Multicomponent, Mannich-type assembly process for generating novel, biologically-active 2-arylpiperidines and derivatives

Article abstract of DOI:10.1016/j.tet.2014.06.045

A multicomponent, Mannich-type assembly process commencing with commercially available bromobenzaldehydes was sequenced with [3+2] dipolar cycloaddition reactions involving nitrones and azomethine ylides to generate collections of fused, bicyclic scaffolds based on the 2-arylpiperidine subunit. Use of the 4-pentenoyl group, which served both as an activator in the Mannich-type reaction and a readily-cleaved amine protecting group, allowed sub-libraries to be prepared through piperidine N-functionalization and cross-coupling of the aryl bromide. A number of these derivatives displayed biological activities that had not previously been associated with this substructure. Methods were also developed that allowed rapid conversion of these scaffolds to novel, polycyclic dihydroquinazolin-2-ones, 2-imino-1,3-benzothiazinanes, dihydroisoquinolin-3-ones, and bridged tetrahydroquinolines.

Full text of DOI:10.1016/j.tet.2014.06.045

Tetrahedron xxx (2014) 1e16
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Multicomponent, Mannich-type assembly process for generating
novel, biologically-active 2-arylpiperidines and derivatives
*
Simon Hardy, Stephen F. Martin
Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A multicomponent, Mannich-type assembly process commencing with commercially available bromo-
benzaldehydes was sequenced with [3þ2] dipolar cycloaddition reactions involving nitrones and azo-
methine ylides to generate collections of fused, bicyclic scaffolds based on the 2-arylpiperidine subunit.
Use of the 4-pentenoyl group, which served both as an activator in the Mannich-type reaction and
a readily-cleaved amine protecting group, allowed sub-libraries to be prepared through piperidine N-
functionalization and cross-coupling of the aryl bromide. A number of these derivatives displayed bi-
ological activities that had not previously been associated with this substructure. Methods were also
developed that allowed rapid conversion of these scaffolds to novel, polycyclic dihydroquinazolin-2-
ones, 2-imino-1,3-benzothiazinanes, dihydroisoquinolin-3-ones, and bridged tetrahydroquinolines.
Ó 2014 Published by Elsevier Ltd.
Received 28 March 2014
Received in revised form 9 June 2014
Accepted 13 June 2014
Available online xxx
Keywords:
Multicomponent assembly process
Dipolar cycloadditions
Diversity oriented synthesis
Bioactive compounds
Compound libraries
1. Introduction
mimic their structural features represents a major undertaking in
medicinal chemistry and chemical biology. Diversity-oriented
1.1. Methods for the discovery of novel, bioactive compounds
synthesis (DOS) is one method, that is, progressively gaining pop-
ularity as a means of generating architecturally-complex, natural
product-like structures rapidly whilst simultaneously exploring
new regions of chemical space.7 The combination of DOS ap-
proaches with the incorporation of so-called ‘privileged sub-
structures’dstructural subunits, which elicit responses in a variety
of biological receptorsdis a promising method for the discovery of
new structureeactivity relationships.8 One approach to small
molecule discovery that implements such design principles is bi-
ology oriented synthesis (BIOS), which exploits core substructures
of natural products as scaffolds for generating compound
collections.9
There is an ongoing need to discover new compounds that can
modulate biological processes, both for use as probes to study
cellular mechanisms and as drugs for treating disease. Perhaps the
most well-known and utilized set of principles to guide drug dis-
covery efforts toward identifying bioavailable compounds is out-
lined in Lipinski’s ‘rule of five’.1 Related concepts include closer
scrutiny of compounds and their topological polar surface area
(PSA),2 number of rotatable bonds,3 and the degree of incorporation
of sp3 centers (Fsp3).4 Although these paradigms help steer the
design of analogues of lead compounds with enhanced physico-
chemical and biological properties, the design and identification of
truly novel bioactive compounds remains challenging.
1.2. Discovery of a new multicomponent assembly process
Natural products, which frequently induce biological responses
with a high degree of specificity, can be exploited to study the in-
teractions of small molecules with biological receptors, and they
have long served as a source of inspiration for drug design.5 Indeed,
approximately 50% of the small molecule drugs discovered during
the past 30 years are natural products and compounds derived
there from.6 Consequently, the discovery and development of
synthetic techniques to access these compounds and analogs that
As part of our pursuit of the synthesis of biologically natural
products, we developed a new Mannich-type multicomponent
assembly process (MCAP) that allowed a remarkably concise syn-
thesis of the pentacyclic indole alkaloid (ꢀ)-tetrahydroalstonine in
only five steps from tryptamine.10 It occurred to us at the time that
the basic strategy embodied in this synthesis, which involves ad-
dition of a nucleophile to an acyliminium ion generated in situ by
N-acylation of an imine followed by ring-forming and refunction-
alization steps, might be developed into a powerful approach to
natural products and polycyclic nitrogen heterocycles. For example,
we have since exploited this concept in the synthesis of numerous
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180; e-mail
address: sfmartin@mail.utexas.edu (S.F. Martin).
http://dx.doi.org/10.1016/j.tet.2014.06.045
0040-4020/Ó 2014 Published by Elsevier Ltd.
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2
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
natural products,11,12 and we have applied it as a central strategic
element to develop a novel DOS-type approach to generate libraries
of ‘unnatural product’ libraries based around the arylaminomethyl
core subunit, that is, common to many natural products and priv-
ileged substructures.13
During these investigations, we became intrigued by the
structural features present in the fused bicyclic scaffolds 1 and 2
due to their adherence to Lipinski’s rules, high sp3 content and
resemblance to a number of compounds with documented bi-
ological activities (Fig. 1). For example, the octahydro-1H-pyrrolo
[3,2-c]pyridine scaffold present in 2 is represented in the CCR5
antagonist 314 and the bradykinin receptor antagonist martinellic
acid (4).15 Moreover, the privileged 2-arylpiperidine substructure
present in 1 and 2 can be found in the substance P antagonist 516
and the neurokinin 1 receptor antagonist 6.17 Compound 1 itself
displays activity as an activator of both the nuclear receptor DAF-12
(1% activation at 6.8
mM) and the mouse serotonin receptor 2A (19%
activation at 7.6
m
M).18
Scheme 1. Preparation of octahydroisoxazolo[4,3-c]pyridine scaffolds via MCAP/ni-
trone cycloaddition sequences.
spontaneous dipolar cycloaddition under the reaction conditions to
furnish the isoxazolidines 9aec as single diastereoisomers. The
relative stereochemistry of these cycloadducts was confirmed by
obtaining an X-ray crystal structure of compound 9a (Fig. 2).
Fig. 2. X-ray crystal structure of 9a; hydrogen atoms at all but stereogenic carbon
atoms are omitted for clarity.
The N-pentenoyl side chains in compounds 9aec were then
removed upon treatment with iodine in a mixture of THF and
aqueous HCl to give the secondary amines 10aec. It was necessary
to modify the known procedure20 for cleaving this protecting group
by conducting the reaction in the presence of aqueous acid to
minimize deleterious formation of iodohydrin side-products. The
amine 10c exhibited inhibitory activity against Dengue virus 2, as
indicated by an increase in viability of BHK-21 cells incubated with
DENV-2 in a cytopathic effect assay (26% increase in cell viability at
Fig. 1. MCAP-accessible fused bicyclic 2-arylpiperidine scaffolds 1 and 2 and struc-
turally related, biologically active compounds.
Encouraged by this compelling precedent for the diverse bi-
ological activities associated with compounds closely related to 1
and 2, we were motivated to create compound libraries based on
these scaffolds for submission to the National Institutes of Health
Molecular Libraries Small Molecule Repository (MLSMR) for
screening against a large number of biological targets.19 We now
report the details of these studies.
10
m
M).21
The aryl bromide moiety in compounds 9b,c and 10b,c served
as an excellent functional group handle for introducing other
substituents via cross-coupling reactions. For example, 9b un-
derwent facile cross-coupling with morpholine under Buchwald’s
conditions to give the aniline 12 (Scheme 2).22 The corresponding
etherification reaction with phenol was unsuccessful, because
a side reaction involving Heck coupling of the aryl bromide with the
carbonecarbon double bond in the pentenamide group out-
competed the desired etherification process. On the other hand,
Ullmann-type copper-catalyzed cross coupling of 9b with phenol
furnished the diaryl ether 15.23 The pentenamide moieties in 12
and 15 were then cleaved using the modified deprotection pro-
cedure to give 13 and 16, respectively.
2. Results and discussion
2.1. Assembly of core scaffolds for diversification
The regioisomeric aldehydes 8aec were prepared by a two-
stage MCAP that commenced with condensation of the commer-
cially available bromobenzaldehydes 7aec with allylamine, fol-
lowed by subjecting the intermediate imines to an N-acylation with
4-pentenoyl chloride and a TMSOTf-catalyzed addition of vinyl TBS
Similar transformations were used to introduce various sub-
stituents onto 9c (Scheme 3). In the event, BuchwaldeHartwig
coupling of 9c with piperidine gave 17, whereas Ullmann coupling
with imidazole gave 19; deprotection of these intermediates by
treatment with iodine in the presence of aqueous acid gave 18 and
20, respectively. The pentenamide 17 demonstrated activity as an
ether, a p-nucleophile (Scheme 1). Acid chlorides were found to be
more effective activators than chloroformates in this process, and
the pentenoyl group was chosen due to its robustness in sub-
sequent reactions coupled with its ease of removal under mild
conditions.20 The aldehydes 8aec were then condensed with N-
methylhydroxylamine to generate nitrones that underwent
inhibitor (IC50¼52
m
M) of the deubiquitinating enzyme RPN11.24
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S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
3
Scheme 5. Synthesis of biaryls through Suzuki cross-coupling of p-disubstituted
substrate 10c.
nuclear receptor DAF-12 (11% at 6.8
also active in a number of bioassays. For example, it was an inhibitor
(IC50¼0.05 M) of the LMP-1 inducible NF- B pathway in the Eps-
M) of the zinc
m
M).25 The benzofuran 22b was
m
k
teineBarr virus, as well as an inhibitor (IC50¼0.26
m
finger adapter protein Schnurri-3.26 Preliminaryattempts to perform
cross-couplings of the substrate 10a under similar conditions were
unsuccessful, as the reaction stalled after very little conversion.
In order to generate a series of pyrrolidino-fused piperidines, we
turned our attention to employing aldehydes 8aec as precursors of
azomethine ylides. In the event, sarcosine (24) was heated with the
aldehyde 8a in toluene to furnish the pyrrolidine 27 (Scheme 6), but
when this reaction was scaled up, formation of side products
Scheme 2. Diversification of m-disubstituted benzenes via carboneheteroatom cross-
coupling processes.
resulting from b-elimination of the amide moiety from the starting
aldehyde became a significant problem. This difficulty was easily
resolved by treating 8a with the bis(trimethylsilyl)sarcosine de-
rivative 25, which was generated by reacting sarcosine with TMS-Cl
and Et3N, in toluene at room temperature. The putative oxazolidi-
none thus formed27 was heated to generate an intermediate azo-
methine ylide that underwent subsequent cycloaddition to give 27
as a single diastereoisomer. This modified protocol proved more
amenable to scale-up than the aforementioned reaction with sar-
cosine. Iodine-mediated pentenamide deprotection of 27 gave the
secondary amine 28, which underwent facile derivatization. For
example, sulfonylation of 28 gave the benzenesulfonamide 29. The
diamine 28 demonstrated activity as a RAD52 inhibitor (IC50 of
4.6 m
M) in an FRET-based high-throughput screen.28
Scheme 3. Diversification of p-disubstituted benzenes through CeN cross-coupling.
Compound 10b was used as a substrate in Suzuki cross-coupling
with phenylboronic acids to prepare the series of biaryls 21aee,
which incorporate various substitution patterns of electron with-
drawing and donating groups (Scheme 4).
Scheme 4. Synthesis of biphenyls through Suzuki cross-coupling of m-disubstituted
substrate 10b.
The isomeric 4-bromo compound 10c underwent facile cross-
coupling under the same conditions to afford the biaryls 22aec
(Scheme 5).
The biphenyl 22a exhibited activity as an inhibitor of the orphan
Scheme 6. Synthesis and diversification of octahydro-1H-pyrrolo[3,2-c]pyridine scaf-
nuclear receptor NR0B1 (6% at 6.8
mM) and as an activator of the
folds through azomethine ylide cycloadditions.
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4
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
In a variant of the chemistry used to prepare 27, the aldehyde
2312b,c was allowed to react with the silylated reagent 26, which
was generated from N-(4-methoxybenzyl)glycine,29 to give 30 via
sequential azomethine ylide formation and cycloaddition. In order
to determine the relative stereochemistry of the cycloadduct 30
and the viability of the PMB-protected amine as a precursor of
analogs of 30, the PMB group was removed by treatment with 1-
chloroethyl chloroformate (ACE-Cl), followed by methanolysis of
the intermediate carbamate to give the secondary amine 31. Re-
ductive methylation of 31 with paraformaldehyde, NaBH(OAc)3,
and acetic acid in 1,2-dichloroethane (DCE) delivered the tertiary
amine 2, which was identical with an authentic sample that had
been previously prepared and structurally characterized by X-ray
crystallography.12b,c Interestingly, the pyrrolidine 30 was shown to
inhibit the Csn-mediated deconjugation of the Nedd8 protein from
Cullin-ring ligases in a fluorescence polarization assay (160% ac-
tivity at 12.5 m
M).30
Small libraries of N-functionalized piperidines were then pre-
pared from the cross-coupled products 13, 16, and 21c (Scheme 7).
For example, reaction of 13 with dihydrocinnamoyl chloride gave
the amide 32, whereas subjecting 16 to reductive alkylation by
treatment with 3,5-dichlorobenzaldehyde and NaBH(OAc)3 fur-
nished the amine 33, and sulfonylation of 21c with 2-
methylbenzenesulfonyl chloride provided the sulfonamide 34. In
biological testing, the amine 33 was found to be an inhibitor of the
JMJD2A tudor domain (IC50¼89
m
M) and an agonist of the mouse
serotonin receptor 2A (15% activation at 7.6
m
M).31
Scheme 8. Diversification of p-disubstituted benzenes through piperidine N-
functionalization.
processes for tandem urea formation/cyclization commencing from
the amine 10a to give dihydroquinazolin-2-ones.34 Our interest in
dihydroquinazolin-2-ones arose following their identification in
several biologically active compounds, including T-type calcium
channel antagonists and anticonvulsants.35 Accordingly, reaction of
the piperidine 10a with phenyl isocyanate and Cs2CO3 in toluene in
the presence of Pd(OAc)2 and (ꢀ)-BINAP at room temperature led to
the rapid formation of the urea 39. When this mixture was simply
heated, the cyclized dihydroquinazoline-2-one 40 was produced in
92% yield (Scheme 9). Pd(PPh3)4 and Pd(OAc)2/JohnPhos (11) were
also examined as catalysts for this transformation, but the use of
(ꢀ)-BINAP was critical to obtaining complete cyclization. We also
discovered that it was essential to ensure complete formation of the
intermediate urea prior to heating because otherwise mixtures of
Scheme 7. Diversification of cycloadducts through piperidine N-functionalization.
The p-disubstituted-2-arylpiperidines 18, 20, 22a, and 22c were
also derivatized using similar methods (Scheme 8). For example,
the urea 35 was obtained by reaction of 18 with ethyl isocyanate,
and the sulfonamide 36 was prepared by treating 20 with mesity-
lenesulfonyl chloride. The 4-methoxybenzylamine 37, which was
prepared by reductive alkylation of 22a using p-anisaldehyde and
NaBH(OAc)3, is an inhibitor (IC50¼11
mM) of Transforming Growth
Factor beta (TGF-
b
).32 Acylation of 22c using pivaloyl chloride gave
the amide 38, which is an inhibitor (30% inhibition at 3 mM) of the
human M1 muscarinic receptor.33
We next investigated opportunities for sequencing additional
ring-forming reactions as a strategy for the facile construction of
novel tri- and tetracyclic scaffolds. We began by examining
Scheme 9. Diversification of (2-bromophenyl)piperidine 10a through tandem urea
and thiourea formation/cyclization processes.
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S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
5
uncyclized 39 and the desired product 40 were obtained. This fact,
along with the aforementioned unsuccessful attempts to couple
10a under Suzuki conditions suggests that 10a may poison some Pd
catalysts. We were able to adapt this one-pot procedure to form
cyclic isothioureas as illustrated by the conversion of 10a to the 2-
imino-1,3-benzothiazinane 42,36 although it was necessary to use
Pd[(t-Bu)3P]2 instead of Pd(PPh3)4 or Pd(OAc)2/(ꢀ)-BINAP as the
catalyst to achieve complete cyclization of the intermediate thio-
urea 41.
We also envisioned that 2-bromobenzyl amides, such as 1 might
be amenable to enolate arylation to generate polycyclic dihy-
droisoquinolin-3-ones.37 Indeed, treatment of 1 with excess LDA in
the presence of DMPU, followed by an aqueous workup yielded the
fused tetracycle 44 (Scheme 10). Presumably, this process occurs
through concomitant formation of the amide lithium enolate and
the benzyne through elimination of HBr from the arene, before
cyclization of the enolate onto the benzyne and subsequent proton
transfer to give the secondary enolate 43.
Fig. 3. X-ray crystal structure of the methiodide salt derived from 47 showing iodide
ion (purple); hydrogen atoms at all but stereogenic carbon atoms are omitted for
clarity.
Scheme 11. Isoxazolidine reductive ring-opening and subsequent diversification
through acylation or intramolecular BuchwaldeHartwig coupling.
The densely-functionalized 2-arylpiperidine 49 could be N-ac-
ylated, although this transformation required use of a one-pot,
three-stage process, in which the hydroxyl group was first pro-
tected as its TMS ether before sequential reaction with pivaloyl
chloride and subsequent acid-catalyzed O-desilylation to give the
pivalamide 50. Alternatively, 49 could be subjected to a ring-
forming process, in which the aminomethyl group was coupled
with the aryl bromide moiety via an intramolecular Buch-
waldeHartwig reaction to give the tetrahydroquinoline 51. The
pendant hydroxyl group in 51 was then exploited as a handle for
further elaboration as exemplified by a Mitsunobu reaction to give
52. The tetrahydroquinoline ring system in 51 is a well-recognized
privileged substructure and is present in numerous compounds
with a diverse range of activities, such as antiviral, antibiotic, and
antithrombotic.40 However, there are very few examples of bridged
tetrahydroquinolines, such as 51,41 so the sequence of reactions in
Scheme 11 holds some promise for the discovery of compounds
having interesting biological activities.
Scheme 10. Generation of dihydroisoquinonlin-3-ones through
mediated enolate arylation process.
a cascade base-
We then extended this method to the phenylacetamide 45,
which was prepared in 84% yield by acylation of 10a with phenyl-
acetyl chloride and triethylamine. After subjecting 45 to the lith-
iation/benzyne formation/cyclization, we discovered that the
intermediate enolate 43 could be protonated selectively from the
less hindered face by quenching with 2,6-di-tert-butyl-4-
methylphenol (BHT), a hindered proton source. Whilst this pro-
cess gave crude 46 with high diastereoselectivity (dr>95:5, 1H
NMR), the product underwent rapid epimerization upon purifica-
tion to give an isomeric mixture (w2:1). Motivated by the fact that
several compounds bearing the 4,4-disubstituted dihy-
droisoquinolin-3-one substructure have been reported to show
anticonvulsant and vasorelaxant properties,35b,38 we questioned
whether this initially high facial selectivity in the enolate quench
could be exploited in alkylation reactions to create configuration-
ally stable 4,4-disubstituted analogs.39 In the event, addition of
either methyl iodide or ally bromide to the solution of the enolate
43 generated from 45 at ꢁ100 ꢂC led to 47 or 48, respectively, with
diastereocontrol of >95:5. X-ray crystallography of the methiodide
salt derived from alkylation of the isoxazolidine nitrogen atom in
47 confirm the stereochemical outcome of the enolate alkylation
(Fig. 3).
3. Conclusions
In summary, we have utilized a 4-component, Mannich-type
MCAP followed by [3þ2] dipolar cycloadditions to create a num-
ber of novel pyrrolidino- and isoxazolidino-fused 2-arylpiperidines.
Derivatives of these frameworks were prepared through a variety of
aryl bromide cross-couplings and N-functionalizations. An enabling
discovery was that the N-(4-pentenoyl) group was a competent
activator in the MCAP protocol and a robust protecting group
during carboneheteroatom forming cross-coupling processes that
could be readily cleaved to give amines on treatment with iodine in
aqueous acid. A number of compounds prepared during these in-
vestigations have already been shown to exhibit promising bi-
ological activities. In particular, the range of activities exhibited by
The isoxazolidine ring in nitrone cycloadducts, such as 1 masks
a 1,3-amino alcohol functionality that can be revealed through re-
ductive NeO bond cleavage (Scheme 11). However, it was necessary
to exercise some care in order to avoid reductive debromination,
which was a major side reaction under some conditions; however,
use of zinc in aqueous HCl at 0 ꢂC gave complete NeO bond cleavage
without observable debromination.
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6
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
the 1,4-disubstituted benzenes 10c,17, 22a, 22b, 37, and 38 suggests
that this substructure may be worthy of further exploration by
generating targeted sub-libraries.
Allylamine (1.9 g, 2.5 mL, 33 mmol), MgSO4 (8.1 g, 67 mmol), and
the appropriate bromobenzaldehyde 7aec (4.15 g, 22.4 mmol)
were combined in CH2Cl2 (44 mL) and the mixture was stirred for
3e24 h. The mixture was filtered and the filtrate was concentrated
in vacuo to give the allylimines, which were used without further
purification. Vinyl TBS ether (10.6 g, 67 mmol) and CH2Cl2 (29 mL)
were added and the solution was cooled to 0 ꢂC, before dropwise
addition of 4-pentenoyl chloride (2.9 g, 2.7 mL, 25 mmol). After
5 min, TMSOTf (0.50 g, 0.40 mL, 2.2 mmol) was added dropwise and
the mixture was warmed to room temperature and stirred for 40 h.
The mixture was concentrated under reduced pressure and the
residue was partitioned between CH2Cl2 (70 mL) and saturated
aqueous NaHCO3 (70 mL), and the mixture was stirred rapidly for
1 h. The phases were separated, and the aqueous layer was
extracted with CH2Cl2 (2ꢃ40 mL). The combined organic layers
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography eluting with
ethyl acetate/hexanes/methanol (25:75:1/50:50:1/75:25:1) to
give the desired aldehyde 8aec.
A number of higher-order processes were developed that
allowed the rapid diversification of scaffold 10a in secondary ring-
forming reactions that could be performed by judicious pairing of
functional groups with the 2-bromoaryl moiety. For example, we
developed novel tandem and sequential processes that involve urea
or thiourea formation and cyclization, enolate cycloarylation, and
alkylation, as well as reductive NeO-bond cleavage and intra-
molecular BuchwaldeHartwig coupling. We anticipate that these
and related processes, which enable rapid generation of both
skeletal and functional group diversity, will facilitate future efforts
in DOS and targeted library synthesis. The synthesis and screening
of compounds related to those presented herein is ongoing, and the
results of these studies will be reported in due course.
4. Experimental
4.1. General
4.3. N-Allyl-N-(1-(2-bromophenyl)-3-oxopropyl)pent-4-
Unless otherwise noted, solvents and reagents were reagent-
grade and used without further purification. Benzene, dichloro-
methane (CH2Cl2), triethylamine (Et3N), 1,4-dioxane, diisopropyl-
amine, and N,N0-dimethylpropylene urea (DMPU) were freshly
distilled from CaH2. Tetrahydrofuran (THF) was bubbled with argon
to remove oxygen and dried by passage through two columns of
activated neutral alumina. Toluene was bubbled with argon and
passed through two columns of molecular sieves. DMSO for use in
copper coupling reactions was distilled from CaH2 and degassed by
three freeze-thaw cycles prior to use. All solvents used for
palladium-catalyzed cross-coupling reactions were degassed by
sparging with nitrogen for 20 min prior to use. Reactions were
performed under nitrogen or argon atmosphere in round-bottom
flasks sealed under rubber septa with magnetic stirring, unless
otherwise noted. Water sensitive reactions were performed with
flame- or oven-dried glassware, stir-bars, and steel needles. Re-
action temperatures are reported as the temperatures of the bath
surrounding the vessel. Sensitive reagents and solvents were
transferred using plastic or oven-dried glass syringes and steel
needles using standard techniques. Nuclear magnetic resonance
spectra were acquired in CDCl3 unless otherwise noted. Chemical
enamide (8a)
Prepared according to the general MCAP procedure, starting
from 2-bromobenzaldehyde (7a) (4.15 g, 22.4 mmol) to give 5.50 g
(70%) of the aldehyde 8a as a viscous, golden oil: 1H NMR
(600 MHz) (9:1 rotamer mixture, data given for the major rotamer):
d
9.76 (dd, J¼2.7, 2.1 Hz, 1H), 7.64e7.58 (m, 1H), 7.37e7.30 (comp,
2H), 7.20 (ddd, J¼8.1, 6.6, 2.4 Hz, 1H), 6.26 (dd, J¼8.8, 6.3 Hz, 1H),
5.90e5.79 (m, 1H), 5.54e5.44 (m, 1H), 5.08e4.94 (comp, 4H), 3.72
(ddt, J¼17.4, 5.1, 1.7 Hz, 1H), 3.64 (dd, J¼17.4, 5.9 Hz, 1H), 3.18 (ddd,
J¼15.6, 8.8, 2.7 Hz,1H), 2.99 (ddd, J¼15.6, 6.3, 2.1 Hz,1H), 2.48e2.34
(comp, 4H); 13C NMR (150 MHz) (9:1 rotamer mixture, data given
for the major rotamer):
d 199.6, 172.9, 137.4, 137.2, 133.9, 133.6,
129.8, 129.4, 127.6, 125.5, 117.2, 115.2, 53.2, 47.6, 46.4, 33.0, 29.2; IR
(neat) 2979, 1723, 1643, 1470, 1415, 1025 cmꢁ1; HRMS (ESIþ) m/z
calculated for C17H21NO729Br (Mþ1), 350.07502; found, 350.07504.
4.4. N-Allyl-N-(1-(3-bromophenyl)-3-oxopropyl)pent-4-
enamide (8b)
Prepared according to the general MCAP procedure, starting
from 3-bromobenzaldehyde (7b) (2.48 g, 13.4 mmol) with all other
material amounts scaled accordingly, to give 3.44 g (73%) of the
aldehyde 8b as a viscous, golden oil: 1H NMR (600 MHz, DMSO-d6,
shifts are reported in parts per million (ppm, d), downfield from
trimethylsilane (TMS,
sidual solvent (CDCl3,
d
¼0.00 ppm) and are referenced to the re-
d
¼7.26 ppm (1H) and 77.16 ppm (13C); DMSO-
d6,
d
¼2.50 ppm (1H), and 39.5 ppm (13C); benzene-d6,
d¼7.16 ppm
100 ꢂC):
d 9.68e9.65 (m, 1H), 7.51e7.47 (m, 1H), 7.47e7.43 (m, 1H),
(1H), and 128.4 ppm (13C)). The abbreviations s, d, t, q, m, and comp
stand for the resonance multiplicities singlet, doublet, triplet,
quartet, multiplet, and complex (overlapping multiplets of non-
magnetically equivalent protons), respectively, whereas br stands
for broad and app for apparent. Infra red (IR) spectra were recorded
as films on sodium chloride plates and reported as wavenumbers
(cmꢁ1). Thin-layer chromatography was performed on Merck Kie-
selgel 60 F254 silica gel plates eluting with solvents indicated, vi-
sualized by 254 nm UV lamp and stained with basic KMnO4, acidic
p-anisaldehyde or phosphomolybdic acid solutions. Flash chro-
matography was performed with ICN Silitech 32e63 D 60A silica
gel according to the procedure of Still.42
7.33e7.30 (m, 1H), 7.28 (app t, J¼7.7 Hz, 1H), 5.94 (app br s, 1H),
5.88e5.79 (m, 1H), 5.65e5.57 (m, 1H), 5.10e4.97 (comp, 3H),
4.97e4.92 (m, 1H), 3.91 (dd, J¼17.3, 3.6 Hz, 1H), 3.80e3.72 (m, 1H),
3.23 (dd, J¼16.9, 6.6 Hz, 1H), 3.10 (dd, J¼16.9, 6.6 Hz, 1H), 2.44 (app
br s, 2H), 2.31 (app q, J¼8.4 Hz, 2H); 13C NMR (150 MHz, DMSO-d6,
373 K):
d
199.6, 192.9, 141.9, 2ꢃ137.2, 134.4, 2ꢃ129.8, 129.7, 126.0,
115.8, 114.2, 51.8, 46.3, 44.5, 31.8, 28.2; IR (neat) 3356, 3077, 2978,
2923, 1727, 1643, 1415, 1214, 917, 732; HRMS (ESIþ) m/z calculated
for C17H20NO729BrNa (Mþ23), 372.05659; found, 372.05696.
4.5. N-Allyl-N-(1-(4-bromophenyl)-3-oxopropyl)pent-4-
enamide (8c)
4.2. General multicomponent assembly process (MCAP)
procedure
Prepared according to the general MCAP procedure, starting
from 4-bromobenzaldehyde (7c) (3.21 g, 17.3 mmol) with all other
material amounts scaled accordingly, to give 4.10 g (67%) of the
aldehyde 8c as a viscous, yellow oil: 1H NMR (400 MHz) (5:1
Vinyl TBS ether was prepared according to the procedure of
Kawakamie and co-workers.43 4-pentenoyl chloride was prepared
according to the procedure of Rosenblum and co-workers and pu-
rified by fractional distillation under nitrogen prior to use.44
rotamer mixture, data given for the major rotamer):
d 9.74e9.71
(m, 1H), 7.46 (d, J¼8.3 Hz, 2H), 7.18 (d, J¼8.3 Hz, 2H), 6.26 (app t,
J¼7.6 Hz, 1H), 5.90e5.75 (m, 1H), 5.60e5.49 (m, 1H), 5.16e4.94
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
7
(comp, 4H), 3.80e3.71 (m, 1H), 3.66 (dd, J¼17.8, 5.7 Hz, 1H),
3.14e3.03 (comp, 2H), 2.52e2.34 (comp, 4H); 13C NMR (100 MHz):
199.4, 173.1, 137.5, 137.0, 133.9, 131.6, 129.5, 121.8, 117.3, 115.2, 51.3,
4.9. 1-((3aRS,6SR,7aSR)-6-(4-Bromophenyl)-1-methyl tetrahy-
droisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)pent-4-en-1-one
(9c)
d
47.1, 45.3, 32.8, 29.0; IR (neat) 2978, 1724, 1643, 1409, 1009 cmꢁ1
;
HRMS (ESIþ) m/z calculated for C17H20NO729BrNa (Mþ23),
Prepared according to the general nitrone condensation/cyclo-
addition procedure, starting from aldehyde 8c (3.34 g, 9.54 mmol)
with all other material amounts scaled accordingly, to give 3.23 g
(89%) of the isoxazolidine 9c as a viscous, pale yellow gum: 1H NMR
372.05696; found, 372.05688.
4.6. General nitrone condensation/cycloaddition procedure
(400 MHz) (11:9 rotamer mixture):
d
7.48 (d, J¼8.2 Hz,1.1H), 7.41 (d,
N-Methylhydroxylamine hydrochloride (1.25 g, 15.0 mmol), al-
dehyde 8aec (3.50 g, 9.99 mmol), and Et3N (3.0 g, 4.2 mL, 30 mmol)
were combined in toluene (116 mL) and the mixture was heated
under reflux for 90 min. After cooling to room temperature, water
(60 mL) was added and the layers were separated. The aqueous
layer was saturated with NaCl then extracted with CH2Cl2
(2ꢃ30 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure and the residue was purified
by column chromatography eluting with ethyl acetate/hexanes/
methanol (25:75:1/50:50:1/95:0:5) to afford the isoxazolidine
9aec.
J¼8.2 Hz, 0.9H), 7.15e7.05 (comp, 2H), 5.89e5.75 (m, 0.45H),
5.75e5.62 (m, 0.55H), 5.09e4.83 (comp, 3H), 4.66 (dd, J¼12.3,
5.5 Hz, 0.55H), 4.20e4.06 (comp, 1H), 3.97e3.86 (m, 0.45H),
3.58e3.50 (comp, 1H), 3.42 (t, J¼12.8 Hz, 0.45H), 3.05e2.85 (comp,
2.55H), 2.67 (s, 3H), 2.56e1.80 (comp, 6H); 13C NMR (150 MHz)
(11:9 rotamer mixture): d172.8, 171.2, 142.4, 137.2, 132.3, 131.6,
127.2, 126.7, 121.3, 120.6, 115.4, 115.2, 68.2, 64.6, 55.8, 53.7, 43.6,
43.2, 42.3, 39.2, 35.5, 33.4, 33.2, 32.9, 29.0; IR (neat) 2956, 1644,
1417, 1009 cmꢁ1; HRMS (ESIþ) m/z calculated for C18H23N2O729BrNa
(Mþ23), 401.08351; found, 401.08371.
4.10. General 4-pentenamide deprotection procedures
4.7. 1-((3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl tetrahy-
droisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)pent-4-en-1-one
(9a)
4.10.1. Procedure A. Iodine (1.05 g, 4.12 mmol) was added to a stir-
red solution of the 4-pentenamide (0.85 mmol) in THF (6.6 mL) and
1.5 M aqueous HCl (2.5 mL) at 0 ꢂC. The stirred mixture was warmed
to room temperature and after 45e60 min, saturated aqueous
Na2S2O3 was added until the solution became colorless. The mix-
ture was then diluted with water (10 mL) and washed with ether
(3ꢃ10 mL). The pH of the aqueous layer was adjusted to 12 by
addition of 1 M aqueous NaOH and the solution was then saturated
with NaCl and extracted with ethyl acetate or CH2Cl2 (3ꢃ10 mL).
The combined CH2Cl3 extracts were dried (MgSO4) and concen-
trated under reduced pressure and the residue was purified by flash
column chromatography to give the desired amines.
Prepared according to the general nitrone condensation/cyclo-
addition procedure, starting from aldehyde 8a (3.50 g, 9.99 mmol),
to give 3.63 g (96%) of the isoxazolidine 9a as a highly viscous, pale
yellow gum that crystallized on standing: mp 70e71 ꢂC; 1H NMR
(600 MHz) (3:1 rotamer mixture):
d
7.55 (dd, J¼8.1, 1.1 Hz, 0.75H),
7.51 (d, J¼7.7 Hz, 0.25H), 7.35e7.30 (m, 0.75H), 7.25 (dd, J¼8.5,
1.7 Hz, 0.75H), 7.25e7.20 (m, 0.25H), 7.18e7.13 (m, 0.75H), 7.11 (dd,
J¼7.8, 1.2 Hz, 0.25H), 7.08e7.04 (m, 0.25H), 5.86e5.77 (m, 0.25H),
5.73e5.63 (m, 0.75H), 5.23 (dd, J¼13.7, 4.8 Hz, 0.25H), 5.07e5.00
(comp, 1H), 5.00e4.92 (comp, 1H), 4.91e4.84 (comp, 1.5H),
4.20e4.10 (comp, 1H), 3.97 (dd, J¼13.7, 5.4 Hz, 0.25H), 3.60e3.53
(comp, 1.25H), 3.07e2.88 (comp, 2.75H), 2.70 (s, 3H), 2.55e2.47 (m,
0.25H), 2.47e2.39 (m, 0.25H), 2.39e2.32 (m, 1.5H), 2.32e2.20
(comp, 1.5H), 2.16e2.07 (m, 0.75H), 1.86e1.77 (m, 0.75H), 1.77e1.67
4.10.2. Procedure B. Iodine (242 mg, 0.953 mmol) was added to
a stirred solution of the 4-pentenamide (0.19 mmol) in THF (1.4 mL)
and 3 M aqueous HCl (0.55 mL) at 0 ꢂC and the mixture was
warmed to room temperature. After 45e60 min, saturated aqueous
Na2S2O3 was added until the solution became colorless. The mix-
ture was then diluted with 1 M aqueous HCl (10 mL) and washed
with ether (3ꢃ10 mL). The pH of the aqueous layer was adjusted to
14 by addition of 1 M aqueous NaOH and the solution was then
saturated with NaCl and extracted with CHCl3 (4ꢃ10 mL). The
combined CHCl3 extracts were dried (MgSO4) and concentrated
under reduced pressure and the residue was purified by flash col-
umn chromatography to give the desired amines.
(comp, 1H); 13C NMR (150 MHz) (3:1 rotamer mixture):
d 173.2,
171.2,142.7,142.5,137.4,137.2,133.2,129.2,128.7,128.3,127.9,126.4,
125.3, 121.8, 121.1, 115.3, 115.1, 68.3, 68.0, 64.6, 55.7, 54.6, 43.9, 43.7,
42.8, 39.6, 33.3, 33.1, 32.6, 31.8, 29.0, 28.9; IR (neat) 2956, 2876,
1650, 1418, 1240, 1026, 915, 756 cmꢁ1; HRMS (ESIþ) m/z calculated
for C18H24N2O729Br (Mþ1), 379.10157; found, 379.10165.
4.8. 1-((3aRS,6SR,7aSR)-6-(3-Bromophenyl)-1-methyl tetrahy-
droisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)pent-4-en-1-one
(9b)
4.11. (3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl octahy-
droisoxazolo[4,3-c]pyridine (10a)
Prepared according to the general nitrone condensation/cyclo-
addition procedure, starting from aldehyde 8b (3.44 g, 9.82 mmol)
with all other amounts scaled accordingly, to give 3.38 g (89%) of
the isoxazolidine 9b as a highly viscous, pale yellow gum: NMR
Prepared according to the general 4-pentenamide deprotection
procedure A, starting from amide 9a (2.00 g, 5.27 mmol), with all
other material amounts scaled accordingly. Purification by flash
column chromatography eluting with ethyl acetate/methanol
(100:1/90:10 along a gradient) gave 1.40 g (89%) of the amine 10a
as a brown solid: mp 106e108 ꢂC (pale yellow needles from ethyl
(600 MHz, DMSO-d6, 100 ꢂC):
d 7.41 (s, 1H), 7.40e7.36 (m, 1H),
7.30e7.22 (comp, 2H), 5.77 (app br s, 1H), 5.04e4.86 (comp, 3H),
4.22 (app br s, 1H), 4.01 (app t, J¼8.5, 1H), 3.44 (dd, J¼8.5, 4.9, 1H),
3.14 (app br s, 1H), 2.98 (ddd, J¼11.1, 9.0, 5.2 Hz, 1H), 2.90 (app br s,
1H), 2.57 (s, 3H), 2.45 (app br s,1H), 2.27e2.12 (comp, 3H), 2.15 (app
dt, J¼13.8, 5.3 Hz, 1H), 1.74 (ddd, J¼13.8, 12.0, 11.1 Hz, 1H); 13C NMR
acetate/hexanes); 1H NMR (400 MHz):
d 7.60e7.49 (comp, 2H),
7.34e7.27 (m, 1H), 7.11 (td, J¼7.7, 1.6 Hz, 1H), 4.24 (dd, J¼9.2, 7.2 Hz,
1H), 3.96 (dd, J¼9.8, 2.2 Hz, 1H), 4.02e3.94 (m, 1H), 3.29 (d,
J¼12.5 Hz, 1H), 3.26e3.16 (comp, 2H), 3.07e2.95 (m, 1H), 2.68 (s,
3H), 2.12e2.02 (m, 1H), 1.68e1.50 (comp, 2H); 13C NMR (100 MHz):
(150 MHz, DMSO-d6, 373 K): d 170.6, 146.4,137.2, 129.9, 128.9, 127.6,
123.8, 121.2, 114.1, 66.9, 63.3, 53.0 (br), 42.2, 42.0 (br), 32.6, 31.7,
28.0 (one signal is believed to be undetectable due to peak broad-
ening); IR (neat) 2956, 2882, 1643, 1472, 1416, 1238, 1070, 917,
754 cmꢁ1; HRMS (ESIþ) m/z calculated for C18H23N2O729BrNa
(Mþ23), 401.08396; found, 401.08351.
d
142.7, 132.7, 128.7, 2ꢃ127.9, 123.2, 68.0, 64.4, 57.7, 2ꢃ44.6, 37.8,
34.8; IR (neat) 3313, 2950, 2880, 1469, 1438, 1158, 1119, 1023,
755 cmꢁ1; HRMS (ESIþ) m/z calculated for C13H18NO729Br (Mþ1),
297.0602; found, 297.0597.
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

8
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
4.12. (3aRS,6SR,7aSR)-6-(3-Bromophenyl)-1-methyl octahy-
droisoxazolo[4,3-c]pyridine (10b)
4.15. (3aRS,6SR,7aSR)-1-Methyl-6-(3-morpholinophenyl) oc-
tahydroisoxazolo[4,3-c]pyridine (13)
Prepared according to the general 4-pentenamide deprotection
procedure A, starting from amide 9b (1.00 g, 2.64 mmol), with all
other material amounts scaled accordingly. Purification by flash
column chromatography eluting with ethyl acetate/methanol
(100:1/90:10 along a gradient) gave 0.753 g of the amine 10b
Iodine (1.33 g, 5.25 mmol) was added to a stirred solution of
amide 12 (405 mg, 1.05 mmol) in THF (8.1 mL) and 1.5 M aqueous
HCl (3.0 mL) at room temperature, and the reaction was stirred for
45 min. After 45 min, saturated aqueous Na2S2O3 (4.6 mL total) was
added dropwise until the solution turned yellow, and 1 M NaOH
was added dropwise until the pH of the solution reached 8. The
mixture was then concentrated under reduced pressure, and the
dry residue was triturated with methanol. The methanol extract
was dry-loaded onto silica and purified by column chromatogra-
phy, eluting with ethyl acetate/methanol (9:1/6:4) to afford
248 mg (78%) of the amine 13 as a brown gum: 1H NMR (400 MHz):
(96%) as a yellow gum: 1H NMR (400 MHz):
d 7.53 (s, 1H), 7.38 (d,
J¼7.8 Hz, 1H), 7.28 (d, J¼7.8 Hz, 1H), 7.18 (t, J¼7.8 Hz, 1H), 4.23 (dd,
J¼9.0, 7.2 Hz, 1H), 3.96 (dd, J¼9.0, 7.6 Hz, 1H), 3.58e3.48 (m, 1H),
3.29 (d, J¼12.1 Hz, 1H), 3.22e3.10 (comp, 2H), 3.05e2.90 (m, 1H),
2.67 (s, 3H), 2.03e1.92 (m, 1H), 1.80e1.54 (comp, 2H); 13C NMR
(100 MHz): d 144.6, 130.4, 130.1, 129.9, 125.3, 122.5, 67.9, 64.3, 58.9,
2ꢃ44.5, 37.7, 36.4; IR (neat) 3313, 2950, 2880, 2807, 1594, 1567,
1473, 1436, 1158, 1070, 996, 784, 698 cmꢁ1; HRMS (ESIþ) m/z cal-
culated for C13H18NO729Br (Mþ1), 297.0602; found, 297.0597.
d
7.23 (app t, J¼7.9 Hz, 1H), 7.01e6.97 (m, 1H), 6.89e6.85 (m, 1H),
6.84e6.80 (m, 1H), 4.24e4.16 (m, 1H), 3.97e3.89 (m, 1H), 3.85 (app
t, J¼4.9 Hz, 4H), 3.67 (app d, J¼11.9 Hz, 1H), 3.29e2.93 (comp, 9H),
2.66 (s, 3H), 2.08e1.97 (m, 1H), 1.81e1.70 (m, 1H); 13C NMR
(100 MHz):
d 151.6, 143.2, 129.4, 118.6, 115.0, 114.2, 68.0, 66.9, 64.3,
4.13. (3aRS,6SR,7aSR)-6-(4-Bromophenyl)-1-methyl octahy-
droisoxazolo[4,3-c]pyridine (10c)
58.9, 49.3, 44.4, 43.9, 37.5, 34.8; IR (neat) 3322, 2955, 2855, 1602,
1448, 1244, 1121, 784, 730 cmꢁ1; HRMS (ESIþ) m/z calculated for
C17H26N3O2 (Mþ1), 304.20195; found, 304.20203.
Prepared according to the general 4-pentenamide deprotection
procedure A, starting from amide 9c (313 mg, 0.852 mmol). Puri-
fication by flash column chromatography eluting with ethyl ace-
tate/methanol (100:1/90:10 along a gradient) gave 210 mg (87%)
of the amine 10c as a brown solid: mp 106e107 ꢂC (white needles
4.16. (3aRS,6SR,7aSR)-6-(3-Phenoxyphenyl)-5-(pent-4-enoyl)-
1-methyloctahydroisoxazolo[4,3-c]pyridine (15)
Cs2CO3 (678 mg, 2.11 mmol), CuBr (77 mg, 0.54 mmol), ethyl 2-
cyclohexanone-1-carboxylate (14) (191 mg, 1.12 mmol), and de-
gassed DMSO (1 mL) were combined in a screw-capped vial and
stirred at room temperature for 30 min. A solution of bromide 9b
(200 mg, 0.527 mmol) and phenol (198 mg, 0.53 mmol) in de-
gassed DMSO (0.5 mL) was then added and the mixture was
heated at 130 ꢂC for 5 h. The mixture was cooled to room tem-
perature, and then filtered through a pad of Celite, rinsing with
toluene (30 mL), and water (30 mL). The layers of the filtrate were
separated and the aqueous layer was extracted with toluene
(3ꢃ30 mL). The combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure. The residue was purified by
column chromatography, eluting with ethyl acetate/hexanes/
methanol (50:50:1/90:0:10) to afford 189 mg (91%) of the diaryl
ether 15 as a pale yellow oil: 1H NMR (400 MHz) (6:4 rotamer
from ethyl acetate/hexanes); 1H NMR (400 MHz):
d 7.44 (d,
J¼8.3 Hz, 2H), 7.24 (d, J¼8.3 Hz, 2H), 4.23 (app t, J¼8.2 Hz, 1H), 3.96
(app t, J¼8.2 Hz, 1H), 3.52 (dd, J¼11.7, 2.0 Hz,1H), 3.29 (d, J¼12.7 Hz,
1H), 3.20e3.11 (comp, 2H), 3.04e2.93 (m, 1H), 2.66 (s, 3H),
2.00e1.91 (m, 1H), 1.80e1.54 (comp, 2H); 13C NMR (75 MHz):
d
143.3, 131.5, 128.4, 121.0, 67.9, 64.3, 58.8, 2ꢃ44.5, 37.7, 36.5; IR
(neat) 3322, 2950, 1487, 1071, 1010 cmꢁ1; HRMS (ESIþ) m/z calcu-
lated for C13H18NO729Br (Mþ1), 297.0602; found, 297.0605.
4.14. 1-((3aRS,6SR,7aSR)-Tetrahydro-1-methyl-6-(3-
morpholinophenyl)isoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)
pent-4-en-1-one (12)
A solution of Pd(OAc)2 (5.2 mg, 0.023 mmol) and (2-biphenyl)di-
tert-butylphosphine (11) (6.4 mg, 0.021 mmol) in toluene (0.40 mL)
was stirred at room temperature for 5 min, giving a clear brown
mixture) d 7.38e7.17 (comp, 3H), 7.16e7.04 (comp, 1H), 7.02e6.80
(comp, 5H), 5.76e5.63 (m, 0.6H), 5.89e5.77 (m, 0.4H), 5.10e4.82
(comp, 3H), 4.65 (dd, J¼12.3, 5.5 Hz, 0.6H), 4.20e4.05 (comp, 1H),
3.95e3.84 (m, 0.4H), 3.58e3.50 (comp, 1H), 3.39 (t, J¼12.7 Hz,
0.4H), 3.05e2.85 (comp, 2.6H), 2.67 (s, 3H), 2.56e1.83 (comp, 6H);
solution. Morpholine (12 mg, 12
mL, 0.14 mmol) was added to
a separate vial containing bromide 9b (40.0 mg, 0.105 mmol) in
toluene (0.225 mL, de-gassed by N2 injection), followed by NaOtBu
(13 mg, 0.137 mmol). An aliquot of the catalyst mixture (0.10 mL,
0.0053 mmol) was added, before purging the vial with N2, sealing
and heating under reflux for 20 h. The mixture was then cooled to
room temperature and filtered through a plug of Celite, rinsing with
toluene. The filtrate was evaporated under reduced pressure and
purified by column chromatography, eluting with ethyl acetate/
pentane (50:50/100:0) to afford 34.1 mg (84%) of the aniline 12 as
a clear, colorless gum: 1H NMR (400 MHz) (7:3 rotamer mixture):
13C NMR (150 MHz) (6:4 rotamer mixture):
d 172.9, 171.2, 157.9,
157.5, 157.1, 156.8, 145.5, 145.3, 137.3, 130.6, 129.9, 129.7, 123.6,
123.2, 120.2, 119.5, 118.9, 117.7, 117.1, 115.5, 115.1, 68.3, 67.9, 64.7,
56.1, 53.8, 43.5, 43.2, 39.2, 35.5, 33.3, 32.9, 29.1; IR (neat) 2955,
2876, 1647, 1584, 1487, 1420, 1251, 695 cmꢁ1; HRMS (ESIþ) m/z
calculated for C24H29N2O3 (Mþ1), 393.21727; found, 393.21714.
4.17. (3aRS,6SR,7aSR)-1-Methyl-6-(3-phenoxyphenyl) octahy-
droisoxazolo[4,3-c]pyridine (16)
d
7.28e7.15 (comp, 1H), 6.84e6.67 (comp, 3H), 5.92e5.76 (m, 0.3H),
5.76e5.60 (m, 0.7H), 5.10e4.80 (comp, 3H), 4.65 (dd, J¼12.0, 4.4 Hz,
0.7H), 4.22e4.06 (comp, 1H), 3.95e3.77 (comp, 4.3H), 3.58e3.50
(comp, 1H), 3.43 (t, J¼11.5 Hz, 0.3H), 3.22e3.06 (comp, 4H),
3.05e2.87 (comp, 2.7H), 2.67 (s, 3H), 2.58e1.84 (comp, 6H); 13C
Prepared according to the general 4-pentenamide deprotection
procedure A, starting from amide 13 (72 mg, 0.18 mmol), with all
other material amounts scaled accordingly. Purification by flash
column chromatography eluting with ethyl acetate/methanol
(19:1/9:1 along a gradient) gave 45 mg of the amine 16 (78%) as
NMR (100 MHz) (7:3 rotamer mixture):
d 173.1, 171.1, 151.9, 151.4,
144.5, 144.2, 137.4, 129.9, 129.3,116.8, 116.4, 115.3, 115.0, 114.5, 114.3,
113.1, 111.7, 68.2, 67.8, 66.9, 66.8, 64.7, 64.5, 56.4, 54.2, 49.3, 49.1,
43.6, 43.2, 42.4, 39.3, 35.7, 33.5, 33.2, 32.8, 29.0; IR (neat) 2959,
2855, 1643, 1601, 1446, 1244, 1121, 918, 713 cmꢁ1; MS (ESIþ) m/z
408.22576 [C22H31N3O3Na (MþNa) requires 408.22602].
a yellow gum: 1H NMR (400 MHz):
d 7.36e7.25 (comp, 3H),
7.14e7.06 (comp, 2H), 7.06e7.02 (m, 1H), 7.02e6.96 (m, 2H), 6.89
(ddd, J¼8.2, 2.5, 1.0 Hz, 1H), 4.24e4.16 (m, 1H), 3.96e3.89 (m, 1H),
3.57 (app d, J¼11.0 Hz, 1H), 3.26 (app d, J¼12.5 Hz, 1H), 3.19e3.10
(comp, 2H), 3.03e2.92 (m, 1H), 2.65 (s, 3H), 2.09e1.93 (comp, 2H),
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
9
1.71e1.57 (m, 1H); 13C NMR (150 MHz):
d
157.3, 157.2, 145.9, 129.8,
1.31 mmol) and imidazole (404 mg, 5.94 mmol) in DMSO (1.0 mL)
was then added. The mixture was heated at 120 ꢂC for 22 h and
cooled to room temperature. The mixture was then filtered through
Celite, rinsing with CH2Cl2 (5 mL). The combined filtrate and
washings were partitioned between water (50 mL) and CH2Cl2
(50 mL) and the phases were separated. The CH2Cl2 layer was dried
(MgSO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with CH2Cl2/meth-
anol (100:1/95:5) to give 357 mg (74%) of the N-phenylimidazole
19 as a brown gum: 1H NMR (400 MHz) (11:9 rotamer mixture):
129.7, 123.2, 121.5, 118.8, 117.9, 117.3, 67.9, 64.4, 58.9, 44.5, 44.3, 37.7,
36.1; IR (neat) 3307, 2950, 2880, 1582, 1488, 1439, 1248, 1215,
695 cmꢁ1; HRMS (ESIþ) m/z calculated for C19H23N2O2 (Mþ1),
311.17540; found, 311.17520.
4.18. 1-((3aRS,6SR,7aSR)-1-Methyl-6-(4-(piperidin-1-yl)phe-
nyl)tetrahydroisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)pent-4-
en-1-one (17)
A solution of Pd(OAc)2 (47 mg, 0.21 mmol) and (2-biphenyl)di-
tert-butylphosphine (11) (63 mg, 0.21 mmol) in toluene (4 mL) was
stirred at room temperature for 20 min. This solution was then
added to a mixture of piperidine (1.6 g, 1.9 mL, 19 mmol), NaOt-Bu
(526 mg, 1.37 mmol), and bromide 9c (794 mg, 2.09 mmol) in tol-
uene (7.2 mL) and the resulting mixture was heated at 100 ꢂC for
2.5 h. The mixture was cooled to room temperature and filtered
through Celite, rinsing with methanol (5 mL). The combined filtrate
and washings were concentrated under reduced pressure, and the
residue was partitioned between ether (100 mL) and 1.5 M aqueous
HCl (100 mL). The phases were separated and the aqueous layer
was washed with ether (100 mL). 1 M aqueous NaOH was added to
the aqueous layer to adjust the pH to 14 and the solution was
saturated with NaCl. The aqueous layer was extracted with CH2Cl2
(6ꢃ50 mL) and the combined CH2Cl2 extracts were dried (MgSO4)
and concentrated under reduced pressure. The residue was purified
by flash chromatography eluting with ethyl acetate/hexanes/
methanol (25:75:1/90:0:10) to give 676 mg (84%) of the aniline
17as a pale brown gum: 1H NMR (400 MHz) (7:3 rotamer mixture):
d 7.89e7.78 (comp, 1H), 7.44e7.16 (comp, 6H), 5.90e5.76 (m,
0.55H), 5.76e5.63 (m, 0.45H), 5.12e4.85 (comp, 3H), 4.77 (dd,
J¼12.1, 5.5 Hz, 0.45H), 4.25e4.09 (comp, 1H), 4.01e3.90 (m, 0.55H),
3.63e3.54 (comp, 1H), 3.49 (t, J¼12.8 Hz, 0.55H), 3.10e2.90 (comp,
2.45H), 2.70 (s, 3H), 2.59e1.86 (comp, 6H); 13C NMR (100 MHz)
(11:9 rotamer mixture):
d 172.9, 171.4, 142.9, 142.7, 137.2, 136.7,
136.2, 135.5, 130.6, 130.3, 126.9, 126.5, 122.2, 121.9, 118.4, 118.2,
115.5, 115.2, 68.2, 67.9, 64.6, 64.4, 55.8, 53.8, 43.5, 43.3, 42.3, 39.3,
35.5, 35.1, 33.6, 33.3, 33.0, 29.0; IR (neat) 2956, 1640, 1522,
1428 cmꢁ1; HRMS (ESIþ) m/z calculated for C21H27N4O (Mþ1),
367.2134; found, 367.2134.
4.21. (3aRS,6SR,7aSR)-6-(4-(1H-Imidazol-1-yl)phenyl)-1-
methyloctahydroisoxazolo[4,3-c]pyridine (20)
Prepared according to the general 4-pentenamide deprotection
procedure B, starting from amide 19 (472 mg, 1.29 mmol), with all
other material amounts scaled accordingly. Flash chromatography,
eluting with CH2Cl2/methanol (100:1/95:5/80:20) gave 254 mg
(69%) of the amine 20 as a brown gum: 1H NMR (CD3OD, 400 MHz):
d
7.18e7.10 (m, 0.6H), 7.06 (d, J¼8.4 Hz, 1.4H), 6.90 (d, J¼8.4 Hz, 2H),
5.90e5.75 (m, 0.3H), 5.75e5.62 (m, 0.7H), 5.10e4.83 (comp, 3H),
4.60 (dd, J¼12.3, 5.7 Hz, 0.7H), 4.19e4.07 (comp, 1H), 3.91e3.81 (m,
1H), 3.58e3.52 (comp, 1H), 3.42 (t, J¼12.1 Hz, 0.3H), 3.18e3.06
(comp, 4H), 3.03e2.86 (comp, 2.7H), 2.67 (s, 3H), 2.56e1.84 (comp,
6H), 1.78e1.64 (comp, 4H), 1.64e1.50 (comp, 2H); 13C NMR
d 8.12 (app s, 1H), 7.59e7.50 (comp, 5H), 7.14 (app s, 1H), 4.28e4.20
(m, 1H), 4.00e3.92 (m, 1H), 3.69 (app d, J¼12.3 Hz, 1H), 3.44e3.35
(m, 1H), 3.34e3.26 (comp, 2H), 3.18 (app d, J¼11.9 Hz, 1H),
3.13e3.01 (m, 1H), 2.66 (s, 3H), 2.03e1.94 (m, 1H), 1.55 (app q,
J¼12.3 Hz, 1H); 13C NMR (CD3OD, 75 MHz):
d 144.6, 137.6, 136.9,
130.2, 129.4, 122.3, 119.7, 68.9, 65.4, 59.3, 44.9, 44.5, 38.4, 37.1; IR
(100 MHz) (7:3 rotamer mixture):
d
73.2, 151.5, 137.5, 133.6, 126.4,
125.7, 116.7, 115.2, 114.9, 68.3, 64.8, 55.8, 53.3, 50.5, 43.7, 42.5, 39.2,
35.8, 33.3, 32.9, 29.1, 25.8, 24.2; IR (neat) 2933, 1643, 1514, 1419,
1234 cmꢁ1; HRMS (ESIþ) m/z calculated for C23H34N3O2 (Mþ1),
384.2651; found, 384.2647.
(neat) 3393, 2951, 1524, 1305 cmꢁ1; HRMS (ESIþ) m/z calculated for
C16H21N4O (Mþ1), 285.1715; found, 285.1712.
4.22. General procedure for Suzuki cross-coupling
4.19. 3aRS,6SR,7aSR)-1-Methyl-6-(4-(piperidin-1-yl) phenyl)
octahydroisoxazolo[4,3-c]pyridine (18)
Bromide 10b or 10c (150 mg, 0.505 mmol), arylboronic acid
(74 mg, 0.61 mmol), 2 M aqueous K2CO3 (0.25 mL, 0.50 mmol), and
Pd(PPh3)4 (47 mg, 0.041 mmol) were combined in ethanol (2.5 mL)
and toluene (2.5 mL). The mixture was heated under reflux for 14 h.
After cooling to room temperature, the mixture was concentrated
under reduced pressure and the residue was partitioned between
1 M aqueous HCl (10 mL) and ether (10 mL). The phases were
separated and the ether layer was extracted with 1 M aqueous HCl
(10 mL). The pH of the combined aqueous layers was adjusted to 14
by addition of 4 M aqueous NaOH. The solution was then saturated
with NaCl and extracted with CH2Cl2 (4ꢃ10 mL). The combined
CH2Cl2 layers were dried (MgSO4) and concentrated under reduced
pressure and the residue was purified by flash column chroma-
tography to give the biaryl product 21aee or 22aec.
Prepared according to the general 4-pentenamide deprotection
procedure B, starting from amide 17 (743 mg, 1.93 mmol). Purifi-
cation by flash chromatography, eluting with CH2Cl2/methanol
(100:1/95:5/90:10) gave 461 mg (79%) of the amine 18 as
a brown gum: 1H NMR (400 MHz):
d
7.23 (d, J¼8.6 Hz, 2H), 6.89 (d,
J¼8.6 Hz, 2H), 4.24e4.15 (m, 1H), 3.96e3.88 (m, 1H), 3.53 (app d,
J¼11.7 Hz, 1H), 3.22 (app d, J¼12.9 Hz, 1H), 3.18e3.09 (comp, 6H),
3.03e2.90 (m, 1H), 2.66 (s, 3H), 2.30 (br s, 1H), 1.97 (app dd, J¼12.7,
5.3 Hz, 1H), 1.75e1.64 (comp, 5H), 1.60e1.52 (comp, 2H); 13C NMR
(75 MHz):
d 151.9, 134.0, 127.7, 116.6, 68.2, 64.8, 58.6, 50.8, 44.8,
44.5, 37.8, 35.7, 26.1, 24.5; IR (neat) 3322, 2933, 1613, 1516,
1234 cmꢁ1; HRMS (ESIþ) m/z calculated for C18H28N3O (Mþ1),
302.2228; found, 302.2232.
4.23. (3aRS,6SR,7aSR)-6-(3-(Benzo[d][1,3]dioxol-5-yl)phenyl)-
1-methyloctahydroisoxazolo[4,3-c]pyridine (21a)
4.20. 1-((3aRS,6SR,7aSR)-6-(4-(1H-Imidazol-1-yl)phenyl)-1-
methyltetrahydroisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)
pent-4-en-1-one (19)
Prepared according to the general Suzuki coupling procedure
from bromide 10b (93 mg, 0.31 mmol) with all other material
amounts scaled accordingly, to give 59 mg (56%) of the biaryl 21a as
A
mixture of CuBr (190 mg, 1.32 mmol), ethyl 2-
a brown gum: 1H NMR (400 MHz):
d
7.51 (s, 1H), 7.39 (d, J¼7.3 Hz,
oxocyclohexanecarboxylate (14) (0.45 g, 0.42 mL, 2.6 mmol), and
Cs2CO3 (1.72 g, 5.28 mmol) in DMSO (2.5 mL) was stirred at room
temperature for 30 min. A solution of bromide 9c (498 mg,
1H), 7.35 (app t, J¼7.3 Hz, 1H), 7.28 (d, J¼7.3 Hz, 1H), 7.06 (s, 1H),
7.05 (d, J¼7.9 Hz, 1H), 6.86 (d, J¼7.9 Hz, 1H), 5.98 (s, 2H), 4.23 (app t,
J¼8.0 Hz, 1H), 3.98 (app t, J¼8.0 Hz, 1H), 3.60 (d, J¼11.3 Hz, 1H), 3.29
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10
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
(d, J¼12.7 Hz, 1H), 3.24e3.10 (comp, 2H), 3.04e2.90 (m, 1H), 2.66 (s,
3H), 2.11 (br s, 1H), 2.08e1.98 (m, 1H), 1.78e1.65 (m, 1H); 13C NMR
(d, J¼8.6 Hz, 1H), 4.22 (dd, J¼8.9, 7.1 Hz, 1H), 3.96 (dd, J¼8.9, 7.4 Hz,
1H), 3.80 (s, 3H), 3.64e3.55 (m, 1H), 3.29 (d, J¼12.5 Hz, 1H),
3.24e3.10 (comp, 2H), 3.04e2.90 (m,1H), 2.67 (s, 3H), 2.10e1.99 (m,
(100 MHz):
d
148.1, 147.1, 144.6, 141.1, 135.5, 128.9, 125.9, 2ꢃ125.3,
120.7,108.5,107.7,101.1, 68.0, 64.5, 59.4, 2ꢃ44.6, 37.7, 36.3; IR (neat)
3324, 2951, 2884, 1603, 1476, 1230, 1039, 910, 793, 731 cmꢁ1; HRMS
(ESIþ) m/z calculated for C20H23N2O3 (MþH), 339.17037; found,
339.17032.
1H), 1.86e1.64 (comp, 2H); 13C NMR (100 MHz):
d 156.4, 143.8,
138.7, 130.9, 130.6, 128.6, 128.0, 127.9, 125.2, 120.7, 111.1, 68.0, 64.6,
59.4, 55.5, 2ꢃ44.6, 37.7, 36.3; IR (neat) 3322, 2951, 1600, 1462, 1240,
1026, 911, 731 cmꢁ1; HRMS (ESIþ) m/z calculated for C20H25N2O2
(Mþ1), 325.19146; found, 325.19105.
4.24. (3aRS,6SR,7aSR)-6-(3-(2-Methylphenyl)phenyl)-octahy-
dro-1-methylisoxazolo[4,3-c]pyridine (21b)
4.28. (3aRS,6SR,7aSR)-6-(4-Phenylphenyl)-octahydro-1-
methylisoxazolo[4,3-c]pyridine (22a)
Prepared according to the general Suzuki coupling procedure
from bromide 10b (400 mg, 1.35 mmol) with all other material
amounts scaled accordingly, to give 308 mg (74%) of the biaryl 21b
Prepared according to the general Suzuki coupling procedure
from bromide 10c (150 mg, 0.505 mmol) to give 134 mg (90%) of the
biaryl 22a as a pale yellow solid: mp 150e152 ꢂC (off-white crystals
as a brown gum: 1H NMR (400 MHz):
d 7.29e7.39 (comp, 3H),
7.28e7.19 (comp, 5H), 4.22 (dd, J¼9.1, 7.1 Hz, 1H), 3.96 (dd, J¼9.1,
7.4 Hz, 1H), 3.60 (dd, J¼12.1, 1.8 Hz, 1H), 3.30 (d, J¼12.5 Hz, 1H),
3.24e3.12 (comp, 2H), 3.04e2.90 (m, 1H), 2.67 (s, 3H), 2.25 (s, 3H),
2.09e1.99 (m, 1H), 1.76e1.62 (m, 1H), 1.60 (br s, 1H); 13C NMR
from CHCl3); 1H NMR (400 MHz):
d
7.84 (d, J¼8.2 Hz, 2H), 7.55 (d,
J¼8.2 Hz, 2H), 7.47e7.39 (comp, 4H), 7.33 (t, J¼7.4 Hz, 1H), 4.23 (app
t, J¼8.2 Hz, 1H), 3.99 (app t, J¼8.2 Hz, 1H), 3.60 (d, J¼11.6 Hz, 1H),
3.31 (d, J¼12.3 Hz, 1H), 3.24e3.14 (comp, 2H), 3.05e2.92 (m, 1H),
(100 MHz):
d
144.1, 142.2, 141.8, 135.3, 130.3, 129.8, 2ꢃ128.2, 127.6,
2.68 (s, 3H), 2.09e1.93 (m,1H),1.78e1.64 (m,1H),1.57 (br s,1H); 13
C
127.2, 125.7, 125.0, 68.0, 64.5, 59.4, 2ꢃ44.6, 37.7, 36.6, 20.5; IR (neat)
3320, 2949, 1476, 1437, 1157, 1117, 912, 760, 729 cmꢁ1; HRMS (ESIþ)
m/z calculated for C20H25N2O (MþH), 309.19658; found, 309.19614.
NMR (100 MHz):
d
143.4, 140.9, 140.3, 128.8, 2ꢃ127.3, 127.2, 127.1,
68.1, 64.6, 59.2, 2ꢃ44.7, 37.8, 36.4; IR (neat) 3323, 2950, 2880, 1487,
1437 cmꢁ1; HRMS (ESIþ) m/z calculated for C19H23N2O (Mþ1),
295.1805; found, 295.1802.
4.25. (3aRS,6SR,7aSR)-6-(3-Phenylphenyl)-octahydro-1-
methylisoxazolo[4,3-c]pyridine (21c)
4.29. (3aRS,6SR,7aSR)-6-(4-(Benzofuran-2-yl)phenyl)-1-
methyloctahydroisoxazolo[4,3-c]pyridine (22b)
Prepared according to the general Suzuki coupling procedure
from bromide 10b (400 mg, 1.35 mmol) with all other material
amounts scaled accordingly, to give 327 mg (80%) of the biaryl 21c
Prepared according to the general Suzuki coupling procedure
from bromide 10c (130 mg, 0.44 mmol) with all other amounts
scaled accordingly, to give 96 mg (65%) of the biaryl 22b as a white
as a brown gum: 1H NMR (400 MHz):
d 7.64e7.55 (comp, 3H), 7.49
(d, J¼7.3 Hz, 1H), 7.43 (app t, J¼7.2, 2H), 7.38 (d, J¼7.6 Hz, 1H),
7.36e7.30 (comp, 2H), 4.24 (dd, J¼9.0, 7.0 Hz, 1H), 3.99 (dd, J¼9.0,
7.4 Hz, 1H), 3.67e3.58 (m, 1H), 3.30 (d, J¼12.9 Hz, 1H), 3.24e3.14
(comp, 2H), 3.05e2.93 (m, 1H), 2.68 (s, 3H), 2.10e2.00 (m, 1H),
foam: 1H NMR (400 MHz):
d
7.82 (d, J¼8.2 Hz, 2H), 7.57 (dd, J¼7.5,
1.2 Hz, 1H), 7.51 (dd, J¼7.5, 0.8 Hz, 1H), 7.44 (d, J¼8.2 Hz, 2H), 7.27
(app dt, J¼7.5, 1.2 Hz, 1H), 7.22 (app dt, J¼7.5, 0.8 Hz, 1H), 7.00 (s,
1H), 4.25 (app t, J¼8.2 Hz, 1H), 3.99 (app t, J¼8.2 Hz, 1H), 3.60 (app
d, J¼10.8 Hz, 1H), 3.31 (app d, J¼12.5 Hz, 1H), 3.24e3.14 (comp, 2H),
3.05e2.94 (m, 1H), 2.68 (s, 3H), 2.02 (app dd, J¼12.5, 5.7 Hz, 1H),
1.88e1.50 (comp, 2H); 13C NMR (100 MHz):
d 144.8, 141.5, 141.1,
128.9,128.7, 127.3, 127.2,126.2,125.7, 125.6, 68.0, 64.5, 59.5, 2ꢃ44.6,
37.8, 36.4; IR (neat) 3323, 2951, 1599, 1478, 1437, 911, 760,
704 cmꢁ1; HRMS (ESIþ) m/z calculated for C19H23N2O (MþH),
295.1805; found, 295.1805.
1.69 (app q, J¼12.5 Hz,1H); 13C NMR (75 MHz):
d 155.8,154.8, 144.6,
129.5, 129.2, 127.1, 125.1, 124.2, 122.9, 120.8, 111.1, 101.1, 68.0, 64.4,
59.1, 2ꢃ44.6, 37.7, 36.4; IR (neat) 3320, 2927, 1452, 1257 cmꢁ1
;
HRMS (ESIþ) m/z calculated for C21H23N2O2 (Mþ1), 335.17540;
4.26. (3aRS,6SR,7aSR)-6-(3-(4-Cyanophenyl)phenyl)-octahy-
dro-1-methylisoxazolo[4,3-c]pyridine (21d)
found, 335.17546 cmꢁ1
.
4.30. (3aRS,6SR,7aSR)-1-Methyl-6-(4-(pyridin-3-yl) phenyl)
octahydroisoxazolo[4,3-c]pyridine (22c)
Prepared according to the general Suzuki coupling procedure
from bromide 10b (400 mg, 1.35 mmol) with all other material
amounts scaled accordingly, to give 377 mg (89%) of the biaryl 21d
Prepared according to the general Suzuki coupling procedure
from bromide 10c (130 mg, 0.44 mmol) with all other amounts
scaled accordingly, to give 85 mg (65%) of the biaryl 22c as an or-
as a brown glass: 1H NMR (400 MHz):
d
7.72 (d, J¼8.6 Hz, 2H), 7.68
(d, J¼8.6 Hz, 2H), 7.60 (s, 1H), 7.48 (app dt, J¼6.9, 1.9 Hz, 1H),
7.46e7.38 (comp, 2H), 4.25 (dd, J¼9.0, 7.4 Hz, 1H), 3.99 (dd, J¼9.0,
7.2 Hz, 1H), 3.62 (dd, J¼12.2, 2.1, 1H), 3.32 (d, J¼12.5 Hz, 1H),
3.26e3.14 (comp, 2H), 3.07e2.94 (m, 1H), 2.68 (s, 3H), 2.09e2.00
ange gum: 1H NMR (400 MHz):
d
8.84 (d, J¼2.4 Hz, 1H), 8.58 (dd,
J¼4.8, 1.4 Hz, 1H), 7.87 (app dt, J¼7.9, 1.9 Hz, 1H), 7.55 (d, J¼8.2 Hz,
2H), 7.47 (d, J¼8.2 Hz, 2H), 7.35 (dd, J¼7.9, 4.8 Hz, 1H), 4.25 (app t,
J¼8.2 Hz,1H), 3.99 (app t, J¼8.2 Hz,1H), 3.63 (dd, J¼11.8, 1.8 Hz, 1H),
3.32 (app d, J¼12.1 Hz, 1H), 3.25e3.16 (comp, 2H), 3.07e2.95 (m,
1H), 2.68 (s, 3H), 2.09e1.90 (m, 1H), 1.94 (br s, 1H), 1.70 (app q,
(m, 1H), 1.85e1.62 (comp, 2H); 13C NMR (100 MHz):
d 145.6, 145.3,
139.4, 132.6, 129.3, 127.8, 127.2, 126.3, 125.6, 119.0, 110.9, 68.0, 64.4,
59.3, 44.6, 44.5, 37.7, 36.5; IR (neat) 3324, 2951, 2882, 2226, 1605,
1481, 1437, 913, 795, 732 cmꢁ1; HRMS (ESIþ) m/z calculated for
J¼11.8 Hz, 1H); 13C NMR (100 MHz):
d 148.6, 148.5, 144.5, 137.1,
C
20H22N3O (MþH), 320.17618; found, 320.17574.
137.1,134.5,127.7,127.5, 123.8, 68.2, 64.7, 59.3, 2ꢃ44.8, 38.0, 36.6; IR
(neat) 3342, 2952, 1474, 1435 cmꢁ1; HRMS (ESIþ) m/z calculated for
4.27. (3aRS,6SR,7aSR)-6-(3-(2-Methoxyphenyl)phenyl)-octa-
hydro-1-methylisoxazolo[4,3-c]pyridine (21e)
C18H22N3O (Mþ1), 296.17574; found, 296.17597.
4.31. General procedure for the preparation of bis(-
trimethylsilyl) amino acid derivatives
Prepared according to the general Suzuki coupling procedure
from bromide 10b (400 mg, 1.35 mmol) with all other material
amounts scaled accordingly, to give 354 mg (80%) of the biaryl 21e
The N-alkylamino acid (sarcosine or N-(4-methoxybenzyl)gly-
cine,27 13.3 mmol), Et3N (5.4 g, 7.4 mL, 53 mmol), and TMSCl (4.3 g,
5.1 mL, 40 mmol) were combined in dry CH2Cl2 (27 mL). The
as a brown gum: 1H NMR (400 MHz):
d
7.49 (s, 1H), 7.44 (d,
J¼7.2 Hz, 1H), 7.40e7.27 (comp, 4H), 7.02 (td, J¼7.4, 0.9 Hz, 1H), 6.97
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
11
resulting slurry was stirred for 20 h and then the volatile compo-
nents were removed under reduced pressure. The residue was
suspended in dry benzene (12 mL) and the solid was removed by
Schlenk filtration under nitrogen. The filtrate was concentrated in
vacuo to afford the crude N,O-bis(trimethylsilyl)amino acid 25 or
26, which was used immediately without further purification.
as a yellow gum: 1H NMR (400 MHz) (2:1 rotamer mixture):
7.54e7.46 (comp, 1H), 7.33e7.08 (comp, 4.7H), 7.06e7.00 (m,
d
0.3H), 6.82 (d, J¼8.5 Hz, 2H), 5.12 (dd, J¼13.3, 4.8 Hz, 0.3H),
4.92e4.83 (comp, 1.4H), 3.89e3.73 (comp, 1.3H), 3.78 (s, 3H),
3.52e3.37 (comp,1.3H), 2.94e2.83 (comp,1.7H), 2.79e2.69 (m, 1H),
2.50e2.36 (m, 1H), 2.32e2.20 (comp, 2H), 2.11 (s, 0.9H), 1.97e1.87
(m, 1H), 1.72 (s, 2.1H), 1.55 (app q, J¼13.0 Hz, 1H), 1.50e1.38
4.32. 1-((3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl tetra-
hydro-1H-pyrrolo[3,2-c]pyridin-5(6H,7H,7aH)-yl)pent-4-en-1-
one (27)
(m, 1H); 13C NMR (100 MHz) (2:1 rotamer mixture):
d 171.3, 169.3,
158.8, 143.6, 143.1, 142.8, 133.1, 130.2, 128.9, 128.6, 128.0, 127.8,
126.2, 125.3, 121.8, 121.1, 113.7, 60.2, 59.9, 58.1, 57.7, 56.7, 55.3, 54.8,
52.9, 52.7, 47.0, 41.9, 39.1, 38.2, 34.5, 28.0, 22.4, 21.9; IR (neat) 2931,
1645, 1513, 1416, 1249 cmꢁ1; HRMS (CIþ) m/z calculated for
N,O-Bis(trimethylsilyl)sarcosine (25) (0.56 g, 2.4 mmol) and al-
dehyde 8a (0.413 g, 1.18 mmol) were combined in dry toluene
(4.6 mL) under nitrogen. After stirring for 1 h, the solution was
heated at 135 ꢂC for 20 h. The mixture was cooled to room tem-
perature and then concentrated to dryness. The residue was puri-
fied by flash column chromatography eluting with CH2Cl2/
methanol (100:1/90:10 along a gradient) to give 275 mg (62%) of
the pyrrolidine 27 as a pale brown gum: 1H NMR (2:1 rotamer
C
23H27N2O729Br (Mþ), 442.1256; found, 442.1252.
4.35. (3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl-5-(acetyl)
octahydro-1H-pyrrolo[3,2-c]pyridine (2)
1-Chloroethyl chloroformate (13 mg, 10 mL, 0.093 mmol) was
added to a solution of amine 30 (20.7 mg, 0.0467 mmol) and Et3N
(47 mg, 0.047 mmol) in CH2Cl2 (0.2 mL) at 0 ꢂC. After 15 min, the
mixture was concentrated under reduced pressure. The residue was
redissolved in methanol (5 mL) and the mixture was heated under
reflux for 1 h, then concentrated under reduced pressure. The
residue was partitioned between CH2Cl2 (10 mL) and saturated
aqueous NaHCO3 (10 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢃ10 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure and the residue was passed through a plug of silica, eluting
with (100:1/4:1 along a gradient) to give the crude intermediate
amine 31 (7.8 mg). This was combined with acetic acid (1.5 mg,
0.0025 mmol), paraformaldehyde (8 mg, 0.3 mmol), and NaB-
H(OAc)3 (31 mg, 0.15 mmol) in 1,2-dichloroethane (0.4 mL) and the
mixture was stirred at room temperature for 30 h, then the mixture
was partitioned between CH2Cl2 (10 mL) and saturated aqueous
NaHCO3 (10 mL). The phases were separated and the aqueous layer
was extracted with CH2Cl2 (10 mL). The combined organic layers
were dried (MgSO4) and concentrated under reduced pressure, and
the residue was purified by flash column chromatography, eluting
with CH2Cl2/methanol (100:1/4:1 along a gradient) to give 6.8 mg
(44% over two steps) of the amine 2 as a yellow gum. Spectroscopic
data were identical to those obtained from a sample prepared
previously.12b,c
mixture) (600 MHz):
d
7.54 (dd, J¼8.0, 1.1 Hz, 0.7H), 7.50 (dd, J¼7.7,
1.0 Hz, 0.3H), 7.33e7.28 (m, 0.7H), 7.26 (dd, J¼7.7, 1.7 Hz, 0.7H),
7.23e7.19 (m, 0.3H), 7.16e7.10 (td, J¼7.6, 1.7 Hz, 1H), 7.06e7.01 (m,
0.3H), 5.86e5.77 (m, 0.3H), 5.72e5.63 (m, 0.7H), 5.15 (dd, J¼13.7,
4.7 Hz, 0.3H), 5.02 (dd, J¼17.1, 1.5 Hz, 0.3H), 5.00e4.94 (comp, 1H),
4.92e4.84 (comp, 2.1H), 3.89 (dd, J¼13.6, 5.3 Hz, 0.3H), 3.45e3.38
(m, 0.3H), 3.00e2.94 (comp, 1H), 2.90 (app t, J¼12.6 Hz, 0.7H),
2.53e2.31 (comp, 7.2H), 2.31e2.18 (comp, 2.4H), 2.13e2.05 (m,
0.7H), 2.01e1.94 (comp, 1H), 1.79 (ddd, J¼14.3, 8.1, 5.2 Hz, 0.7H),
1.60e1.45 (comp, 2H); 13C NMR (150 MHz) (2:1 rotamer mixture):
d
173.1, 171.2, 143.5, 143.3, 137.6, 137.3, 2ꢃ133.0, 128.9, 128.6, 128.0,
127.8, 126.6, 125.5, 121.8, 121.1, 115.1, 114.9, 62.1, 61.9, 55.8, 55.7,
55.6, 54.9, 46.0, 42.0, 40.5, 40.2, 39.4, 38.6, 34.6, 33.4, 2ꢃ33.4, 32.7,
29.1, 29.0, 28.6, 28.3; IR (neat) 2936, 2782, 1649, 1417, 1238, 1024,
911, 755; HRMS (ESIþ) m/z calculated for C19H26N2O79Br (Mþ1),
377.12230; found, 377.12228.
4.33. (3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl octahy-
dro-1H-pyrrolo[3,2-c]pyridine (28)
Prepared according to the general 4-pentenamide deprotection
procedure B, starting with amide 27 (70 mg, 0.19 mmol). Purifica-
tion by flash column chromatography eluting with CH2Cl2/metha-
nol/Et3N (100:1:1/90:10:1) gave 42 mg (77%) of the amine 28 as
a pale yellow gum: 1H NMR (400 MHz):
d
7.59 (dd, J¼7.9,1.7 Hz,1H),
4.36. General N-acylation or sulfonylation procedure
7.52 (dd, J¼7.9, 0.9 Hz,1H), 7.31 (td, J¼7.9, 0.9 Hz,1H), 7.10 (td, J¼7.9,
1.7 Hz, 1H), 3.96 (dd, J¼11.6, 2.4 Hz, 1H), 3.15e3.00 (comp, 3H),
2.93e2.84 (m, 1H), 2.74 (td, J¼9.6, 4.1 Hz, 1H), 2.48e2.36 (m, 1H),
The amine substrate (0.091 mmol) was combined with Et3N
(28 mg, 0.28 mmol) and the required acid chloride or sulfonyl
chloride (0.14 mmol) in CH2Cl2 (1.0 mL). After the reaction had
reached completion (as judged by TLC) the mixture was concen-
trated under reduced pressure and the residue was suspended in
ethyl acetate (2 mL). The mixture was then filtered and the filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography to afford the desired amides or
sulfonamides.
2.39 (s, 3H), 2.08e1.87 (comp, 3H), 1.31 (app q, J¼11.6 Hz, 1H); 13
C
NMR (75 MHz):
d 144.0, 132.8, 128.5, 128.0, 127.9, 123.1, 62.3, 57.1,
52.9, 47.1, 38.2, 37.5, 30.1, 26.3; IR (neat) 3392, 2936, 2787, 1468,
1440, 1022 cmꢁ1; HRMS (CIþ) m/z calculated for C14H20N729Br
(Mþ1), 295.0810; found, 295.0804.
4.34. (3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-(4-methoxy ben-
zyl)-5-(acetyl)octahydro-1H-pyrrolo[3,2-c]pyridine (30)
4.37. (3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl-5-(phe-
nylsulfonyl)octahydro-1H-pyrrolo[3,2-c]pyridine (29)
N,O-Bis(trimethylsilyl)-N-(4-methoxybenzyl)
glycine
(26)
(224 mg, 0.66 mmol) was combined with aldehyde 23 (100 mg,
0.32 mmol) in toluene (3.3 mL). The mixture was stirred for 30 min
at room temperature and then heated at 105 ꢂC for a further 3 h.
The mixture was cooled to room temperature and partitioned be-
tween water (10 mL) and toluene (10 mL). The phases were sepa-
rated, and the toluene layer was dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash chro-
matography eluting with CH2Cl2/methanol (100:1 then 95:5 then
90:10 along a gradual gradient) to give 86 mg (60%) of the amine 30
Prepared according to the general sulfonylation procedure
from the amine 28 (27 mg, 0.091 mmol). Purification by flash
column chromatography, eluting with CH2Cl2/methanol/Et3N
(100:1:1/90:10:1) gave 29 mg (73%) of the sulfonamide 29 as
a yellow gum: 1H NMR (400 MHz):
d
7.67 (d, J¼7.8 Hz, 2H), 7.50 (t,
J¼7.5 Hz, 1H), 7.45 (d, J¼7.9 Hz, 1H), 7.43e7.35 (m, 2H), 7.26 (dd,
J¼7.3, 1.4 Hz, 1H), 7.15 (t, J¼7.3 Hz, 1H), 7.04 (td, J¼7.9, 1.4 Hz, 1H),
5.03 (dd, J¼13.0, 4.1 Hz, 1H), 4.05 (dd, J¼14.4, 5.5 Hz, 1H), 3.37e3.28
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

12
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
(m, 1H), 3.13e3.02 (m, 1H), 2.57e2.43 (m, 1H), 2.41 (s, 3H),
2.35e2.21 (comp, 3H), 2.00e1.88 (m, 1H), 1.86e1.65 (m, 1H),
The residue was purified by column chromatography, eluting with
ethyl acetate/pentane/methanol (50:50:5/100:0:5) to give 25 mg
(85%) of the amine 33 as a colorless gum: 1H NMR (400 MHz):
1.58e1.44 (m, 1H); 13C NMR (100 MHz):
d 142.1, 139.8, 132.8, 132.7,
129.0, 128.8, 128.0, 127.9, 127.4, 121.5, 62.5, 56.0, 55.5, 46.2, 39.9,
37.4, 33.4, 28.0; IR (neat) 2941, 2783, 1446, 1352, 1163 cmꢁ1; HRMS
(ESIþ) m/z calculated for C20H24N2O2S79Br (Mþ1), 435.0738; found,
435.0736.
d
7.36e7.25 (comp, 3H), 7.20 (app d, J¼1.7 Hz, 1H), 7.15e7.07 (comp,
4H), 7.06e7.03 (m, 1H), 6.98 (2H, d, J¼7.8 Hz, 2H), 6.90 (ddd, J¼8.0,
2.4, 0.8 Hz, 1H), 4.18e4.09 (m, 1H), 3.94e3.84 (m, 1H), 3.75 (d,
J¼14.1 Hz, 1H), 3.16 (dd, J¼11.5, 2.35 Hz, 1H), 3.15e3.04 (m, 1H),
3.04e2.92 (comp, 2H), 2.80 (d, J¼14.1 Hz, 1H), 2.62 (s, 3H), 2.33 (dd,
J¼13.3, 4.3 Hz, 1H), 2.02e1.93 (m, 1H), 1.92e1.79 (m, 1H); 13C NMR
4.38. (3aRS,6SR,7aSR)-6-(3-Morpholinophenyl)-5-(3-
phenylpropionyl)-1-methyloctahydroisoxazolo[4,3-c]pyridine
(32)
(100 MHz):
d 157.7, 157.0, 145.5, 143.2, 134.8, 130.1, 129.8, 127.1,
126.5, 123.4, 122.2, 118.9, 118.0, 117.5, 68.1, 66.2, 63.8, 57.9, 50.6,
44.4, 38.5, 37.4; IR (neat) 2952, 2881, 2805, 1585, 1568, 2487, 1432,
Prepared according to the general acylation procedure from the
amine 13 (24 mg, 0.077 mmol), with all other material amounts
scaled accordingly. Purification by column chromatography, eluting
with pentane/ethyl acetate/methanol (25:75:1/0:9:1) gave 26 mg
(77%) of the amide 32 as a brown gum: 1H NMR (400 MHz) (3:1
1251, 1217, 797, 752 cmꢁ1; HRMS (ESIþ) m/z calculated for
35
C
H
Cl2N2O2 (Mþ1), 469.14441; found, 469.14419.
26 27
4.41. (3aRS,6SR,7aSR)-N-Ethyl-1-methyl-6-(4-(piperidin-1-yl)
phenyl)hexahydroisoxazolo[4,3-c]pyridine-5(1H)-carbox-
amide (35)
rotamer mixture):
d 7.33e7.14 (comp, 4.5H), 7.07e6.98 (comp,
1.5H), 6.72 (comp, 1.5H), 6.70e6.62 (comp, 1.5H), 5.03 (dd, J¼12.7,
5.3 Hz, 0.25H), 4.94e4.85 (m, 0.75H), 4.38 (dd, J¼12.5, 5.5 Hz,
0.75H), 4.17e4.07 (m, 0.75H), 4.08e4.00 (m, 0.25H), 3.89e3.80 (m,
4.25H), 3.52 (dd, J¼9.0, 4.7 Hz, 0.75H), 3.47 (dd, J¼8.6, 5.3 Hz,
0.25H), 3.36 (app t, J¼13.0 Hz, 0.25H), 3.22e3.04 (comp, 4H),
3.20e2.78 (comp, 8.25H), 2.45 (dt, J¼14.7, 9.0 Hz, 0.75H), 2.27 (ddd,
J¼14.7, 8.6, 5.7 Hz, 0.75H), 2.23e2.12 (m, 0.25H), 2.12e2.01 (m,
0.75H), 1.99e1.86 (m, 0.25H), 1.91e1.77 (m, 0.75H); 13C NMR
Amine 18 (20.0 mg, 0.0664 mmol), Et3N (6.8 mg, 0.067 mmol),
and ethyl isocyanate (9.5 mg, 0.13 mmol) were combined in CH2Cl2
(0.5 mL). After 14 h, the mixture was concentrated under reduced
pressure and the residue was purified by flash column chroma-
tography
(50:50:1/100:0:1) to give 24 mg (98%) of the urea 35 as an orange
gum: 1H NMR (400 MHz):
eluting
with
ethyl
acetate/pentane/methanol
d
7.15 (d, J¼8.7 Hz, 2H), 6.93 (d, J¼8.7 Hz,
(100 MHz) (3:1 rotamer mixture):
d
173.3, 171.1, 152.0, 144.5, 141.1,
2H), 4.63 (dd, J¼12.7, 5.5 Hz, 1H), 4.28 (dd, J¼13.0, 4.4 Hz, 1H),
4.17e4.07 (comp, 2H), 3.52 (dd, J¼8.9, 4.8 Hz, 1H), 3.20e3.13 (comp,
4H), 3.12e3.01 (comp, 3H), 3.01e2.80 (comp, 2H), 2.67 (s, 3H),
2.10e2.01 (m, 1H), 1.92e1.81 (m, 1H), 1.76e1.67 (comp, 4H),
1.63e1.54 (comp, 2H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
130.0, 129.4, 128.5, 128.4, 126.1, 116.9, 116.5, 114.5, 114.4, 113.4, 111.8,
68.2, 67.9, 66.9, 66.8, 64.6, 56.5, 54.3, 49.4, 49.1, 43.6, 43.3, 42.3,
39.3, 35.9, 35.4, 35.3, 31.7, 31.3; IR (neat) 2958, 2855, 1644, 1602,
1449, 1418, 1244, 1122, 753, 701 cmꢁ1; HRMS (ESIþ) m/z calculated
for C26H34N3O3 (Mþ1), 436.25947; found, 436.25949.
d
158.4, 151.8, 133.1, 126.0, 116.9, 68.4, 65.1, 55.6, 50.4, 43.7, 42.8,
40.2, 35.9, 35.5, 25.7, 24.2, 15.3; IR (neat) 3416, 2934, 1633, 1515,
1236 cmꢁ1; HRMS (ESIþ) m/z calculated for C21H33N4O2 (Mþ1),
373.2598; found, 373.2597.
4.39. (3aRS,6SR,7aSR)-6-(Biphenyl-3-yl)-1-methyl-5-(o-tol-
ylsulfonyl)octahydroisoxazolo[4,3-c]pyridine (34)
Prepared according to the general sulfonylation procedure from
the amine 21c (20 mg, 0.067 mmol), with all other material amounts
scaled accordingly. Purification by column chromatography eluting
with pentane/ethyl acetate/methanol (75:25:1/50:50:1) gave
24 mg (80%) of the sulfonamide 34 as a colorless gum: 1H NMR
4.42. (3aRS,6SR,7aSR)-6-(4-(1H-Imidazol-1-yl)phenyl)-5-(me-
sitylsulfonyl)-1-methyloctahydroisoxazolo[4,3-c] pyridine
(36)
Prepared according to the general sulfonylation procedure from
the amine 20 (19 mg, 0.067 mmol), with all other material amounts
scaled accordingly. Purification by column chromatography eluting
with pentane/ethyl acetate/methanol (75:25:1/50:50:1) gave
26 mg (84%) of the sulfonamide 36 as a colorless gum: 1H NMR
(400 MHz):
d
7.64 (dd, J¼7.8, 1.0 Hz, 1H), 7.45e7.31 (comp, 5H),
7.27e7.22 (m,1H), 7.16e7.07 (comp, 3H), 7.01e6.89 (comp, 3H), 4.82
(dd, J¼12.4, 5.0 Hz, 1H), 4.27 (dd, J¼14.0, 5.8 Hz, 1H), 4.23e4.14 (m,
1H), 3.52 (dd, J¼9.0, 5.0 Hz, 1H), 3.40 (dd, J¼14.0, 11.9 Hz, 1H),
3.26e3.14 (m, 1H), 3.15e3.00 (m, 1H), 2.69 (s, 3H), 2.39 (s, 3H),
2.21e2.11 (m, 1H), 2.02 (ddd, J¼14.1, 12.5, 11.0 Hz, 1H); 13C NMR
(400 MHz):
d
7.71 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 7.08 (d, J¼8.7 Hz,
2H), 7.03 (d, J¼8.7 Hz, 2H), 6.65 (s, 2H), 4.72 (dd, J¼12.3, 4.8 Hz, 1H),
4.26 (dd, J¼14.1, 5.7 Hz, 1H), 4.22e4.14 (m, 1H), 3.52 (dd, J¼9.0,
4.8 Hz, 1H), 3.34 (dd, J¼14.1, 12.1 Hz, 1H), 3.25e3.03 (comp, 2H),
2.69 (s, 3H), 2.45 (s, 6H), 2.19e2.08 (comp, 4H), 1.96 (ddd, J¼14.1,
(100 MHz):
d 141.6, 141.1, 140.7, 138.1, 137.3, 132.5, 132.0, 129.9,
2ꢃ128.7, 128.6, 127.3, 127.0, 126.2, 125.6, 125.1, 68.3, 64.6, 56.4, 43.5,
43.4, 43.1, 34.0, 20.1; IR (neat) 2954, 2852, 1602, 1489, 1448, 1263,
1247, 1122, 956, 785, 753 cmꢁ1; mass spectrum (CIþ) m/z calculated
for C26H28N2O3S (Mþ), 448.1821; found, 448.1818.
12.5, 10.8 Hz, 1H); 13C NMR (75 MHz):
d 142.4, 140.9, 139.5, 136.2,
135.4, 133.5, 131.5, 130.4, 127.3, 120.9, 118.1, 68.3, 64.4, 55.6, 43.4,
43.2, 42.8, 34.0, 22.7, 20.7; IR (neat) 2956, 1523, 1307, 1153,
1057 cmꢁ1; HRMS (ESIþ) m/z calculated for C25H31N4O3S (Mþ1),
467.2109; found, 467.2111.
4.40. (3aRS,6SR,7aSR)-5-(3,5-Dichlorobenzyl)-1-methyl-6-(3-
phenoxyphenyl)octahydroisoxazolo[4,3-c]pyridine (33)
The amine 16 (21 mg, 0.065 mmol) was combined with 3,5-
dichlorobenzaldehyde (68 mg, 0.39 mmol), acetic acid (5 mg,
0.08 mmol), and sodium triacetoxyborohydride (82 mg, 0.39 mmol)
in 1,2-dichloroethane (1.4 mL) and the mixture was stirred for 19 h.
Saturated aqueous NaHCO3 (3 mL) was added and the mixture was
stirred vigorously for 10 min. The mixture was filtered through
Celite, rinsing with ethyl acetate (3 mL), and saturated NaHCO3
(2 mL). The phases were separated and the aqueous layer was
extracted with ethyl acetate (2ꢃ3 mL). The combined organic ex-
tracts were dried (MgSO4) and evaporated under reduced pressure.
4.43. (3aRS,6SR,7aSR)-6-Biphenyl-4-yl)-5-(4-methoxy ben-
zyl)-1-methyloctahydroisoxazolo[4,3-c]pyridine (37)
Amine 22a (23 mg, 0.77 mmol) was combined with NaBH(OAc)3
(100 mg, 0.47 mmol), acetic acid (4.6 mg, 0.77 mmol), and p-ani-
saldehyde (63 mg, 0.46 mmol) in DCE (1.5 mL) was stirred at room
temperature for 16 h before addition of 1.5 M aqueous HCl (1 mL)
and further stirring for 30 min. The mixture was then partitioned
between ether (3 mL) and 1.5 M aqueous HCl (3 mL) and the phases
were separated. The aqueous layer was washed with ether
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
13
(2ꢃ3 mL). 4 M aqueous NaOH was added to the aqueous layer to
4.46. (1SR,9Z,12RS,16SR)-15-Methyl-N-(2-phenylethyl)-14-
oxa-8-thia-10,15-diazatetracyclo[8.7.0.02,7.012,16] heptadeca-
2(7),3,5-trien-9-imine (42)
adjust the pH to 14 and the solution was saturated with NaCl. The
solution was then extracted with ethyl acetate (3ꢃ5 mL). The
combined ethyl acetate extracts were dried (MgSO4) and evapo-
rated and the residue was purified by flash chromatography eluting
with CH2Cl2/methanol (100:1 to 90:10 along a gradient), to give
22 mg (69%) of the amine 37as a colorless gum: 1H NMR (400 MHz):
Amine 10a (40 mg, 0.14 mmol), Cs2CO3 (92 mg, 0.28 mmol), Pd[(t-
Bu)3P]2 (7.0 mg, 0.014 mmol), and phenethyl isothiocyanate (24 mg,
0.15 mmol) were combined in 1,4-dioxane (0.40 mL). The mixture
was stirred at room temperature for 5 h and then heated under reflux
for 11 h. The mixture was diluted with CH2Cl2 (3 mL) and filtered
through Celite. The filtrate was concentrated under reduced pressure
and the residue was purified by flash column chromatography
eluting with CHCl3/methanol (49:1) then CH2Cl2/methanol/Et3N
(95:5:1) to give 41 mg (79%) of the 2-imino-1,3-benzothiazinane 42
d
7.61e7.53 (comp, 4H), 7.49 (d, J¼7.8 Hz, 2H), 7.42 (app t, J¼7.6 Hz,
2H), 7.32 (t, J¼7.6 Hz, 1H), 7.17 (d, J¼8.1 Hz, 2H), 6.82 (d, J¼8.1 Hz,
2H), 4.11 (app t, J¼7.9 Hz, 1H), 3.96 (app t, J¼7.9 Hz, 1H), 3.82e3.73
(m, 1H), 3.78 (s, 3H), 3.22 (app dd, J¼11.6, 2.8 Hz, 1H), 3.16e2.91
(comp, 3H), 2.78 (d, J¼13.5 Hz, 1H), 2.63 (s, 3H), 2.33 (dd, J¼12.9,
3.3 Hz, 1H), 2.04e1.86 (comp, 2H); 13C NMR (100 MHz):
d 158.5,
143.2, 140.9, 140.1, 131.6, 129.3, 128.7, 127.9, 127.3, 127.1, 127.0, 113.6,
68.3, 66.1, 64.1, 58.0, 55.2, 50.1, 44.5, 38.7, 37.8; IR (neat) 2951, 1511,
1249, 1036 cmꢁ1; HRMS (ESIþ) m/z calculated for C27H30N2O2Na
(Mþ23), 437.21995; found, 437.21989.
as a yellow gum: 1H NMR (400 MHz):
d 7.36e7.16 (comp, 9H),
4.58e4.44 (m,1H), 4.22e4.11 (comp, 2H), 3.66 (dt, J¼13.2, 7.9 Hz,1H),
3.58 (dt, J¼13.2, 7.9 Hz,1H), 3.57e3.51 (m,1H), 3.12e2.94 (comp, 3H),
2.87 (t, J¼7.9 Hz, 2H), 2.79 (s, 3H), 2.53e2.41 (m, 1H), 2.31e2.19 (m,
1H); 13C NMR (75 MHz):
d 151.5,140.7,138.5,132.2,129.1,128.3,128.0,
127.1, 126.9, 126.0, 123.2, 68.6, 65.1, 54.1, 52.7, 43.9, 42.4, 41.0, 38.2,
27.6; IR (neat) 2857, 1613, 1443, 1380, 1240 cmꢁ1; HRMS (ESIþ) m/z
calculated for C22H26N3OS (Mþ1), 380.1791; found, 380.1790.
4.44. (3aRS,6SR,7aSR)-1-Methyl-5-trimethylacetyl-6-(4-(pyr-
idin-3-yl)phenyl)octahydroisoxazolo[4,3-c]pyridine (38)
4.47. (8aRS, 11aSR, 12aSR)-11-Methyl-8a9,11,11a, 12,12a-hex-
ahydro-5H-isoxazolo[30,40:4,5]pyrido[2,1-a]isoquinolin-6-
(8H)-one (44)
Prepared according to the general acylation procedure from the
amine 22c (20 mg, 0.068 mmol), with all other material amounts
scaled accordingly. Purification by column chromatography, eluting
with pentane/ethyl acetate/methanol (25:75:1/0:9:1) gave 22 mg
LDA was prepared by addition of n-butyllithium (2.4 M in hex-
anes, 1.24 mL, 3.0 mmol) to a solution of diisopropylamine (0.35 g,
0.48 mL, 3.4 mmol) in THF (6.0 mL) at 0 ꢂC. After 30 min, the so-
lution was warmed to room temperature. A portion of the LDA
solution so obtained (0.41 M in THF/hexanes, 3.5 mL, 1.4 mmol) was
(85%) of the amide 38 as a brown gum: 1H NMR (400 MHz):
d 8.82
(d, J¼1.7 Hz, 1H), 8.59e8.54 (m, 1H), 7.84 (app dt, J¼7.8, 1.7 Hz, 1H),
7.51 (d, J¼8.1 Hz, 2H), 7.34 (d, J¼7.8, 4.9 Hz, 1H), 7.31 (d, J¼8.1 Hz,
2H), 5.10e4.99 (m, 1H), 4.38e4.27 (m, 1H), 4.23e4.12 (m, 1H), 3.57
(dd, J¼8.7, 4.2 Hz, 1H), 3.61e3.41 (m, 1H), 3.09e2.91 (comp, 2H),
2.70 (s, 3H), 2.27e2.15 (m, 1H), 1.93 (app q, J¼12.7 Hz, 1H), 1.30 (s,
added dropwise to
a
stirred solution of amide
1 (30 mg,
0.088 mmol) and DMPU (90 mg, 85
m
L, 0.70 mmol) in THF (1 mL) at
9H); 13C NMR (100 MHz):
d
177.0, 2ꢃ148.5,144.5,136.7,136.5,134.5,
ꢁ78 ꢂC. The solution was warmed to 0 ꢂC and stirred for 1 h. Sat-
urated aqueous NH4Cl (1 mL) was added and the mixture was
concentrated under reduced pressure to remove the THF. The res-
idue was partitioned between water (10 mL) and CH2Cl2 (10 mL)
and the phases were separated. The aqueous layer was extracted
with CH2Cl2 (2ꢃ10 mL) and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The residue
was purified by column chromatography, eluting with ethyl ace-
tate/toluene/methanol (1:1:0/9:0:1) to afford 18.6 mg (contain-
ing approximately 9% w/w DMPU, corrected yield¼74%) of the
127.8,125.8,123.8, 68.2, 64.6, 55.6, 2ꢃ43.8, 39.1, 34.2, 28.4; IR (neat)
2957, 1627, 1477, 1411, 1365 cmꢁ1; HRMS (ESIþ) m/z calculated for
C
23H29N3O2Na (Mþ23), 402.21520; found, 402.21518.
4.45. (1SR,12RS,16SR)-15-Methyl-8-phenyl-14-oxa-8,10,15-
triazatetracyclo[8.7.0.02,7.012,16]heptadeca-2(7),3,5-trien-9-one
(40)
Pd(OAc)2 (2.4 mg, 0.011 mmol) and (ꢀ)-BINAP (7.8 mg,
0.032 mmol) were combined in toluene (0.8 mL) and heated at
40 ꢂC until all solid dissolved. The mixture was cooled to room
temperature, then combined with amine 10a (30 mg, 0.10 mmol)
and Cs2CO3 (67 mg, 0.21 mmol) in a sealable tube. The mixture was
cooled to 0 ꢂC before dropwise addition of a solution of phenyl
isocyanate (24 mg, 0.20 mmol) in toluene (0.2 mL). The mixture
was warmed to room temperature and stirred for 30 min, before
heating at 120 ꢂC (sealed tube) for 13 h. The mixture was filtered
through Celite and concentrated under reduced pressure and the
residue was purified by flash column chromatography eluting with
ethyl acetate/methanol (100:1/90:10 along a gradient) to give
31 mg (92%) of the dihydroquinazolin-2-one 40 as a yellow glass:
lactam 44 as a pale yellow gum: 1H NMR (400 MHz):
d 7.31e7.24
(comp, 2H), 7.20e7.14 (comp, 2H), 7.46 (app d, J¼12.7, 1H), 4.40 (dd,
J¼13.9, 3.7 Hz, 1H), 4.30e4.21 (m, 1H), 3.72 (d, J¼19.7 Hz, 1H), 3.63
(d, J¼19.7 Hz, 1H), 3.59 (app t, J¼8.2 Hz, 1H), 3.52e3.43 (m, 1H),
3.35e3.24 (m, 1H), 3.12e3.02 (m, 1H), 2.71 (s, 3H), 2.45e2.34 (m,
1H), 1.84e1.71 (m, 1H); 13C NMR (150 MHz):
d 168.3, 134.0, 131.4,
127.8, 127.6, 126.9, 124.4, 67.9, 64.3, 56.5, 44.2, 39.8, 39.4, 36.4, 34.8;
IR (neat) 2952, 2878, 1643, 1454, 1313, 1624, 760, 731; HRMS (ESIþ)
m/z calculated for C15H19N2O2 (Mþ1), 259.14410; found, 259.14416.
4.48. 1-((3aRS,6SR,7aSR)-6-(2-Bromophenyl)-1-methyl tetra-
hydroisoxazolo[4,3-c]pyridin-5(1H,3H,6H)-yl)-2-phenyl etha-
none (45)
1H NMR (400 MHz):
d
7.50 (t, J¼7.6 Hz, 2H), 7.41 (t, J¼7.6 Hz, 1H),
7.30e7.25 (m, 2H), 7.10 (dd, J¼7.3, 1.6 Hz, 1H), 7.04 (td, J¼8.0, 1.6 Hz,
1H), 6.98 (td, J¼7.3, 1.1 Hz, 1H), 6.21 (dd, J¼8.0, 1.1 Hz, 1H), 4.62 (dd,
J¼14.3, 2.0 Hz, 1H), 4.56 (dd, J¼12.5, 2.3 Hz, 1H), 4.25 (app t,
J¼8.6 Hz, 1H), 3.78 (app t, J¼8.6 Hz, 1H), 3.39e3.23 (comp, 2H),
3.13e3.02 (m, 1H), 2.69 (s, 3H), 2.29e2.18 (m, 1H), 1.99 (app q,
Phenylacetyl chloride (64 mg, 55
dropwise to a solution of amine 10a (100 mg, 0.336 mmol) and Et3N
(47 mg, 65 L, 0.46 mmol) in CH2Cl2 (2 mL). After 1 h, the mixture
mL, 0.41 mmol) was added
m
was diluted with CH2Cl2 (10 mL) and partitioned with saturated
aqueous NaHCO3 (10 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢃ10 mL). The combined
organic extracts were dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by flash column chroma-
tography eluting with ethyl acetate/hexanes (1:1/3:1) to afford
J¼12.5 Hz, 1H); 13C NMR (75 MHz):
d
153.9, 139.1, 138.3, 2ꢃ129.8,
128.2, 128.1, 125.1, 122.3, 121.4, 115.1, 67.8, 64.1, 55.0, 44.3, 41.5, 38.5,
35.6; IR (neat) 2952, 1659, 1465, 1289, 1266 cmꢁ1; HRMS (ESIþ) m/z
calculated for C20H22N3O2 (Mþ1), 336.1707; found, 336.1706.
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

14
S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
117 mg (84%) of the amide 45 as a white foam: 1H NMR (400 MHz)
(2:1 rotamer mixture):
(m, 1H), 3.77 (dd, J¼14.0, 6.8 Hz, 1H), 3.39e3.28 (m, 1H), 3.14e2.97
(comp, 3H), 2.88 (dd, J¼14.0, 7.2 Hz, 1H), 2.58 (s, 3H), 2.26e2.16 (m,
d
7.57 (d, J¼8.0 Hz, 0.7H), 7.51 (d, J¼7.8 Hz,
0.3H), 7.35e7.03 (comp, 7.7H), 7.00 (d, J¼6.6 Hz, 0.3H), 5.24 (dd,
J¼13.5, 4.7 Hz, 0.3H), 5.04 (dd, J¼12.5, 5.1 Hz, 0.7H), 5.01e4.93 (m,
0.7H), 4.20e4.08 (m, 0.7H), 4.05e3.92 (comp, 0.6H), 3.75 (s, 0.6H),
3.60e3.53 (m, 0.7H), 3.48e3.39 (comp, 0.6H), 3.36 (d, J¼15.1 Hz,
0.7H), 3.28 (d, J¼15.1 Hz, 0.7H), 3.10e2.82 (comp, 2.4H), 2.75e2.53
(m, 0.3H), 2.66 (s, 2H), 2.64 (s, 1H), 2.44e2.27 (comp, 1H), 1.77e1.57
1H), 1.47 (app q, J¼12.6 Hz, 1H); 13C NMR (75 MHz):
d 170.4, 145.0,
136.0,134.4,134.2,129.0,128.5,127.8,127.3,127.2,127.1,125.4,118.3,
67.4, 64.0, 57.4, 53.8, 44.5, 43.4, 40.6, 38.1, 37.9; IR (neat) 2953,
2680, 1643, 1443, 1243 cmꢁ1; HRMS (CIþ) m/z calculated for
C24H26N2O2 (Mþ1), 374.1994; found, 374.1994.
(comp, 1H); 13C NMR (100 MHz) (2:1 rotamer mixture):
d
171.8,
4.52. 1-((2SR,4SR,5RS)-2-(2-Bromophenyl)-5-(hydroxy
169.9, 142.5, 142.4, 134.6, 134.5, 133.4, 133.2, 129.4, 129.0, 128.8,
128.7, 128.5, 128.4, 127.8, 127.1, 126.8, 126.4, 125.3, 121.9, 121.1, 68.3,
67.9, 64.5, 55.8, 54.7, 44.3, 43.7, 43.5, 42.5, 42.1, 40.6, 39.9, 32.8, 31.8;
IR (neat) 2955, 2874, 1646, 1414, 1026 cmꢁ1; HRMS (ESIþ) m/z cal-
culated for C22H25N2O729Br (Mþ1), 415.1016; found, 415.1016.
methyl)-4-(methylamino)piperidin-1-yl)ethanone (49)
Zinc dust (3.9 g, 59 mmol) was added at 0 ꢂC to a stirred solution
of isoxazolidine 1 (1.00 g, 2.95 mmol) in 10% aqueous HCl (45 mL).
After 1 h, the mixture was filtered through Celite rinsing with 10%
aqueous HCl (20 mL). The pH of the combined filtrate and rinsings
was adjusted to 12 by the addition of 30% aqueous NH4OH and the
mixture was extracted with CH2Cl2 (4ꢃ50 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure and the residue was purified by flash column chromatog-
raphy eluting with CH2Cl2/methanol (100:1/1:1 along a gradient)
to give 837 mg (83%) of the amino alcohol 49 as a clear, colorless
4.49. General procedure for the synthesis of dihy-
droisoquinoline-3-ones via one-pot enolate arylation/
alkylation
LDA was prepared by addition of n-butyllithium (2.4 M in hex-
anes, 1.24 mL, 3.0 mmol) to a solution of diisopropylamine (0.35 g,
0.48 mL, 3.4 mmol) in THF (6.0 mL) at 0 ꢂC. After 30 min, the so-
lution was warmed to room temperature. A portion of the LDA
solution so obtained (0.41 M in THF/hexanes, 3.5 mL, 1.4 mmol),
was added dropwise to a solution of phenylacetamide 45 (100 mg,
0.241 mmol) and DMPU (0.37 g, 0.35 mL, 2.9 mmol) in THF (3 mL) at
ꢁ78 ꢂC. The solution was then warmed to 0 ꢂC and stirred for 1 h.
The mixture was then cooled to ꢁ100 ꢂC, and a solution of alkyl
halide (2.9 mmol) in THF (2 mL) was added dropwise. The mixture
was warmed to ꢁ78 ꢂC and held at this temperature for 20 min,
before warming to 0 ꢂC. Toluene (5 mL) and saturated aqueous
NH4Cl (5 mL) were added, and the mixture was concentrated under
reduced pressure to remove the THF. The residue was partitioned
between water (5 mL) and toluene (5 mL), and the layers were
separated. The toluene layer was washed with water (4ꢃ10 mL),
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by column chromatography, eluting with
pentane/ethyl acetate/methanol (25:75:1/0:100:1) to afford the
desired 4,4-disubstituted dihydroisoquinolin-3-ones.
gum: 1H NMR (500 MHz, DMSO-d6,130 ꢂC):
d 7.57e7.53 (m,1H), 7.32
(dd, J¼7.9,1.2 Hz,1H), 7.32e7.27 (m,1H), 7.14 (ddd, J¼7.9, 6.0, 2.7 Hz,
1H), 5.21 (app t, J¼7.7 Hz, 1H), 4.16 (dd, J¼13.7, 6.1 Hz, 1H), 3.59 (dd,
J¼11.0, 5.4 Hz, 1H), 3.55 (dd, J¼11.0, 6.4 Hz, 1H), 3.03 (br s, 2H), 2.84
(ddd, J¼9.1, 6.1, 3.3 Hz, 1H), 2.18e2.12 (comp, 2H), 2.16 (s, 3H),
1.95e1.90 (m, 1H), 1.94 (ddd, J¼13.9, 8.8, 7.7 Hz, 1H), 1.92 (s, 3H); 13
C
NMR (125 MHz, DMSO-d6, 130 ꢂC):
d 168.9, 142.5, 132.0, 127.6, 127.1,
126.0, 120.4, 59.9, 54.6, 54.5, 41.5, 39.2, 33.1, 31.0, 20.6; IR (neat)
3323, 2923, 1633, 1420, 1024 cmꢁ1; HRMS (ESIþ) m/z calculated for
C
15H22N2O729Br (Mþ1), 341.0859; found, 341.0858.
4.53. N-((2SR,4SR,5RS)-1-Acetyl-2-(2-bromophenyl)-5-(hy-
droxymethyl)piperidin-4-yl)-N-methylpivalamide (50)
A solution of TMSCl (15 mg, 0.14 mmol) in CH2Cl2 (0.2 mL) was
added dropwise to a solution of amino alcohol 49 (40 mg,
0.12 mmol) and Et3N (36 mg, 0.36 mmol) in CH2Cl2 (0.2 mL). After
30 min, the mixture was cooled to 0 ꢂC and a solution of pivaloyl
chloride (16 mg, 0.13 mmol) in CH2Cl2 (0.2 mL) was added drop-
wise. After a further 30 min, the mixture was warmed to room
temperature and stirred for 1 h. Methanol (0.79 g, 1.0 mL, 25 mmol)
was added and after 1 h, the mixture was concentrated under re-
duced pressure. The residue was suspended in ethyl acetate (3 mL)
and the insoluble salts were removed by filtration. The filtrate was
concentrated under reduced pressure then dissolved in methanol/
acetic acid (9:1, 5 mL) and concentrated under reduced pressure
after 1 h. The residue was purified by flash column chromatography
eluting with ethyl acetate/methanol (100:1/90:10) to give 45 mg
(91%) of the amide 50 as a colorless gum: 1H NMR (600 MHz,
4.50. (1SR,8RS,12RS,16SR)-8,15-Dimethyl-8-phenyl-14-oxa-
10,15-diazatetracyclo[8.7.0.02,7.012,16] heptadeca-2(7),3,5-trien-
9-one (47)
Prepared according to the general enolate arylation/alkylation
procedure using methyl iodide as the alkylating agent, to afford
52 mg (62%) of the dihydroisoquinolin-3-one 47 as a yellow gum:
1H NMR (600 MHz):
d 7.36e7.30 (m, 2H), 7.25e7.14 (comp, 5H), 7.12
(d, J¼7.3 Hz, 2H), 4.93 (d, J¼13.9 Hz, 1H), 4.46 (dd, J¼12.6, 1.8 Hz,
1H), 4.08e3.97 (m, 1H), 3.38e3.28 (m, 1H), 3.10e2.96 (comp, 3H),
2.67 (s, 3H), 2.24e2.13 (m, 1H), 2.01 (s, 3H), 1.48 (app q, J¼12.6 Hz,
DMSO-d6, 130 ꢂC):
d
7.56 (dd, J¼7.9, 1.1 Hz, 1H), 7.40e7.34 (m, 1H),
1H); 13C NMR (75 MHz):
d
171.5, 145.7, 138.5, 133.1, 128.2, 128.0,
7.32 (dd, J¼7.8, 1.8 Hz, 1H), 7.21e7.14 (m, 1H), 5.18 (dd, J¼11.6,
6.3 Hz, 1H), 4.41e4.33 (m, 1H), 4.32 (dd, J¼13.2, 6.2 Hz, 1H), 4.10 (br
s, 1H), 3.51 (app t, J¼13.2 Hz,1H), 3.45 (d, J¼5.3 Hz, 2H), 2.96 (s, 3H),
2.57e2.48 (m, 1H), 2.20e2.07 (comp, 2H), 1.91 (s, 3H), 1.26 (s, 9H);
127.8,127.0,126.9,126.8,125.3, 67.2, 63.9, 57.4, 49.4, 44.3, 40.6, 38.0,
37.1, 26.6; IR (neat) 2937, 1644, 1444, 1260 cmꢁ1; HRMS (ESIþ) m/z
calculated for C22H25N2O2 (Mþ1), 349.1916; found, 349.1915.
13C NMR (150 MHz, DMSO-d6, 130 ꢂC):
d 176.2, 168.5, 142.0, 132.1,
4.51. (1SR,8RS,12RS,16SR)-8-Allyl-15-methyl-8-phenyl-14-oxa-
10,15-diazatetracyclo[8.7.0.02,7.012,16]heptadeca-2(7),3,5-trien-
9-one (48)
127.9, 127.5, 125.6, 120.3, 58.5, 56.7, 52.4, 42.4, 39.0, 38.0, 32.9, 30.3,
27.5, 20.5; IR (neat) 3410, 2971, 1633, 1435 cmꢁ1; HRMS (ESIþ) m/z
calculated for C20H30N2O739Br (Mþ1), 425.1434; found, 425.1436.
Prepared according to the general enolate arylation/alkylation
procedure using allyl bromide as the alkylating agent, to afford
60 mg (66%) of the dihydroisoquinolin-3-one 48 as a yellow gum:
4.54. 1-[(1SR,9SR,10RS)-10-(Hydroxymethyl)-8-methyl-8,12-
diazatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-12-yl] ethan-1-
one (51)
1H NMR (400 MHz):
d 7.36e7.27 (m, 2H), 7.26e7.12 (comp, 7H),
5.50e5.38 (m, 1H), 5.04 (dd, J¼17.1, 1.5 Hz, 1H), 5.03e4.94 (m, 1H),
Pd(OAc)2 (6.0 mg, 0.027 mmol) and (ꢀ)-BINAP (20 mg,
4.90 (dd, J¼10.3, 1.5 Hz, 1H), 4.45 (dd, J¼12.6, 2.2 Hz, 1H), 4.08e4.00
0.032 mmol) were combined in toluene (5 mL) and heated at 40 ꢂC
Please cite this article in press as: Hardy, S.; Martin, S. F., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.045

S. Hardy, S.F. Martin / Tetrahedron xxx (2014) 1e16
6. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311e335.
15
until all solid dissolved. The solution was cooled to room temper-
ature over 10 min, then combined with amine 49 (92 mg,
0.27 mmol) and Cs2CO3 (177 mg, 0.543 mmol). The mixture was
heated under reflux for 14 h, then cooled to room temperature, and
filtered through Celite, rinsing with toluene (5 mL). The combined
filtrate and rinsings were concentrated under reduced pressure and
the residue was purified by flash column chromatography eluting
with CHCl3/methanol (95:5) to afford 49 mg (70%) of the tetrahy-
droquinoline 51 as a pale yellow gum: 1H NMR (600 MHz) (3:2
7. (a) Nielson, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48e56; (b)
Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300e1308; (c) Spring, D.
R. Org. Biomol. Chem. 2003, 1, 3867e3870.
8. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V.
J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J.
Med. Chem. 1988, 31, 2235e2246; (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893e930; (c) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R.
Curr. Opin. Chem. Biol. 2010, 14, 347e361.
9. For leading references, see: (a) Koch, M. A.; Schuffenhauer, A.; Scheck, M.;
Wetzel, S.; Casaulta, M.; Odermatt, A.; Ertl, P.; Waldmann, H. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 17272e17277; (b) Wetzel, S.; Schuffenhauer, A.; Roggo, S.;
Ertl, P.; Waldmann, H. Chimia 2007, 61, 355e360.
10. Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc. 1988, 110, 5925e5927.
11. For a review, see: Martin, S. F. Acc. Chem. Res. 2002, 35, 894e904.
12. (a) Cheng, B.; Sunderhaus, J. D.; Martin, S. F. Org. Lett. 2010, 12, 3622e3625; (b)
Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223e4226;
(c) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Tetrahedron 2009, 65,
6454e6469.
13. (a) Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852e855; (b) Sahn, J. J.; Su, J. Y.;
Martin, S. F. Org. Lett. 2011, 13, 2590e2593; (c) Hardy, S.; Martin, S. F. Org. Lett.
2011, 13, 3102e3105; (d) Granger, B. A.; Kaneda, K.; Martin, S. F. Org. Lett. 2011,
13, 4542e4545; (e) Donald, J. R.; Granger, B. A.; Hardy, S.; Sahn, J. J.; Martin, S. F.
Heterocycles 2012, 84, 1089e1112; (f) Sahn, J. J.; Martin, S. F. Tetrahedron Lett.
2011, 52, 6855e6858; (g) Wang, Z.; Kaneda, K.; Fang, Z.; Martin, S. F. Tetrahe-
dron Lett. 2012, 53, 477e479; (h) Donald, J. R.; Wood, R. R.; Martin, S. F. ACS
Comb. Sci. 2012, 14, 135e143; (i) Granger, B. A.; Kaneda, K.; Martin, S. F. ACS
Comb. Sci. 2012, 14, 75e79; (j) Sahn, J. J.; Martin, S. F. ACS Comb. Sci. 2012, 14,
496e502; (k) Granger, B. A.; Wang, Z.; Kaneda, K.; Fang, Z.; Martin, S. F. ACS
Comb. Sci. 2013, 15, 379e386.
14. Shah, S. K.; Chen, N.; Guthikonda, R. N.; Mills, S. G.; Malkowitz, L.; Springer, M.
S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A.;
MacCoss, M. Bioorg. Med. Chem. Lett. 2005, 15, 977e982.
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Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc.
1995, 117, 6682e6685.
rotamer mixture):
d
7.22e7.15 (comp, 1.6H), 7.01 (dd, J¼7.6, 1.5 Hz,
0.4H), 6.62e6.55 (comp, 2H), 5.91 (app br s, 0.6H), 4.93 (app br s,
0.4H), 4.36 (dd, J¼13.3, 4.8 Hz, 0.4H), 3.83 (d, J¼1.8 Hz, 0.4H), 3.72
(d, J¼2.1 Hz, 0.6H), 3.66 (dd, J¼10.4, 7.6 Hz, 0.6H), 3.60e3.49 (comp,
2H), 3.14 (s, 1.2H), 3.08 (s, 1.8H), 2.72 (br s, 1H), 2.69 (app t,
J¼12.8 Hz, 0.6H), 2.34 (s, 1.2H), 2.11 (app t, J¼13.3 Hz, 0.4H),
2.05e1.81 (comp, 3H), 2.04 (s, 1.8H); 13C NMR (150 MHz) (3:2
rotamer mixture):
d 168.7, 168.1, 146.5, 146.4, 129.9, 129.7, 129.2,
128.9, 120.5, 119.3, 115.6, 115.3, 109.7, 109.5, 62.7, 62.3, 54.4, 53.6,
46.6, 45.8, 45.7, 42.0, 40.0, 39.8, 36.4, 29.3, 28.4, 22.0, 22.0; IR (neat)
3392, 2931, 1614, 1503, 1436, 1045 cmꢁ1; HRMS (CIþ) m/z calculated
for C15H20N2O2 (Mꢄþ), 260.1525; found, 260.1522.
4.55. 1-{[(1RS,9RS,10SR)-12-Acetyl-8-methyl-8,12-
diazatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-10-yl]methyl}
pyrrolidine-2,5-dione (52)
DIAD (40 mg, 39 mL, 0.20 mmol) was added dropwise to a solu-
tion of alcohol 51 (21 mg, 0.081 mmol), triphenylphosphine (51 mg,
0.19 mmol), and succinimide (19 mg, 0.19 mmol) in THF (0.3 mL).
The mixture was stirred at room temperature for 4 h, before con-
centration under reduced pressure. The residue was purified by
flash column chromatography eluting with ethyl acetate/methanol
(100:1/80:20 along a gradient) to give 25 mg (90%) of the succi-
nimide 52 as a yellow gum: 1H NMR (400 MHz) (1:1 rotamer
16. Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994,
4, 2545e2550.
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1071e1079.
18. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼44825521 (accessed
22 Feb 2014).
mixture):
d
7.25e7.16 (comp, 1.5H), 7.01 (dd, J¼7.6, 1.6 Hz, 0.5H),
19. See: https://commonfund.nih.gov/molecularlibraries/index (accessed 22 Feb
2014).
20. Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 7920e7926.
21. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼46902472 (accessed
02 Feb 2014).
6.67e6.61 (comp, 2H), 5.88 (app br s, 0.5H), 4.90 (app br s, 0.5H),
4.21 (dd, J¼13.5, 4.9 Hz, 0.5H), 3.69 (dd, J¼13.5, 4.1 Hz, 0.5H),
3.66e3.59 (comp, 1H), 3.59e3.54 (comp, 1H), 3.41 (dd, J¼13.4,
9.0 Hz, 0.5H), 3.31 (dd, J¼13.2, 4.9 Hz, 0.5H), 3.16 (s, 1.5H), 3.13 (s,
1.5H), 2.85 (app t, J¼13.2 Hz, 0.5H), 2.75 (s, 2H), 2.72 (s, 2H), 2.31 (s,
1.5H), 2.29 (app t, J¼13.4 Hz, 0.5H), 2.16e2.03 (comp, 1H), 1.99 (s,
1.5H), 1.98e1.94 (comp, 1H), 1.94e1.83 (comp, 1H); 13C NMR
22. Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413e2415.
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22 Feb 2014).
25. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼46902475 (accessed
22 Feb 2014).
(100 MHz) (1:1 rotamer mixture): d 177.4, 177.3, 168.5, 167.8, 146.6,
146.3,130.0,129.8,129.3,129.0,120.7,119.5,116.3,116.0,110.5,110.4,
57.0, 56.9, 51.5, 45.3, 43.7, 43.1, 42.4, 41.2, 40.9, 40.6, 37.4, 29.6, 28.4,
28.2, 22.2, 21.9; IR (neat) 2935, 1696, 1633, 1432, 1175 cmꢁ1; HRMS
(CIþ) m/z calculated for C19H23N3O3 (Mꢄþ), 341.1739; found,
341.1737.
26. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼46902457 (accessed
22 Feb 2014).
27. Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987,
49e51.
28. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼56588939 (accessed
22 Feb 2014).
29. Schering Corporation, US2003/232987 A1, 2003.
30. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼51360973 (accessed
22 Feb 2014).
Acknowledgements
31. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼44825811 (accessed
22 Feb 2014).
We thank the National Institutes of Health (GM 86192) and the
Robert A. Welch Foundation (F-0652) for their generous support of
this work. We also thank Dr. Vincent Lynch (University of Texas at
Austin) for performing X-ray crystallography, and Dr. James J. Sahn
(University of Texas at Austin) for invaluable discussions and
assistance.
32. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼51360892 (accessed
22 Feb 2014).
33. See: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid¼51360893 (accessed
22 Feb 2014).
34. Ferraccioli, R.; Carenzi, D. Synlett 2003, 1383e1386.
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