C(sp2)-H Functionalization of 2H-Indazoles at C3-Position via Palladium(II)-Catalyzed Isocyanide Insertion Strategy Leading to Diverse Heterocycles

Article abstract of DOI:10.1021/acs.joc.6b00048

Herein, we have reported an efficient Pd-catalyzed C-H functionalization of 2H-indazole at C3-position via an isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles, indazoloquinaoxalines and benzoxazinoindazolones for the f

Full text of DOI:10.1021/acs.joc.6b00048

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Article
C(sp2)-H Functionalization of 2H-indazoles at C3-
position via palladium(II)-catalyzed isocyanide
insertion strategy leading to diverse heterocycles
Shinde Vidyacharan, Arumugavel Murugan, and Duddu S. Sharada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00048 • Publication Date (Web): 08 Mar 2016
Downloaded from http://pubs.acs.org on March 9, 2016
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C(sp2)−H Functionalization of 2H−indazoles at C3ꢀposition via
palladium(II)−catalyzed isocyanide insertion strategy leading to
diverse heterocycles
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Shinde Vidyacharan, Arumugavel Murugan and Duddu S. Sharada*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak District 502285,
Telangana, India. Ph. No: +91(40) 2301 7058, Eꢀmail: sharada@iith.ac.in
Abstract:
Abstract: Herein, we have reported an efficient Pdꢀcatalyzed CꢀH functionalization of 2Hꢀindazole at C3ꢀposition via an
isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles, indazoloquinaoxalines and
benzoxazinoindazolones for the first time. Our new method provides an operationally simple and versatile route for a
selective synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols. Furthermore, we developed a sequential oneꢀpot strategy for the
synthesis of benzoxazinoindazolone under metalꢀoxidantꢀfree conditions. We also achieved the isocyanide insertion
between C(sp2)−H and oxygen heteroatom for the first time. The key features of the present protocol are construction of 4
bonds in oneꢀpot, synthesis of new skeletally diverse scaffolds, broad substrate scope, high yields and environmentally
benign conditions.
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Introduction
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Heterocyclic compounds are widely distributed among natural products and biologically active molecules
and have vast number of applications in various fields.1 Among them indazoles occupy a special place
owing to their wide range of biological activities,2 including antiꢀtumor,3 antiꢀmicrobial,4 antiꢀ
inflammatory,5 HIVꢀprotease inhibition6 etc. For example, drugs like MKꢀ4827 (anticancer)7 and
pazopanib (tyrosine kinase inhibitor)8 incorporate this basic scaffold. The benzoꢀ1,4ꢀoxazine,9
quinoxaline10 and cyclic amidine ring11 systems have also been proved to exhibit various potent biological
activities (Figure 1).
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Figure 1. Representative example of bioꢀactive scaffolds and our designed target molecules
.
Though many methods are well documented in the literature for the construction of 2Hꢀindazoles,12 there
are very few reports on further exploration of 2Hꢀindazoles leading to fused indazoles.13 Very recently,
there have been reports on C3ꢀfunctionalization of 2Hꢀindazoles like direct arylation,14 Heck,15 and cross
coupling12b reactions (Figure 2, eq.1, aꢀc & e) however there are no reports developed for the construction
of fused indazoles systems via CꢀH activation except annulation13c reaction reported by Lautens (Figure 2,
eq.1, d). Moreover, most of the C3−functionalization methods used expensive ligand, base, oxidant and
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additives. As a part of our research program on C−H functionalization,13b&d we were interested in
developing a new approach for the C3−functionalization of 2Hꢀindazoles. Herein, we are delighted to
report for the first time, C(sp2)−H functionalization of 2Hꢀindazole leading to fused indazole scaffolds by
isocyanide insertion strategy in a mild and convenient manner.
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Figure 2. Present study vs representative previous approaches for the C3ꢀfunctionalization and synthesis of fusedꢀindazoles.
The versatility of CꢀH activation reactions has been well established by its applications in
synthesis of natural products and drugs over the past decades.16 The key features of its being directing
group assisted selective functionalization of specific/proximate CꢀH bonds. Usage of isocyanides as one
carbon unit for a facile and simultaneous Pdꢀcatalyzed stitching of CꢀC and Cꢀheteroatom bonds has an
impact on contemporary synthetic methods development in the production of structural and diverse
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heterocyclic molecules.17 Though isocyanide insertion chemistry was developed in the past decades18
using transition metals, only recently after substantial efforts made by several groups17 it gained eminence
owing to its significance in replacement of hazardous CO gas.19
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Though, Interꢀ and intramolecular isocyanide insertion reactions were reported for the synthesis
of diverse heterocycles, in most of the cases starting materials were preꢀfunctionalized19 and very few
reactions21 are reported employing inꢀsitu generated functionalized starting materials.
Nowadays mild and ecofriendly reactions are more interesting and are in demand, in this regard,
oxidative palladium catalysis using molecular oxygen as the terminal oxidant have drawn much attention,
due to avoidance of expensive and toxic metal oxidants.17&19 Recently, we have reported oneꢀpot
palladiumꢀcatalyzed ligandꢀ and metalꢀoxidantꢀfree aerobic oxidative isocyanide insertion leading to 2ꢀ
aminosubstitutedꢀ4(3H)ꢀquinazolinones.20b Encouraged by the result, we envisioned the aerobic oxidative
C(sp2)−H functionalization of 2Hꢀindazole via isocyanide insertion using palladium catalysis could
provide a wide range of fused benzoxazinoindazoles and indazoloquinaoxalines.
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Results and discussion
We started our probe by a benchmark reaction between 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenol 3aa and
o
cyclohexylisocyanide 4a in presence of Pd(OAc)2 as catalyst, toluene as solvent at 110 C. As expected,
isocyanide insertion product 5a was obtained, albeit in very poor yield (Table 1, entry 1). Inspired by this
result, we screened various catalysts, bases, solvents and isocyanide equivalents (see in table 4 of SI), and
found very good yield i.e 90% with Ag2CO3 as oxidant (Table 1, entry 14). As aimed, we pursued our
efforts to increase the yields further, by replacing the metalꢀoxidant with molecular oxygen under various
solvents (Table 1, entries 15ꢀ22) and were pleased to obtained good yields of the products. Surprisingly,
on addition of 4Å MS in the reaction, we obtained quantitative yield of the product with decrease in the
reaction time (Table 1, entry 22). We are delighted to mention here that this is first such report for the
isocyanide insertion between C(sp2)ꢀH and oxygen hetero atom under metalꢀoxidant free condition.
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Table 1. Optimization conditions for the synthesis of benzoxazinoindazole 5aa,b
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Entry
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Catalyst
Base/oxidant
ꢀ
Solvent (2 mL)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Time (h)
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Product (%)b
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Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2(PPh3)2
Pd(PPh3)4
−
10 c
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nd c
nd c
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80
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70
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90
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98
K2CO3
K2CO3
K2CO3
K2CO3
−
K2CO3
Et3N
CS2CO3
KOAc
NaOAc
NaOtBu
KOtBu
Ag2CO3
O2
O2
O2
O2
O2
O2
O2
O2
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
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22d
CH3CN
DMSO
DMF
1,4ꢀdioxane
DME
Toluene
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aAll reactions were carried out on 1 mmol scale of 3 and 1.5 mmol of 4 and entry 3ꢀ14 used 1 equiv base. bIsolated yields of
chromatographically pure products. cStarting material was recovered. d4Å MS (100 mg) were used.
.
Having established the optimal reaction conditions, we wanted to investigate the scope of
methodology for the various 2Hꢀindazoles and isocyanides. Accordingly, we focused our efforts towords
synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols, unfortunately our attempts to make the same from 2ꢀ
azidobenzaldehyde and 2ꢀaminophenol by reported methods went in vain. However, we were successful
in developing an alternative method for the synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols in a selective and
efficient manner under solventꢀfree and catalystꢀfree conditions (Table 2).
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Table 2. Synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols 3aaꢀ3aha, b
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b
aReaction conditions: 1a (1 mmol), 2a (1 mmol). Yields in the parentheses are isolated yields of chromatographically pure
products.
When we evaluated the scope of this methodology for different 2Hꢀindazoles, the methelenedioxy
substitution (5d) gave more yields compared to halo substitution at 5th and 6th position (Table 3, 5b, 5c).
Similarly, good yields were obtained in the case of Meꢀ, Clꢀ substitution on amine partner of aryl group
(Table 3, 5e, 5f) whereas nitro substituent resulted in comparatively less yield (Table 3, 5g). When we
investigated the influence of different isocyanides on the efficiency of insertion reaction, cyclohexyl
isocyanide (CyꢀNC) provided more yields (Table 3, 5aꢀ5g) compared to tertꢀbutyl isocyanide, (tBuꢀNC)
(Table 3, 5hꢀn) while other isocyanides failed to give the expected products (Table 3, 5oꢀ5q). Compound
5a was further confirmed by single crystal Xꢀray difraction (See SI, Figure 1).
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Table 3. Scope and generality for the synthesis of benzoxazinoindazoles 5aꢀ5qa,b
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aReaction conditions: 3aa−3ah (1 mmol), 4aꢀ4e (1.5 equiv), Pd(OAc)2 (5 mol%), 4Å MS (100 mg) in 2 mL toluene, at 110 ˚C for
21h. bYields in the parentheses are isolated yields of chromatographically pure products. Compound 5a was further confirmed by
single crystal XRD (See SI, Figure 1).
To our surprise, when we used excess of isocyanide in the case of halo substitution at 6th position
of indazole, we observed along with insertion, amidation of halo group (CꢀC coupling) with isocyanide
(5r). The literature methods for the amidation of halo group with isocyanides used metalꢀoxidants, ligand
and base,22 conversely, we have achieved the same using mild catalyst with molecular oxygen as oxidant
(Scheme 1).
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Scheme 1.
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Furthermore, at the next diversity point, we wanted to expand our method for the synthesis of
indazoloquinaoxalines by replacing one of the starting material 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenol with 2ꢀ(2Hꢀ
indazolꢀ2ꢀyl)aniline, as this entity is present in various alkaloids and drugs.10,11 Accordingly, we
envisioned to perform the reaction between 2ꢀ(2Hꢀindazolꢀ2ꢀyl)aniline 3ba and cyclohexylisocyanide 4a
under standard conditions (Table 1, entry 22) and our gratified to the expected product in 45% yield.
Then, to increase the yield we tuned the reaction with respect to catalyst, base, oxidant and solvents
(Table 5 in SI), and found good yield (72%) with Pd(OAc)2 as catalyst, CuCl2.2H2O as oxidant and
Cs2CO3 as base (Table 5 entry 17 in SI). After successfully establishing the optimized conditions we
employed various 2Hꢀindazoles and obtained indazoloquinaoxalines (6aꢀ6h) in moderate to good yields
(Table 4).
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Table 4. Scope and generality for the synthesis of indazoloquinaoxalines 6aꢀ6ha,b
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aReaction conditions: 3ba−3bg (1 mmol), 4a & 4b (2 mmol), Pd(OAc)2 (10 mol%), CuCl2.2H2O (30 mol%) and Cs2CO3 (0.5
equiv) in 2 mL toluene, at 110 ˚C for 12−15h. bYields in the parentheses are isolated yields of chromatographically pure
products.
17a&19d,e
Based on the literature reports,
we have proposed a plausible reaction mechanism for the
synthesis of benzoxazinoindazole and indazoloquinaoxaline as shown in figure 4. At first, indazole XH
(3) (XH = OH, NH) forms a coordination complex with isocyanide ligated Pd(II) giving complex I.
Subsequent electrophilic palladation22 of the indazole ring furnishes Pd(II) intermediate II followed by
migratory insertion of an isocyanide resulting in cyclic imidoyl palladium intermediate III. This further
undergoes reductive elimination to form 5 (XH = OH) & IV (XH = NH) and resultant Pd(0) species is
reoxidized to Pd(II) by molecular oxygen. IV further undergoes tautomerization to afford the product 6
(Figure 4).
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Figure 4. Credible pathway for the synthesis of benzoxazinoindazoles/indazoloquinoxaline (5/6)
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To examine the synthetic utility of the synthesized compounds benzoxazinoindazoles (5) we
explored the Nꢀalkylimine hydrolysis leading to benzoxazinoindazolones, as this entity is present in bioꢀ
potent molecules.9 To our delight, we have demonstrated the utility of 5 leading to diverse
benzoxazinoindazolones (7aꢀ7e) in quantitative yields (95ꢀ99%, Table 5).
Table 5. Synthesis of benzoxazinoindazolones 7aꢀ7ea,b
aReaction conditions: 5 (1 mmol) refluxed in THF/HCl (5 mL of THF and 1M, 1 mL HCl) for 3h. bYields in the parentheses are
isolated yields of chromatographically pure products.
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Recent achievements made by our group in the area of developing sustainable chemistry,23&13a,d intrigued
us to further probe the scope of oneꢀpot method for the synthesis of fused indazole scaffolds starting from
2ꢀazidobenzaldehyde 1a and 2ꢀaminophenol 2a. Delightfully, we obtained the expected product 7a in
84% of yield. The robustness of this oneꢀpot protocol was demonstrated by the synthesis of diverse
benzoxazinoindazolones (7aꢀ7e) in good yields (58ꢀ80%) shown in table 6. This straight forward
synthesis of tetracyclic frameworks constitutes an interesting alternative to the conventional stepwise
isocyanide insertion reactions.
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Table 6. Sequential oneꢀpot strategy for the synthesis of benzoxazinoindazolones 7aꢀ7ea,b
aReaction conditions:1st step: 1aꢀ1e (1 mmol), 2aꢀ2d (1 mmol), 2nd step: CyꢀNC (4), Pd(OAc)2 (5 mol %), 4Å MS (100 mg) in 2
mL toluene, at 110 ˚C for 21h, 3rd step: refluxed in THF/HCl for 3h. bYields in the parentheses are isolated yields of
chromatographically pure products.
Conclusion
We have successfully demonstrated an efficient Pdꢀcatalyzed direct CꢀH activation of 2Hꢀindazole via an
isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles,
indazoloquinaoxalines and benzoxazinoindazolones for the first time. Our new method provides an
operationally simple and versatile route for a selective synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols.
Furthermore, we developed a sequential oneꢀpot strategy for the synthesis of benzoxazinoindazolone
under metalꢀoxidantꢀfree conditions. We also achieved the isocyanide insertion between C(sp2)ꢀH and
oxygen hetero atom under metalꢀoxidantꢀfree conditions for the first time. The key features of the present
protocol are construction of 4 bonds in oneꢀpot, synthesis of new skeletally diverse scaffolds, broad
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substrate scope, high yields and environmentally benign conditions. This methodology can open up
opportunities for development of various diverse heterocycles via CꢀH functionalization of 2Hꢀindazoles
and in our laboratory selective CꢀH functionalization of 2Hꢀindazoles is under way.
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Experimental Section
General Considerations
IR spectra were recorded on a FTIR spectrophotometer. 1H NMR spectra were recorded on 400 MHz
spectrometer at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported in
standard fashion with reference to either internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or
CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometer at RT in CDCl3;
chemical shifts (δ ppm) are reported relative to CHCl3 [δC = 77.00 ppm (central line of triplet)]. In the
1HNMR, the following abbreviations were used throughout: s = singlet, d = doublet, t = triplet, q =
quartet, qui = quintet, m = multiplet and br s. = broad singlet. The assignment of signals was confirmed
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by 1H, C CPD, and DEPT spectra. Highꢀresolution mass spectra (HRꢀMS) were recorded using QꢀTOF
multimode source. Melting points were determined on an electrothermal melting point apparatus and are
uncorrected. oꢀazidobenzaldehydes prepared by using literature known procedures, 2ꢀaminophenols all
were commercial available. Pdꢀcatalysts andall bases were purchased from Sigma Aldrich. All dry
solvents were used, toluene and THF were dried over sodium metal and DMSO, CH3CN and DMF were
dried over calcium hydride and which are commercial available.
All small scale dry reactions were carried out using standard syringeꢀseptum technique. Reactions were
monitored by TLC on silica gel using a combination of petroleum ether and ethyl acetate as eluents.
Reactions were generally run under argon, nitrogen and oxygen atmosphere wherever necessary. Solvents
were distilled prior to use; petroleum ether with a boiling range of 40 to 60 ˚C was used. Acme’s silica gel
(60–120 mesh) was used for column chromatography (approximately 20 g per one gram of crude
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(I) Synthesis of 2ꢀAzidoꢀ4ꢀchlorobenzaldehyde (1d): To a stirring solution of 2ꢀNitroꢀ4ꢀ
chlorobenzaldehyde (1.0 equiv) in HMPA was added sodium azide (2.0 equiv). The reaction mixture was
stirred at ambient temperature and monitored by TLC. After consumption of the starting material, the
mixture was diluted with iceꢀcold water and extracted with diethyl ether (3 × 25 mL). The ether layer was
washed with water (3 × 25 mL), brine (1 × 10 mL). The organic layer was dried over Na2SO4, filtered and
concentrated to give the crude compound, which was further purified by column chromatography to give
the final analytically pure product (82% yield).
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2ꢀazidoꢀ4ꢀchlorobenzaldehyde (1d): White solid (3.9 mg, 80%); mp 84−86 ˚C; IR (MIRꢀATR, 4000–600
cmꢀ1): ʋmax = 3340, 3261, 3034, 2864, 2768, 2408, 2342, 2216, 2120, 1679, 1591, 1568, 1492, 1426, 1396,
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1330, 1289, 1265, 1203, 1077, 949, 841, 816; H NMR (CDCl3, 400 MHz): δH = 10.22 (s, 1H), 7.88 (d,
1H, J = 8.3 Hz), 6.89 (dd, 1H, Ja = 8.3 and Jb = 1.5 Hz), 6.81 (d, 1H, J = 1.5 Hz); 13C NMR (CDCl3, 100
MHz): 187.1 (s, ꢀCHO), 147.4 (s, ArꢀC), 144.8 (s, ArꢀC), 130.9 (d, ArꢀCH), 123.9 (s, ArꢀC), 115.5 (d, Arꢀ
CH), 109.1 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for [C7H4ClN3O]+ = [M]+: 181.0037; found:
181.0030
(II) General procedure (GP I) for the synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl) phenols (3aaꢀ3ah). 2ꢀ
Azidobenzaldehyde 1 (1 mmol) and 2ꢀaminophenol 2 (1 mmol) were taken in a 10 mL oven dried
schlenck tube and it was closed with stopcock with argon balloon and placed in external heating oil bath
at 120 ˚C for 15–30 min (oil bath temperature). After completion of the starting material, the mixture was
cooled to room temperature and was purified on a silica gel column chromatography (hexane/ethylacetate
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95:5) which furnished the respective solids. All the compounds were confirmed by FTIR, H NMR, C
NMR and HRꢀMS spectral analyses.
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(III) General procedure (GP II) for the synthesis of 2ꢀ(2Hꢀindazolꢀ2ꢀyl) aniline (3ba–3bg). 2ꢀ
Azidobenzaldehyde 1 (1 mmol) and Boc protected oꢀphenylenediamine 2 (1 mmol) were taken in a 10
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mL round bottom flask and it was closed with stopper and placed in external heating oil bath at 120 C
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(oil bath temperature) for 1–1.5h. After completion of the starting materials, the mixture was cooled to
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room temperature and DCE solvent was added followed by BF3 Et2O and refluxed at 85 C. Progress of
the reaction was monitored by TLC until the reaction completed. The reaction mixture was quenched by
addition of aq. NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL). The organic layers were
dried (Na2SO4) and concentrated in vacuo. Purification of the residue on a silica gel column
chromatography using petroleum ether/ethyl acetate as eluent (hexane/ethylacetate 85:15 to 80:20)
provided the product (3ba–3bg). For known compounds (3baꢀ3bc) (see Ref. 13b and 24a).
(IV) General procedure (GP III) for the synthesis of benzaoxizinoindazoles (5aꢀ5r). In an oven dried
10 ml schlenck tube, under oxygen atmosphere, 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenols 3aa–3ah (1 mmol),
Pd(OAc)2 (5 mol%) and 4Å MS (100 mg) were added. Subsequently, the vessel was placed under vacuum
and backfilled with O2. Then, toluene solvent (2.5 mL) and isocyanide (4aꢀ4e) were added and the
resulting mixture was stirred at 110 ˚C for 21 hours under oxygen atmosphere. Progress of the reaction
was monitored by TLC until the reaction is completed. The mixture was filtered through Celite,
concentrated, then washed with water and extracted in ethyl acetate (3 × 10 mL). The organic layer was
dried (Na2SO4) and concentrated in vacuo. Purification of the residue on a silica gel column
chromatography using petroleum ether/ethyl acetate as eluent (hexane/ethylacetate 95:5 to 90:10) yielded
the product benzoxazinoindazoles (5a–5q).
(V) General procedure (IV) for the synthesis of indazoloquinaoxalines (6aꢀ6h). In an oven dried 10
ml schlenck tube, under oxygen atmosphere, 2ꢀ(2Hꢀindazolꢀ2ꢀyl)aniline 3ba–3bg (1 mmol), isocyanides
4a–4b (2 mmol), Pd(OAc)2 (10 mol%) and CuCl2.2H2O (10 mol%) were added and followed by addition
of toluene (2 mL). The resulting reaction mixture was stirred at 110 °C for 12ꢀ15h under oxygen
atmosphere. Progress of the reaction was monitored by TLC until the reaction was completed. The
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reaction mixture was quenched by addition of aq. NH4Cl solution and extracted with ethyl acetate (3 × 10
mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue on a
silica gel column chromatography using petroleum ether/ethyl acetate as (hexane/ethylacetate 90:10 to
85:15) eluent furnished the product indazoloquinaoxalines (6aꢀ6h).
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(VI) General procedure (V) for the synthesis of benzoxazinoindazolone (7aꢀ7e). To a 10 mL roundꢀ
bottom flask containing 5a–5c, 5e and 5f (1 mmol) THF (5 mL) and hydrochloric acid (1 M, 1 mL) were
added. The resulting reaction mixture was stirred at 85 °C for 2–3h. Progress of the reaction was
monitored by TLC until the reaction was completed. The reaction mixture was quenched by addition of
aq. NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried (Na2SO4)
and concentrated in vacuo. Purification of the residue on a silica gel column chromatography using
petroleum ether/ethyl acetate as eluent (hexane/ethylacetate 85:15to 80:20) provided the product 7aꢀ7e.
(VII) General procedure (VI) for sequential oneꢀpot synthesis of benzoxazinoindazolone (7aꢀ7e). 2ꢀ
Azidobenzaldehyde 1 (1 mmol) and 2ꢀaminophenol 2 (1 mmol) were taken in a 25 mL oven dried
schlenck tube and it was closed with stopcock with argon balloon and placed in external heating oil bath
at 120 oC (oil bath temperature) for 15–30 min. The completion of first step was monitored by TLC. Once
intermediate A (dinucleophile) was formed Pd(OAc)2 (5 mol%), CyNC (1.5 equiv) and solvent were
added in same pot under argon atmosphere. Subsequently, the vessel was placed under vacuum and
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backfilled with O2. The resulting reaction mixture was heated at 110 C. Progress of the reaction was
monitored by TLC, which took 21h. On confirming the completion of reaction, to the same pot THF (10
mL) and hydrochloric acid (1 M, 2 mL) were added and the resulting reaction mixture was stirred at 85
°C for 2–3h. Progress of the reaction was monitored by TLC until the reaction was completed. The
mixture was filtered through Celite, concentrated, Then reaction mixture was quenched by addition of aq.
NaHCO3 solution and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried (Na2SO4) and
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concentrated in vacuo. Purification of the residue on a silica gel column chromatography using petroleum
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ether/ethyl acetate as (hexane/ethylacetate 85:15 to 80:20) eluent yielded the product 7aꢀ7e.
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(VIII) Spectroscopic Data of all unknown compounds. 2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenol (3aa): White solid
(202 mg, 95%); mp 80−82 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3134, 3056, 2923, 2853, 1741,
1631, 1595, 1517, 1499, 1459, 1420, 1396, 1373, 1309, 1281, 1253, 1253, 1160, 1128, 1035, 964, 915,
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839, 792, 779, 749, 523; H NMR (CDCl3, 400 MHz): δH = 12.1 (s, 1H), 8.45 (s, 1H), 7.72 (dd, 2H, Ja =
8.8 and Jb = 3.4 Hz), 7.56 (dd, 1H, Ja = 8.3 and Jb = 1 Hz), 7.38−7.35 (m, 1H), 7.28−7.23 (m, 1H),
7.17−7.13 (m, 2H), 6.97−6.93 (m, 1H); 13C NMR (CDCl3, 100 MHz): 150.5 (s, ArꢀC), 147.6 (s, ArꢀC),
129.1 (d, ArꢀCH), 127.7 (d, ArꢀCH), 124.9 (s, ArꢀC), 123.0 (d, ArꢀCH), 121.3 (s, ArꢀC), 120.3 (d, Arꢀ
CH), 120.2 (d, ArꢀCH), 119.7 (d, ArꢀCH), 119.5 (d, ArꢀCH), 119.2 (d, ArꢀCH), 116.8 (d, ArꢀCH); HRꢀ
MS (ESI+) m/z calculated for [C13H11N2O]+ = [M+H]+: 211.0866; found: 211.0865.
2ꢀ(5ꢀBromoꢀ2Hꢀindazolꢀ2ꢀyl)phenol (3ab): Light yellow solid (163 mg, 85%); mp 140−142 ˚C; IR (MIRꢀ
ATR, 4000–600 cmꢀ1): ʋmax = 3147, 2921, 2852, 1743, 1599, 1498, 1454, 1422, 1377, 1329, 1284, 1250,
1
1193, 1161, 1034, 795, 735, 536; H NMR (CDCl3, 400 MHz): δH = 11.78 (s, 1H), 8.43 (s, 1H), 7.9 (s,
1H), 7.63−7.56 (m, 2H), 7.44 (dd, 1H, Ja = 9.3 and Jb = 1.5 Hz), 7.31−7.26 (m, 1H), 7.18 (d, 1H, J = 7.8
Hz), 6.99 (t, 1H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz): 150.4 (s, ArꢀC), 146.0 (s, ArꢀC), 131.4 (d, Arꢀ
CH), 129.5 (d, ArꢀCH), 124.6 (s, ArꢀC), 122.6 (s, ArꢀC), 122.3 (d, ArꢀCH), 119.8 (d, ArꢀCH), 119.7 (d,
ArꢀCH), 119.6 (d, ArꢀCH), 119.3 (d, ArꢀCH), 118.6 (d, ArꢀCH), 116.5 (s, ArꢀC); HRꢀMS (ESI+) m/z
calculated for [C13H10BrN2O]+ = [M+H]+: 288.9971; found: 288.9966.
2ꢀ(6ꢀbromoꢀ2Hꢀindazolꢀ2ꢀyl)phenol (3ac): Light yellow solid (168 mg, 88%); mp 124−126 ˚C; IR (MIRꢀ
ATR, 4000–600 cmꢀ1): ʋmax = 3139, 3076, 2924, 2855, 1745, 1700, 1600, 1496, 1458, 1417, 1390, 1356,
1
1277, 1249, 1187, 1123, 1036, 924, 880, 798, 735, 741, 588; H NMR (CDCl3, 400 MHz): δH = 11.7 (s,
1H), 8.41 (s, 1H), 7.91 (s, 1H), 7.59−7.52 (m, 2H), 7.29−7.21 (m, 2H), 7.16 (dd, 1H, Ja = 8.3 and Jb = 1.5
Hz), 6.98−6.94 (m, 1H); 13C NMR (CDCl3, 100 MHz): 150.4 (s, ArꢀC), 148.2 (s, ArꢀC), 129.5 (d, Arꢀ
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CH), 126.9 (d, ArꢀCH), 124.6 (s, ArꢀC), 121.9 (d, ArꢀCH), 121.6 (s, ArꢀC), 120.9 (d, ArꢀCH), 120.0 (d,
ArꢀCH), 119.8 (s, ArꢀC), 119.3 (d, ArꢀCH), 119.2 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for
[C13H10BrN2O]+ = [M+H]+: 288.9971; found: 288.9971.
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2ꢀ(6ꢀChloroꢀ2Hꢀindazolꢀ2ꢀyl)phenol (3ad): Dark golden rod solid (166 mg, 82%); mp 116−118 ˚C; IR
(MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3612, 3140, 2727, 2309, 2107, 1934, 1807, 1597, 1553, 1500, 1425,
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1360, 1312, 1258, 1148, 1092, 1032, 956, 816, 781, 741, 706, 655, 608, 527; H NMR (CDCl3, 400
MHz): δH =11.89 (s, 1H), 8.39 (s, 1H) 7.67 (d, 1H, J = 8.8 Hz), 7.51 (dd, 1H, Ja = 8.1 and Jb = 1.2 Hz),
7.30−7.23 (m, 2H), 7.15 (dd, 1H, Ja = 8.3 and Jb = 1.5 Hz), 6.97−6.93 (m, 1H), 6.82 (dd, 1H, Ja = 8.8 and
Jb = 2 Hz); 13C NMR (CDCl3, 100 MHz): 150.4 (s, ArꢀC), 147.8 (s, ArꢀC), 139.9 (s, ArꢀC), 129.2 (d, Arꢀ
CH), 124.7 (s, ArꢀC), 122.0 (d, ArꢀCH), 120.7 (d, ArꢀCH), 119.7 (d, ArꢀCH), 119.5 (d, ArꢀCH), 119.2 (s,
ArꢀC), 119.1 (d, ArꢀCH), 117.3 (d, ArꢀCH), 104.4 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for
[C13H10ClN2O]+ = [M+H]+: 245.0476; found: 245.0478.
2ꢀ(2Hꢀ[1,3]dioxolo[4,5ꢀf]indazolꢀ2ꢀyl)phenol (3ae): White solid (81 mg, 88%); mp 134−136 ˚C; IR
(MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3145, 2911, 1651, 1622, 1602, 1555, 1504, 1486, 1437, 1379, 1356,
1
1285, 1254, 1219, 1181, 1115, 1046, 1036, 951, 820, 728; H NMR (CDCl3, 400 MHz): δH = 11.91 (s,
1H), 8.23 (s, 1H), 7.47 (d, 1H, J = 7.8 Hz), 7.23−7.19 (m, 1H), 7.14−7.12 (m, 1H), 6.96−6.90 (m, 3H),
5.99 (s, 2H); 13C NMR (CDCl3, 100 MHz): 150.3 (s, ArꢀC), 149.9 (s, ArꢀC), 146.5 (s, ArꢀC), 145.2 (s, Arꢀ
C), 128.3 (d, ArꢀCH), 125.0 (s, ArꢀC), 119.6 (d, ArꢀCH), 119.5 (d, ArꢀCH), 119.2 (d, ArꢀCH), 118.5 (s,
ArꢀC), 101.3 (t, ꢀCH2ꢀ), 94.8 (d, ArꢀCH), 93.4 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for
[C14H11N2O3]+ = [M+H]+: 255.0764; found: 255.0774.
2ꢀ(2Hꢀindazolꢀ2ꢀyl)ꢀ4ꢀmethylphenol (3af): White solid (194 mg, 85%); mp 76−78 ˚C; IR (MIRꢀATR,
4000–600 cmꢀ1): ʋmax = 3135, 3061, 2923, 2854, 1737, 1632, 1603, 1520, 1463, 1392, 1370, 1284, 1251,
1210, 1128, 1049, 917, 795, 754; 1H NMR (CDCl3, 400 MHz): δH =11.85 (br s, 1H), 8.48 (s, 1H), 7.48 (d,
2H, J = 8.8 Hz), 7.39−7.36 (m, 2H), 7.17 (dd, 1H, Ja = 8.1 and Jb = 7.1 Hz ), 7.08 (s, 1H), 2.37 (s, 3H);
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13C NMR (CDCl3, 100 MHz): 148.2 (s, 2C, ArꢀC), 147.7 (s, ArꢀC), 129.8 (d, ArꢀCH), 129.1 (s, 2C, Arꢀ
C), 127.6 (d, ArꢀCH), 124.4 (s, ArꢀC), 122.9 (d, ArꢀCH), 121.3 (s, ArꢀC), 120.3 (d, ArꢀCH), 120.2 (d, Arꢀ
CH), 119.6 (d, ArꢀCH), 119.7 (d, ArꢀCH), 116.9 (d, ArꢀCH), 20.7 (q, ꢀCH3); HRꢀMS (ESI+) m/z
calculated for [C14H13N2O]+ = [M+H]+: 225.1022; found: 225.1021.
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4ꢀChloroꢀ2ꢀ(2Hꢀindazolꢀ2ꢀyl)phenol (3ag): White solid (200 mg, 80%); mp 118−120 ˚C; IR (MIRꢀATR,
4000–600 cmꢀ1): ʋmax = 3449, 3322, 3148, 3057, 2919, 1621, 1591, 1497, 1458, 1395, 1366, 1330, 1284,
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1247, 1155, 1099, 1043, 965, 917, 842, 772, 746, 713, 654, 626, 535; H NMR (CDCl3, 400 MHz): δH =
12.16 (s, 1H), 8.44 (s, 1H), 7.72 (d, 2H, J = 9.3 Hz), 7.58 (d, 1H, J = 2.4 Hz), 7.40 (dd, 1H, Ja = 8.6 and Jb
= 7.1 Hz), 7.26−7.16 (m, 2H), 7.11 (d, 1H, J = 8.8 Hz); 13C NMR (CDCl3, 100 MHz): 149.2 (s, ArꢀC),
147.7 (s, ArꢀC), 128.9 (d, ArꢀCH), 128.1 (d, ArꢀCH), 125.2 (s, ArꢀC), 124.2 (s, ArꢀC), 123.3 (d, ArꢀCH),
121.4 (s, ArꢀC), 120.6 (d, ArꢀCH), 120.4 (d, ArꢀCH), 120.2 (d, ArꢀCH), 119.1 (d, ArꢀCH), 116.8 (d, Arꢀ
CH); HRꢀMS (ESI+) m/z calculated for [C13H10ClN2O]+ = [M+H]+: 245.0476; found: 245.0475.
2ꢀ(2Hꢀindazolꢀ2ꢀyl)ꢀ4ꢀnitrophenol (3ah): Yellow solid (202 mg, 78%); mp 166−168 ˚C; IR (MIRꢀATR,
4000–600 cmꢀ1): ʋmax = 3449, 3138, 3087, 2752, 2348, 1632, 1618, 1521, 1412, 1399, 1374, 1342, 1304,
1
1285, 1252, 1193, 1148, 1079, 1036, 967, 943, 880, 815, 796, 752, 739, 623; H NMR (CDCl3, 400
MHz): δH =12.8 (br s, 1H), 8.55 (s, 1H), 8.01 (d, 1H, J = 2.4 Hz), 7.84 (dd, 1H, Ja = 8.8 and Jb = 2.4 Hz),
7.75−7.70 (m, 3H), 7.45−7.41 (m, 1H), 7.23 (dd, 1H, Ja = 15.9 and Jb = 8.6 Hz); 13C NMR (CDCl3, 100
MHz): 151.1 (s, ArꢀC), 147.9 (s, ArꢀC), 147.3 (s, ArꢀC), 129.1 (s, ArꢀC), 128.9 (d, ArꢀCH), 124.0 (d, Arꢀ
CH), 121.6 (s, ArꢀC), 121.0 (d, ArꢀCH), 120.3 (d, ArꢀCH), 119.2 (d, ArꢀCH), 116.9 (d, ArꢀCH), 115.2 (d,
ArꢀCH), 114.7 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for [C13H10N3O3]+ = [M+H]+: 256.0717; found:
256.0716.
2ꢀ(6ꢀChloroꢀ2Hꢀindazolꢀ2ꢀyl)aniline (3bd): Golden yellow solid (171 mg, 85%); mp 114−116 ˚C; IR
(MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3447, 3343, 3200, 3127, 3060, 2105, 1616, 1552, 1510, 1462, 1392,
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MHz): δH = 8.18 (s, 1H), 7.71 (d, 1H, J = 8.8 Hz), 7.37 (s, 1H), 7.31 (dd, 1H, Ja = 8.1 and Jb = 1.2 Hz),
7.26−7.20 (m, 1H), 6.88−6.81 (m, 3H), 4.90 (br s, 2H). 13C NMR (CDCl3, 100 MHz): 149.7 (s, ArꢀC),
141.3 (s, ArꢀC), 138.8 (s, ArꢀC), 129.6 (d, ArꢀCH), 126.3 (s, ArꢀC), 124.7 (d, ArꢀCH), 124.1 (d, ArꢀCH),
122.2 (d, ArꢀCH), 119.8 (s, ArꢀC), 118.1 (d, ArꢀCH), 117.6 (d, ArꢀCH), 116.4 (d, ArꢀCH), 105.2 (d, Arꢀ
CH); HRꢀMS (ESI+) m/z calculated for [C13H11ClN3]+ = [M+H]+: 244.0636; found: 244.0639.
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2ꢀ(2Hꢀ[1,3]dioxolo[4,5ꢀf]indazolꢀ2ꢀyl)aniline (3be): Light yellow solid (72 mg, 88%); mp 132−134 ˚C;
IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3451, 3347, 3128, 2920, 2779, 1732,1613, 1548, 1503, 1478,
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1389, 1346, 1316, 1264, 1221, 1169, 1040, 950, 831, 792, 734, 702; H NMR (CDCl3, 400 MHz): δH =
7.98 (s,1H), 7.27ꢀ7.26 (m, 1H), 7.18 (t, 1H, J = 7.1 Hz), 7.01 (s, 1H), 6.92 (s, 1H), 6.86ꢀ6.78 (m, 2H),
5.97 (s, 2H), 4.84 (br s, 2H); 13C NMR (CDCl3, 100 MHz): 149.5 (s, ArꢀC), 147.0 (s, ArꢀC), 145.9 (s, Arꢀ
C), 141.2 (s, ArꢀC), 128.9 (d, ArꢀCH), 126.7 (s, ArꢀC), 124.6 (d, ArꢀCH), 123.0 (d, ArꢀCH), 118.1 (d, Arꢀ
CH), 117.4 (s, ArꢀC), 117.4 (d, ArꢀCH), 101.0 (t, ꢀCH2ꢀ), 95.0 (d, ArꢀCH), 94.0 (d, ArꢀCH); HRꢀMS
(ESI+) m/z calculated for [C14H12N3O2]+ = [M+H]+: 254.0924; found: 254.0934.
4ꢀChloroꢀ2ꢀ(2Hꢀindazolꢀ2ꢀyl)aniline (3bf): Light yellow solid (164 mg, 82%); mp 96−98 ˚C; IR (MIRꢀ
ATR, 4000–600 cmꢀ1): ʋmax = 3452, 3335, 3202, 3124, 3060, 1619, 1582, 1499, 1460, 1426, 1385, 1350,
1304, 1263, 1199, 1151, 1099, 1042, 962, 864, 813, 788, 751, 731, 652; 1H NMR (CDCl3, 400 MHz): δH
= 8.18 (s, 1H), 7.74 (dd, 2H, Ja = 14.9 and Jb = 8.6 Hz), 7.37−7.34 (m, 2H), 7.17−7.12 (m, 2H), 6.78 (d,
1H, J = 8.8 Hz), 4.98 (s, 2H); 13C NMR (CDCl3, 100 MHz): 149.6 (s, ArꢀC), 140.1 (s, ArꢀC), 129.2 (d,
ArꢀCH), 127.1 (d, ArꢀCH), 126.7 (s, ArꢀC), 124.6 (d, ArꢀCH), 123.6 (d, ArꢀCH), 122.6 (d, ArꢀCH), 122.2
(s, ArꢀC), 121.9 (s, ArꢀC), 120.4 (d, ArꢀCH), 118.4 (d, ArꢀCH), 117.5 (d, ArꢀCH); HRꢀMS (ESI+) m/z
calculated for [C13H11ClN3]+ = [M+H]+: 244.0636; found: 244.0625.
(3ꢀAminoꢀ4ꢀ(2Hꢀindazolꢀ2ꢀyl)phenyl)(phenyl)methanone (3bg): Light yellow solid (249 mg, 78%); mp
166−168 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3457, 3355, 3057, 2124, 1652, 1609, 1516, 1439,
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3H), 7.38−7.32 (m, 2H), 7.22 (dd, 1H, Ja = 8.1 and Jb = 1.7 Hz), 7.17ꢀ7.13 (m, 1H), 5.25 (br s, 2H); 13C
NMR (CDCl3, 100 MHz): 196.2 (s, ꢀCOꢀ), 149.7 (s, ArꢀC), 141.2 (s, ArꢀC), 138.1 (s, ArꢀC), 137.4 (s, Arꢀ
C), 132.6 (d, ArꢀCH), 130.1 (d, 2C, ArꢀCH), 128.9 (s, ArꢀC), 128.4 (d, 2C, ArꢀCH), 127.2 (d, ArꢀCH),
124.3 (d, ArꢀCH), 123.6 (d, ArꢀCH), 122.7 (d, ArꢀCH), 121.9 (s, ArꢀC), 120.4 (d, ArꢀCH), 119.7 (d, Arꢀ
CH), 119.0 (d, ArꢀCH), 117.6 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for [C20H16N3O]+ = [M+H]+:
314.1288; found: 314.1287.
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(Z)ꢀNꢀ(6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)cyclohexanamine (5a): White solid (102 mg,
98%); mp 116−118 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3069, 2926, 2852, 1671, 1606, 1529,
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1498, 1488, 1448, 1432, 1371, 1305, 1281, 1229, 1188, 1116, 1096, 1030, 994, 933, 746, 634; H NMR
(CDCl3, 400 MHz): δH = 8.25 (d, 2H, J = 8.3 Hz), 7.8 (d, 1H, J = 8.8 Hz), 7.42−7.38 (m, 1H), 7.31ꢀ7.20
(m, 4H), 4.15−4.09 (m, 1H), 1.90−1.85 (m, 4H), 1.68−1.36 (m, 6H); 13C NMR (CDCl3, 100 MHz): 149.5
(s, ArꢀC), 144.7 (s, ArꢀC), 139.6 (s, ArꢀC), 128.2 (d, ArꢀCH), 128.0 (d, ArꢀCH), 124.4 (d, ArꢀCH), 124.1
(s, ArꢀC), 124.0 (d, ArꢀCH), 122.2 (d, ArꢀCH), 122.1 (s, ArꢀC), 120.8 (s, ArꢀC), 117.6 (d, ArꢀCH), 116.9
(d, ArꢀCH), 116.6 (d, ArꢀCH), 54.1 (d, ꢀCHꢀ), 33.9 (t, 2C, ꢀCH2ꢀ), 26.1 (t, ꢀCH2ꢀ), 24.6 (t, 2C, ꢀCH2ꢀ);
HRꢀMS (ESI+) m/z calculated for [C20H20N3O]+ = [M+H]+: 318.1601; found: 318.1599.
(Z)ꢀNꢀ(8ꢀbromoꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)cyclohexanamine (5b): White solid
(84 mg, 87%); mp 128−130 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3070, 2927, 2853, 1675, 1605,
1517, 1490, 1446, 1416, 1367, 1339, 1301, 1271, 1229, 1178, 1133, 1096, 1030, 989, 941, 909, 882, 803,
748, 701, 668; 1H NMR (CDCl3, 400 MHz): δH = 8.38 (d, 1H, J =1.5 Hz), 8.21 (dd, 1H, Ja = 8.1 and Jb =
1.2 Hz), 7.66 (d, 1H, J = 9.3 Hz), 7.44 (dd, 1H, Ja = 9.0 and Jb = 1.7 Hz), 7.36−7.31 (m, 1H), 7.27−7.22
(m, 2H), 4.12−4.05 (m, 1H), 1.88−1.84 (m, 4H), 1.61−1.32 (m, 6H); 13C NMR (CDCl3, 100 MHz): 147.9
(s, ArꢀC), 144.8 (s, ArꢀC), 139.2 (s, ArꢀC), 131.7 (d, ArꢀCH), 128.6 (d, ArꢀCH), 124.4 (d, ArꢀCH), 124.1
(d, ArꢀCH), 123.8 (s, ArꢀC), 121.8 (s, ArꢀC), 121.6 (s, ArꢀC), 119.2 (d, ArꢀCH), 118.1 (s, ArꢀC), 117.0
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(d, ArꢀCH), 116.7 (d, ArꢀCH), 54.4 (d, ꢀCHꢀ), 33.8 (t, 2C, ꢀCH2ꢀ), 26.0 (t, ꢀCH2ꢀ), 24.8 (t, 2C, ꢀCH2ꢀ);
HRꢀMS (ESI+) m/z calculated for [C20H19BrN3O]+ = [M+H]+: 396.0706; found: 396.0705.
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(80 mg, 84%); mp 182−154; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3067, 2926, 2853, 1674, 1604, 1540,
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NMR (CDCl3, 400 MHz): δH = 8.10 (d, 1H, J = 8.3 Hz), 7.99 (d, 1H, J = 8.8 Hz), 7.86 (s, 1H), 7.26−7.20
(m, 2H), 7.17−7.12 (m, 2H), 4.04−3.99 (m, 1H), 1.81−1.79 (m, 4H), 1.6 (d, 2H, J = 9.8 Hz), 1.49−1.39
(m, 4H); 13C NMR (CDCl3, 100 MHz): 150.0 (s, ArꢀC), 144.8 (s, ArꢀC), 139.9 (s, ArꢀC), 128.5 (d, Arꢀ
CH), 128.0 (d, ArꢀCH), 124.1 (d, ArꢀCH), 123.8 (s, ArꢀC), 123.6 (d, ArꢀCH), 122.6 (s, ArꢀC), 122.1 (s,
ArꢀC), 120.0 (d, ArꢀCH), 119.2 (s, ArꢀC), 117.0 (d, ArꢀCH), 116.6 (d, ArꢀCH), 54.2 (d, ꢀCHꢀ), 33.8 (t,
2C, ꢀCH2ꢀ), 26.0 (t, 2C, ꢀCH2ꢀ), 24.5 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for [C20H19BrN3O]+ =
[M+H]+: 396.0706; found: 396.0694.
(Z)ꢀNꢀ(6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb][1,3]dioxolo[4,5ꢀf]indazolꢀ6ꢀylidene)cyclohexanamine
(5d):
White solid (95 mg, 96%); mp 194−196 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 2927, 2854, 2780,
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1674, 1605, 1508, 1469, 1397, 1360, 1337, 1287, 1215, 1097, 1036, 986, 957, 850, 819, 751; H NMR
(CDCl3, 400 MHz): δH = 8.13 (s, 1H), 7.49 (s, 1H), 7.27−7.21 (m, 3H), 7.06 (s, 1H), 6.03 (s, 2H),
4.13−4.07 (m, 1H), 1.88 (d, 4H, J = 8.3 Hz), 1.69−1.67 (m, 1H), 1.56−1.33 (m, 5H); 13C NMR (CDCl3,
100 MHz): 150.5 (s, ArꢀC), 147.4 (s, ArꢀC), 147.2 (s, ArꢀC), 144.1 (s, ArꢀC), 139.7 (s, ArꢀC), 127.2 (d,
ArꢀCH), 124.2 (s, ArꢀC), 123.9 (d, ArꢀCH), 121.7 (s, ArꢀC), 117.0 (s, ArꢀC), 116.5 (d, ArꢀCH), 116.1 (d,
ArꢀCH), 101.4 (t, ꢀCH2ꢀ), 97.3 (d, ArꢀCH), 94.2 (d, ArꢀCH), 53.9 (d, ArꢀCHꢀ), 33.9 (t, 2C, ꢀCH2ꢀ), 26.0 (t,
ꢀCH2ꢀ), 25.6 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for [C21H20N3O3]+ = [M+H]+: 362.1499; found:
362.1501.
(Z)ꢀNꢀ(2ꢀmethylꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)cyclohexanamine (5e): White solid
(89 mg, 87%); mp 118−120 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3066, 2927, 2852, 1672, 1617,
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1H), 2.33 (s, 3H), 1.90ꢀ1.87 (m, 4H), 1.69ꢀ1.34 (m, 6H); 13C NMR (CDCl3, 100 MHz): 149.4 (s, ArꢀC),
142.6 (s, ArꢀC), 139.9 (s, ArꢀC), 133.9 (s, ArꢀC), 128.7 (d, ArꢀCH), 127.9 (d, ArꢀCH), 124.2 (d, ArꢀCH),
123.5 (s, ArꢀC), 122.2 (d, ArꢀCH), 122.1 (s, ArꢀC), 120.7 (s, ArꢀC), 117.5 (d, ArꢀCH), 116.9 (d, ArꢀCH),
116.1(d, ArꢀCH), 54.0 (d, ꢀCHꢀ), 33.9 (t, 2C, ꢀCH2ꢀ), 26.1 (t, ꢀCH2ꢀ), 24.6 (t, 2C, ꢀCH2ꢀ), 20.8 (q, ꢀCH3);
HRꢀMS (ESI+) m/z calculated for [C21H22N3O]+ = [M+H]+: 332.1757; found: 332.1754.
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(Z)ꢀNꢀ(2ꢀchloroꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)cyclohexanamine (5f): White solid
(85 mg, 85%); mp 140−142 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3071, 2926, 2852, 1673, 1605,
1528, 1489, 1448, 1432, 1369, 1307, 1262, 1231, 1186, 1146, 1109, 1073, 996, 941, 871, 845, 809, 749,
632; 1H NMR (CDCl3, 400 MHz): δH = 8.27 (d, 1H, J = 2H), 8.23 (d, 1H, J = 8.8 Hz), 7.8 (d, 1H, J = 8.8
Hz), 7.44−7.40 (m, 1H), 7.29−7.24 (m, 2H), 7.22−7.20 (m, 1H), 4.13−4.10 (m, 1H), 1.88−1.80 (m, 4H),
1.60−1.35 (m, 6H); 13C NMR (CDCl3, 100 MHz): 149.8 (s, ArꢀC), 143.3 (s, ArꢀC), 138.9 (s, ArꢀC), 129.3
(s, ArꢀC), 128.4 (d, ArꢀCH), 128.0 (d, ArꢀCH), 124.7 (d, ArꢀCH), 122.2 (d, ArꢀCH), 122.1 (s, 2C, ArꢀC),
120.8 (s, ArꢀC), 117.8 (d, ArꢀCH), 117.7 (d, ArꢀCH), 117.0 (d, ArꢀCH), 54.2 (d, ꢀCHꢀ), 33.8 (t, 2C, ꢀCH2ꢀ
), 26.0 (t, 2C, ꢀCH2ꢀ), 24.5 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for [C20H19ClN3O]+ = [M+H]+:
352.1211; found: 352.1207.
(Z)ꢀNꢀ(2ꢀnitroꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)cyclohexanamine (5g): yellow solid
(67 mg, 68%); mp 140−142 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3054, 2926, 2852, 1676, 1602,
1531, 1502, 1450, 1423, 1374, 1342, 1308, 1263, 1184, 1143, 1119, 1074, 994, 961, 894, 838, 735, 702,
662, 624, 603, 582; 1H NMR (CDCl3, 400 MHz): δH = 8.27 (d, 1H, J = 2H), 8.23 (d, 1H, J = 8.8 Hz), 7.8
(d, 1H, J = 8.8 Hz), 7.44−7.40 (m, 1H), 7.29−7.24 (m, 2H), 7.22−7.20 (m, 1H), 4.13−4.10 (m, 1H),
1.88−1.80 (m, 4H), 1.60−1.35 (m, 6H); 13C NMR (CDCl3, 100 MHz): 150 (s, ArꢀC), 146.6 (s, ArꢀC),
144.4 (s, ArꢀC), 137.8 (s, ArꢀC), 129.2 (d, ArꢀCH), 128.7 (s, ArꢀC), 125.4 (d, ArꢀCH), 122.5 (d, Arꢀ
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CH), 122.3 (s, ArꢀC), 121.1 (s, ArꢀC), 119.4 (d, ArꢀCH), 117.9 (d, ArꢀCH), 117.5 (d, ArꢀCH), 112.7 (d,
ArꢀCH), 54.5 (d, ꢀCHꢀ), 33.8 (t, 2C, ꢀCH2ꢀ), 26.0 (t, ꢀCH2ꢀ), 24.4 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z
calculated for [C20H19N4O3]+ = [M+H]+: 363.1452; found: 363.1448.
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(Z)ꢀNꢀ(6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)ꢀ2ꢀmethylpropanꢀ2ꢀamine (5h): White solid
(85 mg, 88%); mp 128−130 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3068, 2966, 2928, 2905, 1681,
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NMR (CDCl3, 400 MHz): δH = 8.29 (dd, 1H, Ja = 8.1 and Jb = 1.2 Hz), 8.25 (d, 1H, 8.3 Hz), 7.82 (d, 1H,
J = 8.3 Hz), 7.44−7.40 (m, 1H), 7.34−7.30 (m, 1H), 7.30−7.27 (m, 2H), 7.27−7.24 (m, 1H), 1.54 (s, 9H);
13C NMR (CDCl3, 100 MHz): 149.6 (s, ArꢀC), 144.7 (s, ArꢀC), 138.2 (s, ArꢀC), 128.2 (d, ArꢀCH), 128.0
(d, ArꢀCH), 124.4 (d, ArꢀCH), 124.0 (d, ArꢀCH), 122.6 (s, ArꢀC), 122.3 (d, ArꢀCH), 120.8 (s, 2C, ArꢀC),
117.6 (d, ArꢀCH), 117.0 (d, ArꢀCH), 116.7 (d, ArꢀCH), 54.8 (s, ꢀCꢀ), 30.4 (q, 3C, ꢀCH3); HRꢀMS (ESI+)
m/z calculated for [C18H18N3O]+ = [M+H]+: 292.1444; found: 292.1445.
(Z)ꢀNꢀ(8ꢀbromoꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)ꢀ2ꢀmethylpropanꢀ2ꢀamine
(5i):
White solid (77 mg, 80%); mp 140−142 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3070, 2967, 2927,
1680, 1606, 1516, 1490, 1446, 1414, 1361, 1335, 1300, 1267, 1249, 1216, 1171, 1130, 1094, 1032, 985,
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1H, Ja = 8.1 and Jb = 1.2 Hz), 7.67 (d, 1H, J = 9.3 Hz), 7.45 (dd, 1H, Ja = 9 and Jb = 1.7 Hz), 7.35ꢀ7.33
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(m, 1H), 7.28ꢀ7.23 (m, 2H), 1.53 (s, 9H); C NMR (CDCl3, 100 MHz): 147.9 (s, ArꢀC), 144.7 (s, ArꢀC),
137.8 (s, ArꢀC), 131.7 (d, ArꢀCH), 128.6 (d, ArꢀCH), 124.4 (d, ArꢀCH), 124.1 (d, ArꢀCH), 123.8 (s, Arꢀ
C), 122.0 (s, ArꢀC), 121.8 (s, ArꢀC), 119.2 (d, ArꢀCH), 118.0 (s, ArꢀC), 117.1 (d, ArꢀCH), 116.8 (d, Arꢀ
CH), 54.9 (q, ꢀCꢀ), 30.3 (q, CH3); HRꢀMS (ESI+) m/z calculated for [C18H17BrN3O]+ = [M+H]+:
370.0550; found: 370.0550.
(Z)ꢀNꢀ(9ꢀbromoꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)ꢀ2ꢀmethylpropanꢀ2ꢀamine
(5j):
White solid (70 mg, 78%); mp 116−118 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3069, 2968, 2929,
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950, 914, 810, 751, 700, 598; H NMR (CDCl3, 400 MHz): δH = 8.26 (dd, 1H, Ja = 7.8 and Jb = 1.5 Hz),
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8.17 (d, 1H, J = 8.8 Hz), 7.47 (s, 1H), 7.37−7.33 (m, 1H), 7.30−7.26 (m, 2H), 7.07 (dd, 1H, Ja = 8.8 and
Jb = 1.5 Hz), 1.47 (s, 9H); 13C NMR (CDCl3, 100 MHz): 150.2 (s, ArꢀC), 144.6 (s, ArꢀC), 141.0 (s, ArꢀC),
128.1 (d, ArꢀCH), 124.1 (d, ArꢀCH), 123.2 (d, ArꢀCH), 122.7 (s, 2C, ArꢀC), 122.5 (d, ArꢀCH), 120.8 (s,
ArꢀC), 116.9 (d, ArꢀCH), 116.7 (d, ArꢀCH), 109.5 (d, ArꢀCH), 106.1 (s, ArꢀC) 54.8 (s, ꢀCꢀ), 30.3 (q, 3C,
ArꢀCH3); HRꢀMS (ESI+) m/z calculated for [C18H17BrN3O]+ = [M+H]+: 370.0550; found: 370.0554.
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(Z)ꢀNꢀ(6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb][1,3]dioxolo[4,5ꢀf]indazolꢀ6ꢀylidene)ꢀ2ꢀmethylpropanꢀ2ꢀamine
(5k): White solid (83 mg, 90%); mp 136−138 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3738, 2955,
2900, 2781, 2133, 1744, 1664, 1597, 1553, 1503, 1473, 1433, 1352, 1282, 1255, 1205, 1123, 1093, 1032,
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953, 912, 853, 815, 736; H NMR (CDCl3, 400 MHz): δH = 8.15 (d, 1H, d, J = 6.8 Hz), 7.48 (s, 1H),
7.29−7.22 (m, 3H), 7.07 (s, 1H), 6.08 (s, 2H), 1.53 (s, 9H); 13C NMR (CDCl3, 100 MHz): 150.5 (s, Arꢀ
C), 147.3 (s, ArꢀC), 147.2 (s, ArꢀC), 144.1 (s, ArꢀC), 138.4 (s, ArꢀC), 127.2 (d, ArꢀCH), 124.2 (s, ArꢀC),
124.0 (d, ArꢀCH), 122.2 (s, ArꢀC), 117.1 (s, ArꢀC), 116.6 (d, ArꢀCH), 116.2 (d, ArꢀCH), 101.4 (t, ꢀCH2ꢀ),
97.3 (d, ArꢀCH), 94.2 (d, ArꢀCH), 54.6 (s, ꢀCꢀ), 30.4 (q, 3C, ꢀCH3); HRꢀMS (ESI+) m/z calculated for
[C19H18N3O3]+ = [M+H]+: 336.1343; found: 336.1341.
(Z)ꢀ2ꢀmethylꢀNꢀ(2ꢀmethylꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)propanꢀ2ꢀamine
(5l):
White solid (81 mg, 85%); mp 138−140 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3040, 2989, 2961,
2952, 2870, 1670, 1616, 1525, 1498, 1431, 1367, 1331, 1275, 1249, 1216, 1182, 1116, 1190, 1010, 944,
862, 804, 740, 635; 1H NMR (CDCl3, 400 MHz): δH = 8.22 (d, 1H, J = 8.3 Hz), 8.08 (s, 1H), 7.79 (d, 1H,
J = 8.8 Hz), 7.41ꢀ7.35 (m, 1H), 7.26ꢀ7.21 (m, 1H), 7.16ꢀ7.09 (m, 2H), 2.41 (s, 3H), 1.5 (s, 9H); 13C NMR
(CDCl3, 100 MHz): 149.5 (s, ArꢀC), 142.7 (s, ArꢀC), 138.5 (s, ArꢀC), 134.1 (s, ArꢀC), 128.9 (d, ArꢀCH),
128.0 (d, ArꢀCH), 124.3 (d, ArꢀCH), 123.6 (s, ArꢀC), 122.7 (s, ArꢀC), 122.3 (d, ArꢀCH), 120.8 (s, ArꢀC),
117.5 (d, ArꢀCH), 117.1 (d, ArꢀCH), 116.4 (d, ArꢀCH), 54.7 (s, ꢀCꢀ), 30.4 (q, 3C, CH3), 20.9 (q, ꢀCH3);
HRꢀMS (ESI+) m/z calculated for [C19H20N3O]+ = [M+H]+: 306.1601; found: 306.1601.
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(Z)ꢀNꢀ(2ꢀchloroꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)ꢀ2ꢀmethylpropanꢀ2ꢀamine
(5m):
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Golden yellow solid (76 mg, 82%); mp 110−112 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3054, 2968,
2925, 2853, 1679, 1602, 1526, 1485, 1431, 1361, 1306, 1262, 1214, 1182, 1146, 1106, 1067, 998, 891,
858, 842, 803, 752, 633, 607; 1H NMR (CDCl3, 400 MHz): δH = 8.32 (d, 1H, J = 2.4 Hz), 8.23 (d, 1H, J =
8.3 Hz), 7.82 (d, 1H, J = 8.8 Hz), 7.46−7.43 (m, 1H), 7.32−7.29 (m, 1H), 7.27ꢀ7.22 (m, 2H), 1.53 (s, 9H);
13C NMR (CDCl3, 100 MHz): 149.8 (s, ArꢀC), 143.2 (s, ArꢀC), 137.4 (s, ArꢀC), 129.4 (s, ArꢀC), 128.4 (d,
ArꢀCH), 128.0 (d, ArꢀCH), 127.0 (s, ArꢀC), 124.7 (d, ArꢀCH), 122.5 (s, ArꢀC), 122.2 (d, ArꢀCH), 120.9
(s, ArꢀC), 117.8 (d, ArꢀCH), 117.7 (d, ArꢀCH), 117.1 (d, ArꢀCH), 55.0 (s, ꢀCꢀ), 30.4 (q, ꢀCH3); HRꢀMS
(ESI+) m/z calculated for [C18H17ClN3O]+ = [M+H]+: 326.1055; found: 326.1052.
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(Z)ꢀ2ꢀmethylꢀNꢀ(2ꢀnitroꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀylidene)propanꢀ2ꢀamine
(5n):
Golden yellow solid (57 mg, 62%); mp 152−154 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3058, 2955,
2920, 2851, 1688, 1619, 1603, 1527, 1502, 1458, 1421, 1373, 1343, 1307, 1285, 1263, 1224, 1177, 1119,
1075, 992, 878, 840, 796, 737, 703, 668, 628, 571; 1H NMR (CDCl3, 400 MHz): δH = 8.42 (d, 1H, J = 9.3
Hz), 8.22−8.14 (m, 3H), 7.81 (d, 1H, J = 8.8 Hz), 7.48−7.44 (m, 1H), 7.33−7.26 (m, 1H), 1.57 (s, 9H);
13C NMR (CDCl3, 100 MHz): 150.5 (s, ArꢀC), 146.5 (s, ArꢀC), 144.4 (s, ArꢀC), 136.1 (s, ArꢀC), 129.2 (d,
ArꢀCH), 128.6 (s, ArꢀC), 125.4 (d, ArꢀCH), 122.9 (s, ArꢀC), 122.3 (d, ArꢀCH), 121.2 (s, ArꢀC), 119.4 (d,
ArꢀCH), 117.9 (d, ArꢀCH), 117.5 (d, ArꢀCH), 112.7 (d, ArꢀCH), 55.4 (s, ꢀCꢀ), 30.4 (q, ꢀCH3); HRꢀMS
(ESI+) m/z calculated for [C18H17N4O3]+ = [M+H]+: 337.1295; found: 337.1313.
Nꢀcyclohexylꢀ6ꢀ(cyclohexylamino)ꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazoleꢀ9ꢀcarboxamide
(5r):
White solid (69 mg, 55%); mp 128−130 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3736, 2926, 2853,
2120, 1674, 1638, 1605, 1555, 1495, 1447, 1367, 1312, 1272, 1227, 1188, 1114, 1029, 990, 952, 916,
851, 811, 752, 619; 1H NMR (CDCl3, 400 MHz): δH =8.24 (dd, 1H, Ja = 7.8 and Jb = 1.5 Hz), 8.18 (d, 1H,
J = 8.8 Hz), 7.46 (d, 1H, J = 1H), 7.36−7.24 (m, 3H), 7.08 (dd, 1H, Ja = 9 and Jb = 1.7 Hz), 4.15−4.09 (m,
1H), 3.57−3.50 (m, 1H), 2.05 (dd, 2H, Ja = 8.6 and Jb = 4.2 Hz), 1.89−1.66 (m, 6H), 1.59−1.25 (m, 12H);
13C NMR (CDCl3, 100 MHz): 150.3 (s, ArꢀC), 144.6 (s, ArꢀC), 141.1 (s, ArꢀC), 139.5 (s, ArꢀC), 135.6 (s,
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ArꢀC), 128.1 (d, ArꢀCH), 124.1 (s, ArꢀC), 124.2 (d, ArꢀCH), 123.1 (d, ArꢀCH), 122.6 (d, ArꢀCH), 122.4
(s, ArꢀC), 118.4 (s, ArꢀC), 116.8 (d, ArꢀCH), 116.6 (d, ArꢀCH), 109.5 (d, ArꢀCH), 56.8 (d, ꢀCHꢀ), 54.1 (d,
ꢀCHꢀ), 35.0 (t, 2C, ꢀCH2ꢀ), 33.8 (t, 2C, ꢀCH2ꢀ), 26.0 (t, 2C, ꢀCH2ꢀ), 25.3 (t, ꢀCH2ꢀ), 24.5 (t, 2C, ꢀCH2ꢀ),
24.4 (t, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for ([C27H31N4O2]+NH4)+[ꢀH2O] = ([M]+NH4)+[ꢀH2O]:
440.2450; found: 440.2443.
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Nꢀcyclohexylindazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6a): Light yellow solid (75 mg, 72%); mp 122−124 ˚C;
IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3742, 3447, 3284, 3059, 2926, 2853, 1652, 1583, 1527, 1444,
1369, 1219, 1156, 1107, 890, 748, 635; 1H NMR (CDCl3, 400 MHz): δH = 8.64 (dd, 1H, Ja = 8.1 and Jb =
1.2 Hz), 8.05 (d, 1H, J = 8.8 Hz), 7.92 (d, 1H, J = 8.3 Hz), 7.84−7.82 (m, 1H), 7.58−7.53 (m, 2H),
7.45−7.37 (m, 2H), 5.26 (d, 1H, J = 7.3 Hz), 4.49−4.42 (m, 1H), 2.29 (dd, 2H, Ja = 12.2 and Jb = 2.9
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Hz),1.87−1.71 (m, 4H), 1.64−1.41 (m, 4H); C NMR (CDCl3, 100 MHz): 149.3 (s, ArꢀC), 148.8 (s, Arꢀ
C), 138.9 (s, ArꢀC), 128.1 (d, ArꢀCH), 127.3 (d, ArꢀCH), 126.8 (d, ArꢀCH), 125.8 (s, ArꢀC), 123.9 (d, Arꢀ
CH), 123.1 (d, ArꢀCH), 119.2 (s, ArꢀC), 118.8 (d, ArꢀCH), 117.9 (d, ArꢀCH), 116.2 (d, ArꢀCH), 115.7 (s,
ArꢀC), 49.2 (d, ꢀCHꢀ), 33.4 (t, 2C, ꢀCH2ꢀ), 25.9 (t, ꢀCH2ꢀ), 24.9 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z
calculated for [C20H21N4]+ = [M+H]+: 317.1761; found: 317.1762.
8ꢀBromoꢀNꢀcyclohexylindazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6b): Light yellow solid (58 mg, 60%); mp
136−138 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3742, 3447, 2925, 2851, 2116, 1631, 1579, 1524,
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1441, 1356, 1265, 1244, 1217, 1189, 1153, 1104, 1040, 926, 890, 853, 790, 742, 669, 564; H NMR
(CDCl3, 400 MHz): δH = 8.57 (d, 1H, J = 8.3 Hz), 8.18 (s, 1H), 7.83 (d, 1H, J = 8.3 Hz), 7.74 (d, 1H, J =
8.8 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.44−7.40 (m, 2H), 5.12 (d, 1H, J = 7.3 Hz), 4.46−4.39 (m, 1H), 2.28
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(dd, 2H, Ja = 12 and Jb = 3.2 Hz), 1.86−1.72 (m, 4H), 1.60−1.42 (m, 4H); C NMR (CDCl3, 100 MHz):
149.4 (s, ArꢀC), 148.9 (s, ArꢀC), 139.0 (s, ArꢀC), 128.4 (d, ArꢀCH), 126.9 (d, ArꢀCH), 126.6 (d, ArꢀCH),
125.5 (s, ArꢀC), 124.2 (d, ArꢀCH), 121.2 (s, ArꢀC), 120.3 (d, ArꢀCH), 120.0 (d, ArꢀCH), 119.4 (s, ArꢀC),
116.2 (d, ArꢀCH), 114.3 (s, ArꢀC), 49.4 (d, ꢀCHꢀ), 33.3 (t, 2C, ꢀCH2ꢀ), 25.8 (t, ꢀCH2ꢀ), 24.9 (t, 2C, ꢀCH2ꢀ);
HRꢀMS (ESI+) m/z calculated for [C20H20BrN4]+ = [M+H]+: 395.0866; found: 395.0863.
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9ꢀBromoꢀNꢀcyclohexylindazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6c): Light yellow solid (63 mg, 65%); mp
158−160 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3742, 3447, 3062, 2922, 2851, 1727, 1620, 1578,
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1527, 1454, 1360, 1217, 1156, 1105, 1042, 928, 854, 793, 752, 590; H NMR (CDCl3, 400 MHz): δH =
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8.59 (dd, 1H, Ja = 8.3 and Jb = 1 Hz), 8.2 (d, 1H, J = 1 Hz), 7.83 (d, 1H, J = 7.3 Hz), 7.77 (d, 1H, J = 8.8
Hz), 7.59ꢀ7.55 (m, 1H), 7.46ꢀ7.41 (m, 2H), 5.14 (d, 1H, J = 7.3 Hz), 4.47ꢀ4.70 (m, 1H), 2.28 (dd, 2H, Ja =
12 and Jb = 3.2 Hz), 1.87ꢀ1.62 (m, 4H), 1.54ꢀ1.36 (m, 4H); 13C NMR (CDCl3, 100 MHz): 149.4 (s, Arꢀ
C), 148.9 (s, ArꢀC), 139.0 (s, ArꢀC), 128.4 (d, ArꢀCH), 126.9 (d, ArꢀCH), 126.5 (d, ArꢀCH), 125.5 (s, Arꢀ
C), 124.2 (d, ArꢀCH), 121.2 (s, ArꢀC), 120.3 (d, ArꢀCH), 120.0 (d, ArꢀCH), 119.4 (s, ArꢀC), 116.3 (d, Arꢀ
CH), 114.3 (s, ArꢀC), 49.4 (d, ꢀCHꢀ), 33.3 (t, 2C, ꢀCH2ꢀ), 25.9 (t, ꢀCH2ꢀ), 24.9 (t, 2C, ꢀCH2ꢀ); HRꢀMS
(ESI+) m/z calculated for [C20H20BrN4]+ = [M+H]+: 395.0866; found: 395.0873.
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NꢀCyclohexylꢀ[1,3]dioxolo[4',5':5,6]indazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6d): Light yellow solid (73 mg,
74%); mp 180−182 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3447, 3055, 2925, 2852, 2782, 1704,
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1651, 1585, 1526, 1473, 1399, 1337, 1268, 1200, 1158, 1118, 1041, 955, 891, 825, 754, 693, 526. H
NMR (CDCl3, 400 MHz): δH = 8.46 (dd, 1H, Ja = 8.1 and Jb = 1.2 Hz), 7.77ꢀ7.75 (m, 1H), 7.49ꢀ7.45 (m,
1H), 7.39ꢀ7.35 (m, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.04 (s, 2H), 4.93 (d, 1H, J = 7.3 Hz), 4.43ꢀ4.36 (m,
1H), 2.27 (dd, 2H, Ja = 12.2 and Jb = 2.9 Hz), 1.86ꢀ1.71 (m, 4H), 1.62ꢀ1.35 (m, 4H); 13C NMR (CDCl3,
100 MHz): 149.6 (s, ArꢀC), 148.9 (s, ArꢀC), 146.5 (s, ArꢀC), 146.3 (s, ArꢀC), 138.0 (s, ArꢀC), 127.2 (d,
ArꢀCH), 126.6 (d, ArꢀCH), 126.1 (s, ArꢀC), 123.8 (d, ArꢀCH), 119.4 (s, ArꢀC), 115.4 (d, ArꢀCH), 110.7
(s, ArꢀC), 101.6 (t, ꢀCH2ꢀ), 94.9 (d, ArꢀCH), 94.6 (d, ArꢀCH), 49.2 (d, ꢀCHꢀ), 33.4 (d, 2C, ꢀCH2ꢀ), 25.9 (d,
ꢀCH2ꢀ), 24.9 (d, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for ([C21H20N4NaO2]+[ꢀH2O]) = ([M+Na]+[ꢀ
H2O]): 365.1372; found: 365.1355.
3ꢀChloroꢀNꢀcyclohexylindazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6e): Light yellow solid (78 mg, 78%); mp
172−174 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3055, 2929, 2349, 2330, 2121, 2100, 1997, 1955,
1717, 1528, 1420, 1264, 967, 895, 731, 702, 643; 1H NMR (CDCl3, 400 MHz): δH = 8.62 (s, 1H), 8.01 (d,
1H, J = 8.8 Hz), 7.88 (d, 1H, J = 8.3 Hz), 7.74 (d, 1H, J = 8.8 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.48 (dd, 1H,
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Ja = 8.8 and Jb = 2 Hz), 7.41−7.37 (m, 1H), 5.26 (d, 1H, J = 7.3 Hz), 4.46−4.37 (m, 1H), 2.27 (dd, 2H, Ja
= 12.2 and Jb = 2.9 Hz), 1.85 (dt, 2H, Ja = 13.4 and Jb = 3.8 Hz), 1.64−1.53 (m, 3H), 1.49−1.31 (m, 3H);
13C NMR (CDCl3, 100 MHz): 149.3 (s, ArꢀC), 148.8 (s, ArꢀC), 137.4 (s, ArꢀC), 129.2 (s, ArꢀC), 128.4 (d,
ArꢀCH), 127.9 (d, ArꢀCH), 127.6 (d, ArꢀCH), 126.0 (s, ArꢀC), 123.5 (d, ArꢀCH), 119.2 (s, ArꢀC), 118.7
(d, ArꢀCH), 118.0 (d, ArꢀCH), 116.0 (d, ArꢀCH), 115.7 (s, ArꢀC), 49.3 (d, ꢀCHꢀ), 33.3 (t, 2C, ꢀCH2ꢀ), 25.8
(t, ꢀCH2ꢀ), 24.9 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated for [C20H20ClN4]+ = [M+H]+: 351.1371;
found: 351.1366.
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(6ꢀ(Cyclohexylamino)indazolo[2,3ꢀa]quinoxalinꢀ3ꢀyl)(phenyl)methanone (6f): Light yellow solid (54 mg,
58%); mp 166−168 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3857, 3736, 3447, 3050, 2928, 2854,
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8.8 Hz), 8.23 (d, 1H, J = 2H), 8.04 (d, 1H, J = 8.3 Hz), 7.91ꢀ7.86 (m, 4H), 7.64ꢀ7.57 (m, 2H), 7.55ꢀ7.51
(m, 2H), 7.42ꢀ7.38 (m, 1H), 5.33 (d, 1H, J = 7.8 Hz), 4.43ꢀ4.41 (m, 1H), 2.20 (dd, 2H, Ja = 11.7 and Jb =
2.9 Hz), 1.86ꢀ1.80 (m, 4H), 1.61ꢀ1.37 (m, 4H); 13C NMR (CDCl3, 100 MHz): 196.2 (s, ꢀCOꢀ), 149.8 (s,
ArꢀC), 149.2 (s, ArꢀC), 138.4 (s, ArꢀC), 137.8 (s, ArꢀC), 136.9 (s, ArꢀC), 132.5 (d, ArꢀCH), 130.1 (d, 2C,
ArꢀCH), 129.4 (d, ArꢀCH), 128.4 (d, 2C, ArꢀCH), 128.2 (s, ArꢀC), 127.8 (d, ArꢀCH), 124.8 (d, ArꢀCH),
123.7 (d, ArꢀCH), 119.6 (s, ArꢀC), 118.8 (d, ArꢀCH), 118.1 (d, ArꢀCH), 116.4 (d, ArꢀCH), 115.8 (s, Arꢀ
C), 49.4 (d, ꢀCHꢀ), 33.3 (t, 2C, ꢀCH2ꢀ), 25.8 (t, ꢀCH2ꢀ), 24.9 (t, 2C, ꢀCH2ꢀ); HRꢀMS (ESI+) m/z calculated
for [C27H25N4O]+ = [M+H]+: 421.2023; found: 421.2016.
Nꢀ(Tertꢀbutyl)indazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6g): Light yellow solid (63 mg, 65%); mp 84−86 ˚C;
IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3736, 3455, 2959, 2924, 2855, 1717, 1582, 1527, 1465, 1442,
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1365, 1313, 1210, 1161, 1097, 967, 743, 643; H NMR (CDCl3, 400 MHz): δH = 8.63 (m, 1H), 8.04 (d,
1H, J = 8.8 Hz), 7.89−7.84 (m, 2H), 7.58−7.54 (m, 2H), 7.45−7.39 (m, 2H), 5.24 (s, 1H), 1.73 (s, 9H);
13C NMR (CDCl3, 100 MHz): 149.3 (s, ArꢀC), 148.7 (s, ArꢀC), 138.7 (s, ArꢀC), 128.0 (d, ArꢀCH), 127.3
(d, ArꢀCH), 127.1 (d, ArꢀCH), 125.6 (s, ArꢀC), 123.9 (d, ArꢀCH), 123.0 (d, ArꢀCH), 119.5 (s, ArꢀC),
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118.8 (d, ArꢀCH), 117.9 (d, ArꢀCH), 116.1 (d, ArꢀCH), 115.5 (s, ArꢀC), 52.8 (s, ꢀCꢀ), 29.3 (q, 3C,ꢀCH3);
HRꢀMS (ESI+) m/z calculated for [C18H19N4]+ = [M+H]+: 291.1604; found: 291.1607.
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8ꢀBromoꢀNꢀ(tertꢀbutyl)indazolo[2,3ꢀa]quinoxalinꢀ6ꢀamine (6h): Light yellow solid (53 mg, 60%); mp
150−152 ˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3738, 3454, 3060, 2926, 2924, 2856, 1719, 1527,
1471, 1438, 1386, 1292, 1263, 1210, 1101, 1066, 1040, 948, 804, 752; 1H NMR (CDCl3, 400 MHz): δH =
8.6 (dd, 1H, Ja = 8.3 and Jb = 1 Hz), 7.99 (d, 1H, J = 1 Hz), 7.91 (d, 1H, J = 9.3 Hz), 7.85−7.83 (m, 1H),
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7.63−7.53 (m, 2H), 7.46−7.42 (m, 1H), 5.1 (s, 1H), 1.73 (s, 9H); C NMR (CDCl3, 100 MHz): 148.9 (s,
ArꢀC), 147.1 (s, ArꢀC), 137.1 (s, 2C, ArꢀC), 130.8 (d, ArꢀCH), 128.3 (d, ArꢀCH), 127.2 (d, ArꢀCH), 125.
4 (s, ArꢀC), 124.2 (d, ArꢀCH), 121.2 (d, ArꢀCH), 119.5 (d, ArꢀCH), 118.9 (s, ArꢀC), 116.72 (s, ArꢀC),
116.2 (d, ArꢀCH) , 53.04 (s, ꢀCꢀ), 29.31 (q, ꢀCH3); HRꢀMS (ESI+) m/z calculated for [C18H18BrN4]+ =
[M+H]+: 369.0709; found: 369.0705.
6HꢀBenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀone (7a): White solid (37 mg, 99%); mp 190−192 ˚C; IR
(MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3067, 2921, 1739, 1605, 1528, 1484, 1422, 1283, 1226, 1184, 1119,
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1099, 1032, 999, 895, 744; H NMR (CDCl3, 400 MHz): δH = 8.43 (d, 1H, J = 8.3 Hz), 8.27 (d, 1H, J =
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8.8 Hz), 7. 99 (d, 1H, J = 8.3 Hz), 7.58−7.52 (m, 3H), 7.50−7.44 (m, 2H); C NMR (CDCl3, 100 MHz):
167.6 (s, ꢀCOꢀ), 149.3 (s, ArꢀC), 138.7 (s, ArꢀC), 133.0 (d, ArꢀCH), 132.9 (d, ArꢀCH), 129.3 (d, ArꢀCH),
127.8 (s, ArꢀC), 126.7 (d, ArꢀCH), 125.6 (d, ArꢀCH), 123.0 (d, ArꢀCH), 122.4 (s, 2C, ArꢀC), 120.6 (d, Arꢀ
CH), 117.2 (d, ArꢀCH); HRꢀMS (ESI+) m/z calculated for [C14H9N2O2]+ = [M+H]+: 237.0659; found:
237.0656.
8ꢀBromoꢀ6Hꢀbenzo[5,6][1,4]oxazino[4,3ꢀb]indazolꢀ6ꢀone (7b): White solid (37 mg, 95%); mp
208−210˚C; IR (MIRꢀATR, 4000–600 cmꢀ1): ʋmax = 3096, 2924, 2853, 2152, 1747, 1516, 1483, 1404,
1298, 1275, 1175, 1137, 1098, 991, 894, 807, 756; 1H NMR (CDCl3, 400 MHz): δH = 8.42 (d, 1H, J = 1.5
Hz), 8.38 (dd, 1H, Ja = 8.1 and Jb = 1.2 Hz), 7.84 (d, 1H, J = 9.3 Hz), 7.6 (dd, 1H, Ja = 9.3and Jb = 2.1 Hz)
7.56−7.52 (m, 2H), 7.50−7.44 (m, 1H); 13C NMR (CDCl3, 100 MHz): 152.5 (s, ꢀCOꢀ), 147.7 (s, ArꢀC),
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