A microwave-assisted diastereoselective multicomponent reaction to access dibenzo[ c, e ]azepinones: Synthesis and biological evaluation

Article abstract of DOI:10.1021/jo200251q

An unprecedented microwave-assisted multicomponent strategy has been elaborated for the fast, efficient, and diastereoselective generation of the dibenzo[c,e]azepinone scaffold. The generated compounds were evaluated for their bioactivity.

Full text of DOI:10.1021/jo200251q

ARTICLE
pubs.acs.org/joc
A Microwave-Assisted Diastereoselective Multicomponent Reaction
To Access Dibenzo[c,e]azepinones: Synthesis and Biological
Evaluation
Vaibhav P. Mehta,†,^ Sachin G. Modha,† Eelco Ruijter,§ Kristof Van Hecke,‡ Luc Van Meervelt,‡
Christophe Pannecouque,|| Jan Balzarini,|| Romano V. A. Orru,§ and Erik Van der Eycken*,†
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC) and ‡Biomolecular Architecture, Department of Chemistry,
Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
§Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam,
The Netherlands
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
S Supporting Information
b
ABSTRACT:
An unprecedented microwave-assisted multicomponent strategy has been elaborated for the fast, efficient, and diastereoselective
generation of the dibenzo[c,e]azepinone scaffold. The generated compounds were evaluated for their bioactivity.
’ INTRODUCTION
resemblance with the framework of the γ-secretase inhibitor
LY411575, which was developed by Eli Lilly9 (Figure 1, I). The
importance of biaryls in biological, synthetic, and materials
chemistry has inspired the development of numerous methods
for their assembly with control of axial chirality.10 With this in
mind, we were attracted by the retrosynthesis shown in Figure 1,
where the key step of our approach consists of a microwave-
assisted intramolecular Ugi 4CR of an appropriate biaryl com-
pound bearing the required aldehyde and carboxylic acid moiety.
This precursor can easily be assembled applying our previously
reported microwave-assisted coupling protocol11 of an o-formyl
phenylboronic acid with a suitable methyl o-bromo benzoate.
The structures of small molecules from Nature have been
optimized by evolution, and many of them are tailored to interact
with larger biomolecules to induce a physiological response.1
These small natural products represent an invaluable source for
the discovery process of new therapeutic agents. Since the active
natural product is usually not equipped with advanced biological
properties required for a chemotherapeutic agent (e.g., toxicity
issues), usually a series of skeletal and stereochemical analogues
have to be generated synthetically. Promising strategies for this
purpose are diversity-oriented synthesis2 (DOS) and diverted
total synthesis3 (DTS). Multicomponent reactions4 (MCRs) are
increasingly recognized as valuable tools in the realization of
DOS and DTS. Since the pioneering work of Passerini and Ugi,
MCRs have become popular tools for diversity generation during
drug development.4g MCRs are convergent reactions in which
three or more starting materials react to form a product, and all or
most of the atoms contribute to the newly formed compound.4
As MCRs have been combined with various cyclization
strategies,5 they often result in the formation of rather complex
molecular structures.6 It has been shown that MCRs can greatly
benefit from the use of microwave irradiation in terms of reaction
time and yield.7
’ RESULTS AND DISCUSSION
We started our synthesis from the commercially available
substituted o-bromo benzoates A1ꢀ3. Our goal was to perform
the SuzukiꢀMiyaura cross-coupling reactions with substituted
2-formyl-phenylboronic acids B1ꢀ3 (Scheme 1). A mixture of
the aryl bromide, boronic acid, and Pd(PPh3)4 as catalyst was
dissolved in 1,4-dioxane/H2O (1.5:1). To this solution was
added Na2CO3 as base, and the resulting mixture was irradiated
at a ceiling temperature of 120 ꢀC and maximum power of 100 W
We were interested in the development of the dibenzo-
Received: February 1, 2011
Published: March 10, 2011
[c,e]azepinone scaffold8 as it shows interesting structural
r
2011 American Chemical Society
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Figure 1. Structure of LY411575 (I) and retrosynthesis for the diversity-oriented generation of the dibenzo[c,e]azepinone scaffold (4).
Scheme 1. Synthesis of Functionalized Biaryl Compounds 1aꢀf
for 25 min. The reactions were found to proceed smoothly, and
the resulting biaryl-ester derivatives C1ꢀ6 were purified by
column chromatography over silica gel. The corresponding
compounds C1ꢀ6 were dissolved in THF, and then LiOH
(1 M soln in H2O) was added to perform the saponification.
This mixture was stirred at 40 ꢀC overnight. After standard
workup the desired biaryl compounds 1aꢀf were obtained in
good to excellent yields.
Table 1. Optimization Study for the Synthesis of Dibenzo-
[c,e]azepinone 4aa
The feasibility of the Ugi 4CR reaction was evaluated applying
20-formylbiphenyl-2-carboxylic acid (1a), p-methoxybenzyla-
mine (2a), and tert-butyl isocyanide (3a) (Table 1). In accor-
dance with literature procedures we opted to use MeOH as the
solvent in the presence of anhydrous MgSO4.4b,e The three
components were employed in a (1:1:1) ratio. Gratifyingly, after
48 h of stirring at rt the desired product 4a could be isolated in
45% yield along with unreacted starting material 1a (Table 1,
entry 1). Therefore, we decided to run the reaction at 60 ꢀC.
Although this resulted in a significant increase of the reaction rate
(24 h to reach the same conversion), the total yield remained
more or less the same (Table 1, entry 2) due to the presence of
unreacted starting material 1a along with some unidentifiable
side products. Microwave irradiation has been described as a
valuable technique to decrease the reaction time typically accom-
panied by suppression of side reactions.7d When the reaction
mixture was irradiated at a ceiling temperature of 80 ꢀC for 30
min, the desired product 4a was obtained in a moderate yield of
62% (Table 1, entry 3). An increased reaction temperature even
in combination with a longer reaction time did not affect the yield
entry
conditions
MeOH, rt, 48 h, MgSO4
yield of 4a (%)b
1
2
3
4
5
6
7
8
45c
49d
62
64
65
82
78
54
MeOH, Δ, 60 ꢀC, 24 h, MgSO4
MeOH, MW, 80 ꢀC, 30 min, MgSO4
MeOH, MW, 100 ꢀC, 30 min, MgSO4
MeOH, MW, 110 ꢀC, 45 min, MgSO4
CF3CH2OH, MW, 110 oC, 50 min, Na2SO4
CH2Cl2, MW, 110 ꢀC, 50 min, Na2SO4
MeCN, MW, 110 ꢀC, 50 min, Na2SO4
a Thereactionswere runata0.2 Mconcentrationofstartingmaterialin the
indicated solvent. To a solution of 1a (0.44 mmol) was added amine 2a
(1.0 equiv) along with drying agent. The mixture was allowed to stir for 2
min at rt before isocyanide 3a (1.0 equiv) was added and then was allowed
to react according to the described conditions. For MW conditions, once
isocyanide was added, the vial was flushed with argon (2 times) and sealed
with a Teflon crimp cap. The mixture was irradiated in a CEM Explorer at
the indicated ceiling temperature using a maximum power of 75 W for the
stipulatedtime. b Isolatedyields (single runs). c Unreacted starting material
1a was detected along with product 4a. d Unreacted starting material 1a
was detected along with some unidentified side product.
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Scheme 2. Tentative Mechanism for the Diastereoselective Formation of Dibenzo[c,e]azepinones 4
Scheme 3
noticeably (Table 1, entries 4 and 5). However, when switching
to 2,2,2-trifluoroethanol as solvent at a ceiling temperature of
110 ꢀC using a maximum power of 75 W for 50 min, the
corresponding dibenzo[c,e]azepine-5-carboxamide 4a was iso-
lated in a good yield of 82% (Table 1, entry 6). Switching the
solvent to CH2Cl2 resulted in a slightly diminished yield
(Table 1, entry 7), and the use of MeCN afforded compound
4a in a moderate yield of 54% (Table 1, entry 8). Interestingly,
1
according to H NMR, compound 4a was obtained as a single
diastereomer.
Having optimized the reaction conditions we evaluated the
scope of the procedure. An array of differently substituted biaryl
compounds 1aꢀf were reacted with various amines and iso-
cyanides (Table 2).12 The corresponding dibenzo[c,e]azepinon-
es 4bꢀak were obtained in good to excellent yields. The
reactions were found to proceed well with benzylic amines as
well as with a variety of linear and branched aliphatic amines,
while a wide range of substituted isocyanide components could
also be applied without diminishing the yields. Interestingly,
also tryptamine, worked well using the optimized conditions
(Table 2, entry 9). The application of phenylhydrazine in
this Ugi reaction unexpectedly resulted in the formation of
the 6-(phenylamino)-7-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-
dibenzo[c,e]azepin-5-one 5 (Table 2, entry 13). When the chiral
amines (S)-(þ)-2-phenylglycine methyl ester 2e and L-leucinol
2p were used, the corresponding Ugi products 4g and 4w were
obtained as diastereomeric mixtures (1:1) as was indicated by
1HNMR (Table 2, entry 6 and 23). Both diastereomers of
compound 4g could be separated by column chromatography
affording one diastereomer with mp (210ꢀ212 ꢀC) whose
stereochemistry (aR,14S,20S) was unambiguously deduced by
X-ray crystallography. This diastereomer crystallized in the chiral
space group P212121, and hence only one enantiomer is present
in the structure.13 The second diastereomer showed a mp
(155ꢀ158 ꢀC) but could not be crystallized. Compound 4w
obtained as a mixture was also unequivocally proven by X-ray
crystallography. Interestingly, compound 4w was crystallized in
the chiral space group P21. The asymmetric unit contains two
molecules, which are diastereoisomers, related by a noncrystallo-
graphic inversion center (90% fit). Moreover, we could also
observe an intramolecular H-bonding between the hydroxyl
group of (L)-leucinol and the carbonyl group resulting from the
isocyanide.
Interestingly, also R-acidic isocyanides such as TosMIC (entry
5) and 9-isocyanofluorene (entries 17 and 18) are converted to
the corresponding Ugi products. Such R-acidic isocyanides often
display different reactivity,14 affording imidazole15 or imidazo-
line16 products.
A tentative mechanism is given in Scheme 2. The primary
amine 2 first reacts with the carbonyl compound 1 to give an
intermediate iminium ion 7a after intramolecular protonation by
the carboxylic acid moiety. Conformer 7a, which is plausibly
stabilized by favorable electrostatic interaction between the
iminium and carboxylate moieties, may undergo direct nucleo-
philic attack by the isocyanide 3 to give 8 (pathway A). Nitrilium
ion intermediate 8 then undergoes intramolecular acylation to
give 9.17 The resulting imino anhydride 9 typically undergoes an
irreversible transacylation (Mumm rearrangement)18 to give the
final Ugi 4CR product 4. The relative stereochemistry of 8 can be
deduced from the relative stereochemistry of 4, which was
elucidated by X-ray crystallography (See Supporting Informa-
tion, Figure 1 and 2). Alternatively, conformer 7b may be in
equilibrium with N,O-acetal intermediate 10 (pathway B) as in
the mechanism proposed earlier by Banfi et al.19 The proposed
SN2 inversion to give 9 (via 8) would, however, be very hindered
in this case. Therefore, we believe the exclusive formation of the
observed diastereomer of 4 supports the involvement of pathway
A rather than pathway B.
Having successfully established the methodology for the
synthesis of the dibenzo[c,e]azepinone scaffold, we next explored
a possibility for further transformation. We discovered that
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Table 2. Scope of the Optimized Protocol for the Diversity-Oriented Generation of Dibenzo[c,e]azepinones
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Table 2. Continued
a Isolated yields (single runs); the compounds were obtained as single diastereomer. b Combined yield for the mixture of two diastereomers that is
formed (approximate ratio of 1:1). c Contrary to all previous results, the unexpected structure 5 was formed, as could be deduced from its 1H and 13
C
NMR data and X-ray crystal structure; see Supporting Information.
compound 4a, when reacted with Lawesson’s reagent in toluene
at reflux temperature for 3 h, was turned into the corresponding
thioamide 6 in 67% yield (Scheme 3). It might be clear that a
further functionalization of the scaffold is possible via both amide
moieties.
Biological Screening Results: Cytotoxicity Study. The
4aꢀz series of compounds have been evaluated for their
inhibitory effect against a wide variety of DNA and RNA viruses
in cell culture, but none of them proved inhibitory at subtoxic
concentrations. The compounds have also been investigated for
their antiproliferative activity against two murine (leukemia
L1210 and mammary carcinoma FM3A) and human
(lymphocyte CEM and cervix carcinoma HeLa) tumor cell lines.
The cytostatic activities (50% inhibitory concentrations) varied
between 13 and 828 μM depending the nature of the test
compounds. There was in general a fairly good correlation for
the cytostatic activities of the compounds between the murine
and human tumor cell lines (r = 0.8991), and between the murine
leukemia L1210 and the FM3A, CEM and HeLa cell lines (r =
0.911, 0.9348 and 0.8863, respectively).12
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There were three compounds that consistently showed IC50
values equal or slightly less than 20 μM against all four tumor cell
lines (e.g., 4 h, 4q, and 4s).
virus), HeLa (vesicular stomatitis virus, Coxsackie virus B4, and
respiratory syncytial virus), CrFK (feline herpes virus (FHV) and feline
coronavirus (FIPV)), and MDCK (influenza virus A (H1N1, H3N2)
and B) cell cultures. Confluent cell cultures in microtiter 96-well plates
were inoculated with 100 cell culture inhibitory dose-50 (CCID50) of
virus (1 CCID50 being the virus dose to infect 50% of the cell cultures) in
the presence of varying concentrations (100, 20, 4, ... μg/mL) of the test
compounds. Viral cytopathicity was recorded as soon as it reached
completion in the control virus-infected cell cultures that were not
treated with the test compounds.
Most closely related to 4h were 4j, 4n, 4p, and 4t, which dif-
fered only in the nature of the substituent at the azepinone ring
nitrogen. Their cytostatic activities, however, were substantially
lower than 4h. Therefore, the benzyl moiety should be further
substituted with a variety of para, ortho, or meta substituents.
The only compound closely related to 4q was 4r, which was 3- to
7-fold less cytostatic. When in compound 4s the nonyl chain was
replaced by a propynyl moiety, the cytostatic activity dropped by
10- to 20-fold. It might be interesting to combine potential
beneficial substituents in the three lead structures to find out
whether superior antiproliferative activity can be achieved. For
example, a para, meta, or ortho alkylbenzyl moiety on the N atom
of the seven-membered azepinone ring in which the alkyl might
represent a butyl, pentyl, or hexyl group might be worth
considering for further research. Also, replacing the tert-butyl
moiety on the amide function by a tricyclic entity such as in 4q
might be synthesized and evaluated.
The compounds 4e and 4i display some borderline anti-HIV-1
activity with IC50 values of g12.6 μg/mL (SI e 4) and g21.4
μg/mL (SI e 2), respectively. Furthermore both compounds
completely lack anti-HIV-2 activity, pointing to a possible
NNRTI mode of action. When the anti-HIV activity of com-
pounds 4e and 4i was assessed using a typical NNRTI-resistant
double (K103N and Y181C) mutant strain, the anti-HIV-1
activity completely disappears, confirming the typical first gen-
eration NNRTI mode of action of these compounds. In an
attempt to improve on the potency and selectivity of the
compounds, the substitution pattern on the benzyl moiety was
further explored leading to the synthesis of derivatives 4aaꢀak
(Table 2) having other substitution patterns than the p-methoxy
commonly present in 4e and 4i. Unfortunately none of the
derivatives, 4aaꢀak, surpassed the anti-HIV activity of the lead
molecules 4e and 4i.
Evaluation of the antiviral activity of the compounds against HIV in
MT-4 cells was performed by using a 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay as previously described.20
Stock solutions (10ꢁ final concentration) of test compounds were
added in 25-μL volumes to two series of triplicate wells to allow the
simultaneous evaluation of their effects on mock- and HIV-infected cells
at the beginning of each experiment. Serial 5-fold dilutions of test
compounds were made directly in flat-bottomed 96-well microtiter trays
using a Biomek 3000 robot (Beckman Instruments, Fullerton, CA).
Untreated HIV- and mock-infected cell samples were included as
controls. An HIV stock (50 μL) at 100 to 300 50% cell culture infectious
doses (CCID50) or culture medium was added to either the infected or
mock-infected wells of the microtiter tray. Mock-infected cells were used
to evaluate the effects of the test compound on uninfected cells in order
to assess the cytotoxicity of the test compounds. Exponentially growing
MT-4 cells were centrifuged for 5 min at 1,000 rpm, and the supernatant
was discarded. The MT-4 cells were resuspended at 6 ꢁ 105 cells/ml,
and 50-μL volumes were transferred into the microtiter tray wells. Five
days after infection, the viability of mock- and HIV-infected cells was
examined spectrophotometrically by using the MTT assay. The MTT
assay is based on the reduction of yellow MTT (Acros Organics, Geel,
Belgium) by the mitochondrial dehydrogenase of metabolically active cells
to a blue-purple formazan that can be measured spectrophotometrically.
The absorbances were read in an eight-channel computer-controlled
photometer (Multiscan Ascent reader; Labsystems, Helsinki, Finland) at
two wavelengths (540 and 690 nm). All data were calculated by using the
median optical density (OD) value of three wells. The 50% cytotoxic
concentration (CC50) was defined as the concentration of the test
compound that reduced the absorbance (OD at 540 nm [OD540]) of the
mock-infected control sample by 50%. The concentration achieving 50%
protection against the cytopathic effect of the virus in infected cells was
defined as the 50% effective concentration (EC50).
In conclusion, we have developed an efficient procedure for
the generation of the dibenzo[c,e]azepinone scaffold via an
intramolecular Ugi 4CR of a suitably substituted biaryl com-
pound. Excellent yields, high diastereoselectivities, and tolerance
of various groups toward the reaction conditions are the merits of
this protocol. It has been demonstrated that the reaction greatly
benefits from the use of microwave irradiation. Several lead
compounds were discovered with antiproliferative activity
against tumor cell lines in the lower micromolar range.
General Remarks for Newly Synthesized Compounds. 1H
and 13C NMR spectra were recorded on 250, 300, 400, and 500 MHz
NMR instrument. The 1H chemical shifts are reported in ppm relative to
tetramethylsilane. High-resolution mass spectra were recorded by using
ion source temperature 150ꢀ250 ꢀC as required. High-resolution
electron impact (EI) mass spectra were performed with a resolution
of 10000. EI mass spectrometry was carried out with an electron
ionization voltage of 70 eV. Fast atom bombardment (FAB) mass
spectrometry was carried out using a four-sector mass spectrometer,
coupled to a system program (samples were loaded in a matrix solution
(3-nitrobenzyl alcohol) onto a stainless steel probe and bombarded with
xenon atoms (3 KeV)). For thin layer chromatography, analytical TLC
plates SIL G/UV254 and 70ꢀ230 mesh silica gel were used. Reagents
were used without further purification. Solvents such as cyclohexane,
CH2Cl2, heptane, and ethyl acetate were distilled prior to use; CH2Cl2
was dried under molecular sieves. Melting points are uncorrected.
Microwave Irradiation Experiments. All microwave irradiation
experiments were carried out in a dedicated CEM-Explorer and CEM-
Discover monomode microwave apparatus, operating at a frequency of
2.45 GHz with continuous irradiation power from 0 to 300 W with
utilization of the standard absorbance level of 300 W maximum power.
The reactions were carried out in 10-mL glass tubes, sealed with a Teflon
’ EXPERIMENTAL SECTION
Cytostatic Assays. Murine leukemia L1210, murine mammary
carcinoma FM3A, human T-lymphocyte CEM, and human cervix
carcinoma (HeLa) cells were suspended at 300,000ꢀ500,000 cells/
mL of culture medium, and 100 μL of a cell suspension was added to 100
μL of an appropriate dilution of the test compounds in wells of 96-well
microtiter plates. After incubation at 37 ꢀC for 2 (L1210, FM3A) or 3
(CEM, HeLa) days, the cell number was determined using a Coulter
counter. The IC50 was defined as the compound concentration required
to inhibit cell proliferation by 50%.
Antiviral Assays. The antiviral assays [except antihuman immu-
nodeficiency virus (HIV) assays] were based on inhibition of virus-
induced cytopathicity in HEL [herpes simplex virus type 1 (HSV-1),
HSV-2 (G), vaccinia virus, and vesicular stomatitis virus], Vero
(parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, and Punta Toro
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septum and placed in the microwave cavity. Initially, microwave irradia-
tion of required watts was used, and the temperature was ramped from
room temperature to the desired temperature. Once this was reached the
reaction mixture was held at this temperature for the required time. The
reaction mixture was continuously stirred during the reaction. The
temperature was measured with an IR sensor on the outer surface of the
process vial. After the irradiation period, gas jet cooling rapidly cooled
the reaction vessel to ambient temperature.
60.7, 56.1, 52.0. HRMS (EI): calcd for C18H18O6 330.1103, found
330.1106.
Methyl 20-Formyl-4,40,5,6-tetramethoxy-[1,10-biphenyl]-2-carboxy-
late (C6). Yellow viscous oil, 82% yield. 1H NMR (300 MHz, CDCl3): δ
9.75 (s, 1H), 7.52 (d, J = 2.64 Hz, 1H), 7.35 (s, 1H), 7.15 (dd, J = 2.64,
8.49 Hz, 1H), 7.09 (d, J = 8.46 Hz, 1H), 3.96 (s, 3H), 3.95 (m, 6H), 3.90
(s, 3H), 3.57 (s, 3H), 3.51 (s, 3H). HRMS (EI): calcd for C19H20O7
360.1209, found 360.1211.
General Procedure for the Synthesis of Biarylacid (1) by
SuzukiꢀMiyaura Cross-Coupling. Bromoester A (5 mmol), o-
formylphenylboronic acid B (5.5 mmol, 1.1 equiv) and tetrakis-
(triphenylphosphine)palladium(0) (0.11 mmol, 1 mol %) were sus-
pended in 1,4-dioxane (3 mL) in a 10 mL glass reaction vial containing a
stirring bar. To this were added Na2CO3 (10 mmol, 2 equiv) and water
(2 mL), and the vial was sealed tightly with a Teflon crimp top. The
mixture was irradiated for 25 min at a preselected temperature of 120 ꢀC,
with an irradiation power of 100 W. After the reaction, the vial was
cooled to 40 ꢀC by gas jet cooling. The crude mixture was partitioned
between ethyl acetate (25 mL) and brine (25 mL), and the aqueous layer
(brine þ H2O) was extracted with ethyl acetate (3 ꢁ 25 mL). The
combined organic layers were dried on MgSO4, and solvent was
removed under reduced pressure to yield the crude product C1ꢀ6 as
yellow oil. Column chromatography [silica gel, 20% ethyl acetate/
heptanes] afforded analytically pure product as a colorless or yellow
oil. These compounds were further used for hydrolysis of the ester
group. To a solution of corresponding ester C1ꢀ6 in THF (25 mL) was
added LiOH (1 M soln in H2O, 5 equiv), and the reaction mixture was
heated overnight at 40 ꢀC. The resulting solution was neutralized with 1
N HCl solution until the pH = 7.0 (careful addition of acid and proper
check with pH paper). A white hazy solution was obtained at the neutral
pH and was extracted with ethyl acetate (100 mL). The organic layer was
dried over MgSO4, and the solvent was evaporated under reduced
pressure to afford the corresponding biaryl acid 1aꢀf as a white or
yellow solid.
Characterization of Compounds 1aꢀf. 20-Formylbiphenyl-2-
carboxylic Acid (1a)1. The characteristic data of the compound were in
accordance with the one reported in the literature.
20-Formyl-4-methoxybiphenyl-2-carboxylic Acid (1b). White solid
mp 179ꢀ181 ꢀC in 99% yield. 1H NMR (250 MHz, CDCl3): δ 9.79 (s,
1H), 7.97ꢀ7.94 (d, J = 7.65 Hz, 2H), 7.60ꢀ7.44 (m, 3H), 7.22ꢀ7.14
(m, 3H), 3.89 (s, 3H). 13C NMR (62.5 MHz, CDCl3): 192.0, 171.1,
159.4, 144.8, 134.2, 133.3, 133.2, 132.4, 130.6, 130.2, 127.8, 127.6, 118.9,
115.6, 55.7. HRMS (EI): calcd for C15H12O4 256.0736, found 256.0737.
20-Formyl-4,40-dimethoxybiphenyl-2-carboxylic Acid (1c). Yellow
solid mp 164ꢀ166 ꢀC in 97% yield. 1H NMR (300 MHz, DMSO): δ
12.80 (bs, 1H), 9.67 (s, 1H), 7.58 (bs, 1H), 7.41ꢀ7.22 (m, 5H), 3.85 (s,
6H). 13C NMR (75 MHz, DMSO): 167.9, 158.6, 158.4, 134.6, 133.3,
133.1, 132.1, 131.5, 131.4, 129.8, 128.8, 128.6, 120.0, 116.9, 114.4, 109.8,
55.4 (ꢁ 2). HRMS (EI): calcd for C16H14O5 286.0841, found 286.0845.
2-(2-Formylthiophen-3-yl)-5-methoxybenzoic Acid (1d). White so-
lid mp 158ꢀ160 ꢀC in 92% yield. 1H NMR (300 MHz, CDCl3): δ 9.61
(s, 1H), 7.69ꢀ7.68 (d, J = 3.78 Hz, 1H), 7.64 (s, 1H), 7.30 (s, 1H),
7.18ꢀ7.15 (m, 1H), 7.04ꢀ7.05 (d, 1H), 3.92 (s, 3H). 13C NMR (75
MHz, CDCl3): 183.7, 171.1, 159.9, 150.2, 139.0, 133.4, 133.1, 131.4,
130.7, 127.7, 118.8, 116.3, 55.8. HRMS (EI): calcd for C13H10O4S
262.0300, found 262.0302.
20-Formyl-4,5,6-trimethoxybiphenyl-2-carboxylic Acid (1e). White
1
solid mp 142ꢀ144 ꢀC in 94% yield. H NMR (300 MHz, CDCl3): δ
9.79 (s, 1H), 7.99 (d, J = 7.53 Hz, 1H), 7.60ꢀ7.54 (dt, J = 1.29, 7.44 Hz,
1H), 7.48 (t, J = 7.53 Hz, 1H), 7.17 (d, J = 7.53 Hz, 1H), 3.96ꢀ3.95 (m,
6H), 3.49 (s, 3H). 13C NMR (75 MHz, CDCl3): 192.1, 171.1, 153.0,
151.6, 146.3, 140.3, 134.2, 133.2, 130.8, 128.1, 127.8, 127.6, 124.2, 110.3,
61.1, 60.8, 56.3. HRMS (EI): calcd for C17H16O6 316.0947, found
316.0948.
Characterization of Compounds C1ꢀ6. Methyl 20-Formyl-[1,10-
1
biphenyl]-2-carboxylate (C1). Colorless oil, 84% yield. H NMR (300
MHz, CDCl3): δ 9.79 (s, 1H), 8.06ꢀ7.99 (m, 2H), 7.62ꢀ7.48 (m, 4H),
7.31ꢀ7.23 (m, 2H), 3.61 (s, 3H). 13C NMR (75 MHz, CDCl3): 191.6,
167.1, 145.1, 139.3, 133.7, 133.1, 131.6 (ꢁ 2), 130.4, 130.0, 128.2, 127.8,
127.3, 52.0. HRMS (EI): calcd for C15H12O3 240.0786, found 240.0790.
Methyl 20-Formyl-4-methoxy-[1,10-biphenyl]-2-carboxylate (C2). Col-
orless oil, 98% yield. 1H NMR (250 MHz, CDCl3): δ 9.81 (s, 1H), 8.0 (dd,
J = 8.90 Hz, 1.2 Hz, 1H), 7.58 (dt, J = 15.1, 7.45, 1.52 Hz, 1H), 7.55 (d, J =
2.45 Hz, 1H), 7.46 (t, J = 15.00, 7.51 Hz, 1H), 7.24ꢀ7.20 (m, 1H), 7.19 (s,
1H), 7.11 (dd, J = 11.13 Hz, 2.69 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H). 13C
NMR (62.5 MHz, CDCl3): 191.9, 167.1, 159.3, 145.1, 134.2, 133.1, 132.9,
131.6, 131.5, 130.5, 127.7, 127.3, 117.8, 115.0, 55.6, 52.1. HRMS (EI): calcd
for C16H14O4 270.0892, found 270.0895.
20-Formyl-4,40,5,6-tetramethoxybiphenyl-2-carboxylic Acid (1f). White
solid mp 132ꢀ134 ꢀC in 87% yield. 1H NMR (300 MHz, CDCl3): δ 9.73
(s, 1H), 7.49ꢀ7.43 (m, 2H), 7.15ꢀ7.07 (m, 2H), 3.95ꢀ3.91 (m, 9H), 3.49
(s, 3H). HRMS (EI): calcd for C18H18O7 346.1053, found 346.1056.
General Procedure for Intermolecular U4CR Reaction for
the Synthesis of the Dibenzo[c,e]azepinone Ring System. In
a microwave vial equipped with a magnetic stir bar, biaryl acid 1aꢀf (100
mg, 1.0 equiv) was dissolved in 3 mL of 2,2,2-trifluoroethanol along with
Na2SO4 (0.25 g). Then the corresponding amine 2aꢀu (1.0 equiv) was
added, and the mixture was allowed to stir for 5 min at room
temperature. After a light yellow solution is obtained the corresponding
isocyanide 3aꢀi (1.0 equiv) was added, and the vial was flushed with
nitrogen (3 times) and sealed with Teflon crimp. Then it was irradiated
with CEM-Explorer or CEM-Discover microwave for 50 min at a ceiling
temperature of 110 ꢀC. After the completion of the reaction the mixture
was allowed to cool to room temperature with external gas jet cooling (∼
2 min). The resulting mixture was diluted with EtOAc and was extracted
with brine solution. The organic layer was separated, the aqueous layer
(brine þ water) was extracted with EtOAc (2 ꢁ 10 mL), and combined
organic layers were dried on Na2SO4, evaporated to give crude mixture,
loaded on a silica gel column, and eluted with (20% ethyl acetate/
heptane mixture) or (20% ethyl acetate/cyclohexane mixture) to afford
the desired dibenzo[c,e]azepinone scaffold (4aꢀak) and 5.
Methyl 20-Formyl-4,40-dimethoxybiphenyl-2-carboxylate (C3). HRMS
(EI): calcd for C17H16O5 300.0998, found 300.1004. The compound was
used for the hydrolysis without furthur characterization.
Methyl 2-(2-Formylthiophen-3-yl)-5-methoxybenzoate (C4). Yel-
low oil, 92% yield. 1H NMR (300 MHz, CDCl3): δ 9.60 (s, 1H), 7.69
(d, J = 4.89 Hz, 1H), 7.53 (d, J = 2.64 Hz, 1H), 7.29ꢀ7.26 (m (merged
with chloroform peak), 1H), 7.11 (dd, J = 2.64, 8.47 Hz, 1H), 7.04 (d, J =
4.89 Hz, 1H), 3.90 (s, 3H), 3.69 (s, 3H). HRMS (EI): calcd for
C14H12O4S 276.0456, found 276.0459.
Methyl 20-Formyl-4,5,6-trimethoxy-[1,10-biphenyl]-2-carboxylate (C5).
Yellow oil, 54% yield. 1H NMR (300 MHz, CDCl3):δ9.82 (s, 1H), 8.01 (d,
J = 6.60 Hz, 1H), 7.59 (dt, J = 1.32, 7.53 Hz, 1H), 7.49 (t, J = 7.53 Hz, 1H),
7.37 (s, 1H), 7.18 (d, J = 7.17 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.53 (s,
3H), 3.52 (s, 3H). 13C NMR (75 MHz, CDCl3): 192.0, 166.8, 153.0, 151.4,
145.4, 140.6, 134.2, 133.1, 130.7, 127.7, 127.3, 127.0, 125.7, 109.4, 61.0,
Characterization of Compounds 4aꢀak and 5. N-tert-Butyl-
6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-
5-carboxamide (4a). White solid mp 168ꢀ170 ꢀC in 82% yield. H
1
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ARTICLE
NMR (250 MHz, CDCl3): δ 7.95 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.7 Hz,
1H), 7.51ꢀ7.42 (m, 4H), 7.31 (t, J = 8.6 Hz, 3H), 7.01 (d, J = 7.4 Hz,
1H), 6.87 (d, J = 8.6 Hz, 2H), 5.16 (d, J = 14.2 Hz, 1H), 5.04 (s, 1H),
4.75 (s, 1H), 4.52 (d, J = 14.3 Hz, 1H), 3.81 (s, 3H), 0.75 (s, 9H). 13C
NMR (62.5 MHz, CDCl3): 168.5, 166.8, 159.6, 137.5, 137.4, 136.9,
134.6, 131.1, 130.9, 130.4 (ꢁ 2), 129.5, 129.4, 129.3, 129.1, 128.7, 128.1
(ꢁ 2), 114.4, 65.8, 55.4, 51.9, 51.0, 27.8, 26.9. HRMS (FAB): calcd for
C27H29O3N2 (MHþ) 429.2173, found 429.2166.
N,6-Di-tert-butyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-car-
boxamide (4b). White solid mp 143ꢀ145 ꢀC in 69% yield. 1H NMR
(500 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 1.1, 7.7 Hz,
1H), 7.5 (dd, J = 1.4, 7.6 Hz, 1H), 7.47ꢀ7.44 (m, 2H), 7.41ꢀ7.39 (m,
2H), 7.35 (dd, J = 1.2, 7.5 Hz, 1H), 5.27 (s, 1H), 5.17 (s, 1H), 1.59 (s,
9H), 0.86 (s, 9H). 13C NMR (62.5 MHz, CDCl3): 169.1, 167.8, 138.6,
137.4 (ꢁ 2), 135.5, 131.2, 130.4, 129.3, 129.2, 129.0, 128.3, 128.0, 127.6,
62.6, 59.7, 51.0, 29.1, 27.9. HRMS (FAB): calcd for C23H29O2N2
(MHþ) 366.2224, found 365.2215.
combined yield. 1H NMR (500 MHz, CDCl3): δ 8.25 (bs, 1H), 7.91 (d,
J = 7.55 Hz, 1H), 7.54ꢀ7.45 (m, 7H), 7.34ꢀ7.31 (m, 1H), 7.25ꢀ7.20
(d, J = 7.55 Hz, 2H), 7.08ꢀ7.05 (dt, J = 1.25, 7.47 Hz, 1H), 6.17 (s, 1H),
6.07 (d, J = 7.6 Hz, 1H), 4.64 (s, 1H), 3.87 (s, 3H), 1.01 (s, 9H). 13C
NMR (62.5 MHz, CDCl3): 173.3, 169.3, 167.8, 138.7, 137.8, 137.4,
133.3, 132.4, 131.6, 130.4, 130.0, 129.7, 129.2, 129.1, 128.9, 128.6, 127.8,
127.7, 62.1, 53.1, 51.1, 28.1, 27.0. HRMS (FAB): calcd for C28H29O4N2
(MHþ) 457.2122, found 457.2123. [R]20D = þ55.9 (c 0.294, CHCl3)
2nd Diastereoisomer: (S)-Methyl 2-((R)-5-(tert-Butylcarbamoyl)-7-
oxo-5H-dibenzo[c,e]azepin-6(7H)-yl)-2-phenylacetate (4g). (Struc-
ture assumed from X-ray crystallographic data of first diastereoisomer)
1
Light pink solid mp 155ꢀ158 ꢀC in 64% combined yield. H NMR
(500 MHz, CDCl3): δ 7.92 (d, J = 15.1 Hz, 1H), 7.59ꢀ7.33 (m, 11H),
7.24 (d, J = 14.8 Hz, 1H), 6.28 (s, 1H), 5.56 (bs, 1H), 4.92 (s, 1H), 3.65
(s, 3H), 0.77 (s, 9H). 13C NMR (62.5 MHz, CDCl3): 170.0, 168.9,
166.7, 137.9, 137.2 (ꢁ 2), 134.1, 131.4, 130.7, 129.7, 129.4, 129.2,
129.1, 129.0, 129.0, 128.0 (ꢁ 2), 64.5, 64.4, 52.5, 51.0, 27.8. HRMS
N-tert-Butyl-6-isobutyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-
1
(FAB): calcd for C28H29O4N2 457.2122, found 457.21236. [R]20
ꢀ34.3 (c 0.396, CHCl3)
=
5-carboxamide (4c). White solid mp 128ꢀ130 ꢀC in 88% yield. H
D
NMR (500 MHz, CDCl3): δ 7.92 (d, J = 7.1 Hz, 1H), 7.62 (d, J = 7.7 Hz,
1H), 7.49ꢀ7.48 (m, 3H), 7.43ꢀ7.37 (m, 2H), 7.33 (d, J = 6.3 Hz, 1H),
5.18 (s, 1H), 4.72 (s, 1H), 3.65 (dd, J = 7.7, 13.15, 1H), 3.50 (dd, J = 7.1,
13.5, 1H), 2.03 (septet, J = 6.8 Hz, 1H), 1.01 (d, J = 6.65 Hz, 3H), 0.87
(s, 9H), 0.76 (d, J = 6.65 Hz, 3H). 13C NMR (62.5 MHz, CDCl3): 168.8,
166.9, 137.7, 137.6, 136.4, 131.1, 129.8, 129.6, 129.5, 128.5, 128.4, 67.7,
57.5, 51.3, 28.1, 28.0, 27.0, 20.6, 19.8. HRMS (FAB): calcd for
C23H29O2N2 (MHþ) 365.2224, found 365.2223.
N-tert-Butyl-7-oxo-6-(2,4,6-trimethylbenzyl)-6,7-dihydro-5H-dibe-
nzo[c,e]azepine-5-carboxamide (4h). White solid mp 70ꢀ72 ꢀC in
86% yield. 1H NMR (500 MHz, CDCl3): δ 8.05 (d, J = 7.1 Hz, 1H), 7.58
(d, J = 6.7 Hz, 1H), 7.54ꢀ7.42 (m, 4H), 7.20ꢀ7.17 (m, 1H), 6.89 (s,
2H), 6.43 (d, J = 6.6 Hz, 1H), 5.19 (d, J = 14.5 Hz, 1H), 5.00 (s, 1H),
4.87 (d, J = 14.5 Hz, 1H), 4.48 (s, 1H), 2.34 (s, 3H), 2.18 (s, 6H), 0.82 (s,
9H). 13C NMR (62.5 MHz, CDCl3): 168.4, 167.3, 138.7, 138.0, 137.4,
137.3, 136.5, 135.0, 131.2, 130.9, 129.5, 129.4, 129.3, 129.2, 128.4, 128.2,
127.9, 62.9, 51.1, 45.1, 27.9, 26.9, 21.0, 19.9. HRMS (FAB): calcd for
C29H33O2N2 (MHþ) 441.2537, found 441.2555.
N-tert-Butyl-6-(cyclopropylmethyl)-7-oxo-6,7-dihydro-5H-dibenzo-
[c,e]azepine-5-carboxamide (4d). Colorless Oil in 83% yield. 1H NMR
(500 MHz, CDCl3): δ 7.91 (d, J = 7.85 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H),
7.52ꢀ7.51 (m, 2H), 7.45ꢀ7.43 (m, 2H), 7.39ꢀ7.36 (m, 2H), 5.64 (s,
1H), 4.93 (s, 1H), 3.77 (dd, J = 7.7, 14.1, 1H), 3.47 (dd, J = 6.6, 14.1,
1H), 1.12ꢀ1.18 (m, 1H), 0.91 (s, 9H), 0.61ꢀ0.58 (m, 2H), 0.48ꢀ0.45
(m, 1H), 0.39ꢀ0.37 (m, 1H). 13C NMR (62.5 MHz, CDCl3): 168.4,
167.1, 137.7, 137.5, 136.7, 134.8, 131.0, 129., 129.5, 129.3, 128.7, 128.1,
128.1, 66.9, 53.4, 51.1, 28.0, 26.9, 10.3, 4.1, 4.0. HRMS (FAB): calcd for
C23H27O2N2 (MHþ) 363.2067, found 363.2077.
6-(4-Methoxybenzyl)-7-oxo-N-pentyl-6,7-dihydro-5H-dibenzo[c,
e]azepine-5-carboxamide (4e). White solid mp 158ꢀ160 ꢀC in 78%
yield. 1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 7.7 Hz, 1H), 7.60 (d,
J = 7.7 Hz, 1H), 7.51ꢀ7.41 (m, 4H), 7.30ꢀ7.27 (m, 3H), 6.93 (d, J = 6.6
Hz, 1H), 6.85 (d, J = 8.65 Hz, 2H), 5.17 (t, J = 5.35 Hz, 1H), 5.01 (d, J =
14.5 Hz, 1H), 4.76 (s, 1H), 4.73 (d, J = 14.5 Hz, 1H), 3.80 (s, 3H),
2.75ꢀ2.72 (m, 1H), 2.60ꢀ2.57 (m, 1H), 1.10ꢀ1.09 (m, 2H),
0.86ꢀ0.84 (m, 4H), 0.79 (t, J = 7.5 Hz, 3H). 13C NMR (62.5 MHz,
CDCl3): 167.6, 159.4, 137.7, 137.0, 136.4, 134.6, 131.0, 130.9, 130.3,
129.5, 129.4, 129.3, 128.9, 128.5, 128.1 (ꢁ 2), 114.2, 65.0, 55.3, 51.8,
39.6, 28.7 (ꢁ 2), 26.9, 22.1, 13.8. HRMS (FAB): calcd for C28H31O3N2
(MHþ) 443.2329, found 443.2345.
6-(4-Methoxybenzyl)-7-oxo-N-(tosylmethyl)-6,7-dihydro-5H-dibe-
nzo[c,e]azepine-5-carboxamide (4f). Colorless oil 88% yield. 1H NMR
(250 MHz, CDCl3): δ 7.90 (dd, J = 1.9, 8.0 Hz, 1H), 7.57 (d, J = 6.7 Hz,
1H), 7.49ꢀ7.38 (m, 6H), 7.30ꢀ7.19 (m, 6H), 6.93 (d, J = 8.6 Hz, 2H),
6.84 (d, J = 6.6 Hz, 1H), 5.99 (t, J = 6.7 Hz, 1H), 4.89 (d, J = 14.4 Hz,
1H), 4.68 (d, J = 14.5 Hz, 1H), 4.57 (s, 1H), 4.06 (d, J = 6.8 Hz, 2H),
3.84 (s, 3H), 2.41 (s, 3H). 13C NMR (62.5 MHz, CDCl3): 168.6, 167.8,
159.7, 145.5, 137.7, 136.2, 135.7, 134.2, 133.8, 131.4, 130.8, 130.4, 130.0,
129.9, 129.8, 129.2, 128.6, 128.5 (ꢁ 2), 128.4, 128.3, 114.6, 64.2, 60.2,
55.5, 51.4, 30.2, 27.0 (ꢁ 2), 21.8, 14.3. HRMS (FAB): calcd for
C31H29O5N2S (MHþ) 541.1792, found 541.1790.
N-Cyclohexyl-6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-diben-
zo[c,e]azepine-5-carboxamide (4i). White solid mp 164ꢀ166 ꢀC in
91% yield. 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 7.4 Hz, 1H), 7.59
(d, J = 7.7 Hz, 1H), 7.52ꢀ7.41 (m, 4H), 7.33ꢀ7.28 (m, 3H), 6.99 (d, J =
7.5 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.14 (d, J = 14.3 Hz, 1H), 4.99 (d,
J = 8.3 Hz, 1H), 4.76 (s, 1H), 4.57 (d, J = 14.3 Hz, 1H), 3.81 (s, 3H),
3.19ꢀ3.17 (m, 1H), 1.50ꢀ1.30 (m, 3H), 1.23ꢀ0.95 (m, 5H), 0.57ꢀ0.44
(m, 2H). 13C NMR (62.5 MHz, CDCl3): 168.6, 166.7, 159.6, 137.8, 137.1,
136.7, 134.5, 131.2, 131.0, 130.4, 129.6, 129.4 (ꢁ 2), 128.6, 128.2, 114.5,
65.3, 55.4, 51.8, 48.0, 32.4, 32.3, 27.0, 25.4, 24.6. HRMS (FAB): calcd for
C29H31O3N2 (MHþ) 455.2329, found 455.2342.
6-(2-(1H-Indol-3-yl)ethyl)-N-tert-butyl-7-oxo-6,7-dihydro-5H-dibe-
nzo[c,e]azepine-5-carboxamide (4j). White solid mp 185ꢀ187 ꢀC in
84% yield. 1H NMR (500 MHz, CDCl3): δ 8.07 (bs, 1H), 7.89 (d, J = 7.7
Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 6.6 Hz, 1H), 7.50ꢀ7.41
(m, 4H), 7.34 (t, J = 7.55 Hz, 2H), 7.22ꢀ7.15 (m, 4H), 5.18 (s, 1H),
4.78 (s, 1H), 4.48ꢀ4.42 (m, 1H), 3.88ꢀ3.83 (m, 1H), 3.31ꢀ3.24 (m,
1H), 3.16ꢀ3.11 (m, 1H), 0.61 (s, 9H). 13C NMR (62.5 MHz, CDCl3):
168.8, 167.0, 137.7, 137.4, 136.6, 135.1, 131.1, 130.6, 129.6 (ꢁ 2), 129.4,
128.7, 128.3, 128.2, 127.5, 122.2, 122.1, 119.5, 118.6, 112.2, 111.4, 67.6,
50.9, 49.3, 46.3, 27.6, 24.1, 11.7. HRMS (FAB): calcd for C29H30O2N3
(MHþ) 452.2333, found 451.2349.
N-tert-Butyl-6-cyclohexyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]aze-
pine-5-carboxamide (4k). White solid mp 75ꢀ77 ꢀC in 74% yield. 1H
NMR (500 MHz, CDCl3): δ 7.91 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz,
1H), 7.49ꢀ7.42 (m, 4H), 7.40ꢀ7.38 (m, 2H), 5.26 (s, 1H), 4.93 (s, 1H),
4.82ꢀ4.77 (m, 1H), 1.98 (m, 1H), 1.91 (m, 1H), 1.77 (m, 1H), 1.68 (m,
2H), 1.52 ꢀ1.46 (m, 4H), 1.40ꢀ1.37 (m, 2H), 1.17ꢀ1.14 (m, 1H), 0.86
(s, 9H). 13C NMR (62.5 MHz, CDCl3): 168.2, 167.6, 139.0, 137.7,
136.4, 135.5, 131.2, 130.9, 129.6, 129.5, 129.3, 128.6, 128.3, 128.2, 61.4,
55.1, 51.3, 32.0, 31.3, 28.1, 26.0, 25.8, 25.7. HRMS (FAB): calcd for
C25H31O2N2 (MHþ) 391.2371, found 391.2383.
Two diastereoisomers separated for 4g:
1st Diastereoisomer: (S)-Methyl 2-((S)-5-(tert-Butylcarbamoyl)-7-
oxo-5H-dibenzo[c,e]azepin-6(7H)-yl)-2-phenylacetate (4g). (Con-
firmed by X-ray crystallography) White solid mp 210ꢀ214 ꢀC in 64%
6-(4-Methoxybenzyl)-N-(4-methoxyphenyl)-7-oxo-6,7-dihydro-5H-
dibenzo[c,e]azepine-5-carboxamide (4l). White solid mp 217ꢀ219 ꢀC
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ARTICLE
in 89% yield. 1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 7.4 Hz, 1H),
7.66 (d, J = 7.6 Hz, 1H), 7.52ꢀ7.50 (m, 3H), 7.42ꢀ7.40 (m, 3H), 7.36
(t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.72
(s, 1H), 6.65 (d, J = 9.1 Hz, 2H), 6.59 (d, J = 9.1 Hz, 2H), 5.23 (d, J = 14.5
Hz, 1H), 4.93 (s, 1H), 4.62 (d, J = 14.3 Hz, 1H), 3.84 (s, 3H), 3.70 (s,
3H). 13C NMR (62.5 MHz, CDCl3): 168.7, 166.2, 159., 156.8, 137.9,
136.8, 136.6, 134.4, 131.3, 130.9, 130.5, 129.7 (ꢁ 2), 129.6, 129.4, 129.0,
128.6, 128.4, 128.3, 122.4, 114.6, 113.9, 65.4, 55.5 (ꢁ 2), 51.7. HRMS
(FAB): calcd for C30H27O4N2 (MHþ) 479.1965, found 479.1981.
6-Isobutyl-7-oxo-N-(2,4,4-trimethylpentan-2-yl)-6,7-dihydro-5H-
dibenzo[c,e]azepine-5-carboxamide (4m). Colorless oil in 78% yield.
1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.5
Hz, 1H), 7.50ꢀ7.38 (m, 5H), 7.35 (d, J = 6.6 Hz, 1H), 5.26 (s, 1H), 4.67
(s, 1H), 3.73 (dd, J = 8.0, 13.5, 1H), 3.41 (dd, J = 6.9, 13.4, 1H), 2.02
(septet, J = 7.1 Hz, 1H), 1.30 (d, J = 15 Hz, 1H), 1.21 (d, J = 14.9 Hz,
1H), 1.01ꢀ0.99 (m, 6H), 0.77ꢀ0.74 (m, 15H). 13C NMR (62.5 MHz,
CDCl3): 168.6, 166.3, 137.6 (ꢁ 2), 136.0, 135.5, 131.2, 130.8, 129.7,
129.6, 129.4, 128.4, 128.3 (ꢁ 2), 67.8, 57.6, 55.3, 52.9, 31.4, 31.2, 27.9,
27.4, 20.5, 19.7. HRMS (FAB): calcd for C27H37O2N2 (MHþ)
421.2850, found 421.2860.
in 86% yield. 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 6.7 Hz, 1H),
7.61ꢀ7.58 (m, 4H), 7.52ꢀ7.45 (m, 3H), 7.35ꢀ7.29 (m, 3H), 7.25 (d, J =
8.6 Hz, 2H), 7.17ꢀ7.14 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.5
Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 7.55 Hz, 1H), 5.69 (d, J = 8.6
Hz, 1H), 5.49 (d, J = 8.7 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H), 4.99 (s, 1H),
4.63 (d, J = 14.3 Hz, 1H), 3.77 (s, 3H). 13C NMR (62.5 MHz, CDCl3):
168.8, 168.3, 159.4, 143.3, 143.1, 140.2, 140.1, 137.5, 136.5, 136.3, 134.3,
1314, 131.2, 130.2, 129.8, 129.5, 129.4, 128.6, 128.5 (ꢁ 2), 128.4, 128.2,
127.5 (ꢁ 2), 125.2, 125.0, 119.6, 114.3, 65.2, 55.1, 54.6, 51.8. HRMS
(FAB): calcd for C36H29O3N2 537.2173, found 537.2057.
N-tert-Butyl-3,9-dimethoxy-6-nonyl-7-oxo-6,7-dihydro-5H-dibenz-
o[c,e]azepine-5-carboxamide (4s). Brownish Oil in 76% yield. 1H
NMR (400 MHz, CDCl3): δ 7.49 (d, J = 11.5 Hz, 1H), 7.41 (d, J =
3.52 Hz, 1H), 7.34 (d, J = 11.5 Hz, 1H), 7.06ꢀ6.98 (m, 2H), 6.88 (d, J =
3.52 Hz, 1H), 5.18 (s, 1H), 4.65 (s, 1H), 3.87ꢀ3.86 (m, 6H), 3.75ꢀ3.65
(m, 2H), 1.67ꢀ1.65 (m, 2H), 1.2 (bs, 12H), 0.90ꢀ0.80 (m, 12H). 13C
NMR (100 MHz, CDCl3): 168.1, 166.8, 159.1, 159.0, 138.3, 135.7,
130.5, 129.7, 129.6, 129.0, 118.8, 115.2, 114.3, 113.6, 67.4, 55.5, 55.4,
51.2, 50.3, 31.8, 29.4, 29.3, 29.2, 28.2, 27.9, 26.8, 22.6, 14.1. HRMS (EI):
calcd for C30H42O4N2 494.3145, found 494.3149.
N-tert-Butyl-6-(4-hydroxyphenethyl)-7-oxo-6,7-dihydro-5H-diben-
zo[c,e]azepine-5-carboxamide (4n). White solid mp 107ꢀ109 ꢀC in
98% yield. 1H NMR (500 MHz, CDCl3): δ 7.93 (d, J = 7.4 Hz, 1H), 7.61
(d, J = 7.7 Hz, 1H), 7.51ꢀ7.50 (m, 3H), 7.45ꢀ7.38 (m, 3H), 7.27 (d, J =
7.4 Hz, 1H), 7.01 (d, J= 6.95 Hz, 2H), 6.72 (d, J= 8.2 Hz, 2H), 5.12 (s, 1H),
4.79 (s, 1H), 4.06ꢀ4.01 (m, 1H), 3.92ꢀ3.86 (m, 1H), 3.00ꢀ2.94 (m, 1H),
2.91ꢀ2.86 (m, 1H), 0.82 (s, 9H). 13C NMR (62.5 MHz, CDCl3): 168.8,
166.9, 155.1, 137.5 (ꢁ 2), 136.5, 134.9, 131.2, 131.0, 129.8 (ꢁ 2), 129.7,
129.6, 128.7, 128.6, 128.4, 115.7, 67.9, 52.0, 51.4, 33.6, 28.0. HRMS (FAB):
calcd for C27H29O3N2 429.2173, found 429.2182.
N-Benzyl-6-isobutyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-
carboxamide (4o). White solid mp 158ꢀ160 ꢀC in 80% yield. 1H NMR
(500 MHz, CDCl3): δ 7.94 (d, J = 6.45 Hz, 1H), 7.63 (d, J = 7.55 Hz,
1H), 7.53ꢀ7.38 (m, 6H), 7.21ꢀ7.19 (m, 3H), 6.78 (d, J = 6.00 Hz, 2H),
5.58 (t, J = 5.2 Hz, 1H), 4.85 (s, 1H), 4.15ꢀ4.12 (m, 1H), 3.94ꢀ3.90 (m,
1H), 3.76ꢀ3.71 (m, 1H), 3.50ꢀ3.46 (m, 1H), 2.08ꢀ2.03 (m, 1H), 1.03
(d, J = 6.60 Hz, 3H), 0.76 (d, J = 6.60 Hz, 3H). 13C NMR (62.5 MHz,
CDCl3): 168.6, 167.9, 137.8, 137.4, 137.0, 135.7, 135.1, 131.1, 130.9,
129.9, 129.8, 129.5, 128.6, 128.4 (ꢁ 2), 128.3, 127.7, 127.4, 67.2, 57.5,
43.8, 27.9, 20.5, 19.7. HRMS (FAB): calcd for C26H27O2N2 (MHþ)
399.2067, found 399.2060.
6-Allyl-N-tert-butyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-
carboxamide (4p). White solid mp 120ꢀ122 ꢀC in 80% yield. 1H NMR
(500 MHz, CDCl3): δ 7.94 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),
7.52ꢀ7.48 (m, 3H), 7.46ꢀ7.42 (m, 1H), 7.38 (dt, J = 1.2, 6.9 Hz, 1H),
7.30 (d, J = 6.5 Hz, 1H), 5.90ꢀ5.83 (m, 1H), 5.35 (dd, J = 1.4, 17.0, 1H),
5.29 (dd, J = 2.2, 9.4, 1H), 5.16 (s, 1H), 4.79 (s, 1H), 4.39 (d, J = 5.3 Hz,
2H), 0.86 (s, 9H). 13C NMR (62.5 MHz, CDCl3): 168.3, 166.9, 137.7,
137.3, 136.5, 135.0, 133.4, 129.8, 129.6, 128.6, 128.4, 128.3, 119.5, 65.7,
52.1, 51.3, 28.0. HRMS (FAB): calcd for C22H25O2N2 (MHþ)
349.1911, found 349.1912.
N-(9H-Fluoren-9-yl)-6-isopropyl-7-oxo-6,7-dihydro-5H-dibenzo[c,
e]azepine-5-carboxamide (4q). White solid mp 238ꢀ240 ꢀC in 72%
yield. 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 7.9 Hz, 1H),
7.61ꢀ7.59 (m, 3H), 7.56ꢀ7.53 (m, 1H), 7.48ꢀ7.42 (m, 4H), 7.39 (d, J =
7.4 Hz, 1H), 7.36ꢀ7.33 (m, 2H), 7.20ꢀ7.14 (m, 2H), 7.03 (d, J = 7.5 Hz,
1H), 6.74 (d, J = 7.4 Hz, 1H), 5.84 (d, J = 8.8 Hz, 1H), 5.65 (d, J = 8.7 Hz,
1H), 5.28ꢀ5.22 (m, 1H), 5.14 (s, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.20 (d, J =
6.7 Hz, 3H). 13C NMR (62.5 MHz, CDCl3): 169.4, 167.9, 143.4, 140.3,
140.2, 137.7, 135.7, 135.2, 131.4, 131.1, 129.8, 129.6, 128.6, 128.5, 128.4 (ꢁ
2), 127.7 (ꢁ 2), 125.1, 125.0, 119.7, 60.4, 54.9, 46.7, 21.3, 20.3. HRMS
(FAB): calcd for C31H27O2N2 (MHþ) 459.2067, found 459.2058.
N-(9H-Fluoren-9-yl)-6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-
dibenzo[c,e]azepine-5-carboxamide (4r). White solid mp 108ꢀ110 ꢀC
N-tert-Butyl-6-cycloheptyl-7-oxo-6,7-dihydro-5H-dibenzo[c,e]aze-
pine-5-carboxamide (4t). White solid mp 72ꢀ74 ꢀC in 79% yield. 1H
NMR (300 MHz, CDCl3): δ 7.91 (d, J = 7.35 Hz, 1H), 7.60 (d, J = 7.56
Hz, 1H), 7.48ꢀ7.38 (m, 6H), 5.19 (s, 1H), 4.90 (m, 2H), 1.67ꢀ1.52 (m,
12H), 0.85 (s, 9H). 13C NMR (75 MHz, CDCl3): 167.7, 167.5, 139.0,
137.6, 135.5, 131.1, 130.8, 129.6, 129.5, 129.3, 128.5, 128.3, 128.2, 62.1,
57.4, 51.2, 35.5, 33.9, 33.1, 28.0, 27.6, 27.3, 26.5, 25.4, 25.0. HRMS (EI):
calcd for C26H32O2N2 404.2464, found 404.2470.
N-tert-Butyl-6-isobutyl-9-methoxy-7-oxo-6,7-dihydro-5H-dibenzo-
[c,e]azepine-5-carboxamide (4u). White solid mp 201ꢀ203 ꢀC in 70%
yield. 1H NMR (500 MHz, CDCl3): δ 7.57 (d, J = 7.4 Hz, 1H), 7.48 (t,
J = 7.4 Hz, 1H), 7.44(d, J = 2.6 Hz, 1H), 7.40ꢀ7.34 (m, 3H), 7.07 (dd,
J = 2.8, 8.6 Hz, 1H), 5.15 (s, 1H), 4.71 (s, 1H), 3.87 (s, 3H), 3.64 (dd, J =
7.7, 13.5 Hz, 1H), 3.49 (dd, J = 7.2, 13.4 Hz, 1H), 2.06ꢀ2.00 (m, 1H),
1.02 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H), 0.77 (d, J = 6.6 Hz, 3H). 13C NMR
(62.5 MHz, CDCl3): 168.5, 167.0, 159.7, 137.4, 137.1, 136.5, 130.0,
129.6, 129.4 (ꢁ 2), 129.2, 127.8, 119.0, 113.9, 67.7, 57.6, 55.7, 51.3, 28.1,
28.0, 27.0, 20.6, 19.8. HRMS (FAB): calcd for C24H31O3N2 (MHþ)
395.2329, found 395.2314.
N-tert-Butyl-3,9-dimethoxy-7-oxo-6-(prop-2-ynyl)-6,7-dihydro-5H-
dibenzo[c,e]azepine-5-carboxamide (4v). White solid mp 170ꢀ172 ꢀCin
80% yield. 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 8.4 Hz, 1H), 7.39
(d, J = 8.6 Hz, 2H), 7.09ꢀ6.98 (m, 2H), 6.93 (d, J = 2.5 Hz, 1H), 5.47 (s,
1H), 5.01 (s, 1H), 4.83 (d, J = 17.7 Hz, 1H), 4.39 (d, J = 19.9 Hz, 1H),
3.87ꢀ3.86 (m, 6H), 2.38 (s, 1H), 0.93 (s, 9H). 13C NMR (75 MHz,
CDCl3): 168.0, 166.7, 159.2, 159.0, 137.6, 134.6, 130.0, 129.9, 129.7, 119.3,
115.5, 114.6, 113.8, 78.7, 73.6, 65.8, 55.7, 55.5, 51.4, 38.1, 28.1. HRMS (EI):
calcd for C24H26O4N2 406.1893, found 406.1895.
5-(1-Hydroxy-4-methylpentan-2-yl)-8-methoxy-6-oxo-N-(2,4,4-tri-
methylpentan-2-yl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-4-
carboxamide (4w). (Mixture of two diastereoisomers) White crystalline
solid (mixture of diastereomers) in 40% combined yield. 1H NMR (400
MHz, CDCl3): δ 7.55ꢀ7.52 (m, 2H), 7.35ꢀ7.33 (m, 6H), 7.07ꢀ7.04 (m,
2H), 5.55 (s, 1H), 5.39 (s, 1H), 5.35ꢀ5.21 (m, 2H), 4.93 (bs, 2H), 4.68
(bm, 1H), 4.51ꢀ4.46 (m, 1H), 3.87ꢀ3.86 (m, 6H), 3.77ꢀ3.70 (m, 2H),
3.65ꢀ3.51 (m, 2H), 2.14ꢀ2.09 (m, 1H), 1.44ꢀ1.39 (m, 3H), 1.35ꢀ1.10
(m, 4H), 1.05- 0.90 (m, 9H), 0.85ꢀ0.65 (m, 35H). 13C NMR (100 MHz,
CDCl3): 169.5, 168.6, 168.0, 167.6, 159.4, 159.3, 139.4, 138.8, 136.9, 136.8,
133.6, 133.5, 128.0, 127.9, 127.4, 127.3, 125.9, 125.8, 124.7, 124.5, 119.4,
119.3, 115.6, 115.2, 63.8, 63.2, 55.9, 55.8, 55.7 (ꢁ 2), 53.3 (ꢁ 2), 53.1, 38.0,
37.8, 31.4, 31.3, 31.2, 27.6, 27.5, 27.4, 27.3, 25.0, 24.7, 23.2, 23.1, 22.4, 22.0.
HRMS (EI): calcd for C28H40O4N2S 500.2709, found 500.2713.
N-tert-Butyl-9,10,11-trimethoxy-6-(4-methoxybenzyl)-7-oxo-6,7-di-
hydro-5H-dibenzo[c,e]azepine-5-carboxamide (4x). Colorless oil in
2836
dx.doi.org/10.1021/jo200251q |J. Org. Chem. 2011, 76, 2828–2839

The Journal of Organic Chemistry
ARTICLE
1
60% yield. H NMR (250 MHz, CDCl3): δ 7.74 (d, J = 7.7 Hz, 1H),
7.60 (d, J = 7.5 Hz, 1H), 7.51ꢀ7.39 (m, 4H), 7.29ꢀ7.15 (m, 8H), 6.90
(d, J = 7.0 Hz, 1H), 6.71ꢀ6.69 (m, 2H), 5.40 (bs, 1H), 5.06 (d, J = 14.8
Hz, 1H), 4.82 (d, J = 14.8 Hz, 1H), 4.77 (s, 1H), 4.04 (dd, J = 6.5, 14.6
Hz, 1H), 3.82 (dd, J = 5.2, 14.6 Hz, 1H). 13C NMR (75 MHz, CDCl3):
168.7, 167.5, 138.7, 137.6, 137.1, 136.3, 136.0, 134.5, 134.2, 131.2,
131.1, 129.8 (ꢁ 2), 129.3, 128.7, 128.5, 128.4, 128.3, 128.0, 127.6,
127.4, 126.8, 65.7, 52.2, 43.8. HRMS (EI): calcd for C29H23ClO2N2
466.1448, found 466.1438.
7.40ꢀ7.33 (m, 3H), 7.22 (s, 1H), 7.08 (d, J = 6.4 Hz, 1H), 6.90 (d, J = 8.7
Hz, 2H), 5.30 (d, J = 14.2 Hz, 1H), 5.17 (s, 1H), 4.68 (s, 1H), 4.23 (d, J =
14.2 Hz, 1H), 3.94ꢀ3.92 (m, 6H), 3.81 (s, 3H), 3.52 (s, 3H), 0.82 (s,
9H). 13C NMR (62.5 MHz, CDCl3): 168.1, 166.7, 159.8, 153.2, 150.9,
145.2, 137.7, 132.7, 131.9, 130.9, 130.4, 129.2, 129.1, 128.0, 127.6, 125.3,
114.7, 108.7, 66.4, 61.3, 60.7, 56.3, 55.5, 51.8, 50.9, 28.1. HRMS (EI):
calcd for C30H34O6N2 518.2417, found 518.2424.
3,9,10,11-Tetramethoxy-6-(4-methoxybenzyl)-N-(4-methoxyphen-
yl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-carboxamide (4y).
White solid mp 215ꢀ218 ꢀC in 71% yield. 1H NMR (400 MHz, CD-
Cl3): δ 7.69ꢀ7.64 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.19 (s, 1H),
6.95ꢀ6.89 (m, 2H), 6.81 (s, 1H), 6.73 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 9.0
Hz, 2H), 6.49 (s, 1H), 5.06 (d, J = 14.3 Hz, 1H), 4.76 (s, 1H), 4.64 (d, J =
14.3 Hz, 1H), 3.83ꢀ3.79 (m, 12H), 3.69 (s, 3H), 3.51 (s, 3H). 13C NMR
(100 MHz, CDCl3): 168.3, 165.9, 159.7, 159.0, 156.7, 152.9, 150.2,
144.9, 138.4, 133.4, 132.2, 132.1, 130.7, 130.5, 129.9, 128.9, 128.6, 128.5,
125.2, 124.3, 121.9, 114.5, 114.3, 114.0, 113.8, 108.9, 65.6, 60.9, 60.6,
56.1, 55.4 (ꢁ 2), 55.3, 51.6. HRMS (EI): calcd for C34H34O8N2
598.2315, found 598.2319.
N-tert-Butyl-6-(3,4-dimethoxyphenethyl)-3,9,10,11-tetramethoxy-
7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-carboxamide (4z).
(∼9:1 mixture of rotamers) Yellow solid mp 65ꢀ67 ꢀC in 77% yield. 1H
NMR (400 MHz, CDCl3): δ 7.69ꢀ7.64 (m, 2H), 7.56ꢀ7.44 (m, 2H),
7.15 (s, 1H), 6.94 (dd, J = 2.28, 8.68 Hz, 1H), 6.80 (m, 2H), 5.28 (s, 1H),
4.63 (s, 1H), 4.21ꢀ4.15 (m, 1H), 3.91 (s, 6H), 3.86 (s, 9H), 3.70ꢀ3.63
(m, 1H), 3.56 (s, 3H), 3.06ꢀ2.90 (m, 2H), 0.89 (s, 9H). 13C NMR (100
MHz, CDCl3): 168.5, 166.7, 159.1, 152.9, 150.6, 149.3, 147.9, 145.1,
139.2, 133.2, 132.2, 132.1, 132.0, 131.9, 131.0, 130.9, 128.6, 128.5, 124.8,
124.5, 120.6, 115.2, 113.1, 112.0, 111.7, 108.6, 68.1, 61.1, 60.6, 56.2, 56.0
(ꢁ 2), 55.4, 51.1, 51.0, 34.0, 28.1. HRMS (EI): calcd for C33H40O8N2
592.2785, found 592.2784.
N-tert-Butyl-6-(3-methylbenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,
e]azepine-5-carboxamide (4aa). White solid mp 123ꢀ125 ꢀC in 60%
yield. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.5 Hz, 1H), 7.58 (d,
J = 7.5 Hz, 1H), 7.51ꢀ7.50 (m, 2H), 7.47ꢀ7.42 (m, 2H), 7.30ꢀ7.20 (m,
3H), 7.17ꢀ7.13 (m, 2H), 7.01 (d, J = 7.3 Hz, 1H), 5.21 (d, J = 14.3 Hz,
1H), 5.07 (bs, 1H), 4.75 (s, 1H), 4.53 (d, J = 14.1 Hz, 1H), 2.30 (s, 3H),
0.74 (s, 9H). 13C NMR (75 MHz, CDCl3): 168.5, 166.8, 138.8, 137.4,
137.2, 136.9, 136.8, 134.4, 131.1 130.7, 129.7, 129.5, 129.4, 129.2, 129.1,
129.0, 128.9, 128.7, 128.0 (ꢁ 2), 126.2, 65.9, 52.3, 50.9, 27.7, 21.3.
HRMS (EI): calcd for C27H28O2N2 412.2151, found 412.2151.
N-tert-Butyl-6-(3-chlorobenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,
e]azepine-5-carboxamide (4ab). White solid mp 69ꢀ71 ꢀC in 63%
yield. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 7.5 Hz, 1H), 7.61 (d,
J = 7.5 Hz, 1H), 7.53ꢀ7.45 (m, 4H), 7.31ꢀ7.24 (m, 5H), 6.96 (d, J = 7.5
Hz, 1H), 5.01ꢀ4.98 (m, 2H), 4.83 (d, J = 14.6 Hz, 1H), 4.69 (s, 1H),
0.78 (s, 9H). 13C NMR (75 MHz, CDCl3): 168.7, 166.4, 139.0, 137.4,
137.0, 136.6, 134.7, 134.3, 131.2, 130.9, 130.1, 129.7, 129.5, 129.4, 128.8,
128.6, 128.2 (ꢁ 2), 128.1, 127.0, 66.2, 52.2, 51.1, 27.8. HRMS (EI):
calcd for C26H25ClO2N2 432.1605, found 432.1604.
N-Benzyl-6-(3-methylbenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]-
azepine-5-carboxamide (4ac). White solid mp 165ꢀ167 ꢀC in 51%
yield. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.5 Hz, 1H), 7.59 (d,
J = 7.5 Hz, 1H), 7.51ꢀ7.40 (m, 4H), 7.27ꢀ7.06 (m, 8H), 6.91 (d, J = 7.5
Hz, 1H), 6.70 (d, J = 7.04 Hz, 2H), 5.01 (bs, 1H), 5.00 (d, J = 14.3 Hz,
1H), 4.82ꢀ4.79 (m, 2H), 3.95 (dd, J = 6.0, 14.6 Hz, 1H), 3.79 (dd, J =
5.3, 14.6 Hz, 1H), 2.21 (s, 3H). 13C NMR (75 MHz, CDCl3): 168.6,
167.7, 138.7, 137.6, 137.1, 136.6, 136.5, 136.3, 134.2, 131.2, 129.6, 129.4
(ꢁ 2), 128.8, 128.5, 128.2, 128.0, 127.6, 127.3, 126.0, 65.2, 52.3, 43.7,
21.2. HRMS (EI): calcd for C30H26O2N2 446.1994, found 446.1995.
N-Benzyl-6-(3-chlorobenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]a-
zepine-5-carboxamide (4ad). White solid mp 184ꢀ187 ꢀC in 68%
yield. 1H NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 1.2, 7.4 Hz, 1H),
N-Butyl-6-(3-chlorobenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]aze-
pine-5-carboxamide (4ae). White solid mp 164ꢀ166 ꢀC in 63% yield.
1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.3
Hz, 1H), 7.53ꢀ7.43 (m, 4H), 7.30ꢀ7.21 (m, 5H), 6.90 (d, J = 7.1 Hz,
1H), 5.12 (bs, 1H), 5.04 (d, J = 14.8 Hz, 1H), 4.84 (d, J = 14.8 Hz, 1H),
4.71 (s, 1H), 2.88ꢀ2.80 (m, 1H), 2.66ꢀ2.58 (m, 1H), 0.94ꢀ0.81 (m,
4H), 0.72 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): 168.7, 167.3,
138.8, 137.6, 136.6, 136.1, 134.5, 134.4, 131.1, 131.0, 130.0, 129.7 (ꢁ 2),
129.3, 128.7, 128.4, 128.3, 128.2, 128.0, 126.9, 65.7, 52.2, 39.3, 31.2, 19.7,
13.6. HRMS (EI) calcd for C26H25ClO2N2: 432.1605, found 432.1604.
N-Butyl-6-(3-methylbenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,e]az-
epine-5-carboxamide (4af). White solid mp 145ꢀ147 ꢀC in 68% yield.
1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.3
Hz, 1H), 7.52ꢀ7.41 (m, 4H), 7.28ꢀ7.26 (m(peak merged wih chloro-
form peak), 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H),
7.12ꢀ7.10 (m, 2H) 6.90 (d, J = 7.0 Hz, 1H), 5.17 (bs, 1H), 5.00 (d, J =
14.8 Hz, 1H), 4.81 (d, J = 14.8 Hz, 1H), 4.75 (s, 1H), 2.79ꢀ2.70 (m,
1H), 2.65ꢀ2.57 (m, 1H), 2.28 (s, 3H), 0.94ꢀ0.81 (m, 4H), 0.72 (t, J =
6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): 168.6, 167.6, 138.6, 137.6,
136.9, 136.6, 136.5, 134.4, 131.1, 130.8, 129., 129.5, 129.3, 128.7, 128.5,
128.1, 128.0, 126.0, 65.2, 52.4, 39.2, 31.1, 21.3, 19.7, 13.6. HRMS (EI):
calcd for C27H28O2N2 412.2151, found 412.2150.
N-Cyclohexyl-6-(3-chlorobenzyl)-7-oxo-6,7-dihydro-5H-dibenzo[c,
e]azepine-5-carboxamide (4ag). White solid mp 171ꢀ173 ꢀC in 71%
yield. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.0 Hz, 1H), 7.62 (d,
J = 7.3 Hz, 1H), 7.54ꢀ7.42 (m, 4H), 7.32ꢀ7.25 (m(peak merged wih
chloroform peak), 5H), 6.96 (d, J = 7.0 Hz, 1H), 4.98ꢀ4.95 (m, 2H),
4.87 (d, J = 14.8 Hz, 1H), 4.70 (s, 1H), 3.27ꢀ3.19 (m, 1H), 1.46ꢀ1.30
(m, 4H), 1.12ꢀ0.93 (m, 4H), 0.67ꢀ0.57 (m, 1H), 0.50ꢀ0.40 (m, 1H).
13C NMR (75 MHz, CDCl3): 168.7, 166.3, 138.9, 137.6, 136.7, 136.3,
134.6, 134.3, 131.2, 131.0, 130.1, 129.7, 129.6, 129.3, 128.8, 128.5, 128.3,
128.2, 128.1, 127.0, 65.7, 52.1, 48.1, 32.3 (ꢁ 2), 25.2, 24.5 (ꢁ 2). HRMS
(EI): calcd for C28H27ClO2N2 458.1761, found 458.1759.
N-tert-Butyl-6-(2-fluorobenzyl)-7-oxo-6,7-dihydro-5H-dibenzo-
[c,e]azepine-5-carboxamide (4ah). White solid mp 62ꢀ64 ꢀC in
70% yield. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.5 Hz, 1H),
7.58 (d, J = 7.3 Hz, 1H), 7.52ꢀ7.42 (m, 5H), 7.33ꢀ7.29 (m, 2H),
7.14ꢀ7.07 (m, 3H), 5.29 (d, J = 14.6 Hz, 1H), 5.20 (bs, 1H), 4.81 (s,
1H), 4.69 (d, J = 14.6 Hz, 1H), 0.77 (s, 9H). 13C NMR (75 MHz,
CDCl3): 168.6, 166.7, 162.8, 159.6, 137.3, 137.2, 136.7, 134.5, 132.0,
131.9, 131.2, 130.6, 130.1, 130.0, 129.6, 129.4, 129.3, 128.7, 128.1
(ꢁ 2), 124.9, 124.8, 123.9, 123.7, 115.7, 115.4, 66.2, 51.0, 45.8 (ꢁ 2),
27.7. HRMS (EI): calcd for C26H25FO2N2 416.1900, found
416.1894.
N-tert-Butyl-6-(3,5-dimethylbenzyl)-7-oxo-6,7-dihydro-5H-diben-
zo[c,e]azepine-5-carboxamide (4ai). White solid mp 183ꢀ186 ꢀC in
76% yield. 1H NMR (300 MHz, CDCl3): δ 7.95 (d, J = 7.5 Hz, 1H),
7.58 (d, J = 7.5 Hz, 1H), 7.52ꢀ7.41 (m, 4H), 7.33ꢀ7.28 (m, 1H), 7.04
(d, J = 7.4 Hz, 1H), 6.99ꢀ6.96 (m, 3H), 5.25 (d, J = 14.1 Hz, 1H), 5.11
(bs, 1H), 4.76 (s, 1H), 4.40 (d, J = 14.1 Hz, 1H), 2.28 (s, 6H), 0.74 (s,
9H). 13C NMR (75 MHz, CDCl3): 168.5, 166.9, 138.7, 137.4, 137.7,
136.9, 136.7, 134.4, 131.1, 130.7, 129.7, 29.5 (ꢁ 2), 129.1, 128.7, 128.0,
127.9, 126.9, 65.8, 52.2, 50.8, 27.7, 21.2. HRMS (EI): calcd for
C28H30O2N2 426.2307, found 426.2313.
N-Cyclohexyl-6-(3,5-dimethylbenzyl)-7-oxo-6,7-dihydro-5H-dib-
enzo[c,e]azepine-5-carboxamide (4aj). White solid mp 223ꢀ226 ꢀC
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The Journal of Organic Chemistry
ARTICLE
in 71% yield. 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 7.5 Hz, 1H),
7.59 (d, J = 7.0 Hz, 1H), 7.51ꢀ7.39 (m, 4H), 7.33ꢀ7.27 (m, 1H),
7.00ꢀ6.95 (m, 4H), 5.16 (d, J = 14.3 Hz, 1H), 5.09 (d, J = 8.5 Hz, 1H),
4.76 (s, 1H), 4.52 (d, J = 14.3 Hz, 1H), 3.23ꢀ3.10 (m, 1H), 2.28 (s, 6H),
1.45ꢀ1.42 (m, 2H), 1.23ꢀ0.93 (m, 6H), 0.60ꢀ0.40 (m, 2H). 13C NMR
(75 MHz, CDCl3): 168.6, 166.7, 138.7, 137.6, 137.0, 136.8, 136.6, 134.3,
131.1, 130.8, 129.7, 129.5, 129.4, 129.2, 128.6, 128.0, 127.9, 126.8, 65.2,
52.1, 47.8, 32.3, 32.2, 25.3, 24.5, 21.2. HRMS (EI): calcd for
C30H32O2N2 452.2464, found 452.2467.
N-Butyl-6-(3,5-dimethylbenzyl)-7-oxo-6,7-dihydro-5H-dibenzo-
[c,e]azepine-5-carboxamide (4ak). White solid mp 188ꢀ191 ꢀC in
79% yield. 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J = 7.3 Hz, 1H),
7.60 (d, J = 7.0 Hz, 1H), 7.51ꢀ7.40 (m, 4H), 7.30ꢀ7.26 (m(peak
merged wih chloroform peak), 1H), 6.93ꢀ6.90 (m, 4H), 5.22 (bs,
1H), 5.00 (d, J = 14.5 Hz, 1H), 4.76ꢀ4.70 (m, 2H), 2.79ꢀ2.68 (m,
1H), 2.67ꢀ2.56 (m, 1H), 2.26 (s, 6H), 0.95ꢀ0.80 (m, 4H), 0.73 (t,
J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): 168.6, 167.7, 138.5,
137.6, 137.0, 136.6, 136.5, 134.4, 131.1, 130.8, 129.6, 129.5, 129.4,
129.3, 128.5, 128.1, 127.9, 126.8, 65.1, 52.3, 39.2, 31.1, 21.2, 19.7,
13.6. HRMS (EI): calcd for C28H30O2N2 426.2307, found:426.
2309.
Present Addresses
^Institut fur Organische and Biomoleculare Chemie, Georg-
August-Universit€at G€ottingen, Tamannstr. 2, Goettingen 37077,
Germany.
’ ACKNOWLEDGMENT
The authors wish to thank the FWO (Fund for Scientific
ResearchꢀFlanders (Belgium)) and the Research Fund and the
Concerted Research Actions (GOA 10/15) of the Katholieke
Universiteit Leuven for financial support. V.P.M. is grateful to the
IRO (Interfacultaire Raad voor Ontwikkelingssamenwerking)
for obtaining a doctoral scholarship. The authors thank Ir. B.
Demarsin for HRMS measurements.
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1
enzo[c,e]azepin-5-one (5). Yellow oil in 54% yield. H NMR (400
MHz, CDCl3): δ 8.00 (d, J = 8.0, 1H), 7.73 (d, J = 8.0 Hz, 1H),
7.63ꢀ7.58 (m, 3H), 7.50ꢀ7.45 (m, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.15
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Thionation of Compound 4a To Give Corresponding Co-
mpound 6. To a solution of compound 4a (43 mg, 0.1 mmol) in 3 mL
of dry toluene was added Lawesson’s reagent (25 mg, 0.06 mmol). The
resulting solution was heated at reflux under conventional heating until
all the starting material was consumed (as determined by TLC and mass
analysis, ∼3.0 h). The solvent was evaporated, and the crude reaction
mixture was applied to silica gel column chromatography. The corre-
sponding product was isolated with EtOAC/heptane (2:8) solvent
system to afford as yellow solid.
N-tert-Butyl-6-(4-methoxybenzyl)-7-thioxo-6,7-dihydro-5H-diben-
zo[c,e]azepine-5-carboxamide (6). Yellow solid mp 186ꢀ188 ꢀC in
67% yield. 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 7.53 Hz, 1H),
7.64 (d, J = 7.53 Hz, 1H), 7.50ꢀ7.30 (m, 7H), 6.97ꢀ6.87 (m, 3H), 5.94
(d, J = 14.31 Hz, 1H), 5.10ꢀ5.04 (m, 2H), 4.83 (s, 1H), 3.82 (s, 3H),
0.77 (s, 9H). 13C NMR (75 MHz, CDCl3): 198.5, 165.1, 159.9, 141.1,
137.6, 136.0, 133.7, 130.5 (ꢁ 2), 129.9, 129.3 (ꢁ 2), 128.4, 128.3, 127.8,
127.7, 114.5, 69.1, 59.6, 55.5, 51.3, 28.0. HRMS (EI): calcd for
C27H28O2N2S 444.1871, found 444.1879.
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proto-
b
cols, spectroscopic data for all newly synthesized compounds,
biological screening protocols and results, crystallographic data for
compound 4g, 4w, and 5 in CIF format, and copies of 1HNMR and
13CNMR of all newly synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Ph: þ32 16 327406. Fax: þ32 16 327990. E-mail:
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Toppet, S.; Van Hecke, K.; Van Meervelt, L.; Voet, A.; De Maeyer, M.;
erik.vandereycken@chem.kuleuven.be.
2838
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porting Information for two enantiomers overlapped for compound
4w.)
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