Synthesis of diverse heterocyclic scaffolds via tandem additions to imine derivatives and ring-forming reactions

Article abstract of DOI:10.1016/j.tet.2009.05.009

A novel strategy has been developed for the efficient syntheses of diverse arrays of heterocyclic compounds. The key elements of the approach comprise a Mannich-type, multicomponent coupling reaction in which functionalized amines, aromatic aldehydes, acy

Full text of DOI:10.1016/j.tet.2009.05.009

Tetrahedron 65 (2009) 6454–6469
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of diverse heterocyclic scaffolds via tandem additions to imine
derivatives and ring-forming reactions
*
James D. Sunderhaus, Chris Dockendorff, Stephen F. Martin
Department of Chemistry and Biochemistry, The Texas Institute for Drug and Diagnostic Development, The University of Texas at Austin, 1 University Station A5300,
Austin, TX 78712-0165, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel strategy has been developed for the efficient syntheses of diverse arrays of heterocyclic com-
pounds. The key elements of the approach comprise a Mannich-type, multicomponent coupling reaction
Received 26 March 2009
Received in revised form 1 May 2009
Accepted 5 May 2009
in which functionalized amines, aromatic aldehydes, acylating agents, and
p- and organometallic nu-
cleophiles are combined to generate intermediates that are then further transformed into diverse het-
erocyclic scaffolds via a variety of cyclization manifolds. Significantly, many of these scaffolds bear
functionality that may be exploited by further manipulation to create diverse collections of compounds
having substructures found in biologically active natural products and clinically useful drugs. The
practical utility of this strategy was exemplified by its application to the first, and extraordinarily concise
synthesis of the isopavine alkaloid roelactamine.
Available online 9 May 2009
Keywords:
Imine
Acyliminium ion
Multicomponent reaction
Drug-like scaffolds
Natural products
Mannich reaction
Heck reaction
Ó 2009 Elsevier Ltd. All rights reserved.
Ring-closing metathesis
Alkaloids
1. Introduction
discovering new drugs and drug leads. However, the immense
challenges and potential lack of flexibility in working with such
The discovery of potent, selective, and bioavailable small
molecules that modulate biological systems of interest continues to
be one of the most important endeavors for contemporary organic
and medicinal chemists. Despite the increasing importance of bi-
ological macromolecules in medicine, small molecules remain as
important as ever. Relative to biological therapeutics, small mole-
cule drugs usually exhibit enhanced bioavailability, especially oral,
and they are easier and less costly to manufacture. Perhaps more
importantly, small molecules can be easily designed to be cell
permeable, a property that gives them access to intracellular tar-
gets that may be more difficult or impossible to modulate with
protein or nucleic acid derived agents. The demand for novel small
molecules with favorable biological properties thus continues to be
high. Accordingly, developing strategies that enable their identifi-
cation is a priority for both basic biological research and trans-
lational medicine.
complex molecules have inspired synthetic chemists in both in-
dustry and academia to develop alternative strategies for creating
compounds with desirable biological properties. Such approaches
often involve generating diverse sets of compounds that can probe
a broad swath of biological space, thereby improving the odds of
finding compounds with desired properties. These strategies have
become an important element of drug discovery, owing in part to
our inability to design molecules with predictable biological
properties.
The classical strategy for new lead discovery in medicinal
chemistry is the scaffold-based approach, wherein derivatives of
certain core structures, often so-called privileged structures,1 are
prepared and screened. More recently, a number of innovative
strategies have emerged for discovering new leads. One productive
approach is diversity-oriented synthesis (DOS),2,3 the objective of
which is the rapid synthesis of molecules with diverse skeletons
and substitution patterns derived from common starting materials.
Two strategies that rely more on natural products for the creation
of collections of compounds are diverted total synthesis (DTS),4
wherein intermediates in the synthesis of biologically active nat-
ural products are modified, and biology oriented synthesis (BIOS),5
wherein the core structures of natural products are used as
The isolation, identification, and direct modification of suitable
natural products has traditionally been a fruitful endeavor for
* Corresponding author.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.009

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6455
scaffolds for generating compound collections using a structural
classification of natural products (SCONP) as a design principle.
The design of synthetic approaches that enable rapid and effi-
cient generation of collections of organic compounds that are
structurally and functionally diverse and that possess skeletal
frameworks found in natural products and drug-like molecules is
a significant challenge.6 In our view one of the more promising
ways to achieve this goal is by combining multicomponent re-
actions (MCRs),7 which allow the rapid synthesis of differentially
substituted intermediates from three or more reactants, with fur-
ther transformations involving cyclizations via selective functional
group pairing to fabricate polycyclic carbo- and heterocyclic scaf-
folds with a variety of substituents and functional groups as
depicted graphically in Figure 1.8 This general strategy has been
utilized by a number of groups who have sequenced various ring-
forming reactions with multicomponent processes, including the
Ugi four-component reaction,9 the van Leusen reaction,10 and the
Petasis reaction.11 The sequencing of a MCR or related methods for
constructing intermediates that may then be elaborated by ring-
forming reactions has recently been referred to as the ‘Build-
Couple-Pair’ approach.12
Scheme 2.
then be N-acylated.16 Each of the four components could be
endowed with added functionality that would then enable further
transformation of 8 via a variety of ring-forming reactions to gen-
erate various polycyclic scaffolds 9 bearing functionality for further
diversification and for the preparation of focused libraries. We now
report some of the details of our studies that have been directed
toward developing the strategy outlined in Scheme 2 for the rapid
synthesis of a variety of heterocyclic scaffolds.17
2. Results and discussion
2.1. Preliminary considerations
Before presenting specific applications of the strategy outlined
in Scheme 2, a few comments are appropriate. Unlike the venerable
Ugi and some other multicomponent reactions, the components in
our process must be combined, at least in part, in a sequential
fashion because of the inherent reactivity of the different inputs.
The first stage of the sequence involves imine formation, and
depending upon whether one wants to perform a three or a four-
component coupling, this intermediate may or may not be isolated
in crude form. For example, the aldehyde and amine may be con-
densed in a suitable solvent in the presence of activated molecular
sieves to give a solution of the imine. This mixture may then be
used directly in the next step, or the molecular sieves may be re-
moved by filtration and the resulting solution used in the next step.
Alternatively, the solvent may be removed to provide the crude
imine, which could either be stored or redissolved to provide
a stock solution for convenient use in different reactions. When
imines of allylamine are desired, a practical and convenient method
for their preparation involves the reaction of the aldehyde with
commercially available N,N-bis(trimethylsilyl)allylamine in the
presence of catalytic amounts of trimethylsilyl triflate (TMSOTf).
These solutions of N-allylimines were then used directly.
Figure 1. Approach to synthesis of diverse collections of polycyclic scaffolds by tan-
dem MCR and cyclizations.
A number of years ago we discovered a multicomponent re-
action that featured vinylogous Mannich reactions of electron rich
dienes with N-acyl iminium ions that had been formed in situ by N-
acylation of imines to give adducts that were readily transformed
into complex indole alkaloids such as tetrahydroalstonine (3)
(Scheme 1).13,14 Based upon this finding, we envisioned a new
strategy for the rapid synthesis of diverse collections of heterocyclic
compounds that entailed the combination of an alkylamine 4, an
aromatic aldehyde 5, and an acylating agent 6 to generate an N-acyl
iminium ion that could be subsequently trapped with a nucleophile
7 to give a highly functionalized amide or carbamate 8 (Scheme
2).15 A variant of this route to 8 would involve addition of a nucle-
ophile to the imine to provide an intermediate amine that could
The tactics employed for completing the sequence to give 8
were dictated somewhat by the nature of the nucleophilic part-
ner. When weak
acetals were used, it was necessary to treat the imine with the
-nucleophile and the acylating agent, usually in the presence of
p-nucleophiles such as enol ethers and ketene
p
catalytic amounts of TMSOTf. With reactive nucleophiles such as
allylmetals, the nucleophile could optionally be added directly to
the solution of the imine and the resulting metal amide trapped
by reaction with the acylating agent. Although the majority of the
reactions presented herein were conducted as one-pot processes,
some were performed as two-pot sequences in which the crude
imines were isolated. It should be noted that overall yields in the
component assembly step to give compounds related to 8 can
vary depending upon how the imine-forming step is conducted.
It should be noted, however, that we did not always optimize
conditions for the formation of the intermediate imines or for
their subsequent conversion into adducts 8, because our overall
goal was to illustrate the scope and potential of the general plan
outlined in Scheme 2.
Having established a protocol for the facile synthesis of in-
termediates 8, a number of post-condensation reactions, including
Heck reactions, ring-closing metathesis (RCM), Dieckmann cycli-
zations, and Diels–Alder and dipolar cycloadditions, together with
Scheme 1.

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selected combinations of these reactions, were examined to gen-
erate heterocyclic scaffolds. The results are presented according to
the types of reaction(s) that were implemented to generate the
final scaffolds.
2.2. Scaffolds via Heck cyclization
An example of using a Heck reaction in tandem with the mul-
ticomponent process in Scheme 2 is illustrated in Scheme 3. The
indole 1018 was first allowed to react with commercially available
N,N-bis(trimethylsilyl)allylamine in the presence of TMSOTf,
whereupon acetyl chloride and the silyl ketene acetal 1119 were
added to provide 12, with TMSOTf catalyzing both imine formation
and the Mannich reaction. The resulting amide 12 underwent an
intramolecular Heck reaction with microwave heating to afford
tricycle 13, the structure of which was established by X-ray crys-
tallography,20 in 60% overall yield together with a small amount of
the isomeric olefin 14.
Scheme 4.
overall yield from commercially available 19 (Scheme 5). Conden-
sation of 20 with methylamine gave the intermediate imine 21 that
was treated in situ with carbobenzyloxy chloride and allylzinc
bromide to give carbamate 22, which underwent facile RCM in the
presence of Grubbs II catalyst to provide the benzazocine 23. In
a parallel sequence of reactions, imine 21 was treated with acetyl
chloride and vinylzinc bromide to give 24, which cyclized via a RCM
in the presence of Grubbs II catalyst to give the benzazepine 25.
Benzazepine rings are found in a variety of biologically active and
clinically useful compounds such as Mozavaptan, which is a sodium
level regulator that is marketed in Japan, and other benzazepines
have been reported to act as cholesterol ester transfer protein
(CETP) inhibitors.21
Scheme 3.
2.3. Scaffolds via RCM
The reaction of unsaturated organometallic reagents as nucleo-
philes with imines derived from allylamine or other unsaturated
amines gives rise to intermediates that may be easily elaborated
by RCM reactions. For example, addition of vinylmagnesium
bromide to the iminium ion generated upon reaction of the
imine 16 and benzyl chloroformate gave carbamate 17, which
underwent RCM to provide the 2-aryl dihydropyrrole 18
(Scheme 4). Similar yields were observed with vinylzinc chlo-
ride and vinylzinc bromide, which were generated in situ by
reaction of the Grignard reagent with the corresponding zinc
halide and would be expected to have better functional group
tolerance. In order to obtain optimal yields and to ensure
complete formation of the intermediate N-acylated imine or the
Scheme 5.
corresponding
a-chlorocarbamate, the solution of imine and
chloroformate was generally heated prior to addition of the
nucleophile. Such heating does not appear necessary when acid
chlorides are employed as acylating agents. The aryl bromide
function of 18 might be exploited in a variety of palladium-
catalyzed cross-coupling reactions to generate focused libraries,
and compound collections with alternative substitution patterns
would be accessible with benzaldehydes other than 15.
2-Aryltetrahydropyridines such as 27 may also be readily
accessed by the reaction of imines such as 16 with benzyl chloro-
formate and then methyl 2-carboxylzinc bromide (Scheme 6).22
Subsequent RCM of 26 then gave 27, which was contaminated with
about 10% of an inseparable impurity that appears to be an isomeric
cycloalkene.
2-Aminobenzaldehydes may also be utilized as starting mate-
rials, although preliminary work suggests that better results are
obtained when the amine is fully substituted. For example, the
aminobenzaldehyde derivative 20 was easily prepared in 74%
We have thus demonstrated the underlying utility of the general
strategy outlined in Scheme 2 for the rapid preparation of simple
heterocycles. It then remained to apply this approach to the syn-
thesis of more complex heterocyclic scaffolds. Toward this goal, we

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6457
Scheme 6.
turned our attention to elaborating more highly functionalized
adducts 8 via sequential ring-forming reactions.
2.4. Scaffolds via sequential RCM/Heck reactions
Bridged azabicycles having the framework found in 30 are
known to have activity in an acute pain model for mice in the same
order of magnitude as codeine.23 Compound 30 was rapidly as-
sembled from 28, which was formed via a one-pot multicomponent
reaction starting with 15 (Scheme 7). The RCM reaction of 28 pro-
ceeded smoothly in the presence of Grubbs II catalyst to give 29 in
86% overall yield from 15. Some screening of conditions was then
required in order to optimize the subsequent Heck reaction to give
30. It was necessary to use microwave heating and to employ
a hindered base in the reaction, and to conduct the reaction in the
presence of chloride ion.
Scheme 8.
Indole 10 was also used as a starting material in a related MCR
followed by sequential RCM and Heck cyclizations to generate the
novel bridged indole derivative 39, which bears some resemblance
to the ring system found in the ergoline alkaloids (Scheme 9). It is
noteworthy that the conversion of 10 into 38 could be telescoped
with a simple solvent exchange for the second step. Best results
were achieved when the allylmagnesium bromide was added to the
imine prior to the acylation step. Because a metal salt of an amine is
the intermediate, there is considerable flexibility in selecting the
acylating agent. The Heck cyclization of 38 to furnish 39 proceeded
without event.
Scheme 7.
Because derivatives of azabicycles such as 30 might have useful
activities, we briefly explored tactics that might be employed to
create a small library of compounds related to 30. In the event, the
known aldehyde 3124 was converted into the carbamate 32
(Scheme 8). Cyclization of 32 via RCM in the presence of Grubbs II
catalyst gave 33. We discovered that the Heck reaction could be
telescoped with the RCM step by simply adding 2-mercaptonico-
tinic acid and activated charcoal to remove the residual Ru cata-
lyst.25 The solvent was exchanged with acetonitrile and Pd(OAc)2,
P(o-tol)3, Hu¨nig’s base, and Bu4NCl were added, and the mixture
was heated in a microwave oven to deliver 34. The olefin was re-
duced via ionic reduction,26 and the carbamate group was removed
with TMSI27 to give the key intermediate 35. In preliminary and
unoptimized experiments, we discovered that 35 may be processed
via Buchwald–Hartwig28 and Suzuki29 cross-coupling reactions to
give 36 and 37, respectively.
Scheme 9.
In order to broaden the scope of this approach to bridged het-
erocyclic ring systems, we explored the possibility of accessing
different ring sizes by varying the nature of the nucleophile. For
example, use of homoallylzinc chloride30 in the MCR with aldehyde
15, allylamine, and benzyl chloroformate gave carbamate 40
(Scheme 10). Sequential cyclizations via a RCM and a Heck reaction
generated an easily separable mixture (3.4:1) of isomers 42 and 43,
whose structures were assigned by 2D NMR (COSY and HSQC). The
major isomer 42 is a substructure of the isopavine alkaloids.

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J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
Scheme 10.
Scheme 12.
2.5. Scaffolds via sequential RCM/Dieckmann reactions
The aromatic aldehydes used thus far have contained a bromo
group that was paired with alkenes in Heck cyclizations. Other
functionality can be incorporated into the starting aldehyde to
enable other cyclization manifolds. For example, an ester group in
the starting benzaldehyde might be used in Dieckmann cycliza-
tions. Accordingly, 4431 was employed as a starting input in a MCR
using allylamine, acetyl chloride, and allylzinc bromide to give 45
(Scheme 11). Allyltributylstannane could also be used in this MCR
giving 45 in 77% yield, but in a preliminary experiment use of
allyl(trimethyl)silane in the presence of a catalytic amount of
TMSOTf gave 45 in only 17% yield. RCM of 45 followed by Die-
ckmann cyclization then delivered 47 in about 70% overall yield
from 45.
Scheme 13.
to give an intermediate that was cyclized via a Dieckmann cycli-
zation to give diene 54 in good overall yield.33 Other terminal
olefins, including methyl acrylate, methyl vinyl ketone, allyl-
trimethylsilane, and allyl alcohol, also underwent RCM/CM,34 albeit
in lower yields, but no effort was made to optimize those
sequences.
2.6. Scaffolds via [3D2] cycloadditions
Dipolar cycloaddition reactions comprise a versatile class of
reactions for generating heterocyclic ring systems.35 This fact to-
gether with the prevalence of bioactive heterocycles containing the
pyrrolidine substructure inspired us to sequence our MCR process
with different [3þ2] reactions. Two intriguing examples are pre-
sented in Scheme 14. The aldehyde 56, which served as a common
Scheme 11.
An ester group required for a Dieckmann condensation may also
be introduced if a silyl ketene acetal is used as the nucleophile in
the MCR. In order to exemplify this process 2-vinylbenzaldehyde
(48)32 and silyl ketene acetal 49 were employed as two compo-
nents in a MCR to generate 50 (Scheme 12). Cyclization of 50 via
a Dieckmann reaction followed by RCM provided 52 in about 70%
overall yield from 50. If the order of these cyclizations was reversed
the overall yield of 52 was significantly lower. Moreover, the
presence of the geminal groups in 50 obviates enolization
a to the
ester moiety and elimination of the amide side chain.
Incorporation of a carbon–carbon triple bond into MCR adducts
can also enable the incorporation of a fifth component via an enyne
RCM/CM sequence. For example, propargyl amine was utilized as
the amine component in a MCR with 44, acetyl chloride, and
allylzinc bromide to generate amide 53 in moderate yield from
aldehyde 44 (Scheme 13). In this instance, consistently higher
yields were obtained when the intermediate imine was isolated in
crude form. When enyne 53 was treated with excess styrene in the
presence of Hoveyda–Grubbs II catalyst, a RCM/CM process ensued
Scheme 14.

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6459
intermediate in the two sequences, was isolated in 77% yield
starting from 2-bromobenzaldehyde (15) using the silyl enol ether
5536 as the nucleophile. Condensation of 56 with sarcosine in
refluxing toluene led to the formation of 57 in 65% yield. The rel-
ative stereochemistry of 57 was established by comparisons of its
NMR spectra with that of 59, which was synthesized from 2-
iodobenzaldehyde by the same procedure used to prepare 57 and
the structure of which was determined by X-ray analysis of its
hydrochloride salt.20 When the aldehyde 56 was condensed with
N-methyl hydroxylamine, the intermediate nitrone underwent
cyclization to give 58 in 87% yield. The structure of 58 was assigned
by X-ray analysis of its hydrochloride salt.20 Significantly, the het-
erocyclic scaffolds present in 57 and 58 are found in compounds
that are chemokine CCR5 receptor antagonists37 and inhibitors of
dipeptidyl peptidase IV (DPP-IV).38 Of course, 56 and related
compounds may be transformed by other dipolar cycloaddition
reactions, and such efforts are in progress.
Scheme 16.
Another interesting sequence involving an intramolecular [3þ2]
cycloaddition is shown in Scheme 15. In this particular case the
MCR adduct derived from the azido benzaldehyde 6039 underwent
spontaneous intramolecular cycloaddition to give triazole 61. Pre-
liminary attempts to cyclize 61 via a Dieckmann reaction were
unsuccessful. Nevertheless, it is noteworthy that the skeletal
framework in 61 is found in related compounds that have been
reported to be weak inhibitors of the benzodiazepine receptor.40
Scheme 17.
Scheme 15.
chromatography in 49% yield. The structure of 71 was assigned
from analysis of 2D NMR and NOE spectroscopy. The stereo-
chemical mode of this cycloaddition is consistent with literature
reports for similar intramolecular Diels–Alder reactions of
furans.43
2.7. Scaffolds via Diels–Alder cycloadditions
We have used intramolecular Diels–Alder reactions as key
steps in the synthesis of a number of alkaloid natural prod-
ucts.13,41 Based upon this work, it occurred to us that such con-
structions might be used to access heterocyclic scaffolds
comprising subunits of the berbane, yohimbine, and hetero-
yohimbine alkaloids. In order to explore this exciting possibility,
it would simply be necessary to incorporate a diene into the
multicomponent process. Accordingly, when the pentadienylsi-
lane 6342 was employed as the nucleophile in the multicompo-
nent process involving the allylimine derived from 15 and
acryloyl chloride in the presence of 10 mol % TMSOTf, the adduct
64 thus formed underwent spontaneous Diels–Alder cyclization
to generate the hydroisoquinoline 66 in good yield as a single
detectable diastereomer (Scheme 16). The scope of this process
was expanded to include variably functionalized benzaldehydes,
such as 3,4-dimethoxybenzaldehyde (62), that led to the forma-
tion of 67 in good yield and diastereoselectivity. The structure of
67 was assigned based upon the X-ray analysis of the methiodide
salt of 68. Correlations of the NMR spectra of 67 and 66 allowed
assignment of the relative stereochemistry of 66.
2.8. Scaffolds via Friedel–Crafts reaction
Friedel–Crafts reactions may also be used to transform ad-
ducts generated by the multicomponent process in Scheme 2. In
order to illustrate how this might be accomplished, we turned
our attention again to the synthesis of compounds having the
isopavine skeleton, which incorporates an azabicyclo[3.2.2]no-
nane substructure (cf. Scheme 10). Both natural and unnatural
members of the isopavine family have been shown to possess
interesting biological properties for the treatment of disorders
like Alzheimer’s and Parkinson’s disease, Huntington’s chorea,
and Down’s syndrome.44 Indeed, an approach to the isopavine
alkaloid roelactamine (74)45 was developed that represents the
first synthesis of this alkaloid and constitutes the most concise
approach to alkaloids of this class.46
The synthesis of roelactamine commenced with the sequential
reaction of piperonal (72) with methylamine, the Grignard reagent
75, and diacetoxyacetyl chloride (76), which was easily prepared in
gram quantities from glyoxylic acid,47 to give amide 73 (Scheme
18). When 73 was simply treated with HCl and MeOH, roelactamine
(74) was formed and isolated in good overall yield from 72. The
synthetic (ꢀ)-roelactamine thus obtained gave spectral character-
istics (1H and 13C NMR, IR, and mass spectral data) consistent with
Another example of the sequencing of a Diels–Alder reaction
with the MCR is illustrated in Scheme 17, wherein furfural (69) is
utilized as the aldehyde component. The initially formed adduct
70 was not stable, as the Diels–Alder reaction proceeded slowly
at room temperature. Consequently, 70 was simply isolated in
crude form and heated under reflux in toluene to give a mixture
of isomers from which the major product 71 was isolated by

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J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
metal was activated by washing with 1 M HCl. The 4 Å molecular
sieves were activated under high vacuum at w300 ꢁC for 7 h. All
reactions were run under a positive pressure of N2 or argon gas in
glassware that had been oven or flame dried. Vinylzinc halide so-
lution (in THF) was made by adding a commercial solution of
vinylmagnesium bromide in THF to ZnX2 (1.1 equiv). ZnCl2 was
dried by fusing under vacuum. Reaction temperatures are reported
as the temperatures of the bath surrounding the vessel, or pro-
grammed temperatures for microwave reactions. Microwave re-
actions were performed using a CEM Discover Labmate microwave
synthesizer, which varies the power (generally 150 W max) auto-
matically to reach and maintain the set temperature.
Nuclear magnetic resonance spectra were acquired at 300 K in
CDCl3 unless otherwise noted. Chemical shifts are reported in parts
Scheme 18.
per million (ppm,
d), downfield from tetramethylsilane (TMS,
those reported for the natural product. Although dichloroacetyl
chloride could also be used in the first step, the correspond-
ing dichloro analog of 73 did not undergo efficient cyclization
to give 74.
d
¼0.00 ppm), and are referenced to the residual solvent: CDCl3,
d
¼7.26 ppm (1H) and 77.16 ppm (13C); CD3OD,
d
¼3.31 ppm (1H) and
49.0 ppm (13C); DMSO-d6,
d
¼2.50 ppm (1H) and 39.5 ppm (13C);
acetone-d6,
d
¼2.05 ppm (1H) and 29.8 ppm (13C). The abbreviations
s, d, t, q, p, hex, hep, m, and comp stand for the resonance multi-
plicities singlet, doublet, triplet, quartet, pentuplet, hextuplet,
heptuplet, multiplet, and complex (overlapping multiplets), re-
spectively; br¼broad; app¼apparent. In some cases where NMR
suggested the presence of rotamers, NMR data were collected at
high temperature to coalesce the signals. Otherwise, the existence
of rotamers is noted in the spectral data. Infrared (IR) spectra were
recorded as films on sodium chloride plates and reported as
wavenumbers (cmꢂ1).
3. Conclusion
The representative examples presented herein clearly establish
the merits of this new strategy for the facile synthesis of diverse
collections of nitrogen heterocycles. The approach features an ini-
tial Mannich-type multicomponent reaction to combine function-
alized amines, aromatic aldehydes, acylating agents, and
p- and
organometallic nucleophiles to create useful templates. These key
intermediates are then further transformed into a diverse array of
heterocyclic frameworks via a variety of cyclization manifolds, in-
cluding Heck, RCM, Dieckmann, and Friedel–Crafts reactions as well
as dipolar and Diels–Alder cycloadditions; numerous other cycli-
zations can be readily envisioned. Significantly, these scaffolds bear
orthogonal functionality that may be selectively exploited for fur-
ther manipulation and diversification to create novel sets of com-
pounds having substructures found in biologically active natural
products and clinically useful drugs. Hence, this chemistry would
appear to have considerable potential for generating novel drug
leads and tools for studying biological pathways and for trans-
lational medical research. Inasmuch as the underlying inspiration
for this approach to creating compound libraries emerged from our
work in alkaloid synthesis, it is perhaps not surprising that these
basic principles were applied to an extraordinarily concise syn-
thesis of the isopavine alkaloid roelactamine. Further applications
of the concepts outlined in Scheme 2 for both the synthesis of
natural products and diverse collections of scaffolds that are
endowed with reactive sites or handles for the preparation of fo-
cused libraries are in progress. The results of these investigations
will be reported in due course.
4.2. Experimental procedures
4.2.1. Methyl 3-(N-allylacetamido)-3-(4-bromo-1-tosyl-1H-
indol-3-yl)propanoate (12)
TMSOTf (6.5 mL, 8 mg, 0.036 mmol) was added to a solution of
4-bromoindole-3-carboxaldehyde 1018 (140 mg, 0.37 mmol) and
bis(trimethylsilyl)allylamine (0.10 mL, 82 mg, 0.40 mmol) in CH2Cl2
(1 mL), and the mixture was stirred for 3 h at room temperature.
Silyl ketene acetal 1119 (135 mg, 0.95 mmol) and freshly distilled
acetyl chloride (35 mL, 39 mg, 0.49 mmol) were then added, and the
mixture was stirred for 4 h at room temperature. The solution was
partitioned between CH2Cl2 (5 mL) and saturated aqueous NaHCO3
(5 mL). The organic phase was removed, and the aqueous layer was
extracted with CH2Cl2 (2ꢃ5 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with 50%
EtOAc/hexanes, to give 142 mg (72%) of amide 12 as a white solid,
1
mp 134.5–136 ꢁC. H NMR (500 MHz, DMSO, 130 ꢁC)
d 7.95 (d,
J¼7.8 Hz, 1H), 7.95 (s, 1H), 7.77 (d, J¼8.2 Hz, 2H), 7.45 (d, J¼7.8 Hz,
1H), 7.36 (d, J¼8.2 Hz, 2H), 7.23 (t, J¼8.2 Hz, 1H), 6.41 (s, 1H), 5.31
(dddd, J¼15.8, 10.2, 5.3, 5.3 Hz, 1H), 4.72 (d, J¼17.1 Hz, 1H), 4.65 (d,
J¼10.2 Hz, 1H), 3.86 (dd, J¼17.3, 5.3 Hz, 1H), 3.70 (dd, J¼17.3, 5.3 Hz,
1H), 3.54 (s, 3H), 3.18 (dd, J¼15.3, 9.3 Hz, 1H), 3.00 (dd, J¼15.3,
5.9 Hz, 1H), 2.34 (s, 3H), 2.03 (s, 3H); 13C NMR (125 MHz, DMSO,
4. Experimental
4.1. General
130 ꢁC)
d 169.8, 169.3, 145.1, 135.5, 134.2 133.7, 129.5, 127.6, 127.4,
Unless otherwise noted, solvents and reagents were reagent
grade and used without further purification. Dichloromethane
(CH2Cl2), diisopropylamine (i-Pr2NH), and triethylamine (Et3N)
were freshly distilled over CaH2. Tetrahydrofuran (THF), ether
(Et2O), acetonitrile (CH3CN), toluene, and dimethylformamide
(DMF) were dried according to the procedure described by
Grubbs.48 1,4-Dioxane was distilled twice from sodium and stored
in a Schlenk flask over molecular sieves and under nitrogen.
TMSOTf and styrene were distilled from CaH2 under reduced
pressure. Acetyl chloride was freshly distilled from P2O5 immedi-
ately prior to use, and acryloyl chloride was distilled immediately
prior to use. Allyl bromide was dried over MgSO4 and distilled. Zinc
125.9, 125.3, 119.7, 114.7, 112.7, 112.1, 50.5, 47.2, 46.0, 36.4, 21.4, 20.2;
IR (neat) 1736, 1644, 1411, 1374, 1258, 1174, 675, 574 cmꢂ1; mass
spectrum (CI) m/z 533.0754 [C24H2679BrN2O5S (Mþ1) requires
533.0746].
4.2.2. Methyl 2-((Z)-9-acetyl-2,8,9,10-tetrahydro-2-tosylazo-
cino[3,4,5-cd]indol-10-yl)acetate (13) and methyl 2-((Z)-9-
acetyl-2,6,9,10-tetrahydro-2-tosylazocino[3,4,5-cd]indol-10-yl)-
acetate (14)
Pd(OAc)2 (2 mg, 0.001 mmol), PPh3 (6 mg, 0.025 mmol), and
Et3N (0.06 mL, 43 mg, 0.43 mmol) were added to a solution of amide
12 (0.057 mg, 0.11 mmol) in CH3CN (4.2 mL) and the mixture was

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6461
heated to 125 ꢁC in a microwave reactor for 30 min. The solutionwas
cooled to room temperature and concentrated under reduced
pressure. The residue was purified by flash chromatography, eluting
with 50% EtOAc/hexanes, to give 6 mg (12%) of enamine 14 as
a yellowish gum and 40 mg (83%) of amide 13 as a brownish solid.
Recrystallization of 13 via slow evaporation from benzene provided
large colorless prisms, mp¼170–172 ꢁC. Compound 13 (major): 1H
a colorless oil. 1H NMR (400 MHz, CDCl3) (rotamers)
d
7.51 (d app t,
J¼8.0, 1.0 Hz, 1H), 7.40–7.06 (comp, 7H), 6.92 (m, 1H), 5.99 (m, 1H),
5.89 (m, 1H), 5.84 (m, 1H), 5.19 (d, J¼12.3 Hz, 0.4H), 5.09 (d,
J¼12.3 Hz, 0.4H), 5.06 (d, J¼12.7 Hz, 0.6H), 4.97 (d, J¼12.7 Hz, 0.6H),
4.41 (m, 2H); 13C NMR (100 MHz, CDCl3) (rotamers)
d 154.6, 154.4,
141.1, 140.3, 136.9, 136.6, 133.1, 132.8, 130.0, 128.9, 128.8, 128.6,
128.3, 128.2, 128.1, 128.0, 127.7, 127.5, 127.4, 127.1, 125.00, 124.96,
122.1, 68.2, 67.5, 67.1, 66.8, 54.6, 54.3; IR (neat) 3321, 1709, 1412,
1356, 1114, 1025, 753, 697 cmꢂ1; mass spectrum (CIþ) m/z 358.0445
[C18H17NO279Br (Mþ1) requires 358.0443].
NMR (500 MHz, DMSO, 130 ꢁC)
d
7.88 (d, J¼8.3 Hz, 1H), 7.78 (s, 1H),
7.77 (d, J¼8.3 Hz, 2H), 7.37 (d, J¼8.3 Hz, 2H), 7.34 (t, J¼8.3 Hz, 1H),
7.12 (d, J¼7.5 Hz, 1H), 6.92 (d, J¼10.9 Hz,1H), 5.99 (ddd, J¼10.5, 10.5,
6.9 Hz,1H), 5.84 (m,1H), 4.34 (br,1H), 3.82 (br,1H), 3.37 (s, 3H), 2.96
(dd, J¼15.0, 9.8 Hz, 1H), 2.88 (dd, J¼15.0, 4.7 Hz, 1H), 2.34 (s, 3H),
4.2.5. N-Allyl-N-(2-formylphenyl)-4-methylbenzene-
sulfonamide (20)
2.14 (s, 3H); 13C NMR (125 MHz, DMSO, 130 ꢁC)
d
169.4, 168.1, 144.8,
135.2,134.1,133.5,129.4,128.6,127.1,126.6,126.5,125.9,124.3,124.1,
118.2, 112.5, 50.5, 50.1, 41.3, 40.6, 20.9, 20.1; IR (neat) 1736, 1638,
1419, 1371, 1307, 1259, 1176, 1149, 1091, 731 cmꢂ1; mass spectrum
A
solution of N-(2-formylphenyl)-4-methylbenzenesulfon-
amide49 (853 mg, 3.10 mmol) in dry DMF (4 mL) was added to
a stirred suspension of 95% sodium hydride (89 mg, 3.5 mmol) in
dry DMF (8 mL) at 0 ꢁC. The mixture was removed from the ice bath
and stirred for 15 min at room temperature, whereupon it was
again cooled to 0 ꢁC. Allyl bromide (755 mg, 0.54 mL, 6.2 mmol)
was added dropwise by syringe, and the solution was stirred for 1 h
at 0 ꢁC and then for 20 h at room temperature. A solution of 1 M
aqueous NaOH (20 mL) and EtOAc (80 mL) were added, and the
layers were separated. The organic layer was washed with 1 M
NaOH (2ꢃ50 mL), water (3ꢃ50 mL), brine (50 mL), dried (MgSO4),
filtered, and concentrated to give 974 mg (100%) of 20 as an off-
white solid. The 20 thus obtained gave spectral data that were
consistent with those reported.50
(CI) m/z 453.1487 [C24H25N2O5S (Mþ1) requires 453.1484]. Com-
1
pound 14 (minor): H NMR (500 MHz, DMSO, 130 ꢁC)
d 7.74 (d,
J¼8.3 Hz, 2H), 7.73 (d, J¼8.3 Hz, 1H), 7.65 (s, 1H), 7.34 (d, J¼8.3 Hz,
2H), 7.21 (t, J¼7.4 Hz, 1H), 7.05 (d, J¼7.4 Hz, 1H), 6.45 (d, J¼9.1 Hz,
1H), 5.94 (t, J¼7.1 Hz, 1H), 5.34–5.29 (m, 1H), 3.65 (dd, J¼7.5, 3.7 Hz,
2H), 3.53 (s, 3H), 3.31 (dd, J¼15.7, 6.4 Hz,1H), 3.10 (dd, J¼15.7, 7.7 Hz,
13
1H), 2.33 (s, 3H), 2.00 (s, 3H); C NMR (125 MHz, DMSO, 130 ꢁC)
d
169.8, 168.8, 144.6, 134.8, 134.2, 132.1, 129.3, 128.2, 127.2, 125.8,
125.2,124.3,123.2,119.8,115.1,111.0, 50.4, 49.9, 38.6, 31.2, 22.2, 20.1;
IR (neat) 2950, 1737, 1642, 1425, 1368, 1290, 1175, 1091, 912,
743 cmꢂ1; mass spectrum (CI) m/z 453.1482 [C24H25N2O5S (Mþ1)
requires 453.1484].
4.2.6. 1-{2-[Allyl(toluene-4-sulfonyl)amino]phenyl}but-3-
4.2.3. Allyl-[1-(2-bromophenyl)allyl]carbamic acid
enylmethyl carbamic acid benzyl ester (22)
benzyl ester (17)
A mixture of methylamine in THF (2 M, 5.0 mL, 10.0 mmol) and
aldehyde 20 (315 mg, 1.00 mmol) containing 3 Å molecular sieves
(600 mg) was stirred for 16 h at room temperature. The sieves were
removed by filtration through Celite, and the filtrate was concen-
trated under reduced pressure to give 328 mg (ca. 100%) of crude
21. A portion of 21 (82 mg, 0.25 mmol) was dissolved in THF (1 mL),
A mixture of allylamine (59 mg, 0.77 mL, 10.2 mmol) and 2-
bromobenzaldehyde (1.85 g, 10.0 mmol) in THF (25 mL) containing
4 Å molecular sieves (3.0 g) was stirred for 12 h at room tempera-
ture. The sieves were removed by filtration through Celite, and the
filtrate was concentrated under reduced pressure to give 2.24 g (ca.
100%) of crude imine 16. A portion of 16 (56 mg, 0.25 mmol) was
benzyl chloroformate (45 mg, 38 mL, 0.26 mmol) was added, and
dissolved in THF (1 mL), benzyl chloroformate (45 mg, 38
m
L,
the mixture was heated at 60 ꢁC for 1 h. The solution was then
0.26 mmol) was added, and the mixture was heated at 60 ꢁC for 1 h.
cooled to ꢂ78 ꢁC, and a solution of allylzinc bromide51 in THF
The mixture was then cooled to ꢂ78 ꢁC, and a solution of vinyl-
(0.90 M, 333 mL, 0.30 mmol) was added. The cooling bath was re-
magnesium bromide in THF (1.04 M, 288
m
L, 0.30 mmol) was
moved, and the solution was stirred at room temperature for 1.5 h.
Saturated aqueous NH4Cl (w0.5 mL) was added, and the mixture
was partitioned between water (30 mL) and Et2O (30 mL), the
layers were separated, and the organic layer was washed with
NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography, eluting with 0–30% EtOAc/hexanes,
to give 105 mg (83%) of 22 as a colorless oil. 1H NMR (500 MHz,
added. The cooling bath was removed, and the mixture was stirred
at room temperature for 1.5 h. Saturated aqueous NH4Cl (w0.5 mL)
was added, and the mixture was partitioned between water
(20 mL) and Et2O (20 mL), and the layers were separated. The or-
ganic layer was washed with NaHCO3 (20 mL) and brine (20 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography, eluting
with 0–25% EtOAc/hexanes, to give 68 mg (70%) of 17 as a colorless
DMSO-d6, 120 ꢁC) (rotamers)
d 7.63–7.25 (comp, 12H), 7.22 (app td,
oil. 1H NMR (400 MHz, CDCl3) (rotamers)
6.15–5.98 (comp, 2H), 5.63–5.45 (comp, 1H), 5.45–5.05 (comp, 4H),
4.81 (d, J¼10.0 Hz, 1H), 4.73 (d, J¼17.0 Hz, 1H), 3.93 (dd, J¼15.9,
5.1 Hz, 1H), 3.63 (br dd, 1H); 13C NMR (100 MHz, CDCl3) (rotamers)
d
7.60–7.05 (comp, 9H),
J¼7.8, 1.7 Hz, 1H), 6.76 (br s, 1H), 5.83 (br s, 1H), 5.68–5.54 (comp,
2H), 5.19 (d, J¼12.4 Hz, 1H), 5.14–4.83 (comp, 5H), 4.07 (br m, 1H),
3.94 (br m, 1H), 2.75 (m, 1H), 2.64 (br s), 2.63 (s, 3H), 2.43 (s), 2.41
13
(br s, total 3H); C NMR (125 MHz, DMSO-d6, 120 ꢁC) (rotamers)
d
156.2, 141.7, 138.5, 138.3, 136.8, 134.9, 134.3, 133.3, 130.3, 129.5,
d 154.8, 142.9, 134.4, 131.8, 128.8, 127.5, 127.4, 127.3, 126.9, 116.0,
129.2, 128.5, 128.3, 128.1, 127.96, 127.93, 127.4, 126.0, 117.2, 116.1,
115.7, 73.6, 67.4, 67.3, 61.7, 47.4; IR (neat) 1702, 1441, 1404, 1277,
1251, 1140, 922, 754, 697 cmꢂ1; mass spectrum (ESIþ) m/z 386.0750
[C20H21NO279Br (Mþ1) requires 386.0760].
65.7, 20.2; IR (neat) 2928, 1695, 1450, 1401, 1349, 1165, 664,
576 cmꢂ1; mass spectrum (CIþ) m/z 505.2157 [C29H33N2O4S (Mþ1)
requires 505.2161].
4.2.7. Methyl-[1-(toluene-4-sulfonyl)-1,2,5,6-tetrahydro-
benzo[b]azocin-6-yl] carbamic acid benzyl ester (23)
4.2.4. 2-(2-Bromophenyl)-2,5-dihydropyrrole-1-carboxylic
acid benzyl ester (18)
A solution of 22 (52 mg, 0.10 mmol) in CH2Cl2 (5 mL) containing
Grubbs II catalyst (8.5 mg, 0.01 mmol) was stirred at room tem-
A solution of 17 (31 mg, 0.079 mmol) in CH2Cl2 (4 mL) con-
taining Grubbs II catalyst (3.4 mg, 0.004 mmol) was stirred at room
temperature for 3 h. The solution was concentrated and the crude
product was purified by flash chromatography, eluting with 0–25%
EtOAc/hexanes, to give 23 mg of dihydropyrrole 18 (81%) as
perature for 6 h. DMSO (44 mg, 40 m
L, 0.56 mmol) was added52 and
stirring continued for 4 h. The solvents were removed under re-
duced pressure, and the product was purified by flash chroma-
tography, eluting with 0–50% EtOAc/pentane, to give 40 mg of 23

6462
J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
1
(81%) as a colorless oil. H NMR (500 MHz, DMSO-d6, 120 ꢁC)
(rotamers)
cooled to ꢂ78 ꢁC, and a portion of the solution of methyl 2-carb-
d
7.71 (d, J¼8.0 Hz, 2H), 7.46 (d, J¼8.0 Hz, 2H), 7.40–7.28
oxyallylzinc bromide (ca. 0.75 M based on iodometric titration)
(comp, 7H), 7.23–7.14 (comp, 2H), 6.71 (d, J¼7.8 Hz, 1H), 5.73 (m,
1H), 5.63 (br s, 1H), 5.34 (d app t, J¼11.0, 3.4 Hz, 1H), 5.19 (s, 2H),
(800 mL, 0.60 mmol) was added. The cooling bath was removed, and
the mixture was stirred at room temperature for 1.5 h. Saturated
aqueous NH4Cl (w0.5 mL) was added, and the mixture was parti-
tioned between water (30 mL) and Et2O (30 mL). The layers were
separated, and the organic layer was washed with NaHCO3 (20 mL)
and brine (20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography, eluting with 0–30% EtOAc/hexanes, to give 145 mg
(63%) of carbamate 26 (63%) as a colorless oil. 1H NMR (500 MHz,
2.82 (s, 3H), 2.45 (s, 3H); 13C NMR (125 MHz)
d 143.1, 136.3, 129.2,
128.3, 127.6, 127.0, 126.8, 126.7, 125.4, 66.0, 58.1, 20.2; IR (neat)
2936, 1696, 1491, 1445, 1401, 1344, 1325, 1163, 1096, 674, 577,
548 cmꢂ1; mass spectrum (CIꢂ) m/z 477.1846 [C27H29N2O4S (M)
requires 477.1848].
4.2.8. N-(1-{2-[Allyl-(toluene-4-sulfonyl)amino]phenyl}-allyl)-
N-methylacetamide (24)
DMSO-d6, 90 ꢁC)
d
7.60 (dd, J¼7.8, 1.5 Hz, 1H), 7.58 (dd, J¼7.8, 1.2 Hz,
Imine 21 (49 mg, 0.15 mmol) was dissolved in THF (0.5 mL),
1H), 7.38 (ddd, J¼7.7, 7.7, 1.2 Hz, 1H), 7.36–7.27 (comp, 4H), 7.23
(ddd, J¼7.7, 7.7, 1.7 Hz, 1H), 6.05 (d, J¼1.2 Hz, 1H), 5.64 (dd, J¼9.5,
5.6 Hz, 1H), 5.57 (d, J¼1.2 Hz, 1H), 5.41 (dddd, J¼16.6, 10.7, 5.9,
5.9 Hz, 1H), 5.12 (d, J¼12.7 Hz, 1H), 5.01 (d, J¼12.7 Hz, 1H), 4.77 (d,
J¼0.7 Hz, 1H), 4.74 (dm, J¼8.8 Hz, 1H), 3.76 (ddm, J¼16.1, 5.6 Hz,
1H), 3.63 (dm, J¼4.6 Hz, 1H), 3.61 (s, 3H), 3.04 (dd, J¼14.0, 10.0 Hz,
1H), 2.90 (ddd, J¼14.0, 5.6, 1.0 Hz, 1H); 13C NMR (125 MHz, DMSO-
acetyl chloride (12.8 mg, 11.6
mixture was stirred for 1 h. The solution was then cooled to –78 ꢁC,
and a solution of vinylzinc bromide in THF solution (0.60 M, 310 L,
mL, 0.16 mmol) was added, and the
m
0.19 mmol) was added. The cooling bath was removed, and the
mixture was stirred at room temperature for 1.5 h. Saturated aque-
ous NH4Cl (w0.5 mL) was added, and the mixture was partitioned
betweenwater (20 mL) and Et2O (20 mL), the layers were separated,
and the organic layer was washed with NaHCO3 (15 mL) and brine
(15 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography,
eluting with 0–60% EtOAc/pentane, to give 47 mg (79%) of 24 as
d6, 90 ꢁC)
d 165.8, 154.8, 137.6, 136.43, 136.38, 134.1, 132.5, 129.23,
129.19, 127.7, 127.2, 127.12, 127.09, 126.8, 124.7, 115.1, 66.0, 56.8, 51.0,
45.5, 33.7; IR (neat) 2950, 1698, 1437, 1406, 1228, 1134, 993, 757,
697 cmꢂ1; mass spectrum (CIþ) m/z 458.0967 [C23H25NO479Br
(Mþ1) requires 458.0967].
a colorless oil.1H NMR (400 MHz, CDCl3)
d
7.51 (d, J¼8.2 Hz,1H), 7.40
(dd, J¼7.8, 1.8 Hz, 1H), 7.37–7.29 (comp, 3H), 7.18 (app t d, J¼7.8,
1.6 Hz,1H), 6.52–6.45 (comp, 2H), 6.05 (ddd, J¼17.3,10.6, 3.3 Hz,1H),
5.49 (m, 1H), 5.42 (dm, J¼10.6 Hz, 1H), 5.25 (ddd, J¼17.3, 2.3, 1.0 Hz,
1H), 4.98 (d, J¼9.6 Hz, 1H), 4.90 (dd, J¼16.8, 1.0 Hz, 1H), 4.44 (ddm,
J¼13.5, 5.9 Hz, 1H), 3.75 (dd, J¼13.5, 8.4 Hz, 1H), 2.47 (s, 3H), 2.47 (s,
4.2.11. N-Allyl-N-[1-(2-bromophenyl)-but-3-enyl]-2-
phenylacetamide (28)
A mixture of allylamine (57 mg, 75 mL, 1.0 mmol) and 2-bro-
mobenzaldehyde (185 mg,1.00 mmol) in dry THF (2 mL) containing
crushed 4 Å molecular sieves (300 mg) was stirred at room tem-
3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
172.1, 144.3, 139.7,
perature for 7 h. Phenylacetyl chloride (170 mg, 145 mL, 1.1 mmo1)
138.9, 134.9, 133.9, 131.37, 129.6, 128.63, 128.57, 128.51, 128.0, 120.9,
116.2, 58.5, 54.9, 28.7 (two overlapping peaks), 21.7; IR (neat) 3750,
1652, 1344, 1163, 665, 576 cmꢂ1; mass spectrum (CIþ) m/z 399.1747
[C22H27N2O3S (Mþ1) requires 399.1742].
was added, and the mixture was stirred for another 1.5 h. The
mixture was then cooled to ꢂ78 ꢁC, and a solution of allylzinc
bromide (w1.4 mmol) in dry THF (1 mL) was added. The bath was
removed, and the mixture was stirred for 2.5 h at room tempera-
ture. Saturated aqueous NH4Cl solution (1 mL) was added, and the
mixture was partitioned between water (20 mL) and Et2O (20 mL).
The layers were separated, and the aqueous layer was extracted
with Et2O (10 mL). The combined organics were washed with
NaHCO3 (20 mL), brine (20 mL), dried (MgSO4), filtered, and con-
centrated under reduced pressure to give a colorless oil. The crude
product was purified by flash chromatography, eluting with 0–30%
EtOAc/hexanes, to give 325 mg (91%) of amide 28 as a colorless oil.
4.2.9. N-Methyl-N-[1-(toluene-4-sulfonyl)-2,5-dihydro-1H-
benzo[b]azepin-5-yl]acetamide (25)
A solution of 24 (47 mg, 0.12 mmol) in CH2Cl2 (6 mL) containing
Grubbs II catalyst (15.3 mg, 0.018 mmol) was stirred at room tem-
perature for 24 h. The reaction was quenched by adding DMSO
(55 mg, 50 m
L, 0.70 mmol)52 and stirring for 4 h. The crude product
was purified by flash chromatography, eluting with 0–100% EtOAc/
pentane, to give 37 mg of 25 (85%) as a brown oil. 1H NMR
1H NMR (400 MHz, CDCl3) (rotamers)
d 7.63–7.54 (m, 1H), 7.44–7.36
(400 MHz, CDCl3) (rotamers)
d
7.67 (d, J¼8.2 Hz, 2H), 7.39–7.22
(m, 1H), 7.34–7.20 (comp, 6H), 7.19–7.10 (m, 1H), 5.96 (app t,
J¼7.8 Hz, 0.8H), 5.75 (dddd, J¼17.2, 10.2, 6.9, 6.9 Hz, 0.8H), 5.56 (m,
2ꢃ0.2H), 5.37 (m, 0.8H), 5.29 (app t, J¼7.6 Hz), 5.13–4.93 (comp,
3.8H), 4.81 (d, J¼10.0 Hz, 0.2H), 4.74 (d, J¼17.6 Hz, 0.2H), 4.06 (d,
J¼15.5 Hz, 0.2H), 4.03 (d, J¼15.3 Hz, 0.2H), 3.89–3.59 (comp, 4H),
3.45–3.36 (comp, 0.2H), 2.88–2.65 (m, 2H); 13C NMR (100 MHz,
(comp, 4.3H), 7.15 (dd, J¼7.8, 1.2 Hz, 0.7H), 6.94 (d, J¼7.6 Hz, 1H),
6.13–5.37 (comp, 3H), 4.96 (d app t, J¼19.3, 3.1 Hz, 0.7H), 4.68 (br d,
J¼17.6 Hz, 0.3H), 4.01 (br d, J¼18.2 Hz, 0.3H), 3.84 (dm, J¼19.3 Hz,
0.7H), 2.95 (s, 2.1H), 2.94 (s, 0.9H), 2.43 (s, 0.9H), 2.43 (s, 2.1H), 2.16
(s, 0.9H), 1.84 (s, 2.1H); 13C NMR (100 MHz, CDCl3) (rotamers)
d
171.8, 170.6, 143.9, 141.2, 138.6, 137.4, 130.3, 129.9, 129.3, 128.7,
CDCl3) (rotamers) d 171.3, 171.1, 137.7, 137.3, 135.4, 135.3, 134.6,
128.6, 128.2, 127.7 (br), 127.3, 125.6, 59.0 (br), 48.7, 48.4, 21.7, 21.6,
21.5 (br); IR (neat) 2922, 1649, 1484, 1396, 1342, 1159, 1099, 714,
578, 542 cmꢂ1; mass spectrum (CIþ) m/z 371.1426 [C20H23N2O3S
(Mþ1) requires 371.1429].
134.5, 133.7, 133.5, 130.1, 129.7, 129.5, 129.4, 129.3, 129.2, 128.6,
127.5, 127.2, 127.1, 126.8, 126.6, 126.0, 118.6, 117.7, 116.7, 115.9, 60.2,
56.7, 46.9, 45.4, 41.3, 41.0, 36.7, 35.9; IR (neat) 3064, 2925, 1644,
1438,1404,1176,1027, 992, 918, 754, 725, 697 cmꢂ1; mass spectrum
(CIþ) m/z 384.0960 [C21H23NO79Br (Mþ1) requires 384.0963].
4.2.10. 4-(Allylbenzyloxycarbonylamino)-4-(2-bromophenyl)-2-
methylenebutyric acid methyl ester (26)
4.2.12. 1-[2-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-
2-phenylacetamide (29)
One drop of solution of methyl 2-(bromomethyl) acrylate
(268 mg, 180
m
L, 1.50 mmol) in THF (1 mL) was added to a mixture
A solution of 28 (1.40 g, 3.65 mmol) in CH2Cl2 (180 mL) con-
taining Grubbs II catalyst (78 mg, 0.091 mmol) was stirred at room
temperature for 24 h. The crude product was purified by flash
chromatography, eluting with 0–25% EtOAc/hexanes, to give 1.22 g
(94%) of 29 as a pale brown oil. 1H NMR (500 MHz, DMSO-d6,
of acid washed and dried zinc filings (137 mg, 2.10 mmol) and THF
(0.25 mL), and the mixture was stirred vigorously for 10 min. The
remaining solution of the bromide was then added dropwise over
10 min. In a separate flask, a solution of imine 16 (112 mg,
0.50 mmol) and benzyl chloroformate (90 mg, 75
THF (2 mL) was heated at 60 ꢁC for 1 h. The solution was then
m
L, 0.53 mmol) in
120 ꢁC) (rotamers)
(comp, 9H), 5.87 (br s, 1H), 5.77 (br m, 1H), 5.14 (br s, 2H), 4.31 (dd,
d
7.91 (br s, 1H), 7.63 (d, J¼8.4 Hz, 2H), 7.49–7.00

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6463
1H), 2.78 (br d, 1H), 2.45 (br d), 2.26 (br s, 2H); 13C NMR (126 MHz,
DMSO-d6, 120 ꢁC)
168.2, 136.3, 135.2, 128.3, 127.5, 127.4, 126.9,
126.0, 125.6, 123.5, 123.4, 120.6, 118.4, 118.1, 112.7, 108.8, 39.8, 31.6,
28.4; IR (neat) 2924, 1646, 1406, 1026, 720 cmꢂ1; mass spectrum
(CIþ) m/z 356.0651 [C19H19NO79Br (Mþ1) requires 356.0650].
for 15 h. 2-Mercaptonicotinic acid (230 mg, 1.48 mmol) was added
to aid with catalyst removal, and stirring at room temperature was
continued for 1 h.25 The mixture was then washed twice with
aqueous NaHCO3 (20 mL) and brine (20 mL) and then stirred for
0.5 h over activated charcoal (3 g). The mixture was filtered and
concentrated to ca. 10 mL. This solution was diluted to make
a w0.04 M stock solution of 33. A 10-mL portion of this solution (ca.
0.37 mmol) was added to a 40-mL CEM microwave vial and sparged
with argon for 15 min. Tetrabutylammonium chloride (139 mg,
0.50 mmol), Pd(OAc)2 (11 mg, 0.049 mmol), P(o-tol)3 (30 mg,
d
4.2.13. 1-(9-Azatricyclo[6.3.1.02,7]dodeca-2(7),3,5,10-tetraen-9-yl)-
2-phenylacetamide (30)
A microwave vial (CEM Corp., 10 mL) containing tetrabutyl-
ammonium chloride (56 mg, 0.20 mmol), [Pd(P(t-Bu)3)]2 (5.1 mg,
0.010 mmol), and amide 29 (71 mg, 0.20 mmol) was sealed and
0.10 mmol), and (i-Pr)2NEt (129 mg, 174 mL, 1.0 mmol) were added.
flushed with argon. CH3CN (4.5 mL) and (i-Pr)2NEt (52 mg, 70
m
L,
The vial was capped, flushed with argon, and heated via microwave
at 100 ꢁC for 1 h. The mixture was filtered through a plug of SiO2,
which was washed with 50% EtOAc/hexanes. The combined filtrate
and washings were concentrated, and the residue was purified by
flash chromatography, eluting with 0–25% EtOAc/hexanes, to yield
93 mg (77% from 32) of 34 as a colorless oil. 1H NMR (400 MHz,
0.40 mmol) were added, and the solution was heated via micro-
wave for 1 h at 120 ꢁC. The catalyst was removed by filtration
through a plug of silica gel, which was washed with 50% EtOAc/
hexanes. The filtrate and washings were concentrated under re-
duced pressure, and the residue was purified by flash chromato-
graphy, eluting with 0–35% EtOAc/hexanes, to give 40 mg (72%) of
azabicycle 30 as a pale yellow oil, which slowly solidified upon
storing in the freezer, mp¼117–119 ꢁC. 1H NMR (500 MHz, CDCl3)
CDCl3) (rotamers)
d 7.49–7.30, 7.20–7.07 (comp, 8H), 6.50 (d,
J¼7.9 Hz, 0.42H), 6.40 (d, J¼7.9 Hz, 0.58H), 5.58 (d, J¼4.1 Hz, 0.58H),
5.45 (d, J¼4.1 Hz, 0.42H), 5.38–5.06 (comp, 4H), 3.33 (dd, J¼10.7,
5.1 Hz, 1H), 2.32 (m, 1H), 2.10 (d, J¼10.7 Hz, 0.42H), 2.09 (d,
d
7.46–7.03 (m, 9H); rotamer 1 (major): 6.24 (dd, J¼7.9, 1.3 Hz, 0.8H),
6.03 (d, J¼3.4 Hz, 0.8H), 5.30 (ddd, J¼7.9, 6.5, 1.7 Hz, 0.8H), 3.73 (d,
J¼15.6 Hz, 0.8H), 3.68 (d, J¼15.6 Hz, 0.8H), 3.38 (dd, J¼6.5, 4.1 Hz,
0.8H), 2.38 (dddd, J¼10.7, 4.1, 4.1, 1.7 Hz, 0.8H), 2.03 (d, J¼10.7 Hz,
0.8H); rotamer 2 (minor): 6.85 (dd, J¼8.0, 1.3 Hz, 0.2H), 6.71 (d,
J¼7.3 Hz, 0.2H), 5.49 (ddd, J¼8.0, 6.6, 1.7 Hz, 0.2H), 4.07 (d,
J¼15.4 Hz, 0.2H), 4.00 (d, 15.4 Hz, 0.2H), 3.35 (dd, J¼6.6, 4.0 Hz,
0.2H), 2.30 (dddd, J¼10.6, 4.0, 4.0, 1.7 Hz, 0.2H), 2.09 (d, J¼10.6 Hz,
J¼10.7 Hz, 0.58H); 13C NMR (100 MHz, CDCl3) (rotamers)
d 152.1,
152.0, 147.24, 147.15, 140.7, 140.5, 136.1, 135.9, 132.3, 132.1, 128.8,
128.59, 128.59, 128.56, 128.4, 128.3, 128.2, 124.4, 124.0, 122.1, 121.9,
121.75, 121.72, 110.7, 109.9, 67.90, 67.85, 57.8, 57.4, 37.99, 37.94, 37.8,
37.5; IR (neat) 1702, 1399, 1336, 1250, 1112, 694 cmꢂ1; mass spec-
trum (CIþ) m/z 326.0949 [C19H17NO235Cl (Mþ1) requires 326.0948].
0.2H); 13C NMR (100 MHz, CDCl3) (rotamer 1)
d
167.5, 148.8, 139.3,
4.2.16. 5-Chloro-9-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6-triene-9-
carboxylic acid benzyl ester
134.5, 128.8, 128.6, 128.2, 126.89, 126.85, 124.3, 121.7, 120.5, 112.1,
55.6, 40.2, 38.6, 38.1; IR (neat) 2925, 1657, 1619, 1397, 1362, 1237,
1035, 756, 725, 696, 620 cmꢂ1; mass spectrum (CIþ) m/z 276.1390
[C19H18NO (Mþ1) requires 276.1388].
Triethylsilane (186 mg, 0.25 mL, 1.6 mmol) and trifluoroacetic
acid (308 mg, 0.2 mL, 2.7 mmol) were added to a solution of 34
(84 mg, 0.26 mmol) in CH2Cl2 (5 mL) at 0 ꢁC. The solution was
stirred for 2 h at 0 ꢁC and then at room temperature for 10 h. Sat-
urated aqueous NaHCO3 (5 mL) was added, and the layers were
separated. The aqueous layer was extract with CH2Cl2 (2ꢃ5 mL),
and the combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography, eluting with 0–50% EtOAc/hexanes, to yield
78 mg (91%) of product as a colorless oil. 1H NMR (400 MHz, CDCl3)
4.2.14. Allyl-[1-(2-bromo-5-chlorophenyl)-but-3-enyl]-carbamic
acid benzyl ester (32)
A
solution of allyl-(2-bromo-5-chlorobenzylidene)amine
(2.20 g, 8.51 mmol), which was prepared from allylamine and 31
according to the procedure given for the preparation of 16, in THF
(17 mL) and benzyl chloroformate (1.34 mL, 9.39 mmol) was heated
at 60 ꢁC for 1 h. The mixture was then cooled to ꢂ78 ꢁC, and a so-
lution of allylzinc bromide (ca. 13.1 mmol) in THF (10 mL) was
added.51 The cooling bath was removed, and the mixture was stirred
at room temperature for 1.5 h. Saturated aqueous NH4Cl (w4 mL)
was added, and the mixture was partitioned between water
(100 mL) and Et2O (100 mL), and the layers were separated. The
organic layer was washed with NaHCO3 (100 mL) and brine (50 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography, eluting
with 0–20% EtOAc/hexanes, to give 3.31 (89%) of 32 as a pale yellow
(rotamers)
d 7.48–7.10 (comp, 8H), 5.49 (br s, 0.55H), 5.38 (br s,
0.45H), 5.15 (m, 2H), 3.83 (br m,1H), 3.25 (br m,1H), 2.43 (br m,1H),
2.19 (br m, 1H), 1.98 (br m, 1H), 1.87 (d, J¼11.0 Hz, 1H), 1.57 (br m,
1H); 13C NMR (100 MHz, CDCl3) (rotamers)
d 154.9, 154.7 (br),144.7,
142.9 (br), 142.7 (br), 136.8 (br), 136.7, 132.6, 128.5, 127.9, 124.2,
123.8 (br), 67.1, 57.4 (br), 57.2, 43.6, 39.3, 38.5, 30.1; IR (neat) 2943,
1693, 1415, 1305, 1263, 1200, 1097, 1055, 697 cmꢂ1; mass spectrum
(CIþ) m/z 328.1106 [C19H19NO235Cl (Mþ1) requires 328.1104].
4.2.17. 5-Chloro-9-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6-triene (35)
oil. 1H NMR (400 MHz, CDCl3) (rotamers)
d
7.46 (d, J¼8.4 Hz, 1H),
TMSI (258 mg, 183 mL, 1.29 mmol) was added dropwise to
7.43–7.28 (comp, 6H), 7.12 (dd, J¼8.4, 2.4 Hz,1H), 5.75 (br s,1H), 5.60
(br m, 1H), 5.44 (app t, J¼12.8 Hz, 1H), 5.21 (d, J¼14.0 Hz, 1H), 5.20
(d, J¼14.0 Hz, 1H), 5.10 (d, J¼17.6 Hz, 1H), 5.04 (d, J¼10.4 Hz, 1H),
4.89 (d, J¼10.4 Hz, 1H), 4.87 (d, J¼17.6 Hz, 1H), 3.75 (dd, J¼16.0,
5.6 Hz,1H), 3.64 (br m,1H), 2.77 (br m,1H), 2.67 (br m,1H); 13C NMR
a stirred solution of the carbamate from the previous experiment
(211 mg, 0.644 mmol) in dry CH2Cl2 (6.4 mL) at 0 ꢁC. The solution
was stirred for 1 h, whereupon methanolic HCl (ca. 7 mmol in
2.5 mL MeOH) was added dropwise. The solution was concen-
trated and then partitioned between 1 M HCl (15 mL) and Et2O
(15 mL). The layers were separated, and the aqueous phase was
washed with Et2O (2ꢃ10 mL). The aqueous layer was then basified
to pH 10, saturated with NaCl, and extracted with EtOAc
(2ꢃ10 mL). The organic phase was dried (Na2SO4), filtered, and
concentrated to give 106 mg (85%) of amine 35 as a colorless oil.
(100 MHz, CDCl3) (rotamers)
d 155.9, 140.3, 136.7 (br), 134.5, 134.4,
134.0, 133.4, 129.6 (br), 129.3, 128.5, 128.2 (br), 128.0, 123.8, 118.1,
116.4, 67.4, 58.5, 47.0, 36.3; IR (neat) 3076, 2938, 1698, 1453, 1406,
1236, 1142, 1096, 1025, 992, 918, 814, 766, cmꢂ1; mass spectrum
(CIþ) m/z 434.0524 [C21H22NO235Cl79Br (Mþ1) requires 434.0522].
1H NMR (400 MHz, CDCl3)
d 7.23–7.16 (comp, 2H), 7.12 (d,
4.2.15. 5-Chloro-9-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6,10-tetraene-
9-carboxylic acid benzyl ester (34)
A solution of 32 (1.29 g, 2.97 mmol) in benzene (30 mL) con-
taining Grubbs II catalyst (63 mg, 0.074 mmol) was heated at 80 ꢁC
J¼7.6 Hz, 1H), 4.19 (d, J¼4.7 Hz, 1H), 2.72 (dd, J¼12.1, 5.9 Hz, 1H),
2.28 (ddd, J¼12.4, 12.4, 4.7 Hz, 1H), 2.18 (m, 1H), 1.95 (dddd,
J¼12.4, 12.4, 5.9, 2.1 Hz, 1H), 1.91 (app br d, J¼10.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 145.0, 144.7, 132.3, 127.5, 123.5, 123.3,

6464
J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
58.8, 45.3, 39.8, 39.1, 31.0; IR (neat) 2939, 2854, 1464, 1394, 1304,
(400 MHz, CDCl3) (rotamers) d 7.91 (br m, 1H), 7.64 (app d,
1077, 877, 823 cmꢂ1
;
mass spectrum (CIþ) m/z 194.0740
J¼6.8 Hz, 2H), 7.44 (s, 1H), 7.41–7.02 (m, 9H), 6.33 (d, J¼6.4 Hz,
1H), 5.87 (br s, 1H), 5.77 (br m, 1H), 5.15 (br s, 2H), 4.31 (dd,
J¼18.8, 3.2 Hz, 1H), 3.75 (d, J¼18.8 Hz, 1H), 2.79 (br d, J¼14.4 Hz,
1H), 2.45 (br d, J¼14.4 Hz), 2.29 (br s, 3H); 13C NMR (100 MHz,
[C11H13N35Cl (Mþ1) requires 194.0737].
4.2.18. 5-Chloro-9-p-tolyl-9-aza-tricyclo[6.3.1.02,7]dodeca-
2,4,6-triene (36)
CDCl3) (rotamers)
d 155.7, 145.4, 136.4, 134.6, 130.0, 128.5 (br),
A solution of 35 (24 mg, 0.12 mmol), sodium tert-butoxide
(14 mg, 0.15 mmol), Pd2dba3 (5.7 mg, 0.006 mmol), and rac-BINAP
(5.8 mg, 0.009 mmol) in anhydrous toluene (0.3 mL) was stirred at
80 ꢁC for 15 h. The solvent was evaporated under reduced pressure,
and the residue was purified by flash chromatography using
a 10 mL glass pipette packed with SiO2 (3 mL), eluting with 0–25%
EtOAc/hexanes, to yield 22 mg (62%) of 36 as a pale yellow oil. 1H
128.3, 128.0 (br), 126.9 (br), 125.6, 124.9, 124.2 (br), 113.0, 67.3,
45.0, 42.3, 29.8, 21.7; IR (neat) 1702, 1412, 1373, 1172, 1096,
1005 cmꢂ1; mass spectrum (CIþ) m/z 565.0795 [C28H26N2O4S79Br
(Mþ1) requires 565.0797].
4.2.21. Indole 39
A microwave vial (CEM corp., 10 mL) containing tetrabutyl-
ammonium chloride (36 mg, 0.13 mmol), palladium(II) acetate
(0.9 mg, 0.004 mmol), tri(o-tolyl)phosphine (2.4 mg, 0.008 mmol),
and 38 (74 mg, 0.13 mmol) was sealed and flushed with argon,
NMR (400 MHz, CDCl3)
d
7.17 (d, J¼1.8 Hz, 1H), 7.16 (br s, 1H), 7.05
(d, J¼8.4 Hz, 2H), 6.93 (m, 1H), 6.78 (dm, J¼8.4 Hz, 2H), 4.96 (d,
J¼4.6 Hz, 1H), 3.24 (m, 1H), 3.10 (dd, J¼5.6, 11.4 Hz, 1H), 2.27 (s, 3H),
2.27 (m, 1H), 2.21 (dd, J¼4.6, 11.4 Hz, 1H), 2.11 (d, J¼10.8 Hz, 1H),
whereupon CH3CN (3.3 mL) and NEt3 (39 mg, 55 mL, 0.39 mmol)
2.11 (m, 1H), 1.71 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
148.2, 144.6,
were added. The mixture was heated via microwave at 120 ꢁC for
0.5 h. The catalyst was removed by filtering through a plug of silica
gel that was washed with 50% EtOAc/hexanes. The combined fil-
trate and washings were concentrated, and the residue was puri-
fied by flash chromatography, eluting with 0–100% EtOAc/hexanes,
to give 46 mg (72%) of 39 as a colorless oil. 1H NMR (400 MHz,
142.1, 132.2, 129.8, 128.7, 127.9, 123.6, 123.5, 116.8; IR (neat) 2937,
2854, 1614, 1511, 1462, 1379, 1297, 1192, 1079, 871 cmꢂ1; mass
spectrum (CIþ) m/z 284.1208 [C18H19N35Cl (Mþ1) requires
284.1206].
4.2.19. 5-Phenyl-9-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6-triene (37)
CDCl3) (rotamers)
d
7.79 (d, J¼8.4 Hz, 1H), 7.66 (app dt, J¼10.6,
A
solution of 35 (19.4 mg, 0.10 mmol), PhB(OH)2 (24 mg,
9.4 Hz, 2H), 7.55–7.13 (m, 10H), 6.98 (d, J¼7.2 Hz, 1H), 6.79 (d,
J¼8.4 Hz, 0.45H), 6.70 (d, J¼8.2 Hz, 0.55H), 5.54 (br s, 0.55H), 5.45
(br s, 0.45H), 5.37 (d, J¼11.9 Hz, 0.45H), 5.30–5.10 (m, 2H), 5.05
(ddd, J¼8.2, 6.5, 1.8 Hz, 0.55H), 3.54 (m, 1H), 2.33 (s, 3H), 2.19 (ddd,
J¼12.5, 5.3, 3.1 Hz, 1H), 2.08 (ddd, J¼12.7, 4.3, 2.4 Hz, 0.55H), 2.01
(ddd, J¼12.5, 4.3, 2.4 Hz, 0.45H); 13C NMR (100 MHz, CDCl3)
0.20 mmol), Cs2CO3 (98 mg, 0.30 mmol), and PEPPSI catalyst
(3.4 mg, 0.005 mmol) in 1,4-dioxane (0.5 mL) was heated at 90 ꢁC
for 1.5 h. The crude mixture was filtered through Celite, the filtrated
was concentrated under reduced pressure, and the residue was
dissolved in THF (2 mL). Water (0.5 mL) and 30% aqueous NaOH
solution (two drops) were added, and the mixture was stirred at
room temperature for 6 h. Et2O (10 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O
(2ꢃ5 mL), and the combined organic layers were washed with
brine (15 mL), dried (Na2SO4), filtered, and concentrated. The resi-
due was purified by flash chromatography, eluting with 10% MeOH/
CH2Cl2 saturated with NH3, to yield 13.2 mg (56%) of 37 as a pale
(rotamers)
d 152.9, 152.6, 145.0, 144.9, 136.6, 136.5, 136.13, 136.07,
135.8, 135.6, 133.7, 133.6, 130.03, 130.00, 129.0, 128.9, 128.8, 128.7,
128.4, 128.2, 128.1, 127.9, 127.1, 126.9, 125.6, 125.5, 123.7, 123.4,
121.3, 120.8, 120.7, 120.6, 118.8, 118.7, 111.6, 111.5, 110.3, 109.6, 68.2,
67.9, 43.9, 43.7, 30.4, 30.2, 30.0, 21.7; IR (neat) 1706, 1640, 1402,
1340, 1176, 1110, 1017, 951, 746, 702, 662 cmꢂ1; mass spectrum
(CIþ) m/z 485.1532 [C28H25N2O4S (Mþ1) requires 485.1535].
orange oil. 1H NMR (400 MHz, CDCl3)
d 7.63–7.58 (comp, 2H), 7.49–
7.40 (comp, 4H), 7.33 (tt, J¼7.4 Hz, 1H), 7.26 (dm, J¼7.2 Hz, 1H), 4.27
(d, J¼4.1 Hz, 1H), 3.22 (br m, 1H), 2.73 (dd, J¼12.1, 5.9 Hz, 1H), 2.37
(td, J¼12.3, 4.7 Hz, 1H), 2.24 (m, 1H), 1.99 (tdd, J¼12.7, 6.0, 2.3 Hz,
1H), 1.95 (d, J¼10.6 Hz, 1H), 1.55 (m, 1H); mass spectrum (CIþ) m/z
236.1434 [C17H18N (Mþ1) requires 236.1436].
4.2.22. Allyl-[1-(2-bromophenyl)-pent-4-enyl]-carbamic acid
benzyl ester (40)
A solution of benzyl chloroformate (92 mg, 77 mL, 0.54 mmol)
and imine 16 (112 mg, 0.50 mmol) in dry THF (2 mL) was heated at
60 ꢁC for 1 h. The mixture was then cooled to ꢂ78 ꢁC, whereupon
a solution of butenylzinc chloride (0.8 M, 0.75 mL, 0.60 mmol)30
was added slowly. The bath was removed, and the mixture stirred
at room temperature for 2 h. Saturated aqueous NH4Cl (1 mL) was
added, and the mixture was partitioned between water (20 mL) and
Et2O (20 mL). The layers were separated, and the aqueous layer was
extracted with Et2O (10 mL). The combined organic layers were
washed with NaHCO3 solution (20 mL) and brine (20 mL), dried
(MgSO4), filtered, and concentrated. The crude product was puri-
fied by flash chromatography, eluting with 0–30% EtOAc/hexanes,
to give 146 mg (70%) of diene 40 as a colorless oil. 1H NMR
4.2.20. Benzyl 6-(4-bromo-1-tosyl-1H-indol-3-yl)-5,6-
dihydropyridine-1(2H)-carboxylate (38)
A mixture of allylamine (0.1 mL, 1.34 mmol) and aldehyde 10
(100 mg, 0.26 mmol) in THF (2 mL) containing crushed 4 Å mo-
lecular sieves (80 mg) was stirred at room temperature for 16 h.
The sieves were removed by filtration, and the solvent was re-
moved under reduced pressure. The crude imine was redissolved
in THF (1.5 mL) and cooled to ꢂ78 ꢁC, whereupon allylmagnesium
bromide (1.12 M in Et2O, 0.26 mL, 0.29 mmol) was added slowly.
The cooling bath was removed, and the solution was stirred for
1 h at room temperature, whereupon it was recooled to ꢂ78 ꢁC
(400 MHz, CDCl3)
d
7.55 (d, J¼8.0 Hz), 7.48–7.27 (m, 6H), 7.14 (app
td, J¼7.8, 1.8 Hz, 1H), 5.80 (br s, 1H), 5.56 (br m, 1H), 5.42 (br m, 1H),
and benzyl chloroformate (97%, 56
m
L, 0.38 mmol) added drop-
5.20 (br s, 2H), 4.96 (br m, 2H), 4.84 (br m, 2H), 3.61 (br s, 2H), 2.08
wise. The cooling bath was removed, and the mixture was stirred
for 1 h. Saturated NaHCO3 (2 mL) was added, and the mixture was
partitioned between water (20 mL) and Et2O (20 mL). The layers
were separated, and the organic layer was washed with 1 M HCl
(20 mL) and brine (20 mL). The organic phase was dried (MgSO4),
filtered, and concentrated. The crude carbamate was then dis-
solved in CH2Cl2 (25 mL) containing 6 mol % of Grubbs II catalyst,
and the solution was stirred for 17 h. The solvent was removed by
flash chromatography, eluting with 5–20% EtOAc/hexanes, to give
140 mg (95% from 10) of 38 as a pale yellow oil. 1H NMR
(br m, 4H); 13C NMR (100 MHz, CDCl3)
d (rotamer 1) 156.2, 138.5,
137.7, 134.8, 133.6, 129.3, 128.5, 128.0 (br), 127.3, 126.4, 116.2, 115.2,
67.4, 58.7 (br), 46.7, 31.5, 30.7; IR (neat) 2937, 1698, 1406,1248,1137,
914, 753, 697 cmꢂ1
;
mass spectrum (ESIþ) m/z 414.1063
[C22H25NO279Br (Mþ1) requires 414.1071].
4.2.23. 2-(2-Bromophenyl)-2,3,4,7-tetrahydroazepine-1-
carboxylic acid benzyl ester (41)
A solution of 40 (100 mg, 0.24 mmol) in CH2Cl2 (12 mL) con-
taining Grubbs II catalyst (20 mg, 0.024 mmol) was stirred at room

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6465
temperature for 24 h. The solvent was evaporated under reduced
pressure, and the crude product was purified by flash chromato-
graphy, eluting with 0–25% EtOAc/hexanes, to give 86 mg (92%) of
chromatography, eluting with 40% EtOAc/hexanes, to give 189 mg
(82%) of amide 45 as a viscous colorless oil. 1H NMR (500 MHz,
DMSO, 100 ꢁC)
d
7.62 (d, J¼7.9 Hz, 1H), 7.6 (d, J¼7.2 Hz, 1H), 7.52 (t,
41 as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.53 (m, 1H), 7.38–
J¼7.5 Hz, 1H), 7.38 (t, J¼7.5 Hz, 1H), 6.00 (br, 1H), 5.73 (dddd, J¼17.0,
10.2, 6.7, 6.7 Hz, 1H), 5.51–5.43 (m, 1H), 5.09 (d, J¼17.2 Hz, 1H), 5.00
(d, J¼10.2 Hz, 1H), 4.88 (comp, 2H), 3.80 (s, 3H), 3.82–3.68 (comp,
2H), 2.79–2.69 (comp, 2H), 2.00 (s, 3H); 13C NMR (125 MHz, DMSO,
7.16 (comp, 6H), 7.10 (m, 1H), 6.97 (m, 1H), 5.51 (dd, J¼12.3, 3.8 Hz,
0.4H), 5.39 (dd, J¼12.3, 3.8 Hz, 0.6H), 5.15 (d, J¼12.3 Hz, 0.4H), 5.11
(d, J¼12.7 Hz, 0.4H), 5.05 (d, J¼13.0 Hz, 0.6H), 5.00 (d, J¼12.7 Hz,
0.6H), 4.70 (dd, J¼16.7, 7.2 Hz), 4.50 (dd, J¼16.8, 6.2 Hz, 0.4H), 4.18
(m, 1H), 2.55–2.20 (comp, 3H), 2.08 (m, 1H); 13C NMR (100 MHz,
130 ꢁC)
d 169.3, 167.6, 138.1, 134.7, 134.5, 132.0, 130.2, 128.4, 127.7,
126.7, 116.3, 114.9, 54.0, 51.3, 45.8, 35.3, 21.1; IR (neat) 1722, 1649,
1405, 1270, 918, 749 cmꢂ1; mass spectrum (CI) m/z 288.1601
[C17H22NO3 (Mþ1) requires 288.1600].
CDCl3)
d 156.2, 143.4, 142.7, 137.0, 136.6, 133.5, 133.2, 131.8, 131.5,
128.6, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6, 127.1, 127.0, 125.7 (br),
122.9,122.4, 67.3, 67.1, 61.6, 41.7, 31.4, 31.1, 29.9, 29.4; IR (neat) 2937,
1702, 1411, 1242, 1208, 1112, 748 cmꢂ1; mass spectrum (CIþ) m/z
386.0753 [C20H21NO279Br (Mþ1) requires 386.0756].
4.2.26. Methyl 2-(1-acetyl-1,2,3,6-tetrahydropyridin-2-yl)-
benzoate (46)
Grubbs II catalyst (4 mg, 0.0053 mmol) was added to a solution
of 45 (152 mg, 0.53 mmol) in CH2Cl2 (20 mL), and the solution was
heated under reflux for 3 h. The mixture was cooled to room
temperature and concentrated under reduced pressure. The residue
was purified by flash chromatography, eluting with 50% EtOAc/
4.2.24. 12-Azatricyclo[6.3.2.02,7]trideca-2(7),3,5,9-tetraene-12-
carboxylic acid benzyl ester (42) and 12-azatricyclo-
[6.3.2.02,7]trideca-2(7),3,5,9-tetraene-12-carboxylic
acid benzyl ester (43)
A microwave vial (CEM Corp., 10 mL) containing tetrabutyl-
ammonium chloride (76 mg, 0.27 mmol), [Pd(P(t-Bu)3)]2 (6.9 mg,
0.014 mmol), and 41 (104 mg, 0.27 mmol) was sealed and flushed
with argon, whereupon CH3CN (4.5 mL) and (i-Pr)2NEt (70 mg,
hexanes, to give 129 mg (94%) of amide 46 as a tan solid, mp 104–
1
106 ꢁC. H NMR (500 MHz, DMSO, 130 ꢁC)
d
7.70 (d, J¼7.6, 1.4 Hz,
1H), 7.46 (t, J¼7.6 Hz), 7.33 (t, J¼7.6 Hz, 1H), 7.25 (d, J¼7.6 Hz, 1H),
6.11 (br, 1H), 5.85 (ddd, J¼6.2, 3.1, 3.1 Hz, 1H), 5.81–5.77 (m, 1H),
4.23 (dd, J¼18.4, 2.3 Hz, 1H), 3.86 (s, 3H), 3.82 (d, J¼18.4 Hz, 1H),
2.74–2.68 (m, 1H), 2.34 (dd, J¼17.5, 6.2 Hz, 1H), 1.97 (m, 3H); 13C
95 mL, 0.54 mmol) were added. The mixture was heated via mi-
crowave for 1 h at 120 ꢁC. The catalyst was removed by filtering
through a plug of silica gel, which was washed with 50% EtOAc/
hexanes (20 mL). The combined filtrate and washings were con-
centrated, and the residue was purified by flash chromatography,
eluting with 0–25% EtOAc/hexanes, to give 43 (14 mg, 17%) and 42
(47 mg, 57%) as colorless oils. Compound 42: 1H NMR (400 MHz,
NMR (125 MHz, DMSO, 130 ꢁC)
d 168.8, 167.2, 142.8, 130.5, 129.1,
128.9, 130.2, 126.1, 126.0, 123.8, 122.5, 51.2, 48.2, 41.4, 29.1, 20.7; IR
(neat) 1722, 1649, 1405, 1270, 918, 749 cmꢂ1; mass spectrum (CI)
m/z 260.1291 [C15H18NO3 (Mþ1) requires 260.1287].
CDCl3) (rotamers)
d
7.43–7.14 (comp, 8H), 7.10 (m, 1H), 6.07 (m, 1H),
4.2.27. 1,12b-Dihydrobenzo[c]pyrido[1,2-a]azepine-6,8(4H,7H)-
dione (47)
5.41–5.10 (comp, 4H), 4.11 (dd, J¼11.2, 2.0 Hz, 0.4H), 4.06 (dd,
J¼11.0, 2.0 Hz, 0.6H), 3.43 (m, 1H), 3.38 (dm, J¼8.4 Hz, 0.4H), 3.31
(dm, J¼8.4 Hz, 0.6H), 2.88 (dm, J¼18.6 Hz, 0.6H), 2.78 (dm,
J¼18.4 Hz, 0.4H), 2.28 (m, 1H); 13C NMR (100 MHz) (rotamers)
NaHMDS (1.85 M in THF, 0.93 mL, 1.72 mmol) was added to
a solution of 46 (179 mg, 0.69 mmol) in THF (30 mL), and the so-
lution was stirred for 2 h at room temperature. Saturated aqueous
NH4Cl (10 mL) was then added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2ꢃ5 mL). The organics
were combined and dried (MgSO4), filtered, and concentrated un-
der reduced pressure. The residue was purified by flash chroma-
tography, eluting with 50% EtOAc/hexanes, to give 106 mg (67%) of
amide 47 as a tan solid, mp 151.5–153 ꢁC. 1H NMR (400 MHz, CDCl3)
d
155.9, 155.6, 142.8, 142.6, 137.6, 137.4, 137.01, 136.97, 130.2, 130.0,
129.0, 128.7, 128.60, 128.56, 128.1, 128.1, 128.0, 127.9, 127.7, 127.59,
127.57, 127.1, 126.9, 126.8, 125.9, 125.7, 124.3, 124.1, 67.3, 67.1, 55.0,
54.8, 52.0, 51.2, 38.05, 38.02, 36.8, 36.2; IR (neat) 3025, 2881,
1697, 1411, 1331, 1219, 1115, 1094, 753, 697 cmꢂ1; mass spectrum
(CIþ) m/z 306.1489 [C20H20NO2 (Mþ1) requires 306.1494]. Com-
pound 43: 1H NMR (400 MHz, CDCl3)
d
7.44–7.14 (comp, 8H), 7.09
d
7.95 (dd, J¼7.7,1.4Hz,1H), 7.50 (td, J¼7.7,1.4 Hz,1H), 7.38 (td, J¼7.7,
(m, 1H), 6.51 (d, J¼9.2 Hz, 0.3H), 6.43 (d, J¼9.2 Hz, 0.7H), 5.61 (d,
J¼6.1 Hz, 0.7H), 5.45 (d, J¼6.3 Hz, 0.3H), 5.28–5.04 (comp, 3H), 3.09
(m, 1H), 2.45 (m, 1H), 2.09 (m, 1H), 1.85 (m, 1H); 13C NMR (100 MHz,
1.1 Hz, 1H), 7.28 (d, J¼7.7 Hz, 1H), 6.15–6.11 (m, 1H), 5.84 (ddd,
J¼6.3, 3.1, 3.1 Hz, 1H), 5.69 (d, J¼5.6 Hz, 1H), 4.43 (d, J¼17.3 Hz, 1H),
4.19–4.12 (m, 1H), 3.79 (d, J¼17.3 Hz, 1H), 3.55–3.47 (m, 1H), 2.95–
2.86 (m, 1H), 2.82 (dd, J¼17.4, 5.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 153.3, 145.3, 136.2, 135.1, 128.8, 128.6, 128.3, 128.2, 128.1,
127.4, 127.0, 126.9, 126.8, 125.4, 124.7, 124.5, 124.3, 112.1, 111.3, 68.0,
53.9, 53.7, 36.8, 36.7, 30.8, 30.6, 27.6; IR (neat) 1702, 1388, 1321,
1272, 1221, 1006, 754, 697 cmꢂ1; mass spectrum (CIþ) m/z 306.1495
[C20H20NO2 (Mþ1) requires 306.1494].
CDCl3) d 192.1, 169.8, 142.2, 136.5, 134.1, 131.3, 129.2, 126.0, 124.5,
122.6, 54.7, 51.6, 41.6, 26.0; IR (neat) 2906, 2853, 1681, 1650, 1409,
1248, 1137, 923 cmꢂ1; mass spectrum (CI) m/z 228.1027 [C14H14NO2
(Mþ1) requires 228.1025].
4.2.25. Methyl 2-(1-(N-allylacetamido)but-3-enyl)benzoate (45)
A mixture containing freshly distilled methyl formyl benzoate
(44)31 (135 mg, 0.83 mmol), allylamine (0.06 mL, 46 mg,
0.80 mmol), and activated 4 Å molecular sieves (w500 mg) in
CH2Cl2 (2.6 mL) was stirred for 12 h. Freshly distilled acetyl chloride
(0.06 mL, 66 mg, 0.84 mmol) was added and the solution was
stirred for 1 h. The solution was then cooled to ꢂ78 ꢁC, freshly
prepared allylzinc bromide (2.1 M in THF, 0.5 mL, 1.05 mmol) was
added, and the mixture was stirred for 1.5 h. The dry ice bath was
removed, and the mixture was filtered through a Celite pad that
was washed with CH2Cl2 (3ꢃ5 mL). The combined filtrate and
washings were washed with saturated aqueous NH4Cl (10 mL). The
aqueous layer was backwashed with CH2Cl2 (2ꢃ5 mL), and the
combined organics were dried (MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash
4.2.28. Methyl 3-(N-allylacetamido)-2,2-dimethyl-3-
(2-vinylphenyl)propanoate (50)
TMSOTf (23.0 mL, 28 mg, 0.13 mmol) was added to a solution of
2-vinylbenzaldehyde32 (172 mg, 1.30 mmol) and bis(trimethylsilyl)-
allylamine (0.33 mL, 269 mg,1.34 mmol) in CH2Cl2 (3.2 mL), and the
solution was stirred for 30 min at room temperature. Silyl ketene
acetal 49 (0.53 mL, 455 mg, 2.60 mmol) and freshly distilled acetyl
chloride (0.11 mL, 121 mg, 1.55 mmol) were added, and the solution
was stirred for 19 h at room temperature. The mixture was parti-
tioned between CH2Cl2 (5 mL) and saturated aqueous NaHCO3
(5 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2ꢃ5 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with 25%
EtOAc/hexanes, to give 328 mg (80%) of amide 50 as a viscous

6466
J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
yellowish oil. 1H NMR (400 MHz, CDCl3)
d
7.47 (d, J¼7.5 Hz,1H), 7.38
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography, elut-
(d, J¼7.9 Hz, 1H), 7.26 (t, J¼7.5 Hz, 1H), 7.20 (dt, J¼7.9, 1.5 Hz, 1H),
7.04 (dd, J¼17.1,10.9 Hz,1H), 6.36 (s, 1H), 5.57 (dd, J¼17.1,1.7 Hz,1H),
5.32 (dd, J¼10.9, 1.7 Hz, 1H), 5.07–4.98 (m, 1H), 4.80 (dd, J¼7.5,
1.4 Hz, 1H), 4.77 (dd, J¼14.2, 1.4 Hz, 1H), 3.78–3.79 (comp, 2H), 3.57
(s, 3H), 2.11 (s, 3H), 1.45 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz,
ing with 25% EtOAc/hexanes, to give 158 mg (63%) of amide 53 as
a viscous colorless oil. 1H NMR (500 MHz, DMSO, 120 ꢁC)
d 7.67 (d,
J¼8.0 Hz, 1H), 7.65 (d, J¼9.9 Hz, 1H), 7.55 (t, J¼7.6 Hz, 1H), 7.39 (t,
J¼7.6 Hz, 1H), 6.02 (t, J¼7.3 Hz, 1H), 5.77 (dddd, J¼17.1, 10.4, 6.7,
6.7 Hz, 1H), 5.12 (d, J¼17.1 Hz, 1H), 5.02 (d, J¼10.2 Hz, 1H), 4.03 (d,
J¼18.4 Hz,1H), 3.80 (s, 3H), 3.80–3.78 (comp, 1H), 2.82–2.79 (comp,
CDCl3)
d 178.3, 173.1, 140.4, 136.2, 136.1, 135.4, 128.8, 128.5, 128.2,
127.8, 117.6, 117.1, 58.9, 52.8, 50.6, 48.5, 27.5, 24.9, 23.5; IR (neat)
2981, 1729, 1651, 1456, 1396, 1252, 1147, 918, 779 cmꢂ1; mass
spectrum (CI) m/z 316.1912 [C19H25NO3 (Mþ1) requires 316.1913].
3H), 2.08 (s, 3H); 13C NMR (125 MHz, DMSO, 120 ꢁC)
d 169.2, 167.4,
138.0, 134.3, 131.5, 130.5, 128.8, 127.6, 126.9, 116.5, 80.1, 72.5, 54.3,
51.4, 35.2, 32.4, 21.2; IR (neat) 1721, 1654, 1406, 1269, 913,
747 cmꢂ1; mass spectrum (CI) m/z 286.1448 [C17H20NO3 (Mþ1)
requires 286.1443].
4.2.29. 1-Allyl-5,5-dimethyl-6-(2-vinylphenyl)piperidine-
2,4-dione (51)
NaHMDS (540 mg, 2.95 mmol) was added to a solution of 50
(308 mg, 0.98 mmol) in THF (38 mL), and the solution was stirred
for 2 h at room temperature. Saturated NH4Cl (15 mL) and H2O
(15 mL) were then added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2ꢃ10 mL). The com-
bined organic layers were washed with saturated aqueous NaCl
(20 mL), dried (MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography, eluting with 30% EtOAc/
hexanes, to give 240 mg (87%) of 51 as a light brownish solid. 1H
4.2.32. (E)-3-Styryl-1,12b-dihydrobenzo[c]pyrido[1,2-a]azepine-
6,8(4H,7H)-dione (54)
The Hoveyda–Grubbs II catalyst (0.012 g, 0.018 mmol) was
added to a solution of amide 53 (0.077 mg, 0.26 mmol) and
freshly distilled styrene (0.46 mL, 42 mg, 4.01 mmol) in CH2Cl2
(11 mL) and the mixture was heated under reflux for 24 h. The
mixture was cooled to room temperature and DMSO (0.25 mL)
was added.52 The mixture was stirred for 20 h and then concen-
trated under reduced pressure. The residue was quickly purified
by flash chromatography, eluting with 50% EtOAc/hexanes, to give
a brownish oil, which was immediately dissolved in THF (11 mL).
NaHMDS (2 M in THF, 0.26 mL, 0.52 mmol) was added, and the
mixture was stirred for 5 min, whereupon saturated aqueous
NH4Cl (5 mL) was added. The organic phase was removed, and the
aqueous layer was washed with Et2O (2ꢃ5 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography, eluting with 30% EtOAc/hexanes, to give 52 mg (58%)
of amide 54 as a solid, contaminated with approximately 3% of the
NMR (400 MHz, CDCl3)
d
7.43 (dd, J¼7.5, 1.7 Hz, 1H), 7.29–7.21
(comp, 2H), 6.99 (dd, J¼17.1, 10.9 Hz, 1H), 6.74 (dd, J¼7.7, 1.2 Hz,
1H), (dddd, J¼17.1, 9.9, 8.9, 4.4 Hz, 1H), 5.64 (dd, J¼17.1, 1.0 Hz, 1H),
5.42 (dd, J¼10.9, 1.4 Hz, 1H), 5.28 (d, J¼9.9 Hz, 1H), 5.23 (d,
J¼17.1 Hz, 1H), 4.80 (ddt, J¼14.7, 4.4, 1.7 Hz, 1H), 4.74 (s, 1H), 3.63
(d, J¼21.2 Hz, 1H), 3.5 (d, J¼21.2 Hz, 1H), 2.96 (dd, J¼14.7, 8.9 Hz,
1H), 1.42 (s, 3H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 207.3,
166.9, 139.2, 135.9, 135.1, 133.3, 129.7, 129.5, 128.1, 125.8, 120.6,
119.5, 64.2, 50.7, 48.5, 45.4, 26.6, 20.3; IR (neat) 2979, 1723, 1650,
1463, 1282, 931, 755 cmꢂ1; mass spectrum (CI) m/z 284.1658
[C18H21NO2 (Mþ1) requires 284.1651].
terminal vinyl derivative. 1H NMR (400 MHz, CDCl3)
d 7.99 (dd,
4.2.30. 1,1-Dimethyl-1,12b-dihydrobenzo[c]pyrido[1,2-a]azepine-
2,4(3H,6H)-dione (52)
J¼7.9, 1.0 Hz, 1H), 7.49 (td, J¼7.5, 1.4 Hz, 1H), 7.41–7.20 (comp, 7H),
6.79 (d, J¼16.4 Hz, 1H), 6.49 (d, J¼16.4 Hz, 1H), 6.24 (m, 1H), 5.72
(d, J¼6.2 Hz, 1H), 4.46 (d, J¼17.4 Hz, 1H), 4.43 (d, J¼18.1 Hz, 1H),
3.88 (d, J¼17.4 Hz, 1H), 3.84 (d, J¼18.1 Hz, 1H), 3.11–3.06 (m, 1H),
Grubbs II catalyst (4 mg, 0.0053 mmol) was added to a solution
of 51 (76 mg, 0.27 mmol) in CH2Cl2 (10 mL), and the mixture was
heated under reflux for 22 h. The mixture was then cooled to room
temperature and concentrated under reduced pressure. The residue
was purified by flash chromatography, eluting with 40% EtOAc/
hexanes, to give 55 mg (80%) of 52 as a brownish solid. 1H NMR
2.98 (dd, J¼18.3, 5.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 192.0,
169.9, 142.0, 137.8, 136.6, 134.3, 133.4, 131.4, 129.6, 129.4, 128.6,
128.5, 128.1, 127.2, 126.0, 123.8, 55.0, 51.8, 41.4, 26.9; IR (neat)
2358, 1680, 1641, 1596, 1410, 1247, 957 cmꢂ1; mass spectrum (CI)
m/z 330.1492 [C22H20NO2 (Mþ1) requires 330.1494].
(400 MHz, CDCl3)
d
7.29–7.24 (comp, 2H), 7.15 (dt, J¼8.2, 4.2 Hz, 1H)
6.97 (d, J¼7.9 Hz, 1H), 6.60 (d, J¼12.3 Hz, 1H), 5.95 (dt, J¼12.3,
3.4 Hz, 1H), 5.30 (d, J¼19.2 Hz, 1H), 4.57 (s, 1H), 3.85 (d, J¼19.2 Hz,
1H), 3.32 (d, J¼20.5 Hz, 1H), 3.17 (d, J¼20.5 Hz, 1H), 1.45 (s, 3H), 1.30
4.2.33. N-Allyl-N-(1-(2-bromophenyl)-2-formylethyl)-
acetamide (56)
(s, 3H); 13C NMR (100 MHz, CDCl3)
d
209.4, 166.6, 137.4, 136.1, 132.2,
TMSOTf (15.5 mL, 19 mg, 0.086 mmol) was added to a solution of
130.3, 129.9, 128.8, 127.6, 125.3, 65.2, 49.2, 47.8, 47.0, 26.2, 21.5; IR
(neat) 3426, 2974, 2244, 1722, 1660, 1462, 1376, 1310, 1269,1181,
952, 734 cmꢂ1; mass spectrum (CI) m/z 256.1328 [C16H17NO2
(Mþ1) requires 256.1337].
2-bromobenzaldehyde (0.1 mL, 158 mg, 0.86 mmol) and bis-
(trimethylsilyl)allylamine (0.22 mL, 179 mg, 0.89 mmol) in CH2Cl2
(2.2 mL), and the solution was stirred for 1 h at room temperature.
The solution was cooled to 0 ꢁC and silyl enol ether 5536 (420 mg,
2.66 mmol) and freshly distilled acetyl chloride (0.07 mL, 77 mg,
0.98 mmol) were then added, and the solution was stirred for
10 min. The ice bath was removed and the solution was stirred
for 40 h at room temperature. The mixture was concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy, eluting with 50% EtOAc/hexanes, to give 207 mg (77%) of amide
56 as a brownish solid, mp¼56–58 ꢁC. 1H NMR (500 MHz, DMSO,
4.2.31. Methyl 2-(1-(N-(prop-2-ynyl)acetamido)but-3-
enyl)benzoate (53)
A mixture containing freshly distilled methyl formyl benzoate
(44) (146 mg, 0.89 mmol), propargyl amine (0.06 mL, 48 mg,
0.87 mmol), and activated 4 Å molecular sieves (w500 mg) in
CH2Cl2 (2.2 mL) was stirred for 12 h. Freshly distilled acetyl chloride
(65
mL, 72 mg, 0.91 mmol) was added, and the solution was stirred
100 ꢁC)
d
9.66 (s, 1H), 7.64 (d, J¼7.8 Hz, 1H), 7.54 (d, J¼7.8 Hz, 1H),
for 1 h. The solution was then cooled to ꢂ78 ꢁC, freshly prepared
allylzinc bromide (2.2 M in THF, 0.46 mL, 1.01 mmol) was added,
and the mixture was stirred for 1 h. The dry ice bath was removed,
and the mixture was filtered through a Celite pad that was washed
with CH2Cl2 (3ꢃ5 mL). The combined filtrate and washings were
washed with saturated aqueous NH4Cl (10 mL). The aqueous layer
was backwashed with CH2Cl2 (2ꢃ5 mL), and the combined organics
7.40 (t, J¼7.8 Hz, 1H), 7.26 (t, J¼7.8 Hz, 1H), 6.02 (br, 1H), 5.52–5.45
(m,1H), 4.94–4.92 (comp, 2H), 3.81 (dd, J¼17.2, 5.2 Hz, 2H), 3.73 (dd,
J¼17.2, 5.7 Hz), 3.24–3.19 (m, 1H), 3.10 (dd, J¼16.4, 7.6 Hz, 1H), 2.08
(s, 3H); 13C NMR (125 MHz, DMSO,130 ꢁC)
d 199.2,169.3,137.1,134.0,
132.5, 129.2, 129.0, 127.0, 124.0, 115.3, 52.7, 46.2, 44.9, 21.0; IR (neat)
1720, 1645, 1405, 1024, 913, 749 cmꢂ1; mass spectrum (CI) m/z
310.0446 [C14H1679BrNO2 (Mþ1) requires 310.0443], 312.0426.

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6467
4.2.34. 1-(Hexahydro-6-(2-bromophenyl)-1-methyl-1H-
4.2.37. 2-Allyl-3-(2-bromophenyl)-2,3,4,4a,8,8a-
pyrrolo[3,2-c]pyridin-5(6H)-yl)ethanone (57)
hexahydroisoquinolin-1(7H)-one (66)
Sarcosine (84 mg, 0.95 mmol) was added to a solution of 56
(166 mg, 0.54 mmol) in toluene (1 mL). The solution was heated
under reflux for 3 h. The solution was cooled to room temperature
and then was partitioned between water (5 mL) and CH2Cl2
(5 mL). The organic layer was removed and the aqueous layer was
washed with CH2Cl2 (2ꢃ5 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with
25% MeOH/EtOAc, to give 118 mg (65%) of 57 as a brownish gum.
TMSOTf (15.5 mL, 19 mg, 0.086 mmol) was added to a solution of
2-bromobenzaldehyde (0.1 mL, 158 mg, 0.86 mmol) and bis-
(trimethylsilyl)allylamine (0.22 mL, 179 mg, 0.89 mmol) in CH2Cl2
(2.2 mL), and the solution was stirred for 30 min at room temper-
ature. Pentadienyl TMS 6342 (303 mg, 2.16 mmol) and freshly dis-
tilled acryloyl chloride (85 mL, 94 mg, 1.05 mmol) were then added,
and the solution stirred for 22 h. The mixture was partitioned be-
tween CH2Cl2 (5 mL) and saturated aqueous NaHCO3 (5 mL). The
organic phase was removed, and the aqueous layer was washed
with CH2Cl2 (3ꢃ4 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography, eluting with 15%
EtOAc/hexanes, to give 251 mg (84%) of amide 66 as a colorless oil.
1H NMR (500 MHz, DMSO, 130 ꢁC)
d
7.54 (d, J¼7.9 Hz, 1H), 7.33–
7.27 (comp, 2H), 7.14 (t, J¼7.0 Hz, 1H), 4.97 (dd, J¼12.8, 4.8 Hz, 1H),
4.20 (br, 1H), 3.14 (br, 1H), 2.88–2.84 (m, 1H), 2.50–2.47 (m, 1H),
2.38 (br, 1H), 2.30 (s, 3H), 2.27–2.23 (comp, 2H), 1.94–1.84 (comp,
13
4H), 1.51–1.38 (comp, 2H); C NMR (125 MHz, DMSO, 130 ꢁC)
1H NMR (500 MHz, CDCl3)
d
7.51 (d, J¼7.6 Hz, 1H), 7.29 (t, J¼7.6 Hz,
d
168.4, 143.1, 131.9, 127.5, 127.5, 125.8, 120.2, 61.0, 54.2, 37.9, 32.6,
1H), 7.16 (d, J¼7.6 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 5.74–5.66 (comp,
2H), 5.55–5.52 (m, 1H), 5.08 (d, J¼10.0 Hz, 1H), 4.97 (dd, J¼10.1,
5.4 Hz, 1H), 4.87 (d, J¼17.2 Hz, 1H), 4.66 (dd, J¼14.8, 4.2 Hz, 1H),
2.94 (dd, J¼14.8, 7.7 Hz, 1H), 2.7 (d, J¼10.9 Hz, 1H), 2.56–2.55 (m,
1H), 2.21–2.08 (comp, 4H), 1.85–1.77 (m, 1H), 1.64–1.56 (m, 1H); 13C
27.3, 20.8, 19.9; IR (neat) 1648, 1413, 1243, 1023, 757 cmꢂ1; mass
spectrum (CI) m/z 337.0912 [C16H2179BrN2O (Mþ1) requires
337.0915], 339.0902.
4.2.35. 1-((3aR,6S,7aS)-6-(2-Bromophenyl)-tetrahydro-1-
NMR (125 MHz, CDCl3) d 174.9, 141.2, 133.8, 133.0, 129.7, 129.2,
methylisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)ethanone (58)
128.9, 128.8, 128.8, 123.5, 118.9, 60.4, 47.6, 42.0, 35.5, 32.6, 25.9,
23.6; IR (neat) 2933, 1651, 1568, 1410, 1338, 1283, 1188, 1024, 925,
760 cmꢂ1; mass spectrum (CI) m/z 346.0799 [C18H2079BrNO (Mþ1)
requires 346.0807], 348.0784.
N-Methyl hydroxylamine hydrochloride (70 mg, 0.84 mmol)
and Et3N (0.24 mL, 174 mg, 1.72 mmol) were added to a solution of
55 (166 mg, 0.54 mmol) in toluene (10 mL). The mixture was
heated under reflux for 5 h. The mixture was cooled to room
temperature and then concentrated under reduced pressure. The
residue was then partitioned between water (5 mL) and CH2Cl2
(5 mL). The organic phase was removed, and the aqueous layer
was washed with CH2Cl2 (3ꢃ5 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography,
eluting with EtOAc, to give 158 mg (87%) of amide 58 as a pale
4.2.38. 2-Allyl-2,3,4,4a,8,8a-hexahydro-3-(3,4-dimethoxy-
phenyl)isoquinolin-1(7H)-one (67)
TMSOTf (12 mL, 55 mg, 0.066 mmol) was added to a solution of
3,4-dimethoxybenzaldehyde (62) (111 mg, 0.67 mmol) and bis-
(trimethylsilyl)allylamine (0.17 mL, 139 mg, 0.69 mmol) in CH2Cl2
(1.7 mL), and the solution was stirred for 30 min at room temper-
ature. Freshly distilled acryloyl chloride (65 mL, 72 mg, 0.80 mmol)
orange gum. 1H NMR (500 MHz, DMSO, 130 ꢁC)
d
7.55 (d, J¼7.9 Hz,
and pentadienylsilane 63 (214 mg, 1.53 mmol) were then added,
and the mixture was stirred for 24 h at room temperature. The
mixture was partitioned between CH2Cl2 (5 mL) and saturated
aqueous NaHCO3 (5 mL). The organic phase was removed, and the
aqueous layer was extracted with CH2Cl2 (2ꢃ5 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated un-
der reduced pressure. The residue was purified by flash chroma-
tography, eluting with 40% EtOAc/hexanes, to give 172 mg (78%) of
amide 67 (6:1 inseparable mixture of diastereomers) as a viscous
1H), 7.34 (t, J¼7.1 Hz, 1H), 7.28 (d, J¼7.1 Hz, 1H), 7.16 (t, J¼7.3 Hz,
1H), 5.04 (dd, J¼12.9, 5.0 Hz, 1H), 4.10 (br s, 1H), 4.04 (t, J¼8.3 Hz,
1H), 3.46 (dd, J¼8.7, 5.0 Hz, 1H), 3.26 (br s, 1H), 3.06–3.00 (m, 1H),
2.95 (s, 1H) 2.58 (s, 3H), 2.20 (dt, J¼13.7, 5.2 Hz, 1H), 1.86 (s, 3H),
1.59 (q, J¼12.7 Hz, 1H); 13C NMR (100 MHz, CDCl3, mixture of
rotamers, major rotamer reported)
d 172.2, 143.1, 134.0, 130.0,
129.6, 127.0, 122.0, 69.1, 65.3, 57.1, 44.5, 43.4, 40.3, 33.8, 22.6; IR
(neat) 1651, 1417, 1361, 1253, 1026, 998, 967, 917, 757, 726,
642 cmꢂ1; mass spectrum (CI) m/z 339.0705 [C15H1979BrN2O2
(Mþ1) requires 339.0708] 341.0692.
colorless oil. 1H NMR (400 MHz, CDCl3, major diastereomer)
d 6.82
(d, J¼8.2 Hz, 1H), 6.74 (dd, J¼8.2, 2.0 Hz, 1H), 6.66 (d, J¼1.7 Hz, 1H),
5.78–5.65 (comp, 2H), 5.58–5.54 (m, 1H), 5.08 (dd, J¼10.2, 1.0 Hz,
1H), 4.89 (dd, J¼17.1, 1.0 Hz, 1H), 4.62 (dd, J¼15.0, 4.4 Hz, 1H), 4.42
(dd, J¼10.9, 4.8 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.07 (dd, J¼15.0,
1.0 Hz, 1H), 2.72–2.68 (m, 1H), 2.58–2.52 (m, 1H), 2.24–2.14 (comp,
3H), 2.12–2.04 (comp, 2H), 1.89–1.74 (comp, 2H); 13C NMR
4.2.36. 14,14a-Dihydrobenzo[f]pyrido[1,2-d][1,2,3]triazolo[1,5-
a][1,4]diazepine-11,13(9H,12H)-dione (61)
A
mixture containing propargyl amine (0.06 mL, 48 mg,
0.87 mmol), 2-azidobenzaldehyde39 (116 mg, 0.79 mmol), and ac-
tivated 4 Å molecular sieves (w500 mg) in CH3CN (2 mL) was
stirred for 12 h. Freshly distilled acetyl chloride (0.07 mL, 77 mg,
0.98 mmol) and silyl ketene acetal 11 (286 mg, 2.01 mg) were
added, and the mixture was stirred for 28 h. The mixture was then
filtered through Celite washing with CH2Cl2 (3ꢃ5 mL), and the
combined washings were concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with
EtOAc, to give 181 mg (76%) of triazole 61 as a viscous colorless oil.
(100 MHz, CDCl3, major diastereomer)
d 174.2, 149.5, 148.8, 134.2,
133.2, 128.7, 128.1, 119.6, 117.3, 111.3, 109.8, 61.3, 56.1, 56.1, 46.5, 41.5,
37.1, 32.3, 25.5, 23.3; IR (neat) 2934, 1634, 1516, 1442, 1410, 1262,
1138, 1027, 928; mass spectrum (CI) m/z 328.1913 [C20H26NO3
(Mþ1) requires 328.1913].
4.2.39. Epoxy isoindolone 71
TMSOTf (21 mL, 26 mg, 0.12 mmol) was added to a solution of
1H NMR (500 MHz, DMSO, 130 ꢁC)
d
7.94 (d, J¼7.9 Hz, 1H), 7.91 (s,
furfural (0.1 mL, 116 mg, 1.21 mmol) and bis(trimethylsilyl)allyl-
amine (0.31 mL, 253 mg, 1.26 mmol) in CH2Cl2 (3.0 mL), and the
solution was stirred for 30 min. Freshly distilled acetyl chloride
(0.12 mL, 132 mg, 1.48 mmol) and silyl enol ether 55 (411 mg,
2.60 mmol) were added, and the mixture was stirred for 6 h. The
mixture was then partitioned between CH2Cl2 (5 mL) and saturated
aqueous NaHCO3 (5 mL). The organic phase was removed and the
aqueous layer was washed with CH2Cl2 (3ꢃ4 mL). The combined
1H), 7.63 (t, J¼7.9 Hz, 1H), 7.58 (d, J¼7.3 Hz, 1H), 7.51 (t, J¼7.3 Hz,
1H), 5.84 (s,1H), 5.21 (d, J¼15.5 Hz,1H), 4.28 (d, J¼15.5 Hz,1H), 3.43
(s, 3H), 2.41 (dd, J¼15.3, 6.1 Hz, 1H), 2.21 (s, 3H), 1.80 (m, 1H); 13C
NMR (125 MHz, DMSO, 130 ꢁC)
d 168.7, 168.1, 134.1, 132.2, 132.1,
131.0, 129.4, 128.5, 122.6, 55.1, 50.4, 38.0, 36.6, 20.8; IR (neat) 1738,
1650, 1500, 1411, 1305, 1234, 1168, 980, 767 cmꢂ1; mass spectrum
(CI) m/z 301.1304 [C15H17N4O3 (Mþ1) requires 301.1301].

6468
J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
organic layers were dried (MgSO4), filtered, and concentrated un-
der reduced pressure. The residue was dissolved in toluene (35 mL)
and heated under reflux for 18 h. The mixture was cooled to room
temperature and concentrated under reduced pressure. The residue
was purified by flash chromatography, eluting with 75–100% Et2O/
hexanes followed by EtOAc, to give 139.2 mg (49%) of amide 71 as
mass spectrum (CI) m/z 338.1026 [C19H16NO5 (Mþ1) requires
338.1028].
Acknowledgements
a dark yellowish oil. 1H NMR (500 MHz, CDCl3)
d 9.90 (s, 1H), 6.41
We thank the National Institutes of Health (GM 25439 and GM
86192), the Robert A. Welch Foundation (F-0652), The Texas In-
stitute for Drug and Diagnostic Development, and Welch Founda-
tion Grant #H-F-0032, Merck Research Laboratories, and
Boehringer Ingelheim Pharmaceuticals for their generous support
of this research. We are also grateful to Dr. Richard Pederson
(Materia, Inc.) for providing metathesis catalysts used in these
studies. We additionally thank Dr. Vincent Lynch (The University of
Texas) for X-ray crystallography data and Dr. James Sahn and Dr.
Jotham Coe (Pfizer Laboratories) for other assistance and helpful
discussions.
(d, J¼5.9 Hz, 1H), 6.27 (d, J¼5.9 Hz, 1H), 5.73 (dddd, J¼17.0, 10.3, 5.9,
5.9 Hz, 1H), 5.25 (d, J¼17.0 Hz), 5.21 (d, J¼10.3 Hz, 1H), 5.06 (d,
J¼3.9 Hz, 1H), 4.34 (t, J¼6.1 Hz, 1H), 4.27 (dd, J¼15.9, 4.0 Hz, 1H),
3.61 (dd, J¼15.9, 6.5 Hz, 1H), 2.96 (d, J¼6.1 Hz, 2H), 2.53 (dd, J¼8.8,
3.9 Hz, 1H), 2.20 (d, J¼11.7 Hz, 1H), 1.60 (dd, J¼11.7, 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 198.4, 174.0, 137.5, 132.1, 131.4, 118.1, 92.0,
79.0, 54.5, 45.9, 44.4, 43.9, 28.3; IR (neat) 2951, 2735, 1721, 1688,
1440, 1348, 1253, 1045, 946, 700 cmꢂ1; mass spectrum (CI) m/z
234.1131 [C13H15NO3 (Mþ1) requires 234.1130].
4.2.40. N-[1,2-Bis(3,4-ethylenedioxyphenyl)ethyl]-2,2-diacetoxy-
N-methylacetamide (73)
References and notes
A solution of methylamine (w1.9 M in THF, 0.5 mL, 0.95 mmol)
was added to a mixture of piperonal (72) (0.92 mg, 0.61 mmol) in
THF (1 mL) containing activated 3 Å molecular sieves (8–12 mesh,
w750 mg), and the mixture was stirred for 18 h. In a separate
flask, a solution of piperonyl chloride53 (728 mg, 4.27 mmol) in
THF (6 mL) was added dropwise over 2 h to a suspension of
magnesium turnings (170 mg) in THF (2.5 mL) at 0 ꢁC, and the
mixture was stirred for 3 h at 0 ꢁC. A solution of the Grignard re-
agent (75) thus prepared (0.4 M in THF, 3.5 mL, 1.40 mmol) was
added, and the reaction mixture was heated under reflux for 20 h.
The mixture was cooled to ꢂ78 ꢁC, and diacetoxyacetyl chloride
(76)47 (358 mg, 1.83 mmol) was added. The mixture was stirred for
2.5 h at ꢂ78 ꢁC. The cold bath was removed, and the mixture was
partitioned between CH2Cl2 (5 mL) and saturated NaHCO3 (5 mL).
The organic phase was removed, and the aqueous layer was
washed with CH2Cl2 (3ꢃ4 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with
30% EtOAc/hexanes, to give 173 mg (61%) of amide 73 as a pale
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1
yellow solid, mp 141–143 ꢁC. H NMR (500 MHz, DMSO, 130 ꢁC)
d
6.95 (s, 1H), 6.88 (s, 1H), 6.84 (comp, 2H), 6.77 (d, J¼1.4 Hz, 1H),
6. Shaw, J. T. Nat. Prod. Rep. 2009, 26, 11.
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9. For reviews, see: (a) Do¨mling, A. Chem. Rev. 2006, 106, 17; (b) Akritopoulou-
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6.74 (d, J¼7.9 Hz, 1H), 6.70 (dd, J¼7.9, 1.5 Hz, 1H), 5.97 (d, J¼1.5 Hz,
2H), 5.91 (s, 2H), 5.63 (br, 1H), 3.26 (dd, J¼14.3, 6.1 Hz, 1H), 3.10
(dd, J¼14.3, 9.5 Hz, 1H), 2.74 (s, 3H), 2.04 (s, 6H); 13C NMR
(125 MHz, DMSO, 130 ꢁC)
d 167.4, 167.3, 162.8, 147.0, 146.6, 146.1,
145.1, 132.1, 131.0, 121.2, 120.2, 108.4, 107.3, 107.3, 107.2, 100.3, 99.9,
83.9, 57.5, 35.0, 28.4, 19.3, 19.2; IR (neat) 1767, 1668, 1490, 1441,
1246, 1198, 1038, 924 cmꢂ1; mass spectrum (CI) m/z 458.1453
[C23H23NO9 (Mþ1) requires 458.1451].
10. (a) Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005, 7, 3183; (b) Gracias,
V.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett. 2005, 46, 9049; (c) Gracias, V.;
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1107; (b) Fischer, C.; Carriera, E. M. Org. Lett. 2004, 6, 1497; (c) Davis, J. L.;
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4.2.41. (ꢀ)-Roelactamine (74)
A solution of concentrated HCl/MeOH (2:1, 5 mL) was added to
amide 73, and the mixture was stirred for 8 h at room temperature.
The mixture was diluted with CH2Cl2 (5 mL) and carefully
quenched with 2 M Na2CO3 (10 mL) and saturated NaHCO3 (5 mL).
The organic phase was removed, and the aqueous layer was washed
with CH2Cl2 (3ꢃ5 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography, eluting with 40%
EtOAc/hexanes, to give 58 mg (68%) of 74 as a white foam. 1H NMR
(400 MHz, CDCl3) d 6.75 (s,1H), 6.73 (s, 1H), 6.69 (s,1H), 6.46 (s,1H),
5.93 (d, J¼1.4 Hz, 1H), 5.89 (d, J¼1.4 Hz, 1H), 5.87 (d, J¼1.4 Hz, 1H),
5.85 (d, J¼1.4 Hz, 1H), 4.39 (dd, J¼4.2, 2.6 Hz, 1H), 4.25 (s, 1H), 3.33
(dd, J¼17.3, 4.2 Hz, 1H), 3.10 (s, 3H), 2.95 (dd, J¼17.3, 2.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 173.6, 148.1, 148.0, 147.4, 147.0, 135.1, 130.3,
130.2, 127.0, 112.2, 110.0, 107.0, 106.3, 102.1, 101.9, 61.5, 57.4, 34.8,
33.3; IR (neat) 2895, 1661, 1504, 1482, 1228, 1038, 941, 873 cmꢂ1
;

J.D. Sunderhaus et al. / Tetrahedron 65 (2009) 6454–6469
6469
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