Photoassisted diversity-oriented synthesis: Accessing 2,6-epoxyazocane (oxamorphan) cores

Article abstract of DOI:10.1021/jo5019848

The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the aniline nitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.

Full text of DOI:10.1021/jo5019848

Article
pubs.acs.org/joc
Photoassisted Diversity-Oriented Synthesis: Accessing
2,6-Epoxyazocane (Oxamorphan) Cores
Olga A. Mukhina, N. N. Bhuvan Kumar, Teresa M. Cowger, and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
S
* Supporting Information
ABSTRACT: The modular synthesis of photoprecursors and
their photoinduced cyclization into substituted 1-benzazocanes
of two distinct topologies is described. The key step producing
an extended polyheterocyclic system involves the photo-
generation of azaxylylenes and their subsequent intramolecular
cycloaddition with furan-containing pendants tethered either
via the aniline nitrogen or through the carbonyl group contain-
ing arm. The primary photoproductssecondary or tertiary
anilines which are not acylated at the nitrogen atomundergo
facile acid-catalyzed or spontaneous ring-opening−ring-closing
rearrangement to yield fused polyheterocyclic structures pos-
sessing a 2,6-epoxyazocane (or oxamorphan) core.
INTRODUCTION
■
Nitrogen heterocycles are ubiquitous in nature: a large number
of biochemical pathways involve N-heterocycles as substrates,
products, or coenzymes.1 This ensures their prominence among
top pharmaceuticals, with 23 out of the 50 top-selling drugs in the
US in 2012 containing N-heterocycles.2 It is not surprising that
their methods of synthesis and properties have long been a focus
of sustained research efforts.3 As a result, the methods for five-
and six-membered N-containing heterocycle preparation are
countless and also diverse.4 However, access to seven- and espe-
cially eight-membered heterocycles remains challenging, mostly
because these medium-sized rings are less entropically favored.
Such structures, their properties, and methods of synthesis
deserve closer examination and further development. They either
can be found in a number of bioactive molecules, for example
nakadomarin A and manzamine A, or are intermediates in their
Figure 1. Some members of mitomycinoid alkaloids and their
congeners.
biosynthesis (Figure 1).5
The 1-benzazocine core is of particular interest: it can serve as
an important intermediate in the synthesis of mitomycinoid
alkaloids,6 which are potent cytotoxins as they can cross-link
DNA, and exhibits a broad range of biological activity, including
potent anticancer activity.7 Moreover, it has been suggested that
the biochemistry of several alkaloids of the mitomycine family,
FR-66979 and FR-900482, as well as their semisynthetic
analogues, FK-973 and FK-317, can be rationalized by invoking
in vivo formation of the benzazocane intermediate that starts a
biochemical cascade.8 Several approaches to the synthesis of the
benzazocine/benzazocane moiety have been described, includ-
ing ingenious examples of olefin metathesis,9 Mizoroki−Heck
reaction,10 ring expansion,11 cycloaddition,12 and condensation13
strategies. Most of these approaches, however, imply multistep
synthesis; therefore, the development of new short synthetic
pathways to the benzazocane scaffold is well justified.
The route to 1-benzazocanes that is being developed in
our laboratory is based on [4 + 4] cycloaddition reactions of
azaxylylenesshort-lived species generated via excited-state
intramolecular proton transfer, ESIPT,14 in aromatic o-amino
ketones and aldehydes. Transient C-hydroxyazaxylylenes gen-
erated via ESIPT have been observed in the past and charac-
terized by time-resolved photophysical methods.14 However,
they were not trapped chemically, as any addition reaction would
have to compete with very fast back proton transfer. Alternative
(i.e., non-ESIPT) approaches to azaxylylenes require exotic pre-
cursors such as benzosultams and benzoazetines and often occur
Received: August 27, 2014
Published: November 5, 2014
© 2014 American Chemical Society
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under the harsh conditions of flash vacuum pyrolysis;15 thus,
their utilization in the synthesis of delicate complex organic
architectures remains very limited. An exception is Corey’s mild
generation of azaxylylenes via 1,4-dehydrochlorination of o-
aminobenzyl chlorides.16 However, azaxylylenes generated via
nonphotochemical methods exclusively undergo [4 + 2]
cycloadditions, limiting the structural scaffolds accessible via
these reactions to quinolines. The [4 + 4] cycloaddition path is
not available for these ground-state reactions.
Another optionintramolecular reactions of the ESIPT-
generated azaxylylenes in their excited state which could suc-
cessfully compete with the wasteful back proton transferhas
not been explored before our work. Recently we found that pho-
togenerated azaxylylenes can indeed react intramolecularly with
the appropriately tethered unsaturated pendants (Scheme 1).17
reactions to tether unsaturated pendants to the photoactive o-
amino ketone core of the azaxylylene precursor.
In the current study we extend the scope to azaxylylenes
derived from o-amines, i.e. not amides, and also explore topo-
logical variations related to the nature and the attachment point
of the tether linking the photoactive core with the unsaturated,
mostly dienic, pendant. For cycloadditions of ESIPT-generated
azaxylylenesin the context of DOSit is desirable not only to
modulate the topology resulting from the competing [4 + 2] and
[4 + 4] photoinduced processes but also to take advantage of the
fact that a variety of additional (poly)cyclic moieties can be
installed in the photoproducts utilizing strategically chosen link-
ing groups and their attachment points. Our original topology of
tethering the furan-containing unsaturated pendant via the
aniline moiety of the photoprecursor was predicated on the sim-
plicity of the coupling reaction: i.e., the amide bond formation
(Figure 2, top; the “south-bridged” topology). In this paper
Scheme 1. Photogeneration of Azaxylylenes and Their
Intramolecular Cycloadditions
Figure 2. Original “south-bridged” and new “north-bridged” topology.
we report an alternative approach to the assembly of photo-
precursorsvia the ketone arm of the aromatic amino ketone
(Figure 2, bottom; the “north-bridged” topology). This alter-
native linking offers access to new topologically unique poly-
heterocyclic core structures.
In this context, furans and other five-membered heterocycles
are particularly suitable as unsaturated pendants, because they
can participate in the cycloaddition reaction not only as an alkene
component, leading to the products of [4 + 2] cycloadditions, but
also as a diene component, furnishing azacanes as the products of
[4 + 4] cycloadditions. Our initial studies with azaxylylenes and
furan as a pendant demonstrated predominant formation of the
[4 + 4] products in a 3:1 or lower ratio to the [4 + 2] products in
the majority of cases. This scaffold diversity and complexity
arising in one step from the same photoprecursor is appealing
from a diversity-oriented synthesis (DOS) standpoint.
Although furan derivatives have been employed in Diels−
Alder reactions18 both as 4π and less commonly as 2π19 com-
ponents, to the best of our knowledge there have not been
observations of the borderline behavior where both [4 + 4] and
[4 + 2] reaction pathways are realized from the same starting
material under the same reaction conditions.20 According to our
recent experimental and theoretical mechanistic study,21 it is
likely that the intramolecular cycloaddition of azaxylylenes pho-
togenerated via ESIPT occurs in a stepwise manner in the triplet
manifold, thus offering a rationale for the formation of both
[4 + 4] and [4 + 2] cycloadducts. From our prior work we infer
that the ratio of [4 + 4] to [4 + 2] products is affected by the
length of the tether between the azaxylylene precursor and the
nature of unsaturated pendants, with longer linkers often favor-
ing [4 + 4] products. The same bias toward [4 + 4] cycloaddition
was observed when the azaxylylenophile, i.e. a furan-based
pendant, was tethered via a carbonyl group, as in furanoyls. Also,
in the past we utilized ubiquitous amide bond forming coupling
RESULTS AND DISCUSSION
■
The departure from the original south-bridged topology is
realized by linking the unsaturated pendant and the azaxylylene
precursor through the α carbon of the carbonyl group (Figure 2,
north-bridged topology). Thus, this new scaffold consists of
a primary aromatic amine and an unsaturated pendant joined
through the α substitution in aminoacetophenone, which entails
differences in both stereo and electronic properties of the
photoprecursors. The synthetic route and the nature of the linker
between the azaxylylene precursor and the unsaturated pendant
were deliberately chosen to be attuned with a modular approach
within the framework of diversity-oriented synthesis.22 The
implemented pathway to the photoprecursors comprises two
simple steps: aldol condensation of the o-furyl aromatic (or α-
furyl vinyl) carboxaldehyde followed by the conjugate (Michael)
addition of a nucleophile to the obtained α,β-unsaturated ketone.
The starting aldehyde can be prepared by the Suzuki reaction of
2-furanboronic acid with the corresponding o- or β-halogen-
substituted aromatic or vinyl aldehyde. Thus, a diverse library of
compounds can be accessed through the variation of the follow-
ing building blocks and pendants: the polycyclic aldehyde
obtained via the Suzuki reaction, the Michael nucleophile, and
aromatic or α substitution in o-aminoacetophenone.
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Similarly, heterocyclic analogues 15 and 16 were prepared,
starting the sequence with 2-bromonicotinaldehyde (9) or
2-formyl-3-bromothiophene (10) (Scheme 3). In both of these
cases, nitromethane was used as a Michael nucleophile.
Further diversification of photoprecursors was achieved by
making use of vinyl carboxaldehydes 20−22 as starting materials.
These aldehydes are readily obtained via a variation of the
Vilsmeier−Haack reaction28 from commercially available cyclic
ketones on a multigram scale, using DMF and PBr3. In these
cases, the developed synthetic sequence of Suzuki coupling,
followed by aldol condensation and conjugate addition to
chalcone, gives the photoprecursors 29−31 in good yields
(Scheme 4).
Scheme 2. Synthesis of the Initial Batch of Photoprecursors
The photoprecursors, obtained as described above, have an
(n,π*) UV absorption maximum around 350 nm. Methanol was
the solvent of choice for irradiation after a few solvent opti-
mization runs. Irradiations were carried out with a Rayonet
broad-band 300−400 nm UV source (RPR-3500 lamps).
Curiously, irradiation of the photoprecursors possessing the
north-bridged topology yielded exclusively the products of [4 + 4]
addition: i.e., no [4 + 2] products were detected (Scheme 5 and
Table 1).
The stereochemistry of the primary [4 + 4] photoproducts
was assigned on the basis of their NMR spectra and the X-ray
structure of 34. We hypothesize that the [4 + 4] intramolecular
cycloaddition of the ESIPT-generated azaxylylene occurs via a
transition state (Figure 3), in which the stereochemistry of
folding of the α-(nitromethyl)ethylphenyl tether to form a six-
membered ring is biased by the nitromethyl group assuming the
shown pseudoequatorial conformation. The alternative folding,
with the nitromethyl assuming a pseudoaxial conformation, leads
The initial synthetic studies were conducted using
o-bromobenzaldehyde (1) as a starting material (Scheme 2).
The Suzuki coupling with furanboronic acid 2, catalyzed by 5 mol %
of PdCl2(PPh3)2, yielded aldehyde 323 (89%), which serves as the
carbonyl component in the subsequent aldol condensation24
with o-aminoacetophenone (4), giving chalcone 5, a reactive
Michael acceptor for a variety of nucleophiles, including nitro-
methane,25 diethyl malonic ester,26 and phenylboronic acid,27 in
a Pd0-catalyzed reaction. Thus, the photoprecursors 6−8 are
readily available in three simple steps in moderate to good yields.
Scheme 3. Access to Photoprecursors Containing Heterocyclic Moieties
Scheme 4. Synthesis of Alicyclic Derivatives
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Scheme 5. Intramolecular Cycloadditions of Photogenerated Azaxylylenes
Table 1. Primary Photoproducts from the “North-Bridged” Photoprecursors and Their Acid-Catalyzed Rearrangement
Figure 3. Nitromethyl moiety biasing the folding of the furanyl tether in the transition state, leading to the [4 + 4] intramolecular cycloadducts. The
ORTEP structure of 34 is shown with 50% thermal ellipsoids.
to a severe steric clash and therefore is not expected to be a
feasible reaction channel.
of the rearrangement reported by Padwa and co-workers,29 except
that in our case the transient cation is captured by the benzylic
hydroxy group, leading to the formation of the unprecedented
oxazobicyclo[3.3.1]nonadiene or oxamorphan substructure.
Another observation was that in some cases primary photo-
products underwent a partial rearrangement, similar to a carbo-
hydrate transformation from a furanose to a pyranose form.
Further probing the stability of the primary photoproducts, we
subjected compound 34 to acidic conditions (1 vol % of TFA in
DCM), which resulted in a 100% conversion into the “pyranose”
form (Scheme 6). Presumably, such a rearrangement is facilitated by
the amino stabilization of the cation formed upon the opening of the
2,5-dihydrofuran moiety. The initial step of it is somewhat reminiscent
This rearrangement appears to be general for all the photo-
products in Table 1. It proceeds smoothly upon the addition of a
catalytic amount of acid or simply upon heating of the reaction
mixture in DMSO. The structures of the rearranged products
were supported by NMR data. Additionally the structures of
photoproduct 34 and rearranged product 40 were unambigu-
1
ously determined by X-ray analysis. H NMR spectra of the
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a
Scheme 6. Bicyclo[4.2.1] to [3.3.1] Rearrangement and the
ORTEP Structure of 42
Scheme 7. Rearrangement of Tetralone-Derived 49
a
a
Shown with 50% thermal ellipsoids.
a
Computed J values are given in parentheses.
cycloaddition products and is supported by our calculations. A
plausible mechanism for such 1,3-allylic migration is presented in
Scheme 7 and involves protonation of the amine, scission of the
aminal C−N bond (i.e., not C−O bond), and subsequent
nucleophilic attack by aniline at C-3 of the furan ring.
This outlier notwithstanding, the north-bridged anilines, lack-
ing acyl substitution at the nitrogen atom, exclusively undergo a
photoinduced intramolecular [4 + 4] cycloaddition, with sub-
sequent heat- or acid-catalyzed [4.2.1] → [3.3.1] rearrangement
yielding a polycyclic aminal possessing an oxamorphan core.
We identified a case in which this rearrangement occurs spon-
taneously during the photolysis. Sulfide 52, which is readily
synthesized via the substitution in α-bromo-2′-nitroacetophe-
none 51 and a subsequent reduction of the nitro group with tin
chloride (Scheme 8) undergoes irradiation in wet acetonitrile,
Figure 4. Experimental and calculated (in parentheses) proton spin−
spin coupling constants (in Hz) for primary and rearranged products
exemplified by compounds 34 and 42.
rearranged products differ considerably from the NMR spectra
of nonrearranged compounds (Figure 4). In compound 34 the
vinyl protons appear as a doublet and a doublet of doublets with
a common spin−spin coupling constant of 5.6 Hz. After the
rearrangement the vicinal coupling constant of vinyl protons
increases to 10.0 Hz, which is in keeping with the proposed
change in the molecule’s geometry. The experimental NMR data
were supported by our relativistic force field computations of
proton spin−spin coupling constants,30 with the predicted
constants, shown in Figure 4, matching the experimental values
very well.
Scheme 8. Spontaneous Post-Photochemical Rearrangement
in Sulfide 52
The only exception in this series was the rearrangement of
photoproduct 49, derived from tetralone-based precursor
48. The photoprecursor 48 was obtained as a mixture of
diastereomers. However, only one diastereomer of the photo-
product 49 is formed with an isolated yield of 27%. We
hypothesize that one of the diastereomers 48 is photoinactive
due to unfavorable folding of the tether in the transition
state. We were unable to obtain an X-ray structure of the
photoproduct and could not assign its stereochemistry on the
basis of NMR data.
During column chromatography compound 49 isomerized on
silica gel into the [4 + 2] product 50. The structure of the product
was established on the basis of its 1H NMR and COSY spectra.
Protons Ha, Hb, and Hc (Scheme 7) of the primary photoproduct
49 are characterized by the set of spin−spin coupling constants
typical of the series: 5.6 Hz for the vinylic Ha and Hb protons
and 1.3 Hz for Hb and Hc (bridge). In contrast to both these
experimental observations and the spin−spin coupling constants
observed for other compounds possessing the [4.2.1] scaffold,
the rearranged product 50 exhibited a set of much smaller
constants: vinyl Jab = 2.4 Hz and Jac = 0.9 Hz. Such a distinctive
set of values has been observed earlier for [4 + 2] azaxylylene
yielding only the rearranged compound 54 as a single product.
The [4 + 4] cycloadduct 53, which is a presumed intermediate,
could not be isolated. While we do not have an X-ray structure for
54, the predicted NMR spectra better match the syn stereo-
chemical configuration of the hydroxy group. The spontaneous
[4.2.1] → [3.3.1] rearrangement without added acid also provides
circumstantial evidence for the syn configuration. As we show
below, the anti photoproducts do not undergo this rearrangement
in the absence of acids.
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The observed rearrangement into the pyranose form is clearly
facilitated by the fact that the aniline moiety is not acylated,
resulting in a more stable iminium ion (Scheme 6) as the key
intermediate in this rearrangement. Additional questions are
whether this lack of N-acylation (or further electron-donating
alkyl substitution on the nitrogen) possibly affects the [4 + 4] vs
[4 + 2] partitioning of the primary photoproducts and also
whether the [4.2.1] → [3.3.1] transformation is unique to the
north-bridged architecture of the photoprecursors.
We therefore revisited the south-bridged structures, but
instead of amide-forming coupling of the furan pendant we
explored reductive amination to furnish alkylated anilines, not
anilides. First, we synthesized the secondary amine 57, through
the sequence of reductive amination of 3-furylpropanal (56) with
2-aminophenylmethanol (55) and the oxidation of the benzylic
alcohol with MnO2 (Scheme 9).
To test the scope of the reaction, additional secondary amines
were similarly synthesized. The reductive amination approach is
again amenable to the modular synthesis of photoprecursors,
allowing for access to diverse structures from various aldehydes
and amines used for the reductive amination. A heterocyclic
(pyridine) moiety was readily incorporated into photoprecursors
60 and 63, synthesized with 2-amino-3-pyridinylmethanol. Upon
irradiation both produced the desired photoproducts, which is, to
the best of our knowledge, the first example of azaxylylene
generation from heterocyclic precursors.
The modular synthesis of photoprecursors benefits from
the fact that the aldehydes obtained via Suzuki coupling
(Schemes 2−4) and utilized to assemble the north-bridged pre-
cursors via aldol condensation can also be used in the reductive
amination synthetic sequence, as exemplified by the south-bridged
photoprecursors 63 and 64. The matrix of synthesized photo-
precursors and their respective photoproducts is presented in Table 2.
As it is evident from Table 2, upon irradiation all photo-
precursors produced the rearranged oxabicyclo[3.3.1]nonadiene
core, supporting the mechanistic rationale that additional alkyl
stabilization of the transient iminium cation is needed for the
spontaneous [4.2.1] to [3.3.1] rearrangement. It should also be
noted that, with the exception of 65, the only isolated stereo-
isomer was that with the OH group syn to the bridge oxygen. In
the case of the tetralone-derived photoproduct 70, the NMR-
based structural assignment was also supported by X-ray data.
Introduction of halogen substitution into the aromatic ring
(58, 59) accelerates the photochemical step, which is in keeping
with our prior observations.21 It also sets the product up for a
subsequent Suzuki coupling,31 allowing for another diversity
input in the resulting [3.3.1] scaffold. The presence of the
Me−C* stereogenic center in the tether of photoprecursor 61
expectedly does not impose any diastereoselection in the
transition state of the primary photoinduced cycloaddition step
and leads to the formation of a 1:1 mixture of diastereomers
(69a,b), which can be separated via column chromatography.
Diastereomers 69a,b both have the same syn configuration of the
hydroxy group but differ in the stereoconfiguration of the methyl
group in the pyrroline moiety.
Scheme 9. Typical Synthesis of South-Bridged Alkylamines
via Reductive Amination
Similar to the case for the previously studied amides, photo-
precursor 57 has a UV absorption band in the range 320−
350 nm. After screening the solvents methanol, methanol−water,
acetonitrile, acetonitrile−water, benzene, and tert-butyl alcohol,
we arrived at methanol as the optimal medium for the initial
photoinduced cycloaddition. Irradiation of 57 with a Rayonet
broad-band 300−400 nm UV source is accompanied by a
spontaneous [4.2.1] → [3.3.1] rearrangement, yielding diaster-
eomeric oxamorphans 65a (OH is syn to the bridge oxygen) and
65b (anti) (Scheme 10). The structural assignment of the
Scheme 10. Irradiation of Alkylamine 57
Indanone-derived 73 was the only photoprecursor which
did not undergo spontaneous [4.2.1] to [3.3.1] rearrangement.
Instead, we observed dehydration in the primary photoproduct
74 to yield indene 75 (Scheme 11). A plausible explanation for
this is that the [4.2.1] → [3.3.1] rearrangement in this case is less
energetically favorable. This hypothesis is corroborated by our
DFT calculations, which predict that generally the rearranged
bicyclo[3.3.1]nonadienes are 7−12 kcal/mol more stable than
the primary photoproducts possessing the bicyclo[4.2.1]non-
adiene structure. Even the tetralone-based 70 is 6.9 kcal/mol
more stable than its [4.2.1] precursor. However, in the indanone
case the [4.2.1] and the [3.3.1] structures are nearly (within 0.6
kcal/mol) energy degenerate. An analysis of the experimental
and predicted NMR spectra of 75 does not leave any doubt of the
correct structural assignment. In the 5.0−6.0 ppm region of the
NMR spectrum of the photoproduct, in addition to the two
expected alkenyl protons (Jexp = 5.6 Hz, Jcalc = 5.5 Hz) and the
allylic bridgehead proton (Jexp = 2.0, 1.2 Hz, Jcalc = 2.0, 1.3 Hz),
there is an additional triplet with Jexp = 2.2 Hz (calculated dd,
products was guided by calculations of their proton spin−spin
coupling constants. Both syn and anti products have a large
vicinal coupling constant between vinylic protons, Jcd = 9.8 Hz
(calculated 9.6 Hz) for the syn isomer and 10.0 Hz (calculated
9.9 Hz) for the anti isomer, indicative of oxabicyclo[3.3.1]
scaffold formation. There is, however, a significant difference in
spin−spin coupling for the α-hydroxy proton Hb: the syn isomer
has the large constant Jbc = 5.2 Hz (calculated 5.1 Hz) and a small
constant Jab = 1.3 Hz (calculated 1.5 Hz); in contrast, the anti
isomer has a small constant Jbc = 1.7 Hz (calculated 2.0 Hz) and a
large constant Jab = 5.9 Hz (calculated 5.9 Hz). The near-perfect
match of the experimental and calculated spin−spin coupling con-
stants leaves no doubt that the conversion of the primary
photoproducts into the 9-oxabicyclo[3.3.1]nonadiene compounds
65a,b occurs spontaneously at room temperature in these amines.
J
calc = 2.4, 2.3 Hz), corresponding to the new vinyl proton of the
indene moiety.
In the majority of the cases, as follows from Table 2, the pho-
toinduced cycloaddition is always followed by the spontaneous
[4.2.1] → [3.3.1] rearrangement, which is clearly accelerated by
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a
Table 2. South-Bridged Alkylamines
a
The asterisk indicates that the yields for synthesis of photoprecursors 57−61 and 63 are given over two steps: reductive amination and benzylic
alcohol oxidation.
Scheme 11. Spontaneous Dehydration of the Primary
Photoproduct 74
Scheme 12. [4.2.1] → [3.3.1] Rearrangement in Amides
the lack of acyl substitution on nitrogen. While the acyl linker
explored in our previous work should indeed retard the rate of
this rearrangement, we hypothesized that such acyl substitution
should not necessarily affect the position of the equilibrium
between [4.2.1] and [3.3.1]. Our DFT B3LYP/6-311+G(d,p)
calculations indeed revealed that this equilibrium has a very
similar 7−12 kcal/mol energy bias toward the rearranged [3.3.1]
products in the amido series. We therefore revisited the amide-
derived photoproducts synthesized earlier to test whether this
rearrangement can be induced in the structures with an electron-
withdrawing acyl substituent on the nitrogen atom. Indeed, we
found that the heat- or acid-promoted [4.2.1] → [3.3.1]
rearrangement in this series is possible as well (Scheme 12).
Moreover, as is illustrated by the rearrangement of the keto-
piperazine 82, the rearrangement is not limited to three-atom
tethers but occurs in photoproducts with four-atom linkers as well.
It is instructive that the barrier for the [4.2.1] → [3.3.1] trans-
formation in the absence of acid catalysis is much higher for anti
photoproducts to a point that, while syn-76 photoproduct re-
arranges in DMSO at 150 °C, there is no thermal reaction at all
for the anti photoproduct (Scheme 13).
varying from ambient to 70−80 °C. On the other, they undergo a
clean transformation in DMSO when heated to 140 °C,
furnishing the rearranged products with the oxamorphan core.
CONCLUSIONS
■
We have developed a versatile approach to the synthesis of
bicyclic 1-benzoazocine structures of two distinct topologies.
The method is amenable to a straightforward modular synthesis
of both south- and north-bridged photoprecursors in three to
four simple steps. Irradiation of photoprecursors results in a
significant growth of complexity, giving a single primary photo-
product of the [4.2.1] oxabicyclic core structure in the case of
north-bridged primary amines and the [3.3.1] oxabicyclic core
structure as a result of spontaneous [4.2.1] → [3.3.1] rearrange-
ment in the case of secondary amines. The [4.2.1] → [3.3.1]
The versatility of the [4.2.1] → [3.3.1] transformation in the
syn photoproducts of the amido series is hard to underestimate.
On one hand, the initial photoproducts are very stable at temperatures
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times with EtOAc/Et2O (1/1). The combined organic layer was washed
with brine (3 × 10 mL) and dried over MgSO4. The reaction mixture
was then concentrated in vacuo, and the crude residue was purified by
silica gel column chromatography if necessary (petroleum ether/
EtOAc) to afford the coupling products.23
Scheme 13. Thermal Rearrangement: Anti vs Syn Reactivity
2-(Furan-2-yl)cyclopent-1-enecarbaldehyde34 (23). Following the
general procedure for Suzuki coupling from 2.40 g (13.71 mmol) of 20,
1.20 g (54%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 10.61 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 3.4 Hz,
1H), 6.53 (dd, J = 3.4, 1.8 Hz, 1H), 2.94 (m, 2H), 2.77 (m, 2H), 1.99 (p,
J = 7.6 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 191.2, 151.0, 145.3,
144.8, 137.4, 114.0, 111.8, 36.0, 31.1, 21.7.
2-(Furan-2-yl)cyclohex-1-enecarbaldehyde34 (24). Following the
general procedure for Suzuki coupling from 1.20 g (6.34 mmol) of 21,
0.83 g (74%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 10.14 (s, 1H), 7.55 (s, br, 1H), 6.54 (d, J = 3.3 Hz, 1H), 6.50
(m, 1H), 2.63 (m, 2H), 2.41 (m, 2H), 1.77 (m, 2H), 1.69 (m, 2H). 13C
NMR (126 MHz, CDCl3): δ 193.5, 151.9, 144.1, 143.8, 135.8, 113.1,
111.5, 29.19, 23.0, 22.1, 21.4.
transformation can be achieved either by heat or under acid
catalysis. The generality of this rearrangement was demonstrated
using the amides of the same topology as secondary amines.
2-(Furan-2-yl)cyclohept-1-enecarbaldehyde (25). Following the
general procedure for Suzuki coupling from 2.10 g (10.3 mmol) of 22,
1.08 g (55%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 9.97 (s, 1H), 7.57 (dd, J = 1.8, 0.6 Hz, 1H), 6.55 (d, J = 3.4 Hz,
1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 2.81 (m, 2H), 2.65 (m, 2H), 1.85 (m,
2H), 1.70 (dt, J = 11.6, 6.1 Hz, 2H), 1.52 (p, J = 6.0 Hz, 2H). 13C NMR
(126 MHz, CDCl3): δ 192.6, 151.9, 150.5, 144.7, 141.8, 114.8, 111.7,
33.9, 32.2, 26.0, 25.9, 25.3.
EXPERIMENTAL SECTION
■
Commercial solvents were used as is, except for THF, which was
refluxed over and distilled from potassium benzophenone ketyl prior to
use. Common reagents were purchased from commercial sources and
used without additional purification, unless indicated otherwise. NMR
spectra were recorded at 25 °C on a 500 MHz spectrometer in CDCl3
with TMS as an internal standard (unless noted otherwise). Flash
column chromatography was performed using 230−400 mesh silica gel.
Synthesis of Photoprecursors. General Procedure for
Vilsmeier−Haack Reaction. To a solution of N,N-dimethylforma-
mide (2.40 mL, 30.6 mmol) in chloroform (20 mL) at 0 °C was added
phosphorus tribromide (2.60 mL, 27.5 mmol). After 30 min the reaction
mixture was warmed to room temperature and a solution of ketone
(10.2 mmol) in chloroform (10 mL) added. The reaction mixture was
heated to reflux for 3 h then cooled to room temperature and poured
onto ice−water (50 mL). Solid sodium bicarbonate was added to
neutralize the aqueous phase, which was then separated and extracted
with ether (3 × 75 mL). The combined organic phases were washed with
saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4,
and concentrated in vacuo.28
2-(Furan-2-yl)benzaldehyde35 (3). Following the general procedure
for Suzuki coupling from 0.92 g (4.97 mmol) of 2-bromobenzaldehyde
(1), 0.76 g (89%) of the title compound was obtained. 1H NMR
(500 MHz, CDCl3): δ 10.41 (s, 1H), 8.00 (m, 1H), 7.71 (m, 1H), 7.65
(m, 2H), 7.47 (m, 1H), 6.66 (m, 1H), 6.59 (dd, J = 3.4, 1.8 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 192.4, 151.1, 144.0, 133.6, 133.4, 133.1,
128.4, 128.1, 128.0, 111.9, 111.3.
2-(Furan-2-yl)nicotinaldehyde36 (11). Following the general proce-
dure for Suzuki coupling from 0.92 g (4.97 mmol) of nicontinaldehyde
(9), 0.52 g (60%) of the title compound was obtained. 1H NMR
(500 MHz, CDCl3): δ 10.72 (d, J = 0.8 Hz, 1H), 8.82 (dd, J = 4.6, 1.8 Hz,
1H), 8.28 (dd, J = 7.9, 1.8 Hz, 1H), 7.71 (dd, J = 1.7, 0.8 Hz, 1H), 7.35
(m, 1H), 7.23 (dd, J = 3.5, 0.7 Hz, 1H), 6.66 (dd, J = 3.5, 1.8 Hz, 1H).
13C NMR (126 MHz, CDCl3): δ 191.9, 153.4, 150.0, 152.6, 145.3, 136.2,
128.2, 122.3, 113.8, 112.4.
3-(Furan-2-yl)thiophene-2-carbaldehyde37 (12). Following the
general procedure for Suzuki coupling from 1.00 g (5.23 mmol) of
3-bromo-thiophene-2-carbaldehyde (10), 0.84 g (90%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 10.50 (d, J =
1.2 Hz, 1H), 7.68 (dd, J = 5.1, 1.2 Hz, 1H), 7.60 (dd, J = 1.8, 0.7 Hz, 1H),
7.36 (m, 1H), 6.80 (dd, J = 3.4, 0.6 Hz, 1H), 6.57 (dd, J = 3.4, 1.8 Hz,
1H). 13C NMR (126 MHz, CDCl3): δ 184.6, 149.7, 143.9, 137.4, 134.2,
128.5, 127.5, 112.0, 110.8.
1-Bromo-2-formyl-1-cyclopentene32 (20). Following the general
procedure for the Vilsmeier−Haack reaction from 0.86 g (10.2 mmol) of
cyclopentanone, 1.20 g (67%) of the title compound was obtained,
1
which was used without further purification. H NMR (500 MHz,
CDCl3): δ 9.93 (s, 1H), 2.93 (m, 2H), 2.56 (m, 2H), 2.04 (m, 2H). 13
NMR (126 MHz, CDCl3): δ 189.3, 141.5, 140.0, 42.6, 29.3, 21.4.
C
1-Bromo-2-formyl-1-cyclohexene32 (21). Following the general
procedure for the Vilsmeier−Haack reaction from 1.00 g (10.2 mmol) of
cyclohexanone, 1.08 g (56%) of the title compound was obtained, which
was used without further purification. 1H NMR (500 MHz, CDCl3): δ
10.05 (s, 1H), 2.77 (m, 2H), 2.30 (m, 2H), 1.79 (m, 2H), 1.71 (m, 2H).
13C NMR (126 MHz, CDCl3): δ 193.8, 143.6, 135.3, 38.8, 25.0,
24.3, 21.1.
General Procedure for Aldol Condensation. Procedure A.24 2′-
Aminoacetophenone (10 mmol, 1 equiv) was added to a solution of the
corresponding aldehyde (10 mmol, 1 equiv) in EtOH (10 mL) contain-
ing NaOH (0.3 of a pellet), and the mixture was stirred at 5 °C for 8 h.
The precipitate was filtered, washed with EtOH and then with water,
and finally dried under vacuum to yield a product pure enough for
subsequent transformations.
1-Bromo-2-formyl-1-cycloheptene33 (22). Following the general
procedure for the Vilsmeier−Haack reaction reaction from 1.34 g
(10.2 mmol) of cycloheptanone, 0.87 g (42%) of the title compound was
obtained, which was used without further purification. 1H NMR
(500 MHz, CDCl3): δ 9.95 (s, 1H), 3.04 (m, 2H), 2.52 (m, 2H), 1.82
(m, 2H), 1.69 (m, 2H), 1.48 (m, 2H). 13C NMR (126 MHz, CDCl3): δ
193.3, 148.3, 140.5, 44.3, 31.4, 25.7, 25.2, 24.8.
Procedure B.38 Ethanolic solutions (10 mL) of equimolar amounts of
2′-aminoacetophenone (2.8 mmol), the corresponding aldehyde, and
20% aqueous NaOH (0.5 mL, 2.5 mmol) were heated to reflux for 10−
20 min. After the mixture was cooled, the precipitate was filtered off,
washed with EtOH and then with water, and finally dried under vacuum.
(E)-1-(2-Aminophenyl)-3-(2-(furan-2-yl)pyridin-3-yl)prop-2-en-1-
one (13). Following the general procedure A for aldol condensation
from 0.35 g (2.02 mmol) of 11, 0.38 g (65%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 8.70 (dd, J = 4.7, 1.6 Hz, 1H),
8.29 (d, J = 15.5 Hz, 1H), 8.01 (dd, J = 7.9, 1.3 Hz, 1H), 7.91 (d, J =
8.1 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.57 (d, J = 15.4 Hz, 1H), 7.34 (m,
1H), 7.30 (m, 1H), 6.97 (dd, J = 3.4, 0.6 Hz, 1H), 6.74 (m, 2H), 6.60
(dd, J = 3.4, 1.8 Hz, 1H), 6.42 (s, 2H). 13C NMR (126 MHz, CDCl3): δ
General Procedure for Suzuki Coupling. Under a nitrogen
atmosphere, α-formyl aryl (or cycloalkyl) halide (10 mmol), arylboronic
acid (12 mmol), K2CO3 (30 mmol), and PdCl2(PPh3)2, (5 mol %,
350 mg) were suspended in DMF/H2O (15 mL/1.5 mL). The resulting
solution was stirred at 110 °C until the completion of the reaction. After
it was cooled to room temperature, the resulting mixture was filtered
through a short path of silica gel. The filtrate was then extracted several
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191.2, 152.2, 151.2, 150.1, 144.3, 140.2, 135.6, 134.6, 132.1, 131.1, 128.5,
126.7, 122.0, 118.6, 117.4, 115.9, 113.5, 112.0.
obtained. 1H NMR (500 MHz, CDCl3): δ 7.81 (dd, J = 8.4, 1.4 Hz, 1H),
7.61−7.55 (m, 1H), 7.54−7.49 (m, 1H), 7.31−7.23 (m, 6H), 7.18 (dd,
J = 13.1, 7.1 Hz, 3H), 6.69−6.61 (m, 2H), 6.52−6.43 (m, 2H), 6.19 (s,
2H), 5.42 (dd, J = 8.2, 6.4 Hz, 1H), 3.82 (dd, J = 17.1, 8.4 Hz, 1H), 3.65
(dd, J = 17.1, 6.2 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 199.7, 153.4,
150.4, 144.0, 142.2, 142.1, 134.2, 130.9, 130.5, 129.4, 128.4, 128.3, 128.3,
127.9, 126.3, 126.1, 118.0, 117.3, 115.7, 111.2, 108.8, 45.3, 41.8. HRMS
(ESI): calcd for C25H22NO2+ (MH+) 368.1645, found 368.1650.
Procedure for Addition of Diethyl Malonate.26 To a solution of
1 mmol of chalcone and 5 mL of diethyl malonate in 25 mL of ethanol
was added 0.25 g of sodium in 2.5 mL of ethanol, the mixture was
refluxed for 2 h, quenched with NH4Cl, and extracted with ether, and the
extract was dried over Na2SO4, concentrated, and chromatographed.
Diethyl 2-(3-(2-Aminophenyl)-1-(2-(furan-2-yl)phenyl)-3-
oxopropyl)malonate (7). Following the procedure for addition of
diethyl malonate from 0.30 g (1.03 mmol) of 5, 0.27 g (58%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 7.80 (dd, J =
8.1, 1.2 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.45 (m, 1H), 7.40 (m,
1H), 7.25 (m, 3H), 6.69 (d, J = 3.3 Hz, 1H), 6.62 (m, 1H), 6.59 (d, J =
8.3 Hz, 1H), 6.47 (dd, J = 3.3, 1.8 Hz, 1H), 6.13 (s, 2H), 4.83 (td, J = 8.6,
5.2 Hz, 1H), 4.18 (dq, J = 10.7, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.5,
7.0 Hz, 1H), 4.00 (m, 2H), 3.94 (d, J = 8.6 Hz, 1H), 3.60 (dd, J = 16.2,
5.2 Hz, 1H), 3.48 (dd, J = 16.2, 8.6 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.04
(t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 199.7, 168.5, 168.0,
153.1, 150.3, 142.1, 138.5, 134.1, 131.2, 130.9, 129.4, 128.1, 127.5, 126.9,
117.9, 117.1, 115.7, 111.3, 108.9, 61.4, 61.3, 57.0, 42.7, 36.7, 13.9, 13.7.
(E)-1-(2-Aminophenyl)-3-(3-(furan-2-yl)thiophen-2-yl)prop-2-en-
1-one (14). Following the general procedure B for aldol condensation
from 0.36 g (2.02 mmol) of 12, 0.40 g (67%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 8.48 (dd, J = 15.1, 0.8, 1H),
7.88 (dd, J = 8.1, 1.3 Hz, 1H), 7.58 (dd, J = 1.8, 0.7 Hz, 1H), 7.49 (d, J =
15.2 Hz, 1H), 7.35 (dd, J = 5.3, 0.7 Hz, 1H), 7.31 (m, 1H), 7.30 (d, J =
5.3 Hz, 1H), 6.73 (m, 2H), 6.65 (dd, J = 3.4, 0.6 Hz, 1H), 6.53 (dd, J =
3.4, 1.8 Hz, 1H), 6.37 (s, 2H). 13C NMR (126 MHz, CDCl3): δ 190.9,
151.0, 150.2, 142.8, 135.1, 134.4, 134.3, 133.8, 130.9, 127.8, 126.9, 123.0,
119.1, 117.3, 115.9, 111.6, 109.3.
(E)-1-(2-Aminophenyl)-3-(2-(furan-2-yl)phenyl)prop-2-en-1-one
(5). Following the general procedure A for aldol condensation from 0.24
g (1.39 mmol) of 3, 0.29 g (72%) of the title compound was obtained.
1H NMR (500 MHz, CDCl3): δ 8.19 (d, J = 15.4 Hz, 1H), 7.92 (dd, J =
8.4, 1.4 Hz, 1H), 7.76 (dd, J = 7.9, 1.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H),
7.59 (m, 1H), 7.57 (d, J = 15.5 Hz, 1H), 7.48 (td, J = 7.6, 1.3 Hz, 1H),
7.39 (m, 1H), 7.31 (m, 1H), 6.73 (m, 2H), 6.56 (m, 2H), 6.39 (s, 2H).
13C NMR (126 MHz, CDCl3): δ 191.6, 152.0, 151.1, 142.9, 142.2, 134.4,
133.0, 131.1, 131.1, 129.6, 127.8, 127.7, 127.6, 125.1, 119.0, 117.3, 115.9,
111.9, 111.0.
(E)-1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclohex-1-en-1-yl)prop-
2-en-1-one (27). Following the general procedure A for aldol
condensation from 0.80 g (4.54 mmol) of 24, 0.45 g (34%) of the
title compound was obtained. 1H NMR (500 MHz, CDCl3): δ 8.24 (d,
J = 15.3 Hz, 1H), 7.84 (m, 1H), 7.52 (dd, J = 1.7, 0.6 Hz, 1H), 7.28 (m,
1H), 7.14 (d, J = 15.3 Hz, 1H), 6.70 (m, 2H), 6.47 (dd, J = 3.4, 1.8 Hz,
1H), 6.44 (d, J = 3.3 Hz, 1H), 6.30 (m, 2H), 2.61 (m, 2H), 2.50 (m, 2H),
1.78 (m, 4H). 13C NMR (126 MHz, CDCl3): δ 192.6, 153.8, 150.7,
143.2, 142.7, 134.7, 133.9, 131.0, 130.9, 121.8, 119.6, 117.2, 115.7, 111.5,
111.3, 29.1, 26.5, 22.3, 22.2.
(E)-1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclopent-1-en-1-yl)prop-
2-en-1-one (26). Following the general procedure B for aldol con-
densation from 1.20 g (7.39 mmol) of 23, 0.75 g (37%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 8.53 (d, J =
15.2 Hz, 1H), 7.84 (dd, J = 8.4, 1.4 Hz, 1H), 7.59 (d, J = 1.3 Hz, 1H),
7.29 (m, 1H), 7.04 (d, J = 15.2 Hz, 1H), 6.70 (m, 2H), 6.48 (d, J =
3.3 Hz, 1H), 6.47 (dd, J = 3.4, 1.8 Hz, 1H), 6.34 (s, 2H), 2.88 (m, 2H),
2.82 (m, 2H), 2.06 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 192.3,
152.3, 150.8, 143.7, 138.5, 136.3, 134.2, 133.9, 131.0, 124.5, 119.5, 117.2,
115.8, 111.3, 111.2, 35.6, 33.7, 21.9.
+
HRMS (ESI): calcd for C26H27LiNO6 (MLi+) 456.1993, found
456.2001.
Procedure for Addition of Nitromethane. Procedure C.25a
A
mixture of chalcone (0.3 mmol) and nitromethane (1.5 mmol) in
DMSO (1 mL) in the presence of MS 4 Å (100 mg) was stirred at room
temperature under an argon atmosphere. After 12 h, the reaction mix-
ture was quenched with a phosphate buffer (pH 7, 20 mL). The organic
materials were extracted with ethyl acetate and dried over anhydrous
MgSO4. If necessary, the product was purified with flash chromatog-
raphy.
Procedure D.25b To a mixture of chalcone (0.3 mmol) and nitro-
methane (1 mL) in DMSO (5 mL) was added 0.3 mmol of tBuOK. After
12 h at room temperature the reaction mixture was quenched with
saturated aqueous NH4Cl. The organic materials were extracted with
ethyl acetate and dried over anhydrous MgSO4. If necessary, the product
was purified with flash chromatography.
(E)-1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclohept-1-en-1-yl)prop-
2-en-1-one (28). Following the general procedure A for aldol con-
densation from 0.76 g (3.99 mmol) of 25, 0.47 g (38%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 8.16 (d, J =
15.2 Hz, 1H), 7.84 (m, 1H), 7.52 (dd, J = 1.8, 0.6 Hz, 1H), 7.28 (m, 1H),
7.17 (d, J = 15.2 Hz, 1H), 6.71 (m, 2H), 6.48 (dd, J = 3.4, 1.8 Hz, 1H),
6.42 (m, 1H), 6.28 (s, 2H), 2.79 (m, 2H), 2.68 (m, 2H), 1.86 (h, J = 7.5,
6.7 Hz, 2H), 1.65 (dq, J = 17.1, 5.8 Hz, 4H). 13C NMR (126 MHz,
CDCl3): δ 192.7, 154.0, 150.7, 143.7, 142.8, 140.6, 137.8, 133.9, 130.9,
122.0, 119.7, 117.2, 115.8, 112.6, 111.5, 32.8, 32.0, 29.9, 26.3, 25.9.
(E)-8-Amino-2-(2-(furan-2-yl)benzylidene)-3,4-dihydronaphtha-
len-1(2H)-one. Following the general procedure A for aldol conden-
sation from 0.34 g (1.97 mmol) of 3, 0.26 g (42%) of the title compound
was obtained. 1H NMR (500 MHz, CDCl3): δ 7.89 (m, 2H), 7.53 (dd,
J = 1.8, 0.7 Hz, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 7.22 (dd, J = 8.3,
7.3 Hz, 1H), 6.63 (s, 2H), 6.58 (d, J = 8.3 Hz, 1H), 6.54 (dd, J = 3.4,
0.7 Hz, 1H), 6.49 (m, 2H), 2.92 (m, 2H), 2.87 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ 190.2, 152.1, 151.8, 145.0, 142.3, 137.1, 135.3,
134.5, 132.7, 130.6, 129.7, 128.3, 126.8, 126.4, 115.9, 115.6, 115.0, 111.9,
110.8, 30.4, 27.1.
1-(2-Aminophenyl)-3-(2-(furan-2-yl)phenyl)-4-nitrobutan-1-one
(8). Following general procedure C for addition of nitromethane from
0.10 g (0.35 mmol) of 5, 0.05 g (43%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 7.69 (dd, J = 8.1, 1.3 Hz, 1H),
7.56 (m, 2H), 7.36 (m, 4H), 6.65 (m, 3H), 6.55 (dd, J = 3.3, 1.9 Hz, 1H),
6.25 (s, 2H), 4.81 (m, 3H), 3.51 (dd, J = 17.3, 5.1 Hz, 1H), 3.39 (dd, J =
17.3, 8.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 198.8, 153.1, 150.5,
142.6, 137.1, 134.7, 130.8, 130.8, 130.1, 128.8, 127.6, 126.7, 117.4, 117.4,
115.9, 111.5, 109.0, 79.0, 42.0, 35.8. HRMS (ESI): calcd for
C20H19N2O4+ (MH+) 351.1339, found 351.1343.
1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclopent-1-en-1-yl)-4-nitro-
butan-1-one (29). Following general procedure D for addition of
nitromethane from 0.74 g (2.65 mmol) of 26, 0.70 g (77%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 7.73 (m, 1H),
7.42 (m, 1H), 7.28 (m, 1H), 6.66 (m, 2H), 6.41 (dd, J = 3.3, 1.8 Hz, 1H),
6.29 (m, 3H), 4.79 (m, 1H), 4.73 (dd, J = 11.7, 6.2 Hz, 1H), 4.62 (dd, J =
11.7, 8.1 Hz, 1H), 3.28 (dd, J = 16.5, 6.1 Hz, 1H), 3.22 (dd, J = 16.5,
7.8 Hz, 1H), 2.70 (m, 2H), 2.56 (m, 2H), 1.93 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ 199.5, 151.8, 150.5, 141.9, 134.8, 134.6, 131.0,
128.4, 117.5, 117.4, 115.8, 110.9, 108.5, 78.0, 40.0, 34.7, 34.4, 33.8, 22.0.
Procedure for Addition of Phenyl Boronic Acid to Enones.27
Enone (1.0 mmol), arylboronic acid (2.0 mmol), Pd2(dba)3 (5 mol %,
0.05 mmol), PPh3 (10 mol %, 0.10 mmol), Cs2CO3 (1.0 mmol, 0.32 g),
and CHCl3 (0.01 mL) in toluene (2 mL) were heated to 80 °C for 24 h.
The mixture was concentrated and purified via chromatography.
1-(2-Aminophenyl)-3-(2-(furan-2-yl)phenyl)-3-phenylpropan-1-
one (6). Following the procedure for addition of boronic acids from
0.27 g (0.93 mmol) of 5, 0.18 g (53%) of the title compound was
+
HRMS (ESI): calcd for C19H21N2O4 (MH+) 341.1496, found
341.1497.
1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclohex-1-en-1-yl)-4-nitro-
butan-1-one (30). Following general procedure D for addition of nitro-
methane from 0.43 g (1.47 mmol) of 27, 0.42 g (81%) of the title com-
pound was obtained. 1H NMR (500 MHz, CDCl3): δ 7.69 (dd, J = 8.2,
1.3 Hz, 1H), 7.35 (m, 1H), 7.27 (m, 1H), 6.65 (m, 2H), 6.38 (dd, J = 3.3,
1.8 Hz, 1H), 6.29 (m, 3H), 4.61 (m, 3H), 3.24 (dd, J = 16.3, 4.9 Hz, 1H),
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3.11 (dd, J = 16.2, 7.8 Hz, 1H), 2.35 (m, 2H), 2.17 (m, 2H), 1.67 (m,
4H). 13C NMR (126 MHz, CDCl3): δ 199.5, 154.2, 150.5, 141.2, 134.6,
132.5, 131.0, 126.4, 117.5, 117.4, 115.8, 110.7, 107.8, 77.5, 40.0, 37.8,
CDCl3): δ 7.35 (dd, J = 1.8, 0.8 Hz, 1H), 7.25 (td, J = 7.9, 1.6 Hz, 1H),
7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.68 (m, 2H), 6.32 (dd, J = 3.1, 1.9 Hz,
1H), 6.05 (m, 1H), 4.68 (s, 2H), 3.24 (t, J = 7.0 Hz, 2H), 2.80 (t, J =
7.4 Hz, 2H), 2.04 (p, J = 7.2 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ
155.4, 147.6, 141.0, 129.7, 129.2, 124.2, 116.3, 110.6, 110.2, 105.1, 64.9,
42.8, 27.7, 25.6.
(2) Following the general procedure for benzylic alcohol oxidation
from 0.78 g (3.37 mmol) of (2-((3-(furan-2-yl)propyl)amino)phenyl)-
methanol, 0.51 g (66%) of the title compound was obtained. 1H NMR
(500 MHz, CDCl3): δ 9.84 (s, 1H), 8.40 (s, 1H), 7.49 (d, J = 7.6 Hz,
1H), 7.41 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H), 6.70 (m, 2H), 6.32 (s, 1H),
6.06 (m, 1H), 3.31 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.06 (p, J = 7.2 Hz,
2H). 13C NMR (126 MHz, CDCl3): δ 193.9, 155.0, 150.7, 141.1, 136.7,
135.8, 118.4, 114.8, 110.8, 110.2, 105.4, 41.6, 27.4, 25.4. HRMS (ESI):
calcd for C14H16NO2+ (MH+) 230.1176, found 230.1176.
5-Chloro-2-((3-(furan-2-yl)propyl)amino)benzaldehyde (58). (1)
(5-Chloro-2-((3-(furan-2-yl)propyl)amino)phenyl)methanol was pre-
pared following the general procedure for reductive amination from
0.50 g (3.18 mmol) of 5-chloro-2-aminophenylmethanol with a yield of
0.48 g (57%) and used without further purification in the next step. 1H
NMR (500 MHz, CDCl3): δ 7.34 (dd, J = 1.8, 0.8 Hz, 1H), 7.18 (dd, J =
8.6, 2.5 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.32
(dd, J = 3.1, 1.9 Hz, 1H), 6.05 (m, 1H), 4.77 (s, br, 1H), 4.63 (s, 2H),
3.20 (t, J = 7.0 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.2 Hz, 2H).
13C NMR (126 MHz, CDCl3): δ 155.2, 146.1, 141.0, 129.1, 128.7, 125.5,
120.8, 111.6, 110.2, 105.2, 64.3, 42.9, 27.6, 25.6.
+
29.3, 25.6, 22.4, 22.4. HRMS (ESI): calcd for C20H23N2O4 (MH+)
355.1652, found 355.1653.
1-(2-Aminophenyl)-3-(2-(furan-2-yl)cyclohept-1-en-1-yl)-4-nitro-
butan-1-one (31). Following the general procedure D for nitromethane
addition from 0.20 g (0.65 mmol) of 28, 0.18 g (75%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 7.66 (dd, J =
8.2, 1.4, 1H), 7.34 (dd, J = 1.8, 0.7, 1H), 7.29 (m, 1H), 6.66 (dd, J = 8.3,
0.9 Hz, 1H), 6.63 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.38 (dd, J = 3.3, 1.8, Hz
1H), 6.27 (s, 2H), 6.24 (dd, J = 3.3, 0.7 Hz, 1H), 4.57 (m, 3H), 3.18 (dd,
J = 16.0, 4.9 Hz, 1H), 3.06 (dd, J = 16.0, 8.3 Hz, 1H), 2.51 (m, 2H), 2.37
(m, 2H), 1.81 (m, 2H), 1.57 (m, 4H). 13C NMR (126 MHz, CDCl3): δ
199.4, 154.6, 150.6, 141.3, 138.3, 134.6, 133.5, 130.9, 117.4, 117.4, 115.8,
110.7, 107.9, 77.5, 39.9, 38.8, 33.7, 32.2, 29.2, 26.6, 26.1. HRMS (ESI):
calcd for C21H25N2O4+ (MH+) 369.1809, found 369.1811.
1-(2-Aminophenyl)-3-(3-(furan-2-yl)thiophen-2-yl)-4-nitrobutan-
1-one (16). Following general procedure C for nitromethane addition
from 0.35 g (1.19 mmol) of 14, 0.28 g (66%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 7.73 (dd, J = 8.4, 1.4 Hz, 1H),
7.51 (dd, J = 1.8, 0.6 Hz, 1H), 7.31 (m, 1H), 7.23 (m, 2H), 6.67 (m, 2H),
6.61 (dd, J = 3.4, 0.6 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 6.28 (s, 2H),
5.16 (m, 1H), 4.88 (dd, J = 12.7, 6.8 Hz, 1H), 4.80 (dd, J = 12.7, 6.9 Hz,
1H), 3.59 (dd, J = 17.4, 6.2 Hz, 1H), 3.52 (dd, J = 17.4, 7.6 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 198.1, 150.6, 150.2, 141.9, 136.7, 134.8,
130.8, 129.2, 127.5, 123.7, 117.5, 117.4, 115.9, 111.4, 107.3, 79.5, 42.6,
33.9. HRMS (ESI): calcd for C18H17N2O4S+ (MH+) 357.0904, found
357.0903.
(2) Following the general procedure for benzylic alcohol oxidation
from 0.48 g (1.80 mmol) of (5-chloro-2-((3-(furan-2-yl)propyl)-
amino)phenyl)methanol, 0.31 g (65%) of the title compound was
1
1-(2-Aminophenyl)-3-(2-(furan-2-yl)pyridin-3-yl)-4-nitrobutan-1-
one (15). Following general procedure C for addition of nitromethane
from 0.35 g (1.21 mmol) of 13, 0.16 g (38%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 8.59 (dd, J = 4.6, 1.5 Hz, 1H),
7.70 (m, 2H), 7.60 (m, 1H), 7.31 (m, 1H), 7.23 (dd, J = 8.0, 4.6 Hz, 1H),
7.14 (d, J = 3.4 Hz, 1H), 6.66 (m, 2H), 6.61 (dd, J = 3.4, 1.8 Hz, 1H),
6.26 (s, 2H), 5.09 (m, 1H), 4.91 (dd, J = 12.9, 6.4 Hz, 1H), 4.87 (dd, J =
12.9, 7.1 Hz, 1H), 3.54 (dd, J = 17.4, 6.1 Hz, 1H), 3.49 (dd, J = 17.4,
7.9 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 198.3, 153.5, 150.6, 148.4,
148.0, 143.6, 135.2, 134.8, 131.6, 130.7, 122.4, 117.5, 117.3, 115.9, 112.0,
obtained. H NMR (500 MHz, CDCl3): δ 9.77 (s, 1H), 8.37 (s, 1H),
7.44 (d, J = 2.6 Hz, 1H), 7.34 (m, 2H), 6.64 (d, J = 9.1 Hz, 1H), 6.32 (dd,
J = 3.1, 1.9 Hz, 1H), 6.06 (m, 1H), 3.28 (m, 2H), 2.78 (t, J = 7.3 Hz, 2H),
2.04 (p, J = 7.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 192.8, 154.7,
149.2, 141.2, 135.8, 135.2, 119.3, 118.9, 112.6, 110.2, 105.5, 41.8, 27.3,
25.3.
5-Bromo-2-((3-(furan-2-yl)propyl)amino)benzaldehyde (59). (1)
(5-Bromo-2-((3-(furan-2-yl)propyl)amino)phenyl)methanol was pre-
pared following the general procedure for reductive amination from
0.5 g (2.48 mmol) of 5-bromo-2-aminophenylmethanol with a yield of
0.34 g (44%) and used without further purification in the next step. 1H
NMR (500 MHz, CDCl3): δ 7.34 (dd, J = 1.8, 0.8 Hz, 1H), 7.31 (dd, J =
8.7, 2.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.32
(dd, J = 3.1, 1.9 Hz, 1H), 6.05 (m, 1H), 4.77 (s, br, 1H), 4.62 (s, 2H),
3.19 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.2 Hz, 2H).
13C NMR (126 MHz, CDCl3): δ 155.2, 146.6, 141.0, 132.1, 131.5, 126.0,
112.1, 110.2, 107.7, 105.2, 64.3, 42.8, 27.5, 25.6.
+
111.9, 78.6, 41.2, 34.7. HRMS (ESI): calcd for C19H18N3O4 (MH+)
352.1297, found 352.1299.
8-Amino-2-(1-(2-(furan-2-yl)phenyl)-2-nitroethyl)-3,4-dihydro-
naphthalen-1(2H)-one (48). Following general procedure D for
addition of nitromethane from 0.24 g (0.76 mmol) of (E)-1-(2-
aminophenyl)-3-(2-(furan-2-yl)phenyl)prop-2-en-1-one, 0.11 g (38%)
of the title compound was obtained as a mixture of diastereomers that
could not be separated. 1H NMR (500 MHz, CDCl3): δ 7.52 (m, 2H),
7.43 (d, J = 3.8 Hz, 2H), 7.36 (m, 1H), 7.17 (m, 1H), 6.59 (d, J = 3.3 Hz,
1H), 6.51 (m, 2H), 6.40 (m, 3H), 5.23 (m, 1H), 4.88 (dd, J = 13.1,
9.4 Hz, 1H), 4.56 (td, J = 9.7, 4.6 Hz, 1H), 2.76 (m, 1H), 2.69 (m, 2H),
1.80 (m, 1H), 1.64 (dtd, J = 13.6, 8.2, 5.1 Hz, 1H). HRMS (ESI): calcd
for C22H21N2O4+ (MH+) 377.1496, found 377.1494.
General Procedure for Reductive Amination. To a solution of
substituted aniline (1 mmol) in MeOH (10 mL) at 0 °C was added
NaOAc (2 equiv), glacial acetic acid (4 equiv), the corresponding
aldehyde (1.5 equiv), and NaCNBH3 (1.1 equiv). The solution was
warmed slowly to room temperature over 1 h. The mixture was then
filtered through a plug of silica gel and washed with 1% glacial acetic acid
in ethyl acetate. The solution was then washed with brine, dried
(Na2SO4), and concentrated to afford the crude material, which was
then purified with flash chromatography.
(2) Following the general procedure for benzylic alcohol oxidation
from 0.34 g (1.10 mmol) of (5-bromo-2-((3-(furan-2-yl)propyl)-
amino)phenyl)methanol, 0.14 g (41%) of the title compound was
1
obtained. H NMR (500 MHz, CDCl3): δ 9.76 (s, 1H), 8.38 (s, 1H),
7.58 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 9.0, 2.4 Hz, 1H), 7.35 (d, J = 1.7
Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 6.32 (dd, J = 3.1, 1.9 Hz, 1H), 6.06 (d,
J = 3.0 Hz, 1H), 3.28 (m, 2H), 2.78 (t, J = 7.3 Hz, 2H), 2.04 (p, J =
7.2 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 192.7, 154.7, 149.5, 141.2,
138.4, 138.3, 119.5, 113.0, 110.2, 105.7, 105.5, 41.7, 27.3, 25.3. HRMS
(ESI): calcd for C14H15BrNO2+ (MH+) 308.0281, found 308.0280.
2-((3-(Furan-2-yl)propyl)amino)nicotinaldehyde (60). (1) (2-((3-
(Furan-2-yl)propyl)amino)pyridin-3-yl)methanol was prepared follow-
ing the general procedure for reductive amination from 0.28 g
(2.25 mmol) of 2-amino-3-pyridinemethanol with a yield of 0.29 g
(55%) and used without further purification in the next step. 1H NMR
(500 MHz, CDCl3): δ 8.12 (dd, J = 5.1, 1.8 Hz, 1H), 7.33 (dd, J = 1.8,
0.8 Hz, 1H), 7.26 (dd, J = 7.1, 1.8 Hz, 1H), 6.54 (dd, J = 7.1, 5.1 Hz, 1H),
6.31 (dd, J = 3.1, 1.9 Hz, 1H), 6.05 (m, 1H), 5.41 (s, 1H), 4.61 (s, 2H),
3.56 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.3 Hz, 2H).
13C NMR (126 MHz, CDCl3): δ 157.6, 155.7, 147.8, 140.9, 135.9, 118.5,
111.7, 110.1, 105.0, 64.0, 40.7, 28.0, 25.7.
General Procedure for Oxidation with MnO2. Benzylic alcohol
(1 equiv) was dissolved in DCM, 7 equiv of MnO2 was added, and the
mixture was stirred overnight and then filtered through a plug of Celite,
concentrated, and purified using flash chromatography.
2-((3-(Furan-2-yl)propyl)amino)benzaldehyde (57). (1) (2-((3-
(Furan-2-yl)propyl)amino)phenyl)methanol was prepared following
the general procedure for reductive amination from 0.60 g (4.46 mmol)
of 2-aminophenylmethanol with a yield of 0.78 g (73%) and used
(2) Following the general procedure for benzylic alcohol oxidation
from 0.15 g (0.65 mmol) of (2-((2-(furan-2-yl)benzyl)amino)pyridin-3-
1
1
without further purification in the next step. H NMR (500 MHz,
yl)methanol, 0.12 g (81%) of the title compound was obtained. H
10965
dx.doi.org/10.1021/jo5019848 | J. Org. Chem. 2014, 79, 10956−10971

The Journal of Organic Chemistry
Article
NMR (500 MHz, CDCl3): δ 9.82 (s, 1H), 8.49 (s, 1H), 8.35 (dd, J = 4.8,
1.9 Hz, 1H), 7.76 (dd, J = 7.5, 2.0 Hz, 1H), 7.33 (m, 1H), 6.66 (dd, J =
7.5, 4.8 Hz, 1H), 6.30 (dd, J = 3.0, 1.9 Hz, 1H), 6.06 (m, 1H), 3.64 (m,
2H), 2.77 (t, J = 7.5 Hz, 2H), 2.05 (p, J = 7.3 Hz, 2H). 13C NMR
(126 MHz, CDCl3): δ 192.8, 157.8, 155.3, 155.0, 144.6, 141.0, 113.7,
111.4, 110.1, 105.1, 40.0, 27.8, 25.5. HRMS (ESI): calcd for
C13H15N2O2+ (MH+) 231.1129, found 231.1128.
2-((2-(Furan-2-yl)benzyl)amino)nicotinaldehyde (63). (1) (2-((2-
(Furan-2-yl)benzyl)amino)pyridin-3-yl)methanol was prepared follow-
ing the general procedure for reductive amination from 0.28 g
(2.25 mmol) of 2-amino-3-pyridinemethanol with a yield of 0.33 g
(52%) and used without further purification in the next step. 1H NMR
(500 MHz, CDCl3): δ 8.06 (m, 1H), 7.69 (dd, J = 7.7, 1.3 Hz, 1H), 7.49
(m, 2H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.27 (td, J = 7.8, 1.4 Hz, 1H), 7.22
(d, J = 7.1 Hz, 1H), 6.60 (d, J = 3.4 Hz, 1H), 6.52 (m, 1H), 6.46 (dd, J =
3.3, 1.8 Hz, 1H), 5.71 (t, J = 5.5 Hz, 1H), 4.83 (d, J = 5.4 Hz, 2H), 4.50
(s, 2H). 13C NMR (126 MHz, CDCl3): δ 157.3, 153.0, 147.5, 142.2,
136.0, 135.8, 130.1, 129.7, 127.9, 127.9, 127.4, 118.9, 112.1, 111.5, 108.7,
63.5, 44.3.
6.57 (d, J = 3.3 Hz, 1H), 6.53 (dd, J = 3.3, 1.8 Hz, 1H), 6.44 (m, 2H),
4.65 (d, J = 5.7 Hz, 2H), 2.92 (m, 2H), 2.67 (m, 2H), 2.08 (p, J = 6.4 Hz,
2H). 13C NMR (126 MHz, CDCl3): δ 201.38, 152.93, 151.66, 146.61,
142.27, 135.08, 134.90, 129.60, 128.08, 128.06, 127.93, 127.24, 115.05,
114.88, 111.48, 109.64, 108.81, 45.50, 40.49, 31.25, 23.01. HRMS (ESI):
calcd for C21H20NO2+ (MH+) 318.1489, found 318.1482.
7-((3-(Furan-2-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one
(73). Following the general procedure for reductive amination from
0.32 g (2.32 mmol) of 7-amino-indan-1-one, 0.29 g (45%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 7.36 (m, 3H),
6.61 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 8.3 Hz, 1H), 6.31 (dd, J = 3.1,
1.9 Hz, 1H), 6.06 (m, 1H), 3.29 (m, 2H), 3.03 (m, 2H), 2.78 (m, 2H),
2.66 (m, 2H), 2.03 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 208.0,
156.9, 155.1, 148.6, 141.0, 136.8, 119.9, 112.1, 110.1, 107.0, 105.3, 41.5,
+
36.2, 27.5, 25.5, 25.4. HRMS (ESI): calcd for C16H18NO2 (MH+)
256.1333, found 256.1338.
1-(2-Aminophenyl)-2-(furan-2-ylmethylthio)ethanone (52). A
2.24 g portion of 2-bromo-2′-nitroacetophenone (51; 9.2 mmol) was
dissolved in 30 mL of dichloromethane along with 1.08 g of
2-furylmercaptan (9.2 mmol) and 1.48 g of dry pyridine (18.4 mmol),
and the reaction mixture was stirred for 1 h before it was quenched with
5% HCl solution (10 mL). The aqueous layer was then extracted with
dichloromethane (2 × 20 mL), and the organic layers were combined
and dried over anhydrous sodium sulfate. The organic layer was then
concentrated to give 2.50 g (98%) of 1-(2-nitrophenyl)-2-(furan-2-
ylmethylthio)ethanone. This was then dissolved in 100 mL of ethanol
along with 5.23 g of tin(II) chloride (27.0 mmol) and heated to 70 °C
under a nitrogen atmosphere for 2 h. Saturated sodium bicarbonate
solution was added slowly until the solution reached pH 8, giving a thick
milky white emulsion. This was filtered through a pad of Celite, and the
filtrate was extracted with EtOAc (3 × 100 mL). The organic phase was
washed with brine (2 × 50 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography to give 1.76 g (78%) of
the title compound. 1H NMR (500 MHz, CDCl3): δ 7.67 (dd, J = 8.2,
1.0 Hz, 1H), 7.40 (dd, J = 1.8, 0.7 Hz, 1H) 7.30 (dt J = 8.4, 1.3 Hz 1H),
6.69 (d, J = 8.4 Hz, 1H), 6.15 (dt J = 8.2, 1.0, 1H) 6.37−6.26 (m, 4H),
3.85 (s, 2H), 3.83 (s, 2H). 13C NMR (126 MHz, CDCl3): δ 196.7, 151.1,
150.7, 142.4, 134.8, 131.4, 117.5, 116.3, 115.8, 110.4, 108.4, 37.6, 28.5.
HRMS (ESI): calcd for C13H14NO2S+ (MH+) 248.0740, found
248.0743.
(2) Following the general procedure for benzylic alcohol oxidation
from 0.33 g (1.17 mmol) of (2-((2-(furan-2-yl)benzyl)amino)pyridin-3-
1
yl)methanol, 0.13 g (40%) of the title compound was obtained. H
NMR (500 MHz, CDCl3): δ 9.83 (s, 1H), 8.83 (s, 1H), 8.37 (dd, J = 4.8,
1.9 Hz, 1H), 7.78 (dd, J = 7.5, 2.0 Hz, 1H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H),
7.60 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38−7.30 (m, 2H),
6.69 (dd, J = 7.5, 4.8 Hz, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.53 (dd, J = 3.3,
1.8 Hz, 1H), 5.01 (d, J = 5.9 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ
192.7, 155.0, 153.2, 144.6, 142.4, 135.3, 130.0, 129.3, 128.0, 128.0, 127.4,
113.8, 111.7, 111.4, 108.6, 43.2, 29.7. HRMS (ESI): calcd for
C17H15N2O2+ (MH+) 279.1128, found 279.1131.
2-((3-(5-Methylfuran-2-yl)butyl)amino)benzaldehyde (61). (1) (2-
((3-(5-Methylfuran-2-yl)butyl)amino)phenyl)methanol was prepared
following general procedure A for reductive amination from 0.52 g
(3.48 mmol) of 3-(5-methyl-2-furyl)butanal and 0.28 g (2.32 mmol) of
2-aminophenylmethanol with a yield of 0.60 g (90%) and used in the
oxidation step without further purification. 1H NMR (500 MHz,
CDCl3): δ 7.23 (td, J = 7.9, 1.6, 1H), 7.08 (m, 1H), 6.67 (m, 2H), 5.91
(d, J = 3.0, 1H), 5.88 (dd, J = 2.9, 1.0, 1H), 4.66 (s, 2H), 3.18 (m, 2H),
2.96 (h, J = 6.9, 1H), 2.29 (s, 3H), 2.02 (m, 1H), 1.90 (ddt, J = 13.4, 8.0,
6.6, 1H), 1.31 (d, J = 7.0, 3H). 13C NMR (126 MHz, CDCl3): δ 157.9,
150.3, 147.6, 129.6, 129.1, 124.2, 116.2, 110.5, 105.7, 104.5, 64.8, 41.4,
35.4, 31.2, 19.5, 13.5.
(2) Following the general procedure for benzilic alcohol oxidation
from 0.60 g (2.32 mmol) of (2-((3-(5-methylfuran-2-yl)butyl)amino)-
phenyl)methanol, 0.42 g (70%) of the title compound was obtained. 1H
NMR (500 MHz, CDCl3): δ 9.83 (s, 1H), 8.34 (s, 1H), 7.48 (dd, J = 7.7,
1.6 Hz, 1H), 7.39 (ddd, J = 8.5, 7.2, 1.2 Hz, 1H), 6.68 (m, 2H), 5.92 (d,
J = 3.0 Hz, 1H), 5.88 (m, 1H), 3.24 (m, 2H), 2.95 (h, J = 6.9 Hz, 1H),
2.29 (s, 3H), 2.04 (dtd, J = 14.0, 8.2, 5.9 Hz, 1H), 1.92 (ddt, J = 13.4, 8.4,
6.6 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
193.9, 157.4, 150.8, 150.4, 136.7, 135.8, 118.3, 114.6, 110.8, 105.7, 104.7,
40.4, 35.0, 31.1, 19.5, 13.5. HRMS (ESI): calcd for C16H20NO2+ (MH+)
258.1489, found 258.1486.
8-((3-(Furan-2-yl)propyl)amino)-3,4-dihydronaphthalen-1(2H)-
one (62). Following the general procedure for reductive amination from
0.40 g (2.48 mmol) of 8-amino-1-tetralone, 0.38 g (57%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 9.34 (s, 1H),
7.34 (dd, J = 1.8, 0.8 Hz, 1H), 7.26 (m, 1H), 6.54 (d, J = 8.5 Hz, 1H),
6.42 (dd, J = 7.2, 0.9 Hz, 1H), 6.31 (dd, J = 3.1, 1.9 Hz, 1H), 6.06 (m,
1H), 3.27 (m, 2H), 2.89 (m, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.65 (m, 2H),
2.05 (m, 4H). 13C NMR (126 MHz, CDCl3): δ 201.3, 155.2, 151.9,
146.7, 141.0, 134.9, 114.7, 114.3, 110.1, 109.1, 105.3, 41.8, 40.5, 31.3,
27.4, 25.5, 23.0. HRMS (ESI): calcd for C17H20NO2+ (MH+) 270.1489,
found 270.1492.
General Procedure for Photochemical Reactions. A 4 mmol
portion of the photoprecursor was dissolved in 200 mL of methanol, and
the solution was degassed and irradiated with RPR-3500 until the reac-
tion was complete.
Diethyl 2-(8b-Hydroxy-4,8b,9,10-tetrahydro-3H-3,14b-
epoxybenzo[b]naphtho[2,1-d]azocin-10-yl)malonate (33). From
0.27 g (0.53 mmol) of 7, following the general procedure for the photo-
chemical reaction, 0.15 g (56%) of the title compound was obtained
upon chromatography. 1H NMR (500 MHz, CDCl3): δ 7.77 (dd, J = 8.1,
1.4, 1H), 7.31 (m, 3H), 7.23 (m, 1H), 7.10 (m, 1H), 6.89 (m, 1H), 6.63
(dd, J = 8.0, 1.1 Hz, 1H), 6.55 (d, J = 5.8 Hz, 1H), 5.94 (d, J = 2.8 Hz,
1H), 5.90 (dd, J = 5.8, 1.5 Hz, 1H), 4.73 (d, J = 3.5 Hz, 1H), 4.09 (m,
6H), 2.73 (dd, J = 14.1, 9.6 Hz, 1H), 2.10 (dd, J = 14.1, 7.2 Hz, 1H), 1.82
(s, 1H), 1.18 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3): δ 168.8, 168.0, 139.1, 136.8, 136.6, 134.4, 132.8,
129.3, 128.7, 128.5, 128.3, 128.1, 127.1, 127.0, 120.2, 120.0, 89.8, 88.5,
82.8, 61.4, 61.1, 56.8, 37.1, 35.2, 14.0, 13.9. HRMS (ESI): calcd for
C26H27NaNO6+ (MNa+) 472.1731, found 472.1737.
10-Phenyl-4,8b,9,10-tetrahydro-3H-3,14b-epoxybenzo[b]-
naphtho[2,1-d]azocin-8b-ol (32). From 0.17 g (0.46 mmol) of 6,
following the general procedure for the photochemical reaction, 0.13 g
1
(76%) of the title compound was obtained upon chromatography. H
NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 8.2, 1.5 Hz, 1H), 7.40 (dd, J =
7.6, 1.6 Hz, 1H), 7.26 (m, 7H), 7.12 (ddd, J = 8.1, 7.1, 1.6 Hz, 1H), 6.98
(d, J = 7.5 Hz, 1H), 6.92 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 6.68 (d, J =
5.7 Hz, 1H), 6.64 (dd, J = 8.0, 1.2, Hz 1H), 6.01 (s, 1H), 5.99 (dd, J = 5.7,
1.5 Hz, 1H), 4.79 (s, 1H), 4.49 (dd, J = 11.4, 6.6 Hz, 1H), 2.70 (ddd, J =
14.1, 11.6, 0.8 Hz, 2H), 2.28 (dd, J = 14.2, 6.6 Hz, 1H), 2.08 (m, 1H).
13C NMR (126 MHz, CDCl3): δ 146.1, 140.1, 138.9, 136.1, 134.6, 132.5,
8-((2-(Furan-2-yl)benzyl)amino)-3,4-dihydronaphthalen-1(2H)-
one (64). Following the general procedure for reductive amination from
0.36 g (2.32 mmol) of 8-amino-1-tetralone, 0.45 g (61%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 9.69 (s, 1H),
7.71 (dd, J = 7.7, 1.3 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.47 (d, J =
7.6 Hz, 1H), 7.35 (td, J = 7.5, 1.3 Hz, 1H), 7.29 (m, 1H), 7.19 (m, 1H),
10966
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129.8, 129.6, 129.0, 128.5, 128.5, 128.2, 128.1, 126.7, 126.3, 120.1, 120.0,
0.17 g (0.46 mmol) of 31, following the general procedure for the
photochemical reaction, 0.10 g (59%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 7.73 (dd, J = 8.2, 1.5 Hz, 1H),
7.11 (ddd, J = 8.1, 7.1, 1.6 Hz, 1H), 6.90 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H),
6.62 (dd, J = 8.0, 1.2 Hz, 1H), 6.41 (dd, J = 5.8, 0.5 Hz, 1H), 5.85 (s, 1H),
5.75 (dd, J = 5.8, 1.6 Hz, 1H), 4.76 (m, 1H), 4.68 (dd, J = 12.1, 3.7 Hz,
1H), 4.24 (dd, J = 12.0, 10.2 Hz, 1H), 3.26 (m, 1H), 2.32 (m, 2H), 2.25
(m, 2H), 2.12 (dd, J = 14.0, 9.3 Hz, 1H), 2.03 (s, 1H), 1.99 (dd, J = 14.0,
6.9 Hz, 1H), 1.82 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ 138.8, 137.6, 137.6, 134.5, 131.8, 129.7, 128.2,
127.2, 120.1, 120.1, 89.2, 89.2, 81.7, 79.5, 38.2, 38.0, 32.1, 31.8, 30.1,
+
89.8, 88.6, 83.1, 77.2, 44.1, 42.9. HRMS (ESI): calcd for C25H22NO2
(MH+) 368.1645, found 368.1649.
10-(Nitromethyl)-4,8b,9,10-tetrahydro-3H-3,14b-epoxybenzo[b]-
naphtho[2,1-d]azocin-8b-ol (34). From 0.18 g (0.51 mmol) of 8,
following the general procedure for the photochemical reaction, 0.10 g
1
(56%) of the title compound was obtained upon chromatography. H
NMR (500 MHz, CDCl3): δ 7.79 (dd, J = 8.1, 1.3, 1H), 7.41 (m, 2H),
7.34 (dd, J = 13.4, 6.9, 2H), 7.16 (m, 1H), 6.95 (m, 1H), 6.68 (m, 1H),
6.60 (d, J = 5.4, 1H), 5.95 (m, 2H), 4.83 (dd, J = 12.4, 4.8, 1H), 4.79 (s,
1H), 4.55 (dd, J = 12.4, 9.8, 1H), 4.10 (m, 1H), 2.40 (dd, J = 13.8, 8.8,
1H), 2.17 (dd, J = 14.2, 7.6, 1H), 1.86 (s, 1H). 13C NMR (126 MHz,
CDCl3): δ 138.9, 136.6, 134.5, 133.6, 132.1, 129.2, 128.9, 128.7, 128.7,
128.5, 127.9, 127.4, 120.3, 120.2, 89.9, 88.3, 82.2, 81.7, 37.7, 34.3. HRMS
(ESI): calcd for C20H19N2O4+ (MH+) 351.1339, found 351.1342.
14-(Nitromethyl)-8,12b,13,14-tetrahydro-7H-4b,7-epoxybenzo-
[2,3]azocino[4,5-h]quinolin-12b-ol (35). From 0.15 g (0.43 mmol) of
15, following the general procedure for the photochemical reaction,
0.04 g (27%) of the title compound was obtained upon chromatography.
1H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 3.9, 1H), 7.78 (dd, J = 8.1,
+
26.5, 26.2. HRMS (ESI): calcd for C21H25N2O4 (MH+) 369.1809,
found 369.1811.
6-(Nitromethyl)-5,5a,5a1,6,13,14-hexahydro-4H-10b,13-
epoxytetrapheno[1,12-bcd]azocin-5a1-ol (49). From 0.11 g (0.29
mmol) of 48, following the general procedure for the photochemical
reaction, 0.03 g (27%) of the title compound and 0.04 g (36%) of 50
were obtained. 1H NMR (500 MHz, CDCl3): δ 7.61 (dd, J = 7.4, 1.6 Hz,
1H), 7.32 (m, 2H), 7.08 (m, 2H), 6.75 (d, J = 7.0 Hz, 1H), 6.68 (d, J =
7.6 Hz, 1H), 6.34 (dd, J = 5.6, 1.3 Hz, 1H), 6.11 (d, J = 5.7 Hz, 1H), 5.77
(m, 1H), 5.24 (s, 1H), 5.21 (dd, J = 13.1, 8.1 Hz, 1H), 4.84 (dd, J = 13.1,
6.8 Hz, 1H), 4.12 (m, 2H), 2.76 (ddd, J = 16.6, 12.7, 4.4 Hz, 1H), 2.67
(dt, J = 16.7, 4.6 Hz, 2.3 Hz, 1H), 2.25 (dt, J = 13.9, 2.5 Hz, 1H), 1.34 (m,
2H), 0.80 (qd, J = 13.3, 4.7 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ
141.9, 137.3, 136.8, 136.7, 134.3, 132.5, 128.2, 128.1, 127.8, 127.3, 125.4,
123.2, 122.7, 118.3, 91.7, 88.3, 82.7, 76.3, 46.0, 37.2, 29.0, 21.0. HRMS
(ESI): calcd for C22H21N2O4+ (MH+) 377.1496, found 377.1496.
10-(Nitromethyl)-4,8,9,9a,9a1,10-hexahydro-3aH-dibenzo[i,lmn]-
furo[3,2-g]phenanthridin-9a1-ol (50). From 0.11 g (0.29 mmol) of 48,
following the general procedure for the photochemical reaction, 0.04 g
(36%) of the title compound and 0.03 g (27%) of 49 were obtained. 1H
NMR (500 MHz, CDCl3): δ 7.53 (m, 1H), 7.40 (m, 2H), 7.30 (m, 1H),
7.10 (t, J = 7.7 Hz, 1H), 6.74 (m, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.24 (dd,
J = 2.7, 0.9 Hz, 1H), 5.40 (m, 1H), 5.10 (t, J = 2.6 Hz, 1H), 4.96 (dd, J =
12.5, 6.0 Hz, 1H), 4.62 (dd, J = 12.5, 8.5 Hz, 1H), 4.38 (m, 1H), 4.04 (s,
1H), 3.98 (s, 1H), 2.89 (m, 3H), 2.05 (dq, J = 11.5, 3.6 Hz, 1H), 1.81 (m,
1H). 13C NMR (126 MHz, CDCl3): δ 146.9, 143.5, 139.2, 137.1, 135.8,
129.4, 129.1, 128.4, 127.7, 125.6, 125.3, 120.8, 114.7, 103.5, 90.9, 81.0,
1.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 7.9, 4.7 Hz, 1H), 7.18
(m, 1H), 6.96 (m, 1H), 6.73 (d, J = 5.8 Hz, 1H), 6.69 (dd, J = 8.0, 1.2 Hz,
1H), 6.03 (m, 1H), 5.96 (dd, J = 5.8, 1.6 Hz, 1H), 4.85 (br s, 1H), 4.79
(dd, J = 12.5, 5.2 Hz, 1H), 4.56 (dd, J = 12.5, 9.0 Hz, 1H), 4.13 (m, 1H),
2.43 (dd, J = 14.2, 9.3 Hz, 1H), 2.21 (dd, J = 14.1, 7.3 Hz, 1H), 1.91 (s,
1H). 13C NMR (126 MHz, CDCl3): δ 155.7, 148.9, 139.1, 135.1, 133.4,
131.8, 130.7, 128.8, 128.6, 127.7, 123.8, 120.3, 120.3, 90.3, 89.6, 82.7,
+
80.7, 37.2, 33.7. HRMS (ESI): calcd for C19H17NaN3O4 (MNa+)
374.1111, found 374.1111.
13-(Nitromethyl)-7,11b,12,13-tetrahydro-6H-3b,6-epoxybenzo-
[b]thieno [3′,2′:3,4]benzo[1,2-d]azocin-11b-ol (36). From 0.19 g
(0.53 mmol) of 16, following the general procedure for the photo-
chemical reaction, 0.04 g (21%) of the title compound was obtained
upon chromatography. 1H NMR (500 MHz, CDCl3): δ 7.81 (dd, J = 8.2,
1.4 Hz, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 6.94 (m, 2H), 6.66 (dd, J = 8.1,
1.1 Hz, 1H), 6.56 (d, J = 5.8 Hz, 1H), 5.99 (dd, J = 5.8, 1.6 Hz, 1H), 5.94
(dd, J = 4.4, 1.4 Hz, 1H), 4.82 (s, 1H), 4.81 (dd, J = 12.7, 5.5 Hz, 1H),
4.48 (dd, J = 12.7, 8.9 Hz, 1H), 4.22 (m, 1H), 2.39 (ddd, J = 13.5, 10.5,
1.3 Hz, 1H), 2.27 (dd, J = 13.6, 6.0 Hz, 1H), 1.99 (d, J = 1.3 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 138.9, 137.3, 137.1, 133.2, 130.7, 130.2,
129.1, 128.8, 126.6, 124.9, 120.3, 120.2, 89.3, 86.2, 83.1, 80.2, 39.3, 32.9.
HRMS (ESI): calcd for C18H17N2O4S+ (MH+) 357.0904, found
357.0907.
+
70.8, 60.6, 42.2, 40.0, 29.5, 26.9. HRMS (ESI): calcd for C22H21N2O4
(MH+) 377.1496, found 377.1495.
9-Aza-10,11-benzo-5-hydroxy-2-oxa-3-thiatricyclo[6.3.1.04,12]-
dodeca-6,10-diene (54). A 0.31 g portion of 52 was dissolved in 50 mL
of acetonitrile (5% H2O by volume) and irradiated in a Pyrex reaction
vessel in a Rayonet reactor equipped with RPR-3500 UV lamps (broad-
band 300−400 nm UV source with peak emission at 350 nm) for 2 h.
The solution was concentrated under reduced pressure and purified via
flash chromatography, with a yield of 0.28 g (89%). 1H NMR (500 MHz,
CDCl3): δ 8.32 (dd, J = 8.1, 1.3 Hz, 1H), 7.24, (dt, J = 8.1, 1.5 Hz, 1H),
6.97 (dt, J = 8.1, 1.3 Hz, 1H), 6.76, (dd, J = 8.0, 1.2 Hz, 1H), 6.31 (d, J =
9.8 Hz, 1H), 5.63 (dd, J = 9.8, 3.2 Hz, 1H), 5.50 (ddd, J = 5.0, 3.4, 0.6 Hz,
1H), 4.60−4.55 (m, 1H), 3.38 (d, J = 9.8 Hz, 1H), 3.07 (m, 2H), 2.91 (d,
J = 9.8 Hz, 1H), 2.85 (t, J = 1.4 Hz, 1H). 13C NMR (126 MHz, CDCl3):
δ 196.7, 151.1, 150.7, 142.4, 134.8, 131.4, 117.5, 116.3, 115.8, 110.4,
108.4, 37.6, 28.5. HRMS (ESI): calcd for C13H14NO2S (MH+)
248.0740, found 248.0739.
10-(Nitromethyl)-3,4,8b,9,10,11,12,13-octahydro-3,13b-
epoxybenzo[b]indeno[5,4-d]azocin-8b-ol (37). From 0.68 g (2.00
mmol) of 29, following the general procedure for the photochemical
1
reaction, 0.23 g (34%) of the title compound was obtained. H NMR
(500 MHz, CDCl3): δ 7.75 (dd, J = 8.1, 1.3 Hz, 1H), 7.13 (m, 1H), 6.91
(m, 1H), 6.63 (m, 1H), 6.44 (d, J = 5.5 Hz, 1H), 5.85 (m, 2H), 4.80 (d,
J = 3.7 Hz 1H), 4.64 (dd, J = 12.3, 5.6 Hz, 1H), 4.25 (dd, J = 12.2, 8.9 Hz,
1H), 3.41 (m, 1H), 2.47 (m, 3H), 2.32 (m, 1H), 2.09 (m, 2H), 2.00 (m,
2H), 1.96 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 138.9, 137.9, 137.2,
133.2, 130.9, 130.4, 128.5, 128.3, 120.2, 120.0, 88.9, 86.3, 83.3, 78.5,
39.0, 33.5, 33.3, 31.9, 21.9. HRMS (ESI): calcd for C19H21N2O4+ (MH+)
341.1501, found 341.1500.
General Procedure for Acid-Induced Rearrangemen. The
photoproducts were dissolved in 5 mL of dichloromethane, 0.05 mL of
trifluoroacetic was added, and the reaction mixture was stirred until the
reaction was complete. The reaction mixture was then concentrated and
purified by flash chromatography. Yields are summarized in Table 1.
2-(14b-Hydroxy-4,9,10,14b-tetrahydro-3H-3,8b-epoxybenzo[b]-
naphtho[2,1-d]azocin-10-yl)malonate (41). From 47 mg (0.105
10-(Nitromethyl)-4,8b,9,10,11,12,13,14-octahydro-3H-3,14b-
epoxybenzo[b]naphtho[2,1-d]azocin-8b-ol (38). From 0.39 g (1.10
mmol) of 30, following the general procedure for the photochemical
1
reaction, 0.21 g (54%) of the title compound was obtained. H NMR
(500 MHz, CDCl3): δ 7.73 (dd, J = 8.2, 1.5 Hz, 1H), 7.11 (m, 1H), 6.89
(ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 6.61 (dd, J = 8.0, 1.2 Hz, 1H), 6.40 (m,
1H), 5.83 (m, 1H), 5.77 (dd, J = 5.8, 1.6 Hz, 1H), 4.77 (d, J = 4.3 Hz,
1H), 4.68 (dd, J = 11.9, 4.6 Hz, 1H), 4.26 (dd, J = 11.9, 9.5 Hz, 1H), 3.25
(m, 1H), 2.15 (dd, J = 13.9, 10.3 Hz, 1H), 2.07 (m, 4H), 1.95 (dd, J =
13.8, 6.2 Hz, 1H), 1.88 (m, 3H), 1.49 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 138.8, 133.6, 131.7, 131.4, 131.3, 129.8, 128.3, 127.7, 120.1,
120.0, 89.1, 88.2, 81.9, 78.8, 38.1, 37.0, 27.9, 26.2, 22.6, 22.4. HRMS
(ESI): calcd for C20H23N2O4+ (MH+) 355.1652, found 355.1657.
10-(Nitromethyl)-3,4,8b,9,10,11,12,13,14,15-decahydro-3,15b-
epoxybenzo[b]cyclohepta[3,4]benzo[1,2-d]azocin-8b-ol (39). From
1
mmol) of 33, 34 mg (72%) of the title compound was obtained. H
NMR (500 MHz, CDCl3): δ 7.53 (m, 1H), 7.45 (dd, J = 7.9, 1.3 Hz,
1H), 7.28 (m, 3H), 7.20 (m, 1H), 6.94 (td, J = 7.8, 1.3 Hz, 1H), 6.79 (dd,
J = 8.0, 1.2 Hz, 1H), 6.48 (d, J = 10.1 Hz, 1H), 5.59 (dd, J = 10.0, 3.2 Hz,
1H), 5.17 (d, J = 3.1 Hz, 1H), 4.27 (d, J = 5.0 Hz, 1H), 4.26 (dq, J = 10.7,
7.2 Hz, 1H), 4.19(dq, J = 10.7, 7.2 Hz, 1H), 4.11 (dq, J = 10.7, 7.2 Hz,
1H), 4.09 (dq, J = 10.7, 7.2 Hz, 1H), 4.02 (m, 1H), 3.58 (s, 1H),
3.28 (dd, J = 13.9, 11.3 Hz, 1H), 1.94 (dd, J = 13.8, 6.4 Hz, 1H), 1.27
10967
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(t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ 168.6, 168.5, 140.5, 139.1, 135.2, 134.8, 129.0, 128.3, 128.1,
127.7, 127.1, 126.8, 125.5, 124.5, 120.2, 118.7, 75.5, 74.9, 69.5, 61.7,
61.2, 55.1, 34.6, 32.0, 14.1, 13.9.
1H), 3.23 (m, 1H), 3.20 (s, 1H), 2.42 (m, 2H), 2.06 (m, 3H), 1.87 (m,
2H), 1.79 (dd, J = 13.2, 5.0 Hz, 1H), 1.45 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 139.0, 133.2, 133.1, 128.4, 128.0, 127.7, 126.1, 125.9, 120.1,
118.8, 78.6, 75.0, 74.2, 69.9, 36.6, 33.9, 27.5, 25.3, 22.5, 22.4. HRMS
(ESI): calcd for C20H23N2O4+ (MH+) 355.1652, found 355.1659.
10-(Nitromethyl)-3,4,9,10,11,12,13,14,15,15b-decahydro-3,8b-
epoxybenzo[b]cyclohepta[3,4]benzo[1,2-d]azocin-15b-ol (47). From
90 mg (0.244 mmol) of 39, 50 mg (56%) of the title compound was
obtained. 1H NMR (500 MHz, CDCl3): δ 7.30 (m, 2H), 7.19 (m, 1H),
6.91 (m, 2H), 6.76 (m, 1H), 6.03 (d, J = 10.1, 1H), 5.65 (dd, J = 10.1,
3.3 Hz, 1H), 5.23 (d, J = 3.2 Hz, 1H), 4.77 (dd, J = 12.0, 3.8 Hz, 1H),
4.33 (dd, J = 12.0, 9.6 Hz, 1H), 3.33 (dq, J = 10.0, 4.9 Hz, 1H), 2.40 (m,
2H), 2.28 (m, 3H), 1.87 (dd, J = 13.3, 5.4, 1H), 1.78 (m, 2H), 1.52 (m,
4H). 13C NMR (126 MHz, CDCl3): δ 139.0, 138.4, 134.7, 132.9, 128.4,
127.6, 126.4, 126.0, 120.1, 118.8, 79.4, 74.9, 74.2, 70.5, 37.3, 34.5, 31.9,
10-Phenyl-4,9,10,14b-tetrahydro-3H-3,8b-epoxybenzo[b]-
naphtho[2,1-d]azocin-14b-ol (40). From 120 mg (0.327 mmol) of 32,
90 mg (75%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 7.59 (dd, J = 7.9, 1.1 Hz, 1H), 7.37 (m, 3H), 7.29 (m, 4H),
7.20 (m, 2H), 6.90 (m, 2H), 6.81 (dd, J = 8.0, 1.1 Hz, 1H), 6.49 (d, J =
10.0 Hz, 1H), 5.68 (dd, J = 10.0, 3.4 Hz, 1H), 5.29 (d, J = 3.3 Hz, 1H),
4.55 (dd, J = 12.4, 5.0 Hz, 1H), 3.34 (s, 1H), 2.93 (m, 1H), 2.16 (dd, J =
13.6, 5.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 145.8, 139.2, 139.1,
138.7, 134.7, 129.4, 129.2, 128.6, 128.4, 128.3, 127.8, 127.5, 126.6, 126.5,
126.1, 124.7, 120.1, 118.7, 75.1, 74.9, 69.6, 42.5, 40.4. HRMS (ESI):
calcd for C25H22NO2+ (MH+) 368.1645, found 368.1648.
10-(Nitromethyl)-4,9,10,14b-tetrahydro-3H-3,8b-epoxybenzo[b]-
naphtho[2,1-d]azocin-14b-ol (42). From 80 mg (0.228 mmol) of 34,
47 mg (59%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 7.60 (dd, J = 7.3, 2.2, 1H), 7.35 (m, 3H), 7.25 (m, 2H), 6.96
(m, 1H), 6.83 (m, 1H), 6.40 (d, J = 10.0 Hz, 1H), 5.66 (dd, J = 10.0, 3.4
Hz, 1H), 5.22 (d, J = 3.3, 1H), 5.05 (dd, J = 12.5 Hz, 4.8, 1H), 4.60 (dd,
J = 12.5, 8.7 Hz, 1H), 4.19 (m, 1H), 2.86 (s, 1H), 2.72 (m, 1H), 2.06 (dd,
J = 13.2, 5.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 139.3, 139.0,
134.2, 133.1, 129.6, 128.7, 128.2, 127.7, 127.5, 125.6, 125.2, 125.0, 120.4,
119.0, 80.1, 75.0, 74.0, 69.4, 34.6, 33.8. HRMS (ESI): calcd for
C20H19N2O4+ (MH+) 351.1339, found 351.1341.
+
30.7, 29.0, 26.8, 25.9 HRMS (ESI): calcd for C21H25N2O4 (MH+)
369.1809, found 369.1816.
General Procedure for the Irradiation of Amines. An
approximately 0.1−0.3 M solution of the photoprecursors in acetonitrile
was irradiated in Pyrex or glass reaction vessels in a Rayonet reactor
equipped with RPR-3500 UV lamps (broad-band 300−400 nm UV
source with peak emission at 350 nm) until the reaction was complete.
syn-2,3,6,7-Tetrahydro-1H-3a,7-epoxybenzo[g]pyrrolo[1,2-a]-
azocin-6-ol (65a). From 150 mg (0.44 mmol) of 57, following the
general procedure for irradiation of amines 60 mg (40%) of the title
1
compound was obtained upon chromatography. H NMR (500 MHz,
14-(Nitromethyl)-7,8,13,14-tetrahydro-4bH-7,12b-epoxybenzo-
[2,3]azocino[4,5-h]quinolin-4b-ol (43). Following the general proce-
dure for rearrangement, from 35 mg (0.099 mmol) of 35 20 mg (57%)
CDCl3): δ 7.23 (m, 1H), 7.10 (m, 1H), 6.85 (td, J = 7.5, 1.1 Hz, 1H),
6.80 (d, J = 8.1 Hz, 1H), 5.99 (ddd, J = 9.8, 5.2 Hz, 1.1, 1H), 5.71 (d, J =
9.8 Hz, 1H), 5.08 (s, 1H), 3.97 (ddd, J = 10.6, 5.2, 1.3 Hz, 1H), 3.77
(ddd, J = 8.9, 7.4, 4.6 Hz, 1H), 3.43 (dt, J = 8.8, 7.2 Hz, 1H), 2.25 (m,
3H), 2.16 (m, 1H), 2.05 (dtd, J = 15.3, 7.5, 4.7 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 141.0, 132.1, 128.3, 125.9, 125.2, 121.4, 118.5,
116.9, 87.1, 77.7, 66.8, 50.3, 38.1, 22.5.
1
of the title compound was obtained upon chromatography. H NMR
(500 MHz, CDCl3): δ 8.63 (d, J = 4.7, 1H), 7.80 (d, J = 8.0, 1H), 7.43
(dd, J = 8.1, 4.9 Hz, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 6.95 (td, J = 7.8,
1.2 Hz, 1H), 6.81 (dd, J = 8.0, 1.0 Hz, 1H), 6.64 (d, J = 10.0 Hz, 1H),
5.74 (dd, J = 10.0, 3.4, 1H), 5.22 (d, J = 3.3 Hz, 1H), 4.94 (s, 1H), 4.92
(dd, J = 12.9, 5.2 Hz, 1H), 4.71 (m, 1H), 4.23 (dq, J = 12.0, 5.4 Hz, 1H),
2.82 (m, 1H), 2.14 (dd, J = 13.3, 5.1 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 158.1, 146.8, 138.5, 136.1, 133.1, 130.4, 128.6, 128.2, 125.8,
125.1, 123.3, 120.3, 118.7, 79.0, 75.3, 73.6, 70.3, 34.1, 33.2. HRMS
(ESI): calcd for C19H18N3O4+ (MH+) 352.1292, found 352.1302.
13-(Nitromethyl)-6,7,12,13-tetrahydro-3bH-6,11b-epoxybenzo-
[b]thieno[3′,2′:3,4]benzo[1,2-d]azocin-3b-ol (44). From 40 mg (0.112
anti-2,3,6,7-Tetrahydro-1H-3a,7-epoxybenzo[g]pyrrolo[1,2-a]-
azocin-6-ol (65b). From 150 mg (0.44 mmol) of 57, following the
general procedure for irradiation of amines 10 mg (7%) of the title
1
compound was obtained upon chromatography. H NMR (500 MHz,
CDCl3): δ 7.27 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.83 (m, 2H), 5.81 (dt,
J = 10.0, 1.4 Hz, 1H), 5.56 (dd, J = 10.0, 2.2 Hz, 1H), 4.98 (d, J = 5.9 Hz,
1H), 4.67 (ddt, J = 9.9, 6.0, 2.0 Hz, 1H), 3.76 (ddd, J = 9.0, 7.5, 4.0 Hz,
1H), 3.36 (m, 1H), 2.27 (m, 1H), 2.16 (m, 2H), 2.04 (ddt, J = 11.4, 7.6,
4.0 Hz, 1H), 1.50 (d, J = 11.9, 1H). 13C NMR (126 MHz, CDCl3): δ
142.2, 130.2, 129.2, 128.7, 127.9, 117.8, 116.7, 87.2, 77.6, 73.9, 67.1,
50.4, 38.1, 22.7.
1
mmol) of 36, 23 mg (58%) of the title compound was obtained. H
NMR (500 MHz, CDCl3): δ 7.32 (m, 2H), 7.30 (m, 1H), 7.25 (m, 1H),
7.12 (d, J = 5.2 Hz, 1H), 6.95 (m, 1H), 6.83 (dd, J = 8.0, 1.0 Hz, 1H),
6.24 (d, J = 10.0 Hz, 1H), 5.24 (d, J = 3.5 Hz, 1H), 4.90 (dd, J = 12.6,
5.2 Hz, 1H), 4.55 (dd, J = 12.6, 9.1 Hz, 1H), 4.17 (m, 1H), 2.70 (br s,
1H),2.64 (dd, J = 13.0, 11.3 Hz, 1H), 2.15 (dd, J = 13.1, 4.8 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 139.0, 138.4, 135.2, 132.7, 128.8, 127.5,
126.4, 125.7, 124.8, 124.7, 120.3, 119.0, 79.8, 74.9, 74.8, 68.7, 35.9, 32.9.
HRMS (ESI): calcd for C18H17N2O4S+ (MH+) 357.0904, found
357.0906.
9-Chloro-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]pyrrolo[1,2-
a]azocin-6-ol (66). From 115 mg (0.44 mmol) of 58, following the
general procedure for irradiation of amines 65 mg (57%) of the title
1
compound was obtained upon chromatography. H NMR (500 MHz,
CDCl3): δ 7.17 (dd, J = 8.6, 2.4 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.71
(d, J = 8.6 Hz, 1H), 6.00 (ddd, J = 9.8, 5.2, 1.0 Hz, 1H), 5.69 (d, J =
9.8 Hz, 1H), 5.03 (s, 1H), 3.94 (ddd, J = 10.6, 5.2, 1.3 Hz, 1H), 3.73
(ddd, J = 8.8, 7.4, 4.5 Hz, 1H), 3.39 (dt, J = 8.8, 7.2 Hz, 1H), 2.25 (m,
2H), 2.17 (m, 2H), 2.05 (m, 1H). 13C NMR (126 MHz, CDCl3): δ
139.6, 131.9, 128.3, 125.6, 125.1, 123.5, 122.8, 118.0, 87.1, 77.4, 66.6,
10-(Nitromethyl)-3,4,9,10,11,12,13,13b-octahydro-3,8b-
epoxybenzo[b]indeno[5,4-d]azocin-13b-ol (45). From 180 mg (0.529
1
mmol) of 37, 130 mg (72%) of the title compound was obtained. H
+
50.3, 37.9, 22.5. HRMS (ESI): calcd for C14H15ClNO2 (MH+)
NMR (500 MHz, CDCl3): δ 7.28 (m, 1H), 7.20 (m, 1H), 6.91 (m, 1H),
6.79 (dd, J = 8.0, 1.1 Hz, 1H), 5.93 (d, J = 10.0 Hz, 1H), 5.69 (dd, J =
10.0, 3.5 Hz, 1H), 5.25 (d, J = 3.5 Hz, 1H), 4.67 (dd, J = 12.2, 5.5 Hz,
1H), 4.34 (dd, J = 12.2, 8.8 Hz, 1H), 3.39 (m, 1H), 2.94 (s, 1H), 2.61
(dddd, J = 11.9, 9.0, 6.1, 3.9 Hz, 1H), 2.41 (m, 4H), 1.95 (m, 2H), 1.90
(dd, J = 13.2, 4.9 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 138.9, 138.1,
135.0, 132.4, 128.5, 127.6, 126.3, 125.3, 120.1, 118.9, 78.6, 75.2, 74.9,
264.0786, found 264.0790.
9-Bromo-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]pyrrolo[1,2-
a]azocin-6-ol (67). From 124 mg (0.44 mmol) of 59, following the
general procedure for irradiation of amines 53 mg (43%) of the title
1
compound was obtained upon chromatography. H NMR (500 MHz,
CDCl3): δ 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.66
(d, J = 8.6, 1H), 6.00 (ddd, J = 9.8, 5.2, 1.0 Hz, 1H), 5.69 (d, J = 9. Hz 8,
1H), 5.03 (s, 1H), 3.94 (ddd, J = 10.6, 5.2, 1.3 Hz, 1H), 3.72 (ddd, J =
8.8, 7.4, 4.5 Hz, 1H), 3.39 (dt, J = 8.8, 7.2 Hz, 1H), 2.24 (m, 2H), 2.17
(m, 2H), 2.05 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 140.0, 131.8,
131.2, 128.5, 125.1, 123.2, 118.3, 110.6, 87.0, 77.3, 66.6, 50.1, 37.9, 22.5.
+
68.9, 35.0, 33.3, 32.8, 31.1, 22.0. HRMS (ESI): calcd for C19H21N2O4
(MH+) 341.1496, found 341.1500.
10-(Nitromethyl)-4,9,10,11,12,13,14,14b-octahydro-3H-3,8b-
epoxybenzo[b]naphtho[2,1-d]azocin-14b-ol (46). From 180 mg
(0.508 mmol) of 38, 110 mg (61%) of the title compound was ob-
tained. 1H NMR (500 MHz, CDCl3): δ 7.28 (m, 1H), 7.18 (td, J = 8.1,
1.4 Hz, 1H), 6.89 (td, J = 7.8, 1.2 Hz, 1H), 6.75 (dd, J = 8.0, 1.0 Hz, 1H),
5.99 (d, J = 10.1 Hz, 1H), 5.63 (dd, J = 10.1, 3.3 Hz, 1H), 5.23 (d, J =
3.2 Hz, 1H), 4.73 (dd, J = 12.0, 4.6 Hz, 1H), 4.34 (dd, J = 12.0, 9.2 Hz,
+
HRMS (ESI): calcd for C14H15BrNO2 (MH+) 308.0281, found
308.0287.
6,9,10,11-Tetrahydro-5H-5,8a-epoxypyrido[3,2-g]pyrrolo[1,2-a]-
azocin-6-ol (68). From 210 mg (0.91 mmol) of 60, following the
10968
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The Journal of Organic Chemistry
Article
general procedure for irradiation of amines 130 mg (62%) of the title
compound was obtained upon chromatography. H NMR (500 MHz,
133.2, 133.1, 132.4, 132.2, 130.5, 128.3, 127.2, 124.8, 124.2, 122.8, 120.4,
117.3, 85.1, 73.6, 35.2, 27.6, 17.5.
1
CDCl3): δ 8.19 (dd, J = 5.0, 1.8 Hz, 1H), 7.32 (ddd, J = 7.4, 1.7, 0.6 Hz,
1H), 6.71 (dd, J = 7.4, 5.0 Hz, 1H), 6.00 (ddd, J = 9.8, 5.1, 1.0 Hz, 1H),
5.74 (d, J = 9.8 Hz, 1H), 5.09 (s, 1H), 3.93 (s, 1H), 3.89 (ddd, J = 10.1,
7.6, 4.4 Hz, 1H), 3.72 (dt, J = 10.1, 7.3 Hz, 1H), 2.69 (s, 1H), 2.26 (m,
2H), 2.15 (m, 1H), 2.04 (m, 1H). 13C NMR (126 MHz, CDCl3): δ
151.4, 148.1, 133.5, 131.8, 125.0, 115.4, 113.4, 87.2, 77.5, 66.7, 47.3,
3,6,7,8-Tetrahydro-1H-3,5a-epoxyindeno[1,7-fg]pyrrolo[1,2-a]-
azocine (75). From 203 mg (1.34 mmol) of 73, following the general
procedure for irradiation of amines 120 mg (67%) of the title compound
1
was obtained upon chromatography. H NMR (500 MHz, CDCl3): δ
7.11 (m, 1H), 6.88 (m, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.10 (dd, J = 5.6,
2.0 Hz, 1H), 6.04 (t, J = 2.1 Hz, 1H), 5.75 (dd, J = 5.6, 1.2 Hz, 1H), 5.62
(s, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 3.37 (m, 2H), 2.39 (m, 2H), 2.17
(m, 1H), 2.01 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 148.6, 146.5,
139.6, 134.5, 129.4, 128.9, 126.2, 121.7, 113.8, 113.6, 105.0, 80.9, 50.1,
38.7, 37.5, 22.1. HRMS (ESI): calcd for C16H16NO+ (MH+) 238.1226,
found 238.1232.
General Procedure for the Rearrangement of Amides. A
solution of the photoproduct in DCM (15 mL) was treated with 0.5 mL
of TFA; when the reaction was complete as monitored by NMR, the
reaction mixture was concentrated and purified using flash chromatog-
raphy.
6-Hydroxy-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]pyrrolo-
[1,2-a]azocin-1-one (79). From 12 mg of 76 following the general
procedure for the rearrangement of amides 10 mg (83%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J =
8.2, 1H), 7.36 (m, 1H), 7.19 (m, 2H), 6.11 (ddd, J = 9.6, 5.2, 0.8, 1H),
5.86 (d, J = 9.8, 1H), 5.20 (s, 1H), 4.37 (s, 1H), 3.98 (dd, J = 5.2, 1.1,
1H), 2.77 (m, 2H), 2.40 (m, 2H). 13C NMR (126 MHz, CDCl3): δ
171.8, 132.4, 129.4, 128.6, 127.2, 125.4, 124.5, 123.4, 120.2, 86.4, 78.0,
66.8, 30.3, 29.8. HRMS (ESI): calcd for C14H14NO3+ (MH+) 244.0969,
found 244.0974.
6-Hydroxy-7-methyl-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]-
pyrrolo[1,2-a]azocin-1-one. From 10 mg of 77, following the general
procedure for the rearrangement of amides 9 mg (90%) of the title
compound was obtained. 1H NMR (500 MHz, CDCl3): δ 8.26 (d, J =
8.1 Hz, 1H), 7.33 (ddd, J = 8.4, 5.9, 3.1 Hz, 1H), 7.17 (m, 2H), 6.13 (dd,
J = 9.7, 5.3 Hz, 1H), 5.78 (d, J = 9.7 Hz, 1H), 3.79 (d, J = 5.3 Hz, 1H),
3.42 (s, 1H), 2.74 (dd, J = 9.1, 7.3 Hz, 2H), 2.36 (m, 2H), 1.67 (s, 3H).
13C NMR (126 MHz, CDCl3): δ 171.6, 132.0, 129.2, 129.1, 128.8, 128.2,
+
37.8, 22.1. HRMS (ESI): calcd for C13H15N2O2 (MH+) 231.1129,
found 231.1127.
syn-3,6-Dimethyl-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]-
pyrrolo[1,2-a]azocin-6-ol (69a). From 165 mg (0.64 mmol) of 61,
following the general procedure for irradiation of amines 55 mg (33%)
of the title compound was obtained upon chromatography together with
60 mg (36%) of 69b. 1H NMR (500 MHz, CDCl3): δ 7.23 (m, 1H), 7.10
(m, 1H), 6.83 (td, J = 7.5, 1.2 Hz, 1H), 6.76 (dd, J = 8.1, 1.0 Hz, 1H),
5.88 (dd, J = 9.8, 1.2 Hz, 1H), 5.48 (d, J = 9.8 Hz, 1H), 4.77 (s, 1H), 3.75
(td, J = 9.3, 7.0 Hz, 1H), 3.41 (td, J = 9.1, 2.6 Hz, 1H), 2.78 (d, J = 1.0 Hz,
1H), 2.40 (dp, J = 11.1, 6.8 Hz, 1H), 2.05 (dtd, J = 12.0, 6.8, 2.6 Hz, 1H),
1.90 (m, 1H), 1.41 (d, J = 1.0 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H). 13C
NMR (126 MHz, CDCl3): δ 142.8, 133.7, 130.0, 128.2, 127.9, 121.4,
118.2, 117.8, 88.0, 80.5, 68.4, 51.9, 43.4, 30.6, 23.1, 12.4.
anti-3,6-Dimethyl-2,3,6,7-tetrahydro-1H-3a,7-epoxybenzo[g]-
pyrrolo[1,2-a]azocin-6-ol (69b). From 165 mg (0.64 mmol) of 61
,following the general procedure for irradiation of amines 60 mg (36%)
of the title compound was obtained upon chromatography together with
55 mg (33%) of 69a. 1H NMR (500 MHz, CDCl3): δ 7.22 (td, J = 8.1,
1.4 Hz, 1H), 7.12 (d, J = 6.3 Hz, 1H), 6.75 (td, J = 7.5, 1.1 Hz, 1H), 6.67
(d, J = 8.1 Hz, 1H), 5.85 (m, 1H), 5.52 (d, J = 10.0 Hz, 1H), 4.83 (s, 1H),
3.66 (t, J = 7.8 Hz, 1H), 3.32 (ddd, J = 10.3, 8.7, 6.2 Hz, 1H), 2.76 (s,
1H), 2.40 (m, 1H), 2.24 (m, 1H), 1.79 (tdd, J = 12.3, 10.3, 7.9 Hz, 1H),
1.40 (s, 3H), 1.19 (d, J = 7.0, 3H). 13C NMR (126 MHz, CDCl3): δ
140.4, 131.5, 128.5, 128.3, 126.5, 118.9,116.5, 113.6, 88.4, 81.9, 68.7,
46.3, 42.9, 30.4, 23.5, 13.6.
2,3,8,9,10,11-Hexahydro-1H-10a,13a-epoxynaphtho[1,8-fg]-
pyrrolo[1,2-a]azocin-11-ol (70). From 360 mg (1.34 mmol) of 62,
following the general procedure for irradiation of amines 170 mg (47%)
1
of the title compound was obtained upon chromatography. H NMR
(500 MHz, CDCl3): δ 7.14 (t, J = 7.8 Hz, 1H), 6.63 (m, 1H), 6.57 (d, J =
8.0 Hz, 1H), 6.06 (ddd, J = 9.7, 5.3, 0.6 Hz, 1H), 5.75 (d, J = 9.7 Hz, 1H),
3.87 (dd, J = 11.0, 5.3 Hz, 1H), 3.72 (ddd, J = 8.9, 7.6, 4.0 Hz, 1H), 3.38
(dt, J = 8.8, 7.2 Hz, 1H), 2.94 (ddd, J = 15.9, 10.6, 5.0 Hz, 1H), 2.84
(ddd, J = 17.4, 9.9, 5.4 Hz, 1H), 2.50 (ddd, J = 12.1, 6.6, 2.2 Hz, 1H), 2.24
(m, 1H), 2.11 (m, 4H), 1.95 (m, 1H), 1.75 (d, J = 11.1 Hz, 1H), 1.42 (td,
J = 12.4, 7.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 139.8, 136.3,
131.5, 127.9, 126.2, 123.5, 118.6, 113.1, 87.4, 76.6, 64.5, 50.1, 38.0, 30.0,
26.3, 22.2, 16.0. HRMS (ESI): calcd for C17H20NO2+ (MH+) 270.1489,
found 270.1491.
125.1, 124.5, 120.3, 86.9, 78.7, 68.5, 30.3, 29.8, 23.5. HRMS (ESI): calcd
for C15H16NO3+ (MH+) 258.1125, found 258.1126.
11-Hydroxy-8,9,10,11-tetrahydro-1H-10a,13a-epoxynaphtho-
[1,8-fg]pyrrolo[1,2-a]azocin-3(2H)-one (81). From 10 mg of 78,
following the general procedure for the rearrangement of amides 9 mg
(90%) of the title compound was obtained. 1H NMR (500 MHz,
CDCl3): δ 8.19 (d, J = 8.2, 1H), 7.27 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H),
6.16 (dd, J = 9.6, 5.3 Hz, 1H), 5.88 (d, J = 9.7 Hz, 1H), 3.82 (d, J =
5.4 Hz, 1H), 2.92 (m, 2H), 2.71 (m, 2H), 2.50 (ddd, J = 12.2, 6.7, 2.3 Hz,
1H), 2.40 (ddd, J = 12.6, 8.4, 4.0 Hz, 1H), 2.31 (dt, J = 13.3, 10.1 Hz,
6,13-Dihydro-5H-5,8a-epoxypyrido[3′,2′:7,8]azocino[2,1-a]-
isoindol-6-ol (71). From 130 mg (0.46 mmol) of 63, following the
general procedure for irradiation of amines 80 mg (62%) of the title
1H), 2.12 (m, 1H), 1.98 (m, 1H), 1.56 (td, J = 12.3, 7.7 Hz, 1H). 13
C
1
compound was obtained upon chromatography. H NMR (500 MHz,
NMR (126 MHz, CDCl3): δ 171.0, 136.2, 131.3, 128.9, 128.3, 128.0,
125.0, 124.6, 116.8, 86.7, 77.4, 64.4, 30.5, 29.8, 29.3, 26.2, 15.9. HRMS
(ESI): calcd for C17H18NO3+ (MH+) 284.1282, found 284.1284.
syn-10-Hydroxy-3-benzyl-7,8-benzo-13-oxa-3,6-diazatricyclo-
[7.3.1.01,6]trideca-7,11-diene-2,5-dione (83): Compound 82 (0.5 g,
1.38 mmol) was dissolved in 5 mL of DMSO and heated to 150 °C for
44 h. The solvent was removed under reduced pressure and purified by
flash chromatography, which afforded 0.41 g (82%) of the title
compound. 1H NMR (500 MHz, CDCl3): δ 8.17 (dd, J = 8.4, 1.2 Hz,
1H), 7.42−7.27 (m, 6H), 7.20 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (dd, J = 7.7,
1.6 Hz, 1H), 6.20 (ddd, J = 9.8, 5.7, 1.0 Hz, 1H), 5.81 (d, J = 9.8 Hz, 1H),
5.30 (s, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.19 (d,
J = 18.1 Hz, 1H), 4.03 (d, J = 18.1 Hz, 1H), 3.91 (dd, J = 5.7, 1.5 Hz, 1H).
13C NMR (126 MHz, CDCl3): δ 162.17, 161.09, 134.3, 133.1, 129.3,
CDCl3): δ 8.30 (dd, J = 4.9, 1.7 Hz, 1H), 7.45 (m, 5H), 6.83 (m, 1H),
6.19 (ddd, J = 9.8, 5.2, 1.0 Hz, 1H), 5.84 (d, J = 9.8 Hz, 1H), 5.23 (s, 1H),
5.10 (d, J = 14.4 Hz, 1H), 4.95 (d, J = 14.4 Hz, 1H), 4.07 (d, J = 5.3 Hz,
1H). 13C NMR (126 MHz, CDCl3): δ 151.0, 148.4, 139.3, 138.4, 133.8,
131.4, 129.9, 128.0, 126.2, 123.4, 123.2, 116.0, 114.4, 89.7, 77.6, 66.4,
+
53.0. HRMS (ESI): calcd for C17H15N2O2 (MH+) 279.1128, found
279.1133.
2,3,4,11-Tetrahydro-1H-3a,6a-epoxynaphtho[1′,8′:6,7,8]azocino-
[2,1-a]isoindol-4-ol (72). From 400 mg (1.26 mmol) of 64 following
the general procedure for irradiation of amines 140 mg (35%) of the title
1
compound was obtained upon chromatography. H NMR (500 MHz,
CDCl3): δ 8.20 (d, J = 8.0 Hz, 1H), 7.94 (dt, J = 7.5, 0.9 Hz, 1H), 7.70
(td, J = 7.4, 1.1 Hz, 1H), 7.65 (dt, J = 7.6, 1.1 Hz, 1H), 7.62 (td, J = 7.4,
1.2 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.04 (m, 1H), 6.04 (dd, J = 9.8, 1.9
Hz, 1H), 5.66 (dd, J = 9.8, 1.9 Hz, 1H), 4.68 (dt, J = 12.0, 2.0 Hz, 1H),
3.11 (ddd, J = 17.6, 9.2, 3.1 Hz, 1H), 2.81 (dt, J = 17.5, 7.7 Hz, 1H), 2.45
(m, 2H), 2.23 (ddd, J = 12.5, 5.9, 2.9 Hz, 1H), 1.91 (m, 3H), 1.26 (d, J =
12.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 165.0, 143.9, 139.5,
128.9, 128.9, 128.8, 128.7, 128.1, 126.6, 126.0, 125.7, 125.3, 124.2, 81.7,
66.6, 50.3, 49.4. HRMS (ESI): calcd for C21H19N2O4+ (MH+) 363.1340,
found 363.1334.
10969
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Article
(17) (a) Mukhina, O. A.; Kumar, N. N. B.; Arisco, T. M.; Valiulin, R. A.;
Metzel, G. A.; Kutateladze, A. G. Angew. Chem., Int. Ed. 2011, 50, 9423−
9428. (b) Nandurkar, N. S.; Kumar, N. N. B.; Mukhina, O. A.;
Kutateladze, A. G. ACS Comb. Sci. 2013, 15, 73. (c) Kumar, N. N. B.;
Mukhina, O. A.; Kutateladze, A. G. J. Am. Chem. Soc. 2013, 135, 9608−
9611.
ASSOCIATED CONTENT
* Supporting Information
Figures and CIF files giving 1D and 2D NMR data and X-ray
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(18) For a review, see: (a) Kappe, C. O.; Murphree, S. S.; Padwa, A.
Tetrahedron 1997, 53, 14179−14233. For recent examples in total
synthesis, see: (b) O’Keefe, B. M.; Mans, D. M.; Kaelin, D. E.; Martin, S.
F. J. Am. Chem. Soc. 2010, 132, 15528. Boonsompat, J.; Padwa, A. J. Org.
Chem. 2011, 76, 2753.
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.G.K.: akutatel@du.edu.
Notes
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(19) (a) Matsuya, Y.; Sasaki, K.; Nagaoka, M.; Kakuda, H.; Toyooka,
N.; Imanishi, N.; Ochiai, H.; Nemoto, H. J. Org. Chem. 2004, 69, 7989−
7993. (b) Wenjert, E.; Peittre, S. R. J. Org. Chem. 1988, 53, 5850−5853.
(c) Heller, H. G.; Hughes, D. S.; Hursthouse, M. B.; Levell, J. R.;
Ottaway, M. J. J. Chem. Soc., Chem. Commun. 1995, 837−838.
(20) Recent examples of theoretical studies on Diels−Alder reactions
of furans: (a) Dadwal, M.; Kesharwani, M. K.; Vaishalee, D.; Ganguly,
B.; Mobin, S. M.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org.
Chem. 2008, 6106−6118. (b) Pieniazek, S. N.; Houk, K. N. Angew.
Chem., Int. Ed. 2006, 45, 1442−1445. (c) Bouacha, S.; Nacereddine, A.
K.; Djerourou, A. Tetrahedron Lett. 2013, 54, 4030−4033.
(21) Mukhina, O. A.; Cronk, W. C.; Kumar, N. N. B.; Sekhar, M.;
Samanta, A.; Kutateladze, A. G. J. Phys. Chem. A 2014, DOI: 10.1021/
jp504281y.
(22) (a) Heidebrecht, R. W., Jr.; Mulrooney, C.; Austin, C. P.; Baker, R.
H., Jr.; Beaudoin, J. A.; Cheng, K. C−.C.; Comer, E.; Dandapani, S.;
Dick, J.; Duvall, J. R.; Ekland, E. H.; Fidock, D. A.; Fitzgerald, M. E.;
Foley, M.; Guha, R.; Hinkson, P.; Kramer, M.; Lukens, A. K.; Masi, D.;
Marcaurelle, L. A.; Su, X.-Z.; Thomas, C. J.; Weiwer, M.; Wiegand, R. C.;
Wirth, D.; Xia, M.; Yuan, J.; Zhao, J.; Palmer, M.; Munoz, B.; Schreiber,
S. L. ACS Med. Chem. Lett. 2012, 3, 112−117. (b) Marcaurelle, L. A.;
Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M.
D., IV; Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.;
Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.;
Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.−N.;
Haggarty, S. J.; Palmer, M.; Foley, M. A. J. Am. Chem. Soc. 2010, 132,
16962−16976. (c) Dow, M.; Marchetti, F.; Nelson, A. Diversity-
Oriented Synthesis of Natural Product-Like Libraries. In Diversity-
Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug
Discovery, and Chemical Biology; Trabocchi, A., Ed.; Wiley: Hoboken, NJ,
2013.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support of this work by the NIH (GM093930) is gratefully
acknowledged.
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REFERENCES
■
(1) Brown, E. G. Ring Nitrogen and Key Biomolecules. The Biochemistry
of N-Heterocycles; Kluwer Academic: Dordrecht, The Netherlands, 1998.
(2) (a) Bartholow, M. Pharmacy Times website, http://www.
pharmacytimes.com/publications/issue/2013/July2013/Top-200-
Drugs-of-2012, 2013. (b) McGrath, N. A.; Brichacek, M.; Njardarson, J.
T. J. Chem. Educ. 2010, 87, 1348.
(3) (a) Katritzky, A. R.; Pozharskii, A. F. Handbook of heterocyclic
chemistry, 2nd ed.; Pergamon Press: Oxford, U.K., 2000. (b) Katritzky,
A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V. Handbook of
heterocyclic chemistry, 3rd ed.; Elsevier: Amsterdam, 2010.
(4) Joule, J. A., Mills, K. Heterocyclic chemistry, 5th ed.; Wiley:
Hoboken, NJ, 2010.
(5) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465. Winkler,
J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425.
(6) For a review, see: Bass, P. D.; Gubler, D. A.; Judd, T. C.; Williams,
R. M. Chem. Rev. 2013, 113, 6816−6863.
(7) (a) Iyer, V. N.; Szybalski, W. Proc. Natl. Acad. Sci. U.S.A. 1963, 50,
355. (b) Iyer, V. N.; Szybalski, W. Science 1964, 145, 55. (c) Rajski, S. R.;
Rollins, S. B.; Williams, R. M. J. Am. Chem. Soc. 1998, 120, 2192.
(d) Rajski, S. R.; Williams, R. M. Bioorg. Med. Chem. 2000, 8, 1331.
(8) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477−2406.
(9) (a) Mak, X. Y.; Crombie, A. L.; Danheiser, R. L. J. Org. Chem. 2011,
76, 1852−1873. (b) Papaioannou, N.; Blank, J. T.; Miller, S. J. J. Org.
Chem. 2003, 26, 2728−2734. (c) Majumdar, K. C.; Samanta, S.;
Chattodhyay, B.; Nandi, R. K. Synthesis 2010, 863−869. (d) Fujiwara,
T.; Kato, Y.; Takeda, T. Heterocycles 2000, 52, 147−150.
(10) (a) Trost, B. M.; O’Boyle, B. M.; Torres, W.; Ameriks, M. K.
Chem. Eur. J. 2011, 17, 7890−7903. (b) Ayala, S. L. G.; Stashenko, E.;
Palma, A.; Bahsas, A.; Amaro-Luis, J. M. Synlett 2006, 14, 2275−2277.
(11) (a) Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.;
Kulikova, L. N.; Titov, A. A.; Varlamov, A. V. Tetrahedron Lett. 2006, 47,
4585−4589. (b) Anand, A.; Singh, P.; Mehra, V.; Amandeep; Kumar, V.;
Mahajan, M. P. Tetrahedron Lett. 2012, 53, 2417−2419.
(12) (a) Aoki, T.; Koya, S.; Yamasaki, R.; Saito, S. Org. Lett. 2012, 14,
4506−4509. (b) Ha, H.-J.; Choi, C.-J.; Ahn, Y.-G.; Yun, H.; Dong, Y.;
Lee, W. K. J. Org. Chem. 2000, 65, 8384−8386.
(13) Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.;
Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. J. Med. Chem.
2006, 49, 2037−2048.
(14) See: Schmidtke, S.; Underwood, D. F.; Blank, D. A. J. Phys. Chem.
A 2005, 109, 7033−7045 and references therein.
(23) Ye, F.; Shi, Y.; Zhou, L.; Xiao, Q.; Zhang, Y.; Wang, J. Org. Lett.
2011, 13, 5020−5023.
(24) Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55, 1757−1761.
(25) (a) Oriyama, T.; Aoyagi, M.; Iwanami, K. Chem. Lett. 2007, 36,
612. (b) Berger, S. T. A.; Seeliger, F. H.; Hofbauer, F.; Mayr, H. Org.
Biomol. Chem. 2007, 5, 3020−3026.
(26) Murai, K.; Matsushita, T.; Nakamura, A.; Hyogo, N.; Nakajima, J.;
Fujioka, H. Org. Lett. 2013, 15, 2526.
(27) Yamamoto, T.; Iizuka, M.; Ohta, T.; Ito, Y. Chem. Lett. 2006, 35,
198−199.
(28) Harrowven, D. C.; Pascoe, D. D.; Guy, I. L. Angew. Chem., Int. Ed.
2007, 46, 425−428.
(29) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304−5305. (b) Li, G.; Padwa, A. Org. Lett. 2011, 13, 3767−3769.
(30) Kutateladze, A. G.; Mukhina, O. A. J. Org. Chem. 2014, 79, 8397−
8406.
(31) Cronk, W. C.; Mukhina, O. A.; Kutateladze, A. G. J. Org. Chem.
2014, 79, 1235−1246.
(15) For a review see: (a) Wojciechowski, K. Eur. J. Org. Chem. 2001,
3587−3605. For examples see: (b) Lancaster, M.; Smith, D. J. H. J.
Chem. Soc., Chem. Commun. 1980, 471−472. (c) Wojciechowski, K.
Tetrahedron 1993, 49, 7277−7286. (d) Ito, Y.; Miyata, S.; Nakatsuka,
M.; Saegusa, T. J. Am. Chem. Soc. 1981, 103, 5250−5251. (e) Bowen, R.
D.; Davies, D. E.; Fishwick, C. W. G.; Glasbey, T. O.; Noyce, S. J.; Storr,
R. C. Tetrahedron Lett. 1982, 23, 4501−4504. (f) Wiebe, J. M.; Caille, A.
(32) Despotopoulou, C.; Bauer, R. C.; Krasovskiy, A.; Mayer, P.;
Stryker, J. M.; Knochel, P. Chem. Eur. J. 2008, 14, 2499−2506.
(33) Park, C.-M.; Bruncko, M.; Adickes, J.; Bauch, J.; Ding, H.; Kunzer,
A.; Marsh, K. C.; Nimmer, P.; Shoemaker, A. R.; Song, X.; Tahir, S. K.;
Tse, C.; Wang, X.; Wendt, M. D.; Yang, X.; Zhang, H.; Fesik, S. W.;
Rosenberg, S. H.; Elmore, S. W. J. Med. Chem. 2008, 51, 6902−6915.
(34) Samanta, K.; Kar, G. K.; Sarkar, A. K. Tetrahedron Lett. 2008, 49,
1461−1464.
̂
S.; Trimble, A. L.; Lau, C. K. Tetrahedron 1996, 52, 11705−11724.
(16) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928.
10970
dx.doi.org/10.1021/jo5019848 | J. Org. Chem. 2014, 79, 10956−10971

The Journal of Organic Chemistry
Article
(35) Platzer, N.; Ronzani, N.; Lang, C.; Lange, C. Org. Magn. Reson.
1982, 18, 14−19.
(36) Baldino, C. M.; Caserta, J. L.; Dumas, S. A.; Lee, C.-S.; Flanders, Y.
L. Aminopiperidine Kinase Inhibitors. US 20120270892 A1, Oct. 25, 2012.
(37) Shi, Z.; Devasagayaraj, A.; Gu, K.; Jin, H.; Marinelli, B.; Samala, L.;
Scott, S.; Stouch, T.; Tunoori, A.; Wang, Y.; Zang, Y.; Zhang, C.;
Kimball, S. D.; Main, A. J.; Yu, X.; Buxton, E.; Patel, S.; Nguyen, N.;
Swaffield, J.; Powell, D. R.; Wilson, A.; Liu, Q. J. Med. Chem. 2008, 51,
3684.
(38) Procedure adapted from: Abonia, R.; Cuervo, P.; Insuasty, B.;
Quiroga, J.; Nogueras, M.; Cobo, J.; Meier, H.; Lotero, E. Open Org.
Chem. J. 2008, 2, 26−34.
10971
dx.doi.org/10.1021/jo5019848 | J. Org. Chem. 2014, 79, 10956−10971