ) 8.5, 2.0 Hz, 1H), 4.57 (d, J ) 2.5
Hz, 1H), 4.48 (d, J ) 15.5 Hz, 1H), 4.38 (ddd, J ) 8.8, 6.8, 1.5
Hz, 1H), 4.12 (d, J ) 15.5 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H),
3.69 (s, 3H), 3.68 (dd, J ) 10.0, 6.5 Hz, 1H), 3.62 (dd, J ) 9.0,
2.5 Hz, 1H), 3.31 (dd, J ) 10.5, 1.5 Hz, 1H); 13C NMR (125 MHz,
CD2Cl2) δ 173.1, 160.5, 158.6, 158.5, 145.8, 142.9, 134.7, 131.3,
2-{(2,4-Dimethoxybenzyl)-[3-(4-methoxyphenyl)-acryoyl]-
amino}-3-phenyl-propionic Acid Methyl Ester (11). Prepared
according to the general procedure for the synthesis of amides. 1H
NMR (400 MHz, CDCl3) δ 7.74 (d, J ) 15.6 Hz, 1H), 7.42 (d, J
) 9.2 Hz, 1H), 7.25 (m, 3H), 7.13 (d, J ) 6.4 Hz, 2H), 7.03 (d, J
) 8.0 Hz, 1H), 6.86 (d, J ) 8.8 Hz, 2H), 6.78 (d, J ) 15.2 Hz,
1H), 6.34 (d, J ) 2.4 Hz, 1H), 6.37 (dd, J ) 8.4, 2.8 Hz, 1H), 4.52
(d, J ) 16.8 Hz, 1H), 4.46 (dd, J ) 7.6, 2.4 Hz, 1H), 4.11 (d, J )
17.2 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.64 (s, 3H),
3.45 (dd, J ) 13.6, 6.4 Hz, 1H), 3.25 (dd, J ) 13.6, 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 171.1, 167.5, 160.7, 160.4, 157.9,
142.7, 138.2, 129.5, 129.3, 129.2, 128.2, 127.9, 126.2, 116.8, 115.3,
114.0, 103.5, 98.2, 60.9, 55.2, 55.2, 55.0, 52.0, 47.2, 35.2; IR 3066,
3002, 2944, 2839, 1742, 1654, 1596, 1503, 1444, 1345 cm-1
;
HRMS calcd for C29H31O6N 489.21514 (M+), found 489.21539.
J. Org. Chem, Vol. 71, No. 15, 2006 5523

Muhuhi and Spaller
N-(1-Benzyl-2-hydroxyethyl)-N-(2,4-dimethoxybenzyl)-3-(4-
methoxyphenyl)-acryl Amide (12). Prepared according to the
general procedure for the synthesis of esters. 1H NMR (500 MHz,
CDCl3) δ 7.73 (d, J ) 15.0 Hz, 1H), 7.43 (d, J ) 8.0 Hz, 2H),
7.27 (t, J ) 7.5 Hz, 3H), 7.21 (m, 3H), 7.00 (d, J ) 8.5 Hz, 1H),
6.89 (d, J ) 9.0 Hz, 2H), 6.77 (d, J ) 16.0 Hz, 1H), 6.43 (d, J )
2.0 Hz, 1H), 6.43 (dd, J ) 8.5, 2.0 Hz, 1H), 4.52 (d, J ) 17.0 Hz,
1H), 4.14 (d, J ) 17.0 Hz, 1H), 3.82 (d, J ) 5.0 Hz, 1H), 3.79 (s,
3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.71 (m, 2H), 3.19 (dd, J ) 13.5,
7.5 Hz, 1H), 3.13 (dd, J ) 13.3, 7.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 169.3, 160.9, 160.6, 158.1, 142.6, 139.0, 129.4, 129.2,
128.4, 127.9, 126.2, 117.0, 116.3, 114.2, 104.0, 98.6, 64.3, 64.1,
55.4, 55.3, 55.2, 48.5, 34.3; IR 3376, 3066, 2996, 2938, 2833, 1643,
1608, 1584, 1520, 1456, 1357 cm-1; HRMS calcd for C28H31O5N
461.22022 (M+), found 461.22076.
N-(1-Benzyl-2-oxoethyl)-N-(2,4-dimethoxybenzyl)-3-(4-meth-
oxyphenyl)-acryl Amide (13). Prepared according to the general
procedure for the oxidation of alcohols. 1H NMR (500 MHz, CDCl3)
δ 9.37 (s, 1H), 7.76 (d, J ) 15.5 Hz, 1H), 7.49 (d, J ) 9.5 Hz,
2H), 7.32 (t, J ) 7.3 Hz, 2H), 7.24 (d, J ) 7.5 Hz, 1H), 7.19 (d,
J ) 7.5 Hz, 2H), 6.91 (d, J ) 9.0 Hz, 2H), 6.88 (d, J ) 2.5 Hz,
2H), 6.41 (s, 1H), 6.39 (d, J ) 2.5 Hz, 1H), 4.62 (d, J ) 16.0 Hz,
1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.69 (m, 1H), 3.57 (d,
J ) 16.0 Hz, 1H), 3.47 (dd, J ) 14.0, 4.5 Hz, 1H), 3.22 (dd, J )
13.5, 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 197.5, 167.3,
161.1, 158.5, 143.2, 138.6, 130.4, 129.5, 129.3, 128.6, 127.8, 126.5,
116.6, 114.3, 113.9, 104.1, 98.7, 68.3, 55.4, 55.3, 55.1, 48.9, 33.1;
IR 3061, 3002, 2938, 2827, 1718, 1637, 1596, 1514, 1444, 1287
cm-1; HRMS calcd for C28H29O5N 459.20457 (M+), found
459.20499.
3-{(2,4-Dimethoxybenzyl)-[3-(4-methoxyphenyl)-acryoyl]-
amino}-3-propionic Acid Methyl Ester (18). Prepared according
to the general procedure for the synthesis of amides. Major rotamer
1H NMR (500 MHz, CDCl3) δ 7.69 (d, J ) 16.0 Hz, 1H), 7.42 (d,
J ) 8.5 Hz, 2H), 7.03 (d, J ) 8.0 Hz, 1H), 6.86 (d, J ) 8.5 Hz,
2H), 6.77 (d, J ) 15.5 Hz, 1H), 6.47 (d, J ) 2.5 Hz, 1H), 6.45
(dd, J ) 8.5, 3.0 Hz, 1H), 4.62 (s, 2H), 3.81 (s, 3H), 3.81 (s, 3H),
3.79 (s, 3H), 3.71 (t, J ) 6.8 Hz, 2H), 3.65 (s, 3H), 2.66 (t, J )
1
7.5 Hz, 2H); minor rotamer H NMR (500 MHz, CDCl3) δ 7.73
(d, J ) 15.5 Hz, 1H), 7.50 (d, J ) 8.0 Hz, 2H), 7.25 (d, J ) 8.5
Hz, 1H), 6.91 (d, J ) 8.0 Hz, 2H), 6.84 (d, J ) 16.5 Hz, 1H), 4.66
(s, 2H), 3.75 (t, J ) 7.3 Hz, 2H), 2.61 (t, J ) 7.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) for both rotamers δ 172.5, 167.4, 160.7,
160.5, 158.0, 142.9, 142.2, 130.8, 129.4, 129.3, 128.3, 128.1, 117.5,
115.4, 114.7, 114.2, 114.1, 104.3, 103.9, 98.6, 98.3, 55.3, 55.3,
55.2, 51.8, 51.6, 47.2, 43.0, 34.0, 32.6; IR 3002, 2944, 2839, 1736,
1649, 1503, 1439, 1369 cm-1; HRMS calcd for C23H27O6N was
413.18384 (M+), found 413.18391.
3-(2,4-Dimethoxybenzylamino)-2,2-dimethylpropan-1-ol (19).
This compound was prepared according to the general procedure
1
for the synthesis of amines. H NMR (500 MHz, CDCl3) δ 7.08
(d, J ) 8.5 Hz, 1H), 6.45 (d, J ) 3.0 Hz, 1H), 6.43 (dd, J ) 8.0,
2.0 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.68 (s, 2H), 3.47 (s, 2H),
2.54 (s, 2H), 0.88 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 160.1,
158.6, 130.4, 119.9, 103.5, 98.4, 74.5, 60.8, 55.2, 55.1, 49.6, 34.8,
23.0; IR 3328, 3002, 2950, 2836, 1614, 1590, 1509, 1462 cm-1
HRMS calcd for C14H23O3N 253.16779 (M+) found 253.16777.
;
N-(2,4-Dimethoxybenzyl)-N-(3-hydroxypropyl)-3-(4-methoxy-
phenyl)-acryl Amide (20). Prepared according to the general
procedure for the reduction of esters. 1H NMR (500 MHz, CDCl3)
δ 7.74 (d, J ) 15.5 Hz, 1H), 7.42 (dt, J ) 9.3, 2.3 Hz, 2H), 7.03
(d, J ) 9.0, 2.3 Hz, 2H), 6.77 (d, J ) 15.5 Hz, 1H), 6.49 (d, J )
2.5 Hz, 1H), 6.47 (dd, J ) 8.5, 2.0 Hz, 1H), 4.55 (s, 2H), 3.83 (s,
3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.62 (t, J ) 5.8 Hz, 2H), 3.54 (t,
J ) 5.3 Hz, 2H), 1.70 (p, J ) 5.8 Hz, 2H); minor rotamer 1H NMR
(500 MHz, CDCl3) δ 7.50 (d, J ) 8.5 Hz, 2H), 7.23 (d, J ) 8.5
Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H), 6.98 (d, J ) 15.5 Hz, 1H), 6.82
(d, J ) 8.5 Hz, 1H), 6.44 (s, 1H), 6.42 (dd, J ) 8.3, 2.0 Hz, 1H),
3.69 (m, 2H), 3.50 (t, J ) 6.3 Hz, 2H), 3.45 (t, J ) 5.5 Hz, 2H);
13C NMR (125 MHz, CDCl3) for both rotamers δ 168.8, 160.9,
160.6, 158.0, 143.1, 129.4, 128.0, 127.9, 116.7, 114.7, 114.1, 113.8,
104.0, 98.6, 58.0, 55.3, 55.3, 55.2, 45.9, 41.9, 30.1; IR 3393, 2996,
2932, 2839, 1649, 1584, 1514, 1456, 1357 cm-1; HRMS calcd for
C22H27O5N was 385.18892 (M+), found 385.18904.
N-(2,4-Dimethoxybenzyl)-N-(3-hydroxy-2,2-dimethylpropyl)-
3-(4-methoxyphenyl)-acryl Amide (21). Prepared according to the
general procedure for the synthesis of amides. 1H NMR (500 MHz,
CDCl3) δ 7.72 (d, J ) 15.0 Hz, 1H), 7.38 (dt, J ) 8.5, 2.0 Hz,
2H), 6.91 (d, J ) 8.5 Hz, 1H), 6.86 (dt, J ) 8.5, 2.5 Hz, 2H), 6.66
(d, J ) 15.0 Hz, 1H), 6.49 (d, J ) 2.0 Hz, 1H), 6.45 (dd, J ) 8.3,
2.0 Hz, 1H), 4.66 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H),
3.34 (s, 1H), 3.20 (s, 2H), 0.97 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 169.6, 160.9, 160.4, 157.6, 143.2, 129.5, 127.8, 127.3,
117.2, 114.6, 114.1, 103.9, 98.6, 68.0, 55.4, 55.3, 55.2, 53.7, 48.8,
38.4, 23.7; IR 3364, 3008, 2961, 2839, 1649, 1584, 1509, 1439,
1363 cm-1; HRMS calcd for C24H31O5N 413.22022 (M+), found
413.22047.
3-Benzyl-2-(2,4-dimethoxybenzyl)-9-(4-methoxyphenyl)-4-
methyl-2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (14).
Prepared according to the general procedure for the cyclization but
1
was refluxed for 12 h. H NMR (500 MHz, CDCl3) δ 7.24 (m,
4H), 7.13 (d, J ) 12.5, 3.0 Hz, 2H), 7.10 (d, J ) 7.0 Hz, 2H), 7.07
(d, J ) 1.0 Hz, 1H), 7.01 (d, J ) 8.5 Hz, 1H), 6.85 (dd, J ) 11.5,
2.5 Hz, 1H), 6.78 (d, J ) 8.0 Hz, 1H), 6.74 (d, J ) 8.5 Hz, 1H),
6.67 (t, J ) 7.3 Hz, 1H), 6.42 (d, J ) 2.0 Hz, 1H), 6.40 (dd, J )
9.8 Hz, 1H), 5.08 (d, J ) 15.5 Hz, 1H), 4.22 (d, J ) 11.0 Hz, 1H),
4.20 (d, J ) 15.5 Hz, 1H), 3.82 (m, 1H), 3.80 (s, 3H), 3.79 (s,
3H), 3.69 (s, 3H), 3.40 (dd, J ) 15.0, 3.5 Hz, 1H), 3.22 (dd, J )
11.0, 8.5 Hz, 1H), 3.08 (dd, J ) 15.0, 4.5 Hz, 1H), 2.93 (t, J )
11.0 Hz, 1H), 2.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 173.0,
160.3, 158.3, 158.1, 148.7, 136.4, 136.2, 131.1, 130.7, 130.1, 129.8,
129.4, 128.6, 127.2, 126.7, 119.3, 116.4, 114.5, 113.6, 104.2, 98.3,
94.7, 61.0, 58.2, 55.3,55.2, 55.1, 49.5, 45.8, 38.4, 36.5, 36.2; IR
3061, 3031, 2996, 2932, 2874, 1707, 1608, 1509, 1462, 1398 cm-1
;
HRMS calcd for C35H36O4N2 was 548.26751 (M+), found 548.26693.
4-Methyl-9-phenyl-3a,4,9,9a-tetrahydrofuro[3,4-b]quinolin-
3(1H)-one (16). Prepared according to the general procedure for
the cyclization. 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 3H), 7.19
(m, 3H), 6.95 (d, J ) 8.5 Hz, 1H), 6.69 (t, J ) 7.5 Hz, 1H), 6.64
(d, J ) 7.5 Hz, 1H), 4.20 (d, J ) 12.0 Hz, 1H), 4.15 (dd, J ) 8.5,
7.0 Hz, 1H), 3.98 (dd, J ) 11.0, 8.5 Hz, 1H), 3.64 (d, J ) 12.5
Hz, 1H), 3.26 (s, 3H), 3.12 (o, J ) 7.0 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 172.8, 148.5, 129.7, 129.0, 128.4, 128.1, 127.9,
127.5, 126,3, 119.2, 114.7, 68.8, 60.1, 48.3, 46.4, 35.9; HRMS calcd
for C18H17O2N was 279.12593 (M+), found 279.12593.
3-(2,4-Dimethoxybenzylamino)-propionic Acid Methyl Ester
(17). This compound was prepared according to the general
procedure for the synthesis of amines. 1H NMR (500 MHz, CDCl3)
δ 7.13 (d, J ) 8.0 Hz, 1H), 6.45 (d, J ) 2.5 Hz, 1H), 6.43 (dd, J
) 8.3 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (s, 2H), 3.67 (s,
3H), 2.86 (t, J ) 6.5 Hz, 2H), 2.54 (t, J ) 6.8 Hz, 2H), 1.99 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 173.2, 160.0, 158.5, 130.3,
120.6, 103.6, 98.5, 55.3, 55.2, 51.5, 48.6, 44.2, 34.6; IR 3335, 3002,
2944, 2827, 1730, 1614, 1584, 1497, 1450 cm-1; HRMS calcd for
C13H18O4N was 252.12358 (M+), found 252.12359.
N-(2,4-Dimethoxybenzyl)-3-(4-methoxyphenyl)-N-(3-oxo-
propyl)-acryl Amide (22). Prepared according to the general
procedure for the oxidation of alcohols. 1H NMR (500 MHz, CDCl3)
δ 9.78 (s, 1H), 7.68 (d, J ) 15.0 Hz, 1H), 7.43 (d, J ) 9.0 Hz,
2H), 7.03 (d, J ) 8.5 Hz, 1H), 6.87 (d, J ) 8.5 Hz, 2H), 6.79 (d,
J ) 15.0 Hz, 1H), 6.47 (s, 1H), 6.46 (dd, J ) 8.3 Hz, 1H), 4.61 (s,
2H), 3.81 (s, 6H), 3.80 (s, 3H), 3.73 (t, J ) 6.8 Hz, 2H), 2.74 (t,
J ) 6.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 201.0, 167.6,
160.7, 160.6, 158.0, 142.3, 129.3, 128.4, 128.0, 117.2, 115.2, 114.1,
103.9, 98.6, 55.4, 55.3, 55.2, 47.2, 43.8, 42.7, 40.9; IR 3070, 3006,
2928, 2837, 2729, 1722, 1649, 1588, 1511, 1459; HRMS calcd for
C22H25O5N was 383.17327 (M+), found 383.17285.
5524 J. Org. Chem., Vol. 71, No. 15, 2006

Intramolecular Aza Diels-Alder Cyclization
N-(2,4-Dimethoxybenzyl)-N-(2,2-dimethyl-3-oxopropyl)-3-(4-
methoxyphenyl)-acryl Amide (23). Prepared according to the
general procedure for the oxidation of alcohols. 1H NMR (500 MHz,
CDCl3) δ 9.63(s, 1H), 7.66 (d, J ) 15.5 Hz, 1H), 7.38 (d, J ) 9.0
Hz, 2H), 6.94 (d, J ) 8.0 Hz, 1H), 6.85 (d, J ) 8.5 Hz, 2H), 6.70
(d, J ) 15.5 Hz, 2H), 6.48 (d, J ) 2.5 Hz, 1H), 6.45 (dd, J ) 8.3,
2.5 Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H),
3.53 (s, 2H), 1.11 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 203.4,
168.3, 160.8, 160.5, 157.8, 143.2, 142.8, 129.5, 129.4, 127.9, 127.3,
117.2, 114.7, 114.6, 114.1, 114.06, 103.9, 98.6, 68.0, 55.3, 55.25,
55.2, 53.8, 48.8, 48.5, 47.7, 38.4, 23.7, 20.2; IR 3066, 2967, 2833,
1719, 1649, 1590, 1509, 1450, 1369 cm-1; HRMS calcd for
C23H29O5N 411.20457 (M+), found 411.20434.
2H), 6.88 (dt, J ) 8.3 Hz, 2H), 6.86 (d, J ) 12.5 Hz, 1H), 5.84 (d,
J ) 12.5 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.8, 160.4, 143.5, 132.1, 127.2, 116.6, 113.4, 55.2,
51.2; IR 3008, 2921, 2851, 1724, 1625, 1608, 1514, 1450 cm-1
;
HRMS calcd for C11H12O3 was 192.07864 (M+), found 192.07829.
3-(4-Methoxyphenyl)-acrylic Acid (28). To 27 (590 mg, 3.3
mmol) dissolved in 20 mL of THF/H2O/MeOH (1:1:1) at 0 °C,
lithium hydroxide (953 mg, 39.7 mmol) was added and was stirred
for 48 h. Upon TLC confirmation of reaction completion, the
mixture was cooled in an ice bath and HCl (1 M) added dropwise
until the pH changed to about 2-3 as indicated by universal pH
paper. The mixture was extracted using CH2Cl2 (3 × 20 mL), dried
(MgSO4), and concentrated to afford a creamy solid weighing 522
mg. Yield 87%. 1H NMR (500 MHz, CDCl3) δ 11.60 (s, 1H), 7.72
(dt, J ) 9.0, 2.5 Hz, 2H), 6.97 (dd, J ) 12.5, 6.0 Hz, 1H), 6.89
(dt, J ) 9.0, 2.5 Hz, 2H), 5.85 (dd, J ) 13.0, 6.5 Hz, 1H), 3.83 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 171.8, 160.7, 145.9, 132.6,
126.9, 116.0, 113.5, 55.3; IR 3037 (broad), 2949, 2839, 2570, 1695,
1602, 1503, 1450 cm-1; HRMS calcd for C29H32O4N2 was
178.06299 (M+), found 178.06299.
2-(2,4-Dimethoxybenzyl)-10-(4-methoxyphenyl)-4,4,5-trimeth-
yl-3,4,4a,5,10,10a-hexahydro-2H-benzo[b][1,6]naphthyridin-1-
one (24). Prepared according to the general procedure for the
cyclization but was refluxed for 12 h and Yb(OTf)3 was used as
1
the catalyst. H NMR (500 MHz, CDCl3) δ 7.22 (d, J ) 9.0 Hz,
2H), 7.13 (d, J ) 7.5 Hz, 1H), 7.07 (t, J ) 7.8 Hz, 1H), 6.92 (d,
J ) 9.0 Hz, 2H), 6.67 (d, J ) 8.0 Hz, 1H), 6.53 (t, J ) 7.8 Hz,
1H), 6.43 (d, J ) 2.0 Hz, 1H), 6.41 (s, 1H), 7.37 (d, J ) 7.5 Hz,
1H), 4.51 (d, J ) 14.5 Hz, 1H), 4.38 (d, J ) 14.0 Hz, 1H), 4.09
(d, J ) 9.5 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H), 3.15
(d, J ) 14.0 Hz, 1H), 3.05 (s, 3H), 2.97 (s, 2H), 2.90 (d, J ) 13.5
Hz, 1H), 0.97 (s, 3H), 0.87 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 171.9, 160.3, 158.5, 157.8, 148.0, 135.3, 131.6, 130.2, 129.9,
127.8, 127.2, 118.2, 117.3, 114.8, 113.7, 104.2, 98.3, 67.7, 58.7,
55.3, 55.2, 55.1, 48.1, 43.2, 42.4, 42.0, 37.9, 29.2, 20.4; IR 2932,
2839, 1712, 1671, 1614, 1514, 1456 cm-1; HRMS calcd for
C18H21O5N 500.26751 (M+), found 500.26822.
{(2,4-Dimethoxybenzyl)-[3-(4-methoxyphenyl)-acryloyl]-
amino}-acetic Acid Methyl Ester (29). Prepared according to the
1
general procedure for the synthesis of amides. Major rotamer H
NMR (500 MHz, CDCl3) δ 7.54 (dt, J ) 8.9, 2.8 Hz, 2H), 6.93 (d,
J ) 8.5 Hz, 1H), 6.88 (dt, J ) 9.0, 2.5 Hz, 2H), 6.64 (d, J ) 13.0
Hz, 1H), 6.43 (d, J ) 2.5 Hz, 1H), 6.40 (d, J ) 8.3, 2.5 Hz, 1H),
6.10 (d, J ) 13.0 Hz, 1H), 4.57 (s, 2H), 4.11 (s, 2H), 3.82 (s, 3H),
1
3.78 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H); minor rotamer H NMR
(500 MHz, CDCl3) δ 7.34 (d, J ) 8.0 Hz, 1H), 7.26 (d, J ) 8.5
Hz, 2H), 6.71 (dt, J ) 9.0, 2.5 Hz, 2H), 6.52 (d, J ) 12.3 Hz, 1H),
6.49 (dd, J ) 8.0, 2.5 Hz, 1H), 6.43 (d, J ) 3.0 Hz, 1H), 5.88 (d,
J ) 12.3 Hz, 1H), 4.67 (s, 2H), 3.97 (s, 2H), 3.81 (s, 3H), 3.77 (s,
3H), 3.62 (s, 3H); 13C NMR (125 MHz, CDCl3) for both rotamers
δ 170.0, 169.8, 169.7, 160.8, 159.8, 159.7, 158.6, 134.6, 133.2,
132.4, 130.5, 130.1, 130.0, 127.8, 127.6, 120.6, 120.1, 116.7, 116.0,
113.8, 113.7, 104.2, 103.9, 98.5, 98.2, 55.3, 55.2, 55.2, 55.1, 52.0,
51.9, 49.3, 47.6, 45.1, 43.2; IR 3072, 3008, 2950, 2838, 1754, 1608,
1514, 1450 cm-1; HRMS calcd for C22H25O6N was 399.16819
(M+), found 399.16832.
2-(2,4-Dimethoxybenzyl)-10-(4-methoxyphenyl)-4,4,5-trimeth-
yl-3,4,4a,5,10,10a-hexahydro-2H-benzo[b][1,6]naphthyridin-1-
one (25). Prepared according to the general procedure for the
cyclization but was refluxed for 12 h and Yb(OTf)3 was used as
the catalyst. 1H NMR (500 MHz, CD2Cl2) δ 7.27 (dd, J ) 8.0, 1.5
Hz, 1H), 7.25 (dd, J ) 7.3, 1.5 Hz, 1H), 7.06 (dd, J ) 6.8, 2.0 Hz,
1H), 6.96 (d, J ) 8.0 Hz, 1H), 6.86 (d, J ) 8.5 Hz, 2H), 6.83 (dd,
J ) 9.0, 2.0 Hz, 2H), 6.35 (d, J ) 2.5 Hz, 1H), 6.15 (dd, J ) 8.0,
2.5 Hz, 1H), 5.96 (d, J ) 8.5 Hz, 1H), 4.90 (d, J ) 15.0 Hz, 1H),
4.80 (d, J ) 3.0 Hz, 1H), 4.02 (d, J ) 15.0 Hz, 1H), 3.78 (s, 3H),
3.76 (s, 3H), 3.71 (s, 3H), 3.39 (dd, J ) 6.5, 3.5 Hz, 1H), 3.35 (d,
J ) 12.0 Hz, 1H), 2.93 (s, 3H), 2.68 (dd, J ) 6.8, 2.0 Hz, 1H),
2.53 (dd, J ) 12.3, 2.0 Hz, 1H), 1.01 (s, 3H), 0.99 (s, 3H); 13C
NMR (125 MHz, CD2Cl2) δ 169.5, 159.5, 157.9, 149.9, 135.0,
129.5, 128.9, 128.7, 128.5, 128.1, 119.8, 119.4, 116.9, 113.7, 104.6,
97.9, 63.7, 55.3, 55.2, 54.7, 49.6, 46.5, 45.2, 43.5, 37.0, 26.5, 25.2;
HRMS calcd for C31H36O4N2 was 500.26751 (M+), found 500.26789.
N-(2,4-Dimethoxybenzyl)-3-(4-methoxyphenyl)-acryl Amide
(26). Prepared according to the general procedure for the cyclization.
1H NMR (500 MHz, CD2Cl2) δ 7.52 (d, J ) 15.5 Hz, 1H), 7.46
(d, J ) 8.5 Hz, 2H), 7.20 (d, J ) 8.5 Hz, 1H), 6.89 (d, J ) 9.0 Hz,
2H), 6.48 (d, J ) 2.0 Hz, 1H), 6.45 (dd, J ) 8.8 Hz, 1H), 6.29 (d,
J ) 16.0 Hz, 1H), 6.07 (m, 1H), 4.43 (d, J ) 6.0 Hz, 2H), 3.84 (s,
3H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR (125 MHz, CD2Cl2) δ
160.9, 140.2, 130.6, 129.5, 128.0, 119.1, 114.5, 104.2, 98.7, 55.7,
39.2; IR 3283, 3070, 3002, 2928, 2833, 1661, 1601, 1511, 1463,
1420; HRMS calcd for C19H21O4N was 327.14706 (M+), found
327.14703.
N-(2,4-Dimethoxybenzyl)-N-(2-hydroxyethyl)-3-(4-methoxy-
phenyl)-acryl Amide (30). Prepared according to the general
procedure for the reduction of esters. Major rotamer 1H NMR (500
MHz, CDCl3) δ 7.44 (d, J ) 9.5 Hz, 2H), 6.92 (d, J ) 8.5 Hz,
1H), 6.87 (dd, J ) 9.0, 2.0 Hz, 2H), 6.63 (d, J ) 12.5 Hz, 1H),
6.43 (d, J ) 2.0 Hz, 1H), 6.40 (dd, J ) 8.3, 2.0 Hz, 1H), 6.07 (d,
J ) 12.5 Hz, 1H), 4.45 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.74 (s,
3H), 3.68 (t, J ) 5.3 Hz, 2H), 3.54 (t, J ) 4.8 Hz, 2H), 3.19 (s,
1
1H); minor rotamer H NMR (500 MHz, CDCl3) δ 7.33 (d, J )
8.0 Hz, 1H), 7.25 (d, J ) 9.0 Hz, 2H), 6.70 (d, J ) 9.0 Hz, 2H),
6.51 (d, J ) 12.5 Hz, 1H), 6.48 (dd, J ) 8.3, 2.0 Hz, 1H), 6.46 (d,
J ) 2.0 Hz, 1H), 6.08 (d, J ) 13.0 Hz, 1H), 4.68 (s, J ) 2H), 3.81
(s, 3H), 3.78 (3, 3H), 3.75 (s, 3H), 3.61 (t, J ) 5.8 Hz, 2H), 3.40
(t, J ) 5.5 Hz, 2H), 3.19 (s, 1H); 13C NMR (125 MHz, CDCl3) for
both rotamers δ 171.5, 169.9, 160.7, 160.3, 159.8, 159.4, 158.4,
134.1, 132.4, 131.6, 130.1, 129.9, 129.5, 129.3, 128.1, 127.9, 121.7,
120.7, 117.4, 116.4, 114.1, 113.8, 113.6, 104.2, 103.9, 98.5, 98.2,
62.3, 62.0, 61.9, 59.9, 55.3, 55.3, 55.2, 55.2, 55.1, 49.7, 48.4, 48.2,
47.9, 41.6; IR 3376, 2996, 2932, 2839, 1602, 1503, 1456, 1351
cm-1; HRMS calcd for C21H25O5N was 371.17327 (M+), found
371.17315.
3-(4-Methoxyphenyl)-acrylic Acid Methyl Ester (27). To a
solution of trifluoroethylphosphonoester (800 µL, 3.8 mmol), 18-
crown-6 (2.5 g, 9.5 mmol) in 60 mL of anhydrous THF was cooled
to -78 °C under argon and treated with KNTMS (0.5 M in toluene)
(7.56 mL, 3.78 mmol). p-Anisaldehyde (400 µL, 3.8 mmol) was
then added, and the resulting mixture was stirred for 30 min at
-78 °C. Saturated NH4Cl (30 mL) was added, and the product
was extracted with CH2Cl2 (3 × 25 mL), dried (MgSO4), and
concentrated. Flash chromatography was performed using hexane/
ethyl acetate (10:1) to afford a clear liquid weighing 630 mg. Yield
N-(2,4-Dimethoxybenzyl)-3-(4-methoxyphenyl)-N-(2-oxoethyl)-
acrylamide (31). Prepared according to the general procedure for
the oxidation of alcohols. Major rotamer 1H NMR (400 MHz,
CDCl3) δ 9.40 (s, 1H), 7.48 (d, J ) 8.8 Hz, 2H), 6.91 (d, J ) 8.8
Hz, 1H), 6.89 (d, J ) 9.2 Hz, 2H), 6.70 (d, J ) 12.8 Hz, 1H), 6.41
(s, 1H), 6.39 (dd, J ) 8.0, 2.4 Hz, 1H), 6.14 (d, J ) 13.3 Hz, 1H),
4.50 (s, 2H), 4.07 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 197.9, 169.9, 161.0, 159.8, 158.6,
134.7, 133.5, 132.7, 130.3, 129.9, 127.8, 120.0, 115.9, 113.8, 104.1,
1
87%. H NMR (500 MHz, CDCl3) δ 7.71 (dt, J ) 9.0, 2.5 Hz,
J. Org. Chem, Vol. 71, No. 15, 2006 5525

Muhuhi and Spaller
1
98.6, 55.3, 55.2, 55.1, 54.1, 48.4; minor rotamer H NMR (400
IR 3370, 2996, 2938, 2833, 1649, 1584, 1503, 1415 cm-1; IR 3002,
2943, 2839, 1730, 1643, 1619, 1509, 1427 cm-1; HRMS calcd for
C18H21O5N was 331.14197 (M+), found 331.14135.
MHz, CDCl3) δ 9.01 (s, 1H), 7.40 (d, J ) 8.0 Hz, 2H), 7.24 (d, J
) 8.8 Hz, 2H), 6.71 (d, J ) 8.8 Hz, 1H), 6.54 (d, J ) 12.0 Hz,
1H), 6.48 (m, 2H), 5.86 (d, J ) 12.8 Hz, 1H), 4.67 (s, 2H), 3.96
(s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.5, 169.9, 161.0, 159.8, 158.6, 134.7, 133.5,
132.7, 130.5, 129.3, 127.5, 120.5, 116.4, 113.8, 104.4, 98.2, 58.1,
N-(2,4-Dimethoxybenzyl)-3-furan-2-yl-N-(2-oxoethyl)-acryl
Amide (35). Prepared according to the general procedure for the
oxidation of alcohols. 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H),
7.54 (d, J ) 15.6 Hz, 1H), 7.45(s, 1H), 7.08 (d, J ) 8.0 Hz, 1H),
7.05 (d, J ) 14.8 Hz, 1H), 6.58 (d, J ) 3.2 Hz, 1H), 6.46 (m, 3H),
4.66 (s, 2H), 4.10 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 199.0, 167.5, 161.0, 158.4, 151.6, 144.1,
130.1, 129.7, 116.4, 114.3, 112.2, 104.0, 98.7, 57.5, 56.3, 55.4,
55.1, 48.2, 45.6; IR 3002, 2944, 2839, 1730, 1643, 1619, 1509,
1427; HRMS calcd for C18H19O5N 329.12632 (M+), found 329.12644
2-(2,4-Dimethoxybenzyl)-9-furan-2-yl-4-methyl-2,3,3a,9,9a-
hexahydropyrrolo[3,4-b]quinolin-1-one (36). Prepared according
43.7; IR 3002, 2944, 2827, 1724, 1608, 1509, 1450, 1380 cm-1
;
HRMS calcd for C21H23O5N was 369.15762 (M+), found 369.15694.
2-(2,4-Dimethoxybenzyl)-9-(4-methoxyphenyl)-4-methyl-
2,3,3a,4,9,9a-hexahydropyrrolo[3,4-b]quinolin-1-one (32). Pre-
1
pared according to the general procedure for the cyclization. H
NMR (500 MHz, CDCl3) δ 7.18 (d, J ) 8.5 Hz, 3H), 7.13 (d, J )
8.3, 3.5 Hz, 4H), 6.98 (dd, J ) 7.8, 2.0 Hz, 1H), 6.92 (d, J ) 9.0
Hz, 1H), 6.87 (d, J ) 7.5 Hz, 1H), 6.86 (d, J ) 9.0 Hz, 2H), 6.78
(m, 5H), 6.67 (dt, J ) 7.3, 1.0 Hz, 1H), 6.45 (dd, J ) 6.0, 2.5 Hz,
1H), 6.42 (d, J ) 2.0 Hz, 1H), 6.39 (d, J ) 2.5 Hz, 1H), 6.36 (dd,
J ) 8.0, 2.5 Hz, 1H), 4.68 (d, J ) 4.5 Hz, 1H), 4.49 (d, J ) 14.5
Hz, 1H), 4.41 (d, J ) 14.5 Hz, 1H), 4.36 (d, J ) 15.0 Hz, 1H),
4.32 (d, J ) 12.0 Hz, 1H), 4.29 (d, J ) 15.0 Hz, 1H), 3.79 (s, 3H),
3.78 (s, 6H), 3.77 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H), 3.48 (dd, J )
8.5, 6.5 Hz, 1H), 3.45 (m, 2H), 3.22 (t, J ) 9.3 Hz, 1H), 3.06 (t,
J ) 9.0 Hz, 1H), 2.95 (dd, J ) 12.0, 4.5 Hz, 1H), 2.89 (t, J ) 7.0
Hz, 1H), 2.81 (s, 3H), 2.75 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 172.5, 171.4, 160.5, 158.5, 158.1, 158.0, 148.2, 148.0, 136.0,
135.3, 131.7, 131.5, 131.4, 131.0, 131.0, 130.6, 130.2, 129.2, 129.1,
128.7, 127.9, 127.3, 125.7, 119.0, 118.8, 117.0, 116.7, 113.7, 113.5,
113.3, 112.9, 104.2, 104.0, 98.4, 98.4, 59.5, 55.3, 55.3, 55.2, 55.1,
52.4, 50.6, 50.0, 49.8, 49.3, 45.1, 42.3, 40.8, 40.4, 36.2, 36.2.
[(2,4-Dimethoxybenzyl)-(3-furan-2-yl-acryloyl)-amino]-
acetic Acid Methyl Ester (33). Prepared according to the general
procedure for the synthesis of amides. 1H NMR (500 MHz, CDCl3)
δ 7.53 (d, J ) 15.0 Hz, 1 H), 7.42 (s, 1H), 7.07 (d, J ) 8.0 Hz,
1H), 6.98 (d, J ) 15.0 Hz, 1H), 6.55 (d, J ) 3.5 Hz, 1H), 6.47
(dd, J ) 4.3, 2.0 Hz, 2H), 6.45 (dd, J ) 8.8, 2.0 Hz, 1H), 4.66 (s,
2H), 4.14 (s, 2H), 3.80 (s, 6H), 3.72 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.9, 167.3, 160.7, 158.4, 151.7, 143.9, 129.9, 129.2,
116.7, 114.9, 113.82, 112.1, 103.9, 98.6, 55.3, 55.1, 52.0, 47.5,
47.3; IR 3113, 2996, 2950, 2836, 1742, 1660, 1619, 1561, 1509
cm-1; HRMS calcd for C19H21O6N was 359.13689 (M+), found
359.13673.
1
to the general procedure for the cyclization. H NMR (500 MHz,
CDCl3) δ 7.32 (t, J ) 1.3 Hz, 1H), 7.14 (d, J ) 8.5 Hz, 1H), 7.11
(dd, J ) 7.8, 1.5 Hz, 1H), 6.87 (dt, J ) 7.6, 1.3 Hz, 1H), 6.78 (dd,
J ) 8.0, 1.0 Hz, 1H), 6.71 (dt, J ) 7.3, 1.0 Hz, 1H), 6.45 (d, J )
2.0 Hz, 1H), 6.44 (dd, J ) 8.0, 2.5 Hz, 1H), 6.37 (dd, J ) 4.3, 2.5
Hz, 2H), 4.49 (d, J ) 14.5 Hz, 1H), 4.44 (d, J ) 12.0 Hz, 1H),
4.39 (d, J ) 14.5 Hz, 1H), 3.79 (s, 3H), 3,77(s, 3H), 3.49 (dd, J )
8.5, 6.5 Hz, 1H), 3.34 (ddd, J ) 11.1, 9.3, 6.5 Hz, 1H), 3.24 (t, J
) 9.0 Hz, 1H), 3.14 (t, J ) 12.0 Hz, 1H), 2.73 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.9, 160.4, 158.5, 154.4, 147.6, 141.4,
130.9, 129.4, 127.7, 124.8, 119.0, 116.9, 113.6, 110.1, 108.1, 104.2,
98.3, 77.2, 59.2, 55.3, 55.2, 49.8, 46.9, 40.5, 39.0, 36.0; IR 3002,
2938, 2833, 1701, 1608, 1514, 1468, 1363, 1299; HRMS calcd for
C25H26O4N2 was 418.18926 (M+), found 418.18927.
2-(2,4-Dimethoxybenzyl)-9-furan-2-yl-4-methyl-2,3,3a,9,9a-
hexahydropyrrolo[3,4-b]quinolin-1-one (37). Prepared according
1
to the general procedure for the cyclization. H NMR (500 MHz,
CD2Cl2) δ 7.34 (d, J ) 1.5 Hz, 1H), 7.20 (dt, J ) 7.9, 1.5 Hz,
1H), 7.09 (dd, J ) 7.0, 1.5 Hz, 1H), 6.75 (dt, J ) 7.5, 1.0 Hz, 1H),
6.58 (d, J ) 3.0 Hz, 1H), 6.47 (d, J ) 8.0 Hz, 1H), 6.40 (d, J )
2.0 Hz, 1H), 6.28 (d, J ) 3.0 Hz, 1H), 6.27 (dd, J ) 8.0, 2.5 Hz,
1H), 5.90 (d, J ) 3.0 Hz, 1H), 4.48 (d, J ) 3.5 Hz, 1H), 4.42 (d,
J ) 15.5 Hz, 1H), 4.16 (d, J ) 15.0 Hz, 1H), 4.03 (ddd, J ) 8.3,
6.0, 2.5 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.50 (dd, J ) 8.5 Hz,
1H), 3.34 (dd, J ) 10.5, 5.5 Hz, 1H), 3.26 (dd, J ) 10.5, 1.5 Hz,
1H), 2.73 (s, 3H); 13C NMR (125 MHz, CD2Cl2) δ 172.6, 160.7,
156.4, 145.7, 141.6, 129.5, 129.4, 128.7, 123.8, 118.1, 116.6, 112.4,
110.6, 105.8, 104.6, 98.4, 55.6, 55.5, 49.9, 47.8, 40.8, 37.7, 36.0;
HRMS calcd for C25H26O4N2 was 418.1893 (M+), found 418.1894.
N-(2,4-Dimethoxybenzyl)-3-furan-2-yl-N-(2-hydroxyethyl)-
acryl Amide (34). The above compound was prepared according
to the general procedure for the reduction of esters. 1H NMR (500
MHz, CDCl3) δ 7.53 (d, J ) 15.5 Hz, 1H), 7.40 (s, 1H), 7.02 (d,
J ) 8.0 Hz, 1H), 6.84 (d, J ) 15.5 Hz, 1H), 6.55 (d, J ) 3.0 Hz,
1H), 6.48 (dd, J ) 5.5, 2.0 Hz, 1H), 6.45 (d, J ) 3.0 Hz, 1H), 6.43
(dd, J ) 8.7, 2.0 Hz, 1H), 4.62 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H),
3.77 (t, J ) 5.0 Hz, 2H), 3.63 (t, J ) 5.0 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 169.4, 160.6, 158.1, 151.6, 144.0, 130.1, 128.4,
116.7, 114.9, 114.2, 112.1, 103.9, 98.6, 62.4, 55.3, 55.2, 50.3, 47.6;
Supporting Information Available: General synthetic proce-
dures and NMR spectra for reported compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060148M
5526 J. Org. Chem., Vol. 71, No. 15, 2006