HOAc-Mediated Cyclocondensation of 2-Formylazaarenes and Cyclic

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HOAc-Mediated Cyclocondensation of 2-Formylazaarenes and Cyclic Amines. Synthesis of Pyrrolo[1,2-a]azaarenes Meng-Yang Chang, and Yan-Shin Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03148 • Publication Date (Web): 26 Feb 2019 Downloaded from http://pubs.acs.org on February 26, 2019

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The Journal of Organic Chemistry

HOAc-Mediated Cyclocondensation of 2-Formylazaarenes and Cyclic Amines. Synthesis of Pyrrolo[1,2-a]azaarenes Meng-Yang Chang*,a,b and Yan-Shin Wua a

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan Supporting Information Placeholder X X

2

Ar

Z

Y

+

N O

N H

Ar

toluene reflux, 3 h

N ( )n N

Z = O, S, CHR n = 0-2

X = CH, CCl, N Y = CH, CPh, N

Z

N

HOAc

( )n

Y

+ 2

H2O

Y X

Ar

ABSTRACT: In this paper, a concise, easy-operational, high-yield one-pot method for the synthesis of pyrrolo[1,2-a]azaarenes is described by straightforward HOAc-mediated double condensation of substituted 2-formylazaarenes (2 equiv.) and cyclic amines (1 equiv.) in refluxing toluene. Only water is generated as a byproduct. A plausible mechanism is proposed and discussed. This protocol provides a highly effective annulation via two carbon-nitrogen (C-N) and one carbon-carbon (C-C) bond formations.

Pyrrolofused azaarene is an important class of scaffolds in a wide range of bioactive molecules, synthetic intermediates and photochromic materials.1-3 Due to its potential applications, the development of a one-pot synthetic route to access these motifs has attracted significant attention and many development attempts have been reported. As shown in Scheme 1, the general approach toward pyrrolo[1,2-a]azaarene core system 1 is based on a domino process by transition-metal (e.g. Rh3+, Pd2+, Cu+, Ir3+, Mo4+) catalyzed annulation.4-6,9-11,13,15 The cyclization reactions mediated by the metal-free reagents (e.g. Ph2PCl, I2, HOAc) are demanding a synthetic route for constructing this core skeleton.7-8,12,14 Organocatalysts promoting pioneering methods have been explored as a unique strategy. 16 Scheme 1. Synthetic Routes of Pyrrolo[1,2-a]azaarene Core AcOH (ref 14)

Mo(IV) (ref 15)

Ar

+

Me

N

S

1

NO2 R

O Ar

Me

Ir(III) (ref 13)

Ar'

N

Me

+

N

Ar' N

OH R2 R2 Rh(III) (refs 4-5) OH Pd(II) (ref 6)

R1

NH2

R1

Ar

Ar

HO

+

HO

Ar X = CH, N

Ar R1

2

CO2R

Pd (II) (ref 9) Cu(I)/Ag(I) (ref 10)

Cu(I) (ref 11)

R

+

Ph2PCl (ref 7) I2 (ref 8) R

pyrrolo[1,2-a]azaarene (1)

Heat (ref 12)

N

Ar'

N

OH

R O

Ar Br

Br O

+

HN

Br

Ar N

Ar'

R2

+ N

X

In spite of these advancements, some problems still exist, such as multi-step reactions, complicated catalytic systems, lack of broad substrate generality and prefunctionalized fragments. Therefore, further investigation of facile and efficient synthetic methods for pyrrolo[1,2-a]azaarenes 4 is still highly desired. Herein, we present a HOAc mediated double condensation of substituted 2-formylazaarenes 2 (2 equiv) and cyclic amines 3 (1 equiv) in refluxing toluene via enamination of 2 and 3 followed by intermolecular ring-closure of the resulting enamine A with another 2 (Scheme 2). In particular, only 2 equivalents of water are generated as a byproduct during the overall cyclocondensation procedure. To the best of our knowledge, no enamine-dependent synthetic routes toward the core skeleton of pyrrolo[1,2-a]azaarene have been reported. Compared with the reports on transition metal mediated intermolecular (4+2), (3+2) and (5+1) annulations or intramolecular cyclizations, we chose inexpensive and commercially available starting materials 2 and 3 to develop a sustainable and gram-scale synthetic process via functionalization of cyclic amines α-C-H bonds. Recently, a redox-neutral method to the α-functionalization of cyclic amines offered attractive alternatives.17 Notably, the challenging topic has been well-explored by Jana18-19 and Seidel20-26 groups. Scheme 2. Our Route toward Pyrrolo[1,2-a]azaarene Core O

Ar

X

N

2

Ar

Z

Y

+

N

Ar'

O

N H

HOAc

( )n

toluene reflux, 3 h

X = CH, CCl, N Z = O, S, CHR Y = CH, CPh, N n = 0-2

Ar'

2

ACS Paragon Plus Environment

3

X

Y

X Z

N Ar

+ H 2O

N Ar

H 2O

A

Z

N Ar

N ( )n Y X

Y

N ( )n N

4

Ar

Y X

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

According to the encouraging literature, the initial study for examining one-step formation of pyrrolo[1,2-a]azaarene skeleton commenced with the treatment of two model substrates, 2formylquinoline (2a, Ar = Ph, X = Y = CH, 1 mmol) and piperidine (3a, Z = CH2, n = 1, 0.5 mmol), using HOAc (1 mmol) as a promoter in refluxing toluene (10 mL, 110 oC) for 3 h under 0.1 M reaction concentration conditions, as shown in Table 1, entry 1. Under the open-vessel conditions, 4a was provided in an 80% yield via a cyclodehydration process. Then, by decreasing the time to 1 h, the yield of 4a was decreased to 54% along with a recovery of a 15% yield of 2a (entry 2). After elongating the time to 6 h, 4a was isolated in a low yield (71%, entry 3). Next, decreasing the temperature to 25 oC and controlling the time at 3 h, major 2a (70%) was recovered and only trace 5% amounts of 4a were produced (entry 4). Even though the time was increased to 24 h at 25 oC, the yield could still not be enhanced (12%, entry 5). In order to obtain better yields of 4a, the solvent volume was switched. In particular, when the reaction concentration was diluted from 0.1 to 0.05 or 0.025 M in toluene, higher yields of 4a were isolated at 88% and 92%, respectively (entries 6-7). From the results, we understood that a diluted solution was appropriate for the formation of 4a. By maintaining the combination of ~100 oC, 0.025 M and 3 h, dioxane and MeNO2 were chosen as the solvents for screening optimal conditions. However, no better yields (83%, 15%) than those for toluene occurred (entries 8-9). Unexpectedly, Entry 9 provided a complex mixture as the major component due to the nitroaldol-type reaction of 2-formylquinoline with MeNO2 that occurred by piperidine. Table 1. Reaction Conditionsa +

2

N O 2a

acids

N N

N H 3a

solvents reflux

N 4a (X-Ray) CCDC 1870443

acids solvent conc temp time 4a (equiv) (mL) (M) (oC) (h) %b 1 HOAc (2) toluene 0.1 110 3 80 2 HOAc (2) toluene 0.1 110 1 54c 3 HOAc (2) toluene 0.1 110 6 71 4 HOAc (2) toluene 0.1 25 3 5c 5 HOAc (2) toluene 0.1 25 24 12c 6 HOAc (2) toluene 0.05 110 3 88 7 HOAc (2) toluene 0.025 110 3 92 8 HOAc (2) dioxane 0.025 100 3 83 9 HOAc (2) MeNO2 0.025 100 3 15d 10 TFA (2) toluene 0.025 110 3 55 11 MsOH (2) toluene 0.025 110 3 50 12 TfOH (2) toluene 0.025 110 3 20 13 HOAc (4) toluene 0.025 110 3 79 14 HOAc (1) toluene 0.025 110 3 75 15 HOAc (0) toluene 0.025 110 3 ―e a The reactions were run on a 1 mmol scale with 2a, 3a (0.5 equiv), Brønsted acids (0, 1, 2, 4 equiv), solvents (10, 20, 40 mL), concentration (0.025, 0.05, 0.1 M), reflux. bIsolated yields. c2a (entry 2, 15%; entry 4, 70%; entry 5, 68%) was recovered. dComplex mixture was observed. eNo reaction. entry

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For other Brønsted acids, TFA, MsOH and TfOH, were examined next. However, these stronger acids produced lower yields (55%, 50%, 20%) than a milder HOAc in the formation of 4a (entries 10-12). Piperidine could trap the proton of TfOH (pKa ~ -14.7) easier than other acids such that the one-pot reaction was proceeded slowly by the releasing triflate (a weaker conjugated base) under diluted solution and reflux temperature conditions. Following, a stoichiometric amount of HOAc was adjusted to a 4 or 1 equivalent, 4a was generated in 79% or 75% yields, respectively (entries 13-14), and in the absence of HOAc, no reaction was observed (entry 15). The phenomena showed that intermolecular cyclocondensation required HOAc to trigger the initial enamination, and sequential (3+2) annulations. Furthermore, the molecular structure of 4a was determined by single crystal X-ray crystallography.27 This expeditious synthetic route sets up a pyrrolo[1,2a]quinoline skeleton, including the bond formations of 1 C-N and 1 C-C bonds via an intermolecular (3+2) ring-closure. Table 2. Synthesis of 4a X 5

2

6 7

X

Ar

4

Y3

N

8

O

2

Z

+

N H

3

HOAc

( )n

Y Z

N Ar

toluene reflux, 3 h

N ( )n N

4

Y X

Ar

entry 2, Ar =, X =, Y = 3, Z =, n = 4, %b 1 2a, Ph, CH, CH 3a, CH2, 1 4a, 92 2 2b, 6-ClC6H3, CH, CH 3a, CH2, 1 4b, 90 3 2c, 7-FC6H3, CH, CH 3a, CH2, 1 4c, 93 4 2d, 6-BrC6H3, CH, CH 3a, CH2, 1 4d, 89 5 2e, 6-FC6H3, CH, CH 3a, CH2, 1 4e, 95 6 2f, Ph, CCl, CH 3a, CH2, 1 4f, 90 7 2g, 8-ClC6H3, CH, CH 3a, CH2, 1 4g, ―c 8 2h, 6-PhC6H3, CH, CH 3a, CH2, 1 4h, 75 9 2i, 6-(4-FC6H4)C6H3, CH, CH 3a, CH2, 1 4i, 80 10 2j, 6-(4-MeC6H4)C6H3, CH, CH 3a, CH2, 1 4j, 83 11 2k, 6-(2-naphthyl)C6H3, CH, CH 3a, CH2, 1 4k, 76 12 2l, 6-(4-PhC6H4)C6H3, CH, CH 3a, CH2, 1 4l, 70 13 2m, Ph, N, CH 3a, CH2, 1 4m, 80 14 2n, 6,7-Cl2C6H2, N, CH 3a, CH2, 1 4n, 84 15 2o, 6,7-Me2C6H2, N, CH 3a, CH2, 1 4o, 83 16 2p, Ph, N, CPh 3a, CH2, 1 4p, 76 17 2q, 6,7-Cl2C6H2, N, CPh 3a, CH2, 1 4q, 78 18 2r, 6,7-Me2C6H2, N, CPh 3a, CH2, 1 4r, 80 19 2s, Ph, CH, N 3a, CH2, 1 4s, ―c 20 2a, Ph, CH, CH 3b, CH2, 0 4t, ―c 21 2a, Ph, CH, CH 3c, CHMe, 1 4u, 64 22 2a, Ph, CH, CH 3d, CHPh, 1 4v, 67 23 2a, Ph, CH, CH 3e, O, 1 4w, 86 24 2a, Ph, CH, CH 3f, S, 1 4x, 84 25 2a, Ph, CH, CH 3g, CH2, 2 4y, 90 26 2a, Ph, CH, CH 3h, CH2, 3 4z, 80 a The reactions were run on a 1 mmol scale with 2a-2s, 3a-3h (0.5 equiv), HOAc (60 mg, 1 mmol), toluene (40 mL), concentration (0.025 M), 3 h, reflux. bIsolated yields. cComplex products.


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To study the substrate scope and limitations of this HOAcmediated one-pot route, diversified 2 and 3 were reacted under optimal reaction conditions (Table 1, entry 7) to afford functionalized 4, as shown in Table 2. Among entries 1-12, by use of piperidine 3a, the formation of pyrrolo[1,2-a]quinolines 4a4l showed that different substituents (halo = fluoro, chloro, bromo, and aryl = Ph, 4-FC6H4, 4-MeC6H4, 2-naphthyl, 4biphenyl) on 2-formylquinolines 2a-2l could maintain the yield in a range of moderate to good yields (70%-95%) except for 2-formyl-8-chloroquinoline (2g). In entry 7, we envisioned that this chloro position on the angular face exhibited a bulkier steric hindrance such that the annulation reaction was inhibited, and no isolation of the desired 4h was observed. Then, for the treatment of 2-formylquinoxalines 2m-2r with piperidine 3a, pyrrolo[1,2-a]quinoxalines 4m-4r were isolated in 76%-84% yields (entries 13-18). Compared with the quinoline core 2a (X = CH, Y = CH), quinoxaline 2m (X = N, Y = CH) provided a similar yield distribution, but quinazoline 2s (X = CH, Y = N) could not generate the desired pyrrolo[1,2-a]quinazoline 4s (entry 19). Overall, 2 with different azaarene cores performed good reactivity for the one-pot reaction. While controlling 2formylquinoline 2a as the dipolarophile, various cyclic amines 3b-3h provided 4u-4z in 64%-90% yields except for pyrrolidine (3b, n = 0). In Entry 20, reactions of 2a with 3b afforded complex results, and 4t was isolated in trace amounts (~3%) probably because the ring strain of the five-membered ring was unsuitable for annulation. Switching the Z from CH2 to CHMe and CHPh, 4u and 4v were detected in slightly lower yields, 64% and 67%, respectively (entries 21-22). In particular, both 4u and 4v possessed an epimer conformation (ratio, ca. 5/3-1/1) between the lone-pair of nitrogen atoms and Me/Ph groups of Z substituents via the one-pot reaction of 2a with 3c-3d. Morpholine (3e, Z = O) and thiomorpholine (3f, Z = S) produced good yields (86% and 84%) in the generation of 4w and 4x (entries 23-24). Azapane (3g, n = 2) and azocane (3h, n = 3), with a higher ring size, accomplished good results (90% and 80%) in the formation of 4y and 4z (entries 25-26). Furthermore, the structures of 4p and 4r were obtained by single crystal X-ray analysis.27

4a is illustrated in Scheme 3.18 Initially, 2a condenses with 3a in the presence of HOAc to provide hemiaminal A.23-24 Afterward, A eliminates acetate ion to form iminium ion B, which can undergo the deprotonation by the resulting acetate ion to lead azomethine ylide C. Then, the protonated D can be formed by proton transfer of C with HOAc. Following, acetate anion removes β-proton of D to afford enamine E. By the introduction of another 2a, the lone-pair electrons of nitrogen atoms on E could promote olefin moiety to attack the formyl position via the C-C bond formation. Subsequently, nitrogen atom of quinoline skeleton attacks the corresponding formed iminium ion to produce quinolinium G via an intramolecular ring-closure. By the removal of H2O, H is yielded. Finally, the construction of 4a is furnished when another released acetate anion mediates the aromatization process. From this possible mechanism, we found that catalytic amounts of HOAc seem to be workable for one-pot cyclocondensation. However, we believe that the stoichiometric amounts of HOAc provide more than enough reaction efficiency and outcome to provide a better yield of 4a under these open-vessel and easyoperational conditions. Scheme 4. Synthesis of 4aa-1, 4ab-1, 4ac-1, 4ad-1 and 4ae-1 Me

Me

2a

HOAc

N

H N

- AcO

- AcOH

N

OH

H

N

N

+ 2a

N

N

H

N

Me

N 2t

N H

Me

3a

V H

+

N

N

CHO N

N

3j

N

(eq 2) N

H

+ 2-methylisoquinoline

N

N

N



(eq 3)

N

- H2CO N

N

N

N

+ 2-methylquinoline VI

4ac-1 (63%)

N

N H

N

3k

HOAc toluene reflux, 3 h

D

N

- H2

N

N

3k

N

(eq 4) N + quinoline

VIII

4ad-1 (34 %)

N H

AcO

IV

4ab-1 (58%, X-Ray)

N

N

N

N

N H

O H

O

- HOAc

N

3a G

- H2 N

VII

- H2 O

Me

Me

4aa-1 (31%)

4ac

N

N

N

N

N N

H

+ AcO

(eq 1)

Me

N

Me

N



OH

N

- H2O

Me

N

OAc

E

N

III OH

O

2a F

Me

Me

N

1

- HOAc

N

N

Me

N II

4aa (ND)

C

N

- AcO

Me

Me

N

N

- AcO

N

CHO N

B

H OAc O

N

N

Me N

2a A

Me

N

3i N

N

N

N

O 2a

N

N

I

AcO H

N

N

OH Me

4ab

AcO

AcO

Me

N


Scheme 3. Plausible Mechanism N H 3a

O

O

N H 3i

4a

On the basis of the experimental results and evidence provided in literature, a plausible mechanism for the formation of

N

HOAc toluene O reflux, 3 h

2v


N

+ 2v

N

N

N

- H2O

N

N

N

N 4ae

N N (eq 5)

N IX

4ae-1 (33 %)


With optimal reaction conditions, replacing cyclic piperidine with acyclic dipropylamine (3i), synthesis of 4aa was examined, as shown in Scheme 4, equation 1. However, no detection of the desired 4aa was observed, and only 4aa-1 was formed in a 31% yield. The plausible mechanism could be that I was formed by condensation of 2a with 3i. Then, intermolecular coupling of I with 2a provided iminium ion II. By the involvement of another 3i, III with a germinal diamine was produced. After the exchange of secondary amine, III generated another iminium ion IV. Furthermore, cyclocondensation of IV afforded 4aa-1. Compared with the isolation of 4y with a seven-membered ring, this is an unexpected result. In the following works, adjusting the relative position of the nitrogen atom and formyl group from the starting 2a to 1-formylisoquinoline (2t), synthesis of 4ab was checked. Interestingly, 4ab-1 was produced in a 58% yield via an intramolecular nitrogen-atom mediated rearrangement of 4ab followed by a dehydrogenative aromatization of the resulting V (equation 2). The molecular structure of 4ab-1 with a tetracyclic diazabenzo[a]fluorene skeleton was obtained from single crystal X-ray analysis.27 Among the afforded products, 4ab was not obtained. Furthermore, cyclocondensation of 2a with 1-formylpiperazine (3j) afforded 4ac-1 in a 63% yield via a spontaneous dehydroformylation of 4ac and then an aromatization process of VI (equation 3). On the other hand, a tetrahydroquinoline (3k, a benzobicyclic piperidine) was involved to react with 2a under optimal conditions (equation 4). However, only 4ad-1 was produced in a 34% yield. This is an unexpected result. The possible reason should be that benzo-fused iminium ion VII was easily to convert into quinolinium ion VIII via a dehydrogenative aromatization such that another 3k could attack the benzylic position of VIII to afford 4ad along with the formation of quinoline. Attempts to react with 1-quinolin-2-yl-ethanone (2u, a ketone) failed under similar conditions. Compared with the bicyclic arenes 2a-2u, treatment of 2-formylpyridine (2v) with piperidine (3a) could not generate the desired 4ae, and only a 33% yield of cyclocondensed tripyridinyl product 4ae-1 was formed (equation 5) by a spontaneous intermolecular coupling of 4ae with another 2v and further dehydration of the corresponding IX. However, when examining other monocyclic 2formylpyrimidine (2w) and 2-formylpyrazine (2x), only a complex unknown mixture was observed. Scheme 5: Cross-cyclocondensation of 3a with 2a and 2m H ( 8.97) 6

N N

N N

N

N

N O

2a

+ N N

2m

H ( 8.62)

N

N HOAc

N H 3a

toluene reflux, 3 h

4a (16%)

4m (25%)

H ( 9.03) 6

N N

O

N N

N

N N N

4af (43%)

4ag (~3%)

As shown in Scheme 5, 2 equivalents of 2-formylarene were decoupled into two different aldehyde components with same equivalent to extend this one-pot cyclocondensation, Based on

Page 4 of 10

the above reaction conditions, cross-cyclocondensation of 3a (0.5 mmol) with a pair of 2a (1 equiv) and 2m (1 equiv) provided 4a, 4m, 4af and 4ag in 16%, 25%, 43% and ~3% yields, respectively. From the observation, we found that 4af was preferred to generate for this cross-cyclocondensation. In the random procedure, four products were not obtained in the equal amounts. Based on the chemical shift of the proton on C-6 of 4m (s,  8.97), the structure of 4af (s,  9.03) could be confirmed by 1H-NMR spectra. In summary, we developed a HOAc mediated synthesis of pyrrolo[1,2-a]azaarenes 4 via intermolecular (3+2) cyclocondensation of substituted 2-formylazaarenes 2 and cyclic amines 3, in moderate to good yields. This one-pot route allowed a direct α,β-difunctionalization of cyclic amines 3 followed by intramolecular cross-coupling of the resulting iminium ion. The process provides a straightforward pathway for one carbon-oxygen and one carbon-carbon bond formations. The substrate scope and related limitations are studied for direct and efficient cyclocondensation reaction. Plausible mechanistic investigations have been proposed. The molecular structures of the key products were determined by Xray analysis. Further investigations regarding the biological activities of pyrrolo[1,2-a]azaarenes are underway in our laboratory. Experimental Section General. All reagents and solvents were commercial grade and were used without further purification. All reactions were routinely performed under a dry nitrogen atmosphere with magnetic stirring. The heating mantle is used to provide a stable heat source. All products in organic solvents were dried with anhydrous MgSO4 before concentration in vacuo. Melting points were obtained with a SMP3 melting apparatus. 1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Varian INOVA-400 spectrometer, respectively. Chemical shifts (δ) are reported in ppm and the J values are given in Hertz. High-resolution mass spectra (HRMS) were measured with a double focusing mass spectrometer by ESI using a hybrid ion-trap. X-ray crystal structures were determined with a diffractometer (CAD4, Kappa CCD). For the starting substrates 2a-2x and 3a-3k, these materials were purchased commercially and were used without further purification. Representative synthetic procedure of compounds 4a-4f, 4h-4r, 4u-4z, 4aa-1, 4ab-1, 4ac-1, 4ad-1 and 4ae-1 is as follows: Cyclic amines 3 (0.5 mmol) was added dropwise to a stirred solution of 2-formylazaarenes 2 (1.0 mmol) in toluene (40 mL) at 25 oC. The reaction mixture was stirred at the same temperature for 10 min. Then, HOAc (60 mg, 1.0 mmol) was added dropwise to the reaction mixture at 25 oC. The reaction mixture was continued to stir at 110 oC for 3 h. The reaction mixture was allowed to cool to 25 oC and the reaction solvent was concentrated. The resulting residue was treated with water (10 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine solution, dried with MgSO4, filtered and evaporated to afford crude product under reduced pressure. Compounds 4a-4f, 4h-4r, 4u-4z, 4aa1, 4ab-1, 4ac-1, 4ad-1 and 4ae-1 were purified by flash chromatography on silica gel using hexanes-EtOAc (15/1~1/1) as the eluent.


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11-Quinolin-2-ylmethyl-8,9,10,11-tetrahydro-11,11bdiazabenzo[c]fluorene (4a). Yield = 92% (334 mg); Colorless solid; mp = 114-115 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H22N3 364.1814, found 364.1815; 1H NMR (400 MHz, CDCl3): δ 9.20 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 1.2, 8.0 Hz, 1H), 7.74 (dt, J = 1.6, 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (dt, J = 0.8, 8.0 Hz, 1H), 7.54 (dt, J = 2.0, 8.4 Hz, 1H), 7.24-7.14 (m, 3H), 6.83 (d, J = 9.2 Hz, 1H), 6.32 (s, 1H), 4.57 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.44-3.34 (m, 2H), 2.90-2.78 (m, 2H), 2.19-2.06 (m, 1H), 1.64-1.58 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.7, 148.1, 136.7, 135.8, 134.7, 129.6, 129.1, 127.6, 127.5, 127.3, 127.0, 126.3, 126.0, 124.9, 122.6, 120.1, 119.1, 117.1, 116.9, 112.7, 100.6, 58.2, 48.6, 21.9, 15.8. Single-crystal X-Ray diagram: crystal of compound 4a was grown by slow diffusion of EtOAc into a solution of compound 4a in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 5.5637(4) Å , b = 16.8977(13) Å , c = 19.6894(16) Å , V = 1835.8(2) Å 3, Z = 4, dcalcd = 1.315 g/cm3, F(000) = 768, 2θ range 1.594~26.412o, R indices (all data) R1 = 0.0594, wR2 = 0.1288. 3-Chloro-11-(6-chloroquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4b). Yield = 90% (388 mg); Colorless solid; mp = 169-170 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20Cl2N3 432.1034, found 432.1038; 1H NMR (400 MHz, CDCl3): δ 9.15 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 2.4, 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.12 (dd, J = 2.4, 8.8 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 6.33 (s, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.26 (d, J = 16.0 Hz, 1H), 3.40-3.31 (m, 2H), 2.89-2.76 (m, 2H), 2.13-2.05 (m, 1H), 1.65-1.60 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 158.6, 146.5, 135.9, 135.8, 132.9, 132.1, 130.8, 130.6, 127.9, 127.8, 126.7, 126.5, 126.4, 126.2, 125.7, 121.0, 120.3, 118.6, 115.8, 113.2, 101.3, 57.7, 48.6, 21.8, 15.7. 2-Fluoro-11-(7-fluoroquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4c). Yield = 93% (371 mg); Colorless solid; mp = 140-142 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20F2N3 400.1625, found 400.1623; 1H NMR (400 MHz, CDCl3): δ 9.15 (dd, J = 2.8, 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.85-7.79 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 2.4, 8.8 Hz, 1H), 7.34 (dt, J = 2.4, 8.8 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.92 (dt, J = 2.4, 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.30 (s, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.27 (d, J = 16.0 Hz, 1H), 3.39-3.28 (m, 2H), 2.91-2.77 (m, 2H), 2.24-2.13 (m, 1H), 1.65-1.60 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.1 (d, J = 248.6 Hz), 160.9 (d, J = 241.8 Hz), 159.2, 149.1 (d, J = 12.2 Hz), 136.6, 135.6, 135.2 (d, J = 11.4 Hz), 129.5 (d, J = 9.8 Hz), 128.6 (d, J = 9.1 Hz), 126.8, 124.4, 121.3 (d, J = 2.2 Hz), 119.7 (d, J = 2.2 Hz), 118.1 (d, J = 3.1 Hz), 116.8 (d, J = 25.0 Hz), 116.5, 113.2, 112.8 (d, J = 20.5 Hz), 110.5 (d, J = 22.7 Hz), 104.2 (d, J = 28.0 Hz), 100.7, 58.4, 48.3, 21.7, 15.5. 3-Bromo-11-(6-bromoquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4d). Yield = 89%

(462 mg); Colorless solid; mp = 179-180 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20Br2N3 520.0024, found 520.0027; 1H NMR (400 MHz, CDCl3): δ 9.09 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.84 Hz, 1H), 7.80 (dd, J = 2.4, 8.8 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 2.4, 9.2 Hz, 1H), 7.20 (dd, J = 9.2 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 6.33 (s, 1H), 4.43 (d, J = 16.4 Hz, 1H), 4.25 (d, J = 16.0 Hz, 1H), 3.38-3.30 (m, 2H), 2.88-2.76 (m, 2H), 2.12-2.04 (m, 1H), 1.64-1.59 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 158.7, 146.7, 135.9, 135.7, 133.3, 133.1, 130.9, 129.6, 129.5, 128.42, 128.37, 126.8, 126.7, 120.9, 120.3, 120.2, 118.8, 115.6, 115.5, 113.2, 101.3, 57.7, 48.5, 21.8, 15.7. 3-Fluoro-11-(6-fluoroquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4e). Yield = 95% (379 mg); Colorless solid; mp = 157-159 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H19F2N3 400.1625, found 400.1622; 1H NMR (400 MHz, CDCl3): δ 9.22 (dd, J = 5.2, 9.2 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 5.6, 9.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (dt, J = 2.8, 8.4 Hz, 1H), 7.48 (dt, J = 2.8, 8.8 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 7.18 (dt, J = 2.8, 9.6 Hz, 1H), 6.92 (ddt, J = 2.8, 8.0, 9.2 Hz, 1H), 6.75 (d, J = 9.2 Hz, 1H), 6.33 (s, 1H), 4.48 (d, J = 16.0 Hz, 1H), 4.27 (d, J = 15.6 Hz, 1H), 3.41-3.31 (m, 2H), 2.90-2.77 (m, 2H), 2.17-2.04 (m, 1H), 1.65-1.59 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.3 (d, J = 246.4 Hz), 158.2 (d, J = 239.5 Hz), 157.7 (d, J = 2.3 Hz), 145.2, 136.1, 135.9 (d, J = 23.5 Hz), 131.6 (d, J = 9.1 Hz), 131.0, 128.8 (d, J = 9.9 Hz), 126.6, 126.5 (d, J = 7.6 Hz), 120.9, 120.3, 119.9 (d, J = 25.8 Hz), 118.8 (d, J = 8.3 Hz), 116.0 (d, J = 3.1 Hz), 113.1 (d, J = 23.5 Hz), 112.8, 112.3 (d, J = 22.0 Hz), 110.6 (d, J = 21.2 Hz), 101.0, 57.6, 48.5, 21.8, 15.8. 5-Chloro-11-(4-chloroquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4f). Yield = 90% (388 mg); Colorless solid; mp = 144-145 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20Cl2N3 432.1034, found 432.1035; 1H NMR (400 MHz, CDCl3): δ 9.24 (dd, J = 1.6, 8.4 Hz, 1H), 8.27 (dd, J = 0.8, 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 1.6, 7.6 Hz, 1H), 7.80 (dt, J = 1.2, 8.4 Hz, 1H), 7.76 (s, 1H), 7.66 (dt, J = 1.2, 8.4 Hz, 1H), 7.34-7.25 (m, 2H), 7.32 (s, 1H), 6.29 (s, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.23 (d, J = 16.0 Hz, 1H), 3.42-3.33 (m, 2H), 2.89-2.76 (m, 2H), 2.16-2.05 (m, 1H), 1.67-1.61 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.4, 148.9, 143.3, 135.9, 134.8, 130.6, 129.5, 127.3, 127.2, 126.1, 125.5, 124.8, 124.0, 123.2, 122.3, 120.4, 120.3, 118.7, 117.0, 113.5, 101.1, 57.6, 48.6, 21.8, 15.7. 3-Phenyl-11-(6-phenylquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4h). Yield = 75% (386 mg); Colorless solid; mp = 180-181 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H30N3 516.2440, found 516.2442; 1H NMR (400 MHz, CDCl3): δ 9.25 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 (dd, J = 2.0, 8.4 Hz, 1H), 7.76-7.74 (m, 4H), 7.61 (d, J = 8.8 Hz, 2H), 7.54-7.39 (m, 6H), 7.33-7.29 (m, 1H), 7.24 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 4.63 (d, J = 16.0 Hz, 1H), 4.37 (d, J = 16.0 Hz, 1H), 3.48-3.38 (m, 2H),



2.92-2.80 (m, 2H), 2.21-2.09 (m, 1H), 1.66-1.62 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 158.6, 147.5, 140.6, 140.4, 139.1, 136.9, 135.8, 135.4, 134.0, 129.6, 129.4, 128.9 (2x), 128.7 (2x), 127.7, 127.5, 127.4 (2x), 127.00, 126.96 (2x), 126.9, 125.7, 125.30, 125.28, 124.9, 120.5, 119.5, 117.5, 117.0, 112.9, 100.8, 58.2, 48.7, 21.9, 15.9. 3-(4-Fluorophenyl)-11-[6-(4-fluorophenyl)quinolin-2ylmethyl]-8,9,10,11-tetrahydro-11,11b-diazabenzo[c]fluorene (4i). Yield = 80% (441 mg); Colorless solid; mp = 114-115 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H28F2N3 552.2251, found 552.2256; 1 H NMR (400 MHz, CDCl3): δ 9.22 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.95 (dt, J = 2.0, 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.72-7.67 (m, 3H), 7.55-7.52 (m, 2H), 7.38 (dd, J = 2.0, 8.8 Hz, 1H), 7.25-7.17 (m, 3H), 7.10-7.06 (m, 2H), 6.88 (d, J = 9.6 Hz, 1H), 6.35 (s, 1H), 4.60 (d, J = 16.0 Hz, 1H), 4.36 (d, J = 16.0 Hz, 1H), 3.47-3.37 (m, 2H), 2.92-2.80 (m, 2H), 2.172.05 (m, 1H), 1.67-1.63 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.7 (d, J = 245.6 Hz), 162.3 (d, J = 244.8 Hz), 158.7, 147.5, 138.1, 136.9, 136.8 (d, J = 3.1 Hz), 136.5 (d, J = 3.8 Hz), 135.8, 134.5, 134.0, 129.7, 129.2, 129.0 (d, J = 8.3 Hz, 2x), 128.5 (d, J = 7.6 Hz, 2x), 127.5, 127.0, 125.5, 125.4, 125.1, 124.7, 120.6, 119.7, 117.6, 116.9, 115.9 (d, J = 22.0 Hz, 2x), 115.5 (d, J = 21.2 Hz, 2x), 113.0, 100.9, 58.1, 48.7, 21.9, 15.9. 3-p-Tolyl-11-(6-p-tolylquinolin-2-ylmethyl)-8,9,10,11tetrahydro-11,11b-diazabenzo[c]fluorene (4j). Yield = 83% (451 mg); Colorless solid; mp = 157-158 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H34N3 544.2753, found 544.2755; 1H NMR (400 MHz, CDCl3): δ 9.24 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 8.01 (dt, J = 2.0, 8.8 Hz, 1H), 7.75-7.73 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.46 (dd, J = 2.0, 8.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 4.62 (d, J = 16.0 Hz, 1H), 4.36 (d, J = 16.0 Hz, 1H), 3.48-3.37 (m, 2H), 2.91-2.80 (m, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.18-2.06 (m, 1H), 1.66-1.61 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.5, 147.4, 139.0, 137.7, 137.5, 137.4, 136.8, 136.7, 135.8, 135.4, 133.8, 129.7 (2x), 129.5, 129.4 (2x), 129.3, 127.6, 127.2 (2x), 127.0, 126.8 (2x), 125.4, 125.3, 124.9, 124.8, 120.5, 119.4, 117.5, 117.1, 112.8, 100.7, 58.2, 48.6, 21.9, 21.1, 21.0, 15.9. 3-Naphthalen-2-yl-11-(6-naphthalen-2-ylquinolin-2ylmethyl)-8,9,10,11-tetrahydro-11,11b-diazabenzo[c]fluorene (4k). Yield = 76% (468 mg); Colorless solid; mp = 207-208 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C45H34N3 616.2753, found 616.2755; 1 H NMR (400 MHz, CDCl3): δ 9.29 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.20-8.14 (m, 3H), 8.05 (s, 1H), 8.00-7.75 (m, 10H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.48-7.43 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.37 (s, 1H), 4.66 (d, J = 16.4 Hz, 1H), 4.40 (d, J = 16.4 Hz, 1H), 3.55-3.40 (m, 2H), 2.94-2.82 (m, 2H), 2.23-2.12 (m, 1H), 1.68-1.61 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 158.7, 147.6, 138.9, 137.9, 137.6, 137.0, 135.9, 135.3, 134.1, 133.7, 132.8, 132.4, 129.7, 129.5, 128.7, 128.4, 128.3, 128.1, 127.7, 127.64,

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127.58, 127.0, 126.5, 126.3, 126.23, 126.20, 126.0, 125.7, 125.6, 125.51 (2x), 125.48, 125.4 (2x), 125.1, 120.6, 119.6, 117.6, 117.1, 113.0, 100.9, 58.2, 48.7, 21.9, 15.9. 3-Biphenyl-4-yl-11-(6-biphenyl-4-ylquinolin-2-ylmethyl)8,9,10,11-tetrahydro-11,11b-diazabenzo[c]fluorene (4l). Yield = 70% (467 mg); Colorless solid; mp = 152-153 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C49H38N3 668.3066, found 668.3069; 1 H NMR (400 MHz, CDCl3): δ 9.26 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 8.07 (dt, J = 2.0, 8.8 Hz, 1H), 7.85-7.81 (m, 3H), 7.78-7.74 (m, 3H), 7.70-7.61 (m, 8H), 7.53-7.33 (m, 7H), 7.26 (d, J = 9.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.36 (s, 1H), 4.63 (d, J = 16.0 Hz, 1H), 4.38 (d, J = 16.0 Hz, 1H), 3.49-3.38 (m, 2H), 2.91-2.85 (m, 2H), 2.17-2.12 (m, 1H), 1.70-1.63 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 158.7, 147.6, 140.7, 140.6, 140.5, 139.8, 139.5, 139.2, 138.5, 136.9, 135.8, 134.9, 134.1, 129.7, 129.2, 128.9 (2x), 128.77 (2x), 127.75 (2x), 127.68 (2x), 127.6, 127.5, 127.4 (2x), 127.3 (2x), 127.2, 127.1 (2x), 127.02, 126.97 (2x), 125.6, 125.4, 125.1, 124.8, 120.6, 119.6, 117.6, 117.0, 113.0, 100.9, 58.2, 48.7, 21.9, 15.9. 11-Quinoxalin-2-ylmethyl-8,9,10,11-tetrahydro-5,11,11btriazabenzo[c]fluorene (4m). Yield = 80% (292 mg); Colorless solid; mp = 184-185 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20N5 366.1719, found 366.1720; 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.95 (dd, J = 2.0, 7.6 Hz, 1H), 8.62 (s, 1H), 8.17-7.12 (m, 2H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.837.77 (m, 2H), 7.31 (dt, J = 1.6, 7.6 Hz, 1H), 7.26 (dt, J = 1.6, 7.6 Hz, 1H), 6.67 (s, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.38 (d, J = 16.0 Hz, 1H), 3.46-3.34 (m, 2H), 2.93-2.77 (m, 2H), 2.042.00 (m, 1H), 1.70-1.67 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.5, 145.5, 144.6, 142.3, 141.9, 137.5, 136.9, 130.4, 129.9, 129.3, 129.2, 129.1, 128.9, 126.1, 124.4, 122.3, 116.5, 115.0, 105.5, 56.1, 48.5, 21.7, 15.8. 2,3-Dichloro-11-(6,7-dichloroquinoxalin-2-ylmethyl)8,9,10,11-tetrahydro-5,11,11b-triazabenzo[c]fluorene (4n). Yield = 84% (421 mg); Colorless solid; mp = 239-240 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H16Cl4N5 502.0160, found 502.0163; 1H NMR (400 MHz, CDCl3 + d6-DMSO): δ 9.06 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 6.65 (s, 1H), 4.40 (d, J = 16.4 Hz, 1H), 4.29 (d, J = 16.0 Hz, 1H), 3.33-3.23 (m, 2H), 2.88-2.71 (m, 2H), 2.01-1.95 (m, 1H), 1.71-1.67 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3 + d6-DMSO): δ 152.8, 146.2, 145.3, 140.9, 140.6, 137.7, 136.3, 134.9, 134.4, 129.8, 129.8, 129.5, 129.0, 127.5, 127.4, 121.7, 117.5, 115.6, 106.6, 55.3, 48.4, 21.4, 15.5. 11-(6,7-Dimethylquinoxalin-2-ylmethyl)-2,3-dimethyl8,9,10,11-tetrahydro-5,11,11b-triazabenzo[c]fluorene (4o). Yield = 83% (350 mg); Colorless solid; mp = 169-170 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H28N5 422.2345, found 422.2344; 1 H NMR (400 MHz, CDCl3): δ 8.92 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.59 (s, 1H), 6.62 (s, 1H), 4.59 (d, J = 16.4 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.40-3.37 (m, 2H), 2.93-2.81 (m, 2H), 2.51 (s, 6H), 2.26 (s, 3H), 2.082.02 (m, 1H), 2.06 (s, 3H), 1.71-1.67 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.6, 144.5, 143.6, 141.3, 141.0, 140.9, 140.4, 137.1, 135.4, 134.9, 133.1, 129.0, 128.3, 128.1, 126.7,


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122.3, 116.8, 114.4, 104.9, 56.0, 48.6, 21.8, 20.4, 20.3, 19.6, 19.3, 15.8.

dcalcd = 1.252 g/cm3, F(000) = 1216, 2θ range 1.318~26.403o, R indices (all data) R1 = 0.0834, wR2 = 0.1599.

6-Phenyl-11-(3-phenylquinoxalin-2-ylmethyl)-8,9,10,11tetrahydro-5,11,11b-triazabenzo[c]fluorene (4p). Yield = 76% (393 mg); Colorless solid; mp = 209-210 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C35H28N5 518.2345, found 518.2340; 1H NMR (400 MHz, CDCl3): δ 9.19 (dd, J = 1.2, 8.4 Hz, 1H), 8.34 (dd, J = 1.2, 8.4 Hz, 1H), 8.19 (dd, J = 1.2, 8.4 Hz, 1H), 7.94-7.91 (m, 3H), 7.88-7.81 (m, 2H), 7.54-7.47 (m, 3H), 7.40-7.31 (m, 6H), 7.24 (dt, J = 1.6, 8.8 Hz, 1H), 6.65 (s, 1H), 4.59 (s, 2H), 3.433.33 (m, 2H), 2.72-2.69 (m, 2H), 1.55-1.40 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.8, 153.9, 150.8, 141.6, 141.1, 138.6, 138.0, 137.7, 137.2, 130.1, 130.0, 129.31, 129.27, 129.2, 128.89, 128.87, 128.6 (2x), 128.5 (2x), 128.44 (2x), 128.38 (2x), 128.1, 125.8, 124.3, 120.9, 116.9, 114.3, 106.8, 54.9, 48.7, 21.6, 16.6. Single-crystal X-Ray diagram: crystal of compound 4p was grown by slow diffusion of EtOAc into a solution of compound 4p in CH2Cl2 to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P -1, a = 9.4459(5) Å , b = 11.1306(7) Å , c = 13.0768(9) Å , V = 1303.27(14) Å 3, Z = 2, dcalcd = 1.319 g/cm3, F(000) = 544, 2θ range 1.575~26.531o, R indices (all data) R1 = 0.0514, wR2 = 0.0970.

8-Methyl-11-quinolin-2-ylmethyl-8,9,10,11-tetrahydro11,11b-diazabenzo[c]fluorene (4u). Epimer (ratio = 5 : 3); Yield = 64% (241 mg); Colorless solid; mp = 149-150 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H24N3 378.1970, found 378.1977; 1 H NMR (400 MHz, CDCl3): δ 9.23 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (dt, J = 1.2, 8.4 Hz, 1H), 7.72 (dt, J = 2.4, 8.4 Hz, 1H), 7.57 (dd, J = 0.8, 8.0 Hz, 1H), 7.54 (dd, J = 1.2, 7.2 Hz, 1H), 7.26-7.16 (m, 3H), 6.84 (d, J = 9.2 Hz, 1H), 6.43 (s, 5/8H), 6.37 (s, 3/8H), 4.58 (d, J = 16.0 Hz, 5/8H), 4.57 (d, J = 16.0 Hz, 3/8H), 4.32 (d, J = 16.0 Hz, 1H), 3.53-3.27 (m, 2H), 3.13-2.99 (m, 1H), 2.34-2.25 (m, 3/8H), 1.81-1.62 (m, 13/8H), 1.37 (d, J = 6.8 Hz, 15/8H), 1.29 (d, J = 7.6 Hz, 9/8H).

2,3-Dichloro-11-(6,7-dichloro-3-phenylquinoxalin-2ylmethyl)-6-phenyl-8,9,10,11-tetrahydro-5,11,11btriazabenzo[c]fluorene (4q). Yield = 78% (509 mg); Colorless solid; mp = 240-242 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C35H24Cl4N5 654.0786, found 654.0784; 1H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.53 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.89-7.87 (m, 2H), 7.53-7.49 (m, 3H), 7.43-7.39 (m, 5H), 6.72 (s, 1H), 4.53 (d, J = 16.8 Hz, 1H), 4.40 (d, J = 16.4 Hz, 1H), 3.37-3.35 (m, 2H), 2.78-2.73 (m, 2H), 1.65-1.55 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3): δ 155.5, 155.0, 151.5, 140.3, 140.0, 138.4, 138.0, 137.1, 136.9, 134.9, 134.7, 129.93, 129.90, 129.8, 129.6, 129.5, 128.7 (2x), 128.6 (3x), 128.5 (4x), 127.8, 126.8, 120.6, 117.7, 115.1, 108.1, 54.8, 49.0, 21.5, 16.4. 11-(6,7-Dimethyl-3-phenylquinoxalin-2-ylmethyl)-2,3dimethyl-6-phenyl-8,9,10,11-tetrahydro-5,11,11btriazabenzo[c]fluorene (4r). Yield = 80% (459 mg); Colorless solid; mp = 220-221 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H36N5 574.2971, found 574.2975; 1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.92-7.89 (m, 2H), 7.71 (s, 1H), 7.52-7.44 (m, 3H), 7.37-7.34 (m, 5H), 6.63 (s, 1H), 4.60 (d, J = 16.4 Hz, 1H), 4.45 (d, J = 16.4 Hz, 1H), 3.42-3.40 (m, 2H), 2.75-2.72 (m, 2H), 2.58 (s, 3H), 2.55 (s, 3H), 2.30 (s, 3H), 2.02 (s, 3H), 1.64-1.55 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.7, 153.0, 149.7 (2x), 140.62, 140.57, 140.5, 140.0, 138.8, 138.1, 137.8, 135.3, 135.0, 132.9, 129.1, 129.0, 128.7, 128.54 (2x), 128.49 (2x), 128.4 (2x), 128.3 (2x), 128.1, 126.0, 120.8, 117.0, 113.8, 106.1, 55.0, 48.8, 21.7, 20.41, 20.37, 19.6, 19.3, 16.4. Single-crystal X-Ray diagram: crystal of compound 4r was grown by slow diffusion of EtOAc into a solution of compound 4r in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 9.9444(5) Å , b = 30.8977(16) Å , c = 10.1941(5) Å , V = 3044.6(3) Å 3, Z = 4,

8-Phenyl-11-quinolin-2-ylmethyl-8,9,10,11-tetrahydro11,11b-diazabenzo[c]fluorene (4v). Epimer (ratio = 2 : 1); Yield = 67% (294 mg); Colorless solid; mp = 190-193 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H26N3 440.2127, found 440.2126; 1 H NMR (400 MHz, CDCl3): δ 9.29 (d, J = 8.4 Hz, 2/3H), 9.26 (d, J = 7.2 Hz, 1/3H), 8.26 (d, J = 8.8 Hz, 2/3H), 8.24 (d, J = 8.8 Hz, 1/3H), 8.14 (d, J = 7.2 Hz, 1/3H), 8.13 (d, J = 8.0 Hz, 2/3H), 7.87 (d, J = 8.0 Hz, 1H), 7.76-7.69 (m, 2H), 7.587.55 (m, 2H), 7.36-7.12 (m, 8H), 6.86 (d, J = 10.0 Hz, 1/3H), 6.83 (d, J = 9.6 Hz, 2/3H), 6.25 (s, 1/3H), 6.06 (s, 2/3H), 4.69 (d, J = 16.4 Hz, 2/3H), 4.65 (d, J = 17.2 Hz, 1/3H), 4.48 (d, J = 16.0 Hz, 2/3H), 4.44 (d, J = 16.8 Hz, 1/3H), 4.36 (dd, J = 6.8, 11.6 Hz, 1/3H), 4.22 (dd, J = 6.8, 11.2 Hz, 2/3H), 3.60 (t, J = 13.6 Hz, 2/3H), 3.50-3.44 (m, 1H), 3.23 (dt, J = 2.8, 11.2 Hz, 1/3H), 2.62-2.53 (m, 1/3H), 2.22-2.12 (m, 2/3H), 1.891.83 (m, 2/3H), 1.58 (d, J = 14.0 Hz, 1/3H). 11-Quinolin-2-ylmethyl-10,11-dihydro-9H-8-oxa-11,11bdiazabenzo[c]fluorene (4w). Yield = 86% (314 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H20N3O 366.1606, found 366.1610; 1H NMR (400 MHz, CDCl3): δ 9.03 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 1.2, 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.76 (dt, J = 1.6, 8.4 Hz, 1H), 7.59 (dd, J = 1.2, 8.0 Hz, 1H), 7.58 (dt, J = 1.2, 8.0 Hz, 1H), 7.29 (dt, J = 1.6, 8.8 Hz, 1H), 7.22-7.18 (m, 2H), 6.93 (d, J = 9.2 Hz, 1H), 6.21 (s, 1H), 4.72 (d, J = 15.6 Hz, 1H), 4.34-4.14 (m, 3H), 3.49-3.36 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.7, 148.1, 137.0, 136.2, 134.3, 129.8, 129.1, 127.9, 127.6, 127.4, 126.5, 126.3, 124.4, 123.9, 122.5, 120.5, 120.1, 118.6, 117.4, 116.3, 89.4, 60.2, 59.4, 47.0. 11-Quinolin-2-ylmethyl-10,11-dihydro-9H-8-thia-11,11bdiazabenzo[c]fluorene (4x). Yield = 84% (320 mg); Colorless solid; mp = 120-123 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H20N3S 382.1378, found 382.1377; 1H NMR (400 MHz, CDCl3): δ 9.38 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.76 (dt, J = 1.2, 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.32 (dt, J = 1.6, 8.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.33 (s, 1H), 4.56 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 15.6 Hz, 1H), 3.86 (dt, J = 2.8, 14.4 Hz, 1H), 3.46 (t, J = 12.8 Hz, 1H), 3.29 (dt, J = 2.8, 12.8 Hz, 1H), 2.60 (dt, J = 2.4, 12.8 Hz, 1H); 13C{1H} NMR



(100 MHz, CDCl3): δ 157.3, 148.0, 136.7, 134.2, 130.0, 129.7, 129.2, 127.7, 127.6, 127.3, 127.2, 126.5, 126.4, 124.5, 122.8, 120.6, 118.3, 118.0, 117.2, 104.8, 98.9, 58.5, 47.5, 17.7. 12-Quinolin-2-ylmethyl-9,10,11,12-tetrahydro-8H-12,12bdiazanaphtho[1,2-a]azulene (4y). Yield = 90% (339 mg); Colorless solid; mp = 128-129 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H24N3 378.1970, found 378.1975; 1H NMR (400 MHz, CDCl3): δ 9.75 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.73 (dt, J = 1.6, 8.4 Hz, 1H), 7.55 (dt, J = 1.6, 8.4 Hz, 1H), 7.54 (dt, J = 0.8, 8.0 Hz, 1H), 7.45 (dt, J = 1.6, 8.4 Hz, 1H), 7.27-7.19 (m, 3H), 6.89 (d, J = 9.2 Hz, 1H), 6.31 (s, 1H), 4.71 (d, J = 13.6 Hz, 1H), 4.45 (d, J = 13.6 Hz, 1H), 3.58 (dt, J = 2.8, 14.4 Hz, 1H), 3.18 (dt, J = 1.6, 14.0 Hz, 1H), 2.83-2.78 (m, 1H), 2.67 (dt, J = 2.4, 15.2 Hz, 1H), 2.24-2.09 (m, 1H), 2.00-1.96 (m, 1H), 1.71-1.67 (m, 1H), 1.54-1.43 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.7, 147.7, 136.6, 136.0, 135.2, 129.2, 129.1, 127.5, 127.4, 127.1, 126.5, 126.2, 126.1, 125.2, 124.9, 122.7, 121.6, 118.8, 117.7, 117.6, 101.9, 58.5, 52.0, 27.9, 27.8, 27.4. 12-Quinolin-2-ylmethyl-9,10,11,12-tetrahydro-8H-12,12bdiazanaphtho[1,2-a]azocine (4z). Yield = 80% (313 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H26N3 392.2127, found 392.2129; 1H NMR (400 MHz, CDCl3): δ 9.01 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.72 (dt, J = 1.6, 8.4 Hz, 1H), 7.59 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 (dt, J = 0.8, 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.36 (dt, J = 1.6, 7.6 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.27 (s, 1H), 4.85 (d, J = 14.0 Hz, 1H), 4.61 (d, J = 14.0 Hz, 1H), 3.44-3.38 (m, 1H), 3.33-3.27 (m, 1H), 2.94-2.87 (m, 1H), 2.76-2.71 (m, 1H), 1.99-1.85 (m, 2H), 1.67-1.54 (m, 2H), 1.48-1.31 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.6, 147.5, 136.1, 134.8, 133.9, 129.3, 129.1, 127.83, 127.76, 127.4, 127.2, 126.6, 126.1, 125.2, 124.9, 122.6, 121.9, 119.0, 117.8, 117.3, 101.4, 61.2, 54.5, 30.9, 26.5, 25.1, 24.8. (2-Methyl-pyrrolo[1,2-a]quinolin-1-yl)dipropylamine (4aa1). Yield = 31% (87 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H25N2 281.2018, found 281.2019; 1 H NMR (400 MHz, CDCl3): δ 9.46 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 1.6, 7.6 Hz, 1H), 7.41 (dt, J = 1.6, 8.4 Hz, 1H), 7.25 (dt, J = 1.2, 8.0 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.27 (s, 1H), 3.24-3.17 (m, 2H), 3.14-3.07 (m, 2H), 2.30 (s, 3H), 1.60-1.47 (m, 4H), 0.84 (t, J = 7.6 Hz, 6H); 13 C{1H} NMR (100 MHz, CDCl3): δ 135.4, 134.3, 127.8, 127.2, 126.1, 125.1, 122.5, 118.84, 118.75, 117.7, 117.6, 103.0, 56.7 (2x), 21.3 (2x), 12.6, 11.8 (2x). 6a,7-Diazabenzo[a]fluorene (4ab-1). Yield = 58% (126 mg); Colorless solid; mp = 124-127 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H11N2 219.0922, found 219.0923; 1H NMR (400 MHz, CDCl3): δ 8.52 (J = 7.6 Hz, 1H), 8.44 (dd, J = 1.6,4.8 Hz, 1H), 8.17-8.15 (m, 1H), 8.10 (dd, J = 1.6, 8.0 Hz, 1H), 7.60-7.58 (m, 1H), 7.53-7.46 (m, 2H), 7.31 (dd, J = 4.8, 8.0 Hz, 1H), 7.08 (d, J = 0.8 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.4, 142.7, 141.6, 134.7, 129.9, 128.3, 128.2, 127.4, 127.1, 125.5, 123.6, 121.2, 118.4, 109.3, 90.2. Single-crystal X-Ray diagram: crystal of compound 4ab-

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1 was grown by slow diffusion of EtOAc into a solution of compound 4ab-1 in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 11.5095(5) Å , b = 6.0108(2) Å , c = 15.9991(7) Å , V = 1046.08(7) Å 3, Z = 4, dcalcd = 1.386 g/cm3, F(000) = 456, 2θ range 1.872~26.381o, R indices (all data) R1 = 0.0486, wR2 = 0.1041. 8,11,11b-Triazabenzo[c]fluorene (4ac-1). Yield = 63% (138 mg); Colorless solid; mp = 135-136 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H10N3 220.0875, found 220.0876; 1H NMR (400 MHz, CDCl3): δ 9.85 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.70-7.66 (m, 2H), 7.41-7.37 (m, 2H), 7.32 (d, J = 9.6 Hz, 1H), 6.88 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 140.4, 139.2, 137.3, 135.7, 134.9, 130.7, 129.9, 128.7, 127.4, 124.2, 123.3, 118.5, 118.0, 94.5. 2-(3,4-Dihydro-2H-quinolin-1-ylmethyl)quinoline (4ad-1). Yield = 34% (93 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2 275.1548, found 275.1543; 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.73 (dt, J = 1.6, 8.4 Hz, 1H), 7.52 (dt, J = 1.2, 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 0.8, 8.0 Hz, 1H), 6.97 (dt, J = 1.2, 8.4 Hz, 1H), 6.62 (dt, J = 0.8, 8.4 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.12-2.06 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.7, 148.0, 145.3, 136.9, 129.5, 129.1, 128.7, 127.6, 127.3, 127.2, 126.0, 122.4, 118.8, 116.3, 111.0, 58.2, 50.6, 28.1, 22.4. 1,5-Bispyridin-2-ylmethyl-1,2,3,4-tetrahydropyrido[3,2b]indolizine (4ae-1). Yield = 33% (117 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H23N4 355.1923, found 355.1922; 1H NMR (400 MHz, CDCl3): δ 8.63 (dt, J = 1.2, 2.8 Hz, 1H), 8.53 (ddd, J = 0.8, 1.6, 4.8 Hz, 1H), 7.787.72 (m, 2H), 7.69 (d, J = 6.8 Hz, 1H), 7.51 (dt, J = 1.6, 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.24 (ddt, J = 2.4, 4.8, 8.8 Hz, 1H), 7.07 (ddd, J = 1.2, 5.2, 9.2 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.47 (dd, J = 6.4, 8.8 Hz, 1H), 6.37 (t, J = 6.8 Hz, 1H), 4.27 (s, 2H), 4.17 (s, 2H), 3.11-3.09 (m, 2H), 2.61 (t, J = 6.4 Hz, 2H), 1.89-1.86 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.8, 159.1, 149.6, 148.9, 136.8, 136.4, 128.9, 125.5, 122.4, 122.3, 122.0, 120.8, 119.8, 116.8, 113.8, 112.7, 109.0, 105.4, 56.4, 48.8, 33.2, 20.5, 17.3. Synthetic procedure of compounds 4a, 4m and 4af is as follows: Piperidine (3a, 43 mg, 0.5 mmol) was added to a solution of 2-formylquinoline (2a, 79 mg, 0.5 mmol) and 2formylquinoxaline (2m, 79 mg, 0.5 mmol) in toluene (40 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 10 min. HOAc (60 mg, 1.0 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at 110 oC for 3 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 30/1~1/1) afforded compounds 4a, 4m and 4af. For 4a, yield = 16% (58 mg). For 4m, yield = 25% (91 mg). 11-Quinolin-2-ylmethyl-8,9,10,11-tetrahydro-5,11,11btriazabenzo[c]fluorene (4af). Yield = 43% (157 mg);


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Colorless gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H21N4 365.1766, found 365.1770; 1H NMR (400 MHz, CDCl3): δ 9.23 (d, J = 8.0 Hz, 1H), 9.03 (s, 1H), 8.18-8.14 (m, 2H), 7.83-7.77 (m, 2H), 7.55 (dd, J = 1.2, 7.6 Hz, 1H), 7.29 (dt, J = 1.6, 8.4 Hz, 1H), 7.21-7.17 (m, 2H), 6.84 (d, J = 9.6 Hz, 1H), 6.31 (s, 1H), 4.58 (d, J = 15.6 Hz, 1H), 4.34 (d, J = 16.0 Hz, 1H), 3.42-3.39 (m, 2H), 2.88-2.78 (m, 2H), 2.15-2.03 (m, 1H), 1.67-1.61 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.3, 144.9, 142.3, 141.8, 135.3, 134.6, 130.2, 129.7, 129.22, 129.21, 127.6, 127.1, 126.1, 124.9, 122.8, 119.1, 117.1, 116.9, 113.0, 100.6, 56.3, 48.6, 21.7, 15.7.

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ASSOCIATED CONTENT Supporting Information Scanned photocopies of NMR spectral data for all compounds and X-ray CIF files of 4a, 4p, 4r and 4ab-1. This information is available free of charge via the Internet at http: //pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author *Email: [email protected]

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ORCID Meng-Yang Chang: 0000-0002-1983-8570

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Notes The authors declare no competing financial interest. (9)

ACKNOWLEDGMENT The authors would like to thank the Ministry of Science and Technology of the Republic of China for financial support (MOST 106-2628-M-037-001-MY3).

REFERENCES (1) Reviews on pyrrolofused azaarenes, see: (a) Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Azancheev, N. M.; Levin, Y. A. Fused Polycyclic Nitrogen-Containing Heterocycles: VI. Pyrrolo[1,2-a]quinoxalines. Russ. J. Org. Chem. 2004, 40, 114-123. (b) Harrak, Y.; Weber, S.; Gomez, A. B.; Rosell, G.; Pujol, M. D. Two Alternatives for The Synthesis of Pyrrolo[1,2-a]quinoxaline Derivatives. ARKIVOC 2007, iv, 251-259. (c) Kalinin, A. A.; Mamedov, V. A. Pyrrolo[1,2a]quinoxalines Based on Pyrroles. Chem. Heterocycl. Comp. 2011, 46, 1423-1442. (2) Selected examples on biological activities of pyrrolofused azaarenes, see: (a) Vidaillac, C.; Guillon, J.; Arpin, C.; ForfarBares, I.; Ba, B. B.; Grellet, J.; Moreau, S.; Caignard, D.-H.; Jarry, C.; Quentin, C. Synthesis of Omeprazole Analogues and Evaluation of These as Potential Inhibitors of the Multidrug Efflux Pump NorA of Staphylococcus aureus. Antimicrob. Agents Chemother. 2007, 51, 831-838. (b) Grande, F.; Aiello, F.; De Grazia, O.; Brizzi, A.; Garofalo, A.; Neamati, N. Synthesis and Antitumor Activities of A Series of Novel Quinoxalinhydrazides. Bioorg. Med. Chem. 2007, 15, 288-294. (c) Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J.-M.; Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi, D. Synthesis, Analytical Behaviour and Biological Evaluation of New 4-Substituted Pyrrolo[1,2a]quinoxalines as Antileishmanial Agents. Bioorg. Med. Chem. 2007, 15, 194-210. (3) Selected examples on photochromic materials of pyrrolofused azaarenes, see: (a) Gryko, D. T.; Piechowska, J.; Tasior, M.; Waluk, J.; Orzanowska, G. From Bifunctional Nucleophilic Behavior of DBU to a New Heterocyclic Fluorescent Platform. Org.

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HOAc-Mediated Cyclocondensation of 2-Formylazaarenes and Cyclic

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