[1,8]naphthyridines: Synthesis and Structural ... - ACS Publications

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Cite This: J. Org. Chem. 2018, 83, 690−702

Dibenzopyrrolo[1,2‑a][1,8]naphthyridines: Synthesis and Structural Modification of Fluorescent L‑Shaped Heteroarenes Kotaro Tateno,*,† Rie Ogawa,† Ryota Sakamoto,‡ Mizuho Tsuchiya,‡ Noriki Kutsumura,§ Takashi Otani,∥ Kosuke Ono,† Hidetoshi Kawai,*,† and Takao Saito*,† †

Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan Department of Chemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan § International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan ∥ Course of Chemical Engineering, National Institute of Technology, Anan Collage, 265 Aoki, Minobayashi, Tokushima 774-0017, Japan ‡

S Supporting Information *

ABSTRACT: The L-shaped, π-extended pentacycle dibenzopyrrolo[1,2-a][1,8]naphthyridine and its derivatives were synthesized using two methods: fully intramolecular [2 + 2 + 2] cycloaddition and oxidative aromatization using substituted carbodiimide and modification of an electron-rich indole ring of an L-shaped skeleton via electrophilic reaction and cross-coupling. These L-shaped compounds emitted fluorescence in high quantum yield. The position of substituents affected the fluorescence color through two different mechanisms, π-conjugation and skeletal distortion, which caused the substituted L-shaped compounds to emit fluorescence in a variety of colors and to exhibit solvato-fluorochromism.

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INTRODUCTION The development of synthetic methods for multifunctionalized N-heteroarenes1 has attracted attention for applications such as organic electronic materials, fluorescent probes, and biologically active compounds.2 Curved N-heteroarenes3−6 have recently emerged as new promising candidates for lightemitting materials due to their unique structural and photophysical properties5,6 in addition to well-developed linear N-heteroacenes.7 Hetero [2 + 2 + 2] cycloaddition is a synthetically important tool for the construction of multisubstituted heterocycles.8 However, only a limited number of examples have been reported for fully intramolecular hetero [2 + 2 + 2] cycloadditions that can yield bi- or tricyclic heteroarenes from a single component.9 Our interest in the synthesis of nitrogen-containing heterocycles using functionalized heterocumulenes10 led to discovery of stoichiometric and catalytic carbodiimide [2 + 2 + 1] cycloadditions (Pauson−Khand reaction) with carbon monoxide in which the C=N bond participates as a 2πcomponent.11 Furthermore, we have developed a synthetic method for the L-shaped π-extended pentacycle, dibenzopyrrolo[1,2-a][1,8]naphthyridine 2, via fully intramolecular hetero [2 + 2 + 2] cycloaddition using carbodiimide 1 with two alkyne portions (Scheme 1).3b Prominent features of the L-shaped pentacycle include • A curved-planar 6−6−6−5−6 ring system3,4 conjugated between an electron-rich indole ring and an electron-poor quinoline ring. © 2017 American Chemical Society

Scheme 1. Synthesis of Dibenzopyrrolo[1,2a][1,8]naphthyridine3b

• Spatially separated frontier molecular orbitals (FMOs) consisting of the HOMO of the indole ring and the LUMO of the quinoline ring. • Fluorescence that is minimally quenched even in polar solvents12 (ΦF = 0.80 in hexane, ΦF = 0.82 in CH2Cl2, ΦF = 0.83 in methanol). This report describes the synthesis of highly fluorescent Lshaped dibenzopyrrolo[1,2-a][1,8]naphthyridine, structural modifications at various positions, and fluorescence properties. The substituted L-shaped pentacycles 2−9 were synthesized Received: October 23, 2017 Published: December 12, 2017 690

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

The Journal of Organic Chemistry

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via fully intramolecular [2 + 2 + 2] cycloaddition of presubstituted carbodiimides 1a−f (Scheme 2, method A) or

Article

RESULTS AND DISCUSSION

Synthesis of Carbodiimides and 6,7-Dimethyl Pentacycle. The preparation of carbodiimides 1a−f is shown in Scheme 3. Addition of lithium trimethylsilylacetylide to 2azidobenzaldehyde 10a gave 11a. Silane reduction and subsequent Staudinger reaction converted phenylazide 12a to iminophosphorane 13a followed by deprotection of the TMS group to give 14a. Dimerization via aza-Wittig reaction with CO2 gave carbodiimide 1a. Similarly, carbodiimides 1b−e with substituents at the R6 and R7 positions were prepared from benzaldehyde 10a or 10e and various alkynes. Azide 17 with a phenyl group at the benzylic position was prepared from azidobenzophenone 15 and converted to amine 18 by successive hydride reductions with triethylsilane and lithium aluminum hydride. Urea formation from 18 using triphosgene and subsequent dehydration gave carbodiimide 1f. Next, rhodium(I) catalysts (5−10 mol %) were screened for the [2 + 2 + 2] cycloaddition of carbodiimide 1b to L-shaped pentacycle 2b (Table 1). Wilkinson catalyst [RhCl(PPh3)3] showed high catalytic activity for reaction in toluene at 120 °C for 1 h to give 2b in 90% yield after aromatization by MnO2 (entry 1). For aromatization of the intermediate cycloadduct by dehydrogenation, MnO2 (3.0 equiv) was the best oxidant when used at room temperature for 6 h. When the amount of the catalyst was reduced to 5 mol %, the yield of 2a decreased to 60% (entry 2). Although [RhCl(cod)]2 (5 mol %) did not give compound 2b (entry 3), the use of [RhCl(cod)]2 (5 mol %) in combination with various bidentate phosphine ligands (20 mol %) worked. The use of 1,1′-bis(diphenylphosphino)ferrocene and 1,2-bis(diphenylphosphino)ethane resulted in low conversion (entries 4 and 5), whereas 1,3-bis(diphenylphosphino)propane or 1,4-bis(diphenylphosphino)butane exhibited high catalytic activity to produce up to 80% yield (entries 6 and 7). The use of prepared Rh(dppp)2Cl (10 mol %) afforded 2b in 91% yield (entry 8), whereas the use of 5 mol % catalyst decreased the yield of 2b to 26% (entry 9). Thus, the optimized conditions used for entries 1 and 8 were employed for the [2 + 2 + 2] cycloaddition reactions.

Scheme 2. Two Methods for the Synthesis of Dibenzopyrrolo[1,2-a][1,8]naphthyridine with Substituents at Various Positions

via postsubstitution at the electron-rich position of the indole ring on 2c (Scheme 2, method B). Most of these substituted Lshaped derivatives emitted fluorescence with a high quantum yield (ΦF ⩾ 0.63) even in polar solvents except for the amino derivatives that exhibited solvato-fluorochromism (ΦF = 0.45− 0.12). Interestingly, the fluorescence properties of the phenyl derivatives depended heavily on the introduced positions of the phenyl and alkyl groups. The 5,6,7,8-tetrasubstituted pentacycle in particular exhibited emission at a longer wavelength while retaining high fluorescence quantum yield. The effect of a bend in the corner unit of the curved Nheteroarenes on the photophysical properties is discussed. Scheme 3. Synthesis of Substituted Carbodiimides 1a−f

Reagents and conditions: (a) 1-heptyne, n-BuLi, THF, −78 °C; (b) Et3SiH, NH4F, TFA, CH2Cl2, −5 °C; (c) PPh3, CH2Cl2, r.t.; (d) K2CO3, MeOH, r.t.; (e) CO2, CH2Cl2, r.t.; (f) LiAlH4, THF, 0 °C; (g) triphosgene, Et3N, THF, 60 °C; (h) PPh3, CBr4, Et3N, CH2Cl2, r.t.

a

691

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

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The Journal of Organic Chemistry Table 1. Screening of Rh Catalysts and Reaction Conditions

entry

catalyst

X/mol %

ligand

time/h

yield/%

1 2 3 4 5 6 7 8 9

Rh(PPh3)3Cl Rh(PPh3)3Cl [RhCl(cod)]2 [RhCl(cod)]2 [RhCl(cod)]2 [RhCl(cod)]2 [RhCl(cod)]2 Rh(dppp)2Cl Rh(dppp)2Cl

10 5 5 5 5 5 5 10 5

none none none dppf dppe dppp dppb none none

1 1 6 3 6 0.3 2 0.3 6

90 60 NRa 28 30 83 80 91 26

Scheme 4. Synthesis of (a) Di- and (b) Tetrasubstituted Dibenzopyrrolo[1,2-a][1,8]naphthyridines 2a−d and 3

a

NR = no reaction.

Derivatization Using Substituted Carbodiimides (Method A). After determining the optimized reaction conditions for the synthesis of 2b (R 6 , R 7 = Me), carbodiimides 1a, 1c, and 1d (R6, R7 = H, Pent, Ph) were converted to 2a, 2c, and 2d, respectively (Scheme 4a). Compounds 2b and 2c with alkyl chains were obtained in good yield, but the yield of phenyl derivative 2d was low (13% yield) due to the formation of dihydrodibenzonaphthyridine 2d′ (70% yield) as a byproduct from the intramolecular 2azadiene-Diels−Alder reaction.13 The 5,8-diphenyl-substituted L-shaped compound 3 (R5, R8 = Ph) was also obtained in 48% yield from carbodiimide 1f via [2 + 2 + 2] reaction along with the Diels−Alder byproduct 3′ (Scheme 4b).14 The formation of byproducts 2d′ and 3′ suggested the acceleration of the dienophilicity through the Thorpe−Ingold effect and/or the reactive-rotamer effect15 in carbodiimides 1d and 1f. The solubilities of 2c and 3 with pentyl side chains were greater than those of pentacycles 2a, 2b, and 2d in organic solvents such as dichloromethane. Therefore, n-pentyl substituents (R6, R7 = Pent) were introduced to all of the Lshaped compounds, except for the pentacycles 2a, 2b, and 2d, to guarantee good solubility of the L-shaped pentacycle derivatives in common organic solvents. Postderivatization of L-Shaped Skeleton (Method B). Next, 3,10-diiodo pentacycle 4a was prepared in 75% yield from carbodiimide 1e via [2 + 2 + 2] cycloaddition and aromatization (Scheme 5). Aryl-substituted derivatives 4b−d were obtained from 4a via Suzuki−Miyaura cross-coupling using Pd(PPh3)4 as a catalyst in aqueous Na2CO3 and tolueneethanol at 100 °C in good yields. Alkynyl groups were also added to 4a through Sonogashira cross-coupling using PdCl2(PPh3)2, CuI, and triethylamine in THF at 80 °C to give 5a−c in good yields. In addition, diamine derivatives 6a−c were obtained by Buchwald−Hartwig cross-coupling of 4a with secondary amines using Pd2(dba)3 as a catalyst, XPhos as a ligand, and KOtBu as a base in toluene at 100 °C in good yields. The structure of 3,10-diphenyl pentacycle 4b was confirmed from X-ray crystallography of a single fluorescent yellow crystal, which revealed the planarity of the L-shaped skeleton (Figure 1).16 Introducing substituents to the 5-position of the pentacycles is easy for L-shaped pentacycle 2c because the electron-rich

pyrrole ring of L-shaped skeleton is the most reactive position (Scheme 6). Thus, bromination of 2c with 1.0 equiv of Nbromosuccinimide (NBS) furnished bromide 7a exclusively, whereas bromination of 2c with 3.0 equiv of NBS furnished dibromide 8a. An aryl group was added to bromide 7a and dibromide 8a through Suzuki−Miyaura cross-coupling. Reaction of 7a and 8a with phenyl, p-methoxyphenyl, and mnitrophenyl boronic acid delivered the aryl-substituted compounds 7b−d and 8b−d in good to excellent yields, whereas the reaction with p-nitrophenyl boronic acid afforded product 7e in moderate yield. Reaction of 2c with Vilsmeier reagent gave formyl derivative 9a in 99% yield. Subsequent Wittig reaction led to acrylic ester 9b in 92% yield. Optical Properties of L-Shaped Pentacycle Derivatives. For studying the effect of substituents of the L-shaped compounds on optical properties, UV−visible absorption spectra and fluorescence spectra of L-shaped pentacycles with substituents at various positions were obtained and compared. Figure 2 and Table 2 summarize absorption and emission wavelengths, fluorescence quantum yields, and fluorescence lifetimes of 6,7-disubstituted L-shaped pentacycle 2a−d and phenyl-substituted L-shaped pentacycles 3, 4b, 7b, and 8b in dichloromethane. The optical properties can be summarized as follows. Fluorescence quantum yields were high 692

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

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λmax of the 3,10-diphenyl derivative 4b (R3, R10 = Ph, λmax = 410, 432, 456 nm) was red-shifted 5 nm from that of 2c (reference compound, λmax = 404, 425, 451 nm), although the maximum absorption wavelength (λmax) of the 6,7-diphenyl derivative 2d (R6, R7 = Ph, λmax = 403, 426, 449 nm) was nearly the same as that of 2c. Interestingly, derivatives with a phenyl group at the 5-position, 7b (R5 = Ph, λmax = 412, 433, 460 nm), 8b (R2, R5 = Ph, λmax = 420, 444, 471 nm), and 3 (R5, R8 = Ph, λmax = 420, 441, 466 nm) had λmax at a more redshifted position than those of 2c, 2d, and 4b. In the fluorescence spectra, the effect of substituent position on the maximum emission wavelength (λem) was more pronounced and depended on the position. The λem of 6,7diphenyl and 3,10-diphenyl derivatives 2d (R6, R7 = Ph, λem = 479, 513 nm) and 4b (R3, R10 = Ph, λem = 486, 508 nm) were red-shifted less than 10 nm from that of 2c (reference compound, λem = 479, 512 nm), the λem of 5-phenyl and 2,5diphenyl derivatives 7b (R5 = Ph, λem = 496, 524 nm) and 8b (R2, R5 = Ph, λem = 509, 535 nm) were red-shifted ∼20 nm from that of 2c. Furthermore, the 5,8-diphenyl derivatives 3 (R5, R8 = Ph, λem = 505, 546 nm) had a λem value that was redshifted ∼35 nm from that of 2c.17 These results suggest that a substitution at the 5- (and 8-) positions of the L-shaped compounds produced an effect on the fluorescence properties that was different compared with substitution at the other positions. Origin of Long Wavelength Emission: Coplanarity or Distortion. For studying the origin of the large red-shift in the λmax and λem of 5,8-diphenyl derivative 3 compared to those of unsubstituted 2c or 3,10-diphenylated 4b, the energy levels of 6,7-diethyl pentacycle (model A), 6,7-diethyl pentacycles with phenyl groups at the 5,8-positions (model B), and 3,10positions (model C) (which have ethyl groups instead of pentyl groups at the 6,7-positions) were determined using DFT calculations at the B3LYP 6-31G(d) level (Figure 3 and Table 3).18 Figure 3 shows the energy levels of FMOs of the model pentacycles A−C. For both model pentacycles B and C, the LUMO was located at the quinoline moiety of the L-shaped skeleton, whereas the HOMO was located at the indole moiety regardless of the position of phenyl groups. Table 3 shows HOMO and LUMO energy levels of model pentacycles A−C. For 3,10-diphenylated model pentacycle B, energy levels of both the HOMO and LUMO were more stable than those of model pentacycle A, probably due to the π-conjugation with the phenyl groups at the 3,10-positions. The energy gap between the HOMO and LUMO levels was slightly smaller than that of model pentacycle A (0.02 eV), which corresponds to the observed small red-shift of λmax for 4b with phenyl groups at the 3,10-positions. In contrast, the effect of phenyl groups on the energy level of LUMO and HOMO for 5,8-diphenylated model pentacycle C was different than that for 3,10-diphenylated B (Table 3). The energy level of the LUMO of C was nearly the same as that of A, whereas the energy level of the HOMO of model pentacycle C was somewhat destabilized. The former negligible effect of phenyl groups at the 5,8-positions on the energy level of LUMO was due to the inability of the introduced phenyl groups to adopt a coplanar conformation with the pyrrolonaphthyridine skeleton because of steric hindrance with the 6,7-diethyl moiety. However, the phenyl groups at the 5,8-positions contributed to the increase in the energy level of the HOMO (Table S1). This destabilization of the HOMO

Scheme 5. Synthesis of 3,10-Disubstituted Dibenzopyrrolo[1,2-a][1,8]naphthyridine 4a−d, 5a−c, and 6a−c

a

Reagents and conditions: (a) RB(OH)2 (2.6 equiv), Pd(PPh3)4 (10 mol %), 2 M Na2CO3 aq, toluene, EtOH, 100 °C; (b) alkyne (2.8 equiv), PdCl2(PPh3)2 (4 mol %), CuI (2 mol %), THF, Et3N, reflux; (c) HNR2 (3.0 equiv), Pd2(dba)3 (5 mol %), XPhos (20 mol %), KOtBu (2.4 equiv), toluene, 100 °C.

Figure 1. X-ray structures of 3,10-diphenyldibenzopyrrolo[1,2a][1,8]naphthyridine 4b:16 (a) top view, (b) side view.

(0.75−0.93), yet fluorescence wavelengths ranged from 450 to 550 nm depending on the type and position of the substituent (i.e., these derivatives produced different-colored emissions). Fluorescence lifetimes of the substituted L-shaped derivatives were on the order of nanoseconds (τs = 4.25−7.07 ns), which implies that these derivatives emit from a singlet excited state. Effect of Substituent Position. First, the effect of substituents at the 6,7-positions of dibenzopyrrolo[1,2-a][1,8]naphthyridine 2a−d were compared (Table 2). The introduction of methyl (2b), pentyl (2c), or phenyl substituents (2d) at the 6,7-positions resulted in a small shift of absorption λmax and emission λem compared to those of parent compound 2a. Next, the absorption and emission wavelengths of the phenyl derivatives of 3, 4b, 7b, and 8b were compared to those of 2c as a reference compound (Table 2). In the UV−vis spectra, 693

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

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The Journal of Organic Chemistry Scheme 6. Synthesis of 5- and 2,5-Disubstituted Dibenzopyrrolo[1,2-a][1,8]naphthyridines 7a−e, 8a−d, 9a, and 9b

Figure 2. (a) UV−vis and fluorescence spectra of reference compound 2c and diphenyl derivatives 3 and 4b in dichloromethane. (b) Fluorescence emission of pentacycles 3 and 4b in dichloromethane.

Figure 3. Calculated FMOs of model pentacycles B and C. Geometry optimization (and energies) were calculated at the B3LYP/6-31G(d) level.

Table 2. Photophysical Properties of Dibenzopyrrolo[1,2a][1,8]naphthyridine Derivatives in Dichloromethane

comp. 2a 2b 2c 2d 4b 7b 8b 3

λmax (abs)/nm [ε/104 cm−1 M−1] a

402 , 420, 447 [0.98], [1.3], [0.95] 403a, 421, 442 [1.5], [1.9], [1.4] 404a, 425, 451 [1.7], [2.2], [1.5] 403a, 426, 449 [1.2], [1.6], [1.2] 410a, 432, 456 [1.3], [1.9], [1.4] 412a, 433, 460a [1.6], [2.0], [1.5] 420a, 444, 471a [1.2], [1.6], [1.2] 420a, 441, 466a [1.5], [1.9], [1.4]

λem/nmb 469, 474, 479, 479, 486, 496, 509, 505a,

501 508 512 513 508 524 535a 546

ΦFb

τs/ns

0.75 0.82 0.89 0.84 0.84 0.90 0.93 0.89

6.24 6.18 6.72 6.62 4.25 6.35 7.07 6.44

Table 3. HOMO and LUMO Energy Levels of Model Pentacycles A−C Optimized at the B3LYP/6-31G(d) Level

comp.

LUMO/eV

HOMO/eV

Δ(LUMO−HOMO)/eV

λcalcd/nm

A B C

−1.81 −1.89 −1.82

−4.99 −5.05 −4.90

3.18 3.16 3.08

431 438 453

Because of this distortion of the skeleton, the HOMO level, where the olefin bond at the 6,7-position constitutes the bonding orbital, is destabilized. In contrast, the bending around the olefinic bond appeared to have no effect on the LUMO level, where the olefin bond constitutes the antibonding orbital. Thus, bending around the 6,7-positions by the phenyl groups at the 5,8-positions contributed to the reduced energy gap between the HOMO and LUMO levels corresponding to the observed red-shift of λmax in the UV−vis spectra for 3. Overall, these relations of the FMO levels with the coplanarity of the L-shaped skeleton suggested that the

Shoulder peak. bExcitation at λmax (abs).

a

level could be caused by bending of the skeleton around the olefinic portion at the 6,7-position due to 1,3-allylic-type strain between the ethyl and phenyl groups, decreasing the coplanarity between indole and quinoline rings (Figure 4, Table 4). 694

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

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3 (R5, R8 = Ph, λem = 505, 546 nm) were red-shifted approximately 10 and 35 nm, respectively, from that of 2c (λem = 479, 512 nm). The extended π-conjugation and inductive effect of the phenyl groups was expected to contribute to the red-shift of the maximum emission wavelength. Although the Stokes shift of 1354 cm−1 for 3,10-diphenylated substituted 4b was larger than that for the unsubstituted 2c (1296 cm−1). In contrast, 5,8-diphenyl derivative 3 had a large Stokes shift (3144 cm−1) and maintained a high quantum yield (ΦF = 0.89). This outstanding fluorescence property was thought to originate in the dynamic conformational change from the bent pentacycle in the ground state to a planar structure in the excited state.19 For gaining insight into the conformational change in the excited state, the coplanarity of 5,8-diphenylated model compound C in the ground state and that of C* in the excited state was compared (Figure 4c−h and Table 4). The calculated structure of model compound C* in the excited state has a charge transfer character between the indole and quinoline rings (Figure 4h). The bent angle of the corner sixmembered ring indicates that 5,8-phenylated model C* had a more flattened skeleton compared to that of ground state structure C. The bond alternation manner also changed significantly from the ground state to the excited state. Whereas the corner ring in the ground state adopted a pquinoidal structure (Figure 4g), that ring in the exited structure adopted a flattened 1,3-cyclohexadiene-type structure (Figure 4h). Thus, this conformational change in the corner ring contributed to the increase in planarity in the excited state leading to intramolecular charge transfer from the HOMO localized on the electron-donating indole to the LUMO localized on the quinoline moiety, causing red-shifted emission from the more planar excited state. Consequently, the larger Stokes shift of 5,8-disubstituted pentacycle 3 compared to those of the other pentacycles derived from planarization in the excited state. Substituent Effect Based on Electron Donor and Acceptor. Next, the effect of other types of substituents, electron-donating amino derivatives 6a−c, and electronwithdrawing acrylic ester derivative 9b (Figure 5, Table 5)

Figure 4. Calculated ground state structures of model pentacycles B and C and excited state structure C*. Geometry optimization was calculated at the B3LYP/6-31G(d) level. Structures are omitted hydrogen atoms. (a, c, and e) Side and (b, d, and f) top views of the calculated pentacycles B, C, and C* along with the bond lengths (Å) for the corner rings. (g, h) Schematic presentations of the skeleton based on calculated bond length.

Table 4. Bent Angle of the Center 6-Membered Ring in the Calculated Model Pentacycles A−C in the Ground State and C* in the Excited State with Geometry Optimization Calculated at the B3LYP/6-31G(d) Level

comp.

bent angle of the central ring/dega

bond length at 6,7-position/Å

A B C C*

2.7 5.0 23.6 18.1

1.369 1.369 1.376 1.453

a

Calculated from the strain of boat conformation.

observed red-shift in the UV−vis spectra originated from πconjugation extension to the phenyl groups for the 3,10diphenyl pentacycle 4b, whereas the bend around the 6,7positions was the main factor for the red-shift of the λmax of 5,8-diphenyl pentacycle 3. In the fluorescence spectra, more drastic red-shifts were observed for the emission wavelength (λem) of 5,8-diphenylated pentacycle 3 compared to that of unsubstituted pentacycle 2c and 3,10-diphenyl pentacycle 4b (Figure 2b). The maximum emission wavelengths λem of 3,10- and 5,8diphenyl derivatives 4b (R3, R10 = Ph, λem = 486, 508 nm) and

Figure 5. UV−vis and fluorescence spectra of 6,7-dipentyl pentacycle 2c, 3,10-diamino pentacycles 6a−c, and 5-acryloyl-substituted pentacycle 9b in dichloromethane. 695

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The Journal of Organic Chemistry Table 5. Photophysical Properties of Various Substituted Derivatives in Dichloromethane comp. 2c 6a 6b 6c 9b

λmax (abs)/nm [ε/104 cm−1 M−1] a

404 , 425, 451 [1.7], [2.2], [1.5] 416a, 440, 464 [1.4], [1.7], [1.6] 413, 437, 465 [1.5], [1.9], [1.7] 421a, 446, 482 [1.4], [1.8], [1.3] 438a, 458, 487a [2.0], [2.2], [1.4]

λem/nmb

ΦFb

τs/ns

479, 522, 500, 500, 519,

0.89 0.12 0.25 0.45 0.69

6.72 9.10 10.1 11.0 4.60

512 565a 528a 530a 556

Shoulder peak. bExcitation at λmax (abs).

a

on the optical properties of L-shaped pentacycles was examined. As shown in Table 5, the emission peak wavelength λem of diaminopentacycles 6b (λem = 500, 528 nm) and 6c (λem = 500, 530 nm) were red-shifted ∼15 nm from that of 2c and the λem of 6a (λem = 522, 565 nm) was shifted ∼40 nm from that of 2c, whereas the quantum yields were decreased (6a: 0.12, 6b: 0.25, 6c: 0.45). This remarkable red-shift of λem for 6a compared to those of 6b and 6c corresponded to the order of electron-donating properties of amino groups, which also correlates with the Hammett σ+ constant of amino groups.20 Moreover, the λem of pentacycle 9b with an acrylic ester group at the 5-position (λem = 519, 556 nm) was also shifted ∼40 nm while maintaining a high quantum yield (0.69) compared to that of 2c. The larger red-shift of acrylic ester 9b compared to that of 5-phenyl substituted pentacycle 7b (λem = 496, 524 nm) implies that the red-shift of 9b was due to the electronwithdrawing property and coplanar extension of π-conjugation by the acrylic ester moiety linked to the indole rings. Substituent Effect Based on Solvent Polarity. For comparing the cause for the red-shift and decrease in the quantum yield of 3,10-diamino pentacycles 6a−c with those of diphenyl derivative 3 that exhibit a similar red-shifted emission with high quantum yield, fluorescence spectra were obtained in various solvents. Figures 6 and 7 and Table 6 show the fluorescence spectra and optical properties of 3,10-diamino pentacycle 6a and 5,8-diphenyl pentacycle 3 in various solvents. As shown in Figure 6 and Table 6, the emission

Figure 7. Effect of solvent on fluorescence spectra of pentacycle 3.

Table 6. Maximum Fluorescence Wavelength and Fluorescence Quantum Yields of Pentacycle 3 and 6a in Various Solvents 6a solvent hexane CHCl3 CH2Cl2 DMF a

λem/nmb a

494, 526 515, 543a 522, 565a 535

3 ΦFb

λem/nmc

ΦFc

0.43 0.20 0.12 0.08

497, 531 503,a 540 505,a 546 505,a 547

0.73 0.92 0.89 0.86

Shoulder peak. bExcitation at 440 nm. cExcitation at 441 nm.

peak wavelength λem of 3,10-diamino pentacycle 6a was affected by solvent polarity. A blue shift of λem was observed in low-polarity solvents (Δλem = −28 nm, hexane: λem = 494 nm, dichloromethane: λem = 522 nm), whereas red-shifts of λem were observed in highly polar solvents (Δλem = +13 nm, DMF: λem = 535 nm). In addition, as the solvent polarity was reduced, the fluorescence quantum yield of pentacycle 6a increased. This solvatochromic behavior of 6a with amino groups is typical for donor−acceptor-type fluorescent dyes.21 In contrast, the emission peak wavelength λem of 5,8-diphenyl pentacycle 3 was minimally affected by solvent polarity compared to that of λem of pentacycle 6a (Figure 7, Table 6). The λem of pentacycle 3 red-shifted only 16 nm in DMF compared to that in hexane. In addition, emission peak strength at shorter wavelengths (∼500 nm) decreased as solvent polarity increased. In addition, pentacycle 3 maintained a high fluorescence quantum yield regardless of solvent polarity (hexane: ΦF = 0.73, DMF: ΦF = 0.86). These observations demonstrate that 5,8-diphenyl pentacycle 3 produced efficient emission at a longer wavelength region while maintaining high fluorescence quantum yield compared to those of other pentacycle derivatives.

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CONCLUSIONS A new series of L-shaped aza aromatic compounds with pyrrolo[1,2-a][1,8]naphthyridine corner units, which possessed highly efficient fluorescence properties, was synthesized. Two effective approaches that introduced substituents into different positions of the L-shaped compounds were also developed: direct construction of the L-shaped skeleton bearing substituents via fully intramolecular [2 + 2 + 2] cycloaddition from presubstituted diyne-carbodiimides and postmodification by introducing substituents through halogenation and subsequent cross-coupling to the ready-made Lshaped compounds. These L-shaped derivatives exhibited different fluorescence properties that depended on the types and the introduced positions of their substituents. In particular,

Figure 6. (a) Effect of solvent on fluorescence spectra of 3,10diamino pentacycle 6a and (b) fluorescence emission of pentacycle 6a in various solutions. 696

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

Article

The Journal of Organic Chemistry

132.0 (C), 131.2 (CH × 2), 130.3 (CH × 2), 130.2 (CH), 129.9 (C), 128.3 (CH × 2), 128.13 (CH × 2), 128.05 (CH), 127.9 (CH), 127.6 (CH), 127.5 (CH), 125.5 (C), 125.0 (CH), 123.7 (CH), 123.0 (CH), 121.3 (C), 120.7 (CH), 118.3 (CH), 102.9 (CH); HRMS (EI) (m/z) [M]+ calcd for C31H20N2 420.1626, found 420.1625. 2d′: white crystal; mp 113.2−115.0 °C; IR (KBr) 3401, 2931, 1581, 1488, 1211 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 4.8, 3.6 Hz, 1H), 7.57−7.53 (m, 2H), 7.52−7.48 (m, 3H), 7.34 (br, 1H), 7.30−7.25 (m, 5H), 7.14 (d, J = 4.8 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.39 (s, 2H), 3.91 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 150.7 (C), 147.3 (C), 144.2 (C), 138.5 (C), 136.7 (C), 132.2 (C), 131.7 (CH × 2), 129.0 (CH × 2), 128.8 (CH × 2), 128.5 (CH), 128.2 (CH × 2), 128.0 (CH), 128.0 (CH), 127.6 (CH), 127.4 (CH), 125.2 (C), 124.9 (CH), 124.0 (C), 122.6 (CH), 121.2 (CH), 119.5 (C), 115.0 (C), 113.8 (CH), 88.7 (C), 83.0 (C), 30.0 (CH2), 21.5 (CH2); HRMS (ESI) (m/z) [M + H]+ calcd for C31H23N2 423.1856, found 423.1856. Synthesis of Pentacycle 3 via Intramolecular [2 + 2 + 2] Cycloaddition of Carbodiimide 1f. Pentacycle 3 (0.64 g, 48%) was obtained from 1f (1.3 g, 2.4 mmol), Rh(PPh3)3Cl (0.22 g, 0.24 mmol), MnO2 (0.10 g, 1.18 mmol), and toluene (2 mL) using the general procedure for [2 + 2 + 2] cycloaddition as a yellow solid: mp 105.4−105.9 °C; IR (ATR) 3062, 2924, 2861, 1951, 1450 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.59−7.28 (m, 15H), 2.45 (t, J = 8.5 Hz, 2H), 2.04 (t, J = 8.5 Hz, 2H), 1.32−1.18 (m, 2H), 1.16−0.97 (m, 6H), 0.85−0.60 (m, 10H); 13C NMR (76 MHz, CDCl3) δ 147.7 (C), 145.1 (C), 144.1 (C), 139.1 (C), 136.1 (C), 133.5 (C), 133.4 (C), 132.0 (C), 131.7 (C), 131.6 (C), 131.3 (CH × 2), 130.1 (CH × 2), 129.1 (CH), 128.3 (CH × 2), 128.0 (CH × 3), 127.5 (CH), 127.1 (CH), 126.3 (CH), 125.9 (C), 124.4 (CH), 123.7 (CH), 122.7 (CH), 119.2 (CH), 118.3 (CH), 117.4 (C), 115.2 (C), 31.7 (CH2 × 2), 30.4 (CH2), 29.4 (CH2), 29.0 (CH2), 28.6 (CH2), 22.4 (CH2), 22.3 (CH2), 14.0 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C41H41N2 561.3264, found 561.3269. Synthesis of Pentacycle 4a via Intramolecular [2 + 2 + 2] Cycloaddition of Carbodiimide 1e. Pentacycle 4a (0.66 g, 75%) was obtained from 1e (1.3 g, 2.4 mmol), Rh(PPh3)3Cl (0.12 g, 0.13 mmol), toluene (15 mL), and MnO2 (0.58 g, 6.7 mmol) using the general procedure for [2 + 2 + 2] cycloaddition as a yellow solid: mp 212.8−213.2 °C; IR (KBr) 2924, 2854, 1589, 1535, 1450 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.28 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.11 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.9, 1.8 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 1.8 Hz, 1H), 6.64 (s, 1H), 2.82 (t, J = 8.2 Hz, 2H), 2.76 (t, J = 8.2 Hz, 2H), 1.72−1.60 (m, 4H), 1.55−1.39 (m, 8H), 0.97 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 146.9 (C), 144.1 (C), 138.0 (CH), 137.3 (C), 136.1 (CH), 133.4 (C), 132.1 (C), 131.2 (CH), 130.4 (C), 129.9 (CH), 129.5 (C), 129.1 (CH), 128.9 (CH), 127.1 (C), 120.2 (C), 119.7 (CH), 98.1 (CH), 89.4 (C), 87.2 (C), 32.3 (CH2 × 2), 29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 27.6 (CH2), 22.5 (CH2 × 2), 14.1 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C29H31I2N2 661.0571, found 661.0571. Synthesis of Diphenylpentacycle 4b via Suzuki−Miyaura Cross-Coupling of 4a. A mixture of diiodide 4a (66 mg, 0.10 mmol), Pd(PPh3)4 (4.0 mg, 0.034 mmol), phenylboronic acid (30 mg, 0.26 mmol), and 2 M aq Na2CO3 (1 mL) in toluene (2 mL) and ethanol (2 mL) was stirred at 100 °C for 3 h. The reaction mixture was extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/ hexane = 1/2) to give compound 4b (48 mg, 83%) as a yellow solid: mp 174.0−174.5 °C; IR (KBr) 2924, 2360, 1589, 1458, 1381 cm−1; 1 H NMR (500 MHz, CDCl3) δ 9.74 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 8.01−7.97 (m, 2H), 7.78−7.73 (m, 5H), 7.52−7.48 (m, 4H), 7.42−7.34 (m, 2H), 6.83 (s, 1H), 2.91 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 1.79−1.67 (m, 4H), 1.58−1.41 (m, 8H), 0.97 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 147.2 (C), 145.0 (C), 142.3 (C), 140.6 (C), 137.7 (C), 137.5 (C),

5,8-diphenyl pentacycle 3 exhibited emission at a longer wavelength while maintaining high fluorescence quantum yield (546 nm and ΦF = 0.89 in CH2Cl2) compared to that of 3,10diphenyl pentacycle 4b (508 nm and ΦF = 0.84 in CH2Cl2). This fluorescence of pentacycle 3 (ΦF = 0.86 in DMF) was in marked contrast to the 3,10-diamino pentacycle 6a, which showed solvato-fluorochromism with decreasing fluorescence quantum yield in polar solvent (ΦF = 0.08 in DMF). The ability to adjust the fluorescence and modify the structural feature, especially to introuce a bend effect in the corner unit of the curved N-heteroarenes, will be useful for application to fluorescent probes, light-emitting devices, and stimuli-responsive materials. Investigation into the practicality and applicability of these poly aza-aromatic compounds is underway.3a,6a

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EXPERIMENTAL SECTION

General. All melting points were determined on a Yanaco melting point apparatus or METTLER TOLEDO MP90. 1H and 13C NMR spectra in ppm downfield from tetramethylsilane (TMS) using an internal standard of TMS or CDCl3. DEPT was used to assign carbon types. IR spectra were taken on a JASCO FT/IR-4600 (ATR) and a HORIBA FT-710. HRMS analysis were performed on a JEOL JMSS3000 SpiralTOF (MALDI-TOF), a Bruker Daltonics microTOF, or a Hitachi double-focusing M-80B spectrometer. UV−vis absorption, fluorescence, quantum yields, and fluorescence lifetime were obtained on the respective spectrometers. The X-ray analysis data were obtained using a Rigaku R-AXIS RAPID II R charge-coupled device (CCD) apparatus (Cu Kα radiation, λ = 1.54178 Å). A numerical absorption correction (μ) was applied. The structures were solved by direct methods and refined by the full-matrix least-squares method on F2 with anisotropic temperature factors for nonhydrogen atoms. All the hydrogen atoms were located at the calculated positions and refined with riding. The compounds 1b,3b 1c,3b 2b,3b 2c,3b 7a−e,3a 8a,3a 8d,3a 13a,11b 13d,11b 15,22 and (2-azido-5-iodophenyl)methanol23 were synthesized according to the reported procedures. Synthesis of Pentacycle 2a via Intramolecular [2 + 2 + 2] Cycloaddition of Carbodiimide 1a. To Rh(dppp)2Cl (38 mg, 0.039 mmol) in heated toluene solution (5 mL) was added a toluene solution (1 mL) of 1a (106 mg, 0.39 mmol) at 120 °C. The mixture was stirred for 1 h followed by addition of MnO2 (1.0 g, 12 mmol) at room temperature and stirring for 12 h. The suspension was filtered through Celite, and the filtrate was concentrated to remove the solvent in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/2) to give 2a (70 mg, 67%) as a yellow solid: mp 140.0−140.6 °C; IR (KBr) 3046, 1550, 1488, 1450, 1180, 1049, 856 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.67 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H) 7.80 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.57 (td, J = 7.4, 1.4 Hz, 1H), 7.46 (td, J = 7.4, 1.4 Hz, 1H), 7.41 (td, J = 7.4, 1.1 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.74 (s, 1H); 13C NMR (76 MHz, CDCl3) δ 147.6 (C), 146.2 (C), 135.8 (C), 134.2 (C), 134.2 (CH), 129.7 (CH), 129.6 (C), 127.9 (CH), 127.3 (CH), 125.3 (C), 124.8 (CH), 123.2 (CH), 122.7 (CH), 122.2 (CH), 120.4 (CH), 120.3 (CH), 119.4 (C), 117.9 (CH), 100.8 (CH); HRMS (ESI) (m/ z) [M + H]+ calcd for C19H13N2 269.1073, found 269.1073. Synthesis of Pentacycle 2d via Intramolecular [2 + 2 + 2] Cycloaddition of Carbodiimide 1d. Pentacycle 2d (22 mg, 16%) and byproduct 2d′ (116 mg, 71%) were obtained from 1d (145 mg, 0.34 mmol), Rh(dppp)2Cl (33 mg, 0.034 mmol), toluene (10 mL), and MnO2 (89 mg, 1.0 mmol) using the general procedure for [2 + 2 + 2] cycloaddition. 2d:8c yellow crystal; mp 226.1−226.3 °C; IR (KBr) 3055, 3024, 2924, 2854, 1944, 1589, 1535, 1443 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.80 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.76−7.66 (m, 3H), 7.55 (td, J = 7.5, 1.1 Hz, 1H), 7.42 (td, J = 7.5, 1.1 Hz, 1H), 7.40 (td, J = 7.5, 1.1 Hz, 1H), 7.36−7.19 (m, 10H), 6.52 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 147.4 (C), 146.3 (C), 137.4 (C), 137.1 (C), 136.6 (C), 135.0 (C), 134.8 (CH), 132.2 (C), 697

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

Article

The Journal of Organic Chemistry 135.9 (C), 134.0 (C), 131.4 (CH), 130.4 (C), 130.2 (C), 129.3 (CH), 129.1 (C), 128.9 (CH × 2), 128.7 (CH × 2), 128.1 (CH), 127.5 (CH × 2), 127.4 (CH), 127.3 (CH × 2), 126.6 (CH), 125.6 (C), 125.4 (CH), 122.6 (CH), 120.4 (C), 118.5 (CH), 118.2 (CH), 99.2 (CH), 32.4 (CH2), 32.4 (CH2), 29.7 (CH2), 29.6 (CH2), 29.4 (CH2), 27.7 (CH2), 22.6 (CH2 × 2), 14.1 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C41H41N2 561.3264, found 561.3262. Synthesis of Ditolylpentacycle 4c via Suzuki−Miyaura Cross-Coupling of 4a. Pentacycle 4c (20 mg, 69%) was obtained from 4a (33 mg, 0.05 mmol), p-methylphenylboronic acid (20 mg, 0.15 mmol), Pd(PPh3)4 (2 mg, 0.0017 mmol), 2 M Na2CO3 aq (0.5 mL), ethanol (1.0 mL), and toluene (3 mL) using the general procedure for Suzuki coupling described for 4b as a yellow solid: mp 196.6−198.1 °C; IR (KBr) 3052, 3029, 2954, 2916, 2854, 1592, 1538, 1519, 1452, 1390 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.72 (d, J = 8.7 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.05−7.93 (m, 3H), 7.73 (dd, J = 8.7, 1.7 Hz, 1H), 7.67 (d, J = 7.8 Hz, 4H), 7.32 (d, J = 7.8 Hz, 4H), 6.81 (s, 1H), 2.97−2.75 (m, 4H), 2.45 (s, 6H), 1.86−1.64 (m, 4H), 1.62−1.36 (m, 8H), 1.06−0.93 (m, 6H); 13C NMR (76 MHz, CDCl3) δ 147.2 (C), 145.0 (C), 139.5 (C), 137.8 (C), 137.7 (C), 137.43 (C), 137.35 (C), 136.4 (C), 135.9 (C), 134.0 (C), 131.4 (CH), 130.5 (C), 130.2 (C), 129.8 (C × 2), 129.6 (CH × 2), 129.3 (CH), 129.2 (C), 128.1 (CH), 127.5 (CH × 2), 127.3 (CH × 2), 125.7 (C), 125.1 (CH), 122.6 (CH), 120.4 (C), 118.3 (CH × 2), 99.2 (CH), 32.6 (CH2), 32.5 (CH2), 29.9 (CH2), 29.7 (CH2), 29.6 (CH2), 27.8 (CH2 × 2), 22.7 (CH2), 21.31 (CH3), 21.27 (CH3), 14.3 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C43H45N2 589.3577, found 589.3584. Synthesis of Bis(p-nitrophenyl)pentacycle 4d via Suzuki− Miyaura Cross-Coupling of 4a. Pentacycle 4d (46 mg, 93%) was obtained from 4a (64 mg, 0.10 mmol), p-nitrophenylboronic acid (43 mg, 0.26 mmol), 2 M Na2CO3 aq (1 mL), Pd(PPh3)4 (4 mg, 0.034 mmol), ethanol (2 mL), and toluene (2 mL) using the general procedure for Suzuki coupling described for 4b as a yellow solid: mp 258.1−258.4 °C; IR (KBr) 3070, 2924, 2854, 1589, 1512, 1450, 1342 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.78 (d, J = 8.7 Hz, 1H), 8.44 (s, 1H), 8.40−8.26 (m, 5H), 8.17 (d, J = 1.8 Hz, 1H), 8.07−7.98 (m, 2H), 7.96−7.84 (m, 4H), 7.76 (t, J = 8.7 Hz, 1H), 6.90 (s, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 8.3 Hz, 2H), 1.86−1.67 (m, 4H), 1.56−1.45 (m, 8H), 0.99 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 148.8 (C), 147.9 (C), 147.3 (C), 147.1 (C), 146.8 (C), 145.8 (C), 138.3 (C), 135.3 (C), 134.9 (C), 133.6 (C), 131.9 (CH), 130.8 (C), 130.7 (C), 129.7 (C), 129.0 (CH), 128.8 (CH), 128.1 (CH × 2), 128.0 (CH × 2), 126.7 (CH), 125.8 (C), 124.4 (CH × 2), 124.3 (CH × 2), 122.7 (CH), 121.0 (C) 119.4 (CH), 118.8 (CH), 99.8 (CH), 32.6 (CH2 × 2), 29.9 (CH2), 29.8 (CH2), 29.6 (CH2), 27.9 (CH2), 22.78 (CH2), 22.75 (CH2), 14.27 (CH3), 14.25 (CH3); HRMS (EI) (m/z) [M]+ calcd for C41H38N4O4 650.2893, found 650.2898. Synthesis of Dialkynylpentacycle 5a via Sonogashira CrossCoupling of 4a. A mixture of diiodide 4a (66 mg, 0.10 mmol), PdCl2(PPh3)2 (3.0 mg, 0.004 mmol), CuI (0.4 mg, 0.002 mmol), triethylamine (1 mL), and phenyl acetylene (30 μL, 0.28 mmol) in THF (3 mL) was stirred at 60 °C for 2 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/4) to give compound 5a (57 mg, 94%) as a yellow solid: mp 101.4−101.8 °C; IR (ATR) 3055, 2924, 2862, 2206, 1597, 1443, 1450, 1389 cm−1; 1 H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 8.7 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 8.7, 2.4 Hz, 1H), 7.67−7.54 (m, 5H), 7.45−7.32 (m, 6H), 6.73 (s, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 8.2 Hz, 2 H), 1.82−1.64 (m, 4H), 1.61−1.40 (m, 8H), 0.99 (t, J = 6.9 Hz, 3H), 0.98 (t, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 147.0 (C), 144.8 (C), 137.6 (C), 133.9 (C), 132.1 (CH), 131.63 (CH × 2), 131.58 (CH × 2), 130.9 (CH), 130.6 (CH), 130.1 (C), 129.7 (C), 129.2 (C), 128.4 (CH × 2), 128.3 (CH × 3), 127.8 (CH), 127.5 (CH), 126.3 (CH), 125.0 (C), 123.9 (C), 123.7 (CH), 123.3 (C),

120.2 (C), 119.4 (C), 118.0 (CH), 117.1 (C), 99.0 (CH), 91.0 (C), 90.0 (C), 89.6 (C), 88.0 (C), 32.39 (CH2), 32.36 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 27.6 (CH2), 22.5 (CH2 × 2), 14.1 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C45H41N2 609.3264, found 609.3263. Synthesis of Dialkynylpentacycle 5b via Sonogashira CrossCoupling of 4a. Pentacycle 5b (46 mg, 72%) was obtained from 4a (66 mg, 0.10 mmol), p-tolyl acetylene (35 μL, 0.28 mmol), CuI (0.3 mg, 0.002 mmol), PdCl2(PPh3)2 (3.0 mg, 0.004 mmol), triethylamine (1 mL), and THF (2 mL) using the general procedure for Sonogashira coupling described for 5a as a yellow solid: mp 178.7− 179.0 °C; IR (KBr) 3024, 2924, 2862, 2206, 1543, 1442 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 8.7 Hz, 1H), 8.24 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 (dd, J = 8.7, 1.6 Hz, 1H), 7.52−7.48 (m, 4H), 7.20 (dd, J = 8.2, 2.1 Hz, 4H), 6.75 (s, 1H), 2.89 (t, J = 7.8 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.40 (s, 6H), 1.77−1.63 (m, 4H), 1.60−1.41 (m, 8H), 0.99 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 147.2 (C), 144.8 (C), 138.5 (C), 137.9 (C), 137.7 (C), 133.9 (C), 132.3 (CH), 131.52 (CH × 2), 131.45 (CH × 2), 130.9 (CH), 130.8 (CH), 130.3 (C), 129.7 (C), 129.3 (C), 129.2 (CH × 2), 129.1 (CH × 2), 127.6 (CH), 126.4 (CH), 125.2 (C), 123.6 (CH), 120.7 (C), 120.4 (C), 120.1 (C), 119.8 (C), 118.0 (CH), 117.4 (C), 99.0 (CH), 90.3 (C), 90.2 (C), 89.8 (C), 88.2 (C), 32.38 (CH2), 32.35 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 27.7 (CH2), 22.6 (CH2 × 2), 21.6 (CH3), 21.5 (CH3), 14.1 (CH3 × 2); HRMS (MALDI-TOF, DCTB) (m/z) [M + H]+ calcd for C47H45N2 637.3577, found 683.3576. Synthesis of Dialkynylpentacycle 5c via Sonogashira CrossCoupling of 4a. Pentacycle 5c (53 mg, 82%) was obtained from 4a (66 mg, 0.10 mmol), cyclohexyl acetylene (37 μL, 0.28 mmol), CuI (0.3 mg, 0.002 mmol), PdCl2(PPh3)2 (3.0 mg, 0.004 mmol), triethylamine (1 mL), and THF (2 mL) using the general procedure for Sonogashira coupling described for 5a as a yellow solid: mp 94.2− 94.6 °C; IR (ATR) 3055, 2931, 2854, 2229, 1589, 1543, 1450, 1389 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 8.6 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.71 (dd, J = 8.6, 1.7 Hz, 1H), 7.49 (dd, J = 8.6, 1.7 Hz, 1H), 6.73 (s, 1H), 2.90 (t, J = 8.0 Hz, 2H), 2.83 (t, J = 8.0 Hz, 2H), 2.73−2.56 (m, 2H), 2.02−1.88 (m, 4H), 1.87−1.57 (m, 13H), 1.52− 1.33 (m, 15H), 0.97 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 147.3 (C), 144.8 (C), 137.8 (C), 133.8 (C), 132.8 (CH), 130.83 (CH), 130.80 (CH), 130.4 (C), 129.8 (C), 129.3 (C), 127.6 (CH), 126.7 (CH), 125.3 (C), 123.7 (CH), 120.6 (C), 120.5 (C), 118.3 (C), 117.9 (CH), 99.0 (CH), 95.4 (C), 93.0 (C), 81.7 (C), 80.7 (C), 33.1 (CH2 × 2), 32.9 (CH2 × 2), 32.52 (CH2 × 2), 32.50 (CH2), 30.0 (CH), 29.94 (CH), 29.85 (CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 27.8 (CH2), 26.2 (CH2), 26.1 (CH2), 25.2 (CH2), 25.1 (CH2), 22.7 (CH2 × 2), 14.3 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C45H53N2 621.4203, found 621.4198. Synthesis of Diaminopentacycle 6a via Buchwald−Hartwig Cross-Coupling of 4a. A toluene solution (2 mL) of Pd2(dba)3 (5.0 mg, 0.005 mmol) and XPhos (10 mg, 0.020 mmol) was stirred at 100 °C for 10 min followed by addition of the mixture of diiodide 4a (66 mg, 0.10 mmol), tBuOK (45 mg, 0.24 mmol), and piperidine (30 μL, 0.30 mmol) and stirring at 100 °C for 5 min. The reaction was quenched by addition of saturated aqueous ammonium dichloride. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/20) to give compound 6a (34 mg, 61%) as a yellow solid: mp 178.7− 179.0 °C; IR (ATR) 3055, 2931, 2854, 1612, 1535, 1458, 1389 cm−1; 1 H NMR (300 MHz, CDCl3) δ 9.52 (d, J = 9.2 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 9.2, 2.5 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 9.2, 2.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.69 (s, 1H), 3.30 (t, J = 5.3 Hz, 4H), 3.23 (t, J = 5.3 Hz, 4H), 2.90 (t, J = 7.8 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 1.86−1.59 (m, 16H), 1.57− 1.39 (m, 8H), 0.97 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 149.1 (C), 148.6 (C), 145.4 (C), 141.1 698

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

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The Journal of Organic Chemistry

diluted with H2O (10 mL) and extracted with CHCl3 (3 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/2) to give 8b (9.5 mg, 61%) as a yellow solid: mp 134.2−134.5 °C; IR (KBr) 3055, 3024, 2954, 2924, 2854, 1597, 1450, 1389 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.20 (d, J = 1.4 Hz, 1H), 8.33 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95−7.85 (m, 3H), 7.73 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.65− 7.45 (m, 9H), 7.44−7.32 (m, 2H), 2.88 (t, J = 8.3 Hz, 2H), 2.56 (t, J = 8.3 Hz, 2H), 1.78−1.62 (m, 2H), 1.55−1.41 (m, 4H), 1.39−1.22 (m, 2H), 1.11 (tq, J = 7.3, 7.3 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H), 0.79 (t, J = 7.3 Hz, 3H), 0.75 (tq, J = 7.9, 7.9 Hz, 2H); 13C NMR (76 MHz, CDCl3) δ 147.8 (C), 145.8 (C), 142.9 (C), 137.0 (C), 136.3 (C), 133.9 (C), 132.6 (C), 131.7 (C), 131.6 (CH × 2), 131.4 (C), 131.0 (CH), 130.0 (C), 129.6 (CH), 129.0 (CH × 2), 128.2 (CH × 2), 127.82 (CH × 2), 127.77 (CH × 2), 127.4 (CH), 126.8 (CH), 125.7 (C), 124.9 (CH), 122.4 (CH), 120.1 (C), 119.6 (CH), 116.9 (CH), 115.2 (C), 32.5 (CH2), 31.9 (CH2), 29.9 (CH2 × 2), 28.8 (CH2), 27.7 (CH2), 22.7 (CH2), 22.5 (CH2), 14.24 (CH3), 14.15 (CH3); HRMS (ESI) (m/z) [M + H]+ calcd for C41H41N2 561.3264, found 561.3271. Synthesis of 2,5-Diarylpentacycle 8c via Suzuki−Miyaura Cross-Coupling of 8a. Pentacycle 8c (9.7 mg, 66%) was obtained from dibromide 8a (13 mg, 0.024 mmol), p-methoxyphenylboronic acid (14 mg, 0.091 mmol), 2 M aq K2CO3 (0.1 mL), Pd(PPh3)4 (1.7 mg, 0.0016 mmol), and 1,4-dioxane (0.3 mL) using the general procedure for Suzuki coupling described for 8b as a yellow solid: mp 170.1−170.5 °C; IR (KBr) 3055, 2954, 2924, 2854, 1605, 1520, 1450, 1396 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.14 (d, J = 1.4 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.72 (td, J = 7.5, 1.4 Hz, 1H), 7.57 (dd, J = 8.2, 1.4 Hz, 1H), 7.48 (td, J = 7.5, 0.9 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.86 (t, J = 8.1 Hz, 2H), 2.58 (t, J = 8.5 Hz, 2H), 1.78−1.63 (m, 2H), 1.56−1.25 (m, 6H), 1.13 (tq, J = 7.5, 7.5 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H), 0.88−0.71 (m, 5H); 13C NMR (76 MHz, CDCl3) δ 159.1(C), 158.9 (C), 147.9 (C), 145.8 (C), 136.7 (C), 135.6 (C), 133.9 (C), 132.5 (CH × 2), 131.9 (C × 2), 131.3 (C), 130.8 (CH), 129.7 (C), 129.6 (CH), 128.7 (CH × 2), 128.3 (C), 127.83 (CH), 127.80 (CH), 125.7 (C), 124.9 (CH), 122.1 (CH), 120.2 (C), 119.5 (CH), 116.4 (CH), 114.9 (C), 114.5 (CH × 2), 113.7 (CH × 2), 55.6 (CH3 × 2), 32.6 (CH2), 32.0 (CH2), 30.0 (CH2), 29.9 (CH2), 28.8 (CH2), 27.7 (CH2), 22.7 (CH2), 22.6 (CH2), 14.24 (CH3), 14.20 (CH3); HRMS (ESI) (m/z) [M + H]+ calcd for C43H45N2O2 621.3476, found 621.3472. Synthesis of Formylpentacycle 9a via Vilsmeir Reaction of 2c. A DMF solution (1 mL) of phosphoryl chloride (0.11 mL, 1.2 mmol) was stirred for 30 min at 0 °C, followed by addition of 2c (120 mg, 0.3 mmol) at room temperature and stirring for 2 h. The reaction mixture was quenched by addition of cooled water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/8) to give compound 9a (127 mg, 99.7%) as a yellow solid: mp 163.2−163.3 °C; IR (KBr) 3055, 2954, 2924, 2862, 1635, 1589, 1551, 1504, 1458 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.66 (s, 1H), 9.86 (dd, J = 7.9, 1.3 Hz, 1H), 8.81 (dd, J = 7.9, 1.2 Hz, 1H), 8.52 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 7.9, 1.3 Hz, 1H), 7.62− 7.49 (m, 3H), 3.13−2.97 (m, 4H), 1.87−1.66 (m. 4H), 1.59−1.40 (m, 8H), 0.99 (t, J = 7.4 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 187.0 (CHO), 146.4 (C), 146.0 (C), 141.5 (C), 136.9 (CH), 134.5 (C), 133.0 (CH), 131.0 (CH), 129.9 (C), 128.4 (C), 128.23 (CH), 128.15 (CH), 126.0 (CH), 125.9 (C), 125.5 (CH), 125.0 (CH), 122.7 (CH), 118.7 (CH), 118.6 (C), 113.4 (C), 32.5 (CH2), 32.2 (CH2), 31.0 (CH2), 30.0 (CH2), 29.1 (CH2), 28.3 (CH2), 22.69 (CH2), 22.65 (CH2), 14.2 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C30H33N2O 437.2587, found 437.2584. Synthesis of Pentacycle 9b via Wittig Reaction of 9a. A xylene solution (1 mL) of aldehyde 9a (10 mg, 0.023 mmol) and methyl(triphenylphosphoranylidene) acetate (38 mg, 0.12 mmol) was

(C), 137.2 (C), 130.4 (C), 129.74 (CH), 129.68 (C), 129.5 (C), 128.6 (C), 128.1 (CH), 126.2 (C), 123.8 (CH), 119.8 (C), 118.2 (CH), 115.9 (CH), 109.8 (CH), 106.6 (CH), 97.8 (CH), 52.7 (CH2 × 2), 51.2 (CH2 × 2), 32.40 (CH2), 32.37 (CH2), 29.8 (CH2), 29.5 (CH2), 29.4 (CH2), 27.6 (CH2), 26.2 (CH2 × 2), 25.9 (CH2 × 2), 24.4 (CH2), 24.3 (CH2), 22.58 (CH2), 22.56 (CH2), 14.1 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C39H51N4 575.4108, found 575.4104. Synthesis of Diaminopentacycle 6b via Buchwald−Hartwig Cross-Coupling of 4a. Title compound 6b (45 mg, 86%) was obtained from 4a (66 mg, 0.10 mmol), morpholine (26 μL, 0.30 mmol), Xphos (10 mg, 0.020 mmol), Pd2(dba)3 (5.0 mg, 0.005 mmol), KOtBu (45 mg, 0.24 mmol), and toluene (2 mL) using the general procedure for Buchwald−Hartwig coupling described for 6a as a yellow solid: mp 208.3−208.7 °C; IR (ATR): 3062, 2954, 2854, 1612, 1535, 1396 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.53 (d, J = 8.7 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.47 (dd, J = 8.7, 2.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.17 (dd, J = 8.7, 2.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.69 (s, 1H), 3.93 (t, J = 4.5 Hz, 8H), 3.28 (t, J = 4.5 Hz, 4H), 3.24 (t, J = 4.5 Hz, 4H), 2.87 (t, J = 8.0 Hz, 2H), 2.80 (t, J = 8.0 Hz, 2H), 1.75−1.64 (m, 4H), 1.55−1.38 (m, 8H), 0.96 (t, J = 6.9 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 148.1 (C), 147.5 (C), 145.6 (C), 141.3 (C), 137.5 (C), 130.5 (C), 129.9 (CH), 129.9 (C), 129.7 (C), 128.7 (C), 128.4 (CH), 126.1 (C), 122.5 (CH), 120.0 (C), 118.4 (CH), 114.6 (CH), 109.6 (CH), 105.9 (CH), 97.9 (CH), 67.2 (CH2 × 2), 66.9 (CH2 × 2), 51.2 (CH2 × 2), 49.9 (CH2 × 2), 32.39 (CH2), 32.38 (CH2), 29.7 (CH2), 29.6 (CH2), 29.4 (CH2), 27.7 (CH2), 22.57 (CH2), 22.55 (CH2), 14.09 (CH3), 14.07 (CH3); HRMS (ESI) (m/z) [M + H]+ calcd for C37H47N4O2 579.3694, found 579.3695. Synthesis of Diaminopentacycle 6c via Buchwald−Hartwig Cross-Coupling of 4a. Pentacycle 6c (63 mg, 86%) was obtained from 4a (66 mg, 0.10 mmol), diphenylamine (51 mg, 0.30 mmol), Xphos (10 mg, 0.020 mmol), Pd2(dba)3 (5.0 mg, 0.005 mmol), KOtBu (45 mg, 0.24 mmol), and toluene (2 mL) using the general procedure for Buchwald−Hartwig coupling described for 6a as a brown solid: mp 68.8−69.3 °C: IR (ATR) 3448, 3055, 2924, 2862, 1589, 1457, 1389 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.61 (d, J = 9.0 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.58−7.51 (m, 3H), 7.40−7.29 (m, 6H), 7.25−7.15 (m, 11H), 7.11 (td, J = 6.8, 1.3 Hz, 2H), 7.00 (td, J = 6.8, 1.3 Hz, 2H), 6.67 (s, 1H), 2.86 (tt, J = 7.5, 7.5 Hz, 4H), 1.80−1.63 (m, 4H), 1.57−1.39 (m, 8H), 0.97 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 148.6 (C × 2), 147.7 (C × 2), 146.2 (C), 144.5 (C), 142.8 (C), 142.4 (C), 137.7 (C), 131.3 (C), 130.8 (C), 130.1 (CH), 130.0 (C), 129.4 (CH × 4), 129.1 (C), 129.0 (CH × 4), 128.5 (CH), 128.2 (CH), 126.3 (C), 124.4 (CH × 4), 123.2 (CH × 4), 123.0 (CH), 122.0 (CH), 121.8 (CH), 120.9 (CH), 120.0 (C), 119.6 (CH), 118.8 (CH), 117.7 (CH), 116.9 (CH), 98.2 (CH), 32.35 (CH2), 32.29 (CH2), 29.8 (CH2), 29.5 (CH2), 29.4 (CH2), 27.6 (CH2), 22.6 (CH2), 22.5 (CH2), 14.1 (CH3 × 2); HRMS (ESI) (m/z) [M + Na]+ calcd for C53H51N4 743.4108, found 743.4103. Synthesis of 5-Phenylpentacycle 7b via Suzuki−Miyaura Cross-Coupling of 7a. To a toluene solution (0.4 mL) of Pd(dba)2 (1.5 mg, 0.0026 mmol) was added 1.0 M tBu3P in toluene (3 μL, 0.003 mmol). The mixture solution was stirred at room temperature for 10 min followed by addition of the mixture of bromide 7a (20.6 mg, 0.042 mmol), K3PO4 (55 mg, 0.26 mmol), and phenylboronic acid (19 mg, 0.16 mmol) and stirring for 9 h at 70 °C. The reaction mixture was quenched by addition of saturated aqueous ammonium dichloride, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/30) to give compound 7b (19 mg, 94%) as a yellow solid: the spectral data of 7b were identical to those reported in the literature.3a Synthesis of 2,5-Diphenylpentacycle 8b via Suzuki− Miyaura Cross-Coupling of 8a. A mixture of dibromide 8a (16 mg, 0.028 mmol), Pd(PPh3)4 (2.0 mg, 0.0017 mmol), phenylboronic acid (13 mg, 0.11 mmol), and 2 M aq K2CO3 (0.1 mL) in 1,4-dioxane (0.3 mL) was stirred at 90 °C for 6 h. The reaction mixture was 699

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

Article

The Journal of Organic Chemistry stirred for 12 h at 140 °C; then, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/1) to give 9b (11 mg, 92%) as a red solid: mp 134.9−135.1 °C; IR (KBr) 3062, 2947, 2924, 2862, 1697, 1612, 1581, 1550, 1496, 1450 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 8.1 Hz, 1H), 8.43−8.36 (m, 2H), 8.20 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.76 (td, J = 7.5, 1.3 Hz, 1H), 7.54 (td, J = 7.5, 0.8 Hz, 1H), 7.51 (td, J = 7.5, 0.8 Hz, 1H), 7.46 (td, J = 8.1, 0.8 Hz, 1H), 6.57 (d, J = 15.8 Hz, 1H), 3.87 (s, 3H), 3.07−2.92 (m, 4H), 1.84−1.58 (m, 8H), 1.51−1.40 (m, 4H), 1.00 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 168.2 (C), 146.0 (C), 139.34 (C), 139.30 (CH), 135.7 (C), 134.9 (C), 133.1 (C), 131.83 (C), 131.81 (CH), 130.9 (C), 130.2 (CH), 128.5 (C), 128.0 (CH), 127.9 (CH), 125.8 (C), 125.4 (CH), 124.4 (CH), 123.9 (CH), 119.9 (CH), 119.5 (C), 119.0 (CH), 109.0 (CH), 51.7 (CH3), 32.5 (CH2), 31.9 (CH2), 30.1 (CH2), 30.0 (CH2), 29.9 (CH2), 27.9 (CH2), 22.8 (CH2), 22.7 (CH2), 14.2 (CH3 × 2); HRMS (EI) (m/z) [M]+ calcd for C33H36N2O2 492.2771, found 429.2779. Synthesis of 2-Azido-5-iodobenzaldehyde 10e. To a dichloromethane suspension (150 mL) of PCC (4.9 g, 23 mmol) and Celite (10 g) was added a dichloromethane solution (20 mL) of (2-azido-5-iodophenyl)methanol (4.2 g, 15 mmol) at room temperature. After being stirred for 16 h, the suspension was filtered through a pad of silica (chloroform: 500 mL), and the filtrate was concentrated to remove the solvent in vacuo. The residue was recrystallized (chloroform/hexane) to give azidoaldehyde 10a (2.4 g, 58%) as a brown solid: mp 81.8−82.8 °C; IR (KBr) 3069, 2862, 2123, 1669, 1573, 1458, 1389, 1292, 1273, 1254 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 8.5, 2.2 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 187.2 (CHO), 143.9 (CH), 142.8 (C), 137.9 (CH), 128.4 (C), 121.1 (CH), 88.5 (C); HRMS (FAB) (m/z) [M + H]+ calcd for C7H5IN3O 273.9477, found 273.9475. Synthesis of Alkynyl Benzylalcohol 11e. To a THF solution (100 mL) of 1-heptyne (2.9 mL, 22 mmol) was added a 2.54 M hexane solution of n-butyllithium (8.1 mL, 21 mmol) at −78 °C. After being stirred for 1 h, a THF solution (5 mL) of 2-azido-5iodobenzaldehyde 10e (4.7 g, 17 mmol) was added. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/ hexane = 1/4) to give alkynyl azide 11e (6.2 g, 98%) as a yellow oil: IR (neat) 3386, 2931, 2862, 2129, 1473, 1296 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.3, 2.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.56 (brs, 1H), 2.52 (d, J = 5.7 Hz, 1H), 2.27 (dt, J = 8.7, 2.0 Hz, 2H), 1.57−1.50 (m, 2H), 1.44−1.27 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 138.0 (CH), 137.0 (CH, C), 134.1 (C), 119.9 (CH), 88.5 (C), 88.0 (C), 78.4 (C), 59.7 (CH), 30.9 (CH2), 28.0 (CH2), 22.1 (CH2), 18.7 (CH2), 13.9 (CH3); HRMS (ESI) (m/z) [M + Na]+ calcd for C14H16IN3ONa 392.0230, found 392.0227. Synthesis of Alkynyl Benzylalcohol 16. Alkynyl benzylalcohol 16 (5.7 g, 84%) was obtained from 15 (4.7 g, 21 mmol), 1-heptyne (3.6 mL, 27 mmol), 2.66 M hexane solution of n-butyllithium (9.5 mL, 25 mmol) and THF (100 mL) using the general procedure for the introduction of alkyne describing for 11e as a yellow oil: IR (neat) 3394, 3062, 2931, 2861, 2129, 1951 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.65 (dt, J = 7.6, 1.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.28−7.00 (m, 6H), 4.09 (t, J = 2.1 Hz, 1H), 2.25 (td, J = 7.2, 2.1 Hz, 2H), 1.52 (quintet, J = 7.2 Hz, 2H), 1.38−1.24 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 144.3 (C), 136.8 (C), 135.4 (C), 129.0 (CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.4 (CH), 126.3 (CH), 125.9 (CH), 124.4 (CH), 119.0 (CH), 88.4 (C), 81.8 (C), 73.6 (C), 30.9 (CH2), 28.1 (CH2), 22.0 (CH2), 18.8 (CH2), 13.8 (CH3); HRMS (ESI) (m/z) [M + Na]+ calcd for C20H21N3ONa 342.1577, found 342.1577. Synthesis of Azidopropargylbenzene 17 by Silane Reduction. To a dichloromethane solution (30 mL) of alcohol 16 (2.0 g,

6.2 mmol), ammonium fluoride (0.45 g, 12 mmol), and triethylsilane (2.0 mL, 12 mmol) was added a dichloromethane solution (10 mL) of trifluoroacetic acid (1.8 mL, 25 mmol) at −40 °C. After being stirred at −5 °C for 1 h, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give 17 (1.1 g, 57%) as a yellow oil: IR (neat) 3062, 2931, 2861, 2121, 1951 cm−1; 1 H NMR (300 MHz, CDCl3) δ 7.53 (dd, J = 7.7, 1.6 Hz, 1H), 7.39− 7.05 (m, 8H), 5.31 (t, J = 2.3 Hz, 1H), 2.26−2.18 (td, J = 7.0, 2.3 Hz, 2H), 1.58−1.25 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 141.7 (C), 136.9 (C), 133.7 (C), 129.6 (CH), 128.3 (CH × 2), 128.1 (CH), 127.7 (CH × 2), 126.6 (CH), 125.0 (CH), 118.0 (CH), 84.5 (C), 80.3 (C), 37.2 (CH), 31.1 (CH2), 28.6 (CH2), 22.2 (CH2), 18.8 (CH2), 14.0 (CH3); HRMS (ESI) (m/z) [M + Na]+ calcd for C20H21N3Na 326.1628, found 326.1625. Synthesis of Iminophosphorane 13a by Staudinger Reaction. A dichloromethane solution (5 mL) of triphenylphosphine (2.0 g, 7.7 mmol) was added to a dichloromethane solution (50 mL) of 12a (1.7 g, 7.0 mmol) at room temperature. After being stirred for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/10) to give iminophosphorane 13a (2.3 g, 72%) as colorless crystals: mp 105.6−107.3 °C; IR (KBr) 3055, 2954, 1589, 1481, 1358, 1103, 841, 748, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.80−7.72 (m, 6H), 7.54−7.48 (m, 3H), 7.48−7.40 (m, 7H), 6.79 (td, J = 7.5, 1.2 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.41 (d, J = 7.7 Hz, 1H), 3.95 (s, 2H), 0.15 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 148.9 (C), 132.7 (CH × 6, d, J = 9.8 Hz), 131.71 (CH × 3, d, J = 2.6 Hz), 131.69 (C × 3, d, J = 99.3 Hz), 130.6 (C, d, J = 22.5 Hz), 128.7 (CH × 6, d, J = 12.4 Hz), 128.2 (CH, d, J = 2.1 Hz), 126.8 (CH), 120.5 (CH, d, J = 9.8 Hz), 117.4 (CH), 107.3 (C), 85.9 (C), 23.8 (CH2), 0.42 (CH3 × 3); HRMS (ESI) (m/z) [M + H]+ calcd for C30H31NPSi 464.1958, found 464.1964. Synthesis of Iminophosphorane 13e by Staudinger Reaction. To a dichloromethane solution (100 mL) of alcohol 11e (6.2 g, 17 mmol), ammonium fluoride (1.3 g, 34 mmol), and triethylsilane (5.4 mL, 34 mmol) was added a dichloromethane solution of trifluoroacetic acid (5.2 mL, 68 mmol) at −40 °C. After being stirred at −5 °C for 1 h, the reaction mixture was quenched by addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give 12e (4.2 g, 12 mmol). A dichloromethane solution (10 mL) of triphenylphosphine (3.4 g, 13 mmol) was added to a dichloromethane solution (50 mL) of 12e (4.2 g, 12 mmol) at room temperature. After being stirred for 1 h, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/8) to give iminophosphorane 13e (6.7 g, 68% in 2 steps) as a brown solid: mp 98.2−98.8 °C; IR (KBr) 3054, 2931, 2862, 1566, 1466 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.77−7.69 (m, 7H), 7.47−7.35 (m, 9H), 7.00 (dd, J = 8.4, 2.3 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 3.84 (s, 2H), 2.21 (tt, J = 7.2, 2.3 Hz, 2H), 1.54−1.27 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.7 (C), 136.7 (CH, d, J = 1.9 Hz), 135.3 (CH), 134.8 (C, d, J = 22.0 Hz), 132.6 (CH × 6, d, J = 9.6 Hz), 131.9 (CH × 3, d, J = 2.4 Hz), 131.1 (C × 3, d, J = 98.5 Hz), 128.8 (CH × 6, d, J = 11.9 Hz), 122.3 (CH, d, J = 9.3 Hz), 83.0 (C), 79.0 (C), 78.7 (C), 31.3 (CH2), 29.0 (CH2), 22.4 (CH2), 22.3 (CH2), 19.1 (CH2), 14.2 (CH3); HRMS (ESI) (m/z) [M + H]+ calcd for C32H32INP 588.1312, found 588.1312. Synthesis of Iminophosphorane 14a by Deprotection. A methanol solution (30 mL) of iminophosphorane 13a (2.9 g, 6.3 mmol) and K2CO3 (175 mg, 12.6 mmol) was stirred at room temperature for 4 h. Then, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4) to give iminophosphorane 14a 700

DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

Article

The Journal of Organic Chemistry

4), 128.1 (CH × 2), 128.0 (CH × 2), 125.9 (CH × 2), 124.9 (CH × 2), 123.8 (C × 2), 87.1 (C × 2), 83.1 (C × 2), 22.5 (CH2 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C31H23N2 423.1856, found 423.1856. Synthesis of Carbodiimides 1e by aza-Wittig Reaction. Title compound 1e (1.8 g, 79%) was obtained from iminophsophorane 13e (4.0 g, 6.8 mmol) and dichloromethane (10 mL) using the general procedure for aza-Wittig reaction described for 1a as a yellow oil: IR (neat) 2931, 2862, 2152, 1473 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 1.8 Hz, 2H), 7.46 (dd, J = 8.2, 1.8 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.57 (s, 4H), 2.19 (tt, J = 7.0, 2.4 Hz, 4H), 1.51 (quintet, J = 7.0 Hz, 4H), 1.41−1.25 (m, 8H), 0.91 (t, J = 7.0 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 138.1 (CH × 2), 136.5 (CH × 2), 135.6 (C × 2), 134.1 (C × 2), 132.4 (C), 126.2 (CH × 2), 89.9 (C × 2), 84.0 (C × 2), 75.8 (C × 2), 31.1 (CH2 × 2), 28.6 (CH2 × 2), 22.2 (CH2 × 2), 21.4 (CH2 × 2), 18.8 (CH2 × 2), 14.0 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C29H33I2N2: 663.0728, found 663.0725. Synthesis of Carbodiimide 1f. To a dichloromethane solution (10 mL) of urea 19 (0.77 g, 1.3 mmol), triphenylphosphine (0.52 g, 2.0 mmol), and triethylamine (46 mL, 3.3 mmol) was added a dichloromethane solution (1 mL) of carbon tetrabromide (0.79 g, 1.4 mmol). After being stirred for 4 h, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/hexane = 1/2) to give 1f (0.73 g, 98%) as a yellow oil: IR (neat) 3062, 3024, 2931, 2861, 2114, 1581, 1481 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.57−7.54 (m, 2H), 7.42−7.40 (m, 4H), 7.26 (t, J = 7.3 Hz, 4H), 7.19−7.10 (m, 6H), 7.03−7.00 (m, 2H), 5.52 (s, 2H), 2.25 (td, J = 7.0, 2.1 Hz, 4H), 1.54 (quintet, J = 7.0 Hz, 4H), 1.41−1.26 (m, 8H), 0.89 (t, J = 7.0 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 141.9 (C × 2), 136.4 (C × 2), 135.7 (C × 2), 134.1 (C), 129.3 (CH × 2), 128.3 (CH × 4), 127.9 (CH × 2), 127.8 (CH × 4), 126.5 (CH × 2), 125.8 (CH × 2), 125.0 (CH × 2), 84.6 (C × 2), 80.5 (C × 2), 38.3 (CH × 2), 31.1 (CH2 × 2), 28.6 (CH2 × 2), 22.2 (CH2 × 2), 18.9 (CH2 × 2), 14.0 (CH3 × 2); HRMS (ESI) (m/z) [M + H]+ calcd for C41H43N2 563.3421, found 563.3421.

(1.1 g, 46%) as colorless crystals: mp 74.8−76.5 °C; IR (KBr) 3294, 3054, 3016, 2113, 1589, 1481, 1180, 1056, 848 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.80−7.71 (m, 6H), 7.56−7.41 (m, 10H), 6.80 (td, J = 7.5, 1.7 Hz, 1H), 6.68 (td, J = 7.4, 0.9 Hz, 1H), 6.43 (dd, J = 7.7, 1.0 Hz, 1H), 3.91 (d, J = 2.7 Hz, 2H), 2.14 (t, J = 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.6 (C), 132.3 (CH × 6, d, J = 9.5 Hz), 131.5 (CH × 3, d, J = 2.5 Hz), 131.0 (C × 3, d, J = 99.5 Hz), 130.0 (C, d, J = 22.4 Hz), 128.4 (CH × 6, d, J = 12.0 Hz), 127.9 (CH, d, J = 1.7 Hz), 126.7 (CH), 120.2 (CH, d, J = 10.0 Hz), 117.2 (CH), 84.0 (C), 69.8 (CH), 21.9 (CH2); HRMS (ESI) (m/z) [M + H]+ calcd for C27H23NP 392.1563, found 392.1556. Synthesis of Propargylaniline 18. To a THF solution (50 mL) of lithium aluminum hydride (0.66 g, 17 mmol) was slowly added a THF solution (20 mL) of alkynyl azide 17 (2.1 g, 6.9 mmol) at 0 °C. After being stirred for 30 min, the reaction mixture was quenched by the addition of water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4) to give 18 (1.6 g, 82%) as a yellow oil: IR (neat) 3448, 3370, 3062, 2931, 2861, 1619 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.4 Hz, 2H), 7.47−7.42 (m, 2H), 7.38 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 5.14 (s, 1H), 3.87 (brs, 2H), 2.42 (dt, J = 7.0, 2.1 Hz, 2H), 1.71 (sx, J = 7.0 Hz, 2H), 1.58−1.45 (m, 4H), 1.07 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 144.1 (C), 140.1 (C), 129.3 (CH), 128.4 (CH × 2), 127.8 (CH), 127.7 (CH × 2), 126.7 (CH), 126.1 (C), 118.4 (CH), 116.5 (CH), 85.4 (C), 79.1 (C), 39.6 (CH), 31.0 (CH2), 28.5 (CH2), 22.0 (CH2), 18.8 (CH2), 13.9 (CH3); HRMS (ESI) (m/z) [M + Na]+ calcd for C20H23NNa 300.1723, found 300.1720. Synthesis of Urea 19. To a THF solution (10 mL) of alkynylaniline 18 (2.3 g, 8.4 mmol) and triethylamine (2.6 mL, 18 mmol) was added triphosgene (0.42 g, 1.4 mmol). After being stirred for 1 h at 60 °C, the reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/10) to give 19 (2.2 g, 92%) as a yellowish oil: IR (neat) 3309, 3062, 2931, 2861, 1951, 1681 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.42 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.1 Hz, 2H), 7.23−7.12 (m, 14H), 6.58 (d, J = 10.0 Hz, 2H), 4.98 (brs, 2H), 2.11− 2.02 (m, 4H), 1.48−1.40 (m, 4H), 1.34−1.22 (m, 8H), 0.86 (t, J = 7.0 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 153.8 (C), 139.9 (C × 2), 135.4 (C × 2), 135.1 (C × 2), 129.2 (CH × 2), 128.5 (CH × 4), 128.0 (CH × 2), 127.6 (CH × 4), 126.8 (CH × 2), 126.2 (CH × 2), 125.6 (CH × 2), 85.9 (C), 85.8 (C), 79.03 (C), 78.97 (C), 39.4 (CH × 2), 31.1 (CH2 × 2), 28.4 (CH2 × 2), 22.0 (CH2 × 2), 18.7 (CH2 × 2), 13.9 (CH3 × 2); HRMS (ESI) (m/z) [M + Na]+ calcd for C41H44N2ONa 603.3346, found 603.3348. Synthesis of Carbodiimides 1a by aza-Wittig Reaction. A dichloromethane solution (10 mL) of iminophosphorane 14a (780 mg, 2.0 mmol) was degassed and charged with carbon dioxide using a balloon and stirred for 10 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/chloroform = 2/1) to give carbodiimide 1a (162 mg, 60%) as a colorless oil: IR (neat) 3286, 3062, 2159, 2113, 1581, 1488, 1172, 1095 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 2H), 7.26−7.24 (m, 4H), 7.24−7.18 (m, 2H), 3.74 (d, J = 2.7 Hz, 4H), 2.25 (t, J = 2.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 136.2 (C × 2), 133.6 (C), 130.2 (C × 2), 129.2 (CH × 2), 127.9 (CH × 2), 125.7 (CH × 2), 124.7 (CH × 2), 81.3 (C × 2), 70.8 (CH × 2), 21.2 (CH2 × 2); HRMS (ESI) (m/z) [M + Na]+ calcd for C19H14N2Na 293.1049, found 293.1049. Synthesis of Carbodiimides 1d by aza-Wittig Reaction. Title compound 1d (211 mg, 69%) was obtained from iminophsophorane 13d (468 mg, 1.0 mmol) and dichloromethane (10 mL) using the general procedure for aza-Wittig reaction described for 1a as a colorless oil: IR (neat) 3062, 3024, 2893, 2188, 1581, 1488, 1218, 1172, 1095, 840 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66−7.61 (m, 2H), 7.51−7.44 (m, 4H), 7.36−7.26 (m, 8H), 7.23−7.16 (m, 4H), 3.96 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 136.6 (C × 2), 133.8 (C), 131.8 (CH × 4), 131.1 (C × 2), 129.6 (CH × 2), 128.4 (CH ×

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02674. Copies of 1H and 13C NMR spectra, UV−vis and fluorescence spectra, X-ray crystallographic data, and DFT data (PDF) X-ray crystallographic data for compound 4b (CCDC: 1574644) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ryota Sakamoto: 0000-0002-8702-1378 Noriki Kutsumura: 0000-0002-1494-2133 Hidetoshi Kawai: 0000-0002-3367-0153 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant 16J08668. REFERENCES

(1) For recent reviews on metal-catalyzed cycloadditions in N-fused heterocycles, see: (a) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W.

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DOI: 10.1021/acs.joc.7b02674 J. Org. Chem. 2018, 83, 690−702

Article

The Journal of Organic Chemistry Chem. Rev. 2015, 115, 1622. (b) Majumdar, K. C.; De, N.; Ghost, T. Tetrahedron 2014, 70, 4827. (c) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (e) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (2) For organic electronic compounds: (a) Li, J.; Zhang, Q. ACS Appl. Mater. Interfaces 2015, 7, 28049. (b) Suzuki, Y.; Yokoyama, K. Biosensors 2015, 5, 337. (c) Mateo-Alonso, A. Chem. Soc. Rev. 2014, 43, 6311 For molecular probes:. (d) Carter, K. P.; Young, A. M.; Palmer, A. E. Chem. Rev. 2014, 114, 4564. (e) Bunz, U. H. F.; Engelhart, J. U.; Lindner, B. D.; Schaffroth, M. Angew. Chem., Int. Ed. 2013, 52, 3810 For biological active compounds:. (f) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421. (g) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (h) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488. (i) Kaila, N.; Janz, K.; DeBernardo, S.; Bedard, P. W.; Camphausen, R. T.; Tam, S.; Tsao, D. H. H.; Keith, J. C., Jr.; Nickerson-Nutter, C.; Shilling, A.; Young-Sciame, R.; Wang, Q. J. Med. Chem. 2007, 50, 21. (3) (a) Tateno, K.; Ogawa, R.; Sakamoto, R.; Tsuchiya, M.; Otani, T.; Saito, T. Org. Lett. 2014, 16, 3215. (b) Otani, T.; Saito, T.; Sakamoto, R.; Osada, H.; Hirahara, A.; Furukawa, N.; Kutsumura, N.; Matsuo, T.; Tamao, K. Chem. Commun. 2013, 49, 6206. (4) (a) Li, S.-S.; Liu, C.-F.; Zhang, G.-T.; Xia, Y.-Q.; Li, W.-H.; Dong, L. Chem. - Asian J. 2017, 12, 415. (b) Kumar, K. S.; Bhaskar, B.; Ramulu, M. S.; Kumar, N. P.; Ashfaq, M. A.; Pal, M. Org. Biomol. Chem. 2017, 15, 82. (c) Morioka, R.; Nobushige, K.; Satoh, T.; Hirano, K.; Miura, M. Org. Lett. 2015, 17, 3130. (d) Shoker, T. A.; Ghattass, K. I.; Fettinger, J. C.; Kurth, M. J.; Haddadin, M. J. Org. Lett. 2012, 14, 3704. (e) Hachiya, S.; Hashizume, D.; Maki, S.; Niwa, H.; Hirano, T. Tetrahedron Lett. 2010, 51, 1401. (f) Volovnenko, T. A.; Turov, A. V.; Volovenko, Y. M. Chem. Heterocycl. Compd. 2009, 45, 1489. (g) Ahmed, E.; Briseno, A. L.; Xia, Y.; Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118. (h) Litvinenko, S. V.; Volovenko, Y. M.; Babichev, F. S. Chem. Heterocycl. Compd. 1993, 29, 194. (i) Litvinenko, S. V.; Volovenko, Y. M.; Babichev, F. S. Chem. Heterocycl. Compd. 1992, 28, 1307. (5) Hahn, S.; Geyer, F. L.; Koser, S.; Tverskoy, O.; Rominger, F.; Bunz, U. H. F. J. Org. Chem. 2016, 81, 8485. (6) (a) Otani, T.; Tsuyuki, A.; Iwachi, T.; Someya, S.; Tateno, K.; Kawai, H.; Saito, T.; Kanyiva, K. S.; Shibata, T. Angew. Chem., Int. Ed. 2017, 56, 3906. (b) Zhang, X.; Clennan, E. L.; Arulsamy, N.; Weber, R.; Weber, J. J. Org. Chem. 2016, 81, 5474. (c) Sakamaki, D.; Kumano, D.; Yashima, E.; Seki, S. Angew. Chem., Int. Ed. 2015, 54, 5404. (d) Nakamura, K.; Furumi, S.; Takeuchi, M.; Shibuya, T.; Tanaka, K. J. Am. Chem. Soc. 2014, 136, 5555. (e) Suzuki, T.; Sakano, Y.; Tokimizu, Y.; Miura, Y.; Katoono, R.; Fujiwara, K.; Yoshioka, N.; Fujii, N.; Ohno, H. Chem. - Asian J. 2014, 9, 1841. (f) Chocholoušová, J. V.; Vacek, J.; Andronova, A.; Míšek, J.; Songis, O.; Š ámal, M.; Stará, I. G.; Meyer, M.; Bourdillon, M.; Pospíšil, L.; Starý, I. Chem. - Eur. J. 2014, 20, 877. (g) Kaneko, E.; Matsumoto, Y.; Kamikawa, K. Chem. Eur. J. 2013, 19, 11837. (7) (a) Biegger, P.; Tverskoy, O.; Rominger, F.; Bunz, U. H. F. Chem. - Eur. J. 2016, 22, 16315. (b) Jahng, Y.; Karim, M. Tetrahedron 2016, 72, 199. (c) Li, J.; Zhang, Q. ACS Appl. Mater. Interfaces 2015, 7, 28049. (d) Miao, Q. In Polycyclic Arenes and Heteroarenes: Synthesis Properties, and Applications; Lakshminarayana, A. N., Chi, C., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA, 2015; Chapter 9. (e) Wang, C.; Zhang, J.; Long, G.; Aratani, N.; Yamada, H.; Zhao, Y.; Zhang, Q. Angew. Chem., Int. Ed. 2015, 54, 6292. (f) Bunz, U. H. F. Acc. Chem. Res. 2015, 48, 1676. (g) Miao, Q. Adv. Mater. 2014, 26, 5541. (8) Recent reviews on partially intramolecular hetero [2 + 2 + 2] cycloaddition, see: (a) Jungk, P.; Täufer, T.; Thiel, I.; Hapke, M. Synthesis 2016, 48, 2026. (b) Satoh, Y.; Obora, Y. Eur. J. Org. Chem. 2015, 2015, 5041. (c) Amatore, M.; Aubert, C. Eur. J. Org. Chem. 2015, 2015, 265. (d) Yamamoto, Y. Heterocycles 2013, 87, 2459. (e) Dominguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2011, 40, 3430. (f) Ishii, M.; Mori, F.; Tanaka, K. Chem. - Eur. J. 2014, 20, 2169. (g) Young, D. D.; Teske, J. A.; Deiters, A. Synthesis 2009, 2009, 3785.

(h) Young, D. D.; Deiters, A. Angew. Chem., Int. Ed. 2007, 46, 5187. (i) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 3262. (9) The examples of fully intramolecular hetero [2 + 2 + 2] cycloaddition were limited to only nitrile-diynes type. For recent reviews on fully intramolecular hetero [2 + 2 + 2] cycloaddition, see: (a) Okamoto, S.; Sugiyama, Y. Synlett 2013, 24, 1044. (b) Broere, D. L. J.; Ruijter, E. Synthesis 2012, 44, 2639. (c) Tanaka, K. Heterocycles 2012, 85, 1017. (d) Weding, N.; Hapke, M. Chem. Soc. Rev. 2011, 40, 4525. (e) Li, S.; Zhou, L.; Kanno, K.; Takahashi, T. J. Heterocycl. Chem. 2011, 48, 517. (f) Perreault, S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149. (10) (a) Hirota, S.; Kato, R.; Suzuki, M.; Soneta, Y.; Otani, T.; Saito, T. Eur. J. Org. Chem. 2008, 2008, 2075. (b) Saito, T.; Ohkubo, T.; Kuboki, H.; Maeda, M.; Tsuda, K.; Karakasa, T.; Satsumabayashi, S. J. Chem. Soc., Perkin Trans. 1 1998, 1, 3065. (c) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron Lett. 1996, 37, 209. (11) For Mo(CO)6-promoted P−K reactions of carbodiimides, see: (a) Saito, T.; Shiotani, T.; Otani, T.; Hasaba, S. Heterocycles 2003, 60, 1045 For Rh(I)-catalyzed P−K reactions of carbodiimides with carbon monoxide, see:. (b) Saito, T.; Furukawa, N.; Otani, T. Org. Biomol. Chem. 2010, 8, 1126. (c) Saito, T.; Sugizaki, K.; Otani, T.; Suyama, T. Org. Lett. 2007, 9, 1239. (12) (a) Shaya, J.; Fontain-Vine, F.; Michel, B. Y.; Burger, A. Chem. Eur. J. 2016, 22, 10627. (b) Niko, Y.; Kawauchi, S.; Konishi, G. Chem. - Eur. J. 2013, 19, 9760. (13) (a) Kutsumura, N.; Koyama, Y.; Tateno, K.; Yamamoto, N.; Nagase, H.; Saito, T. Chem. Pharm. Bull. 2016, 64, 1364. (b) Kimura, H.; Torikai, K.; Ueda, I. Chem. Pharm. Bull. 2009, 57, 393. (14) The [2 + 2 + 2] cycloaddition from carbodiimide 1f gave a mixture of 3 and 3′ without the starting material or other byproducts. (15) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735. (16) Crystal data of 4b: MF C41H40N2, FW 560.78, monoclinic P21/ c, a = 12.3768(2), b = 8.25551(15), c = 30.2129(6) Å, α = 90, β = 98.416(7), γ = 90°, V = 3053.81(11) Å3, ρ(Z = 4) = 1.220 g cm−3, T = 123 K, R = 6.5%. CCDC1574644. See Supporting Information for crystallographic data in CIF. (17) Stokes shift values: 2a, 1049; 2b, 1527; 2c, 1296; 2d, 1395; 4b, 1353; 7b, 1578; 8b, 1585; and 3, 3144 cm−1. (18) (a) Spartan’16; Wavefunction, Inc.: Irvine, CA, 2016. (b) Spartan’14; Wavefunction, Inc.: Irvine, CA, 2014. (19) (a) Zhang, Z.; Wu, Y.-S.; Tang, K.-C.; Chen, C.-L.; Ho, J.-W.; Su, J.; Tian, H.; Chou, P.-T. J. Am. Chem. Soc. 2015, 137, 8509. (b) Yuan, C.; Saito, S.; Camacho, C.; Irle, S.; Hisaki, I.; Yamaguchi, S. J. Am. Chem. Soc. 2013, 135, 8842. (20) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500. (21) Grisanti, L.; D’Avino, G.; Painelli, A.; Guasch, J.; Ratera, I.; Veciana, J. J. Phys. Chem. B 2009, 113, 4718. (22) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884. (23) Sabbatini, P.; Wellendorph, P.; Høg, S.; Pedersen, M. H. F.; Bräuner-Osborne, H.; Martiny, L.; Frølund, B.; Clausen, R. P. J. Med. Chem. 2010, 53, 6506.

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