Intramolecular photoassisted cycloadditions of azaxylylenes and postphotochemical capstone modifications via suzuki coupling provide access to complex polyheterocyclic biaryls

Article abstract of DOI:10.1021/jo4026447

Modular preassembly of azaxylylene photoprecursors, halogen-substituted in the aromatic ring, their intramolecular [4 + 4] or [4 + 2] cycloadditions to tethered unsaturated pendants, and subsequent postphotochemical capstone modification of the primary photoproducts via Suzuki coupling provides rapid access to diverse biaryls of unprecedented topology. This synthetic sequence allows for rapid growth of molecular complexity and is well aligned with methodology of Diversity-Oriented Synthesis.

Full text of DOI:10.1021/jo4026447

Article
pubs.acs.org/joc
Intramolecular Photoassisted Cycloadditions of Azaxylylenes and
Postphotochemical Capstone Modifications via Suzuki Coupling
Provide Access to Complex Polyheterocyclic Biaryls
W. Cole Cronk, Olga A. Mukhina, and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
S
* Supporting Information
ABSTRACT: Modular preassembly of azaxylylene photoprecur-
sors, halogen-substituted in the aromatic ring, their intramolecular
[4 + 4] or [4 + 2] cycloadditions to tethered unsaturated pendants,
and subsequent postphotochemical capstone modification of the
primary photoproducts via Suzuki coupling provides rapid access to
diverse biaryls of unprecedented topology. This synthetic sequence
allows for rapid growth of molecular complexity and is well aligned
with methodology of Diversity-Oriented Synthesis.
Scheme 1. Azaxylylene Formation via ESIPT and Their
Intramolecular Cycloadditions
INTRODUCTION
■
Incorporation of key photochemical steps into synthetic
sequences allow for dramatic increase in chemical complexity
and rapid access to elaborate molecular architectures, rivaled by
no other methods. This is especially true for inter- and
intramolecular photocycloadditions,1 which give rise to four- to
eight-membered rings of complex topology ubiquitous in
nature and perhaps promising from the medicinal chemistry
standpoint.2 Often photoreactions yield strained polycycles
which can be further introduced into postphotochemical steps
for added synthetic benefit. Photoinduced oxametathesis is one
prominent example of such strain harvesting and utilization.3
The most recent example is an elegant work by Porco and
Stephenson4 on a tandem dienone-photorearrangement-cyclo-
addition. The photoinduced step, inspired by Schultz’
chemistry,5 gives highly strained anti-Bredt polycycloalkenes,
which react as dienophiles in the (ground state) postpho-
tochemical step to further grow molecular complexity.
The current research focus in our laboratory is [4+n]
cycloadditions of azaxylylenes,6 short-lived species generated
via the excited state intramolecular proton transfer (ESIPT)
from o-formyl or acyl anilines, Scheme 1. Although azaxylylenes
have been known for over half a century7 and their
photophysics is well-studied,8 the synthetic utility of these
intermediates remains largely underexplored, and is limited to
the generation of azaxylylenes from exotic precursors,7b with
the notable exception of the paper by Corey and Steinhagen
describing a simple and efficient route to azaxylylenes from o-
chloromethylanilines through base-induced elimination.9 To
the best of our knowledge, before our 2011 paper,6a
azaxylylenes generated via ESIPT in aromatic o-aminoketones
were not known to undergo cycloaddition reactions. One
plausible reason for this could be the focus of the previous
research efforts on inter- not intramolecular reactions.
yield novel N,O,S-polyheterocycles,6 demonstrating rapid
growth of molecular complexity and diversity, fully in keeping
with the central paradigm of diversity-oriented synthesis.10 The
synthesis of photoprecursors is straightforward and modular;
they are assembled from readily (and in many cases−
commercially) available starting materials in two to four simple
steps such as amide bond formation, alkylation, acylation and
oxidation, allowing for ready incorporation of multiple diversity
inputs.
One of the questions for the current study focuses on
whether it is possible to incorporate a high yielding
postphotochemical step into this synthetic sequence to further
increase the complexity of the product. The toolbox of a
modern synthetic chemist is vast, and there are a number of
options for postphotochemical transformations. According to
We have found that intramolecular [4 + 4] or [4 + 2]
cycloadditions of azaxylylenes to tethered unsaturated pendants
Received: November 30, 2013
© XXXX American Chemical Society
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Scheme 2. Alternative Pathways To Install the Biaryl Moiety: Pre- or Postphotochemical
the comprehensive study published in 2011 by Roughley and
Jordan,11 the C−C bond forming reactions are the third most-
widely used reaction, after alkylation/arylation or acylation of
heteroatoms, employed by medicinal chemists in “the pursuit of
drug candidates.” These mostly sp2-sp2 cross-coupling reactions
can be used to decorate the target N,O-polyheterocyclic
structures with aryl- or hetaryl- pendants leading to biaryls,
commonly found in various structures including natural
products.12 According to Roughley’s survey, it is the Suzuki-
Miyaura coupling that tops the list, accounting for more than
40% of all C−C bond forming reactions.
Besides a well-established methodology and a vast body of
literature on the subject, the Suzuki reaction enjoys another
advantage: the availability of starting materials. Synthetic
pathways to both boronic acids and aryl halides are well-
documented; many of these starting materials are commercially
available. We rationalized that the Suzuki coupling could be an
ideal starting point for the exploration of possible post-
photochemical modifications, although in the context of the
photoassisted synthesis it was not entirely clear whether the key
photochemical step, i.e. the photoinduced intramolecular
cycloaddition, should precede the Suzuki modification of the
photoproduct or, alternatively, the Suzuki coupling should be
performed on the photoprecursor which is subsequently
photocyclized. In order to streamline the synthesis and make
it amenable to modular-based approach, we introduced halogen
into the phenyl ring of the azaxylylene photoprecursors and
used commercially available aryl and heteroaryl boronic acids.
two competing alternative approaches of incorporating the
Suzuki reaction into the synthesis of novel scaffolds, Scheme 2:
(i) the preassembly of the biaryl photoprecursor outfitted with
the help of Suzuki coupling with a (hetero)aromatic moiety
(path a, Scheme 2) or (ii) photoassisted synthesis of
photoproducts halogenated in the aromatic ring, with
subsequent Suzuki cross-coupling of these [4 + 4] and [4 +
2] products with (hetero)aromatic boronic acids (path b,
Scheme 2). As this considerable extension of conjugation could
potentially affect photoefficiency, the comparison of photo-
chemical behavior of the two substrates and the feasibility of
either synthetic pathway represented the first goal of this study.
5-Bromosubstituted alcohol 1a was synthesized by acylation
of 5-bromophenylmethanol with 2-furanpropanoyl chloride 6
and then carried through two pathways, Scheme 2. Path A
consisted of Suzuki coupling followed by PCC oxidation to get
the photoprecursor, while for the path B bromo alcohol 1a was
simply oxidized with PCC. Both photoprecursors, 3a and 3b,
typical of o-formyl anilines, possess two characteristic emission
bands in their fluorescence spectra: a band at 400 nm,
corresponding to the fluorescence from the initial amide form,
and a band at 540−550 nm attributable to excited state
intramolecular proton transfer (ESIPT). Irradiations were
carried out with a Rayonet broadband 300−400 nm UV
source. The optimal irradiation media for compounds 3a and
3b were found to be 5% aqueous acetonitrile with the reactions
proceeding faster in the presence of water. Both photo-
precursors 3a and 3b gave stable polyheterocycles 4 and 5 as
the products of the irradiation in the ratio of the [4 + 2] (4) to
[4 + 4] (5) products of approximately 1:1. Interestingly, despite
the presence of water capable of stabilizing azaxylylene due to
hydrogen bonding, in contrast to our previous results only
single stereo isomer of [4 + 4] (syn-5) and [4 + 2] (anti-4) is
formed, where syn- and anti- refers to mutual arrangement of
the benzylic hydroxy group in the quinolinole or benzoazacane
rings, and furan’s oxygen.
RESULTS AND DISCUSSION
■
Although transition metal catalyzed cross-coupling reactions are
commonplace in modern synthesis, introduction of heterocyclic
fragments still poses some challenges:13 heteroaryl coupling
partners may poison the catalyst, high temperatures required
for the reaction may not be compatible with delicate starting
materials or the product. Unprotected hydroxy or amino groups
present additional difficulties due to the possibility of boroxines
formation and competitive protodeboronation.14 This results in
an ongoing effort to optimize the catalyst, to lower the catalytic
load and temperature, and to expand the scope of the
reaction.15 Anticipating such problems with complex photo-
products containing aminal moieties, hydroxy- and amido-
groups, and reactive double bonds, we have investigated the
Compounds 4a and 5a were then subjected to Suzuki
coupling under the same conditions as compound 1b, yielding
the mixture of 4b and 5b in the ratio of 1:4. Such a change in
the ratios of [4 + 4] to [4 + 2] isomers is rationalized in terms
of decreased stability and degradation of the [4 + 2] adduct
under Suzuki coupling conditions. The yields of the [4 + 4]
adducts over the three steps were comparable for both paths.
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However, a closer examination revealed that the quantum
efficiency of cycloaddition differs dramatically for halogen- and
heterocycle-substituted photoprecursors, Table 1. While this
proceed on the same singlet (S1) hypersurface or, alternatively,
the generated singlet excited azaxylylene can undergo
intersystem crossing into the triplet state (T1). The overall
effect of the halogen substitution in the phenyl ring can
presumably be dissected into (i) the electron withdrawing effect
on both the ESIPT and on the rate of the inverse electron
demand Diels−Alder step, or (ii) the heavy atom effect on the
rate of intersystem crossing (especially in the case of Br as a
substituent). To clarify the contribution of each of these factors
further quantum yield studies were carried out, Table 1. Among
the three halogen-substituted substrates 3a,c,d the highest
quantum yield was observed for the bromo-, followed by iodo-
and chloro-substituted photoprecursors. Electronegativity
decreases down a group in the Periodic Table, I < Br < Cl
but the nuclear charge increases Cl < Br < I. Our experimental
finding of the bell shaped rate dependence implies that the
observed acceleration may be the result of a combined effect of
the heavy atom and the electron-withdrawing effect, which also
allows us to hypothesize that a triplet excited state might be
involved in cycloadditions of photogenerated azaxylylenes. The
detailed investigation of the underlying mechanism for the
photochemical step is underway in our laboratory and will be
reported elsewhere. On the basis of what we know so far it was
decided to follow path b and to probe the scope of this
photoassisted process, with Suzuki coupling as postphotochem-
ical capstone.
Table 1. Relative Quantum Yields for Selected 5-Substituted
Photoprecursors
fact has little effect on the preparative outcome of the synthetic
sequence as long as the extended irradiation can compensate
for lower quantum yields without causing unwanted side
reactions, it does raise important mechanistic questions. The
relative quantum yield experiment clearly shows that the QY of
halogen-substituted photoprecursor 3a is 3.7 times higher than
that of 3b bearing pyridine group, and 4.3 times higher than for
azaxylylene precursor not substituted in the phenyl ring, 3e.
The explanation for this can probably be found in the
mechanism of the reaction, Scheme 1. After the initial
excitation and the excited-state proton transfer, the intra-
molecular cycloaddition of the formed azaxylylene can either
Azaxylylene photoprecursors contain 2-acylaniline as the
ESIPT-photoactive core, and furan as a tethered unsaturated
pendant and azaxylylenophile. In the context of diversity-
oriented synthesis the system can accommodate at least three
diversity inputs: (i) identity and position of halogen
a
Table 2. Matrix of Photoprecursors
a
Isolated yields of photoprecursors are shown.
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substitution in the aromatic ring, (ii) substituent on the
carbonyl group of azaxylylene precursor, and (iii) the linker
connecting the 2-acylaniline with furan. Such design makes it
possible to implement modular approach and gain access to a
diverse matrix of photoprecursors, Table 2. The synthesis of
photoprecursors 3a−e, 9, 12−16 was carried out in a
straightforward way as shown in Schemes 2 and 3. Upon
Scheme 4. Peptoid Synthesis-Based Diversification of the
Linker
Scheme 3. General Synthesis of Photoprecursors
bromo-substituted substrates, reactions of furyl- and thienylbor-
onic acids, 2c and 2d, required iodo-substituted substrates for
the Suzuki coupling to occur at appreciable yields. Attempts to
run the reaction under milder conditions using MIDA20
boronates failed.
The structure and stereochemistry of Suzuki adducts was
unambiguously established by XRay analysis of several
representative examples and by the analysis of NMR spectra
of the products. Of note is the rearrangement observed for
furyl-substituted coupling product 5g. The oxabicyclo[4.2.1]-
nonene skeleton of the primary [4 + 4] photoproduct
undergoes ring-opening and ring closure when subjected to
silica during chromatography purification, yielding 29 contain-
ing oxabicyclo[3.3.1]nonane core, Scheme 6. Heating 5g in
DMSO also resulted in 29. The mechanistic details of this
rearrangement, the effect of functional groups and reaction
conditions are currently under investigation.
synthesis of halogen-substituted alcohols 7a,c-e, 8 or ketones
10,11 (see SI for the detailed description), they were
introduced into reaction with furanpropanoyl chloride 6. In
case of ketones the immediate products of coupling, 12 or 13,
were directly used for irradiation, while the benzylic alcohols
were first oxidized with PCC to yield the formyl-containing
photoprecursor 3a,c-e. The same result is achieved by the
amide coupling of halogen-substituted methyl anthranilates
with 2-furanpropanoyl chloride, followed by the reduction of
the product to the corresponding benzylic alcohol with LiAlH4,
and its oxidation to aldehyde with PCC. The structure of the
linker can be diversified via the peptoid synthesis-inspired16
approach with bromoacetyl bromide. The initial product of
bromoacetylation of alcohol 7a or ketone 11 obtained in nearly
quantitative yield was introduced into the reaction with benzyl
or furfuryl amines, followed by acylation of the resulting
secondary amine with furoyl or pivaloyl chlorides, respectively,
Scheme 4.
In all cases the irradiation proceeded smoothly to give
products of both [4 + 4] and [4 + 2] cycloaddition, Scheme 5,
ratios and yields are compiled in Table 3. The average reaction
time was under 5 h, and the reactions were highly
diastereoselective as established by NMR analysis. The
photoproducts were not isolated but rather introduced directly
into palladium-catalyzed cross coupling to yield the expected
biaryls, purified by column chromatography. The yields of the
Suzuki-coupling step were found to be sensitive to the presence
of additional heteroatoms: in two of the three cases the
introduction of an additional amide fragment into the linker to
form ketopiperazine resulted in complete degradation of the [4
+ 2] photoproduct dihydrofuran after the coupling step, with a
commensurate decrease of the overall yield to below 40%. The
choice of catalysts, solvents and reaction time depended on the
nature of arylboronic acid. In case of 3-pyridine boronic acid17
2a the catalyst of choice was Pd2(dba)3 with PCy3 as a ligand,
and the catalyst load was as low as 0.9 mol %, while for
reactions of 2-furyl- and 2-thienyl boronic18 acids 2c and 2d 5
mol % of Pd(PPh3)4 was used. Moreover, while 3-pyridine- and
phenyl-19 boronic acids, 2a and 2b, reacted well with the
CONCLUSIONS
■
Azaxylylenes generated from readily available halogen-sub-
stituted o-formyl or acyl anilines via photoinduced proton
transfer undergo [4 + 4] or [4 + 2] intramolecular
cycloadditions with high diastereoselectivity. The photo-
products are introduced into Suzuki reaction to yield
structurally complex and topologically unprecedented hetero-
cyclic biaryls. The whole photoassisted synthetic sequence,
including the postphotochemical coupling, is well aligned with
DOS.
EXPERIMENTAL SECTION
■
General Information. Common reagents and solvents were
purchased from commercial sources and used as is, except for THF,
which was refluxed over and distilled from potassium benzophenone
ketyl prior to use. NMR spectra were recorded at 25 °C in CDCl3 with
TMS as an internal standard, unless noted otherwise. High resolution
mass spectra were obtained on an LC/MS/MS system with triple
quadrupole/TOF analyzer. Flash column chromatography was
performed with 230−400 mesh silica gel using hexanes/EtOAc or
DCM/methanol as an eluent.
2-Amino-5-bromobenzyl Alcohol21 (7a). Methyl 2-amino-5-
bromobenzoate (3.00 g, 13.0 mmol) in THF (9 mL) under nitrogen
atmosphere was cooled to −41 °C. DIBAL-H (39.1 mL of a 1.0 M
solution in hexanes, 43.0 mmol) was slowly added to the stirred
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Scheme 5
Table 3. Photoproduct Ratios and Isolated Yields of Postphotochemical Suzuki Couplings
a
b
b
Photoprecursor
Photoproducts ratio [4 + 2]:[4 + 4]
Suzuki coupling product from [4 + 2]
Suzuki coupling product from [4 + 4]
3a
4a:5a = 1:1
4f, 30%
4b, 7%
5f, 44%
5b, 28%
c
3d
4d:5d = 1:1
4g, 17%
4h, 27%
17b, 30%
19b, 28%
21b, 36%
23b 19%
25b, --
5g, 26%
5h, 39%
9
17a:18a = 1:0.8
19a:20a = 1:1.1
21a:22a = 1:1.9
23a:24a = 1:1.4
25a:26a = 1:1.5
27a:28a = 1:16
18b, 24%
20b, 30%
22b, 16%
24b, 12%
26b, 20%
28b, 36%
12
13
14
15
16
27b, --
a
b
c
determined by NMR of the reaction mixture after completion of irradiation. isolated yields. the primary [4 + 4] photoproduct rearranges from the
bicyclo[4.2.1] to bicyclo[3.3.1] framework.
and the mixture was allowed to stir for 30 min. The organic phase was
extracted with Et2O (3 × 100 mL), and the solvent was removed
under reduced pressure yielding 2.41 g (92%) of the product. 1H
NMR (500 MHz, CDCl3) δ 7.24 (m, 2H), 6.61 (d, J = 8.3 Hz, 1H),
4.66 (d, J = 4.5 Hz, 2H), 4.22 (s, 2H).
Scheme 6
4-Bromo-2-((trimethylsilyl)methyl)aniline (7a′). Chlorotrime-
thylsilane (1.16 mL, 9.14 mmol) was added to a stirred solution of 2-
amino-5-bromobenzyl alcohol (7a) (1.68 g, 8.33 mmol) and
triethylamine (2.32 mL, 16.6 mmol) in DCM (70 mL). The reaction
mixture was stirred at room temperature overnight. The mixture was
quenched with sat. aq. NH4Cl (50 mL), the organic layer was
separated, and the aqueous phase was extracted with DCM (3 × 100
mL). The organic fractions were combined, dried over Na2SO4,
filtered, and the solvent was concentrated yielding 2.35 g (94%) of the
solution. After maintaining at −41 °C for 1.5 h, the solution was
allowed to reach room temperature and left to stir overnight. The
solution was cooled in an ice water bath, quenched by a sequential
addition of methanol and a sat. solution of sodium potassium tartrate,
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product. 1H NMR (500 MHz, CDCl3) δ 7.19 (m, 2H), 6.57 (d, J = 8.2
Hz, 1H), 4.61 (s, 2H), 4.18 (s, 2H), 0.16 (s, 9H).
(10 mL) was added dropwise to an ice-cooled solution of acetic
anhydride (4.08 mL, 43.2 mmol) in EtOH (40 mL). The mixture was
stirred for 16 h at room temperature. The solvent was concentrated to
yield N-(5,6,7,8-tetrahydro-1-naphthyl)-acetamide as a white solid
which was used without further purification 1H NMR (500 MHz,
CDCl3) δ = 7.63 (d, J = 7.9, 1H), 7.15 (t, J = 7.8, 1H), 6.95 (d, J = 7.5,
1H), 6.89 (s, 1H), 2.81 (m, 2H), 2.62 (m, 2H), 2.23 (s, 3H), 1.87 (m,
2H), 1.80 (m, 2H). To a cooled solution of N-(5,6,7,8- tetrahydro-1-
naphthyl)-acetamide in AcOH (55 mL) was slowly added a solution of
Br2 (3.36 mL, 65.2 mmol) in AcOH (4 mL) so that the temperature
remained below 17 °C. The reaction mixture was then allowed to stir
at room temperature for 24 h. The mixture was poured over ice water,
the resulting suspension was filtered, and the collected solid was
washed with water. The solid was dissolved in DCM (200 mL) and
H2O (50 mL), the organic phase was separated, and the aqueous phase
was extracted with DCM (3 × 100 mL). The organic phases were
combined, dried over Na2SO4, filtered, and the solvent was
2-Amino-4-bromobenzyl Alcohol22 (8). Methyl 2-amino-4-
bromobenzoate23 (1.14g, 4.95 mmol) in THF (5.5 mL) under
nitrogen atmosphere was cooled to −41 °C. DIBAL-H (16.35 mL of a
1.0 M solution in hexanes, 16.35 mmol) was slowly added to the
stirred solution. After remaining at −41 °C for 1.5 h, the solution was
allowed to reach room temperature and left to stir overnight. The
solution was cooled in an ice water bath, quenched by the sequential
addition of methanol (35 mL) and a sat. solution of sodium potassium
tartrate (70 mL), and the mixture was allowed to stir for 6 h. The
organic phase was extracted with Et2O (3 × 125 mL), and the solvent
was removed under reduced pressure yielding 0.98 g of (2-amino-4-
1
bromophenyl)methanol. H NMR (500 MHz, CDCl3) δ 6.95 (d, J =
7.9 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H), 6.85 (dd, J = 7.9, 1.9 Hz, 1H),
4.66 (d, J = 5.1 Hz, 2H), 4.29 (s, 2H), 1.54 (m, 1H).
5-Bromo-2-((trimethylsilyloxy)methyl)aniline (8′). Chlorotri-
methylsilane (0.69 mL, 5.4 mmol) was added to a stirred solution of
(2-amino-4-bromophenyl)methanol (8) (0.98g 4.9 mmol) and
triethylamine (1.36 mL, 9.75 mmol) in DCM (43 mL). The reaction
mixture was stirred at room temperature overnight. The mixture was
quenched with sat. aq. NH4Cl (70 mL), the organic layer was
separated, and the aqueous phase was extracted with DCM (3 × 100
mL). The organic fractions were combined, dried over Na2SO4,
filtered, and the solvent was concentrated yielding 1.11 g of 5-bromo-
2-((trimethylsilyloxy)methyl)aniline which was used without further
purification. 1H NMR (500 MHz, CDCl3) δ 6.90 (d, J = 7.8 Hz, 1H),
6.84 (d, J = 1.8 Hz, 1H), 6.82 (dd, J = 7.8, 1.9 Hz, 1H), 4.61 (s, 2H),
4.26 (s, 2H), 0.14 (s, 9H).
1
concentrated yielding 6.98 g (99.6%) of the product. H NMR (500
MHz, CDCl3) δ 7.53 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H),
6.89 (s, 1H), 2.77 (m, 2H), 2.61 (m, 2H), 2.24 (s, 3H), 1.81 (m, 4H).
(ii). N-(4-Bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-
acetamide. N-(4-bromo-5,6,7,8-tetra-hydronaphthalen-1-yl)acetamide
(3.09 g, 11.5 mmol) in acetone (80 mL) and 15% aqueous MgSO4
(1.90 g, 15.8 mmol in 11 mL of H2O) was treated with KMnO4 (5.47
g, 34.6 mmol) in portions. The mixture was allowed to stir for 12 h,
filtered through Celite, and the solids were washed with CHCl3 (100
mL) and H2O (100 mL). The aqueous layer was extracted with CHCl3
(4 × 100 mL). The organic fractions were combined, washed with
brine, and dried over Na2SO4, and concentrated yielding 1.90 g
(58.6%) of the desired product. 1H NMR (500 MHz, CDCl3) δ 12.16
(s, 1H), 8.58 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 3.06 (t, J =
6.2 Hz, 2H), 2.72 (m, 2H), 2.25 (s, 3H), 2.14 (m, 2H). (iii) A stirred
solution of N-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-
acetamide (1.90 g, 6.74 mmol) in 6 M HCl (100 mL) was heated
at 90 °C for 8 h. The mixture was cooled to room temperature and the
volatiles were removed under vacuum. Ice was added to the mixture,
followed by 2 M NaOH until pH of 8 was reached. The aqueous layer
was extracted with EtOAc, the organic fractions were combined,
washed with brine, dried, filtered and concentrated to give 1.26 g of
2-Amino-5-iodobenzyl Alcohol24 (7d). Methyl 5-iodoanthrani-
late (3.00 g, 10.8 mmol) in THF (7.5 mL) under nitrogen atmosphere
was cooled to −41 °C. DIBAL-H (32.7 mL of a 1.1 M solution in
cyclohexane, 36 mmol) was slowly added to the stirred solution. After
remaining at −41 °C for 1.5 h, the solution was allowed to reach room
temperature and left to stir overnight. The solution was cooled in an
ice water bath, quenched by the sequential addition of methanol, a sat.
solution of sodium potassium tartrate, and the mixture was allowed to
stir for 30 min. The organic phase was extracted with Et2O (3 × 100
mL), and the solvent was removed under reduced pressure yielding
2.48 g (92%) of the product. 1H NMR (500 MHz, CDCl3) δ 7.41 (dd,
J = 8.3, 2.2 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H),
4.64 (d, J = 5.3 Hz, 2H), 4.24 (s, 2H).
1
the product (78.9%). H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 8.9
Hz, 1H), 6.55 (s, 2H), 6.43 (d, J = 8.8 Hz, 1H), 2.96 (t, J = 6.2 Hz,
2H), 2.65 (m, 2H), 2.08 (m, 2H).
4-Iodo-2-((trimethylsilyloxy)methyl)aniline (7d′). Chlorotri-
methylsilane (0.49 mL, 3.8 mmol) was added to a stirred solution
of 2-amino-5-iodobenzyl alcohol (7d) (0.87 g, 3.5 mmol) and
triethylamine (0.98 mL, 7.0 mmol) in DCM (32 mL). The reaction
mixture was stirred at room temperature overnight. The mixture was
quenched with sat. aq. NH4Cl (50 mL), the organic layer was
separated, and the aqueous phase was extracted with DCM (3 × 100
mL). The organic fractions were combined, dried over Na2SO4,
filtered, and the solvent was concentrated yielding 0.94 g (83%) of the
Synthesis of Photoprecursors. General Procedure for the
Reaction of 2-Furanpropanoyl Chloride with Amines (A). A
crude solution of 2-furanpropanoyl chloride (1.2−1.5 equiv) in dry
THF (25 mL) was added dropwise to an ice-cooled stirred solution of
substituted anilines (1 equiv) and anhydrous pyridine (1.1 equiv) in
THF (50 mL). The solution was allowed to reach room temperature
and left to stir overnight. The reaction mixture was then diluted with
water (100 mL), extracted with EtOAc (4 × 100 mL), the combined
organic fractions were washed with 10% NaOH (100 mL), dried over
Na2SO4, filtered, and concentrated. The product was purified when
necessary using flash chromatography.
General Procedure for the Synthesis of N-(2-Acetylphenyl)-
2-bromoacetamides (B). Bromoacetyl bromide (1.1 equiv) in dry
DCM (10 mL) was slowly added to a stirred solution of amine (1
equiv), pyridine (1.1 equiv) in dry DCM (20 mL) at 0 °C under
nitrogen atmosphere. The reaction mixture was left stirring overnight,
then it was quenched with water (10 mL) and the aqueous phase was
extracted with DCM (2 × 75 mL). Combined organic layers were
dried over Na2SO4 and concentrated, giving the crude product, which
was used further without purification
N-(4-Chloro-2-formylphenyl)-3-(furan-2-yl)propanamide (3c).
General procedure A was followed using 2-furanpropanoyl chloride
(6) (0.51 g, 3.2 mmol), 2-amino-5-chlorobenzyl alcohol (7c) (0.50 g,
3.2 mmol) and anhydrous pyridine (0.28 mL, 3.5 mmol) in THF (10
mL). The work-up and purification by flash chromatography yielded
0.67 g (2.4 mmol, 75%) of N-(4-chloro-2-(hydroxymethyl)phenyl)-3-
(furan-2-yl)propanamide. 1H NMR (500 MHz, CDCl3) δ 8.45 (s,
1H), 8.03 (d, J = 8.7 Hz, 1H), 7.36 (m, 1H), 7.31 (dd, J = 8.7, 2.4 Hz,
1
product. H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 8.2, 2.2 Hz,
1H), 7.35 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 8.3 Hz, 1H), 4.59 (s, 2H),
4.21 (s, 2H), 0.15 (s, 9H).
2-Amino-5-bromoacetophenone25 (10). o-Aminoacetophe-
none (10 g, 73.96 mmol) was dissolved in Ac2O, stirred for 2 h and
concentrated. The residue was then dissolved in DCM, treated with
Br2 (6 mL), allowed to stir for 3 h, quenched with water, filtered, and
the collected solid was washed with water. The solid residue was
transferred to a round bottomed flask, dissolved in 2 M HCl (200
mL), and the solution was heated at 90 °C for 4 h. The solution was
allowed to reach room temperature, basified to pH 12, extracted with
EtOAc (3 × 50 mL), dried over Na2SO4, and concentrated yielding
1
13.5 g (85%) of the product. H NMR (500 MHz, CDCl3) δ 7.82 (s,
1H), 7.35 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 8.8, 0.9 Hz, 1H), 6.32 (s,
2H), 2.58 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 199.6, 149.1,
137.0, 134.1, 119.4, 119.0, 106.6, 27.8.
8-Amino-5-bromo-3,4-dihydronaphthalen-1(2H)-one (11).
(i). N-(4-Bromo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.26
5,6,7,8-Tetrahydro-1-naphthylamine (3.0 mL, 21.6 mmol) in EtOH
F
dx.doi.org/10.1021/jo4026447 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 7.20 (d, J = 2.4 Hz, 1H), 6.32 (t, J = 2.4 Hz, 1H), 6.11 (d, J = 3.2
Hz, 1H), 4.62 (d, J = 4.5 Hz, 2H), 3.11 (t, J = 7.4 Hz, 2H), 2.77 (t, J =
7.4 Hz, 2H), 2.07 (s, 1H). To a stirred solution of N-(4-chloro-2-
(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide (0.67 g, 2.4
mmol) in dry DCM (100 mL) was added PCC (0.78 g, 3.6 mmol).
The reaction mixture was left stirring overnight, filtered through a
layer of silica gel, and evaporated yielding 0.64g (2.3 mmol, 72%) of
3c. 1H NMR (500 MHz, CDCl3) δ 11.08 (s, 1H), 9.88 (d, J = 0.7 Hz,
1H), 8.77 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.58 (dd, J =
9.1, 2.5 Hz, 1H), 7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.30 (dd, J = 3.2, 1.9
Hz, 1H), 6.09 (m, 1H), 3.11 (m, 2H), 2.84 (m, 2H). 13C NMR (126
MHz, CDCl3) δ 194.3, 171.2, 153.8, 141.3, 139.3, 136.0, 135.0, 128.0,
122.5, 121.6, 110.2, 105.6, 36.5, 23.6.
N-(4-Bromo-2-formylphenyl)-3-(furan-2-yl)propanamide (3a). (i)
General procedure A was followed using 2-furanpropanoyl chloride
(6) (1.67 g, 10.5 mmol), methyl 2-amino-5-bromobenzoate (2.00 g,
8.6 mmol) and anhydrous pyridine (0.76 mL, 9.5 mmol). The work-up
yielded 3.00 g (99%) of Methyl 5-bromo-2-(3-(furan-2-yl)-
propanamido)benzoate. 1H NMR (500 MHz, CDCl3) δ 11.05 (s,
1H), 8.68 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.65 (dd, J =
9.1, 2.5 Hz, 1H), 7.33 (dd, J = 1.9, 0.8 Hz, 1H), 6.29 (dd, J = 3.2, 1.9
Hz, 1H), 6.09 (m, 1H), 3.96 (s, 3H), 3.11 (m, 2H), 2.81 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 170.7, 167.6, 154.0, 141.3, 140.5, 137.4,
133.3, 122.1, 116.4, 114.8, 110.2, 105.5, 52.7, 36.7, 23.7.
(ii) To a suspension of LiAlH4 (0.88 g, 23 mmol) in THF (12 mL)
at −78 °C under nitrogen atmosphere was added methyl 5-bromo-2-
(3-(furan-2-yl)propanamido)benzoate (4.29 g, 12.2 mmol) dissolved
in THF (24 mL). The mixture was allowed to stir overnight, treated
with water (1 mL), 10% NaOH (1 mL), followed by an additional
allotment of water (3 mL), and dried over Na2SO4. The solvent was
filtered and concentrated yielding 3.52 g of N-(4-bromo-2-
(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide (1a) which was
used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.50
(s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 2.4 Hz, 1H), 7.35
(m, 2H), 6.32 (dd, J = 3.1, 1.9 Hz, 1H), 6.11 (m, 1H), 4.61 (s, 2H),
3.10 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.21 (s, 1H). 13C
NMR (126 MHz, CDCl3) δ 170.4, 154.0, 141.3, 136.4, 131.9, 131.5,
131.4, 124.2, 116.9, 110.4, 105.8, 63.8, 36.2, 24.0. To the alcohol (3.52
g) in dry DCM (250 mL) was added PCC (2.63 g, 12.2 mmol). The
reaction mixture was left stirring overnight, filtered through a layer of
silica gel, and evaporated yielding 2.11 g of 3a (54% over two steps).
1H NMR (500 MHz, CDCl3) δ 11.08 (s, 1H), 9.87 (s, 1H), 8.72 (d, J
= 8.9 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 9.0, 2.4 Hz, 1H),
7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 6.09 (m,
1H), 3.11 (m, 2H), 2.84 (m, 2H). 13C NMR (126 MHz, CDCl3) δ
194.2, 171.2, 153.8, 141.3, 139.8, 138.9, 138.0, 122.9, 121.9, 115.0,
110.2, 105.6, 36.5, 23.6. HRMS (ESI) calcd for C14H13BrNO3+ (MH+)
322.0073, found 322.0067.
N-(2-Formyl-4-iodophenyl)-3-(furan-2-yl)propanamide (3d).
General procedure A was followed using 2-furanpropanoyl chloride
(6) (0.79 g, 5.0 mmol), 4-iodo-2-((trimethylsilyloxy)methyl)aniline
(7d′) (0.94 g, 2.9 mmol) and dry pyridine (0.40 mL, 5.0 mmol) in
THF (10 mL). Upon work-up 0.90
g of N-(4-iodo-2-
(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide was isolated
1
which was used without further purification. H NMR (500 MHz,
CDCl3) δ 8.50 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.6, 2.1
Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 1.9, 0.9 Hz, 1H), 6.32
(dd, J = 3.2, 1.9 Hz, 1H), 6.10 (m, 1H), 4.60 (d, J = 5.7 Hz, 2H), 3.10
(t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.10 (s, 1H). To N-(4-
iodo-2-(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide (0.90 g)
in DCM (60 mL) was added PCC (3.15 g, 14.6 mmol). The reaction
mixture was left stirring for 8h, filtered through a layer of silica gel
using EtOAc, the solvent was concentrated, and the mixture was
subjected to flash chromatography yielding 0.37 g of 3d (34% over two
1
steps). H NMR (500 MHz, CDCl3) δ 11.08 (s, 1H), 9.85 (s, 1H),
8.58 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 8.9, 2.2
Hz, 1H), 7.33 (dd, J = 1.8, 0.9 Hz, 1H), 6.29 (dd, J = 3.2, 1.9 Hz, 1H),
6.09 (m, 1H), 3.11 (m, 2H), 2.83 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 194.2, 171.2, 153.8, 144.6, 144.1, 141.4, 140.4, 123.3, 122.0,
+
110.2, 105.6, 84.7, 36.6, 23.6. HRMS (ESI) calcd for C14H13INO3
(MH+) 369.9935, found 369.9945.
N-(2-Acetyl-4-bromophenyl)-3-(furan-2-yl)propanamide (12).
General procedure A was followed using 2-furanpropanoyl chloride
(6) (0.72 g, 2.8 mmol), 1-(2-amino-5-bromophenyl)ethanone (10)
(0.30 g, 1.4 mmol) and anhydrous pyridine (0.17 mL, 2.1 mmol)
yielding 0.45 g (93%) of 12. 1H NMR (500 MHz, CDCl3) δ 11.66 (s,
1H), 8.73 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.66 (dd, J =
9.1, 2.4 Hz, 1H), 7.33 (dd, J = 1.9, 0.8 Hz, 1H), 6.29 (dd, J = 3.2, 1.9
Hz, 1H), 6.08 (m, 1H), 3.10 (m, 2H), 2.81 (m, 2H), 2.68 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 201.6, 171.1, 154.0, 141.3, 139.9, 137.8,
134.0, 123.2, 122.6, 114.6, 110.2, 105.5, 36.7, 28.6, 23.7. HRMS (ESI)
+
calcd for C15H15BrNO3 (MH+) 336.0230, found 336.0235.
N-(4-Bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(furan-
2-yl)propanamide (13). General procedure A was followed using 2-
furanpropanoyl chloride (6) (3.8 mmol), 8-amino-5-bromo-3,4-
dihydronaphthalen-1(2H)-one (11) (0.48 g, 2.0 mmol) and dry
pyridine (0.18 mL, 2.2 mmol). Purification by flash chromatography
1
yielded 0.38 g (50%) of 13. H NMR (500 MHz, CDCl3) δ 12.23 (s,
1H), 8.61 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.33 (dd, J =
1.9, 0.8 Hz, 1H), 6.29 (dd, J = 3.2, 1.9 Hz, 1H), 6.08 (m, 1H), 3.10 (m,
2H), 3.06 (t, J = 6.2 Hz, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.14 (m,
2H). 13C NMR (126 MHz, CDCl3) δ 203.0, 171.2, 154.1, 144.1, 141.3,
141.3, 138.8, 120.0, 119.7, 117.5, 110.2, 105.4, 40.1, 36.8, 31.4, 23.7,
+
21.7. HRMS (ESI) calcd for C17H17BrNO3 (MH+) 362.0386, found
362.0382.
N-(2-(4-Bromo-2-formylphenylamino)-2-oxoethyl)-N-(furan-2-
ylmethyl)pivalamide (14). General procedure B was followed using 4-
bromo-2-((trimethylsilyl)methyl)aniline (7b′) (2.28 g, 8.32 mmol),
DIPEA (1.65 mL, 9.98 mmol) and bromoacetyl bromide (0.86 mL, 9.9
mmol). The work-up yielded 2-bromo-N-(4-bromo-2-(hydroxy-
methyl)phenyl)acetamide (3.07 g) which was used without further
purification. 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 8.02 (d, J =
8.7 Hz, 1H), 7.50 (dd, J = 8.7, 2.4 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H),
4.75 (s, 2H), 4.06 (s, 2H). To N-(4-bromo-2-(hydroxymethyl)-
phenyl)acetamide (1.20 g) and DIPEA (0.71 mL, 4.1 mmol) in DCM
(30 mL) was added furfuryl amine (0.49 mL, 5.5 mmol). The mixture
was allowed to stir overnight, quenched with water (100 mL), the
organic phase was separated, and the aqueous layer was extracted with
DCM (3 × 100 mL). The combined organic fractions were washed
with brine, dried over Na2SO4, filtered, and the solvent was
concentrated yielding N-(4-bromo-2-(hydroxymethyl)phenyl)-2-
(furan-2-ylmethylamino)acetamide (1.53 g crude) which was used
N-(5-Bromo-2-formylphenyl)-3-(furan-2-yl)propanamide (9).
General procedure A was followed using 2-furanpropanoyl chloride
(0.90 g, 5.7 mmol), 5-bromo-2-((trimethylsilyloxy)methyl)aniline (8′)
(1.11 g, 4.05 mmol) and anhydrous pyridine (0.49 mL, 6.1 mmol).
Upon work-up 1.27 g of N-(5-bromo-2-(hydroxymethyl)phenyl)-3-
(furan-2-yl)propanamide was isolated, which was used without further
purification. 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.31 (d, J =
1.2 Hz, 1H), 7.35 (dd, J = 1.9, 0.9 Hz, 1H), 7.20 (dd, J = 8.1, 2.2 Hz,
1H), 7.02 (d, J = 8.1 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.10 (m,
1H), 4.60 (s, 2H), 3.08 (m, 2H), 2.75 (m, 2H). To N-(5-bromo-2-
(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide (1.27 g, 3.71
mmol) in DCM (90 mL) was added PCC (4.80 g, 22.3 mmol).
The reaction mixture was left stirring for 12 h, filtered through a layer
of silica gel using EtOAc, the solvent was concentrated, and the
mixture was subjected to flash chromatography yielding 0.40 g of 9
(24% over four steps). 1H NMR (500 MHz, CDCl3) δ 11.22 (s, 1H),
9.89 (s, 1H), 9.05 (d, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.2,
1.8 Hz, 1H), 7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.30 (dd, J = 3.2, 1.9 Hz,
1H), 6.10 (m, 1H), 3.11 (m, 2H), 2.84 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 194.6, 171.3, 153.8, 141.4, 141.3, 136.8, 131.9, 126.3, 123.0,
1
without further purification. H NMR (500 MHz, CDCl3) δ 10.07 (s,
1H), 8.02 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 (d, J
= 2.4 Hz, 1H), 7.39 (dd, J = 1.9, 0.8 Hz, 1H), 6.36−6.34 (m, 1H),
6.28−6.27 (m, 1H), 4.66 (s, 2H), 3.88 (s, 2H), 3.47 (s, 2H). To N-(4-
bromo-2-(hydroxymethyl)phenyl)-2-(furan-2-ylmethylamino)-
acetamide (1.08 g) and DIPEA (0.30 mL, 1.8 mmol) in DCM (100
+
120.2, 110.2, 105.6, 36.4, 23.5. HRMS (ESI) calcd for C14H13BrNO3
(MH+) 322.0073, found 322.0080.
G
dx.doi.org/10.1021/jo4026447 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL) was added pivaloyl chloride (0.19 mL, 1.5 mmol). The mixture
was allowed to stir overnight, quenched with water (100 mL), the
organic phase was separated, and the aqueous layer was extracted with
DCM (3 × 100 mL). The combined organic fractions were dried over
Na2SO4, filtered, and the solvent was concentrated. Purification by
flash chromatography yielded 0.40 g of N-(2-((4-bromo-2-
(hydroxymethyl)phenyl)amino)-2-oxoethyl)-N-(furan-2-ylmethyl)-
NMR (500 MHz, CDCl3) δ 12.80 (s, 1H), 8.56 (d, J = 9.1 Hz, 1H),
7.76 (d, J = 9.1 Hz, 1H), 4.04 (s, 2H), 3.08 (t, J = 6.2 Hz, 2H), 2.76
(m, 2H), 2.16 (m, 2H). To 2-bromo-N-(4-bromo-8-oxo-5,6,7,8-
tetrahydronaphthalen-1-yl)acetamide (0.70 g) and DIPEA (0.34 mL,
2.0 mmol) in DCM (40 mL) was added benzyl amine (0.29 mL, 2.7
mmol). The mixture was allowed to stir overnight, quenched with
water (50 mL), the organic phase was separated, and the aqueous layer
was extracted with DCM (3 × 100 mL). The combined organic
fractions were dried over Na2SO4, filtered, and the solvent was
concentrated yielding 2-(benzylamino)-N-(4-bromo-8-oxo-5,6,7,8-tet-
rahydronaphthalen-1-yl)acetamide (0.88 g) 1H NMR (500 MHz,
CDCl3) δ 12.92 (s, 1H), 8.67 (d, J = 9.1, 0.7 Hz, 1H), 7.72 (d, J = 9.1
Hz, 1H), 7.47 (m, 2H), 7.37 (m, 3H), 3.93 (s, 2H), 3.50 (s, 2H), 3.07
(t, J = 6.2 Hz, 2H), 2.75 (m, 2H), 2.15 (m, 2H).To 2-(benzylamino)-
N-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (0.88
g) and DIPEA (0.44 mL, 2.5 mmol) in DCM (45 mL) was added 2-
furoyl chloride (0.27 mL, 2.7 mmol). The mixture was allowed to stir
overnight, quenched with water (50 mL), the organic phase was
separated, and the aqueous layer was extracted with DCM (3 × 100
mL). The combined organic fractions were dried over Na2SO4,
filtered, and the solvent was concentrated. Purification by flash
chromatography yielded 0.32 g of 16 (39% over three steps). 1H NMR
1
pivalamide (29% over three steps). H NMR (500 MHz, CDCl3) δ
9.11 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 8.7, 2.4 Hz, 1H),
7.37 (dd, J = 1.8, 0.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 6.36 (dd, J =
3.2, 1.9 Hz, 1H), 6.32 (m, 1H), 4.79 (s, 2H), 4.60 (d, J = 4.8 Hz, 2H),
4.10 (s, 2H), 3.48 (s, 1H), 1.39 (s, 9H). To a stirred solution of N-(2-
((4-bromo-2-(hydroxymethyl)phenyl)amino)-2-oxoethyl)-N-(furan-2-
ylmethyl)pivalamide (0.35 g, 0.83 mmol) in 40 mL of DCM was
added MnO2 (1.02 g, 11.7 mmol). After stirring for 24 h the solution
was filtered through Celite and the solvent was concentrated yielding
14 (0.28 g, 0.67 mmol, 81%). 1H NMR (500 MHz, CDCl3) δ 11.19 (s,
1H), 9.85 (d, J = 0.7 Hz, 1H), 8.68 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 2.4
Hz, 1H), 7.70 (dd, J = 9.0, 2.4 Hz, 1H), 7.34 (dd, J = 1.8, 0.9 Hz, 1H),
6.33 (dd, J = 3.3, 1.8 Hz, 1H), 6.31 (dd, J = 3.3, 0.9 Hz, 1H), 4.87 (s,
2H), 4.17 (s, 2H), 1.45 (s, 9H).). 13C NMR (126 MHz, CDCl3) δ
193.8, 178.5, 168.7 149.7, 142.8, 139.3, 138.7, 137.9, 123.2, 122.0,
115.3, 110.5, 109.2, 52.2, 46.5, 39.2, 28.6. HRMS (ESI) calcd for
1
(500 MHz, CDCl3) H NMR (500 MHz, CDCl3) δ 12.68 (m, 1H),
+
C19H22BrN2O4 (MH+) 421.0757, found 421.0757.
8.63 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.50 (m, 1H), 7.36
(m, 5H), 7.21 (m, 1H), 6.51 (m, 1H), 5.04 (m, 2H), 4.28 (m, 2H),
3.05 (m, 2H), 2.69 (m, 2H), 2.12 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 202.8, 163.5, 144.6, 144.3, 140.7, 138.8, 136.5, 136.2, 135.0,
129.1, 128.9, 128.9, 128.4, 127.8, 127.8, 120.3, 119.7, 118.1, 111.6,
N-(2-(4-Bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-ylamino)-
2-oxoethyl)-N-(furan-2-ylmethyl)pivalamide (15). General proce-
dure B was followed using 8-amino-5-bromo-3,4-dihydronaphthalen-
1(2H)-one (11) (1.15 g, 4.79 mmol), pyridine (0.77 mL, 9.56 mmol),
bromoacetyl bromide (0.50 mL, 5.7 mmol) The work-up yielded 2-
bromo-N-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-
+
52.2, 46.6, 40.0, 31.4, 21.7. HRMS (ESI) calcd for C24H22BrN2O4
(MH+) 481.0757, found 481.0758.
1
acetamide (1.67 g) which was used without further purification. H
N-(2-Formyl-4-(pyridin-3-yl)phenyl)-3-(furan-2-yl)propanamide
(3b). General procedure for Suzuki coupling D with pyridine boronic
acid using pyridine-3-boronic acid (0.39 g, 3.2 mmol), Pd2(dba)3
(0.035 g, 0.038 mmol), PCy3 (0.027 g, 0.096 mmol), and N-(4-bromo-
2-(hydroxymethyl)phenyl)-3-(furan-2-yl)propanamide (1a) (0.61 g,
1.9 mmol), dioxane (5.0 mL), and aqueous K3PO4 (5.0 mmol, 3.9 mL
of a 1.27 M solution) was followed. The crude 3-(furan-2-yl)-N-(2-
(hydroxymethyl)-4-(pyridin-3-yl)phenyl)propanamide (1b) (0.60 g)
NMR (500 MHz, CDCl3) δ 12.80 (s, 1H), 8.56 (d, J = 9.1 Hz, 1H),
7.76 (d, J = 9.1 Hz, 1H), 4.04 (s, 2H), 3.08 (t, J = 6.2 Hz, 2H), 2.76
(m, 2H), 2.16 (m, 2H). To 2-bromo-N-(4-bromo-8-oxo-5,6,7,8-
tetrahydronaphthalen-1-yl)acetamide (1.67 g) and DIPEA (1.21 mL,
6.95 mmol) in DCM (75 mL) was added furfuryl amine (0.61 mL,
0.67 mmol). The mixture was allowed to stir overnight, quenched with
water (50 mL), the organic phase was separated, and the aqueous layer
was extracted with DCM (3 × 100 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, filtered, and the
solvent was concentrated yielding N-(4-bromo-8-oxo-5,6,7,8-tetrahy-
dronaphthalen-1-yl)-2-(furan-2-ylmethylamino)acetamide (1.60 g)
which was used without further purification 1H NMR (500 MHz,
CDCl3) δ 12.85 (s, 1H), 8.66 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 9.1 Hz,
1H), 7.38 (dd, J = 1.9, 0.9 Hz, 1H), 6.34 (dd, J = 3.2, 1.7 Hz, 1H), 6.29
(dd, J = 3.2, 0.8 Hz, 1H), 3.92 (s, 2H), 3.48 (s, 2H), 3.07 (t, J = 6.2
Hz, 2H), 2.73 (m, 2H), 2.14 (m, 2H). To N-(4-bromo-8-oxo-5,6,7,8-
tetrahydronaphthalen-1-yl)-2-(furan-2-ylmethylamino)acetamide
(1.60 g) and DIPEA (0.96 mL, 5.5 mmol) in DCM (75 mL) was
added pivaloyl chloride (0.68 mL, 5.5 mmol). The mixture was
allowed to stir overnight, quenched with water (75 mL), the organic
phase was separated, and the aqueous layer was extracted with DCM
(3 × 100 mL). The combined organic fractions were dried over
Na2SO4, filtered, and the solvent was concentrated. Purification by
flash chromatography yielded 0.43 g of 15 (19% over three steps). 1H
NMR (500 MHz, CDCl3) δ 12.35 (s, 1H), 8.57 (d, J = 9.1 Hz, 1H),
7.71 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 1.8, 0.9 Hz, 1H), 6.34 (dd, J =
3.2, 1.8 Hz, 1H), 6.29 (dd, J = 3.3, 0.9 Hz, 1H), 4.85 (s, 2H), 4.18 (s,
2H), 3.05 (t, J = 6.2 Hz, 2H), 2.70 (m, 2H), 2.12 (m, 2H), 1.42 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 202.6, 178.2, 168.5, 150.1, 144.1,
142.6, 140.8, 138.7, 120.2, 119.9, 117.9, 110.4, 109.0, 52.0, 46.2, 40.0,
1
was used without further purification H NMR (500 MHz, CDCl3) δ
8.81 (s, 1H), 8.63 (s, 1H), 8.56 (dd, J = 4.8, 1.1 Hz, 1H), 8.25 (d, J =
8.4 Hz, 1H), 7.84 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 2.2
Hz, 1H), 7.37 (m, 3H), 6.33 (dd, J = 3.2, 1.9 Hz, 1H), 6.13 (dd, J =
3.1, 0.6 Hz, 1H), 4.75 (s, 2H), 3.14 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5
Hz, 2H), 1.41 (s, 1H) To a stirred solution of 3-(furan-2-yl)-N-(2-
(hydroxymethyl)-4-(pyridin-3-yl)phenyl)propanamide (0.60 g, 1.9
mmol) in DCM (45 mL) was added MnO2 (2.28 g, 26.2 mmol).
After 24 h, the solution was filtered through Celite, concentrated, and
purified by flash chromatography yielding 0.31 g of 3b (51% over two
1
steps). H NMR (500 MHz, CDCl3) δ 11.22 (s, 1H), 10.05 (s, 1H),
8.92 (d, J = 8.7 Hz, 1H), 8.90 (dd, J = 2.4, 0.9 Hz, 1H), 8.66 (dd, J =
4.8, 1.6 Hz, 1H), 7.91 (m, 2H), 7.86 (dd, J = 8.7, 2.3 Hz, 1H), 7.43
(ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.35 (dd, J = 1.9, 0.9 Hz, 1H), 6.31 (dd,
J = 3.2, 1.9 Hz, 1H), 6.11 (m, 1H), 3.14 (m, 2H), 2.88 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 195.3, 171.3, 153.9, 149.0, 147.9, 141.3,
140.6, 134.6, 134.5, 134.2, 133.9, 132.6, 123.7, 122.0, 120.8, 110.2,
+
105.6, 36.6, 23.6. HRMS (ESI) calcd for C19H17N2O3 (MH+)
321.1234, found 321.1241.
General Procedures for the Irradiation and Subsequent
Coupling of Bromo-Substituted Aromatic Compounds with
Pyridine-3-boronic. AcidGeneral Procedure for Irradiation (C).
Solutions with ca. 6 mM of the photoprecursors 3a, 3d, 9−11, 14−16
in 5% aq. acetonitrile were degassed and irradiated in Pyrex or
borosilicate glass reaction vessels in a Rayonet reactor equipped with
RPR-3500 UV lamps (broadband 300−400 nm UV source with peak
emission at 350 nm) until the reaction was complete, as determined by
1H NMR. The solution was concentrated and the cycloaddition
+
39.2, 31.4, 28.6, 21.7. HRMS (ESI) calcd for C22H26BrN2O4 (MH+)
461.1070, found 461.1073.
N-Benzyl-N-(2-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-
ylamino)-2-oxoethyl)furan-2-carboxamide (16). General procedure
B was followed using 8-amino-5-bromo-3,4-dihydronaphthalen-
1(2H)-one (11) (0.42 g, 1.7 mmol), DIPEA (0.36 mL, 2.1 mmol)
and bromoacetyl bromide (0.18 mL, 2.1 mmol). The work-up yielded
2-bromo-N-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-
products were used without further purification.
General Procedure for Suzuki Coupling with Pyridine-3-boronic
acid (D). Aqueous K3PO4 (1.70 mmol, 1.33 mL of a 1.27 M solution),
degassed for 30 min prior to the addition, was added to the reaction
1
acetamide (0.70 g) which was used without further purification. H
H
dx.doi.org/10.1021/jo4026447 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mixture containing pyridine-3-boronic acid (1.1 mmol), Pd2(dba)3
(0.01 mmol, 0.9 mol %), PCy3 (0.024 mmol, 2.2 mol %), and the
heteroaryl bromide (1.0 mmol) in dioxane (2.67 mL) under nitrogen
atmosphere. The mixture was refluxed for 36 h with vigorous stirring.
Then it was cooled to room temperature, filtered through a layer of
silica gel (washed with EtOAc), concentrated, diluted with water (40
mL) and extracted with EtOAc (3 × 75 mL). The combined organic
fractions were dried over Na2SO4, filtered, concentrated, and the
product(s) were purified using flash chromatography.
General Procedure for Suzuki Coupling with Phenylboronic Acid
(E). The heteroaryl halide (0.94 mmol), Pd(PPh3)4 (5.3 mol %, 0.050
mmol), were suspended in dimethoxyethane (4 mL) the mixture was
allowed to stir under nitrogen atmosphere for ∼10 min. Phenylboronic
acid (1.1 mmol) followed by aq. Na2CO3 (1.06 mL, 2 M solution, 2.12
mmol) were added to the mixture, and the resulting solution was
refluxed under nitrogen atmosphere for 24 h. The mixture was allowed
to cool to room temperature, extracted with Et2O (6 × 40 mL), and
the combined organic fractions were washed with water, dried over
Na2SO4, concentrated, and subjected to flash chromatography.
General Procedure for Suzuki Coupling with Thiophene-2-
boronic and Furan-2-boronic Acids (F). To a stirred mixture of the
heteroaryl iodide (0.20 g, 0.54 mmol) and Pd(PPh3)4 (5.2−5.8 mol %,
0.032 g, 0.028 mmol) in DME (16 mL) was added thiophene-2- or
furan-2-boronic acid (0.077 g, 0.60 mmol). The mixture was placed
under nitrogen atmosphere, and NaHCO3 (0.095 g, 1.1 mmol) in
H2O (16 mL) was added. The reaction mixture was heated under
reflux with vigorous stirring for 12 h. Subsequently, the organic solvent
was removed under reduced pressure, an extraction was performed on
the remaining aqueous layer using EtOAc (5 × 25 mL), the organic
layer was dried using MgSO4, filtered, concentrated, and subjected to
flash chromatography
(3a) a mixture of 5-bromo-8-hydroxy-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-16-one (4a) and 5-bromo-
2-hydroxy-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tet-
raen-10-one (5a)in the ratio of 1:1 was formed., which was introduced
into the Suzuki coupling following the general procedure D. From 0.34
g of that mixture, pyridine-3-boronic acid (0.23 g, 1.9 mmol),
Pd2(dba)3 (0.021 g, 0.023 mmol), PCy3 (0.016 g, 0.057 mmol),
dioxane (3.1 mL), and aqueous K3PO4 (2.86 mmol, 2.3 mL of a 1.27
M solution) after chromatographic separation 0.024 g (6.8%) of 4b
and 0.10 g (28%) of 5b was obtained.
1
4b: H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 2.4 Hz, 1H), 8.56
(dd, J = 4.8, 1.6 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.83 (ddd, J = 8.0,
2.4, 1.6 Hz, 1H), 7.57 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz,
1H), 7.36 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 6.29 (t, J = 2.8 Hz, 1H), 4.88
(d, J = 2.2 Hz, 1H), 4.71 (dd, J = 3.1, 2.3 Hz, 1H), 3.93 (q, J = 2.3 Hz,
1H), 2.90 (ddd, J = 16.1, 10.3, 8.2 Hz, 1H), 2.56 (m, 3H), 1.64 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 173.3, 148.4, 148.0, 146.8, 135.7,
135.1,134.4, 134.2, 131.8, 128.2, 127.4, 123.8, 123.6, 101.4, 99.4, 70.3,
56.1, 35.2, 29.8 HRMS (ESI) calcd for C19H17N2O3+ (MH+) 321.1234,
found 321.1241.
1
5b: H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 2.1 Hz, 1H), 8.61
(dd, J = 4.8, 1.6 Hz, 1H), 7.88 (dt, J = 8.0, 1.9 Hz, 1H), 7.65 (d, J = 8.3
Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.39
(ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 6.38 (dd, J = 5.8, 1.8 Hz, 1H), 5.71 (dd,
J = 5.8, 1.2 Hz, 1H), 5.10 (m, 1H), 4.76 (d, J = 3.3 Hz, 1H), 2.91 (dt, J
= 17.2, 9.7 Hz, 1H), 2.67 (ddd, J = 17.2, 9.8, 1.8, 1H), 2.58 (dt, J =
13.8, 9.8, 1H), 2.50 (ddd, J = 13.8, 9.5, 1.8, 1H). 13C NMR (126 MHz,
CDCl3) δ 173.3, 148.7, 148.1, 136.0, 135.4, 134.8, 134.2, 133.9, 132.5,
131.2, 129.3, 128.4, 127.2, 123.6, 103.6, 83.6, 79.4, 30.0, 28.9. HRMS
+
(ESI) calcd for C19H17N2O3 (MH+) 321.1234, found 321.1241.
8-Hydroxy-6-(pyridin-3-yl)-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetra-en-16-one (17b) and 2-
Hydroxy-6-(pyridin-3-yl)-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]-
hexa-deca-3,5,7,14-tetraen-10-one (18b). General procedure C was
followed. From 0.25 g (0.78 mmol) of N-(5-bromo-2-formylphenyl)-
3-(furan-2-yl)propanamide (9) a mixture of 6-bromo-8-hydroxy-12-
oxa-1-azatetracyclo[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-16-one
(17a) and 6-bromo-2-hydroxy-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]-
hexadeca-3,5,7,14-tetraen-10-one (18a) in the ratio of 1:0.8 was
formed, which was introduced into the Suzuki coupling following the
general procedure general procedure D . From 0.25 g of that mixture,
pyridine-3-boronic acid (0.14 g, 1.1 mmol), Pd2(dba)3 (0.014 g, 0.015
mmol), PCy3 (0.012 g, 0.043 mmol), dioxane (2.25 mL), and aqueous
K3PO4 (0.73 mmol, 0.97 mL of a 1.27 M solution) after
chromatographic separation 0.072 g (28%) of 17b and 0.059 g
(23%) of 18b was isolated.
8-Hydroxy-5-phenyl-12-oxa-1-azatetracyclo[11.3.0.02,7.09,13]-
hexadeca-2,4,6,10-tetraen-16-one (4f) and 2-Hydroxy-5-phenyl-16-
oxa-9-azatetracyclo[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tetraen-10-
one (5f). General procedure C was followed. From N-(4-bromo-2-
formylphenyl)-3-(furan-2-yl)propanamide (3a) (1.0 g, 3.1 mmol) a
mixture of 5-bromo-8-hydroxy-12-oxa-1-azatetracyclo[11.3.0.02,7.09,13]-
hexadeca-2,4,6,10-tetraen-16-one (4a) and 5-bromo-2-hydroxy-16-oxa-
9-azatetracyclo[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tetraen-10-one (5a)
in the ratio of 1:1 was formed, which was introduced into Suzuki
coupling following the general procedure E. From 0.3 g of that mixture
(0.94 mmol), phenylboronic acid (0.13 g, 1.1 mmol), Pd(PPh3)4
(0.058 g, 0.05 mmol) Na2CO3 (1.06 mL of a 2 M solution, 2.12
mmol) after chromatographic separation 0.089 g (30%) of 4f and 0.13
g (44%) of 5f were isolated.
(4f): 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.64
(dd, J = 8.3, 2.1 Hz, 1H), 7.59 (m, 2H), 7.46 (m, 3H), 7.38 (m, 1H),
6.27 (t, J = 2.8 Hz, 1H), 4.84 (d, J = 2.1 Hz, 1H), 4.70 (dd, J = 3.1, 2.2
Hz, 1H), 3.89 (q, J = 2.3 Hz, 1H), 2.86 (m, 1H), 2.59 (m, 1H), 2.47
(m, 2H), 2.19(s, 1H). 13C NMR (126 MHz, CDCl3) δ 173.4, 146.7,
140.1, 138.8, 133.3, 131.3, 128.9, 128.2, 127.5, 127.4, 126.9, 123.5,
17b: 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz, 1H), 8.41
(s, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.89 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H),
7.33 (m, 2H), 6.28 (t, J = 2.8 Hz, 1H), 4.86 (d, J = 2.2 Hz, 1H), 4.71
(dd, J = 3.0, 2.2 Hz, 1H), 3.93 (q, J = 2.4 Hz, 1H), 2.88 (m, 1H), 2.56
(m, 4H), 1.64 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 173.3, 148.3,
148.0, 146.7, 139.1, 135.0, 134.7, 131.0, 129.5, 124.3, 123.6, 121.9,
+
101.4, 99.4, 70.5, 56.1, 35.2, 29.8. HRMS (ESI) calcd for C20H18NO3
(MH+) 320.1281, found 320.1281.
+
1
101.5, 99.5, 69.8, 56.2, 35.2, 29.9. HRMS (ESI) calcd for C19H17N2O3
(5f): H NMR (500 MHz, CDCl3) δ 7.60 (m, 4H), 7.54 (m, 1H),
(MH+) 321.1234, found 321.1237.
7.45 (m, 2H), 7.38 (m, 1H), 6.36 (dd, J = 5.9, 1.9 Hz, 1H), 5.70 (dd, J
= 5.8, 1.1 Hz, 1H), 5.09 (m, 1H), 4.75 (d, J = 7.0 Hz, 1H), 3.15 (s,
1H), 2.89 (m, 1H), 2.65 (m, 1H), 2.57 (dt, J = 13.8, 9.8, 1H), 2.48
(ddd, J = 13.9, 9.5, 1.7, 1H) . 13C NMR (126 MHz, CDCl3) δ 173.2,
139.9, 139.5, 134.8, 133.5, 131.6, 131.2, 129.3, 128.8, 128.0, 127.5,
127.2, 127.0, 103.6, 83.7, 79.5, 30.0, 28.9. HRMS (ESI) calcd for
1
18b: H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 8.61 (s, 1H),
7.91 (dt, J = 8.0, 2.0 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.43 (m, 2H),
7.38 (t, J = 7.5, 4.8 Hz, 1H), 6.37 (dd, J = 5.9, 1.9 Hz, 1H), 5.71 (dd, J
= 5.9, 1.2 Hz, 1H), 5.08 (m, 1H), 4.73 (s, 1H), 3.17 (s, 1H), 2.94 (m,
1H), 2.68 (ddd, J = 17.3, 9.8, 1.8 Hz, 1H), 2.58 (dt, J = 13.9, 9.8, 1H),
2.50 (ddd, J = 13.9, 9.5, 1.8, 1H). 13C NMR (126 MHz, CDCl3) δ
173.1, 148.8, 148.2, 138.2, 134.8, 134.5, 133.4, 133.2, 132.8, 129.3,
126.4, 125.1, 123.6, 103.7, 83.6, 79.0, 30.1, 28.9. HRMS (ESI) calcd for
+
C20H18NO3 (MH+) 320.1281, found 320.1283.
8-Hydroxy-5-pyridin-3-yl-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetra-en-16-one (4b) and 2-
Hydroxy-5-pyridin-2-yl-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]-
hexadeca-3,5,7,14-tetraen-10-one (5b). Pathway A. General proce-
dure C was followed. From 0.25 g (0.78 mmol) of N-(2-formyl-4-
(pyridin-3-yl)phenyl)-3-(furan-2-yl)propanamide (3b) after chromato-
graphic separation 0.12 g (47%) of 4b and 0.10 g (40%) of 5b was
obtained.
+
C19H17N2O3 (MH+) 321.1234, found 321.1240.
8-Hydroxy-8-methyl-5-(pyridin-3-yl)-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-16-one (19b) and 2-
Hydroxy-2-methyl-5-(pyridin-3-yl)-16-oxa-9-azatetracyclo
[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tetraen-10-one (20b). General
procedure C was followed. From 0.50 g (1.5 mmol) of N-(2-acetyl-
4-bromophenyl)-3-(furan-2-yl)propanamide (10) a mixture of 5-
bromo-8-hydroxy-8-methyl-12-oxa-1-azatetracyclo[11.3.0.02,7.09,13]-
Pathway B. General procedure C was followed. From 0.34 g (1.1
mmol) of N-(4-bromo-2-formylphenyl)-3-(furan-2-yl)propanamide
I
dx.doi.org/10.1021/jo4026447 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
hexa-deca-2,4,6,10-tetraen-16-one (19a) and 5-bromo-2-hydroxy-2-
methyl-16-oxa-9-azatetracyclo [11.2.1.03,8.05,9]hexadeca-3,5,7,14-tet-
raen-10-one (20a) in the ratio of 1:1 was formed, which was
introduced into the Suzuki coupling following the general procedure
D. From 0.25 g of that mixture, pyridine-3-boronic acid (0.14 g, 1.1
mmol), Pd2(dba)3 (0.014 g, 0.015 mmol), PCy3 (0.012 g, 0.043
mmol), dioxane (2.25 mL), and aqueous K3PO4 (0.73 mmol, 0.97 mL
of a 1.27 M solution) 0.071 g (28%) of 19b and 0.072 g (30%) of 20b
was obtained.
ylmethyl)pivalamide (14) a mixture of 5-bromo-8-hydroxy-15-
pivaloyl-12-oxa-1,15-diazatetracyclo[11.3.0.02,7.09,13]heptadeca-
2,4,6,10-tetraen-17-one (23a) and 5-bromo-2-hydroxy-12-pivaloyl-17-
oxa-9,12-diazatetracyclo[11.2.1.03,8.05,9]heptadeca-3,5,7,15-tetraen-10-
one (24a) in the ratio of 1:1.4 was formed, which was introduced into
the Suzuki coupling following the general procedure D. From 0.26 g of
that mixture, pyridine-3-boronic acid (0.086 g, 0.70 mmol), Pd2(dba)3
(0.0063 g, 0.0069 mmol), PCy3 (0.0046 g, 0.016 mmol), dioxane (2.0
mL), and aqueous K3PO4 (1.1 mmol, 0.84 mL of a 1.27 M solution)
after chromatographic separation 0.050 g, (19%) of 23b and 0.030 g
(12%) of 24b was obtained.
19b:1H NMR (500 MHz, CDCl3) δ 8.43 (dd, J = 4.8, 1.7 Hz, 1H),
8.22 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.73 (ddd, J = 7.9,
2.4, 1.6 Hz, 1H), 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.38 (d, J = 2.1 Hz,
1H), 7.28 (dd, J = 7.8, 4.8 Hz, 1H), 6.25 (t, J = 2.8 Hz, 1H), 4.65 (dd,
J = 3.1, 2.2 Hz, 1H), 4.18 (s, 1H), 3.74 (t, J = 2.4 Hz, 1H), 2.85 (m,
1H), 2.52 (m, 3H), 1.79 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
173.3, 147.9, 147.8, 146.9, 136.1, 134.9, 134.5, 134.3, 134.3, 127.4,
124.1, 123.7, 123.5, 101.6, 99.1, 70.5, 61.3, 35.1, 29.8, 25.4. HRMS
23b: 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 4.3 Hz, 1H), 8.44
(s, 1H), 7.81 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H),
7.54 (dd, J = 8.3, 2.2 Hz, 1H), 7.34 (t, J = 7.8, 4.9 Hz, 1H), 7.32 (d, J =
2.2 Hz, 1H), 6.22 (t, J = 2.7 Hz, 1H), 5.09 (d, J = 18.7 Hz, 1H), 4.76
(dd, J = 3.1, 2.3 Hz, 1H), 4.75 (d, J = 2.2 Hz, 1H), 4.67 (dd, J = 13.9,
1.9 Hz, 1H), 4.14 (d, J = 18.7 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 3.70
(q, J = 2.3 Hz, 1H), 1.66 (s, 1H),1.36 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 176.5, 164.9, 148.4, 147.9, 146.9, 135.9, 135.5, 134.6, 134.3,
133.9, 127.9, 127.8, 127.2, 123.6, 99.8, 94.9, 68.9, 55.1, 51.7, 50.2, 38.9,
+
(ESI) calcd for C20H19N2O3 (MH+) 335.1390, found 335.1396.
1
20b: H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 8.63 (s, 1H),
7.87 (dt, J = 8.1, 1.8 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.56 (m, 2H),
7.40 (dd, J = 8.0, 4.7 Hz, 1H), 6.37 (dd, J = 5.9, 1.9 Hz, 1H), 5.72 (dd,
J = 5.8, 1.1 Hz, 1H), 4.78 (t, J = 1.4 Hz, 1H), 3.57 (s, 1H), 2.95 (dt, J =
17.4, 9.8 Hz, 1H), 2.69 (ddd, J = 17.4, 9.7, 1.8 Hz, 1H), 2.57 (dt, J =
13.9, 9.9, 1H), 2.49 (ddd, J = 13.9, 9.5, 1.8, 1H), 1.80 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 173.0, 148.6, 148.2, 137.1, 136.0, 136.0,
134.8, 134.3, 132.6, 129.3, 129.0, 126.9, 126.4, 123.6, 103.4, 89.2, 78.0,
+
28.3. HRMS (ESI) calcd for C24H26N3O4 (MH+) 420.1918, found
420.1921.
1
24b: H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 8.61 (s, 1H),
7.86 (ddd, J = 8.0, 2.4, 1.5 Hz, 1H), 7.52 (dd, J = 8.3, 2.2 Hz, 1H), 7.43
(d, J = 2.2 Hz, 1H), 7.38 (m, 2H), 6.31 (dd, J = 6.0, 1.8 Hz, 1H), 5.75
(dd, J = 5.9, 1.0 Hz, 1H), 5.16 (m, 1H), 4.92 (dd, J = 18.2, 1.6 Hz,
1H), 4.76 (d, J = 3.6 Hz, 1H), 4.68 (dd, J = 14.0, 1.6 Hz, 1H), 4.26 (d,
J = 18.4 Hz, 1H), 3.96 (d, J = 14.0 Hz, 1H), 3.42 (s, 1H), 1.37 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 176.8, 166.1, 148.8, 148.1, 137.3,
136.3, 135.7, 135.2, 134.3, 134.1, 131.1, 130.3, 128.0, 126.9, 123.6,
96.9, 83.9, 79.1, 49.9, 49.7, 38.9, 28.3. HRMS (ESI) calcd for
+
30.2, 28.5, 24.7. HRMS (ESI) calcd for C20H19N2O3 (MH+)
335.1390, found 335.1398.
11-Hydroxy-16-(pyridine-3-yl)-7-oxa-2-azapentacyclo-
[9.7.1.02,6.06,10.015,19]nonadeca-1(19),8,15(16),17-tetraen-3-one
(21b) and 10-Hydroxy-15-(pyridine-3-yl)-9-oxa-2-azapentacyclo
[8.7.1.16,9.02,6.014,18] nonadeca-1(18),7,14(15),16(17)tetraen-3-one
(22b). General procedure C was followed. From 0.36 g (0.99
mmol) of N-(4-bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)-3-
(furan-2-yl)propanamide (11) a mixture of 11-hydroxy-16-bromo-7-
oxa-2-azapentacyclo[9.7.1.02,6.06,10.015,19]nonadeca-1(19),8,15(16),17-
tetraen-3-one (21a) and 10-hydroxy-15-bromo-9-oxa-2-azapentacyclo-
[8.7.1.16,9.02,6.014,18]nonadeca-(18),7,14(15),16(17) tetraen-3-one
(22a) in the ratio of 1:1.9 was formed, which was introduced into
Suzuki coupling following the general procedure D. From 0.36 g of
that mixture, pyridine-3-boronic acid (0.14 g, 1.1 mmol), Pd2(dba)3
(0.011 g, 0.012 mmol), PCy3 (0.078 g, 0.028 mmol), dioxane (3.1
mL), and aqueous K3PO4 (1.70 mmol, 1.34 mL of a 1.27 M solution)
after chromatographic separation 0.13 g (36%) 21b and 0.057 g (16%)
22b was obtained.
+
C24H26N3O4 (MH+) 420.1918, found 420.1920.
10-Hydroxy-5-pivaloyl-16-(pyridine-3-yl)-20-oxa-2,5-
diazapentacyclo[9.7.1.17,10.02,7.015,19]icosa-1(19),8,15(16),17(18)-
tetraene-3,5-dione (26b). General procedure C was followed. From
0.43 g (0.93 mmol) of N-(2-(4-bromo-8-oxo-5,6,7,8-tetrahydronaph-
thalen-1-ylamino)-2-oxoethyl)-N-(furan-2-ylmethyl)pivalamide (15) a
mixture of 12-hydroxy-17-bromo-6-pivaloyl-8-oxa-2,5-diazapentacyclo-
[10.7.1.02,7.07,11.016,20]icosa-1(20),9,16(17),18-tetraen-3,6-dione (25a)
and 10-hydroxy-5-pivaloyl-16-bromo-20-oxa-2,5-diazapentacyclo-
[9.7.1.17,10.02,7.015,19]icosa-1(19),8, 15(16),17(18)tetraen-3,5-dione
(26a) in the ratio of 1:1.5 was formed, which was introduced into
the Suzuki coupling following the general procedure D. From 0.43 g
(0.93 mmol) of that mixture, using pyridine-3-boronic acid (0.21 g, 1.7
mmol), Pd2(dba)3 (0.020 g, 0.022 mmol), PCy3 (0.015 g, 0.053
mmol), dioxane (3 mL), and aqueous K3PO4 (2.7 mmol, 2.1 mL of a
1.27 M solution) after chromatographic separation 0.086 g, (20%) of
21b: 1H NMR (500 MHz, CDCl3) δ 8.52 (dd, J = 4.8, 1.6 Hz, 1H),
8.04 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.62 (ddd, J = 7.8, 2.3, 1.6 Hz,
1H), 7.32 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.33
(t, J = 2.8 Hz, 1H), 4.76 (dd, J = 3.2, 2.2 Hz, 1H), 3.78 (t, J = 2.4 Hz,
1H), 2.90 (m, 1H), 2.58 (m, 6H), 2.05 (m, 1H), 1.92 (td, J = 13.0, 3.4
Hz, 1H), 1.84 (m, 1H), 1.67 (s, 1H). 13C NMR (126 MHz, CDCl3) δ
173.4, 149.6, 147.9, 146.8, 136.7, 136.6, 135.7, 135.1, 134.2, 130.0,
129.6, 122.9, 121.5, 101.5, 99.4, 69.5, 60.0, 41.0, 35.2, 29.8, 28.7, 18.4.
1
26b was obtained. 26b: H NMR (500 MHz, CDCl3) δ 8.62 (d, J =
3.8 Hz, 1H), 8.54 (s, 1H), 7.62 (dt, J = 7.9, 1.9 Hz, 1H), 7.37 (dd, J =
7.8, 4.8 Hz, 1H), 7.09 (m, 2H), 6.36 (dd, J = 5.9, 1.8 Hz, 1H), 5.80
(dd, J = 5.9, 0.9 Hz, 1H), 4.97 (d, J = 18.5 Hz, 1H), 4.73 (m, 2H), 4.30
(d, J = 18.3 Hz, 1H), 3.93 (d, J = 13.9 Hz, 1H), 3.48 (s, 1H), 2.59 (m,
1H), 2.47 (ddd, J = 17.4, 12.6, 5.5 Hz, 1H), 2.10 (m, 1H), 1.96 (m,
1H), 1.76 (m, 1H), 1.60 (dt, J = 13.5, 2.9 Hz, 1H), 1.39 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 176.8, 166.2, 149.8, 148.4, 138.4, 137.1,
136.9, 136.5, 136.2, 135.6, 135.2, 129.2, 128.6, 128.2, 123.2, 96.3, 88.4,
75.3, 49.9, 49.1, 38.9, 36.2, 30.4, 28.3, 17.8. HRMS (ESI) calcd for
+
HRMS (ESI) calcd for C22H21N2O3 (MH+) 361.1547, found
361.1550.
1
22b: H NMR (500 MHz, CDCl3) δ 8.61 (dd, J = 4.9, 1.7, 1H),
8.55 (dd, J = 2.3, 0.9, 1H), 7.61 (dt, J = 7.8, 2.0, 1H), 7.36 (ddd, J =
7.8, 4.9, 0.9, 1H), 7.28 (m, 1H), 7.15 (d, J = 8.1, 1H), 6.43 (dd, J = 5.8,
1.9, 1H), 5.76 (dd, J = 5.9, 1.1, 1H), 4.62 (m, 1H), 3.51 (s, 1H), 3.03
(ddd, J = 17.4, 10.3, 9.2, 1H), 2.71 (ddd, J = 17.5, 9.6, 1.7, 1H), 2.56
(m, 4H), 2.09 (m, 1H), 1.99 (m, 1H), 1.77 (m, 1H), 1.69 (td, J = 13.5,
3.1, 1H). 13C NMR (126 MHz, CDCl3) δ 173.1, 149.9, 148.3, 137.5,
137.3, 136.5, 136.2, 135.3, 133.8, 129.6, 129.3, 126.4, 123.1, 103.2,
88.0, 75.4, 35.8, 30.4, 30.3, 29.7, 28.6, 17.8. HRMS (ESI) calcd for
+
C27H30N3O4 (MH+) 460.2231, found 460.2234.
10-Hydroxy-5-benzyl-16-(pyridin-3-yl)-20-oxa-2,5-
diazapentacyclo[9.7.1.17,10.02,7.015,19]icosa-1(19),8,15(16),17(18)-
tetraene-3,5-dione (28b). General procedure C was followed. From
0.81 g (1.7 mmol) of N-benzyl-N-(2-(4-bromo-8-oxo-5,6,7,8-tetrahy-
dronaphthalen-1-yl- amino)-2-oxoethyl)furan-2-carboxamide (16) a
mixture of 12-hydroxy-17-bromo-6-benzyl-8-oxa-2,5-diazapentacyclo
[10.7.1.02,7.07,11.016,20]icosa-1(20),9,16(17),18-tetraen-3,6-dione (27a)
and 10-hydroxy-5-benzyl-16-bromo-20-oxa-2,5-diazapentacyclo-
[9.7.1.17,10.02,7.015,19]icosa-1(19),8,15(16),17(18)tetraen-3,5-dione
(28a) in the ratio of 1:16 was formed, which was then introduced into
the Suzuki coupling following the general procedure D From 0.20 g of
that mixture, pyridine-3-boronic acid (0.081 g, 0.66 mmol), Pd2(dba)3
+
C22H21N2O3 (MH+) 361.1547, found 361.1553.
8-Hydroxy-5-pyridin-3-yl-15-pivaloyl-12-oxa-1,15-
diazatetracyclo[11.3.0.02,7.09,13]heptadeca-2,4,6,10-tetraen-17-one
(23b) and 2-Hydroxy-12-pivaloyl-5-(pyridin-3-yl)-17-oxa-9,12-
diazatetracyclo[11.2.1.03,8.05,9]heptadeca-3,5,7,15-tetraen-10-one
(24b). General procedure C was followed. From 0.26 g (0.62 mmol)
of N-(2-(4-bromo-2-formylphenylamino)-2-oxoethyl)-N-(furan-2-
J
dx.doi.org/10.1021/jo4026447 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(0.0090 g, 0.022 mmol), PCy3 (0.0066 g, 0.024 mmol), dioxane (1.2
mL), and aqueous K3PO4 (0.42 mmol, 0.56 mL of a 1.27 M solution)
upon chromatographic separation 0.072 g, (36%) of 28b was obtained.
5g: H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 1H), 7.70
(dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 1.8,
0.7 Hz, 1H), 6.66 (dd, J = 3.3, 0.8 Hz, 1H), 6.50 (dd, J = 3.4, 1.8 Hz,
1H), 6.26 (t, J = 2.8 Hz, 1H), 4.83 (d, J = 2.2 Hz, 1H), 4.68 (dd, J =
3.0, 2.2 Hz, 1H), 3.88 (m, 1H), 2.87 (ddd, J = 16.3, 10.4, 8.2 Hz, 1H),
2.52 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 173.2, 153.1, 146.7,
142.2, 133.2, 131.2, 128.5, 125.0, 124.0, 123.5, 111.8, 105.2, 101.4,
1
28b: H NMR (500 MHz, CDCl3) δ 8.62 (dd, J = 5.0, 1.7 Hz, 1H),
8.51 (m, 1H), 7.62 (dt, J = 7.8, 2.0 Hz, 1H), 7.40 (m, 6H), 7.13 (d, J =
8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.40 (dd, J = 6.0, 1.8 Hz, 1H),
6.10 (d, J = 5.9 Hz, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.87 (m, 1H), 4.57
(d, J = 14.5 Hz, 1H), 4.40 (d, J = 18.2 Hz, 1H), 4.11 (d, J = 18.2 Hz,
1H), 3.16 (s, 1H), 2.59 (m, 1H), 2.47 (ddd, J = 17.5, 12.6, 5.4 Hz,
1H), 2.11 (m, 1H), 1.96 (qdd, J = 13.2, 4.9, 2.5 Hz, 1H), 1.79 (m,
1H), 1.64 (td, J = 13.4, 3.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
167.1, 162.5, 149.8, 148.6, 139.2, 136.9, 136.8, 136.4, 136.1, 135.8,
135.7, 134.6, 129.8, 129.1, 128.5, 128.5, 128.5, 128.4, 123.1, 96.5, 89.6,
+
99.3, 70.4, 55.9, 35.1, 29.8. HRMS (ESI) calcd for C18H16NO4
(MH+) 310.1074, found 310.1081.
1
29: H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 8.7 Hz, 1H), 7.63
(dd, J = 8.6, 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 1.9,
0.8 Hz, 1H), 6.64 (dd, J = 3.4, 0.8 Hz, 1H), 6.50 (dd, J = 3.4, 1.8 Hz,
1H), 6.11 (ddd, J = 9.7, 5.3, 1.2 Hz, 1H), 5.86 (m, 1H), 5.23 (s, 1H),
4.03 (d, J = 5.2 Hz, 1H), 2.74 (m, 2H), 2.40 (m, 2H), 2.28 (s, 1H).
13C NMR (126 MHz, CDCl3) δ 170.9, 153.1, 142.2, 131.6, 129.5,
127.1, 127.0, 124.1, 123.5, 120.6, 120.2, 111.8, 105.0, 86.1, 78.1, 66.8,
+
75.8, 49.9, 49.8, 36.3, 30.2, 17.7. HRMS (ESI) calcd for C29H26N3O4
(MH+) 480.1918, found 480.1927.
8-Hydroxy-5-(thiophen-2-yl)-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-12-one (4h) and 2-Hy-
droxy-5-(thiophen-2-yl)-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]-
hexadeca-3,5,7,14-tetraen-10-one (5h). General procedure C was
followed. From (0.42 g, 1.1 mmol) of N-(2-Formyl-4-iodophenyl)-3-
(furan-2-yl)propanamide (3d) a mixture of 8-hydroxy-5-iodo-2-yl-12-
oxa-1-azatetracyclo[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-12-one
(4d) and 2-hydroxy-5-iodo-16-oxa-9-azatetracyclo[11.2.1.03,8.05,9]-
hexadeca-3,5,7,14-tetraen-10-one (5d) in the ratio 1:1 was formed,
which was introduced into the Suzuki coupling following the general
procedure F. From 0.20 g (0.54 mmol) of that mixture, Pd(PPh3)4
(0.032 g, 0.028 mmol), thiophene-2-boronic acid (0.077 g, 0.60
mmol), NaHCO3 (0.095 g, 1.1 mmol) in H2O (16 mL) upon
chromatographic separion 0.030 g (17%) of 4h and 0.044 g (26%) of
5h
30.3, 29.9. HRMS (ESI) calcd for C18H15LiNO4 (MLi+) 316.1156,
+
found 316.1164.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and XRay data. This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.G.K.: akutatel@du.edu.
Notes
■
4h:1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.3 Hz, 1H), 7.66
(dd, J = 8.3, 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.31 (s, 1H), 7.30
(m, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 6.28 (t, J = 2.8 Hz, 1H), 4.83
(t, J = 2.5 Hz, 1H), 4.70 (dd, J = 3.1, 2.2 Hz, 1H), 3.89 (q, J = 2.3 Hz,
1H), 2.88 (ddd, J = 16.6, 10.6, 8.2 Hz, 1H), 2.60 (m, 1H), 2.54 (dd, J
= 16.5, 8.9 Hz, 1H), 2.45 (ddd, J = 12.7, 10.6, 8.9 Hz, 1H), 1.90 (m,
1H). 13C NMR (126 MHz, CDCl3) δ 173.2, 146.7, 143.3, 133.4, 132.0,
131.3, 128.1, 127.0, 126.2, 125.0, 123.6, 123.3, 101.3, 99.3, 70.4, 55.9,
35.1, 29.8. HRMS (ESI) calcd for C18H15LiNO3S+ (MLi+) 332.0927,
found 332.0935.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this research by the NSF (CHE-1057800) is
gratefully acknowledged
REFERENCES
■
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5h: H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 8.4, 2.2 Hz, 1H),
7.55 (m, 2H), 7.31 (m, 2H), 7.10 (dd, J = 5.1, 3.6 Hz, 1H), 6.36 (dd, J
= 5.8, 1.9 Hz, 1H), 5.70 (dd, J = 5.9, 1.1 Hz, 1H), 5.07 (m, 1H), 4.72
(dd, J = 10.8, 3.3 Hz, 1H), 2.93 (m, 2H), 2.69 (ddd, J = 17.4, 9.8, 1.9
Hz, 1H), 2.58 (m, 1H), 2.49 (ddd, J = 13.9, 9.5, 1.9 Hz, 1H). 13C
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131.6, 129.9, 129.3, 128.1, 126.0, 125.2, 123.4, 103.6, 83.6, 79.3, 30.1,
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5-(Furan-2-yl)-8-hydroxy-12-oxa-1-azatetracyclo-
[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-12-one (4g) and 4-
(Furan-2-yl)-15-hydroxy-16-oxa-8-azatetracyclo[10.3.1.02,7.08,12]-
hexadeca-2,4,6,13-tetraen-9-one (29). General procedure C was
followed. From (0.31 g, 0.84 mmol) of N-(2-Formyl-4-iodophenyl)-3-
(furan-2-yl)propanamide (3d) 0.31 g of a mixture of 8-hydroxy-5-
iodo-12-oxa-1-azatetracyclo[11.3.0.02,7.09,13]hexadeca-2,4,6,10-tetraen-
12-one (4d) and 2-hydroxy-5-iodo-16-oxa-9-azatetracyclo-
[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tetraen-10-one (5d) in the ratio of
2.9:1 was formed, which was introduced into the Suzuki coupling
following the general procedure F. From 0.31 g (0.83 mmol)of that
mixture, Pd(PPh3)4 (0.056 g, 0.048 mmol), furan-2-boronic acid (0.11
g, 0.98 mmol), NaHCO3 (0.16 g, 1.9 mmol) in water (27 mL) upon
chromatographic separation 0.068 g (27%) of 4g and 0.10 g (39%) of
an inseparable mixture of 5-(furan-2-yl)-2-hydroxy-16-oxa-9-
azatetracyclo[11.2.1.03,8.05,9]hexadeca-3,5,7,14-tetraen-10-one (5g)
and 29 was isolated. The latter mixture of 5g and 29 (0.093 g, 0.30
mmol) was dissolved in 4 mL of DMSO and heated at 160 °C for 60
min. Upon cooling the solvent was removed under reduced pressure
and subjected to chromatographic separation yielding 0.043 g of 29.
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