Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Approach to Introducing Substituent on the Dipole Conjugate Chain: The D−π−A Methine Chain Electrophilic Substitution Lanying Wang,*,†,§ Mengqi Yan,†,§ Borui Zhang,‡ Junlong Zhao,† Wenting Deng,† Wenxia Lin,† and Li Guan† †
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi’an 710127, P. R. China ‡ Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States S Supporting Information *
ABSTRACT: The D−π−A methine chain electrophilic substitution reactions for directly introducing some functional groups to the dipole conjugate chain, with mild conditions and good yields, are disclosed. This method is shown to efficiently replace the hydrogen on the D−π−A methine chain with an electrophile to synthesize methine-substituted Cy3.5 in one step.
T
S1, Supporting Information (SI)). The C-terminus of the enamine, that is, the α- or γ-position of the D−π−A methine chain for Cy3.5, has nucleophilic reactivity, which can react with electrophile followed by loss of a proton to restore the D−π−A conjugated structure and to give methine-substituted Cy3.5. Below, we will examine the reaction of the D−π−A methine chain of Cy3.5 and several common types of electrophiles. Electrophilic aromatic halogenations using preformed halogen sources, such as N-halosuccinimides (NXS), are one of the most common methods to make aryl halides.8 Initially, we investigated the influence of different temperatures and solvents on the D−π−A methine chain chlorination of CH3−Cy3.5 (1a) using NCS as halogenating reagent. The reaction of 1a with NCS at varying temperatures of 0−35 °C (Table 1, entries 1−8) in CH2Cl2 offered α-chloro-CH3−Cy3.5 (2aa) in good yields (70− 91%), and an excellent yield (91%) was obtained at 20 °C (Table 1, entry 5). Meanwhile, the yield of the product in various solvents (Table 1, entries 9−15) was screened for this reaction. As a result, a high yield of 2aa could be obtained in CH2Cl2, CHCl3, or ClCH2CH2Cl. The reaction was mild, and the purification could be carried out quickly by silica gel column chromatography. We were very fortunate to purify and verify 2aa by NMR, HRMS, and single crystal X-ray (Figure S2, SI). In order to explore the generality of this reaction, various halogenating reagents were also used instead of NCS. Optimal results are shown in Scheme 1. The reaction of 1a or 1b with chloride reagents NCS, SOCl2, or SO2Cl2 proceeded smoothly in CH2Cl2 at 10−20 °C to afford 2aa and 2ba in 53−91% and 51− 90% yields, respectively. When bromide reagents (NBS, Br2),
he introduction of substituents on the D−π−A methine chain could significantly change the properties of cyanine molecules.1 For example, introducing cyano to the α-position of the methine chain on trimethincyanines provided resistance to photo-oxidative damage, retained high affinity protein-dye binding, and created new protein-dye fluoromodules.2 Introducing substituted phenyl to the methine chain of trimethincyanines gave excellent nucleic acid stains, particularly for fluorescent staining of RNA.3 Previous methods of introducing groups to the D−π−A methine chain are mainly that when a cyanine chromophore is being constructed, some groups are introduced,4 which suffer from severe drawbacks. For example, the preparation of methine-substituted cyanines such as trimethincyanines, giving the central role in many modern biological techniques, often relies on inefficient multistep reactions requiring harsh reaction conditions with poor substrate scope. Besides, some functional groups can not be introduced to the D−π−A methine chain by the reported ways. Furthermore, directly introducing groups to the D−π−A methine chain has only rarely been described.5 Based on our previous work,6 here we report a convenient approach to directly introduce some groups to the D−π−A methine chain for one-step synthesizing methine-substituted trimethincyanines through a new variant of electrophilic substitution reaction. Classical electrophilic substitution reactions use aromatic ring as substrate, with a cyclic large π conjugated system, while here the D−π−A methine chain, with a large chain π conjugated system, is used as substrate, which is the first report of the D−π−A methine chain electrophilic substitution reactions. Benzoindole trimethincyanines (Cy3.5) constitute an important subclass within the trimethincyanine family due to their applications in biomedicine and materials.7 They are of a planar D−π−A methine chain with an enamine structural unit (Figure © XXXX American Chemical Society
Received: October 27, 2017
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DOI: 10.1021/acs.orglett.7b03345 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
The introduction of a nitro group into a delocalized D−π−A system is important, as it provides a general entry into the D−π− A methine chain to obtain nitrogen-substituted Cy3.5. In the D−π−A methine chain nitration, strong nitrating reagents such as nitric acid/sulfuric acid can not be used because the D−π−A methine chain can be destroyed in a strong acid medium. In view of this, we examined the reactions of Cy3.5 with mild nitrating reagents. We first carried out the reaction between 1a and NXS/ AgNO3 in CH2Cl2 and at 0, 10, 20, and 30 °C, respectively (Table S1, entries 1−12, SI). The UV−vis, HRMS, and 1HNMR analysis showed that the desired nitration product was not obtained, while only halogenated products were obtained. When the nitrating reagent was changed to (COCl)2/AgNO3, α-nitroCH3−Cy3.5 (3aa) was obtained in 30% yield after a series of optimization experiments (Table S1, entries 13−16, SI). Then, in trying to find an appropriate nitrating reagent to achieve moderate to good yield of 3aa, we observed that, using SOCl2/ AgNO3 as the nitrating reagent in CH2Cl2, the reaction at 10 °C gave 3aa in 74% yield (Table S1, entry 17, SI). Subsequently, we investigated the influence of different temperatures and solvents on the D−π−A methine chain nitration of 1a using SOCl2/ AgNO3 as the nitrating reagent (Table S1, entries 18−22, SI) and found that the reaction yield reached to 85% in CH2Cl2 at 20 °C (Table S1, entry 19, SI). The reaction of 1b with SOCl2/AgNO3 proceeded smoothly in CH2Cl2 and at 20 °C for 30 min to afford the corresponding product 3ba in 79%. After increasing the usage amount of SOCl2/AgNO3, in CH2Cl2 and at 20 °C for 0.5−1 h, 3ab and 3bb were obtained in 82% and 71% yields, respectively (Scheme 2).
Table 1. Optimization of the D−π−A Methine Chain Chlorination of CH3−Cy3.5a
entry
temp (°C)
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0 5 10 15 20 25 30 35 20 20 20 20 20 20 20
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 (ClCH2)2 C6H5N DMF DMSO CH3OH DMAC
70 78 85 87 91 88 84 83 88 85 20 48 67 40 53
a
The reaction of 1a (1.70 mmol) with NCS (2.20 mmol) was carried out for 1 h in different solvents (60 mL) and at varying temperatures. b Isolated yield.
Scheme 1. Optimal Conditions and Yieldsa of the D−π−A Methine Chain Halogenation of Cy3.5b
Scheme 2. Optimal Conditions and Yieldsa of the D−π−A Methine Chain Nitration of Cy3.5b
a
Isolated yield. bThe reaction of 1 (1.70 mmol) with SOCl2/AgNO3 (0.85−2.20 mmol/1.90−7.65 mmol) was carried out at 20 °C for 10− 60 min in CH2Cl2 (60 mL). a
Isolated yield. bThe reaction of 1 (1.70 mmol) with various halogenating reagents (2.20−4.00 mmol) was carried out for 1−2 h at 10−20 °C and in CH2Cl2 (60 mL).
A proposed reaction pathway for the nitration is shown in Scheme 3. First, the reaction between SOCl2 and AgNO3 produces the intermediate I, which is accompanied by the precipitation of AgCl. Second, the intermediate I reacts with the D−π−A methine chain of 1a to give intermediate II. Finally, proton transfer from II to SO32− forms H2O and SO2 and gives αnitro-Cy3.5 (3aa). When 3aa further reacts with intermediate I, α,γ-dinitration product (3ab) was obtained. The precipitation of AgCl and formation of gas sulfur dioxide during the reaction are considered strong evidence for the proposed mechanism. In electrophilic aromatic substitution−alkylation, adding carbon electrophiles requires reactive carbon electrophiles and that means carbocations. Therefore, we explored the reaction of Cy3.5 with benzyl alcohol (BnOH) derivatives, which readily formed electrophile benzyl carbocation under Lewis acid catalysis. First, the reaction of CH3−Cy3.5 (1a) and p-HOBnOH was carried out using anhydrous AlCl3 as a catalyst at 90 °C in DMF, which offered α-p-HOBn-CH3−Cy3.5 (4aa) in low yield
iodine reagents (NIS, ICl), and fluoro reagent (NFSI) were used, the reactions proceeded efficiently in CH2Cl2 at 20 °C to give 2ab (75−93%), 2bb (71−91%), 2ac (70−88%), 2bc (48−61%), 2ad (90%), and 2bd (88%). However, the Selectfluor reagent afforded 2ad and 2bd in low yields (21−19%). No reaction occurred when halogenating reagents POCl3, (COCl)2, and I2 were used, probably due to their lower electrophilic character. Additionally, when increasing the usage amount of halogenating reagents, α,γ-dihalogenated products were formed, which were detected by TLC, UV−vis, and HRMS. However, when being separated, these products returned to α-halogenated products. In short, the halogenation reactions of the D−π−A methine chain of Cy3.5 using NCS, SOCl2, NBS, Br2, NIS, ICl, or NFSI as halogenating reagent in CH2Cl2 and at 10−20 °C could give the direct synthesis of α-halide-Cy3.5 in good to excellent yields. B
DOI: 10.1021/acs.orglett.7b03345 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
different electrophiles were examined under the optimized reaction conditions (Scheme 4). The reactions of Cy3.5 and
Scheme 3. Proposed Reaction Pathway for the D−π−A Methine Chain Nitration of Cy3.5
Scheme 4. Optimal Conditions and Yieldsa of the D−π−A Methine Chain Alkylation of Cy3.5b
a Isolated yield. bThe reaction of 1 (0.50 mmol) and benzyl alcohol derivatives (2.00 mmol) in DMF (1.5 mL) was carried out at 100 °C for 20 min−20 h under SnCl4 catalyst (60 mol %).
benzyl alcohol derivatives with strongly electron-donating groups, such as p-HO and p-CH3O, proceeded efficiently in DMF at 100 °C to afford the corresponding products 4aa−4bb in 57−73% yields, and the reactions of Cy3.5 and piperonyl alcohol or 2-thiophene methanol gave 4ad−4bd in 53−48% yields or 4ae−4be in 67−61% yields. While Cy3.5 reacted with pCH3BnOH, with weakly electron-donating group CH3, low yields (4ac−4bc, 15−8%) were given in DMF at 100 °C, and no reaction occurred when an electron-withdrawing group such as p-X or p-O2N was attached to the benzene ring. This was because benzyl alcohol derivatives with an electron-withdrawing group were difficult to form carbocation under Lewis acid catalysis. In the acylation of the aromatic ring, the most commonly used acylation reagent is acyl halide. We first carried out the reactions between CH3−Cy3.5 (1a) and acyl halides, such as CH3COCl, CH3CH2COCl, p-CH3OC6H4COCl, or p-O2NC6H4COCl, in the presence of a Lewis acid catalyst such as AlCl3 or SnCl4, in DMF or (CH2Cl)2 and at 30, 50, or 90 °C. Analysis showed no reaction between 1a and acyl halide. Then, 1a and acyl halide were reacted under the above temperature and solvent conditions followed by the addition of a base such as triethylamine or pyridine with agitation. The reaction of 1a and acyl halide still did not take place. After replacing the solvent DMF or (CH2Cl)2 with DMSO, all of the above reactions were carried out, and the chlorinated product 2aa was obtained, which was attributed to the fact that DMSO in situ oxidized chloride to electrophilic intermediate, so that it was reacted with 1a to form 2aa. Satisfactorily, the reaction of 1a and DMF could take place at 70 °C in the presence of POCl3 and offered α-CHO-CH3−Cy3.5 (5aa) in 58% yield. After that, in trying to find appropriate conditions to achieve moderate to good yield of 5aa (Table S2, SI), we observed that the reaction of 1a and DMF in the presence of SOCl2 and at 80 °C for 20 min gave the target product in 80% yield. The reaction of 1b and DMF proceeded smoothly in the presence of SOCl2 and at 80 °C for 40 min, giving 67% yield of αCHO-C3 H 7−Cy3.5 (5ba) (Scheme 5). However, when replacing DMF with dimethylacetamide (DMAC), no reaction occurred. The D−π−A methine chain sulfonation of Cy3.5 is similar to its nitration, as strong sulfonating reagents such as sulfuric acid can not be used. So the reaction of Cy3.5 with mild sulfonating reagent Py/SO3 was examined. The reaction between CH3−
(10%) (Table 2, entry 1). With a view to improve the yield of the product, various catalysts, such as SnCl2, FeCl3, SnCl4, TiCl4, and Table 2. Optimization of the D−π−A Methine Chain Alkylation of CH3−Cy3.5a
entry
cat.
temp (°C)
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12
AlCl3 SnCl2 FeCl3 SnCl4 TiCl4 PdCl2 SnCl4 SnCl4 SnCl4 SnCl4 SnCl4 SnCl4
90 90 90 90 90 90 80 100 110 120 90 90
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO DMA
10 − − 54 48 52 48 73 50 34 − 51
a
The reaction of 1a (0.50 mmol) and benzyl alcohol derivatives (2.00 mmol) in different solvents (1.5 mL) was carried out at varying temperatures for 20 min in the presence of a catalyst (60 mol %). b Isolated yield.
PdCl2 (Table 2, entries 2−6), were screened for this reaction. Among them, SnCl4 gave a slightly better result (Table 2, entry 4). Various temperatures and solvents were also examined (Table 2, entries 7−12). The results showed that, using SnCl4 catalysis, the reaction at 100 °C for 20 min in DMF gave 4aa in 73% yield. In addition, when replacing the solvent DMF with DMSO, all the reactions above were carried out, and chlorinated product 2aa was obtained. This was attributed to the fact that DMSO in situ oxidized chloride to electrophilic intermediate,9 so that it was reacted with 1a to form 2aa. In order to explore the generality of this protocol for the D−π−A methine chain alkylation, the reactions of Cy3.5 with C
DOI: 10.1021/acs.orglett.7b03345 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 5. Optimal Conditions and Yieldsa of the D−π−A Methine Chain Formylation of Cy3.5b
(b) Alexei, T.; Dan-Vinh, N.; Klaus, M. H. Org. Lett. 2007, 9, 2775. (c) Chen, G. W.; Song, F. L.; Wang, X.; Sun, S. G.; Fan, J. L.; Peng, X. J. Dyes Pigm. 2012, 93, 1532. (2) Shank, N. I.; Zanotti, K. J.; Lanni, F.; Berget, P. B.; Armitage, B. A. J. Am. Chem. Soc. 2009, 131, 12960. (3) Jason, D.; David, H.; Ying, C. C.; Jerry, T.; Stephen, Y. PCT Int. Appl. US 09403985, 2016. (4) (a) Shank, N. I.; Pham, H. H.; Waggoner, A. S.; Armitage, B. A. J. Am. Chem. Soc. 2013, 135, 242. (b) Bohläender, P. R.; Wagenknecht, H. A. Eur. J. Org. Chem. 2014, 34, 7547. (c) Chen, C. Y.; Kumar, S. U.S. Pat. Appl. US 20040186278 A1, 2004. (5) Grahn, W.; Johannes, H. H.; Rheinheimer, J.; Knieriem, B.; Wuerthwein, E. U. Liebigs Ann. 1995, 1995, 1003. (6) (a) Guan, L.; Li, A. Y.; Song, Y. Y.; Yan, M. Q.; Gao, D. F.; Zhang, X. H.; Li, B.; Wang, L. Y. J. Org. Chem. 2016, 81, 6303. (b) Wang, S.; Zhang, X. F.; Zhang, J. H.; Bi, W. B.; Wang, L. Y. RSC Adv. 2015, 5, 64626. (c) Jia, H. L.; Lv, Y.; Wang, S.; Sun, D.; Wang, L. Y. RSC Adv. 2015, 5, 4681. (d) Gao, D. F.; Li, A. Y.; Guan, L.; Zhang, X. H.; Wang, L. Y. Dyes Pigm. 2016, 129, 163−173. (e) Guan, L.; Liu, Q.; Zhang, B. R.; Wang, L. Y. J. Photochem. Photobiol., B 2017, 166, 239. (f) Yan, M. Q.; Zhao, J. L.; Sun, D.; Sun, W.; Zhang, B. R.; Deng, W. T.; Zhang, D. D.; Wang, L. Y. Tetrahedron 2017, 73, 3355. (7) (a) Hu, H.; Owens, E. A.; Su, H. R.; Yan, L. L.; Levitz, A.; Zhao, X. Y.; Henary, M.; Zheng, Y. G. J. Med. Chem. 2015, 58, 1228. (b) Sinha, S. H.; Owens, E. A.; Feng, Y.; Yang, Y. T.; Xie, Y.; Tu, Y. P.; Henary, M.; Zheng, Y. G. Eur. J. Med. Chem. 2012, 54, 647. (c) Liu, Y. J.; Wei, M.; Li, Y.; Liu, A. R.; Wei, W.; Zhang, Y. J.; Liu, S. Q. Anal. Chem. 2017, 89, 3430. (d) Klein, W. P.; Diaz, S. A.; Buckhout-White, S.; Melinger, J. S.; Cunningham, P. D.; Goldman, E. R.; Ancona, M. G.; Kuang, W.; Medintz, I. L. Adv. Opt. Mater. 2017, 1700679. (8) (a) Mitchell, R. H.; Lai, Y.; Williams, R. V. J. Org. Chem. 1979, 44, 4733. (b) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221. (c) Gruter, G. J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org. Chem. 1994, 59, 4473. (9) Wan, X. B.; Ma, Z. X.; Li, B. J.; Zhang, K. Y.; Cao, S. K.; Zhang, S.; Shi, Z. J. J. Am. Chem. Soc. 2006, 128, 7416.
a Isolated yield. bThe reaction of 1 (1.70 mmol) and DMF (7.5 mL) was carried out at 80 °C for 20−40 min in the presence of SOCl2 (6.80 mmol).
Cy3.5 and Py/SO3 was carried out in CH2Cl2 under reflux, with (CH2Cl)2, DMF, DMSO, or Py, and at 20, 40, 60, and 90 °C, respectively. As a result, the target product was all not obtained. In summary, we have developed the D−π−A methine chain electrophilic substitution reactions to directly introduce functional groups to the D−π−A methine chain for one-step synthesis of methine-substituted Cy3.5. These reactions were relatively robust and provided several advantages such as simple workup procedure, mild conditions, and good yields within a short time. The substituents on the D−π−A methine chain have a strong influence on the photophysical properties and intermolecular interactions of Cy3.5. The detailed photophysical properties and the application aspect of the prepared methine-substituted Cy3.5 are currently being examined in our laboratory.
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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.7b03345. Full experimental details and copies of NMR and HRMS spectra (PDF) Accession Codes
CCDC 1579128 and 1579133 contain 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
[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 Author
*E-mail:
[email protected]. ORCID
Lanying Wang: 0000-0001-7598-0021 Author Contributions §
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was funded by the National Natural Science Foundation of China under Grant No. 21575111. REFERENCES
(1) (a) Tan, X. H.; Constantin, T. P.; Sloane, K. L.; Waggoner, A. S.; Bruchez, M. P.; Armitage, B. A. J. Am. Chem. Soc. 2017, 139, 9001. D
DOI: 10.1021/acs.orglett.7b03345 Org. Lett. XXXX, XXX, XXX−XXX
