One-Pot Synthesis of Diverse Collections of Benzoxazepine and Indolopyrazine Fused to Heterocyclic Systems

Article abstract of DOI:10.1021/acs.joc.8b02878

The development of efficient and modular synthetic methods for the synthesis of diverse collection of privileged substructures needed for a drug design and discovery campaign is highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of distinct members of biologically significant molecules. Several members of these families have gained attention due to their broad biological activities, which depend on the type of ring-fusion and peripheral substitution patterns. Despite the potential applications of these privileged substructures in drug discovery, efficient, atom-economic, and modular strategies for their access are underdeveloped. Herein, a one-step build/couple/pair strategy that uniquely allows access to diversely functionalized benzoxazepine and indolopyrazine scaffolds is described. The methodology features a one-pot combination of condensation, Mannich, oxidation, and aza-Michael addition reactions, employing a variety of functionalized anilines and aldehydes suitably poised with Micheal acceptor. Scandium triflate (Sc(OTf)₃) in acetonitrile (ACN) was found to promote the construction of benzoxazepines scaffolds, while sodium metabisulfite (Na₂S₂O₅) in aqueous EtOH rapidly enhanced the cascade reaction that led to diverse collections of indolopyrazine frameworks. These protocols represent modular, efficient, and atom-economic access of constrained benzoxazepine and indolopyrazine systems with more than 10 points of diversity and large substrate tolerance.

Full text of DOI:10.1021/acs.joc.8b02878

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Article
One-Pot Synthesis of Diverse Collections of Benzoxazepine
and Indolopyrazine Fused to Heterocyclic Systems
Vunnam Srinivasulu, Ihsan Shehadi, Monther A Khanfar, Omar G. Malik, Hamadah Tarazi, Imad
A. Abu-Yousef, Anusha Sebastian, Nabil Baniodeh, Matthew J. O'Connor, and Taleb H. Al-Tel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02878 • Publication Date (Web): 24 Dec 2018
Downloaded from http://pubs.acs.org on December 24, 2018
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One-Pot Synthesis of Diverse Collections of Benzoxazepine and
Indolopyrazine Fused to Heterocyclic Systems
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Vunnam Srinivasulu,† Ihsan Shehadeh,‡ Monther A. Khanfar,£ Omar G. Malik,‡ Hamadeh
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†
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∥
Tarazi, Imad A. Abu- Yousef, Anusha Sebastian, Nabil Baniowda, Matthew John O’Connor,
and Taleb H. Al-Tel*,†§
†Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE
‡College of Science, Department of Chemistry, University of Sharjah, P.O. Box 27272, Sharjah,
UAE
£Department of Chemistry, University of Jordan, 11942, Amman, Jordan
§College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE
#College of Arts and Sciences, Department of Biology, Chemistry and Environmental Sciences,
American University of Sharjah, Sharjah, UAE
∥
New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island, Abu Dhabi, UAE
taltal@sharjah.ac.ae
ABSTRACT: The development of efficient and modular synthetic methods for the synthesis of
diverse collection of privileged substructures needed for a drug design and discovery campaign, is
highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of
distinct members of biologically significant molecules. Several members of these families have
gained attention due to their broad biological activities, which depend on the type of ring-fusion
and peripheral substitution patterns. Despite the potential applications of these privileged
substructures in drug discovery, efficient, atom-economic and modular strategies for their access
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are underdeveloped. Herein, a one-step build/couple/pair strategy that uniquely allows access to
diversely functionalized benzoxazepine and indolopyrazine scaffolds, is described. The
methodology features a one-pot combination of condensation, Mannich, oxidation and aza-
Michael addition reactions, employing a variety of functionalized anilines and aldehydes suitably
poised with Micheal acceptor. Scandium triflate (Sc(OTf)3) in acetonitrile (ACN) was found to
promote the construction of benzoxazepines scaffolds, while sodium metabisulfite (Na2S2O5) in
aqueous EtOH rapidly enhanced the cascade reaction that led to diverse collections of
indolopyrazine frameworks. These protocols represent modular, efficient and atom-economic
access of constrained benzoxazepine and indolopyrazine systems with more than ten points of
diversity and large substrate tolerance.
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INTRODUCTION
The development of mild and modular synthetic strategies for the construction of diverse
collections of privileged heterocycles is paramount in the field of drug design and discovery.1 Such
strategies should be high yielding, eco-friendly, operationally simple, and result in a rapid increase
in skeletal and structural diversity using readily available starting materials.1 For the ideal
synthesis of privileged substructures needed in a phenotypic screening campaign, the efficiency of
the method is judged not by the number of complex steps involved, but by the use of nontoxic and
inexpensive catalysts, being operationally simple and it allows the use of a variety of substrates.2
Thus, inflexibility of the synthetic methods utilized and long reaction steps constitute a major
constraint in a library design.
Among the important structural options are benzoxazepines and indolopyrazines, privileged
scaffolds that display a broad spectrum of significant biological activities.3-7 Imidazo-, indolo- and
pyrrolo-fused benzoxazepines and indolopyrazines, constitute a range of anticancer,8 autoimmune9
and antibacterial agents.10 Representative examples of bioactive members of these analogues are
shown in Figure 1, and exemplified by the prostaglandin E2 receptor 2 (EP2) antagonist A,3 for the
treatment of Alzheimer’s disease, the receptor interacting protein 1 (RIP1) kinase inhibitor B,5
which has potent anticancer activity, and the retinoic acid‐related orphan receptor gamma (RORγt)
antagonist C, used for autoimmune diseases.9 Other benzoxazepine analogues include pyrrolo-1,5-
benzoxazepines (PBOX)-6 and PBOX-15, represented by structure D (Figure 1), have been shown
to induce apoptosis in acute lymphoblastic leukemia cells.4 Furthermore, recent reports indicated
their potency as inhibitors of phosphoinositide 3-kinases (PI3Ks) for treatment of several diseases
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(Structure E, Figure 1).11a Additionally, pyrrolo-pyrazine system represented by structure F
(Figure 1) has been reported to possess a potent antitumor activity.11b The pentacyclic indole
system G, indicated a potent antimicrobial activity.11c Moreover, the imidazo-fused pyrazine H is
known to be active as antimalarial agent.11d
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Owing to their broad biological significance, the synthesis of fused benzo[b,f]imidazo- and
thiazo[1,2-d][1,4]oxazepine systems, has been carried out through various methods.12
Additionally, the synthesis of heterocycles fused to indolopyrazine scaffolds, is underdeveloped.13
Representative strategies to access heterocyles-fused to benzoxazepine systems include domino
aziridine ring-opening and an isocyanide-insertion reaction,14a and ring-opening/aza-Michael
addition of activated aziridines.14b On the other hand, various methods were utilized for the
synthesis of indolo fused pyrazine frameworks. Among others are, the intramolecular
dehydrogenative cross-coupling with Cu catalyst,15a,b Pd-catalyzed regioselective intramolecular
dehydrogenative cross coupling,15c Ir-catalyzed asymmetric allylic amination15d and
photocyclization and photochemical dehydrogenation reactions.10b
Figure 1. Representative structures of bioactive benzoxazepine and indolopyrazine analogues.
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Although these protocols represent important methods for the synthesis of benzoxazepine and
indole fused pyrazine systems, many of these strategies utilize multi-step procedures, harsh
reaction conditions, toxic catalysts and solvents, preparation of synthetically challenging
intermediates, and poor overall yields. Additionally, the peripheral substitution pattern and the type
of ring fusion have profound effects on their biological activities (Figure 1).3-5,9,11a-e Furthermore,
given the conformational flexibility of the 7-membered ring benzoxazepine core, constrained
analogues might exhibit diverse biological activities that might be largely affected by the ring-
fusion patterns.3-5,9,11a-b Therefore, it was believed that the lack of modular and efficient synthetic
strategies to rapidly access these scaffolds have restricted systematic studies toward multiple
phenotypes. Hence, establishing a modular cascade for the rapid access of these analogues would
be a remarkable achievement. In this context, one of the key objectives of this work, is the
development of efficient and mild methods to rapidly access diverse collections of scaffolds that
represent the basic core of biologically relevant compounds.16 Thus, an operationally simple
protocol for the construction of skeletally diverse benzoxazepine and indolopyrazine scaffolds
fused to various classes of heterocylic rings, is accomplished. This design was inspired by a
previous experience in the reactivity and applications of the central element 1a (Scheme 1).16c-d
Accordingly, it was envisaged that the addition of an aryl diamine-based ambident nucleophile to
a binucleophuge, an aldehyde suitably poised with Michael acceptor, should generate
benzimidazole and/or benzoquinazoline systems which subsequently initiates the intramolecular
aza-Michael addition reaction leading to the tetracyclic benzimidazo- or benzoquinazoline-fused
benzoxazepine scaffolds of the types 6a and 8, respectively (Schemes 2 and 4). Herein, the
successful implementation of this cascade combining condensation/Mannich/oxidation/aza-
Michael addition reactions in one-pot, is presented.
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Scheme 1. Preparation of 2-arylbenzimdazole/thiazole sulfonic acid derivatives
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RESULTS AND DISCUSSION
Synthetic Design. The synthetic plan is commenced as described in Scheme 1. For the synthesis
of the benzimidazole intermediate 3a, many conditions have been reported for the construction of
similar scaffolds.17 However, it was anticipated that only a few would be suited for our strategy to
provide a general one-step protocol that facilitates the proposed cascade and tolerates a wide range
of substrates. Therefore, many relevant reaction parameters were systematically explored. Among
the catalysts utilized to promote the synthesis of benzimidazoles is sodium metabisulfite
(Na2S2O5).17 Thus, it was found that the use of Na2S2O5 in aqueous EtOH rapidly provided the
desired benzimidazole intermediate 3a, which was detected through LCMS analysis. Without
purification, treatment of the latter with another 1.0 equivalent of Na2S2O5 in EtOH/H2O at 60 °C,
gave rise to a product with a structure that is thought to belong to the desired benzoxazepine 4.
Surprisingly, this product was identified to be the unexpected product 5. Clearly, the sulfur atom
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in the SO32- fragment arising from Na2S2O5, added to the -carbon of the Michael adduct in 3a,
leading to 5. This protocol turns out to be a general procedure for the synthesis of these scaffolds.18
Thus, employing various phenylene diamines, i.e. 2a-c and aminothiophenols 2d-e as starting
materials, delivered the corresponding -sulfonic acid products, 5a-e. The structures of these
compounds were confirmed though high resolution mass spectroscopy (HRMS), 1D- and 2D-
NMR analysis (Supporting Information). At this point in time, it was envisioned that these
products might be differentiated to complex systems through coupling between the sulfonic acid
residue and the NH group of the imidazole ring. Thus, many attempts were made to promote this
transformation, if successful; we would have had in hand, an eight-membered ring sulfone amide
system of type I (Scheme 1). Unfortunately, all attempts using different reagents and conditions
(T3P, TBTU, POCl3 and SOCl2), failed to promote the formation of the eight-membered system I.
At this junction, efforts were directed toward finding the best conditions to promote the Mannich
and the aza-Michael addition steps for the construction of systems of type 4 (Scheme 1). Hence,
many reaction conditions and catalysts were explored, including Sc(OTf)3, ACOH, and TFA.
Unfortunately, none of these conditions were found to be compatible with the cascade reaction.
To our delight, it was found that the reaction proceeded smoothly when reacting the
phenylenediamine (2f) with aldehyde 1a at rt for 2h in the presence of molecular sieves to produce
the imine intermediate I (Scheme 2). Subsequent addition of 10 mol% of Sc(OTf)3 was found to
affect the formation of intermediate 3a. Subjecting the latter to another 10 mol% of Sc(OTf)3 under
microwave conditions at 130 oC, produced the benzimidazo- fused benzoxazole system 6a in 65%
yield. The structure of the latter was unambiguously confirmed through 1D- and 2D-NMR
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analysis. A salient feature in the C NMR spectrum of compound 6a is the downfield chemical
shift of the angular methine carbon which appeared at  53.5 ppm (evidenced from its HSQC
spectrum, Supporting Information), unambiguously confirming that the imidazolyl sp3 nitrogen
proceeded to the intramolecular aza-Michael addition leading to the benzoxazepine system
(Scheme 2).
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Scheme 2. One-pot synthesis of imidazole fused benzoxazepines. Step-1: 1a (0.25 mmol), 2a
(0.25 mmol), molecular sieves, ACN (2 mL), rt, 2h, and then Sc(OTf)3 (10 mol%), MW, rt-70
°C, 11h. Step-2: Sc(OTf)3 (10 mol%), MW, 130 °C, 1.5 h
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Scheme 3. Synthesis of various imidazole fused to benzoxazepine and benzodiazapine
scaffolds
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Synthesis of skeletaly diverse benimidazole-fused benzoxazepines. With the optimized
conditions in hand, we next investigated the substrate scope of the cascade using the aldehyde 1a
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and various anilines 2f-h, to yield the corresponding tetracyclic benzimidazole-fused
benzoxazepine systems in fairly good overall yields (6a-c, Scheme 3). Notably, electron-
withdrawing or -donating moieties on the aromatic amines had no significant impact on the overall
yields (Scheme 3). To unambiuously confirm the structures of these systems, the structure of 6c
was confirmed through X-ray crystaloghraphic analysis (Scheme 3 and Table S1). To further
extend the scope of this cascade, naphthylaldehyde 1b, was found to be equally suited for the
tandem process, producing compounds 6d-f in fairly good yields. The structure of 6e was
confirmed through X-ray crystaloghraphic analysis (Scheme 3 and Table S2).
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To increase the skeletal diversity of the pilot library, a quinolizine-fused aldehyde 1c was proposed
as a substrate. While its reaction proceeded slowly (6g-i) the overall isolated yields were relatively
high compared to bicyclic aromatic aldehydes. With the robust reaction conditions in hand, it was
envisaged to widen the scope of the cascade to produce skeletally diverse polycyclic scaffolds.
Thus, the use of N-Ts-substituted aldehyde, 1d, was considered and found to be suitable with the
cascade conditions to deliver the benzoimidazo-fused benzodiazepine systems 6j-l, in fairly good
yields. The latter represents the core scaffold of many biologically significant compounds, that
include anticonvulsant, antipsychotics, muscle relaxant and antimicrobial agents.19 To test the
regiochemistry of the reaction, mono substituted phenylene diamine was introduced as one of the
reaction components. As expected, the reaction of 4-chloro phenelynediamine (2i) under the
obtimized reaction conditions, deilvered a 1:1 mixture of regioisomers (6m and 6n) as concluded
from its 1H and 13C NMR spectra (Scheme 3 and Supporting Information).
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Scheme 4. Synthesis of various quinazoline fused to benzoxazepine and benzodiazapine
derivatives
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Synthesis of quinazolinone-fused benzodiazepines. In addition to the structural diversity of the
anilines and aldehydes used thus far, a second diversity element was incorporated into the library
design by employing aminobenzamides as ambident nucleophiles. Hence, it was envisioned that
applying the same chemistry to the 2-aminobenzamide systems 7a-c (Scheme 4), would allow for
additional skeletal diversity within the pilot library. To demonstrate this, the 2-aminobenzamides
7a-c were reacted with aldehyde 1a under the optimized reaction conditions to furnish the
corresponding quinazolinone fused to benzoxazepine systems 8a-c in good overall yields. A
Salient feature of the 13C-NMR spectrum of compound 8a, is the cyclic methine carbon resonating
at  49.3 ppm, providing a concrete evidence for the formation of the benzoxazepine ring, which
was further confirmed by X-ray crystallographic analysis (Scheme 4 and Table S3). The skeletal
diversity of the quinazoline products arising from the aminobenzamide ambident nucleophile, was
expanded to include the polycyclic systems 8d and 8e. To further diversify this pilot library, the
NTs-tethered aldehyde 1d was introduced in the cascade as a starting material, to deliver
diastereoselectively the quinazolinone fused to benzodiazepine systems 8f-h. Surprisingly, the
oxidation reaction leading to the double bond formation similar to 8a-8e systems, was found to be
incompatible with this scaffold, despite the many attempts to variate the reaction conditions. To
unambiguously confirm the delicate stereochemistry around these systems, NOSEY studies did
not indicate reciprocal interactions between the methine protons resident on the chiral carbons,
confirming their trans-disposition (Supporting Information). An X-ray analysis was carried out for
compound 8g (Scheme 4 and Table S4) to unequivocally confirm the preceding NOSEY results.
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Scheme 5. Synthesis of imidazole fused to pyrrolo- and indolo-pyrazine systems
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Synthesis of indolo- and pyrrolo-benzimidazopyrazine scaffolds. In order to expand the
scaffold diversity in the pilot compound library, it was decided to incorporate a second ring-size
diversity element in the synthetic design. Thus, it was believed that this could be achieved through
the reaction between the aldehyde 9a and the phenylene diamine (2f). If successful, we would have
had in hand a complex ring system that encompasses an indole fused to benzimidazopyrazine
framework of type 10. The latter, represents the basic core of many biologically important
molecules including anticancer and antibacterial motifs.11d,20 To test the validity of this plan, a
solution of Na2S2O5 in aqueous ethanol was utilized as a possible promoter of the proposed cascade
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reaction, Scheme 1 (vide supra). Interestingly, it was found that the use of Na2S2O5 in aqueous
EtOH at 25 to 80 °C for 12h, is compatible with this cascade and gave rise to the desired product
dihydrobenzo[4',5']imidazo[2',1':3,4]- pyrazino[1,2-a]indol 10. Thus, reaction of indolyl aldehyde
9a with phenylene diamine 2f, under the optimized reaction conditions, furnished the
tetrahydropyrazino[1,2-a]indole system 10a. The structure of 10a, was unambiguously confirmed
by extensive 1D- and 2D-NMR studies. A salient feature of the 13C NMR spectrum of 10a, is the
chemical shift of the cyclic methine carbon resonating at  48.7 ppm, which was also concluded
from the correlations in its HSQC-2D spectrum (Supporting Information).
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To explain this controversial reactivity of aldehydes 1a and 9a with phenylene diamine under
Na2S2O5 in EtOH/H2O conditions, one should consider the steric bias that dictates the products
produced by the two reactions. Obviously, under these conditions, the formation of a six-
membered indolo-tetrahydopyrazine scaffold 10a, through intramolecular aza-Michael addition
(intermediate VII, Scheme 6), is rather more preferred than the nucleophilic Michael addition of
the SO32- group due the steric compression imposed by the indolyl group (intermediate V, Scheme
6). However, the nucleophilic Michael addition of the SO32- group on intermediate I dominates,
since the aryloxy arm is relatively away from the -carbon (intermediate II, Scheme 6). Therefore,
the steric compression between the aryloxy and the benzimidazole groups, hinders the attack of
the benzimidazole NH group on the ,-unsaturated ester. In another aspect, the aza-Michael
addition in intermediate III might be deviated from the right angle needed to form IV, when
compared to that in intermediate VII leading to VIII. Besides, the formation of a six membered-
ring system is rather thermodynamically more preferred than a seven-membered ring analogue.
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Scheme 6. Rational for the formation of the sulfonic acid and pyrazine products using sodium
metabisulfite
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With the optimized conditions in hand, the attention is directed towards the synthesis of a pilot
library of these polycyclic tetrahydropyrazine systems. Thus, reactions between aldehydes 9a-b
and phenylene diamines 2f-h, delivered the polysubstituted indolo-tetrahydropyazine systems
10b-f in fairly good yields. To unambiguously confirm the structures of these systems, compound
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10b was chosen as a representative model for X-ray crystallographic analysis (Scheme 5 and Table
S5). To further diversify the library, a ring-based diversity element was introduced when the
pyrolyl aldehyde 9c was used as a nucleophuge. Thus, reaction of 9c with various substituted
phenylene diamines delivered the pyrrolo-fused tetrahydropyrazine systems 10g-i in relatively fair
yields. To broaden the skeletal diversity of the tetrahydropyrazino[1,2-a]indole scaffolds, the
indolyl aldehyde binucleophuge 9 was subjected to reaction with the ambident nucleophile 2-
aminobenzylamine (11) to deliver the indolo-fused pyrazino[1,2-a]quinazoline 12 in satisfactory
yield (Scheme 7). The latter represents the basic core of evodiamine, a natural product isolated
from Evodiae fructus.21a-d Evodiamine has been included in some dietary preparations as it has
been shown to reduce fat uptake in animals.21e Recently, it has also been reported that evodiamine
possesses anticancer activity by inhibition of the human DNA topoisomerase I.21f Interestingly,
stirring compound 12 in the presence of oxone in DMF:water delivered the oxidized product 13 in
a quantitative yield. The structure of which was unambiguously confirmed from its NMR spectra
and X-ray crystallographic analysis (Scheme 7 and Table S6). The absence of the quinazoline
methylene carbon of 12 in its 13C NMR spectrum, was reflected by the amide carbon resonating at
161 ppm. Further confirmation of the structure was concluded from the 2D-NMR connectivities
(HSQC and HMBC, Supporting Information). To further elaborate on the importance of these
systems, a 3D-overlay of compounds 10a, 13 and evodiamine (Figure 2) indicated ca. 79%
similarity when comparing their 3D-shapes. This rationale indicates the value of our approach
toward the synthesis of biologically relevant molecules. In this respect, the flexibility in the choice
of the starting materials and the presence of the ester arm in the final products, allow for the
synthesis of a diverse library similar to that of evodiamine, hence facilitating comprehensive SAR
studies.
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Scheme 7. Synthesis of quinazoline fused to indolo pyrazine systems
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Figure 2 (A). An overlay of evodiamine (brown) and compound 10a (purple), similarity = 72.6%. (B)
An overlay of evodiamine (brown) and compound 13 (magenta), similarity = 79.1%.
CONCLUSION
In summary, the work presented in this article, represents a tandem one-pot route to access diverse
collections of benzoxazepine and indolopyrazine fused to various heterocylic systems. The catalysts,
Sc(OTf)3 or aqueous solution of Na2S2O5, were found to mediate the Mannich/aza-Michael addition-
cyclization reactions. The use of this approach allowed for the access of a range of complex molecular
scaffolds, employing reagent and starting material-based reaction schemes. This concept was validated
by the construction of a 31-membered library with a broad distribution of molecular shapes, starting from
readily accessible building blocks. The combination of reagent- and starting material-based approaches
for the generation of molecular diversity, delivered many important possibilities not achievable by either
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method alone. Work is under way in our laboratories to further explore the biological activities of the
compound collections.
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EXPERIMENTAL SECTION
9
General Experimental Methods. Chemical reagents and anhydrous solvents were purchased from Sigma-
Aldrich and were used without further purification. Solvents for extraction and column chromatography
were distilled prior to use. TLC analysis were performed with silica gel plates (0.25 mm, E. Merck, 60 F254)
using iodine and a UV lamp for visualization. 1H and 13C NMR experiments were performed on a 500 MHz
instrument, respectively. Chemical shifts are reported in parts per million (ppm) downstream from the
internal tetramethylsilane standard. Spin multiplicities are described as s (singlet), bs (broad singlet), d
(doublet), dd (doubledoublet), td (tripledoublet), t (triplet), q (quartet), or m (multiplet). Coupling constants
are reported in Hertz (Hz). ESI mass spectrometry was performed on a Q-TOF high resolution mass
spectrometer or Q-TOF Ultim LC-MS. MW irradiation reactions were performed in a selaed vial on CEM
synergy microwave synthesizer (version; DSCA02.22). The surface temperaute of the reaction vessel was
monitered by IR extrenal surface sensor. Single-crystal X-ray diffraction data were collected using an
Oxford Diffraction XCalibur, equipped with (Mo) X-ray Source (λꢀ=ꢀ0.71073ꢀÅ) at 293(2)ꢀK.
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Methyl (E)-4-(2-formylphenoxy)but-2-enoate (1a).16c NaH (6 mmol) at 0 °C was added to a solution of
salicylaldehyde (5 mmol) in DMF (10 mL). After 30 min, a solution of methyl trans-4-bromo-2-butenoate
(7.0 mmol) in DMF (5 mL) was added dropwise and stirring was continued at rt for 3h. After completion,
reaction mixture was quenched with saturated NH4Cl solution, diluted with ethylacetate (100 mL) and
washed with cold water (2 x 50 mL). The organic layer was separated, dried over Na2SO4 and concentrated
under vacuum. The crude was purified on flash chromatography, using 25% EtOAc in hexane as an eluent
to produce the title compound 1a. White solid (1.1g, 85% yield); 1H NMR (500 MHz, CDCl3) δ 10.56 (s,
1H), 7.90 – 7.86 (m, 1H), 7.63 – 7.50 (m, 1H), 7.20 – 7.06 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.31 – 6.18
(m, 1H), 4.87 – 4.84 (m, 2H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 189.4, 166.3, 160.2, 141.6,
136.0, 129.0, 125.2, 122.2, 121.6, 112.6, 66.9, 51.9. LCMS (ESI): m/z 221 [M+H]+.
Methyl (E)-4-(2-(1H-benzo[d]imidazol-2-yl)phenoxy)but-2-enoate (3a). Sodium metabisulfite (0.75
mmol) in H2O (0.5 mL) was added to a solution of aldehyde (1a, 0.5 mmol) in ethanol (2 mL) at rt. After
30 min, diamine (2, 0.5 mmol) was added and stirring was continued at rt for 2 h. The reaction mixture was
heated to 40 oC for 8 h. After completion, ethanol was completely removed, and the crude reaction mixture
was diluted with EtOAc (20 mL) and extracted with water (10 mL). The organic layer was separated, dried
over Na2SO4 and concentrated under vacuum. The crude was purified on flash chromatography, using 32%
EtOAc in hexane as an eluent to produce the title compound 3a as off white solid (101 mg, 66% yield); 1H
NMR (500 MHz, CDCl3) δ 8.61 (d, J = 7.5 Hz, 1H), 7.78 – 7.62 (m, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.36 –
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7.25 (m, 2H), 7.25 – 7.15 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.21 (d, J = 15.8 Hz, 1H), 5.04 (s, 2H), 3.80 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 166.0, 155.3, 149.2, 141.5, 131.4, 130.7, 123.0, 122.9, 122.6, 118.0,
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112.8, 67.7, 51.9; HRMS (ESI-TOF): m/z calcd for C18H17N2O3, 309.1239 found 309.1236 [M+H]+
.
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General reaction procedure for the preparation of compounds 5a-c. Sodium metabisulfite (0.75 mmol)
in H2O (0.5 mL) was added to a solution of aldehyde (1a, 0.5 mmol) in ethanol (2 mL) at rt. After 30 min,
diamine (2, 0.5 mmol) was added and stirring was continued at rt for 2 h. The reaction mixture was heated
to 40 oC for 8 h. After completion of step-1, another one equivalent of sodium metabisulfite (0.5 mmol) in
water (0.5 mL) was added and the reaction was heated to 60-80 °C for 8-12 h. After completion, ethanol
was completely removed, and the crude reaction mixture was diluted with EtOAc (20 mL) and extracted
with water (10 mL). The aqueous layer was concentrated to minimum. Crystallization of the crude mixture
from water produced a pure product.
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4-Methoxy-1-(2-(6-methyl-1H-benzo[d]imidazol-2-yl)phenoxy)-4-oxobutane-2-sulfonic acid (5a).
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White amorphous solid (147 mg, 73% yield); H NMR (500 MHz, CD3OD+CDCl3) δ 8.00 (d, J = 7.1 Hz,
1H), 7.64 (t, J = 6.5 Hz, 2H), 7.60 – 7.55 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 2H), 4.75
(dd, J = 9.6, 2.4 Hz, 1H), 4.57 (dd, J = 9.6, 5.9 Hz, 1H), 3.83 – 3.75 (m, 1H), 3.67 (d, J = 6.4 Hz, 3H), 3.24
(dd, J = 16.1, 7.6 Hz, 1H), 2.82 (dd, J = 16.1, 10.0 Hz, 1H) 2.50 (s, 3H); 13C{1H} NMR (125 MHz,
CD3OD+CDCl3) δ 172.6, 157.5, 145.7, 137.8, 136.0, 132.1, 129.8, 129.5, 128.7, 122.7, 114.0, 113.9, 113.5,
111.5, 68.5, 55.9, 52.4, 32.5, 21.8; HRMS (ESI-TOF): m/z calcd for C19H21N2O6S, 405.1120 found
405.1120 [M+H]+
.
1-(2-(6-Chloro-1H-benzo[d]imidazol-2-yl)phenoxy)-4-methoxy-4-oxobutane-2-sulfonic acid (5b). Off
white amorphous solid (144 mg, 68% yield); 1H NMR (500 MHz, CD3OD) δ 8.13 (d, J = 7.8 Hz, 1H), 7.76
(d, J = 1.7 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.26 – 7.19 (m,
2H), 4.76 – 4.71 (m, 1H), 4.58 (dd, J = 9.7, 5.8 Hz, 1H), 3.85 – 3.77 (m, 1H), 3.69 (s, 3H), 3.24 (dd, J =
13
17.1, 4.2 Hz, 1H), 2.86 (dd, J = 17.1, 9.6 Hz, 1H); C{1H} NMR (125 MHz, CD3OD+CDCl3) δ 171.9,
156.6, 147.9, 134.3, 132.2, 130.65, 130.61, 129.2, 125.4, 121.8, 115.1, 114.0, 112.8, 112.4, 67.6, 55.3, 51.6,
31.8; HRMS (ESI-TOF): m/z calcd for C18H18ClN2O6S, 425.0574 found 425.0570 [M+H]+.
1-(2-(1H-Benzo[d]imidazol-2-yl)phenoxy)-4-methoxy-4-oxobutane-2-sulfonic acid (5c). Off white
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amorphous solid (126 mg, 65% yield); H NMR (500 MHz, DMSO-d6) δ 8.22 (dd, J = 7.8, 1.2 Hz, 1H),
7.78 (dd, J = 6.1, 3.1 Hz, 2H), 7.75 – 7.67 (m, 1H), 7.54 (dd, J = 6.1, 3.1 Hz, 2H), 7.42 (d, J = 8.5 Hz, 1H),
7.35 – 7.26 (m, 1H), 4.64 (dd, J = 9.7, 2.5 Hz, 1H), 4.45 (dd, J = 9.7, 6.0 Hz, 1H), 3.60 (s, 3H), 3.48 – 3.42
(m, 1H), 2.97 (dd, J = 16.7, 4.8 Hz, 1H), 2.70 (dd, J = 16.7, 8.8 Hz, 1H); 13C{1H} NMR (125 MHz, DMSO-
d6) δ 172.0, 156.9, 146.5, 135.2, 132.8, 130.1, 125.8, 122.0, 114.5, 113.5, 112.3, 68.8, 55.0, 52.1, 32.6.
HRMS (ESI-TOF): m/z calcd for C18H19N2O6S, 391.0963 found 391.0963 [M+H]+.
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General reaction procedure for the preparation of compounds 5d-e. Sodium bisulfite (0.5 mmol) in
H2O (0.5 mL) was added to a solution of aldehyde (1a, 0.5 mmol) in DMF (2 mL) at rt. After 30 min, 2-
aminothiophenol (3, 0.5 mmol) was added and stirring was continued at rt for 2 h. The reaction mixture
o
was heated at 70 C for 8 h. After completion of step-1, another one equivalent of sodium bisulfite (0.5
9
mmol) in H2O (0.5 mL) was added and the reaction was heated to 70 °C for 8-12 h. After completion, the
reaction mixture was diluted with EtOAc (20 mL) and treated with water (10 mL). The aqueous layer was
concentrated to minimum volume. Crystallization of the crude mixture from water produced pure product.
1-(2-(Benzo[d]thiazol-2-yl)phenoxy)-4-methoxy-4-oxobutane-2-sulfonic acid (5d). White amorphous
solid (134 mg, 66% yield); 1H NMR (500 MHz, CD3OD) δ 8.40 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.2 Hz,
1H), 7.98 (d, J = 7.8 Hz, 1H), 7.56 – 7.48 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.17
(t, J = 7.5 Hz, 1H), 4.87 – 4.83 (m, 1H), 4.43 (t, J = 9.9 Hz, 1H), 4.09 – 4.02 (m, 1H), 3.58 (s, 3H), 3.07 (d,
J = 6.4 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 173.4, 164.0, 156.3, 151.7, 135.7, 132.5, 129.8, 126.5,
125.2, 122.6, 122.0, 121.8, 121.5, 112.9, 68.3, 56.2, 52.1, 34.2; HRMS (ESI-TOF): m/z calcd for
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C18H18NO6S2, 408.0575 found 408.0571 [M+H]+
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1-(2-(6-Chlorobenzo[d]thiazol-2-yl)phenoxy)-4-methoxy-4-oxobutane-2-sulfonic acid (5e). White
amorphous solid (136 mg, 62% yield); 1H NMR (500 MHz, CD3OD) δ 8.45 (dd, J = 7.9, 1.7 Hz, 1H), 8.01
(dd, J = 10.8, 5.2 Hz, 2H), 7.59 – 7.55 (m, 1H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.23 – 7.16 (m, 1H), 4.85 – 4.80 (m, 1H), 4.49 – 4.41 (m, 1H), 4.07 – 3.99 (m, 1H), 3.58 (s, 3H), 3.12 –
3.00 (m, 2H); 13C{1H} NMR (125 MHz, CD3OD) δ 172.2, 165.5, 156.3, 152.7, 134.3, 132.4, 131.8, 129.0,
124.9, 122.3, 121.5 (2C), 121.2, 112.7, 68.4, 55.9, 50.9, 33.7; HRMS (ESI-TOF): m/z calcd for
C18H17ClNO6S2, 442.0185 found 442.0184 [M+H]+
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General reaction procedure for the preparation of compounds 6a-c. To a stirred solution of amine (2,
0.25 mmol) and molecular sieves in ACN (1 mL), a solution of aldehyde (1a, 0.25 mmol) in ACN (1 mL)
was added over a period of 1h at rt. After 2h, Sc(OTf)3 (10 mol%) was added and stirring was continued at
rt for another 10h. Next, the reaction mixture was stirred under MW at 70-100 °C for 1h. TLC showed the
complete absence of starting materials and formation of new spots. Next, Sc(OTf)3 (10 mol%) was added
and the reaction mixture was stirred under MW conditions at 100-130°C for 1.5h. After completion, ACN
was removed, and the crude was purified by flash chromatography, using EtOAc in hexane as an eluent.
Methyl 2-(6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepin-7-yl)acetate (6a). Off white
solid (50 mg, 65% yield, eluent: 19% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.86 (dd, J = 8.1,
1.6 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.47 – 7.43 (m, 1H), 7.42 – 7.37 (m, 1H), 7.37 – 7.30 (m, 2H), 7.24 –
7.18 (m, 1H), 7.14 (dd, J = 8.2, 0.9 Hz, 1H), 5.26 – 5.20 (m, 1H), 4.94 (dd, J = 13.1, 3.5 Hz, 1H), 4.35 (d,
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J = 13.1 Hz, 1H), 3.75 (s, 3H), 3.19 (dd, J = 16.8, 9.3 Hz, 1H), 2.89 (dd, J = 16.8, 4.0 Hz, 1H); C{1H}
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NMR (125 MHz, CDCl3) δ 171.1, 156.6, 149.8, 142.9, 135.6, 132.1, 131.6, 123.2, 123.1, 123.0, 120.8,
120.0, 117.7, 109.4, 70.2, 53.5, 52.3, 35.4; HRMS (ESI-TOF): m/z calcd for C18H17N2O3, 309.1239 found
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309.1221 [M+H]+
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Methyl 2-(10,11-dimethyl-6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepin-7-yl) acetate
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(6b). Off white solid (60 mg, 72% yield, eluent: 21% EtOAc in hexane); H NMR (500 MHz, CDCl3) δ
8.82 (dd, J = 8.2, 1.7 Hz, 1H), 7.60 (s, 1H), 7.39 – 7.34 (m, 1H), 7.23 – 7.15 (m, 2H), 7.12 (dd, J = 8.2, 1.1
Hz, 1H), 5.18 – 5.12 (m, 1H), 4.92 (dd, J = 13.1, 3.4 Hz, 1H), 4.32 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.17
(dd, J = 16.8, 9.7 Hz, 1H), 2.91 – 2.85 (m, 1H), 2.44 (s, 3H), 2.42 (s, 3H); 13C NMR{1H} (125 MHz,
CDCl3) δ 171.0, 156.3, 148.8, 141.4, 134.0, 132.4, 132.0, 131.7, 131.0, 122.8, 120.6, 119.9, 117.9, 109.4,
70.0, 53.3, 52.2, 35.2, 20.7, 20.3; HRMS (ESI-TOF): m/z calcd for C20H21N2O3, 337.1552 found 337.1525
[M+H]+
.
Methyl 2-(10,11-dichloro-6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepin-7-yl) acetate
(6c). White solid (45 mg, 48% yield, eluent: 23% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.77
(dd, J = 8.2, 1.7 Hz, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 7.47 – 7.38 (m, 1H), 7.24 – 7.19 (m, 1H), 7.14 (dd, J =
8.2, 1.1 Hz, 1H), 5.16 – 5.11 (m, 1H), 4.93 (dd, J = 13.1, 3.5 Hz, 1H), 4.32 (d, J = 13.1 Hz, 1H), 3.77 (s,
3H), 3.17 (dd, J = 16.9, 8.8 Hz, 1H), 2.84 (ddd, J = 16.9, 5.1, 0.8 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 170.7, 156.7, 151.8, 142.3, 134.8, 132.3, 132.2, 127.3, 127.0, 123.2, 121.1, 120.9, 116.9, 110.9,
70.1, 53.8, 52.5, 35.3; HRMS (ESI-TOF): m/z calcd for C18H15Cl2N2O3, 377.04597 found 377.0441
[M+H]+
.
Methyl (E)-4-((1-formylnaphthalen-2-yl)oxy)but-2-enoate (1b).16c NaH (6 mmol) at 0 °C was added to
a solution of 2-hydroxy-1-naphthaldehyde (5 mmol) in DMF (10 mL). After 30 min, a solution of
methyl trans-4-bromo-2-butenoate (7.0 mmol) in DMF (5 mL) was added dropwise and stirring was
continued at rt for 3h. After completion, reaction mixture was quenched with saturated NH4Cl solution,
diluted with ethylacetate (100 mL) and washed with cold water (2 x 50 mL). The organic layer was
separated, dried over Na2SO4 and concentrated under vacuum. The crude was purified on flash
chromatography, using 28% EtOAc in hexane as an eluent to produce the title compound 1b. Off White
solid (1.21g, 90% yield); 1H NMR (500 MHz, CDCl3) δ 10.99 (s, 1H), 9.29 (d, J = 8.7 Hz, 1H), 8.07 (d, J
= 9.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 – 7.63 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.26 – 7.08 (m, 2H),
6.27 (dd, J = 15.8, 1.7 Hz, 1H), 4.98 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 191.6, 166.3,
162.3, 141.5, 137.7, 131.6, 130.2, 129.0, 128.4, 125.3, 125.2, 122.4, 117.4, 113.3, 67.9, 52.0; LCMS (ESI):
m/z 271 [M+H]+.
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General reaction procedure for the preparation of compounds 6d-f. To a stirred solution of amine (2,
0.25 mmol) and molecular sieves in ACN (1 mL), a solution of aldehyde (1b, 0.25 mmol) in ACN (1 mL)
was added over a period of 1h at rt. After 2h, Sc(OTf)3 (10 mol%) was added and stirring was continued at
rt for another 10h. Next, the reaction mixture is stirred under MW conditions at 70-100 °C for 1h. TLC
showed the complete absence of starting materials and formation of new spots. Next, Sc(OTf)3 (10 mol%)
was added and the reaction mixture was continued at 130-150°C for 1.5h. After completion, ACN was
removed, and the crude was purified by flash chromatography, using EtOAc in hexane as an eluent.
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Methyl 2-(8,9-dihydrobenzo[4,5]imidazo[1,2-d]naphtho[1,2-f][1,4]oxazepin-9-yl) acetate (6d).
Yellowish solid (47 mg, 53% yield, eluent: 24% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 9.14 (d,
J = 8.7 Hz, 1H), 7.95 (dd, J = 6.8, 1.7 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.63 –
7.56 (m, 2H), 7.52 – 7.46 (m, 1H), 7.42 – 7.35 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 5.41 – 5.31 (m, 1H), 4.72
– 4.60 (m, 2H), 3.59 (s, 3H), 2.82 (d, J = 7.1 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.8, 155.1,
149.0, 143.2, 134.9, 132.7 (2C), 131.1, 128.1, 128.0, 127.2, 125.4, 123.4, 122.9, 120.8, 120.3, 114.9, 109.7,
75.1, 52.3, 51.7, 37.0; HRMS (ESI-TOF): m/z calcd for C22H19N2O3, 359.1395 found 359.1367 [M+H]+
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Methyl
2-(12,13-dimethyl-8,9-dihydrobenzo[4,5]imidazo[1,2-d]naphtho[1,2-f][1,4]
oxazepin-9-
yl)acetate (6e). Off white solid (54 mg, 56% yield, eluent: 26% EtOAc in hexane); 1H NMR (500 MHz,
CDCl3) δ 9.16 (d, J = 8.6 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.71 (s, 1H), 7.63 – 7.59 (m, 1H), 7.53 – 7.47 (m,
1H), 7.34 (s, 1H), 7.29 (t, J = 4.4 Hz, 1H), 5.34 – 5.26 (m, 1H), 4.65 (dd, J = 3.8, 1.7 Hz, 2H), 3.63 (s, 3H),
2.83 (d, J = 7.1 Hz, 2H), 2.49 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.0, 154.9, 148.2,
142.1, 133.5, 132.8, 132.6, 132.3, 131.7, 131.1, 128.1, 127.8, 127.4, 125.3, 120.8, 120.3, 115.3, 109.8, 74.9,
52.3, 51.7, 36.9, 20.9, 20.4; HRMS (ESI-TOF): m/z calcd for C24H23N2O3, 387.1708 found 387.1681
[M+H]+
.
Methyl
2-(12,13-dichloro-8,9-dihydrobenzo[4,5]imidazo[1,2-d]naphtho[1,2-f][1,4]
oxazepin-9-
1
yl)acetate (6f). Brownish solid (43 mg, 41% yield, eluent: 27% EtOAc in hexane); H NMR (500 MHz,
CDCl3) δ 9.07 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.71 (s,
1H), 7.66 – 7.61 (m, 1H), 7.55 – 7.51 (m, 1H), 7.30 (d, J = 8.9 Hz, 1H), 5.30 – 5.22 (m, 1H), 4.67 (dd, J =
5.5, 3.9 Hz, 2H), 3.63 (s, 3H), 2.82 (dd, J = 7.1, 3.0 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.5,
155.2, 151.1, 142.6, 134.3, 133.3, 132.5, 131.1, 128.3, 128.2, 127.4, 127.0, 126.9, 125.6, 121.3, 120.8,
114.3, 111.3, 74.9, 52.4, 52.2, 36.8; HRMS (ESI-TOF): m/z calcd for C22H17Cl2N2O3, 427.0616 found
427.0589 [M+H]+
.
Methyl
(E)-4-((9-formyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-yl)oxy)but-2-enoate
(1c). NaH (6 mmol) at 0 °C was added to a solution of 8-hydroxy-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-
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ij]quinoline-9-carbaldehyde (5 mmol) in DMF (10 mL). After 30 min, a solution of methyl trans-4-bromo-
2-butenoate (7.0 mmol) in DMF (5 mL) was added dropwise and stirring was continued at rt for 3h. After
completion, reaction mixture was quenched saturated NH4Cl solution, diluted with ethylacetate (100 mL)
and washed with cold water (2 x 50 mL). The organic layer was separated, dried over Na2SO4 and
concentrated under vacuum. The crude was purified on flash chromatography, using 35% EtOAc in hexane
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as an eluent to produce the title compound 1c. Yellowish solid (1.57g, 74% yield); H NMR (500 MHz,
CDCl3) δ 9.94 (s, 1H), 7.33 (s, 1H), 7.13 – 7.07 (m, 1H), 6.35 – 6.29 (m, 1H), 4.58 (dd, J = 4.2, 2.1 Hz,
2H), 3.79 (s, 3H), 3.39 – 3.24 (m, 4H), 2.76 – 2.70 (m, 4H), 2.10 – 1.87 (m, 4H); 13C{1H} NMR (125 MHz,
CDCl3) δ 187.3, 166.7, 158.7, 149.1, 142.9, 127.8, 121.4, 117.6, 116.9, 112.5, 73.4, 51.8, 50.2, 49.8, 27.4,
21.4, 21.1, 20.8; LCMS (ESI): m/z 316 [M+H]+.
General reaction procedure for the preparation of compounds 6g-i. To a stirred solution of amine (2,
0.25 mmol) and molecular sieves in ACN (1 mL), a solution of aldehyde (1c, 0.25 mmol) in ACN (1 mL)
was added over a period of 1h at rt. After 2h, Sc(OTf)3 (10 mol%) was added and stirring was continued at
rt for another 10h. TLC showed the complete absence of starting materials and formation of new spots.
Next, Sc(OTf)3 (10 mol%) was added and the stirring was continued at rt for another 12h. After completion,
ACN was removed, and the crude was purified by flash chromatography, using EtOAc in hexane as an
eluent.
Methyl
2-(2,3,6,7,9,10-hexahydro-1H,5H-benzo[4',5']imidazo[1',2':4,5][1,4]
oxazepino[7,6-
f]pyrido[3,2,1-ij]quinolin-10-yl)acetate (6g). Brownish solid (68 mg, 68% yield, eluent: 34% EtOAc in
hexane); 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.80 – 7.74 (m, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.30 –
7.19 (m, 2H), 5.16 – 5.09 (m, 1H), 4.88 (dd, J = 12.9, 3.3 Hz, 1H), 4.29 (d, J = 12.9 Hz, 1H), 3.75 (s, 3H),
3.26 – 3.14 (m, 5H), 2.92 – 2.76 (m, 5H), 2.05 – 1.94 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.4,
153.7, 151.5, 145.5, 143.2, 135.4, 129.0, 122.6, 121.7, 118.9, 117.0, 110.0, 108.8, 104.9, 69.8, 53.4, 52.2,
50.1, 49.4, 35.2, 27.4, 22.1, 21.8, 21.5; HRMS (ESI-TOF): m/z calcd for C24H26N3O3, 404.1974 found
404.1943 [M+H]+
.
Methyl
2-(13,14-dimethyl-2,3,6,7,9,10-hexahydro-1H,5H-benzo[4',5']imidazo[1',2':4,5]
[1,4]
oxazepino[7,6-f]pyrido[3,2,1-ij]quinolin-10-yl)acetate (6h). Brownish solid (77 mg, 72% yield, eluent:
34% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.43 (s, 1H), 6.99 (s, 1H), 4.98 – 4.91
(m, 1H), 4.76 (dd, J = 12.9, 3.2 Hz, 1H), 4.17 (d, J = 12.9 Hz, 1H), 3.67 (s, 3H), 3.16 – 3.03 (m, 5H), 2.81
– 2.65 (m, 5H), 2.32 (s, 3H), 2.29 (s, 3H), 1.95 – 1.85 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.5,
153.5, 150.7, 145.2, 141.8, 133.9, 131.2, 130.8, 128.8, 119.2, 117.0, 110.1, 109.1, 105.4, 69.8, 53.4, 52.2,
50.1, 49.4, 35.1, 27.3, 22.2, 21.8, 21.6, 20.7, 20.4; HRMS (ESI-TOF): m/z calcd for C26H30N3O3, 432.2287
found 432.2262 [M+H]+
.
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Methyl
2-(13,14-dichloro-2,3,6,7,9,10-hexahydro-1H,5H-benzo[4',5']imidazo
[1',2':4,5][1,4]
oxazepino[7,6-f]pyrido[3,2,1-ij]quinolin-10-yl)acetate (6i). Brownish solid (73 mg, 62% yield, eluent:
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7
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36% EtOAc in hexane); H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.75 (s, 1H), 7.39 (s, 1H), 5.01 – 4.96
8
9
(m, 1H), 4.83 (dd, J = 13.0, 3.3 Hz, 1H), 4.24 (d, J = 13.0 Hz, 1H), 3.74 (s, 3H), 3.26 – 3.09 (m, 5H), 2.82
– 2.71 (m, 5H), 2.01 – 1.91 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.0, 153.8, 153.6, 146.0, 142.8,
134.8, 129.0, 126.5, 125.2, 119.8, 117.1, 110.1, 109.9, 103.9, 69.7, 53.7, 52.4, 50.1, 49.4, 35.1, 27.4, 22.0,
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21.7, 21.4; HRMS (ESI-TOF): m/z calcd for C24H24Cl2N3O3, 472.1194 found 472.1171 [M+H]+
.
Methyl (E)-4-((N-(2-formylphenyl)-4-methylphenyl)sulfonamido)but-2-enoate (1d).16c K2CO3 (4
mmol) at rt was added to a solution of N-(2-formylphenyl)-4-methylbenzenesulfonamide (2 mmol) in ACN
(8 mL). After 30 min, methyl trans-4-bromo-2-butenoate (2.2 mmol) was added dropwise and stirring was
continued at rt for 12h. After completion, reaction mixture was filtered and ACN was removed. The crude
was dissolved in ethylacetate (100 mL) and washed with water (2 x 50 mL). The organic layer was
separated, dried over Na2SO4 and concentrated under vacuum. The crude was purified on flash
chromatography, using 33% EtOAc in hexane as an eluent to produce the title compound 1d. Yellowish
solid (611 mg, 82% yield); 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.07 – 7.97 (m, 1H), 7.54 – 7.45
(m, 4H), 7.35 – 7.24 (m, 3H), 6.87 – 6.73 (m, 2H), 5.85 (td, J = 15.6, 1.4 Hz, 1H), 3.70 (s, 3H), 2.47 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 189.6, 165.7, 144.7, 141.1, 140.9, 135.8, 134.4, 134.1, 129.9,
129.2, 129.1, 128.1, 128.0, 125.0, 52.5, 51.9, 21.7; LCMS (ESI): m/z 374 [M+H]+.
General reaction procedure for the preparation of compounds 6j-l. To a stirred solution of amine (2,
0.25 mmol) and molecular sieves in ACN (1 mL), a solution of aldehyde (1d, 0.25 mmol) in ACN (1 mL)
was added over a period of 1h at rt. After 2h, Sc(OTf)3 (10 mol%) was added and stirring was continued at
rt for another 10h. Next, the reaction mixture is stirred under MW conditions at 70-100 °C for 1h. TLC
showed the complete absence of starting materials and formation of new spots. Next, Sc(OTf)3 (10 mol%)
was added and the reaction mixture was continued at 100-130°C for 1.5h. After completion, ACN was
removed, and the crude was purified by flash chromatography, using EtOAc in hexane as an eluent.
Methyl 2-(5-tosyl-6,7-dihydro-5H-benzo[f]benzo[4,5]imidazo[1,2-d][1,4]diazepin-7-yl)acetate (6j).
Off white solid (66 mg, 58% yield, eluent: 27% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.16 (dd,
J = 7.3, 1.7 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.61 – 7.51 (m, 2H), 7.30 – 7.21 (m,
2H), 7.17 – 7.12 (m, 1H), 7.11 – 7.04 (m, 2H), 6.55 (d, J = 8.0 Hz, 2H), 5.14 (dd, J = 7.9, 4.6 Hz, 1H), 5.03
(dd, J = 15.3, 7.9 Hz, 1H), 3.88 (dd, J = 15.3, 7.4 Hz, 1H), 3.52 (s, 3H), 2.63 (dd, J = 16.4, 4.6 Hz, 1H),
2.52 (dd, J = 16.4, 8.3 Hz, 1H), 1.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 169.8, 149.6, 143.4,
138.3, 136.2, 134.7, 131.4, 131.2, 130.7, 129.6, 129.2, 125.7, 123.4, 123.1, 119.9, 114.2, 109.9, 54.9, 52.3,
50.5, 38.7, 21.4; HRMS (ESI-TOF): m/z calcd for C25H24N3O4S, 462.1487 found 462.1472 [M+H]+
.
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Methyl 2-(10,11-dimethyl-5-tosyl-6,7-dihydro-5H-benzo[f]benzo[4,5]imidazo[1,2-d][1,4]diazepin-7-
yl)acetate (6k). Yellowish solid (78 mg, 64% yield, eluent: 28% EtOAc in hexane); 1H NMR (500 MHz,
CDCl3) δ 8.17 (s, 1H), 7.70 (d, J = 4.9 Hz, 1H), 7.56 (d, J = 2.7 Hz, 2H), 7.43 (s, 1H), 7.11 (d, J = 7.5 Hz,
2H), 6.87 (s, 1H), 6.57 (d, J = 7.3 Hz, 2H), 5.13 – 4.92 (m, 2H), 3.87 (dd, J = 14.6, 6.9 Hz, 1H), 3.57 (s,
3H), 2.65 (d, J = 13.4 Hz, 1H), 2.52 (dd, J = 16.3, 8.1 Hz, 1H), 2.43 (s, 3H), 2.39 (s, 3H), 1.90 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 169.9, 148.6, 143.1, 138.3 (2C), 136.4 (2C), 133.1, 132.7, 132.1, 131.1,
131.0, 130.5, 129.5, 129.2, 125.7, 119.8, 110.1, 54.8, 52.3, 50.4, 38.6, 21.1, 20.8, 20.3. LCMS (ESI): m/z
490 [M+H]+.
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Methyl 2-(10,11-dichloro-5-tosyl-6,7-dihydro-5H-benzo[f]benzo[4,5]imidazo[1,2-d][1,4]diazepin-7-
yl)acetate (6l). Off white solid (53 mg, 40% yield, eluent: 30% EtOAc in hexane); 1H NMR (500 MHz,
CDCl3) δ 8.13 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.66 – 7.57 (m, 2H), 7.24 (s, 1H), 7.14 (d, J
= 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 5.06 – 4.96 (m, 2H), 3.94 – 3.85 (m, 1H), 3.56 (s, 3H), 2.61 – 2.54
13
(m, 2H), 2.02 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 169.4, 151.8, 143.5, 136.5 (2C), 133.9, 132.1,
131.4, 130.6, 129.8, 129.4, 128.9, 127.4, 127.3, 125.8, 120.9, 111.4, 54.7, 52.4, 50.8, 38.5, 21.2; HRMS
(ESI-TOF): m/z calcd for C25H22Cl2N3O4S, 530.0708 found 530.0687 [M+H]+
.
Regioisomers 6m and 6n. To a stirred solution of amine (2i, 0.25 mmol) and molecular sieves in ACN (1
mL), a solution of aldehyde (1a, 0.25 mmol) in ACN (1 mL) was added over a period of 1h at rt. After 2h,
Sc(OTf)3 (10 mol%) was added and stirring was continued at rt for another 10h. Next, the reaction mixture
is stirred under MW conditions at 70-100 °C for 1h. TLC showed the complete absence of starting materials
and formation of new spots. Next, Sc(OTf)3 (10 mol%) was added and the reaction mixture was continued
at 100-130°C for 1.5h. After completion, ACN was removed, and the crude was purified by flash
chromatography, using 20% EtOAc in hexane as an eluent. Off white amorphous solid (mixture of two
regioisomers, 43 mg, 51% yield); 1H NMR (500 MHz, CDCl3) δ 8.77 (two s, 2H), 7.77 (d, J = 1.8 Hz, 1H),
7.71 (d, J = 8.6 Hz, 1H), 7.43 – 7.31 (m, 4H), 7.29 – 7.23 (m, 2H), 7.21 – 7.14 (m, 2H), 7.11 (d, J = 8.2 Hz,
2H), 5.20 – 5.09 (m, 2H), 4.93 – 4.87 (m, 2H), 4.30 (dd, J = 13.1, 1.1 Hz, 2H), 3.73 (two s, 6H), 3.18 – 3.10
13
(m, 2H), 2.87 – 2.79 (m, 2H); C{1H} NMR (125 MHz, CDCl3) δ (170.9, 170.8) 1C, (156.6, 156.6) 1C,
(151.0, 150.7) 1C, (143.6, 141.4) 1C, (136.1, 134.2) 1C, (132.1, 132.0) 1C, (132.0, 131.9) 1C, (128.9,
128.8) 1C, (123.9, 123.5) 1C, (123.1, 123.1) 1C, (120.8, 120.8) 1C, (120.8,119.6) 1C, (117.2, 117.1) 1C,
(110.3, 109.6) 1C, (70.1, 70.1) 1C, (53.7, 53.7) 1C, (52.4, 52.4) 1C, (35.4, 35.3) 1C; LCMS (ESI): m/z 343
[M+H]+.
General reaction procedure for the preparation of compounds 8a-c. Aldehyde (1a, 0.25 mmol) and
benzamide (7a-c, 0.25 mmol) were mixed in the presence of molecular sieves in ACN (1 mL) at rt. After
2h, a 10 mol% Sc(OTf)3 was added, and stirring was continued at rt for another 10h. Next, the reaction
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mixture is stirred in a MW reactor at 70-100 °C for 1h. TLC showed the complete absence of starting
materials and formation of new spots. Next, Sc(OTf)3 (10 mol%) was added and the stirring was continued
under MW at 100-150°C for 1.5h. After completion, ACN was removed, and the crude was purified by
flash chromatography, using EtOAc in hexane as an eluent.
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Methyl 2-(9-oxo-6,7-dihydro-9H-benzo[6,7][1,4]oxazepino[5,4-b]quinazolin-7-yl)acetate (8a). White
solid (48 mg, 58% yield, eluent: 26% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 7.7 Hz,
2H), 7.83 – 7.77 (m, 2H), 7.56 – 7.45 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.15 –
6.08 (m, 1H), 4.80 (dd, J = 12.7, 4.5 Hz, 1H), 4.49 (dd, J = 12.7, 1.6 Hz, 1H), 3.69 (s, 3H), 2.77 – 2.58 (m,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 161.7, 155.8, 152.6, 147.8, 134.8, 133.9, 133.4, 127.8,
127.3, 127.2, 123.0, 122.5, 120.4, 119.4, 72.4, 52.2, 49.4, 34.2; HRMS (ESI-TOF): m/z calcd for
C19H17N2O4, 337.1188 found 337.1179 [M+H]+
.
Methyl 2-(11-methoxy-9-oxo-6,7-dihydro-9H-benzo[6,7][1,4]oxazepino[5,4-b]quinazolin-7-yl)acetate
1
(8b). White solid (57 mg, 63% yield, eluent: 29% EtOAc in hexane); H NMR (500 MHz, CDCl3) δ 8.28
(d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.40 (dd, J
= 8.8, 2.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.13 (d, J = 2.0 Hz, 1H), 4.79 (dd, J
= 12.6, 4.4 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 3.96 (s, 3H), 3.69 (s, 3H), 2.72 (dd, J = 16.6, 8.9 Hz, 1H),
2.62 (dd, J = 16.6, 6.1 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 161.6, 158.8, 155.6, 150.4,
142.5, 133.7, 133.1, 129.4, 125.2, 123.0, 122.5, 120.4, 120.2, 106.4, 72.4, 56.0, 52.2, 49.4, 34.3; HRMS
(ESI-TOF): m/z calcd for C20H19N2O5, 367.1293 found 367.1279 [M+H]+
.
Methyl 2-(11-chloro-9-oxo-6,7-dihydro-9H-benzo[6,7][1,4]oxazepino[5,4-b]quinazolin-7-yl)acetate
(8c). White solid (38 mg, 41% yield, eluent: 27% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 8.34 –
8.25 (m, 2H), 7.74 (s, 2H), 7.51 (dd, J = 11.1, 4.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.1 Hz,
1H), 6.13 – 6.03 (m, 1H), 4.80 (dd, J = 12.8, 4.6 Hz, 1H), 4.47 (dd, J = 12.8, 1.9 Hz, 1H), 3.69 (s, 3H), 2.72
(dd, J = 16.6, 8.9 Hz, 1H), 2.62 (dd, J = 16.6, 6.3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.2,
160.7, 155.7, 152.7, 146.2, 135.1, 133.7, 133.4, 132.8, 129.4, 126.4, 123.0, 122.1, 120.4, 120.3, 72.3, 52.2,
49.5, 33.9. HRMS (ESI-TOF): m/z calcd for C19H16ClN2O4, 371.0798 found 371.0783 [M+H]+
.
Methyl 2-(11-oxo-8,9-dihydro-11H-naphtho[1',2':6,7][1,4]oxazepino[5,4-b]quinazolin-9-yl)acetate
(8d). Aldehyde (1b, 0.25 mmol) and benzamide (7a, 0.25 mmol) were mixed in the presence of molecular
sieves in ACN (1 mL) at rt. After 2h, a 10 mol% of Sc(OTf)3 was added, and stirring was continued at rt
for another 10h. Next, the reaction mixture is stirred in a MW reactor at 70-100 °C for 1h. TLC showed the
complete absence of starting materials and formation of new spots. Next, Sc(OTf)3 (10 mol%) was added
and the stirring was continued under MW at 100-150°C for 1.5h. After completion, ACN was removed,
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and the crude was purified by flash chromatography, using 27% of EtOAc in hexane as an eluent. White
solid (23 mg, 24% yield); 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J = 7.1 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1H),
7.93 (d, J = 8.0 Hz, 1H), 7.83 (s, 2H), 7.66 – 7.53 (m, 3H), 7.34 (d, J = 8.7 Hz, 1H), 6.42 – 6.33 (m, 1H),
4.91 – 4.82 (m, 1H), 4.40 (d, J = 11.7 Hz, 1H), 3.53 (s, 3H), 2.29 – 2.12 (m, 2H). 13C{1H} NMR (125 MHz,
CDCl3) δ 170.4, 161.6, 153.8, 151.3, 147.3, 134.9, 134.0, 132.1, 131.8, 128.6, 128.3, 127.8, 127.6 (2C),
126.1, 125.6, 123.5, 120.8, 120.2, 76.8, 52.1, 46.1, 38.5. LCMS (ESI): m/z 387 [M+H]+.
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Methyl 2-(8-oxo-2,3,5,6,16,17-hexahydro-1H,8H,15H-pyrido[3'',2'',1'':8',1']quinolino[6',5':6,7][1,4]
oxazepino[5,4-b]quinazolin-6-yl)acetate (8e). Aldehyde (1c, 0.25 mmol) and benzamide (7a, 0.25 mmol)
were mixed in the presence of molecular sieves in ACN (1 mL) at rt. After 2h, a 10 mol% Sc(OTf)3 was
added, and stirring was continued at rt for another 10h. Next, the reaction mixture is stirred in a MW reactor
at 70-100 °C for 1h. TLC showed the complete absence of starting materials and formation of new spots.
Next, Sc(OTf)3 (10 mol%) was added and the stirring was continued under MW at 100-130°C for 1.5h.
After completion, ACN was removed, and the crude was purified by flash chromatography, using 31% of
1
EtOAc in hexane as an eluent. Brownish solid (56 mg, 52% yield); H NMR (500 MHz, CDCl3) δ 8.17 (d,
J = 7.5 Hz, 1H), 7.84 – 7.56 (m, 3H), 7.32 (s, 1H), 6.03 – 5.88 (s, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.35 (d, J
= 11.8 Hz, 1H), 3.58 (s, 3H), 3.27 – 3.05 (m, 4H), 2.84 – 2.50 (m, 6H), 1.99 – 1.75 (m, 4H); 13C{1H} NMR
(125 MHz, CDCl3) δ 170.9, 158.6, 154.4, 152.1, 148.8, 142.6, 134.5, 130.5, 130.0, 129.9, 127.1 (2C), 126.0,
117.0, 109.9, 72.1, 52.1, 50.1, 49.4, 49.2, 34.5, 27.5, 21.9, 21.4, 21.3. HRMS (ESI-TOF): m/z calcd for
C25H26N3O4, 432.1923 found 432.1897 [M+H]+
.
General reaction procedure for the preparation of compounds 8f-h. Aldehyde (1d, 0.25 mmmol) and
benzamide (7a-c, 0.25 mmol) were mixed in the presence of molecular sieves in ACN (1 mL) at rt. After
2h, a 10 mol% Sc(OTf)3 was added, and stirring was continued at rt for another 10h. Next, the reaction
mixture is stirred in a MW reactor at 70-100 °C for 1h. TLC showed the complete absence of starting
materials and formation of new spots. Next, Sc(OTf)3 (10 mol%) was added and the stirring was continued
under MW at 100-150°C for 1.5h. After completion, ACN was removed, and the crude was purified by
flash chromatography, using EtOAc in hexane as an eluent.
Methyl
2-(9-oxo-5-tosyl-5,6,7,9,14,14a-hexahydrobenzo[5,6][1,4]diazepino[7,1-b]quinazolin-7-
yl)acetate (8f). White solid (66 mg, 54% yield, eluent: 31% EtOAc in hexane); 1H NMR (500 MHz, CDCl3)
δ 7.83 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.45 – 7.33 (m, 3H), 7.22 (dd, J = 5.2, 3.7 Hz, 1H),
7.07 (dd, J = 5.5, 3.4 Hz, 2H), 6.94 – 6.81 (m, 3H), 6.18 (s, 1H), 5.58 (s, 1H), 5.04 (bs, 1H), 4.60 (d, J =
14.7 Hz, 1H), 3.74 (s, 3H), 3.41 – 3.29 (m, 2H), 2.97 (dd, J = 16.3, 7.1 Hz, 1H), 2.49 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 171.4, 161.7, 145.3, 144.3, 140.2, 138.8, 138.3, 134.3, 130.1, 129.5, 128.8, 127.9,
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127.6, 126.7, 126.4, 119.5, 115.9, 114.5, 63.2, 52.2, 52.1, 46.8, 34.9, 21.8; HRMS (ESI-TOF): m/z calcd
for C26H26N3O5S, 492.1593 found 492.1575 [M+H]+
.
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Methyl
2-((7R,14aS)-11-methoxy-9-oxo-5-tosyl-5,6,7,9,14,14a-hexahydrobenzo[5,6][1,4]diazepino
[7,1-b]quinazolin-7-yl)acetate (8g). White solid (75 mg, 58% yield, eluent: 36% EtOAc in hexane); 1H
NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.40 – 7.33 (m, 3H), 7.25 – 7.18 (m, 1H), 7.09 – 7.03
(m, 3H), 6.89 (d, J = 8.7 Hz, 1H), 6.86 – 6.79 (m, 1H), 6.15 (s, 1H), 5.58 (d, J = 2.3 Hz, 1H), 4.60 (dd, J =
14.8, 1.3 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.39 – 3.29 (m, 2H), 3.02 (dd, J = 16.2, 7.6 Hz, 1H), 2.49 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.3, 161.5, 153.5, 144.2, 140.2, 138.9, 138.6, 138.2, 130.0,
128.6, 127.8, 127.5, 126.6 (2C), 123.0, 117.2, 117.0, 111.0, 63.2, 55.7, 52.1, 52.0, 46.9, 34.9, 21.6; HRMS
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(ESI-TOF): m/z calcd for C27H28N3O6S, 522.1698 found 522.1682 [M+H]+
.
Methyl
2-(11-chloro-9-oxo-5-tosyl-5,6,7,9,14,14a-hexahydrobenzo[5,6][1,4]
diazepino[7,1-
b]quinazolin-7-yl)acetate (8h). White solid (61 mg, 47% yield, eluent: 33% EtOAc in hexane); 1H NMR
(500 MHz, CDCl3) δ 7.80 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.41 – 7.33 (m, 3H), 7.22 – 7.14
(m, 1H), 7.14 – 7.05 (m, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.84 – 6.80 (m, 1H), 6.20 (s, 1H), 5.54 (d, J = 2.9
Hz, 1H), 5.12 – 5.06 (m, 1H), 4.58 (dd, J = 14.9, 1.4 Hz, 1H), 3.73 (s, 3H), 3.36 – 3.30 (m, 2H), 2.99 (dd,
J = 16.4, 7.4 Hz, 1H), 2.49 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.2, 160.7, 144.4, 143.8, 139.8,
138.8, 138.2, 134.3, 130.2, 129.0, 128.1, 127.6, 127.5, 126.8, 126.3, 124.7, 117.0, 116.0, 63.2, 52.3, 52.2,
47.1, 34.9, 21.8; LCMS (ESI): m/z 526 [M+H]+.
Methyl (E)-4-(2-formyl-1H-indol-1-yl)but-2-enoate (9a).16c K2CO3 (2.2 mmol) at 0 °C was added to a
solution of 1H-indole-2-carbaldehyde (2 mmol) in DMF (14 mL). After 30 min, a solution of methyl trans-
4-bromo-2-butenoate (2.6 mmol) in DMF (14 mL) was added and stirring was continued at rt for 3h. After
completion, reaction mixture was diluted with ethylacetate (100 mL) and washed with cold water (2 x 50
mL). The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. The crude was
purified on flash chromatography, using 17% EtOAc in hexane as an eluent to produce the title compound
9a. Greenish solid (218 mg, 45% yield); 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.79 (d, J = 8.1 Hz,
1H), 7.47 – 7.42 (m, 1H), 7.38 – 7.28 (m, 2H), 7.26 – 7.21 (m, 1H), 7.14 – 7.07 (dt, J = 15.6, 4.6 Hz, 1H),
5.48 (td, J = 15.6, 1.9 Hz, 1H), 5.41 (dd, J = 4.6, 1.9 Hz, 2H), 3.69 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 182.6, 166.3, 143.3, 140.2, 135.0, 127.6, 126.6, 123.8, 121.7, 121.6, 118.6, 110.5, 51.7, 45.3;
LCMS (ESI): m/z 244 [M+H]+.
General reaction procedure for the preparation of compounds 10a-i. Sodium metabisulfite (0.375
mmol) in H2O (0.5 mL) was added to a solution of aldehyde (7, 0.25 mmol) in ethanol (1 mL) at rt. After
30 min, o-phenylenediamine (2, 0.25 mmol) was added and stirring was continued at rt for another 6 h.
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Then another half equivalent of sodium metabisulfite (0.125 mmol) in H2O (0.5 mL) was added and the
reaction was heated at 80 °C for 12 h. After completion, ethanol was removed, and the crude reaction
mixture was diluted with EtOAc (15 mL) and treated with water (10 mL). The organic layer was dried over
Na2SO4 and purified by flash chromatography, using EtOAc in hexane as an eluent.
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Methyl
2-(6,7-dihydrobenzo[4',5']imidazo[2',1':3,4]pyrazino
[1,2-a]indol-7-yl)acetate
(10a).
Yellowish solid (49 mg, 59% yield, eluent: 31% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 7.89 –
7.83 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.39 – 7.33 (m, 3H),
7.26 – 7.20 (m, 1H), 5.38 – 5.32 (m, 1H), 4.84 (d, J = 12.9 Hz, 1H), 4.45 (dd, J = 12.9, 4.1 Hz, 1H), 3.67
(s, 3H), 2.81 (dd, J = 16.6, 9.5 Hz, 1H), 2.71 (dd, J = 16.6, 3.9 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 170.7, 144.0, 143.5, 137.7, 132.7, 128.7, 126.5, 124.0, 123.3, 122.3, 121.1, 120.0, 109.4, 109.0, 103.0,
52.24, 48.7, 43.9, 36.3; HRMS (ESI-TOF): m/z calcd for C20H18N3O2, 332.1399 found 332.1395 [M+H]+
.
Methyl 2-(10,11-dimethyl-6,7-dihydrobenzo[4',5']imidazo[2',1':3,4]pyrazino[1,2-a]indol-7-yl)acetate
(10b). Off white solid (57 mg, 64% yield, eluent: 31% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ
7.76 (d, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.42 – 7.32 (m, 3H), 7.28 (s, 1H), 7.25 – 7.19 (m, 2H), 5.32 – 5.25
(m, 1H), 4.82 (d, J = 12.9 Hz, 1H), 4.43 (dd, J = 12.8, 4.2 Hz, 1H), 3.70 (s, 3H), 2.80 (dd, J = 16.7, 9.8 Hz,
1H), 2.70 (dd, J = 16.6, 4.0 Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.8,
142.8, 142.7, 137.5, 132.7, 132.2, 131.2, 128.8, 127.0, 123.7, 122.1, 121.0, 120.1, 109.3, 109.1, 102.2, 52.2,
48.6, 43.8, 36.1, 20.6, 20.4; HRMS (ESI-TOF): m/z calcd for C22H22N3O2, 360.1712 found 360.1703
[M+H]+
.
Methyl 2-(10,11-dichloro-6,7-dihydrobenzo[4',5']imidazo[2',1':3,4]pyrazino[1,2-a]indol-7-yl)acetate
(10c). Off white solid (58 mg, 58% yield yield, eluent: 32% EtOAc in hexane); 1H NMR (500 MHz, CDCl3)
δ 7.91 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.46 – 7.35 (m, 3H), 7.25 (dd, J = 10.4, 3.9 Hz, 1H),
5.31 – 5.26 (m, 1H), 4.84 (d, J = 13.0 Hz, 1H), 4.47 (dd, J = 12.9, 4.0 Hz, 1H), 3.70 (s, 3H), 2.83 (dd, J =
16.7, 9.2 Hz, 1H), 2.70 (dd, J = 16.7, 4.3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 145.5, 143.8,
137.9, 132.2, 128.7, 127.5, 127.3, 125.9, 124.6, 122.6, 121.5, 121.2, 110.6, 109.5, 104.0, 52.5, 49.2, 44.0,
36.5; HRMS (ESI-TOF): m/z calcd for C20H16Cl2N3O2, 400.0619 found 400.0608 [M+H]+
.
Methyl (E)-4-(5-chloro-2-formyl-3-methyl-1H-indol-1-yl)but-2-enoate (9b). K2CO3 (2.2 mmol) at 0 °C
was added to a solution of 5-chloro-3-methyl-1H-indole-2-carbaldehyde (2 mmol) in DMF (14 mL). After
30 min, a solution of methyl trans-4-bromo-2-butenoate (2.6 mmol) in DMF (14 mL) was added and
stirring was continued at rt for 4h. After completion, reaction mixture was diluted with ethylacetate (100
mL) and washed with cold water (2 x 50 mL). The organic layer was separated, dried over Na2SO4 and
concentrated under vacuum. The crude was purified on flash chromatography, using 19% EtOAc in hexane
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as an eluent to produce the title compound 9b. Yellowish solid (238 mg, 41% yield); 1H NMR (500 MHz,
CDCl3) δ 10.14 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 8.9, 1.9 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H),
7.05 (dt, J = 15.6, 4.5 Hz, 1H), 5.42 (dt, J = 15.6, 1.9 Hz, 1H), 5.34 (dd, J = 4.5, 1.8 Hz, 2H), 3.68 (s, 3H),
13
2.63 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 181.3, 166.2, 143.4, 137.4, 131.2, 128.3, 128.1, 126.6,
9
127.0, 121.6, 120.9, 111.5, 51.7, 45.3, 8.6; LCMS (ESI): m/z 292 [M+H]+.
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Methyl 2-(2-chloro-14-methyl-6,7-dihydrobenzo[4',5']imidazo[2',1':3,4] pyrazino[1,2-a]indol-7-
yl)acetate (10d). Off white solid (60 mg, 64% yield, eluent: 29% EtOAc in hexane); 1H NMR (500 MHz,
CDCl3) δ 7.93 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.52 – 7.44 (m, 1H), 7.42 – 7.25 (m, 5H), 5.42
– 5.28 (m, 1H), 4.76 (d, J = 12.8 Hz, 1H), 4.50 – 4.36 (m, 1H), 3.68 (s, 3H), 2.90 – 2.64 (m, 5H); 13C{1H}
NMR (126 MHz, CDCl3) δ 170.8, 143.7, 135.7, 132.2, 130.4, 126.3, 124.7, 123.6, 123.5, 120.1, 119.9,
110.3, 109.0, 52.4, 48.8, 44.1, 36.3, 9.9; LCMS (ESI): m/z 380 [M+H]+.
Methyl
2-(2-chloro-10,11,14-trimethyl-6,7-dihydrobenzo[4',5']imidazo
[2',1':3,4]pyrazino[1,2-
a]indol-7-yl)acetate (10e). Off white solid (69 mg, 68% yield, eluent: 30% EtOAc in hexane); 1H NMR
(500 MHz, CDCl3) δ 7.66 (s, 1H), 7.28 – 7.23 (m, 2H), 7.19 (s, 1H), 5.28 – 5.22 (m, 1H), 4.73 (d, J = 12.6
Hz, 1H), 4.36 (dd, J = 12.8, 3.9 Hz, 1H), 3.70 (s, 1H), 2.77 (dd, J = 16.6, 9.7 Hz, 1H), 2.69 (dd, J = 15.9,
4.2 Hz, 1H), 2.45 (s, 1H), 2.42 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.8, 143.1, 135.4, 132.6,
132.0, 130.7, 130.3, 125.9, 124.5, 124.1, 120.3, 119.5, 113.5, 110.1, 108.9, 52.2, 48.5, 43.9, 36.1, 20.6,
20.4, 9.7; HRMS (ESI-TOF): m/z calcd for C23H23ClN3O2, 408.1478 found 408.1477 [M+H]+
.
Methyl
2-(2,10,11-trichloro-14-methyl-6,7-dihydrobenzo[4',5']imidazo
[2',1':3,4]pyrazino[1,2-
1
a]indol-7-yl)acetate (10f). Off white solid (55 mg, 49% yield, eluent: 30% EtOAc in hexane); H NMR
(500 MHz, Acetone-d6) δ 7.94 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.32
(dd, J = 8.7, 2.0 Hz, 1H), 5.68 – 5.59 (m, 1H), 5.05 (dd, J = 13.1, 0.9 Hz, 1H), 4.57 (dd, J = 13.1, 4.2 Hz,
1H), 3.52 (s, 3H), 2.94 (dd, J = 16.1, 7.6 Hz, 1H), 2.83 – 2.74 (m, 6H); 13C{1H} NMR (125 MHz, Acetone-
d6) δ 171.1, 146.9, 144.9, 136.8, 133.5, 130.8, 126.5, 126.3, 125.1, 124.8, 121.1, 120.1, 114.9, 112.8, 112.3,
55.0, 52.1, 50.2, 44.9, 37.4, 9.7; HRMS (ESI-TOF): m/z calcd for C21H17Cl3N3O2, 448.0386 found 448.0380
[M+H]+
.
Methyl (E)-4-(2-formyl-1H-pyrrol-1-yl)but-2-enoate (9c). K2CO3 (2.2 mmol) at 0 °C was added to a
solution of 1H-pyrrole-2-carbaldehyde (2 mmol) in DMF (14 mL). After 30 min, a solution of
methyl trans-4-bromo-2-butenoate (2.6 mmol) in DMF (14 mL) was added and stirring was continued at rt
for 3h. After completion, reaction mixture was diluted with ethylacetate (100 mL) and washed with cold
water (2 x 50 mL). The organic layer was separated, dried over Na2SO4 and concentrated under vacuum.
The crude was purified on flash chromatography, using 12% EtOAc in hexane as an eluent to produce the
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