Synthesis of Unsymmetrical Aza-Ullazines by Intramolecular Alkynyl

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 122−125

Synthesis of Unsymmetrical Aza-Ullazines by Intramolecular AlkynylCarbonyl Metathesis Silvio Parpart,† Sebastian Boldt,† Peter Ehlers,*,†,‡ and Peter Langer*,†,‡ †

Universität Rostock, Institut für Chemie, A.-Einstein-Str. 3a, 18059 Rostock, Germany Leibniz-Institut für Katalyse e.V. an der Universität Rostock, A.-Einstein-Str. 29a, 18059 Rostock, Germany

‡

S Supporting Information *

ABSTRACT: A variety of aza-ullazines were synthesized in one step from readily accessible 3,5-dialkynyl-4-pyrrolopyridine via acylation followed by intramolecular alkynyl carbonyl metathesis. The reaction conditions were optimized, and the preparative scope was studied. The optoelectronic properties of selected aza-ullazines were studied by UV/vis and fluorescence spectroscopy.

P

Scheme 2. Starting Material Synthesis13

olycyclic heteroaromatic (PHA) core structures are of considerable current interest in organic chemistry.1 In

Scheme 1. Proposed Reaction Mechanism for AlkynylCarbonyl Metathesis

Scheme 3. Optional Isolation of Intermediate 4

synthesized and characterized by Balli and Zeller in 1983, who were searching for synthetic dyes.7 Other synthetic approaches were reported in the last two decades, including different benzannulation reactions catalyzed by CrCl3,8 InCl3,9 Pd(OAc)2,10 or Rh-6G.11 Delcamp et al.9 as well as Tan et al.12 tested ullazines in dye-sensitive solar cells and achieved up to 8.4% power conversion efficiency. On this basis, our group reported the first synthesis of aza-ullazines by paratoluenesulfonic acid (pTSA)-mediated benzannulation of 3,5dialkynyl-4-pyrrolopyridine.13 Just recently, Pierrat et al.

Figure 1. Previous work and this work.

particular, nitrogen-containing heterocycles are found in many biologically active compounds and pharmaceuticals.2 The interaction between polycyclic aromatics and DNA is well investigated. While many compounds can promote the generation of cancer, some other molecules were found to inhibit carcinogenesis.3 An important field of interest is the employment of PHAs as organic materials with possible applications as field-effect transistors,4 light-emitting diodes,5 and photovoltaics.6 Ullazine is a PHA containing a conjugated 16π-system with one nitrogen atom, isoelectronic to pyrene. It was first © 2017 American Chemical Society

Received: November 9, 2017 Published: December 12, 2017 122

DOI: 10.1021/acs.orglett.7b03477 Org. Lett. 2018, 20, 122−125

Letter

Organic Letters Table 1. Optimization of the Synthesis of 5a

additives (equiv) AlCl3 (1) PtCl3 (1) InCl3 (1) H2SO4 (0.1) FeCl3 (1) NiCl2 (1) CuI (0.5) CuI (1.0) CuI (2.0) CuBr2 (1) AgCl (1) AuCl3 (1) Na2CO3 (0.5) K2CO3 (0.5) K(OAc) (1)

Ag2CO3 (0.5), K2CO3 (0.5) Ag2CO3 (0.5), K2CO3 (2.5) Ag2CO3 (0.5), K2CO3 (2.5) Cu2CO3(OH)2 (0.5), K2CO3 (2.5)

Table 2. Synthesized Derivatives Using TFAA

solvent

temp (°C)

time (h)

yield (%)

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DMF DMA Cl2C6H4 toluene toluene Cl2C6H4 Cl2C6H4

120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 150 160 170 120 120 170 170

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 1 1 1 4 4 1 1

traces traces traces 8 19 25 29 9 23 29 24 34 48 22 22 20 traces traces 18 54 68 75 68

published a microwave-assisted protocol to synthesize symmetric aza-ullazines.14 During our studies on aza-ullazines, we observed that, in the presence of trifluoroacetic anhydride (TFAA), a nonsymmetrical aza-ullazine is formed by alkynyl-carbonyl metathesis (ACM) reaction. While the olefin metathesis reaction is well studied,15 examples for the ACM are still rare. One of the first intermolecular ACM was reported in 1995 by Hayashi et al. using SbF5 as catalyst.16 Meanwhile, other procedures using Yb(OTf)2,17 In(OTf)3,18 FeCl3,19 and BF3·OEt220 have been reported. The use of aldehydes and the need for Lewis acids are common for all these intermolecular reactions. For the intramolecular ACM, ketones can be used as starting materials, as well. Examples include AuCl3,21 AgSbF6,21 CuSO4,22 FeCl3,23 TfOH,24 and TFA25 catalyzed reactions. The reaction mechanism is considered as a formal [2 + 2] cycloaddition, followed by cycloreversion, whereby the presence of a Lewis acid is essential (Scheme 1).21a In the present work, we report a new synthesis of unsymmetrical aza-ullazines by ACM starting from 3,5dialkynyl-4-pyrrolopyridines. The reaction relies on trifluoroacetylation using TFAA, followed by intramolecular ACM in one step (Figure 1). The starting materials 3a−m were synthesized in three steps from commercially available 4-aminopyridine according to our previously published procedure (Scheme 2).13 The reaction of 3a−m with TFAA was next studied. TFAA reacts at increased temperature (70 °C) with 3a to yield the trifluoroacetylated

Figure 2. X-ray structure of 5c.

intermediate 4 in excellent yield (Scheme 3). When the temperature was increased to 170 °C, we observed a cyclization to give aza-ullazine 5a formed by a ACM process. While the acylation could be done with stoichiometric amounts of TFAA, the use of an excess (15 equiv) is crucial to perform the subsequent ACM. To find optimal conditions for the synthesis of 5a by a one-step protocol, various additives were studied (Table 1). First, the influence of different Lewis acids was tested. It turned out that NiCl2, FeCl3, and CuI 123

DOI: 10.1021/acs.orglett.7b03477 Org. Lett. 2018, 20, 122−125

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Organic Letters Table 3. Synthesized Derivatives Using Other Anhydrides

Figure 3. Absorption (solid lines) and emission (dashed lines) spectra of 5g (red), 6d (green), 6g (blue), and 7 (black).

Scheme 5. Previously Published Aza-Ullazine 713

Scheme 4. Friedel−Crafts Acylation Followed by ACM was found that the electronic properties of the alkynyl groups strongly influence the yield. Electron-donating groups (2methyl-4-methoxyphenyl, 4-methoxyphenyl; products 5f,g) gave very good to excellent yields, while electron-withdrawing groups (2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl; products 5h−j) gave only moderate yields. Strongly electrondeficient alkynyl groups (3-trifluoromethylphenyl 5k) as well as aliphatic alkynes (cyclopropyl, n-hexyl; products 5l,m) did not react at all. The structure of compound 5c was independently confirmed by X-ray crystal structure analysis (Figure 2). The aza-ullazine core is planar with the tolyl groups twisted out of plane. The replacement of TFAA by other anhydrides was tested, as well. It was observed that the reaction of 3a with other electron-deficient anhydrides proceeds smoothly, and products 6a−e were synthesized in good to excellent yield (Table 3). Less electron-deficient anhydrides react not directly with 3a. Strong Lewis acids (like commonly used BF3) are needed to activate them but lead to decomposition of the starting material at high temperature. Thus, we decided to perform the acylation for such examples in a separate reaction step. The reaction of 3d,g with acetic anhydride and BF3·OEt2 at 0 °C yielded the acylated intermediates, which were isolated as inseparable mixtures of regioisomeric 2-acetylpyrrole (main product) and 3-acetylpyrrole (side product) in moderate yields (54−59%). In a subsequent ACM, the less electron-deficient intermediates did not cyclize under TFAA and Cu+ mediation. To our delight, the replacement of TFAA by pTSA with Ag2CO3 converted both intermediates to the aza-ullazines 6f,g in 41 and 87% yield (25− 47% overall yield for both steps; Scheme 4). Finally, UV/vis and emission properties for 5a, 5g, 5i, 6d, and 6g were studied. Compounds with different aryl groups (5a,g,i) show similar optoelectronic properties: the absorption maxima are around 390 nm and show one fluorescence maximum around 600 nm. Fluorescence quantum yields are in the range of 7.0−8.4% (Table 3 and Supporting Information). In contrast, different alkyl groups (5g, 6d,g) significantly

Table 4. Absorption and Emission Data* 5a λabs,1 [nm] λabs,2 [nm] λabs,3 [nm] ε390 nmb λem,1 [nm] λem,2 [nm] Stokes shift [cm−1] ϕ [%]c

5g

5i a

6d a

6g

a

7

351 375a 390 14030 604

352 375a 390 11060 600

352 375 390 9580 605

355 374 392 11970 603

373a 386 11820 574

9085

8974

9112

8927

8485

352a 375a 391 8830 516 550 6196

8.4

8.0

7.0

5.7

10.4

6.5

*

Solvent of all samples was DCM. aShoulder. bExtinction in L mol−1 cm−1. cPerylene in cyclohexane as standard (ϕ = 94%).

moderately increased the yield, while AgCl and AuCl3 increased the yield more significantly. Nevertheless, stoichiometric amounts of the Lewis acids are required to get acceptable yields. This is especially problematic for the expensive gold salts. Thus, we focused on easily available copper and silver salts for further optimization. Next, we tested different bases and found that the presence of base can improve the yield, as well. We propose that the formation of a TFA anion is responsible for the increased yield. Polar solvents, like DMF or DMA, resulted in side reactions, while 1,2-dichlorobenzene gave good results at elevated temperatures. The optimized reaction conditions were successfully applied for the synthesis of aza-ullazines 5a−j from 3a−m (Table 2). It 124

DOI: 10.1021/acs.orglett.7b03477 Org. Lett. 2018, 20, 122−125

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Organic Letters

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change the optical properties: when the CF3 group is replaced by a methyl group, the fluorescence maxima are blue-shifted and the quantum yield increases to 10.4% for 6g (Table 4 and Figure 3). Compared to the previously synthesized symmetrical aza-ullazine 7,13 compounds 5a,g,i show higher quantum yields and bathochromically shifted fluorescence maxima (Scheme 5 and Figure 3). In conclusion, we showed a simple synthetic pathway to build up aza-ullazines via ACM in good to excellent yields. Various aryl as well as alkyl groups can be attached to the azaullazine core. The compounds are fluorescent with emission maxima around 600 nm and quantum yields up to 10.4%.

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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.orglett.7b03477. Experimental procedures, Sonogashira derivatives and yields, analytical data, 1H, 13C, and 19F NMR spectra, Xray crystal structure data for 5c, absorption and emission spectra for 5a,g,i, 6d,g, and 7 (PDF) Accession Codes

CCDC 1557186 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

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

Peter Langer: 0000-0002-7665-8912 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the State of Mecklenburg-Vorpommern is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03477 Org. Lett. 2018, 20, 122−125