Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via sequential Cu/Pd/Ru catalysis

Article abstract of DOI:10.1021/jo400974k

Aryl-fused 2-azabicyclo[2.2.2]octanes were prepared by a novel sequence of Cu-catalyzed three-component coupling of diversely substituted N-benzyl o-bromoaryl imines with methacryloyl chloride and vinyltributyl stannane followed by Pd-catalyzed Heck annulation. Subsequent diversification of the aryl-fused 2-azabicyclo[2.2.2]octane core was achieved by attaching a flexible linker and a potential second pharmacophore via Ru-catalyzed cross-metathesis and a nucleophilic substitution.

Full text of DOI:10.1021/jo400974k

Note
pubs.acs.org/joc
Modular Strategy for the Synthesis of Functionalized Aryl-Fused
Azabicyclo[2.2.2]octanes via Sequential Cu/Pd/Ru Catalysis
Lucas F. McCormick†,‡ and Helena C. Malinakova*,†,‡
†Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
‡Center of Excellence in Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence,
Kansas, 66047, United States
S
* Supporting Information
ABSTRACT: Aryl-fused 2-azabicyclo[2.2.2]octanes were prepared
by a novel sequence of Cu-catalyzed three-component coupling of
diversely substituted N-benzyl o-bromoaryl imines with methacry-
loyl chloride and vinyltributyl stannane followed by Pd-catalyzed
Heck annulation. Subsequent diversification of the aryl-fused 2-
azabicyclo[2.2.2]octane core was achieved by attaching a flexible
linker and a potential second pharmacophore via Ru-catalyzed
cross-metathesis and a nucleophilic substitution.
omplex N-heterocyclic structures constitute the core of
potent biologically active natural products and synthetic
aryl-fused 2-azabicyclo[2.2.2.]octanes has recently been de-
scribed.8 Several other methods for the assembly of the general
2-azabicyclo[2.2.2]octane core have been reported,9 including
Diels−Alder reactions of dihydropyridines.10 However, these
methodologies have not been adopted to the synthesis of the
aryl-fused analogues. Furthermore, only in a few instances have
parallel syntheses of combinatorial libraries of bridged N-
heterocycles been achieved.11 Recently, sequences of intra-
molecular RCM and Heck reactions were applied toward the
construction of structurally related aryl-fused bridged N-
heterocycles; these however featured different ring-sizes than
the 2-azabicyclo[2.2.2]octane core.12
C
drugs.1 The isoquinuclidine (2-azabicyclo[2.2.2]octane) motif
has been found in diverse types of iboga and iboga-bisindole
alkaloids,2 grandisine B featuring linked isoquinuclidinone and
indolizidine cores,3 and in others4 like mearsin and dioscorine
(Figure 1). Synthetic analogues featuring the benzomorphan-
We envisioned that a modular method for the assembly of
highly functionalized 2-azabicyclo[2.2.2]octanes followed by a
process that would link them to other potential pharmaco-
phores could be developed by exploring a strategically designed
sequence of multicomponent13 and transition metal-catalyzed
C−C bond-forming reactions.14 Herein, we describe a new
synthetic methodology for a rapid construction of a series of
aryl-fused 2-azabicyclo[2.2.2]octanes via a sequence of Cu(I)-
catalyzed three-component coupling of various imines, vinyl
stannane and methacryloyl chloride, followed by Pd-catalyzed
Heck annulation cascade (Scheme 1). Both the electronic
properties and positions of the substituents in the aromatic ring
of the N-benzyl imines I were varied to afford a series of acyclic
amides II. A regioselective Heck cascade consisting of two
sequential 6-exo cyclizations afforded a mixture of bridged exo
and endo azabicyclooctanes III and IV, respectively (Scheme 1).
Diversification of the allylic C−C bridge in heterocycles III and
IV via Pd-catalyzed allylic acetoxylation was attempted.
Ultimately, we identified conditions for a selective synthesis
of heterocycles III and designed a protocol for their linking to
Figure 1. Naturally occurring and synthetic azabicyclooctanes.
related benzo-fused 5,6-benzo-2-azabicyclo[2.2.2]octane cores
(Figure 1) have been synthesized,5 and their potential to exhibit
analgesic properties has been studied.5
Surprisingly, only an extremely small number of derivatives
of aryl-fused 2-azabicyclo[2.2.2]octanes have been isolated or
prepared.6 Synthesis of aryl-fused 2-azabicyclo[2.2.2]octanes via
the Diels−Alder reaction with benzyne dienophiles7 has been
limited by the challenging task of diversifying the substitution
patterns on the aromatic ring of the benzyne. An intramolecular
radical cyclization of tetrahydropyridines providing an access to
Received: May 3, 2013
Published: August 13, 2013
© 2013 American Chemical Society
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The Cu(I)-catalyzed coupling15 of methacryloyl chloride and
vinyl stannane with N-benzyl imine, derived from 2-bromo-4,5-
methyleneoxy benzaldehyde, afforded amide 2a in a good yield
under conditions analogous to those used in our prior studies16
(entry 1, Table 1). The two olefins in the amide 2a are
positioned to allow for a regioselective 6-exo/6-exo two-step
Heck cascade reaction.17 Thus, treatment of amide 2a with
Pd(OAc)2 (10 mol %), TBAC (1 equiv) and Na2CO3 (1 equiv)
in DMF18 at 80 °C afforded a chromatographically inseparable
mixture of bridged heterocycles 3.1a (exo-olefin) and 3.2a
(endo-olefin) in an excellent combined yield (90%) (entry 1,
Table 1). The ratio of the exo- and endo-olefins (1.5:1) was
Scheme 1
1
assigned on the basis of well-resolved H NMR spectra of the
mixture of azabicyclooctanes 3.1a and 3.2a (entry 1, Table 1).
Initial attempts to eliminate the formation of the double bond
isomers by replacing the Na2CO3 base with KOAc or TEA (1
equiv each) or by replacing the TBAC/Na2CO3 system with
PPh3/Cs2CO3 all in DMF were not successful,19 affording
mixtures of the regioisomeric olefins 3.1a and 3.2a in 1.5−1.9:1
ratios.
The excellent conversion of the diene 2a into the heterocycle
3a points to a high diastereoselectivity of the first 6-exo
carbopalladation providing palladium(II) intermediate VIa
instead of its diastereomer VIb (Figure 2). Assuming that the
palladium(II) intermediate V favors the conformation in which
the phenyl group in the N-benzyl substituent and the vinyl
other pharmacophores via Ru-catalyzed cross metathesis and
subsequent substitution (vide infra). In contrast to the
traditional synthetic methods,6−10 our protocol is well-suited
for the construction of combinatorial libraries of aryl-fused 2-
azabicyclo[2.2.2]octanes allowing for systematic variations of
the positions of electronically diverse aryl substituents with
respect to the fusion of the heterocyclic core, as well as
diversifying the nature of the linked pharmacophore.
Table 1. Preparation of Azabicyclooctanes via Pd-Catalyzed Cascade Reaction
a
b
c
Isolated yield of a single compound. Combined isolated yield for an inseparable mixture of two regioisomers. Molar ratio of the regioisomers
d
e
1
established by H NMR. Combined yield of two regioisomers separated by column chromatography. Isolated yield for a single isomer that was
formed as the only organic product.
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acetates that would afford a single product following a Tsuji−
Trost allylation reaction.23 The mixture of azabicyclooctanes
3.1a/3.2a was treated with Pd(OAc)2/benzoquinone catalyst
and several different stoichiometric oxidants (H2O2, t-BuOOH,
O2/DMSO) in acetic acid, seeking the best conditions for the
preparation of the acetate(s) 4 (Scheme 2). Disappointingly,
Scheme 2
Figure 2. Rationale for diastereoselectivity of the Heck reaction.
group at the stereogenic carbon are located in anti orientation
(Figure 2), the subsequent carbopalladation step would occur
preferentially from the Si-face of the disubstituted olefin. The
developing transition state for the Si-face carbopalladation
would be lower in energy due to the palladium(II) center being
located at the less sterically encumbered bottom face of the
newly created ring. The resulting palladium(II) complex VIa
features cis orentation of the Pd(II) center and the
monosubstituted olefin required for the second carbopallada-
tion. Alternatively, equilibrium between diastereomers VIa and
VIb is rapidly established via a facile β-carbon elimination/
carbopalladation sequence (Figure 2) allowing for a complete
conversion of the substrate 2a into the heterocycle 3a.
despite extensive variations in the ratios of reaction
components, temperature and time, we could only obtain low
yields of an identical single diastereomer of the bridge-
acetoxylated heterocycle 4. Under the optimized conditions
using Pd(OAc)2 (5 mol %), benzoquinone (10 mol %), H2O2
(4 equiv) in acetic acid at (80 °C for 47 h) acetate 4 was
isolated in 30% yield. The relative configuration of the new
1
stereocenter was confirmed by NOE H NMR spectroscopy,
The lack of a significant effect of the choice of base on the
ratios of exo and endo isomers in our case was quite puzzling.
Furthermore, the treatment of the mixture of olefins 3.1a and
3.2a with acids (H2SO4 or TsOH) did not induce a complete
isomerization to the internal olefin 3.2a.20,21 Reasoning that
both regioisomers 3.1 and 3.2 possess an activated allylic C−H
bond that may react to yield an identical allylpalladium
intermediate that can be used for further diversification of the
bridged scaffold, we proceeded to explore the scope of the Cu/
Pd-catalyzed reactions with respect to the substitution in the
aromatic ring of the imine (Table 1). The reaction sequence
proved to have a good scope, affording both the functionalized
amides 2b−g (50−83%) and azabicyclooctanes 3b−3g (65−
92%) featuring electron-rich (OMe, −OCH2O−), electron-
deficient (F), methyl, and fused phenyl groups at different
positions in the aromatic ring in very good yields as an
inseparable mixture of two regioisomeric olefins (2.6−1.1:1
which identified a correlation between the aromatic and
aliphatic hydrogens highlighted in the structure of acetate 4
in Scheme 2. The unreacted substrate could be recovered by
column chromatography as a mixture of isomers 3.1a/3.2a
1
(1.5:1 by H NMR) in 38% yield.
The limited yield of the allylic acetoxylation on the mixture
of isomeric heterocycles 3.1a and 3.2a prompted us to explore
a much broader range of conditions for the initial Heck
annulation, including reductive Heck cascade, Heck cascade
terminated with CO, or with Suzuki coupling.24 Although
neither of these protocols afforded results competitive with the
original method (entry 1, Table 1),20 we observed that
application of THF as the solvent favored the formation of
the exo isomer 3.1a. Under optimized conditions, the treatment
of amide 2a with Pd(PPh3)4 (5 mol %) catalyst and TEA (4
equiv) in anhydrous THF (80 °C, 23 h) delivered the
azabicyclooctane 3.1a in 90% yield as a single product (Scheme
3 and entry 1, Table 1). Conceivably, substituting DMF with
THF solvent decreases the stabilization of the hydrido-
palladium(II) intermediate formed by β-hydride elimination,
favoring its decomposition via reductive elimination instead of
the readdition that causes the undesired isomerization.19 In
order to assess the generality of the dramatic increase in the
regioselectivity delivered by the modified catalytic system, the
Heck cyclization catalyzed by Pd(PPh3)4 with TEA base in the
THF solvent was performed with amides 2b and 2g under the
same conditions as those described for amide 2a (Scheme 3).
In both cases, single regioisomers, e.g., the exocyclic olefins
3.1b and 3.1g, were obtained as the sole organic products in 74
and 70% yields, respectively (entries 2 and 7, Table 1).
1
ratios) (entries 2−7, Table 1). The H NMR and 13C NMR
spectra for these products proved to be well-resolved, providing
analytical data of sufficient quality to fully characterize these
compounds in the mixture of olefinic isomers. An exception
was the 4-fluorophenyl substituted imine 1g that afforded
azabicyclooctanes 3g.1 and 3g.2 as chromatographically
separable compounds (entry 7, Table 1). Disappointingly,
imines derived from heterocyclic aldehydes failed to afford the
bicyclic products, as revealed by the low yield of the thiophene
derivative derived from 3-bromo-2-carbaldehyde thiophene,
and the failure of the sequence to afford the 2-
azabicyclo[2.2.2]octane product from 2-bromo-3-carbaldehyde
pyridine, possibly due to interfering chelation interactions with
the palladium catalyst.
Next, palladium-catalyzed oxidative acetoxylation22 on the
mixture of regiosiomers 3.1a/3.2a was studied, seeking to
synthesize either a single allylic acetate or a mixture of allylic
As a part of the ongoing effort in our group to design
strategic reaction sequences involving Pd- and Ru-catalyzed
reactions,25 we considered the diversification of the azabicy-
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stirred at rt for 30 min; a solution of tributylvinyltin (0.381−1.659 g,
1.2−5.23 mmol, 1.2 equiv) in dichloromethane (0.14 M) was added
dropwise. The mixture was stirred at 45 °C for 6 h, cooled, diluted
with saturated aqueous KF (12 mL), and stirred for 16 h. Standard
Scheme 3
1
workup afforded amides 2a−g. In H NMR spectra of amides 2a−g,
signal broadening caused by hindered rotation about the amide bond
was observed (see the temperature dependent 1H NMR spectra for 2a
in the Supporting Information). In 13C NMR spectra of amides 2a−g,
broadening of peaks at about 50 and 60 ppm was observed.
N-Benzyl-N-(1-(6-bromobenzo[d][1,3]dioxol-5-yl)allyl)-
methacrylamide (2a). (1.304 g, 73%); white solid: mp 100−110 °C;
1
Rf = 0.57; H NMR δ 7.16 (t, J = 7.1 Hz, 2H), 7.13 (d, J = 6.7 Hz,
1H), 7.02 (d, J = 7.3 Hz, 2H), 6.80 (s, 2H), 6.11 (d, J = 4.1 Hz, 1H),
5.99−5.96 (m, 0.7H), 5.94 (d, J = 1.4 Hz, 1H), 5.94−5.93 (m, 0.3H),
5.91 (d, J = 1.4 Hz, 1H), 5.37 (br s, 1H), 5.26 (s, 1H), 5.18 (t, J = 8.2
Hz, 2H), 4.77 (br s, 1H), 4.38 (br s, 1H), 2.01 (s, 3H); 13C NMR δ
21.4, 48.5, 62.7, 102.0, 110.5, 113.0, 115.6, 116.5, 118.1, 126.7, 127.2
(2C), 128.1 (2C), 128.0, 128.9, 135.9, 138.0, 147.5, 148.0, 173.7; IR
(cm−1) 1647, 1618; HRMS calcd for C21H20BrNO3Na (M + Na)+
436.0524, found 436.0516.
N-Benzyl-N-(1-(2-bromo-4,5-dimethoxyphenyl)allyl)meth-
1
acrylamide (2b). (355 mg, 83%); clear oil: Rf = 0.40; H NMR δ
clooctane 3.1a via Ru-catalyzed cross-metathesis. The treat-
ment of heterocycle 3.1a with 1-bromo-4-pentene along with
Grubbs II catalyst (10 mol %)26 provided a good yield of a
single stereoisomer of the cross-metathesis product 5 (Scheme
3). The relative stereochemistry in functionalized bicyclooctane
7.17−7.12 (m, 3H), 7.00 (d, J = 7.3 Hz, 2H), 6.84 (br s, 1H), 6.76 (s,
1H), 6.08 (dt, J = 5.3, 1.5 Hz, 1H), 5.99 (ddd, J = 17.1, 10.4, 5.3 Hz,
1H), 5.36 (br s, 1H), 5.26 (br s, 1H), 5.21 (s, 0.5H), 5.19 (s, 1H), 5.17
(s, 0.5H), 4.69 (br s, 1H), 4.43 (br s, 1H), 3.80 (s, 3H), 3.75 (s, 3H),
2.02 (s, 3H); 13C NMR δ 21.3, 47.8, 56.2, 56.3, 63.0, 113.5, 115.5,
115.7, 115.9, 118.2, 126.8, 127.3 (2C), 128.1 (2C), 129.6, 135.9, 138.0,
140.7, 148.3, 149.2, 173.7; IR (cm−1) 1647, 1620, 1252; HRMS calcd
for C22H24BrNO3Na (M + Na)+ 452.0837, found 452.0835.
1
5 was assigned based on NOE H NMR experiments that
identified a correlation between the vinylic and methine
hydrogens in the structure of azabicyclooctane 5 (Scheme 3).
The presence of a flexible linker and a reactive leaving group in
azabicyclooctane 5 makes it a valuable substrate for the
synthesis of structures with two biologically active cores
connected by a flexible linker. Such compounds could serve
as valuable probes in biomedical research.27 To validate this
concept, azabicyclooctane 5 was reacted with N-homoallyl p-
tolylsulfonamide and K2CO3 in DMF (60 °C, 19 h) to afford
sulfonamide 6 in an excellent yield (89%) (Scheme 3).
In conclusion, the studies described herein completed the
development of a synthetic protocol for the construction of
diversely substituted aryl-fused 2-azabicyclo[2.2.2]octanes
linked to a second pharmacophore delivered as a nucleophile
in the terminal SN2 reaction. The protocol provides an effective
alternative to the limited number of currently available
synthetic methods and opens up many options for the
preparation of diverse analogues.
N-Benzyl-N-(1-(2-bromo-5-methoxyphenyl)allyl)methacryl-
1
amide (2c). (399 mg, 63%); yellow oil: Rf = 0.58; H NMR δ 7.33−
7.27 (m, 1H), 7.16−7.12 (m, 3H), 7.02 (d, J = 7.2 Hz, 2H), 6.85 (d, J
= 3.1 Hz, 1H), 6.61 (dd, J = 8.7, 2.7 Hz, 1H), 6.13 (br s, 1H), 5.97
(ddd, J = 17.2, 10.4, 5.4 Hz, 1H), 5.36 (d, J = 8.1 1H), 5.24 (s, 1H),
5.20 (q, J = 1.1 Hz, 0.5H), 5.18 (s, 1H), 5.16 (q, J = 1.0 Hz, 0.5H),
4.69 (br s, 1H), 4.54 (d, J = 13.0 Hz, 1H), 3.72 (s, 3H), 1.99 (s, 3H)
13C NMR δ 21.3, 47.3, 55.6, 63.3, 114.8, 115.6, 115.7, 117.0, 118.6,
126.8, 127.3 (2C), 128.1 (2C), 122.8, 135.4, 138.1, 138.9, 140.6, 159.0,
173.8. IR (cm−1) 1647, 1624; HRMS calcd for C21H22BrNO2Na (M +
Na)+ 422.0732, found 422.0744.
N-Benzyl-N-(1-(2-bromo-4-methylphenyl)allyl)methacryl-
amide (2d). (1.213 g, 74%); clear oil: Rf = 0.54; 1H NMR δ 7.21 (br s,
1H), 7.18 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 6.7 Hz, 3H), 7.03 (d, J = 7.9
Hz, 1H), 6.98 (d, J = 6.9 Hz, 2H), 6.14 (br s, 1H), 5.98 (ddd, J = 17.2,
10.5, 5.3 Hz, 1H), 5.34 (d, J = 6.7 Hz, 1H), 5.25 (s, 1H), 5.18 (q, J =
1.1 Hz, 0.5H), 5.17 (br s, 1H), 5.15 (q, J = 1.1 Hz, 0.5H), 4.65 (br s,
1H), 4.46 (d, J = 10.2 Hz, 1H), 2.24 (s, 3H), 1.99 (s, 3H); 13C NMR δ
20.7, 21.3, 47.1, 63.0, 115.5, 118.1, 125.3, 126.6, 127.3 (2C), 128.0
(2C), 128.3, 130.4, 133.7, 134.8, 135.8, 138.1, 139.9, 140.6, 173.8; IR
(cm−1) 1649, 1620; HRMS calcd for C21H23BrNO (M + H)+
384.0963, found 384.0963.
N-Benzyl-N-(1-(1-bromonaphthalen-2-yl)allyl)methacryl-
amide (2e). (252 mg, 60%); yellow oil: Rf = 0.32; 1H NMR δ 8.25 (d,
J = 8.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H),
7.56 (td, J = 8.2, 1.2 Hz, 1H), 7.51 (td, J = 8.1, 1.3 Hz, 1H), 7.44 (d, J
= 8.5 Hz, 1H), 7.06 (br s, 2H), 7.01 (d, J = 7.3 Hz, 3H), 6.47 (d, J =
5.4 Hz, 1H), 6.12 (ddd, J = 16.8, 10.4, 5.4 Hz, 1H), 5.36 (d, J = 10.0
Hz, 1H), 5.23 (s, 1H), 5.18 (q, J = 1.0 Hz, 1.5H), 5.14 (q, J = 1.1 Hz,
0.5H), 4.70 (d, J = 12.6 Hz, 1H), 4.63 (d, J = 15.7 Hz, 1H), 1.97 (s,
3H); 13C NMR δ 21.2, 31.1, 64.0, 115.6, 118.5, 126.0, 126.8, 126.8,
127.1, 127.1 (2C), 127.7 (2C), 127.7, 128.0, 128.0, 128.1, 132.4, 134.1,
135.6, 136.1, 138.1, 140.7, 173.8; IR (cm−1) 1647, 1624; HRMS calcd
for C24H22BrNONa (M + Na)+ 442.0782, found 442.0784.
EXPERIMENTAL SECTION
■
General Experimental. 1H NMR (500 MHz) and 13C NMR (125
MHz) were collected in CDCl3 with internal CHCl3 reference (7.26
ppm for 1H and 77.16 ppm for 13C). IR spectra were measured in films
on NaCl plates. MS were measured under electrospray (ES+)
ionization with time-of-flight (TOF) mass analyzer. Commercial silica
gel 60 plates, 0.25 mm thickness, with fluorescent indicator (F-254)
were used for thin-layer chromatography (TLC). Retention factors
(Rf) for TLC were determined in EtOAc/hexane 1:1 mixture, unless
indicated otherwise. Column chromatography was performed with
40−63 mm silica. Solvents and glassware were dried by standard
methods.28 All reactions were performed under dry argon atmosphere.
Imines 1 were prepared by a modified literature procedure.29 Ratios of
1
regioisomers were measured by H NMR. Standard workup protocol
involving aqueous extraction of the organic phases, drying (MgSO4),
and flash chromatography over silica eluting with EtOAc/Hexanes was
followed.
N-Benzyl-N-(1-(2-bromo-5-fluorophenyl)allyl)methacryl-
1
amide (2f). (193 mg, 50%); yellow oil: Rf = 0.61; H NMR δ 7.34−
7.27 (m, 1H), 7.23−7.09 (m, 3H), 7.04 (dd, J = 9.6, 3.0 Hz, 1H), 7.01
(d, J = 7.4 Hz, 2H), 6.78 (dt, J = 8.4, 2.9 Hz, 1H), 6.13 (d, J = 5.0 Hz,
1H), 5.96 (ddd, J = 17.2, 10.4, 5.3 Hz, 1H), 5.39 (br d, J = 6.8 Hz,
1H), 5.24 (s, 1H), 5.21−5.17 (m, 2H), 4.72 (br s, 1H), 4.48 (br s,
General Method for Amides 2a−g. Neat methacryloyl chloride
(1.29−5.66 mmol, 125−550 μL, 1.3 equiv) was injected into a solution
of imine 1 (0.99−4.33 mmol, 1.0 equiv) and CuCl (10−44 mg, 0.1−
0.44 mmol, 0.1 equiv) in acetonitrile (0.27 M). The mixture was
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1H), 2.00 (s, 3H); 13C NMR δ 21.3, 48.2, 62.7, 115.7, 116.7 (d, J =
21.3 Hz), 118.0 (d, J = 23.8 Hz), 119.0, 119.4 (d, J = 2.5 Hz), 126.9,
127.2 (2C), 128.0 (d, J = 82.5 Hz), 128.2 (2C), 134.4 (d, J = 8.8 Hz),
134.8, 137.8, 140.2, 162.0 (d, J = 246.3 Hz), 173.7; IR (cm−1) 1647,
1624; HRMS calcd for C20H20BrFNO (M + H)+ 388.0712, found
388.0719.
N-Benzyl-N-(1-(2-bromo-6-fluorophenyl)allyl)methacryl-
amide (2g). (473 mg, 77%); yellow oil: Rf = 0.68; 1H NMR δ 7.29 (d,
J = 7.8 Hz, 1H), 7.20 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.1 Hz, 1H), 7.08
(d, J = 7.4 Hz, 2H), 7.01 (dt, J = 8.2, 5.8 Hz, 1H), 6.90 (ddd, J = 11.0,
8.5, 0.8 Hz, 1H), 6.41 (br s, 1H), 6.13−6.06 (m, 1H), 5.22 (d, J = 10.3
Hz, 1H), 5.13−5.09 (m, 3H), 4.88−4.80 (m, 2H), 1.83 (s, 3H); 13C
NMR) δ 20.8, 49.2, 60.7, 115.5, 115.7 (d, J = 23.8 Hz), 118.2, 125.8
(d, J = 6.3 Hz), 126.2 (2C), 126.7, 127.3, 128.3 (2C), 128.7, 129.2 (d,
J = 3.8 Hz), 130.0 (d, J = 8.8 Hz), 133.4, 139.7 (d, J = 196.3 Hz), 161.6
(d, J = 250.0 Hz), 173.7; IR (cm−1) 1649, 1624; HRMS calcd for
C20H20FBrNO (M + H)+ 388.0712, found 388.0704.
(t, J = 1.9 Hz, 0.56H), 4.53 (s, 0.56H), 4.48 (d, J = 2.1 Hz, 0.44H),
4.38 (d, J = 15.3 Hz, 0.56H), 4.22 (d, J = 15.1 Hz, 0.44H), 3.90 (s,
1.68H), 3.88 (s, 1.32H), 3.80 (s, 1.32H), 3.79 (s, 1.68H), 2.60 (dt, J =
16.2, 2.2 Hz, 0.56H), 2.19 (dt, J = 16.2, 2.1 Hz, 0.56H), 1.84 (s,
1.32H), 1.71 (s, 1.68H) 1.65 (d, J = 1.8 Hz, 1.32H); 13C NMR δ
[14.2], 16.1, [18.1], 38.8, 47.1, 48.3, [49.2], [53.8], 56.3, 56.4, [56.4],
[56.5], [63.7], 64.4, 106.3, 106.5, [106.6], [107.1], 107.6, 127.5,
[127.7], 128.1 (2C), [128.4 (2C)], 128.6 (2C), [128.7 (2C)], 131.9,
[133.5], 134.8, [135.3], 136.9, [137.1], [137.4], 143.7, [146.3],
[146.7], 147.2, [147.8], 148.6, 174.9, [175.0]; IR (cm−1) 1668,
1607; HRMS calcd for C22H24NO3 (M + H)+ 350.1756, found
350.1758.
Single Isomer 3.1b. Reaction with Pd(PPh3)4 catalyst, TEA in
THF as described for 3.1a afforded 3.1b (65 mg, 74%); clear oil. For
1H NMR spectra, see the Supporting Information.
(1R*,4S*)-10-benzyl-7-methoxy-4-methyl-2-methylene-
1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalen-9-one
(3.1c) and (1R*,4S*)-10-Benzyl-7-methoxy-2,4-dimethyl-1,4-
dihydro-1,4-(epiminomethano)naphthalen-9-one (3.2c). (54
General Method for Azabicyclooctanes 3.1a−g and 3.2a−g.
A solution of amide 2a−g (0.25−3.67 mmol, 1.0 equiv) in DMF (4−
30 mL, 0.12 M) was injected into a vessel containing sodium
carbonate (27−390 mg, 0.26−3.68 mmol, 1.0 equiv), tetrabutylam-
monium chloride (70 mg-1.012 g, 0.25−3.57 mmol, 1.0 equiv) and
palladium acetate (6−83 mg, 0.024−0.37 mmol, 0.1 equiv). The
mixture was stirred at 80 °C for 18−26 h. Standard workup afforded a
mixture of azabicyclooctanes 3.1a−g and 3.2a−g. In 13C NMR
spectra, the signals for the minor regioisomer are provided in brackets.
(5R*,8S*)-11-Benzyl-8-methyl-6-methylene-5,6,7,8-tetrahy-
dro-5,8-(epiminomethano)naphtho[2,3-d][1,3]dioxol-10-one
(3.1a) and (5R*,8S*)-11-Benzyl-6,8-dimethyl-5,8-dihydro-5,8-
(epiminomethano)naphtho[2,3-d][1,3]dioxol-10-one (3.2a).
1
mg, 65%); clear oil, 1.3:1.0 ratio of 3.1c:3.2c: Rf = 0.31; H NMR δ
7.32−7.23 (m, 3H), 7.18 (d, J = 8.3 Hz, 0.56H), 7.15 (d, J = 8.2 Hz,
0.44H), 7.13 (dd, J = 1.8, 8.1 Hz, 0.88H), 7.10 (dd, J = 2.1, 7.8 Hz,
1.12H), 6.79 (dd, J = 8.4, 2.6 Hz, 0.56H), 6.69 (d, J = 2.5 Hz, 0.44H),
6.61 (d, J = 2.5 Hz, 0.22H), 6.59 (d, J = 2.5 Hz, 0.78H), 6.04 (p, J =
1.9 Hz, 0.44H), 4.90 (t, J = 2.3 Hz, 0.56H), 4.82 (d, J = 15.1 Hz,
0.44H), 4.76 (d, J = 15.3 Hz, 0.56H), 4.73 (t, J = 1.9 Hz, 0.56H), 4.56
(s, 0.56H), 4.48 (d, J = 2.1 Hz, 0.44H), 4.44 (d, J = 15.3 Hz, 0.56H),
4.11 (d, J = 15.1 Hz, 0.44H), 3.76 (s, 1.32H), 3.75 (s, 1.68H), 2.60 (dt,
J = 16.2, 2.2 Hz, 0.56H), 2.19 (dt, J = 16.3, 2.2 Hz, 0.56H), 1.83 (s,
1.32H), 1.70 (s, 1.68H) 1.62 (d, J = 1.8 Hz, 1.32H) ; 13C NMR δ
[14.1], 15.9, [18.0], 38.9, 46.7, 48.3, [49.1], [53.3], 55.5, [56.6],
[63.9], 64.8, 108.4, 108.6, [109.1], [109.7], 112.3, [121.8], 123.1,
127.5, [127.7], 128.1 (2C), [128.4 (2C)], 128.6 (2C), [128.7 (2C)],
[133.4], 135.0, 136.7, [136.9], [137.2], 140.6, 143.5, [144.0], [146.4],
[157.6], 158.7, [175.0], 175.1; IR (cm−1) 1612, 1612; HRMS calcd for
C21H21NO2Na (M + H)+ 342.1470, found 342.1466.
1
(1.103 g, 90%); clear oil, 1.5:1.0 ratio of 3.1a:3.2a: Rf = 0.52; H
NMR δ 7.33−7.24 (m, 3H), 7.13−7.08 (m, 2H), 6.83 (s, 0.4H), 6.80
(s, 0.6H), 6.63 (s, 0.4H), 6.52 (s, 0.6H), 6.02 (p, J = 2.0 Hz, 0.4H),
5.95 (d, J = 2.0 Hz, 0.6H), 5.93 (d, J = 2.0 Hz, 0.4H), 5.91 (d, J = 1.0
Hz, 0.6H), 5.90 (d, J = 1.5 Hz, 0.4H), 4.87 (t, J = 2.0 Hz, 0.6H), 4.79
(d, J = 15.3 Hz, 0.6H), 4.78 (d, J = 14.9 Hz, 0.4H), 4.70 (t, J = 2.0 Hz,
0.6H), 4.50 (s, 0.6H), 4.44 (d, J = 2.0 Hz, 0.4H), 4.37 (d, J = 15.0 Hz,
0.6H), 4.13 (d, J = 15.0 Hz, 0.4H), 2.51 (dt, J = 16.5, 2.0 Hz, 0.6H),
2.18 (dt, J = 16.0, 2.0 Hz, 0.6H), 1.80 (s, 1.2H), 1.67 (s, 1.8H) 1.61 (d,
J = 1.4 Hz 1.2H); 13C NMR δ [14.3], 16.2, [18.0], 38.7, 47.3, 48.3,
[49.2], [54.0], [63.8], 64.5, 101.2, [101.3], 103.8, [104.08], 104.12,
[104.2], 107.8, 127.6, [127.7], 128.1 (2C), [128.3 (2C)], 128.6 (2C),
[128.7 (2C)], 133.0, [134.6], 135.2, [136.6], 136.8, [137.1], [139.3],
143.5, [144.8], [145.5], 146.2, [147.27], 147.29, 174.7, [174.9]; IR
(cm−1) 1740, 1682; HRMS calcd for C21H19NO3Na (M + Na)+
356.1263, found 356.1253.
(1R*,4S*)-10-Benzyl-4,6-dimethyl-2-methylene-1,2,3,4-tet-
rahydro-1,4-(epiminomethano)naphthalen-9-one (3.1d) and
(1R*,4S*)-10-Benzyl-2,4,6-trimethyl-1,4-dihydro-1,4-(epimino-
methano)naphthalen-9-one (3.2d). (146 mg, 77%); yellow oil,
1
1.1:1.0 ratio of 3.1d:3.2d: Rf = 0.53; H NMR δ 7.32−7.23 (m, 3H),
7.14 (s, 0.53H), 7.12 (s, 0.47), 7.11−7.08 (m, 2H), 6.98 (s, 0.47), 6.97
(s, 0.53), 6.91 (d, J = 7.5 Hz, 0.53H), 6.85 (d, J = 7.3, 0.47H), 6.02 (p,
J = 1.7 Hz, 0.47H), 4.89 (t, J = 2.3 Hz, 0.53H), 4.83 (d, J = 15.1 Hz,
0.47H), 4.76 (d, J = 15.3 Hz, 0.53H), 4.70 (t, J = 1.8 Hz, 0.53H), 4.58
(s, 0.53H), 4.51 (d, J = 2.1 Hz, 0.47H), 4.44 (d, J = 15.3 Hz, 0.53H),
4.08 (d, J = 15.1 Hz, 0.47H), 2.60 (dt, J = 16.2, 2.2 Hz, 0.53H), 2.37
(s, 1.59H), 2.33 (s, 1.41H), 2.19 (dt, J = 16.2, 2.2 Hz, 0.53H), 1.84 (s,
1.41H), 1.71 (s, 1.59H), 1.61 (d, J = 1.8 Hz, 1.41H); 13C NMR δ
[14.0], 15.8, [18.0], 21.6, [21.7], 38.7, [47.3], 48.3, 49.1, [54.0],
[63.6], 64.4, 107.9, [121.3], 121.8, [122.4], 123.0, [125.4], 127.3,
127.5, [127.7], 128.1 (2C), [128.3 (2C)], 128.6 (2C), [128.7 (2C)],
[134.4], 135.7, 136.5, 136.9, [137.2], [137.6], 139.8, 141.2, [143.7],
[144.8], [147.0], [174.7], 174.8; IR (cm−1) 1672, 1495; HRMS calcd
for C21H22NO (M + H)+ 304.1701, found 304.1698.
Single Isomer 3.1a. THF (4 mL) was injected into a vessel
containing solid amide 2a (142 mg, 0.34 mmol, 1.0 equiv) and
tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol, 0.05
equiv), followed by neat triethylamine (138 mg, 190 μL, 1.36 mmol,
4.0 equiv). The mixture was stirred at 80 °C for 23 h. Standard workup
afforded azabicyclooctane 3.1a (102 mg, 90%) as a white solid: mp
1
120−124 °C; Rf = 0.52; H NMR δ 7.29−7.23 (m, 3H), 7.10 (d, J =
1.9, 1H), 7.08 (d, J = 1.3, 1H), 6.80 (s, 1H), 6.52 (s, 1H), 5.95 (d, J =
1.5 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 4.87 (t, J = 2.3 Hz, 1H), 4.79 (d,
J = 15.3 Hz, 1H), 4.70 (t, J = 1.9 Hz, 1H), 4.50 (s, 1H), 4.38 (d, J =
15.3 Hz, 1H), 2.57 (dt, J = 16.1 Hz, J = 2.2 Hz, 1H), 2.16 (dt, J = 16.2
Hz, J = 2.2 Hz, 1H), 1.67 (s, 3H). 13C NMR δ 16.2, 38.7, 47.3, 48.3,
64.5, 101.2, 103.8, 104.1, 107.8, 127.6, 128.1 (2C), 128.6 (2C), 133.0,
135.2, 136.8, 143.5, 146.2, 147.3, 174.7; IR (cm−1) 1666. HRMS calcd
for C21H19NO3Na (M + Na)+ 356.1263, found 356.1262.
(1R*,4S*)-12-Benzyl-4-methyl-2-methylene-1,2,3,4-tetrahy-
dro-1,4-(epiminomethano)phenanthren-11-one (3.1e) and
(1R*,4S*)-12-Benzyl-2,4-dimethyl-1,4-dihydro-1,4-(epimino-
methano)phenanthren-11-one (3.2e). (123 mg, 65%); yellow
solid, 2.3:1.0 ratio of 3.1e:3.2e: mp 110−120 °C; Rf = 0.52; 1H NMR
δ 8.69 (d, J = 8.8 Hz, 0.7H), 8.65 (d, J = 8.9 Hz, 0.3H), 7.84 (d, J = 8.2
Hz, 0.7H), 7.82 (d, J = 7.7 Hz, 0.3H), 7.68 (d, J = 8.1 Hz, 0.7H), 7.59
(d, J = 8.0 Hz, 0.3H), 7.50 (ddd, J = 8.5, 6.8, 1.6 Hz, 0.7H), 7.48−7.42
(m, 1H), 7.37 (ddd, J = 8.0, 6.8, 0.9 Hz, 0.3H), 7.30−7.28 (m, 1H),
7.25−7.22 (m, 2.4H), 7.14−7.12 (m, 1H), 7.11 (s, 0.3H), 7.09−7.07
(m, 1.3H), 6.16 (p, J = 2.0 Hz, 0.3H), 4.97 (t, J = 2.3 Hz, 0.7H), 4.90
(d, J = 15.3 Hz, 0.7H), 4.79 (d, J = 15.1 Hz, 0.3H), 4.75 (t, J = 1.9 Hz,
0.7H), 4.69 (s, 0.7H), 4.64 (d, J = 2.3 Hz, 0.3H), 4.41 (d, J = 15.3 Hz,
0.7H), 4.23 (d, J = 15.1 Hz, 0.3H), 2.62 (dt, J = 16.4, 2.2 Hz, 0.7H),
2.48 (dt, J = 16.4, 2.2 Hz, 0.7H), 2.44 (s, 0.9H), 2.32 (s, 2.1H), 1.67
(d, J = 1.8 Hz, 0.9H); 13C NMR δ [18.0], [20.1], 21.9, 40.4, 48.3,
(1R*,4S*)-10-Benzyl-6,7-dimethoxy-4-methyl-2-methylene-
1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalen-9-one
(3.1b) and (1R*,4S*)-10-Benzyl-6,7-dimethoxy-2,4-dimethyl-
1,4-dihydro-1,4-(epiminomethano)naphthalen-9-one (3.2b).
1
(166 mg, 68%); yellow oil, 1.3:1.0 ratio of 3.1b:3.2b: Rf = 0.31; H
NMR δ 7.29−7.23 (m, 3H), 7.10 (dd, J = 7.8, 2.2 Hz, 1H), 7.07 (dd, J
= 7.6, 2.0 Hz, 1H), 6.87 (s, 0.44H), 6.82 (s, 0.56H), 6.66 (s, 0.44H),
6.56 (s, 0.56H), 6.05 (p, J = 1.9 Hz, 0.44H), 4.88 (t, J = 2.2 Hz,
0.56H), 4.83 (d, J = 15.3 Hz, 0.56H), 4.73 (d, J = 15 Hz, 0.44H), 4.71
8813
dx.doi.org/10.1021/jo400974k | J. Org. Chem. 2013, 78, 8809−8815

The Journal of Organic Chemistry
Note
[49.4], 51.1, [57.8], [64.8], 65.4, 108.1, [121.0], 121.3, [124.0], 124.4,
[124.7], 125.1, [126.3], 126.4, [126.9], 127.6, 127.7, 128.1 (2C),
[128.4 (2C)], [128.5], 128.6 (2C), [128.8 (2C)], [129.5], 129.7,
130.9, [130.9], [133.2], 134.3, [135.0], 136.8, [137.0], [137.5], 138.8,
[139.6], [142.8], 143.0, [146.8], 174.9, [175.0]; IR (cm−1) 1668, 1607;
HRMS calcd for C24H21NONa (M + Na)+ 362.1521, found 362.1521.
(1R*,4S*)-10-Benzyl-7-fluoro-4-methyl-2-methylene-1,2,3,4-
tetrahydro-1,4-(epiminomethano)naphthalen-9-one (3.1f) and
(1R*,4S*)-10-Benzyl-7-fluoro-2,4-dimethyl-1,4-dihydro-1,4-
(epiminomethano)naphthalen-9-one (3.2f). (129 mg, 66%);
63.0, 73.9, 101.5, 103.6, 105.4, 112.0, 127.7, 128.3 (2C), 128.6 (2C),
131.4, 133.8, 136.5, 143.9, 147.0, 147.6, 171.2, 171.7; IR (cm−1) 1740,
1672; HRMS calcd for C23H21NO5Na (M + Na)+ 414.1317, found
414.1319.
(5R*,8S*,E)-11-Benzyl-6-(4-bromobutylidene)-8-methyl-
5,6,7,8-tetrahydro-5,8-(epiminomethano)naphtho[2,3-d][1,3]-
dioxol-10-one (5). A solution of azabicyclooctane 3.1a (39 mg, 0.12
mmol, 1.0 equiv) in dichloromethane (5 mL) was injected into a
pressure tube containing the Grubbs II catalyst (5 mg, 0.0059 mmol,
0.05 equiv), followed by neat 5-bromo-1-pentene (21 μL, 0.18 mmol,
1.5 equiv). The pressure tube was flushed with argon and sealed, and
the mixture was stirred at 40 °C for 19 h. The crude product was
purified by preparative TLC to afford bromide 5 (35 mg, 66%) as a
colorless oil: Rf = 0.41; 1H NMR δ 7.29−7.27 (m, 2H), 7.26−7.25 (m,
1H), 7.11 (dd, J = 8.0, 1.9 Hz, 2H), 6.81 (s, 1H), 6.53 (s, 1H), 5.94 (d,
J = 1.5 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 5.14 (dt, J = 7.1, 2.1 Hz,
1H), 4.62 (d, J = 15.2 Hz, 1H), 4.51 (d, J = 15.2 Hz, 1H), 4.45 (s, 1H),
3.25 (dd, J = 6.6, 2.3 Hz, 2H), 2.46 (d, J = 16.1 Hz, 1H), 2.10 (d, J =
16.1 Hz, 1H), 2.02−1.93 (m, 2H), 1.79 (p, J = 6.9 Hz, 2H), 1.70 (s,
3H); 13C NMR δ 16.5, 27.1, 32.0, 33.2, 36.7, 47.3, 48.3, 64.7, 101.2,
103.6, 104.1, 121.2, 127.6, 128.2 (2C), 128.6 (2C), 133.2, 135.2, 136.5,
136.9, 146.1, 147.1, 174.7; IR (cm−1) 1666; HRMS calcd for
C24H24BrNO3Na (M + Na)+ 476.0837, found 476.0847.
1
orange oil, 1.2:1.0 ratio of 3.1f:3.2f: Rf = 0.50; H NMR δ 7.30−
7.27 (m, 2H), 7.26 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.4, 5.0 Hz,
0.53H), 7.18 (dd, J = 9.0, 5.0 Hz, 0.47H), 7.11 (dd, J = 7.8, 2.1 Hz,
0.94H), 7.07 (dd, J = 7.7, 2.8 Hz, 1.06H), 6.96 (ddd, J = 9.2, 8.4, 2.6
Hz, 0.53H), 6.81−6.77 (m, 0.94H), 6.73 (dd, J = 8.0, 2.5 Hz, 0.53H),
6.05 (p, J = 1.8 Hz, 0.47H), 4.93 (t, J = 2.4 Hz, 0.53H), 4.81 (d, J = 2.7
Hz, 0.47H), 4.77 (d, J = 2.4 Hz, 0.53H), 4.76 (t, J = 2.0 Hz, 0.53H),
4.57 (s, 0.53H), 4.50 (d, J = 2.1 Hz, 0.47H), 4.41 (d, J = 15.2 Hz,
0.53H), 4.15 (d, J = 15.1 Hz, 0.47H), 2.61 (dt, J = 16.3, 2.2 Hz,
0.53H), 2.19 (dt, J = 16.2, 2.2 Hz, 0.53H), 1.84 (s, 1.41H), 1.71 (s,
1.59H), 1.63 (d, J = 1.8 Hz, 1.41H); 13C NMR δ [14.1], 16.0, [18.0],
38.5, 47.1, 48.3, [49.2], [53.7], [63.5], 64.3, 109.0, [109.8 (d, J = 22.5
Hz)], 110.0 (d, J = 23.8 Hz), [111.6 (d, J = 21.3 Hz)], 111.1 (d, J =
21.3 Hz), [122.2 (d, J = 8.8 Hz)], 123.7 (d, J = 7.5 Hz), 127.7,
[127.85], 128.1 (2C), [128.4 (2C)], 128.7 (2C), [128.8 (2C)], 136.6,
[136.88], 136.9 (d, J = 2.5 Hz), [140.3 (d, J = 2.5 Hz)], [141.1 (d, J =
7.5 Hz)], 142.9, 144.6 (d, J = 7.5 Hz), [146.4], 160.3 (d, J = 113.8
Hz), [162.3 (d, J = 113.8 Hz)], 174.4; IR (cm−1) 1672, 1603; HRMS
calcd for C20H19FNO (M + H)+ 308.1451, found 308.1446.
N-((E)-4-((5R*,8S*)-11-Benzyl-8-methyl-10-oxo-7,8-dihydro-
5,8-(epiminomethano)naphtho[2,3-d][1,3]dioxol-6(5H)-
ylidene)butyl)-N-(but-3-en-1-yl)-4-methylbenzenesulfonamide
(6). A solution of bromide 5 (37 mg, 0.081 mmol, 1.0 equiv) in DMF
(2 mL) was added dropwise at rt to the mixture of N-(but-3-en-1-yl)-
4-methylbenzenesulfonamide (27 mg, 0.12 mmol, 1.5 equiv) and
anhydrous K2CO3 (29 mg, 0.21 mmol, 2.6 equiv) in DMF (1 mL).
The mixture was stirred at 60 °C for 19 h, and the crude product was
purified by preparative TLC yielding sulfonamide 6 (43 mg, 89%) as a
(1R*,4S*)-10-Benzyl-8-fluoro-4-methyl-2-methylene-1,2,3,4-
tetrahydro-1,4-(epiminomethano)naphthalen-9-one (3.1g)
and (1R*,4S*)-10-Benzyl-8-fluoro-2,4-dimethyl-1,4-dihydro-
1,4-(epiminomethano)naphthalen-9-one (3.2g). 3.1g (30 mg,
38%), yellow oil 3.2g (41.8 mg, 54%), clear oil.
1
clear oil: Rf = 0.40; H NMR δ 7.63 (d, J = 8.2 Hz, 2H), 7.27 (d, J =
8.3 Hz, 2H), 7.25 (s, 1H), 7.23 (s, 2H), 7.08 (dd, J = 7.5, 2.0 Hz, 2H),
6.80 (s, 1H), 6.50 (s, 1H), 5.92 (dd, J = 18.9, 1.3 Hz, 2H), 5.71−5.63
(m, 1H), 5.19 (tt, J = 7.1, 2.0 Hz, 1H), 5.03 (dq, J = 7.5, 1.5 Hz, 1H),
5.00 (t, J = 1.0 Hz, 1H), 4.74 (d, J = 15.2 Hz, 1H), 4.44 (s, 1H), 4.38
(d, J = 15.2 Hz, 1H), 3.10 (hept, J = 7.5 Hz, 2H), 3.00 (td, J = 6.9, 1.8
Hz, 2H), 2.41 (s, 3H), 2.38 (d, J = 16.9 Hz, 1H), 2.22 (q, J = 7.6 Hz,
2H), 2.03 (d, J = 16.5 Hz, 1H), 1.81 (hept, J = 7.4 Hz, 2H), 1.70 (s,
3H), 1.49 (p, J = 7.4 Hz, 2H); 13C NMR δ 16.5, 21.6, 25.9, 28.3, 33.4,
36.7, 47.3, 47.9, 48.1, 48.2, 64.6, 101.2, 103.6, 104.1, 117.2, 122.0,
127.2 (2C), 127.5, 128.1 (2C), 128.6 (2C), 129.8 (2C), 133.3, 134.7,
135.3., 135.7, 136.88, 136.91, 143.3, 146.1, 147.1, 174.7; IR (cm−1)
1663, 1479; HRMS calcd for C35H39N2O5S (M + H)+ 599.2580, found
599.2573.
1
3.1g: Rf = 0.5 (EtOAc/hexane 1:2.3); H NMR δ 7.29−7.26 (m,
1H), 7.26−7.21 (m, 3H), 7.12−7.10 (m, 2H), 7.07 (d, J = 7.6 Hz,
1H), 6.89 (dt, J = 8.5, 0.8 Hz, 1H), 5.02 (s, 1H), 4.96 (t, J = 2.4 Hz,
1H), 4.75 (t, J = 2.0 Hz, 1H), 4.72 (d, J = 15.1 Hz, 1H), 4.49 (d, J =
15.1 Hz, 1H), 2.62 (dt, J = 16.3, 2.2 Hz, 1H), 2.21 (dt, J = 16.3, 2.2 Hz,
1H), 1.72 (s, 3H); 13C NMR δ 16.0, 38.3, 47.8, 48.6, 57.9, 108.9, 113.9
(d, J = 20 Hz), 118.0 (d, J = 3.8 Hz), 125.8 (d, J = 18.8 Hz), 127.6,
128.1 (2C), 128.7 (2C), 129.1 (d, J = 7.5 Hz), 136.5, 142.2, 144.4 (d, J
= 5 Hz), 155.8 (d, J = 246.3 Hz), 174.3; IR (cm−1) 1676, 1622; HRMS
calcd for C20H19FNO (M + H)+ 308.1451, found 308.1450.
1
3.2g: Rf = 0.55 (EtOAc/hexane 1:2.3); H NMR δ 7.33−7.28 (m,
3H), 7.14 (dd, J = 7.9, 2.0 Hz, 2H), 7.08−7.06 (m, 2H), 6.81−6.77
(m, 1H), 6.05 (p, J = 1.9 Hz, 1H), 4.96 (d, J = 2.1 Hz, 1H), 4.83 (d, J
= 15.0 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 1.86 (s, 3H), 1.62 (d, J =
1.8 Hz, 3H); 13C NMR δ 14.2, 17.9, 49.3, 54.5, 57.2, 113.0 (d, J = 21.3
Hz), 117.2 (d, J = 2.5 Hz), 127.4 (d, J = 7.5 Hz), 127.8, 128.4 (2C),
128.5 (d, J = 20.0 Hz), 128.8 (2C), 134.8, 136.8, 146.4, 148.4 (d, J = 5
Hz), 156.0 (d, J = 243.8 Hz), 174.5; IR (cm−1) 1682, 1622; HRMS
calcd for C20H19FNO (M + H)+ 308.1451, found 308.1442.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds
prepared in this study, variable temperature 1H NMR for
compound 2a, data from NOE experiments on compounds 4
and 5 and quantitative GC−MS data for compounds 3a−g.
This material is available free of charge via Internet at http://
pubs.acs.org.
Single Isomer 3.1g. Reaction with Pd(PPh3)4 catalyst, TEA in
THF as described for 3.1a afforded 3.1g (85 mg, 70%); yellow oil. For
1H NMR spectra, see the Supporting Information.
(5R*,7S*,8S*)-11-Benzyl-8-methyl-6-methylene-10-oxo-
5,6,7,8-tetrahydro-5,8-(epiminomethano)naphtho[2,3-d][1,3]-
dioxol-7-yl acetate (4). A solution of azabicyclooctane 3a (207 mg,
0.62 mmol, 1.0 equiv) in acetic acid (3 mL) was injected into a vessel
containing benzoquinone (7 mg, 0.065 mmol, 0.1 equiv) and
Pd(OAc)2 (7 mg, 0.033 mmol, 0.05 equiv). 30% aqueous H2O2 (78
μL, 2.55 mmol, 4.1 equiv) was added, and the mixture was stirred at 75
°C for 47 h. Standard workup afforded azabicyclooctane 4 (73 mg,
30%) as a yellow oil and recovered 3a (38%) with the isomer ratio
unchanged.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hmalina@ku.edu. Phone: 785-864-4743.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
4: mp 96−99 °C; Rf = 0.40; 1H NMR δ 7.26−7.27 (m, 3H), 7.15−
7.13 (m, 2H), 6.83 (s, 1H), 6.49 (s, 1H), 5.96 (d, J = 1.4 Hz, 1H), 5.93
(d, J = 1.5 Hz, 1H), 5.37 (s, 1H), 5.01 (d, J = 1.5 Hz, 1H), 4.94 (d, J =
1.8 Hz, 1H), 4.72 (d, J = 15.2 Hz, 1H), 4.58 (d, J = 15.3 Hz, 1H), 4.51
(s, 1H), 2.15 (s, 3H), 1.61 (s, 3H); 13C NMR δ 12.9, 21.3, 48.6, 51.5,
Support from the NIH via the KU Center for Methodology and
Library Development (P 50 GM063966) is acknowledged. We
thank our University of Kansas colleagues Dr. Justin Douglas
for his assistance with NMR spectroscopy, Dr. Todd D.
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The Journal of Organic Chemistry
Note
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Willams for assistance with GC−MS and HRMS spectroscopy,
and Dr. Lei Zhang for important contributions to preliminary
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