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A chemoselective photolabile protecting group for aldehydes
Journal Pre-proofs A Chemoselective Photolabile Protecting Group for Aldehydes Jing Xu, Shouguo Zhang, Hongpeng Yang, Xiaoxue Wen, Tao Peng, Kaijun Xu, Gang Wang, Lin Wang PII: DOI: Reference:
S0040-4039(20)30132-5 https://doi.org/10.1016/j.tetlet.2020.151709 TETL 151709
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Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
30 October 2019 2 February 2020 4 February 2020
Please cite this article as: Xu, J., Zhang, S., Yang, H., Wen, X., Peng, T., Xu, K., Wang, G., Wang, L., A Chemoselective Photolabile Protecting Group for Aldehydes, Tetrahedron Letters (2020), doi: https://doi.org/ 10.1016/j.tetlet.2020.151709
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A Chemoselective Photolabile Protecting Group for Aldehydes
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Jing Xu, Shouguo Zhang, Hongpeng Yang, Xiaoxue Wen, Tao Peng, Kaijun Xu*, Gang Wang*, Lin Wang*
1
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A Chemoselective Photolabile Protecting Group for Aldehydes Jing Xua, Shouguo Zhanga, Hongpeng Yanga, Xiaoxue Wena, Tao Penga, Kaijun Xub,*, Gang Wanga,*, Lin Wanga,* a b
Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, P. R. of China School of Science, China Pharmaceutical University, Nan Jing 211198, P. R. of China.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new and high-efficiency photolabile protecting group (PLPG) for aldehydes is described. The PLPG was introduced to aldehydes by using a Lewis acid. Results showed that the PLPG can be released rapidly and smoothly under ultraviolet (UV) irradiation with high efficiency and low cost. This PLPG can easily synthesized and also be selectively protect aldehydes in the presence of ketones.
Keywords: photolabile protecting group photodeprotection aldehyde compound o-nitrobenzyl group
Photolabile protecting groups (PLPGs) can be removed by irradiation1 and can release substrates in a spatially and temporally controlled manner. The releasing condition is mild, and no extra chemical reagent is not required2. PLPGs can be used to protect various chemical groups, such as alcohols3, amines4, and carboxylic acids5. Therefore, they are widely used in chemical synthesis and life science, such as synthesis of polypeptide6 or DNA7. Many new PLPGs such as nitroaryl8, coumarin-4-ylmethyl9, arylmethyl10, miscellaneous11, and arylsulfonyl groups12 have been developed and extensively used in many areas. However, only a few practically useful photolabile protecting groups for aldehydes, which are commonly used in modern organic synthesis, have been reported16. These are diferent from the traditional protecting groups protected aldehydes through an acetal moiety, and then are deprotected by reactions of acid catalysis13, Lewis acid coordination14 or redox15.The PLPG o-nitrophenylethylene glycol (Npeg, Figure 1) was first reported by Gravel17 et al. in 1984. Npeg can protect aldehyde compounds and ketone compounds, which will later be released under UV irradiation via deprotection. However, Npeg still have deficiencies, such as
Figure 1. Structure of Npeg (left) and Npp (right)
long reaction time for deprotection and inability to protect aldehyde selectively. 2-(2-nitrophenyl) propan1-ol (Npp, Figure 1), a new PLPG, was synthesized and used by Pfleiderer9 et al. for protecting hydroxyl groups in a series of nucleosides nucleosides; Npp was also applied to the synthesis of cyclic peptide as PLPG for carboxylic groups in our previous studies18, and the results of these studies indicated that Npp does not affect the stability of polypeptide. In this study, on the basis of Npeg and Npp, we further developed a new, simple, and efficient PLPG particularly for protecting aldehydes. 2-(2-nitrophenyl)1,3-propanediol (Nppd), as a developed PLPG for protecting aldehydes, was prepared from 2-nitrotoluene, a cheap raw material, via only one step reaction (Scheme 1). Nppd has various advantages, such as simple synthesis with low cost, high efficiency and selectivity for protecting aldehydes without affecting ketones. In addtion, the protected products of aldehydes (acetals) were stable in the absence of light and can rapidly release original aldehydes under UV irradiation with high efficiency.
Scheme 1. Synthesis of Nppd
Tetrahedron Letters
2
Some aldehydes (1a-h) and ketones (1i-k) were used to test Nppd’s protecting efficiency (Scheme 2, Table 1). The protection of aldehydes by Nppd can be achieved by only a onestep reaction in a relatively mild condition. Particularly, 1 equivalent aldehyde and 2 equivalents of Nppd were dissolved in CH2Cl2. Then, 1 equivalent of Lewis acid BF3•OEt2 was added as promoter, and anhydrous magnesium sulfate was added as dehydrating agent. The reaction was conducted at −15℃ for 90 min to generate the protected product (acetal). Results showed that the low temperature can promote the reaction. For example, the protection yield of 1b was 25% at room temperature, 37% at 0 ℃, and 47% at −15 °C (Table 2). However, the protection yield of 1b in the 24 h reaction was nearly the same with that in the 90 min reaction (Table 3). It can be concluded that the protection yield cannot be increased only by extending the reaction time. Other promoters, such as ptoluenesulfonic acid (TsOH), Pyridinium 4-toluenesulfonate (PPTS), and FeCl3, were also used for protecting the aldehyde. Among them, BF3•OEt2 has showed a best result. The reactivity of phenyl carbonyl groups vary depending on the substituents on the benzene ring. The electron-withdrawing substituents can enhance the reactivity while the electrondonating substituents reduce it, both of which will affect Nppd's protective ability. This conclusion has been proven by the production of 2a-c formed by 1a-c. Protective experiments on ketone groups were also studied and the results showed that the protective yields on cyclohexanone, phenylacetone, and diphenyl ketone were 0%, 4%, and 0%, respectively. Even if the MgSO4 was replaced by a more effective dehydrating agent, such as P2O5, the ketone group still can't be protected by Nppd. Therefore, only the aldehyde group can be protected by Nppd even in the presence of the ketone group. Photodeprotection then released the corresponding aldehyde. Some aldehydes releasing reaction was performed under UV light at 365nm in acetonitrile,
Table 2. The protection yields of 1b under different reaction Time(90 min)
instead of methanol reported by Wang16 et al, because the protected product (acetal) has the good solubility in acetonitrile. It is noticed that the photodeprotection reaction will not proceed without the presence of a certain amount of water. On this basis, a possible photodeprotection mechanism (Scheme 3) according to that of Npp9 was infered herein. The photorelease of Nppd from the aldehyde’s protected product (acetal) via a propertylabile semiacetal formed from the acetal by a β-elimination mechanism. The semiacetal was decomposed immediately andyields were lower than the actual values due to their volatility. These aldehydes need to be processed by derivation after the deprotection to eliminate the volatility. For example, if 1a released from 2a after the deprotection is unprocessed by derivation, the releasing yield will fall to 13%. Results of Nppd’s application are illustrated in Table 1, which show that the Nppd can protect aldehydes with relatively high protection and deprotection yields. The protection yields on the aromatic aldehydes (1a, 1b, 1c, 1d, 1e), the unsaturated aldehyde (1f), the amino aldehyde protected by Fmoc (1h), and the aliphatic aldehyde (1g) were 64%, 47%, 78%, 39%, 83%, 70%, 73%, and 59%, respectively. In addition, their deprotection yields were 71%, 83%, 96%, 87%, 86%, 75%, 65%, and 74%. Amino aldehydes are widely used to synthesize medicine and can be served as precursors of synthetic antimicrobial drugs penicillin19 or anticancer drug20, and they also play an important role in synthesizing pseudopeptide. In the meanwhile, the amino groups or aldehyde groups of amino aldehydes are usually protected when they are used because of their chemical instability21. In this study, the amino aldehyde protected by Fmoc (1h) can be protected by the Nppd, with protection yield of 59% and deprotection yield of 65%. Particularly, a certern amount of water (1 equivalent) has been added into the reaction mixture for every 15 min, to inhibit the thermal effects during the illumination, and to avoid side reaction of the amino aldehyde caused by excessive water.
Table 3. The protection yields of 1b under different reaction Time(0℃)
Reaction temperature(℃)
-15
0
25
Reaction time
90 min
24h
Yield
47
37
25
Yield
47
43
Scheme 2. Protection of Carbonyls with Nppd
Scheme 3. Possible photodeprotection mechanism
3 Table 1. Protection and photorelease of the Aldehydes Entry
a
Carbonyl Compounds
Protection Yielda (%)
Deprotection Yield b(%)
Irradiation Time (min)
1
a
64
71c
120
2
b
47
83c
60
3
c
78
96e
60
4
d
39
87e
60
5
e
83
86e
120
6
f
70
75e
75
7
g
73
74d
80
8
h
59
65e
90
9
i
0
--
--
10
j
4
--
--
11
k
0
--
--
Reaction conditions: 1 (1 mmol), Nppd (2 mmol), BF3.OEt2 (1 mmol), MgSO4 (8.0 mmol) in 6 ml CH2Cl2, −15 °C, 90 min, isolated yield.
b
Reaction conditions: Irradiated with a 250 W UV lamp (365 nm) equipped with a Pyrex filter sleeve, CH3CN (0.05 M), isolated yield.
c
Isolated as the oxime derivatives.
d
Isolated as the semicarbazone derivative.
e
Isolated as the aldehyde without derivatization
1c was protected by Nppd to obtain 2c, and the process of deprotection was detected by UV spectrophotometer (Figure 2). A new absorption peak appeared at the wavelength of 265nm in the photolysis reaction and would increase gradually with the
reaction time prolonging . This peak was the characteristic peak of 1c22, indicating that the original compound 1c could be released rapidly at a constant speed from its protected compound 2c under UV at 365nm.
Tetrahedron
4
Table 4. Comparative protecting efficiency of Nppd and Npeg protecting group
Protection yield for
Protection yield for (%)
(%)
Nppd
0
78
Npeg
96
97
Conclusion
Figure 2. UV spectra of 2c
Reversed-phase HPLC was used to investigate the photodeprotection progress of protected aldehydes. For example, 2f (0.02 M in CH3CN) was investigated during irradiation at 365nm (Figure 3).The analysis was performed on Agilent 1100 apparatus equipped with a Agela Venusil ASB C18 column (5 μm, 4.6 mm×250 mm) over a 10-70% gradient of acetonitrile： water with 0.1% TFA using a gradient elution in 30 min and flow rate of 1 mL/min.The wavelength for the detector was set at 220nm, and the injection volume was 10μL. Before irradiation, a peak with a retention time of 31.0 minutes, corresponding to 2f, was observed. During irradiation, this peak gradually disappeared, and a new peak (retention time 21.2 min, corresponding to 1f) appeared instead, proving that 2f released aldehyde under photoirradiation.
0min 1
40min
f
2 f
75min
Figure 3. HPLC traces recorded during irradiation of 2f
The performance of Nppd and Npeg in protecting efficiency, protecting selectivity, and deprotecting efficiency was compared (Table 4). The results shown in Table 2 indicated that Nppd’s protecting efficiency for the carbonyls was lower than that of Npeg. Npeg formed five-membered cyclic acetals, which were easy to obtain, but the aldehyde group cannot be selectively protected by Npeg, and the releasing speed of aldehydes from the Nppd acetal is faster than that from the Npeg acetal. The deprotecting yield of Nppd (65%–96%) is nearly the same with Npeg (31%–90%). However, the reaction time for Nppd was only approximately 33% of that for Npeg. Meanwhile, the amount of solvent for Nppd (15 mL CH3CN) was just only 10% of that for Npeg (200 mL benzene). The speed of Nppd’s releasing protected aldehydes is faster than that of Npeg, and the amount of solvent required is also less, and the solvent is more environmentally friendly.
Nppd, a new PLPG for aldehydes was designed and prepared from a cheap material, namely, 2-nitrotoluene, by a one-step reaction. The aldehydes can be protected by Nppd in mild condition and released rapidly and smoothly under the UV irradiation with high yields. This new PLPG can be used to protect aliphatic, aromatic, unsaturated, and amino aldehydes protected by Fmoc, and has a good application prospect in the field of organic synthesis.
Acknowledgments The authors are grateful to the National Natural Science Foundation of China (Grant No. 81273431, 21102176 and 21272273) for its financial support for this project. References and notes Klán, P.; Šolomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Chem. Rev. 2013, 113, 119. 2. (a) Bochet, C. G. J. Chem. Soc. Perkin Trans. 2002, 125.(b) Ma, C.; Zhang, Y.; Zhang, H.; Li, J.; Nishiyama, Y.; Tanimoto, H.; Morimoto, T.; Kakiuchi, K. Synlett. 2017, 28, 560. 3. Klán, P.; Pelliccioli, A. P.; Pospíšil, T.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 920. 4. Kammari, L.; Plíštil, L.; Wirz, J.; Klán, P. Photochem. Photobiol. Sci. 2007, 6, 50. 5. (a) Griesbeck, A. G.; Gudipati, M. S.; Hirt, J.; Lex, J.; Oelgemoller, M.; Schmickler, H.; Schouren, F. J. Org. Chem. 2000, 65, 7151. (b) Abe, M.; Chitose, Y.; Jakkampudi, S.; Thuy, P. T. T.; Lin, Q.; Van, B. T.; Yamada, A.; Oyama, R.; Sasaki, M.; Katan, C. Synthesis. 2017, 49, 3337. (c) Saneyoshi, H.; Ono, A. Chem. Pharm. Bull. 2018, 66, 147.（d）Tiwari, V.; Singh, A. K.; Chaudhary, P.; Seeberger, P. H.; Kandasamy, J. Org. Chem. Front. 2019, 6, 3859. 6. (a) Goard, M.; Aakalu, G.; Fedoryak, O. D.; Quinonez, C.; St. Julien, J.; Poteet, S. J.; Schuman, E. M.; Dore, T. M. Chem. Biol. 2005, 12, 685.(b) Tamao, K.; Kumada, M. In The Chemistry of the Metal–Carbon Bond; Hartley, F. R., Ed.; Wiley: New York, 1987; Chapter 9, p. 819; 7. (a) Young, D. D.; Lively, M. O.; Deiters, A. J. Am. Chem. Soc. 2010, 132, 6183. (b) Momotake, A.; Lindegger, N.; Niggli, E.; Barsotti, R. J.; Ellis-Davies, G. C. R. Nat. Methods. 2006, 3, 35. 8. (a) Patchornik, A.; Amit, B.; Woodward, R, B. J. Am. Chem. Soc. 1970, 92, 6333.(b) Komori, N.; Jakkampudi, S.; Motoishi, R.; Abe, M.; Kamada, K.; Furukawa, K.; Katan, C.; Sawada, W.; Takahashi, N.; Kasai, H.; Xue, B.; Kobayashi, T. Chem. Commun. 2016, 52, 331. (c) Watuthanthrige, N. D. A.; Kurek, P. N.; Konkolewicz, D. Polymer. Chem. 2018, 9, 1557. 9. (a)Hasan, A.; Stengele, K. P.; Giegrich, H.; Cornwell, P.; Isham, K. R.; Sachleben, R. A.; Pfleiderer, W.; Foote , R, S.Tetrahedron. 1997, 53, 4247. (b) Hammer, C. A.; Falahati, K.; Jakob, A.; Klimek, R.; Burghardt, I.; Heckel, A.;Wachtveitl, J.J. Phys. Chem. Lett, 2018, 9, 1448. 10. Piloto, A. M.; Rovira, D.; Costa, S. P. G.; Gonçalves, M. S. T. Tetrahedron. 2006, 62, 11955. 11. Kotzur, N.; Briand, B.; Beyermann, M.; Hagen, V. J. Am. Chem. Soc. 2009, 131, 16927. 12. Cosa, G.; Lukeman, M.; Scaiano, J. C. Chem. Res. 2009, 42, 599. 1.
5 13. Hiyama, T. ;Oishi, H. ;Saimoto, H. Tetrahedron Lett. 1985, 26, 2459. 14. Johnson, W. ; Edington, C.; Elliott, J. ; Silverman, I. J. Am. Chem. Soc. 1984, 106, 7588. 15. McDonald, C. E.; Nice, L. E.; Shaw, A. W.; Nestor, N. B. Tetrahedron Lett. 1993, 34, 2741. 16. (a)Wang, P.; Hu, H.; Wang, Y .; Organic Letters, 2007, 9, 1533. (b) Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984. (c) Wang, P.; Wang, Y.; Hu, H.; Spencer, C.; Liang, X.; Pan, L. J. Org. Chem. 2008, 73, 6152. 17. Hébert, J.; Gravel, D. Can. J. Chem. 1983, 61, 400. 18. Wang, G.; Peng, T.; Zhang, S.; Wang, J.; Wen, X.; Yang, H. ; Hu, L.; Wang, L. RSC. Adv. 2015, 5, 28344. 19. Sheehan, J. C.; Henbry-Logan, K. R. J. Am. Chem. Soc. 1957, 79, 1262. 20. Acton, E. M.; Fujiwara, A. N.; Henry, D. W. J. Med. Chem. 1974, 17, 659. 21. Mestrom, L.; Bracco, P.; Hanefeld, U. Eur. J. Org. Chem. 2017,47, 7019. 22. Zarei, M.; Zolfigol, M. A.; Moosavi-Zare, A. R.;Noroozizadeh, E. J. Iran.Chem. Soc, 2017, 14, 2187.
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Aldehydes are chemically active and are often need to be protected. Photolabile protecting groups are widely used in organic synthesis. Photolabile protecting group for aldehydes has a good application prospect.
A Chemoselective Photolabile Protecting Group for Aldehydes
Declaration of interests √ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Jing Xua, Shouguo Zhanga, Hongpeng Yanga, Xiaoxue Wena, Tao Penga, Kaijun Xub,*, Gang Wanga,*, Lin Wanga,* a
Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, P. R. of China b School of Science, China Pharmaceutical University, Nan Jing 211198, P. R. of China.
E-mail: [email protected]
A Chemoselective Photolabile Protecting Group for Aldehydes
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Jing Xu, Shouguo Zhang, Hongpeng Yang, Xiaoxue Wen, Tao Peng, Kaijun Xu*, Gang Wang*, Lin Wang*
6
Tetrahedron
7 SⅠ. General information All chemicals and solvents were of analytical grade and were used without further purifications. All organic solutions were concentrated by rotary evaporation under reduced pressure. Flash column chromatography was performed employing 230400 mesh silica gel. The progress of reactions was monitored by silica gel thin layer chromatography (TLC) plates . UV-visible spectra were obtained using a Shimadzu UV-2501PC UV-visible Recoroding spectrophotometer, with the sample concentration of 8.56*10-5 M. 1H and 13C NMR spectra were recorded on a Varian INOVA 600 spectrometer and Bruker 400 NMR spectrometer, chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.26, DMSO-d6: 2.53). Data were presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and /or multiple resonances), coupling constant in Hertz (Hz), integration. Photolysis was with a 250W UV lamp (365nm) . SⅡ-1 Preparation of 2-(2-nitrophenyl)-1,3propanediol(Nppd)
Nitrotoluene (6.86 g, 50 mmol), [HCHO]n (3.15g, 102 mmol) and Triton B (8mL, 40%) were stirred in DMSO (80 mL) for 8h at room temperature in the dark. The reaction was neutralized to pH 7 with 2 M hydrochloric acid, and then H2O (80 mL) was added, extracted with EtOAc(3×40 mL). The organic layer is dried with magnesium sulfate and then condensed. The product was obtained as yellow oil by column chromatography (yield: 6.01g, 61%). 1 H-NMR (CDCl3) δ: 3.64 (m, 1H), 3.70 (m, 2H), 3.72 (m, 2H), 4.72 (t, 2H), 7.58 (m, 1H), 7.59 (m, 2H), 7.69 (m, 1H). 13CNMR (400MHz, CDCl3) δ: 44.59, 61.88, 123.42, 127.20, 129.45, 132.22, 135.26, 151.21. HRMS (ESI) m/e calcd. for (M+Na+) 219.9689, found 220.0724. SⅡ-2 General Procedures for Preparation of 2a, 2b, 2c, 2d, 2e, 2d, 2f, 2g, 2h
(2-nitrophenyl)-1,3-propanediol(394 mg, 2.00 mmol),aldehyde(1.00 mmol), BF3·OEt2(142 mg, 1.00 mmol) and MgSO4 in 6 mL of CH2Cl2 were stirred at –15 °C for 90 min, then saturated NaHCO3 solution(20 mL) was added rapidly , extracted with dichloromethane (DCM) (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The product was purified by flash chromatography (silica, petroleum ether:ethyl acetate= 10:1) . 5-(2-nitrophenyl)-2phenyl-1,3dioxane(2a), 182 mg (64%), Light yellow solid, Rf 0.5 (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, DMSO-d6) δ: 3.54 (m, 1H), 4.20 (m, 4H), 5.74 (s, 1H), 7.38(m,2H)，7.45 (m, 2H), 7.74 (m, 2H), 7.93 (m, 1H). 13CNMR (400MHz, CDCl3) δ: 36.05, 70.73, 71.60, 94.18, 101.81, 124.74, 126.16, 128.21, 128.36, 128.38, 129.41, 131.55, 132.66, 137.89, 151.02. FTIR (neat) 3434, 2852, 1608, 1576, 1523，1375, 1374, 1284, 1174, 1154,1134, 984, 972, 844, 749 , 696, 653, 641, cm -1 ; HRMS (ESI) m/e calcd. for (M+Na+) :308.0901, found 308.0892.
2-(4methoxyphenyl)-5-(2-nitrophenyl)-1,3dioxane(2b), 148 mg (47%), Light yellow solid,Rf 0.5 (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, CDCl3) δ:3.29 -3.84 (m, 4H), 4.07(m,1H), 4.42 (m, 3H), 5.57 (d, 1H), 6.96 (m, 2H), 7.42-7.67 (m, 5H), 7.46-8.49 (dd, 1H). 13 CNMR (400MHz, CDCl3) δ: 36.02, 36.72, 55.34, 70.83, 71.59, 101.75, 101.86, 113.73, 113.77, 124.41, 124.72, 127.41, 127.48, 127.51, 128.16, 128.35, 130.42, 130.77, 131.36, 131.63, 132.63, 133.07, 137.53, 149.42, 151.03. FTIR (neat) 3442, 3074, 2969, 2865, 1613, 1576, 1524, 1388, 1352,1299, 1282, 1249, 1215, 1152, 1133, 1065, 1025,977, 931, 844, 785, 748, 698 cm 1 . HRMS (ESI) m/e calcd. for (M+H+):316.1185, found 316.1179.
Tetrahedron 13 CNMR (400MHz, CDCl3) δ: 35.53, 70.71, 94.16, 100.62, 124.82, 125.27, 125.31, 126.64, 128.28, 128.32, 128.75, 131.35-132.95 (q, J=640Hz), 2-(4132.75, 141.47, 150.92. chlorophenyl)-5-(2-nitrophenyl)-1,3-dioxane(2c), HRMS (ESI) m/e calcd. for (M+H+):354.0917, 249 mg (78%), Light yellow solid,Rf 0.4 found 335.1021. (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, DMSO-d6) δ: 3.49 (m, 1H), 4.09 (m, 2H), 4.12 (m, 2H), 5.36 (d, 1H), 6.31 (dd, 1H), 6.76 (d，1H) 7.36 (m, 3H), 7.52 (m, 3H), 7.71 (m, 2H), 7.91 (m, 1H). 13CNMR (400MHz, 5-(2-nitrophenyl)-2CDCl3) δ: 35.99, 71.54, 100.94, 124.79, 127.65, styryl-1,3-dioxane(2f), 217 mg (70%), Light 128.28, 128.31, 128.53, 131.37, 132.71, 134.90, yellow solid, Rf 0.5 (petroleum ether/ethyl acetate 136.44, 150.98. = 3/1). FTIR (neat) 3434, 2952, 1607, 1577, 1523, 1384, 1 H-NMR (400MHz, DMSO-d6) δ:3.49 (m, 1H), 1348, 1281,1265,1222, 1155, 1135, 1015,846, 806, -1 4.09 (m, 2H), 4.12 (m, 2H), 5.36 (m, 1H), 6.31(dd, 748, 726, 698, 681 cm ; + 1H), 6.76 (d, 1H), 7.36 (m, 3H), 7.51 (m, 3H), 7.71 HRMS (ESI) m/e calcd. for (M+H ): 342.0498, (m, 2H), 7.91 (m, 1H). 13CNMR (400MHz, CDCl3) found 342.0504. δ: 33.69, 36.03, 71.27, 70.47, 100.94, 101.08, 124.36, 124.76, 124.96, 125.21, 126.91, 127.54, 128.30, 128.33, 128.37, 128.61, 128.62, 131.39, 131.55, 132.65, 133.16, 133.76, 133.92, 135.87, 135.90, 137.39, 149.39, 150.96. FTIR (neat) 3433, 3081,3028, 2981, 2839, 1606, 2-methoxy-4-(5-(21575, 1520, 1496, 1461, 1380, 1364, 1343, nitrophenyl)-1,3-dioxan-2-yl)phenol(2d), 129 mg 1280,1270, 1154, 1137, 1056,971, 849, 749, 706, (39%), yellow oil, Rf 0.4 (petroleum ether/ethyl 679cm -1 ; acetate = 2/1). 1 HRMS (ESI) m/e calcd. for (M+ H+) 312.1158, H-NMR (400MHz, DMSO-d6) δ: 3.38 (m, 1H), (M+Na+) 334.0147, found 312.1231, 334.1046 3.77 (m, 3H), 4.15 (m, 2H), 4.20 (m, 2H), 5.62 (s, 1H), 6.75 (d, 1H),6.77 (dd, 1H), 6.91 (d, 1H), 7.55 (m, 1H), 7.72 (m, 2H), 7.91 (m, 1H), 9.11 (s, 1H). 13 CNMR (400MHz, CDCl3) δ: 33.63, 35.91, 55.83, 70.50, 71.71, 101.68, 101.82, 108.24,108.41, 113.89, 104.12,119.19, 119.59, 124.39, 124.64, 2-heptyl-5-(2124.79, 127.48, 128.13, 128.26, 131.26, 132.61, nitrophenyl)-1,3-dioxane（2g）, 222 mg (73 %), 132.94, 146.14, 146.23, 146.31, 146.46,150.67. yellow oil, Rf 0.5 (petroleum ether/ethyl acetate = HRMS (ESI) m/e calcd. for (M+H+):332.1157, 6/1). found 332.1129. 1 H-NMR (400MHz, CDCl3) δ: 1.25 (t, 3H), 1.56 (m, 1H), 3.37 (m, 1H), 4.06 (m, 1H), 4.05 (m, 1H), 4.72 (t,1H), 7.67 (m, 2H), 7.88 (m, 1H), 7.98 (m, 2H). 13 C-NMR (400MHz, CDCl3) δ: 14.12, 22.67, 23.99, 29.21, 29.45, 31.78, 34.82, 36.14, 71.19, 5-(2-nitrophenyl)-2102.59, 124.63, 128.04, 128.31, 131.69, 132.55, (4-(trifluoromethyl)phenyl)-1,3-dioxane(2e）, 353 151.00. mg (83%), white solid, Rf 0.4 (petroleum HRMS (ESI) m/e calcd. for (M+ K+) 346.2767, ether/ethyl acetate = 2/1). found 346.2740. 1 H-NMR (400MHz, DMSO-d6) δ: 3.61 (m, 1H), 3.91 (m, 1H), 4.25 (m, 1H), 4.28 (m,4H), 4.89 (m, 1H), 7.72(m, 1H),7.76 (m, 1H), 6.91 (d, 1H), 7.55 (m, 1H), 7.75-7.76 (m, 6H), 7.77 (m, 1H),. 8
9
(9H-fluoren-9-yl)methyl(2methyl-1-(5-(2-nitrophenyl)-1,3-dioxan-2yl)propyl)carbamate(2h), 270 mg (59%), brown soild, Rf 0.4 (petroleum ether/ethyl acetate = 2/1). 1 H-NMR (400MHz, CDCl3) δ: 0.96 (d, 6H), 1.26 (t, 2H), 1.9 (m, 1H), 4.11 (m, 2H), 4.29 (m, 2H), 4.43 (m, 4H), 5.1 (d, 1H), 7.34 (m, 8H), 7.40 (m, 1H), 7.76 (m, 2H), 7.78 (m, 3H). 13C-NMR (100MHz, CDCl3) δ: 18.45, 20.35, 28.36, 36.60, 47.21, 58.69, 65.91, 100.68, 120.55, 124.75, 125.86, 125.90, 127.50, 128.07, 128.86, 129.66, 131.48, 133.47, 141.18, 144.32, 144.45, 150.96, 157.04. FTIR (neat) 3419, 3066, 2962, 2871, 1723, 1609, 1577, 1526, 1465, 1449, 1387, 1352, 1222, 1153, 1138, 1108, 1035, 982, 879, 847, 784, 759, 741, 698, 649. HRMS (ESI) m/e calcd. for (M+H+) 503.2182, (M+Na+) 525.1992, found 503.2176,525.1992
using a pyrex filter sleeve. After photolysis, the reaction solution was added to HONH3Cl (1.112 g, 16.0 mmol) and NaOAc (1.690 g, 19.2 mmol) in 3 mL of H2O, stirred at room temperature for 24 h. Then H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed, the oxime derivatives of the corresponding aldehydes compounds were obtained by flash coulumn chromatography. SⅡ-4 General procedures for photochemical Deprotection of 2c, 2d, 2e, 2f Protected carbonyl compound ( 0.50 mmol) in acetonitrile/H2O (15 mL/ 2 mL) was photolyzed using a pyrex filter sleeve. After photolysis, H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The corresponding aldehydes compounds were obtained by flash coulumn chromatography. SⅡ-5 Procedure for photochemical Deprotection of 2g and derivatization of the obtained aldehyde product. Photochemical deprotection of 2g and derivatization of the obtained carbonyl product 1g. 2g (198 mg, 0.64 mmol) in acetonitrile/H2O (15 mL/ 2 mL) was photolyzed using a pyrex filter sleeve. The obtained product solution was added to NH2CONHNH3Cl (1.784 g, 16.0 mmol) and NaOAc (1.690 g, 19.2 mmol) in 3 mL of H2O, stirred at 50 °C for 24 h. Then H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed, the oxime derivatives of the corresponding aldehydes compounds were obtained by flash coulumn chromatography.
Figure S1 photolysis apparatus SⅡ-3 General procedures for photochemical Deprotection of 2a, 2b and derivatization of the obtained carbonyl products. Protected carbonyl compound (0.50 mmol) in acetonitrile/ H2O (15 ml/2 ml) was photolyzed
SⅡ-6 Procedure for photochemical Deprotection of 2h Protected carbonyl compound ( 0.50 mmol) in acetonitrile (15 mL) was photolyzed using a pyrex filter sleeve and water (0.50 mmol) was added into the reaction mixture for every 15 min. After photolysis, H2O (10mL) was added to the reaction
Tetrahedron solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The corresponding aldehydes compounds were obtained by flash coulumn chromatography. 10
2-(2-nitrophenyl)propane-1,3-diol
11
5-(2-nitrophenyl)-2-phenyl-1,3-dioxane(2a)
12
2-(4-methoxyphenyl)-5-(2-nitrophenyl)-1,3dioxane(2b)
Tetrahedron
13
2-(4-chlorophenyl)-5-(2-nitrophenyl)-1,3dioxane（2c）
14
Tetrahedron
2-methoxy-4-(5-(2-nitrophenyl)-1,3-dioxan-2yl)phenol(2d)
15
5-(2-nitrophenyl)-2-(4-(trifluoromethyl)phenyl)1,3-dioxane(2e)
16
Tetrahedron
5-(2-nitrophenyl)-2-styryl-1,3-dioxane(2f)
17
2-heptyl-5-(2-nitrophenyl)-1,3-dioxane（2g)
18
Tetrahedron
(9H-fluoren-9-yl)methyl(2-methyl-1-(5-(2nitrophenyl)-1,3-dioxan-2-yl)propyl)carbamate(2h)
19
S0040-4039(20)30132-5 https://doi.org/10.1016/j.tetlet.2020.151709 TETL 151709
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
30 October 2019 2 February 2020 4 February 2020
Please cite this article as: Xu, J., Zhang, S., Yang, H., Wen, X., Peng, T., Xu, K., Wang, G., Wang, L., A Chemoselective Photolabile Protecting Group for Aldehydes, Tetrahedron Letters (2020), doi: https://doi.org/ 10.1016/j.tetlet.2020.151709
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A Chemoselective Photolabile Protecting Group for Aldehydes
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Jing Xu, Shouguo Zhang, Hongpeng Yang, Xiaoxue Wen, Tao Peng, Kaijun Xu*, Gang Wang*, Lin Wang*
1
Tetrahedron Letters journal homepage: www.elsevier.com
A Chemoselective Photolabile Protecting Group for Aldehydes Jing Xua, Shouguo Zhanga, Hongpeng Yanga, Xiaoxue Wena, Tao Penga, Kaijun Xub,*, Gang Wanga,*, Lin Wanga,* a b
Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, P. R. of China School of Science, China Pharmaceutical University, Nan Jing 211198, P. R. of China.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new and high-efficiency photolabile protecting group (PLPG) for aldehydes is described. The PLPG was introduced to aldehydes by using a Lewis acid. Results showed that the PLPG can be released rapidly and smoothly under ultraviolet (UV) irradiation with high efficiency and low cost. This PLPG can easily synthesized and also be selectively protect aldehydes in the presence of ketones.
Keywords: photolabile protecting group photodeprotection aldehyde compound o-nitrobenzyl group
Photolabile protecting groups (PLPGs) can be removed by irradiation1 and can release substrates in a spatially and temporally controlled manner. The releasing condition is mild, and no extra chemical reagent is not required2. PLPGs can be used to protect various chemical groups, such as alcohols3, amines4, and carboxylic acids5. Therefore, they are widely used in chemical synthesis and life science, such as synthesis of polypeptide6 or DNA7. Many new PLPGs such as nitroaryl8, coumarin-4-ylmethyl9, arylmethyl10, miscellaneous11, and arylsulfonyl groups12 have been developed and extensively used in many areas. However, only a few practically useful photolabile protecting groups for aldehydes, which are commonly used in modern organic synthesis, have been reported16. These are diferent from the traditional protecting groups protected aldehydes through an acetal moiety, and then are deprotected by reactions of acid catalysis13, Lewis acid coordination14 or redox15.The PLPG o-nitrophenylethylene glycol (Npeg, Figure 1) was first reported by Gravel17 et al. in 1984. Npeg can protect aldehyde compounds and ketone compounds, which will later be released under UV irradiation via deprotection. However, Npeg still have deficiencies, such as
Figure 1. Structure of Npeg (left) and Npp (right)
long reaction time for deprotection and inability to protect aldehyde selectively. 2-(2-nitrophenyl) propan1-ol (Npp, Figure 1), a new PLPG, was synthesized and used by Pfleiderer9 et al. for protecting hydroxyl groups in a series of nucleosides nucleosides; Npp was also applied to the synthesis of cyclic peptide as PLPG for carboxylic groups in our previous studies18, and the results of these studies indicated that Npp does not affect the stability of polypeptide. In this study, on the basis of Npeg and Npp, we further developed a new, simple, and efficient PLPG particularly for protecting aldehydes. 2-(2-nitrophenyl)1,3-propanediol (Nppd), as a developed PLPG for protecting aldehydes, was prepared from 2-nitrotoluene, a cheap raw material, via only one step reaction (Scheme 1). Nppd has various advantages, such as simple synthesis with low cost, high efficiency and selectivity for protecting aldehydes without affecting ketones. In addtion, the protected products of aldehydes (acetals) were stable in the absence of light and can rapidly release original aldehydes under UV irradiation with high efficiency.
Scheme 1. Synthesis of Nppd
Tetrahedron Letters
2
Some aldehydes (1a-h) and ketones (1i-k) were used to test Nppd’s protecting efficiency (Scheme 2, Table 1). The protection of aldehydes by Nppd can be achieved by only a onestep reaction in a relatively mild condition. Particularly, 1 equivalent aldehyde and 2 equivalents of Nppd were dissolved in CH2Cl2. Then, 1 equivalent of Lewis acid BF3•OEt2 was added as promoter, and anhydrous magnesium sulfate was added as dehydrating agent. The reaction was conducted at −15℃ for 90 min to generate the protected product (acetal). Results showed that the low temperature can promote the reaction. For example, the protection yield of 1b was 25% at room temperature, 37% at 0 ℃, and 47% at −15 °C (Table 2). However, the protection yield of 1b in the 24 h reaction was nearly the same with that in the 90 min reaction (Table 3). It can be concluded that the protection yield cannot be increased only by extending the reaction time. Other promoters, such as ptoluenesulfonic acid (TsOH), Pyridinium 4-toluenesulfonate (PPTS), and FeCl3, were also used for protecting the aldehyde. Among them, BF3•OEt2 has showed a best result. The reactivity of phenyl carbonyl groups vary depending on the substituents on the benzene ring. The electron-withdrawing substituents can enhance the reactivity while the electrondonating substituents reduce it, both of which will affect Nppd's protective ability. This conclusion has been proven by the production of 2a-c formed by 1a-c. Protective experiments on ketone groups were also studied and the results showed that the protective yields on cyclohexanone, phenylacetone, and diphenyl ketone were 0%, 4%, and 0%, respectively. Even if the MgSO4 was replaced by a more effective dehydrating agent, such as P2O5, the ketone group still can't be protected by Nppd. Therefore, only the aldehyde group can be protected by Nppd even in the presence of the ketone group. Photodeprotection then released the corresponding aldehyde. Some aldehydes releasing reaction was performed under UV light at 365nm in acetonitrile,
Table 2. The protection yields of 1b under different reaction Time(90 min)
instead of methanol reported by Wang16 et al, because the protected product (acetal) has the good solubility in acetonitrile. It is noticed that the photodeprotection reaction will not proceed without the presence of a certain amount of water. On this basis, a possible photodeprotection mechanism (Scheme 3) according to that of Npp9 was infered herein. The photorelease of Nppd from the aldehyde’s protected product (acetal) via a propertylabile semiacetal formed from the acetal by a β-elimination mechanism. The semiacetal was decomposed immediately andyields were lower than the actual values due to their volatility. These aldehydes need to be processed by derivation after the deprotection to eliminate the volatility. For example, if 1a released from 2a after the deprotection is unprocessed by derivation, the releasing yield will fall to 13%. Results of Nppd’s application are illustrated in Table 1, which show that the Nppd can protect aldehydes with relatively high protection and deprotection yields. The protection yields on the aromatic aldehydes (1a, 1b, 1c, 1d, 1e), the unsaturated aldehyde (1f), the amino aldehyde protected by Fmoc (1h), and the aliphatic aldehyde (1g) were 64%, 47%, 78%, 39%, 83%, 70%, 73%, and 59%, respectively. In addition, their deprotection yields were 71%, 83%, 96%, 87%, 86%, 75%, 65%, and 74%. Amino aldehydes are widely used to synthesize medicine and can be served as precursors of synthetic antimicrobial drugs penicillin19 or anticancer drug20, and they also play an important role in synthesizing pseudopeptide. In the meanwhile, the amino groups or aldehyde groups of amino aldehydes are usually protected when they are used because of their chemical instability21. In this study, the amino aldehyde protected by Fmoc (1h) can be protected by the Nppd, with protection yield of 59% and deprotection yield of 65%. Particularly, a certern amount of water (1 equivalent) has been added into the reaction mixture for every 15 min, to inhibit the thermal effects during the illumination, and to avoid side reaction of the amino aldehyde caused by excessive water.
Table 3. The protection yields of 1b under different reaction Time(0℃)
Reaction temperature(℃)
-15
0
25
Reaction time
90 min
24h
Yield
47
37
25
Yield
47
43
Scheme 2. Protection of Carbonyls with Nppd
Scheme 3. Possible photodeprotection mechanism
3 Table 1. Protection and photorelease of the Aldehydes Entry
a
Carbonyl Compounds
Protection Yielda (%)
Deprotection Yield b(%)
Irradiation Time (min)
1
a
64
71c
120
2
b
47
83c
60
3
c
78
96e
60
4
d
39
87e
60
5
e
83
86e
120
6
f
70
75e
75
7
g
73
74d
80
8
h
59
65e
90
9
i
0
--
--
10
j
4
--
--
11
k
0
--
--
Reaction conditions: 1 (1 mmol), Nppd (2 mmol), BF3.OEt2 (1 mmol), MgSO4 (8.0 mmol) in 6 ml CH2Cl2, −15 °C, 90 min, isolated yield.
b
Reaction conditions: Irradiated with a 250 W UV lamp (365 nm) equipped with a Pyrex filter sleeve, CH3CN (0.05 M), isolated yield.
c
Isolated as the oxime derivatives.
d
Isolated as the semicarbazone derivative.
e
Isolated as the aldehyde without derivatization
1c was protected by Nppd to obtain 2c, and the process of deprotection was detected by UV spectrophotometer (Figure 2). A new absorption peak appeared at the wavelength of 265nm in the photolysis reaction and would increase gradually with the
reaction time prolonging . This peak was the characteristic peak of 1c22, indicating that the original compound 1c could be released rapidly at a constant speed from its protected compound 2c under UV at 365nm.
Tetrahedron
4
Table 4. Comparative protecting efficiency of Nppd and Npeg protecting group
Protection yield for
Protection yield for (%)
(%)
Nppd
0
78
Npeg
96
97
Conclusion
Figure 2. UV spectra of 2c
Reversed-phase HPLC was used to investigate the photodeprotection progress of protected aldehydes. For example, 2f (0.02 M in CH3CN) was investigated during irradiation at 365nm (Figure 3).The analysis was performed on Agilent 1100 apparatus equipped with a Agela Venusil ASB C18 column (5 μm, 4.6 mm×250 mm) over a 10-70% gradient of acetonitrile： water with 0.1% TFA using a gradient elution in 30 min and flow rate of 1 mL/min.The wavelength for the detector was set at 220nm, and the injection volume was 10μL. Before irradiation, a peak with a retention time of 31.0 minutes, corresponding to 2f, was observed. During irradiation, this peak gradually disappeared, and a new peak (retention time 21.2 min, corresponding to 1f) appeared instead, proving that 2f released aldehyde under photoirradiation.
0min 1
40min
f
2 f
75min
Figure 3. HPLC traces recorded during irradiation of 2f
The performance of Nppd and Npeg in protecting efficiency, protecting selectivity, and deprotecting efficiency was compared (Table 4). The results shown in Table 2 indicated that Nppd’s protecting efficiency for the carbonyls was lower than that of Npeg. Npeg formed five-membered cyclic acetals, which were easy to obtain, but the aldehyde group cannot be selectively protected by Npeg, and the releasing speed of aldehydes from the Nppd acetal is faster than that from the Npeg acetal. The deprotecting yield of Nppd (65%–96%) is nearly the same with Npeg (31%–90%). However, the reaction time for Nppd was only approximately 33% of that for Npeg. Meanwhile, the amount of solvent for Nppd (15 mL CH3CN) was just only 10% of that for Npeg (200 mL benzene). The speed of Nppd’s releasing protected aldehydes is faster than that of Npeg, and the amount of solvent required is also less, and the solvent is more environmentally friendly.
Nppd, a new PLPG for aldehydes was designed and prepared from a cheap material, namely, 2-nitrotoluene, by a one-step reaction. The aldehydes can be protected by Nppd in mild condition and released rapidly and smoothly under the UV irradiation with high yields. This new PLPG can be used to protect aliphatic, aromatic, unsaturated, and amino aldehydes protected by Fmoc, and has a good application prospect in the field of organic synthesis.
Acknowledgments The authors are grateful to the National Natural Science Foundation of China (Grant No. 81273431, 21102176 and 21272273) for its financial support for this project. References and notes Klán, P.; Šolomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Chem. Rev. 2013, 113, 119. 2. (a) Bochet, C. G. J. Chem. Soc. Perkin Trans. 2002, 125.(b) Ma, C.; Zhang, Y.; Zhang, H.; Li, J.; Nishiyama, Y.; Tanimoto, H.; Morimoto, T.; Kakiuchi, K. Synlett. 2017, 28, 560. 3. Klán, P.; Pelliccioli, A. P.; Pospíšil, T.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 920. 4. Kammari, L.; Plíštil, L.; Wirz, J.; Klán, P. Photochem. Photobiol. Sci. 2007, 6, 50. 5. (a) Griesbeck, A. G.; Gudipati, M. S.; Hirt, J.; Lex, J.; Oelgemoller, M.; Schmickler, H.; Schouren, F. J. Org. Chem. 2000, 65, 7151. (b) Abe, M.; Chitose, Y.; Jakkampudi, S.; Thuy, P. T. T.; Lin, Q.; Van, B. T.; Yamada, A.; Oyama, R.; Sasaki, M.; Katan, C. Synthesis. 2017, 49, 3337. (c) Saneyoshi, H.; Ono, A. Chem. Pharm. Bull. 2018, 66, 147.（d）Tiwari, V.; Singh, A. K.; Chaudhary, P.; Seeberger, P. H.; Kandasamy, J. Org. Chem. Front. 2019, 6, 3859. 6. (a) Goard, M.; Aakalu, G.; Fedoryak, O. D.; Quinonez, C.; St. Julien, J.; Poteet, S. J.; Schuman, E. M.; Dore, T. M. Chem. Biol. 2005, 12, 685.(b) Tamao, K.; Kumada, M. In The Chemistry of the Metal–Carbon Bond; Hartley, F. R., Ed.; Wiley: New York, 1987; Chapter 9, p. 819; 7. (a) Young, D. D.; Lively, M. O.; Deiters, A. J. Am. Chem. Soc. 2010, 132, 6183. (b) Momotake, A.; Lindegger, N.; Niggli, E.; Barsotti, R. J.; Ellis-Davies, G. C. R. Nat. Methods. 2006, 3, 35. 8. (a) Patchornik, A.; Amit, B.; Woodward, R, B. J. Am. Chem. Soc. 1970, 92, 6333.(b) Komori, N.; Jakkampudi, S.; Motoishi, R.; Abe, M.; Kamada, K.; Furukawa, K.; Katan, C.; Sawada, W.; Takahashi, N.; Kasai, H.; Xue, B.; Kobayashi, T. Chem. Commun. 2016, 52, 331. (c) Watuthanthrige, N. D. A.; Kurek, P. N.; Konkolewicz, D. Polymer. Chem. 2018, 9, 1557. 9. (a)Hasan, A.; Stengele, K. P.; Giegrich, H.; Cornwell, P.; Isham, K. R.; Sachleben, R. A.; Pfleiderer, W.; Foote , R, S.Tetrahedron. 1997, 53, 4247. (b) Hammer, C. A.; Falahati, K.; Jakob, A.; Klimek, R.; Burghardt, I.; Heckel, A.;Wachtveitl, J.J. Phys. Chem. Lett, 2018, 9, 1448. 10. Piloto, A. M.; Rovira, D.; Costa, S. P. G.; Gonçalves, M. S. T. Tetrahedron. 2006, 62, 11955. 11. Kotzur, N.; Briand, B.; Beyermann, M.; Hagen, V. J. Am. Chem. Soc. 2009, 131, 16927. 12. Cosa, G.; Lukeman, M.; Scaiano, J. C. Chem. Res. 2009, 42, 599. 1.
5 13. Hiyama, T. ;Oishi, H. ;Saimoto, H. Tetrahedron Lett. 1985, 26, 2459. 14. Johnson, W. ; Edington, C.; Elliott, J. ; Silverman, I. J. Am. Chem. Soc. 1984, 106, 7588. 15. McDonald, C. E.; Nice, L. E.; Shaw, A. W.; Nestor, N. B. Tetrahedron Lett. 1993, 34, 2741. 16. (a)Wang, P.; Hu, H.; Wang, Y .; Organic Letters, 2007, 9, 1533. (b) Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984. (c) Wang, P.; Wang, Y.; Hu, H.; Spencer, C.; Liang, X.; Pan, L. J. Org. Chem. 2008, 73, 6152. 17. Hébert, J.; Gravel, D. Can. J. Chem. 1983, 61, 400. 18. Wang, G.; Peng, T.; Zhang, S.; Wang, J.; Wen, X.; Yang, H. ; Hu, L.; Wang, L. RSC. Adv. 2015, 5, 28344. 19. Sheehan, J. C.; Henbry-Logan, K. R. J. Am. Chem. Soc. 1957, 79, 1262. 20. Acton, E. M.; Fujiwara, A. N.; Henry, D. W. J. Med. Chem. 1974, 17, 659. 21. Mestrom, L.; Bracco, P.; Hanefeld, U. Eur. J. Org. Chem. 2017,47, 7019. 22. Zarei, M.; Zolfigol, M. A.; Moosavi-Zare, A. R.;Noroozizadeh, E. J. Iran.Chem. Soc, 2017, 14, 2187.
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Aldehydes are chemically active and are often need to be protected. Photolabile protecting groups are widely used in organic synthesis. Photolabile protecting group for aldehydes has a good application prospect.
A Chemoselective Photolabile Protecting Group for Aldehydes
Declaration of interests √ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Jing Xua, Shouguo Zhanga, Hongpeng Yanga, Xiaoxue Wena, Tao Penga, Kaijun Xub,*, Gang Wanga,*, Lin Wanga,* a
Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, P. R. of China b School of Science, China Pharmaceutical University, Nan Jing 211198, P. R. of China.
E-mail: [email protected]
A Chemoselective Photolabile Protecting Group for Aldehydes
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Jing Xu, Shouguo Zhang, Hongpeng Yang, Xiaoxue Wen, Tao Peng, Kaijun Xu*, Gang Wang*, Lin Wang*
6
Tetrahedron
7 SⅠ. General information All chemicals and solvents were of analytical grade and were used without further purifications. All organic solutions were concentrated by rotary evaporation under reduced pressure. Flash column chromatography was performed employing 230400 mesh silica gel. The progress of reactions was monitored by silica gel thin layer chromatography (TLC) plates . UV-visible spectra were obtained using a Shimadzu UV-2501PC UV-visible Recoroding spectrophotometer, with the sample concentration of 8.56*10-5 M. 1H and 13C NMR spectra were recorded on a Varian INOVA 600 spectrometer and Bruker 400 NMR spectrometer, chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.26, DMSO-d6: 2.53). Data were presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and /or multiple resonances), coupling constant in Hertz (Hz), integration. Photolysis was with a 250W UV lamp (365nm) . SⅡ-1 Preparation of 2-(2-nitrophenyl)-1,3propanediol(Nppd)
Nitrotoluene (6.86 g, 50 mmol), [HCHO]n (3.15g, 102 mmol) and Triton B (8mL, 40%) were stirred in DMSO (80 mL) for 8h at room temperature in the dark. The reaction was neutralized to pH 7 with 2 M hydrochloric acid, and then H2O (80 mL) was added, extracted with EtOAc(3×40 mL). The organic layer is dried with magnesium sulfate and then condensed. The product was obtained as yellow oil by column chromatography (yield: 6.01g, 61%). 1 H-NMR (CDCl3) δ: 3.64 (m, 1H), 3.70 (m, 2H), 3.72 (m, 2H), 4.72 (t, 2H), 7.58 (m, 1H), 7.59 (m, 2H), 7.69 (m, 1H). 13CNMR (400MHz, CDCl3) δ: 44.59, 61.88, 123.42, 127.20, 129.45, 132.22, 135.26, 151.21. HRMS (ESI) m/e calcd. for (M+Na+) 219.9689, found 220.0724. SⅡ-2 General Procedures for Preparation of 2a, 2b, 2c, 2d, 2e, 2d, 2f, 2g, 2h
(2-nitrophenyl)-1,3-propanediol(394 mg, 2.00 mmol),aldehyde(1.00 mmol), BF3·OEt2(142 mg, 1.00 mmol) and MgSO4 in 6 mL of CH2Cl2 were stirred at –15 °C for 90 min, then saturated NaHCO3 solution(20 mL) was added rapidly , extracted with dichloromethane (DCM) (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The product was purified by flash chromatography (silica, petroleum ether:ethyl acetate= 10:1) . 5-(2-nitrophenyl)-2phenyl-1,3dioxane(2a), 182 mg (64%), Light yellow solid, Rf 0.5 (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, DMSO-d6) δ: 3.54 (m, 1H), 4.20 (m, 4H), 5.74 (s, 1H), 7.38(m,2H)，7.45 (m, 2H), 7.74 (m, 2H), 7.93 (m, 1H). 13CNMR (400MHz, CDCl3) δ: 36.05, 70.73, 71.60, 94.18, 101.81, 124.74, 126.16, 128.21, 128.36, 128.38, 129.41, 131.55, 132.66, 137.89, 151.02. FTIR (neat) 3434, 2852, 1608, 1576, 1523，1375, 1374, 1284, 1174, 1154,1134, 984, 972, 844, 749 , 696, 653, 641, cm -1 ; HRMS (ESI) m/e calcd. for (M+Na+) :308.0901, found 308.0892.
2-(4methoxyphenyl)-5-(2-nitrophenyl)-1,3dioxane(2b), 148 mg (47%), Light yellow solid,Rf 0.5 (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, CDCl3) δ:3.29 -3.84 (m, 4H), 4.07(m,1H), 4.42 (m, 3H), 5.57 (d, 1H), 6.96 (m, 2H), 7.42-7.67 (m, 5H), 7.46-8.49 (dd, 1H). 13 CNMR (400MHz, CDCl3) δ: 36.02, 36.72, 55.34, 70.83, 71.59, 101.75, 101.86, 113.73, 113.77, 124.41, 124.72, 127.41, 127.48, 127.51, 128.16, 128.35, 130.42, 130.77, 131.36, 131.63, 132.63, 133.07, 137.53, 149.42, 151.03. FTIR (neat) 3442, 3074, 2969, 2865, 1613, 1576, 1524, 1388, 1352,1299, 1282, 1249, 1215, 1152, 1133, 1065, 1025,977, 931, 844, 785, 748, 698 cm 1 . HRMS (ESI) m/e calcd. for (M+H+):316.1185, found 316.1179.
Tetrahedron 13 CNMR (400MHz, CDCl3) δ: 35.53, 70.71, 94.16, 100.62, 124.82, 125.27, 125.31, 126.64, 128.28, 128.32, 128.75, 131.35-132.95 (q, J=640Hz), 2-(4132.75, 141.47, 150.92. chlorophenyl)-5-(2-nitrophenyl)-1,3-dioxane(2c), HRMS (ESI) m/e calcd. for (M+H+):354.0917, 249 mg (78%), Light yellow solid,Rf 0.4 found 335.1021. (petroleum ether/ethyl acetate = 3/1). 1 H-NMR (400MHz, DMSO-d6) δ: 3.49 (m, 1H), 4.09 (m, 2H), 4.12 (m, 2H), 5.36 (d, 1H), 6.31 (dd, 1H), 6.76 (d，1H) 7.36 (m, 3H), 7.52 (m, 3H), 7.71 (m, 2H), 7.91 (m, 1H). 13CNMR (400MHz, 5-(2-nitrophenyl)-2CDCl3) δ: 35.99, 71.54, 100.94, 124.79, 127.65, styryl-1,3-dioxane(2f), 217 mg (70%), Light 128.28, 128.31, 128.53, 131.37, 132.71, 134.90, yellow solid, Rf 0.5 (petroleum ether/ethyl acetate 136.44, 150.98. = 3/1). FTIR (neat) 3434, 2952, 1607, 1577, 1523, 1384, 1 H-NMR (400MHz, DMSO-d6) δ:3.49 (m, 1H), 1348, 1281,1265,1222, 1155, 1135, 1015,846, 806, -1 4.09 (m, 2H), 4.12 (m, 2H), 5.36 (m, 1H), 6.31(dd, 748, 726, 698, 681 cm ; + 1H), 6.76 (d, 1H), 7.36 (m, 3H), 7.51 (m, 3H), 7.71 HRMS (ESI) m/e calcd. for (M+H ): 342.0498, (m, 2H), 7.91 (m, 1H). 13CNMR (400MHz, CDCl3) found 342.0504. δ: 33.69, 36.03, 71.27, 70.47, 100.94, 101.08, 124.36, 124.76, 124.96, 125.21, 126.91, 127.54, 128.30, 128.33, 128.37, 128.61, 128.62, 131.39, 131.55, 132.65, 133.16, 133.76, 133.92, 135.87, 135.90, 137.39, 149.39, 150.96. FTIR (neat) 3433, 3081,3028, 2981, 2839, 1606, 2-methoxy-4-(5-(21575, 1520, 1496, 1461, 1380, 1364, 1343, nitrophenyl)-1,3-dioxan-2-yl)phenol(2d), 129 mg 1280,1270, 1154, 1137, 1056,971, 849, 749, 706, (39%), yellow oil, Rf 0.4 (petroleum ether/ethyl 679cm -1 ; acetate = 2/1). 1 HRMS (ESI) m/e calcd. for (M+ H+) 312.1158, H-NMR (400MHz, DMSO-d6) δ: 3.38 (m, 1H), (M+Na+) 334.0147, found 312.1231, 334.1046 3.77 (m, 3H), 4.15 (m, 2H), 4.20 (m, 2H), 5.62 (s, 1H), 6.75 (d, 1H),6.77 (dd, 1H), 6.91 (d, 1H), 7.55 (m, 1H), 7.72 (m, 2H), 7.91 (m, 1H), 9.11 (s, 1H). 13 CNMR (400MHz, CDCl3) δ: 33.63, 35.91, 55.83, 70.50, 71.71, 101.68, 101.82, 108.24,108.41, 113.89, 104.12,119.19, 119.59, 124.39, 124.64, 2-heptyl-5-(2124.79, 127.48, 128.13, 128.26, 131.26, 132.61, nitrophenyl)-1,3-dioxane（2g）, 222 mg (73 %), 132.94, 146.14, 146.23, 146.31, 146.46,150.67. yellow oil, Rf 0.5 (petroleum ether/ethyl acetate = HRMS (ESI) m/e calcd. for (M+H+):332.1157, 6/1). found 332.1129. 1 H-NMR (400MHz, CDCl3) δ: 1.25 (t, 3H), 1.56 (m, 1H), 3.37 (m, 1H), 4.06 (m, 1H), 4.05 (m, 1H), 4.72 (t,1H), 7.67 (m, 2H), 7.88 (m, 1H), 7.98 (m, 2H). 13 C-NMR (400MHz, CDCl3) δ: 14.12, 22.67, 23.99, 29.21, 29.45, 31.78, 34.82, 36.14, 71.19, 5-(2-nitrophenyl)-2102.59, 124.63, 128.04, 128.31, 131.69, 132.55, (4-(trifluoromethyl)phenyl)-1,3-dioxane(2e）, 353 151.00. mg (83%), white solid, Rf 0.4 (petroleum HRMS (ESI) m/e calcd. for (M+ K+) 346.2767, ether/ethyl acetate = 2/1). found 346.2740. 1 H-NMR (400MHz, DMSO-d6) δ: 3.61 (m, 1H), 3.91 (m, 1H), 4.25 (m, 1H), 4.28 (m,4H), 4.89 (m, 1H), 7.72(m, 1H),7.76 (m, 1H), 6.91 (d, 1H), 7.55 (m, 1H), 7.75-7.76 (m, 6H), 7.77 (m, 1H),. 8
9
(9H-fluoren-9-yl)methyl(2methyl-1-(5-(2-nitrophenyl)-1,3-dioxan-2yl)propyl)carbamate(2h), 270 mg (59%), brown soild, Rf 0.4 (petroleum ether/ethyl acetate = 2/1). 1 H-NMR (400MHz, CDCl3) δ: 0.96 (d, 6H), 1.26 (t, 2H), 1.9 (m, 1H), 4.11 (m, 2H), 4.29 (m, 2H), 4.43 (m, 4H), 5.1 (d, 1H), 7.34 (m, 8H), 7.40 (m, 1H), 7.76 (m, 2H), 7.78 (m, 3H). 13C-NMR (100MHz, CDCl3) δ: 18.45, 20.35, 28.36, 36.60, 47.21, 58.69, 65.91, 100.68, 120.55, 124.75, 125.86, 125.90, 127.50, 128.07, 128.86, 129.66, 131.48, 133.47, 141.18, 144.32, 144.45, 150.96, 157.04. FTIR (neat) 3419, 3066, 2962, 2871, 1723, 1609, 1577, 1526, 1465, 1449, 1387, 1352, 1222, 1153, 1138, 1108, 1035, 982, 879, 847, 784, 759, 741, 698, 649. HRMS (ESI) m/e calcd. for (M+H+) 503.2182, (M+Na+) 525.1992, found 503.2176,525.1992
using a pyrex filter sleeve. After photolysis, the reaction solution was added to HONH3Cl (1.112 g, 16.0 mmol) and NaOAc (1.690 g, 19.2 mmol) in 3 mL of H2O, stirred at room temperature for 24 h. Then H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed, the oxime derivatives of the corresponding aldehydes compounds were obtained by flash coulumn chromatography. SⅡ-4 General procedures for photochemical Deprotection of 2c, 2d, 2e, 2f Protected carbonyl compound ( 0.50 mmol) in acetonitrile/H2O (15 mL/ 2 mL) was photolyzed using a pyrex filter sleeve. After photolysis, H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The corresponding aldehydes compounds were obtained by flash coulumn chromatography. SⅡ-5 Procedure for photochemical Deprotection of 2g and derivatization of the obtained aldehyde product. Photochemical deprotection of 2g and derivatization of the obtained carbonyl product 1g. 2g (198 mg, 0.64 mmol) in acetonitrile/H2O (15 mL/ 2 mL) was photolyzed using a pyrex filter sleeve. The obtained product solution was added to NH2CONHNH3Cl (1.784 g, 16.0 mmol) and NaOAc (1.690 g, 19.2 mmol) in 3 mL of H2O, stirred at 50 °C for 24 h. Then H2O (10mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed, the oxime derivatives of the corresponding aldehydes compounds were obtained by flash coulumn chromatography.
Figure S1 photolysis apparatus SⅡ-3 General procedures for photochemical Deprotection of 2a, 2b and derivatization of the obtained carbonyl products. Protected carbonyl compound (0.50 mmol) in acetonitrile/ H2O (15 ml/2 ml) was photolyzed
SⅡ-6 Procedure for photochemical Deprotection of 2h Protected carbonyl compound ( 0.50 mmol) in acetonitrile (15 mL) was photolyzed using a pyrex filter sleeve and water (0.50 mmol) was added into the reaction mixture for every 15 min. After photolysis, H2O (10mL) was added to the reaction
Tetrahedron solution, and the mixed solution was extracted with dichloromethane (3×10 mL). The organic layer is dried with magnesium sulfate and then condensed. The corresponding aldehydes compounds were obtained by flash coulumn chromatography. 10
2-(2-nitrophenyl)propane-1,3-diol
11
5-(2-nitrophenyl)-2-phenyl-1,3-dioxane(2a)
12
2-(4-methoxyphenyl)-5-(2-nitrophenyl)-1,3dioxane(2b)
Tetrahedron
13
2-(4-chlorophenyl)-5-(2-nitrophenyl)-1,3dioxane（2c）
14
Tetrahedron
2-methoxy-4-(5-(2-nitrophenyl)-1,3-dioxan-2yl)phenol(2d)
15
5-(2-nitrophenyl)-2-(4-(trifluoromethyl)phenyl)1,3-dioxane(2e)
16
Tetrahedron
5-(2-nitrophenyl)-2-styryl-1,3-dioxane(2f)
17
2-heptyl-5-(2-nitrophenyl)-1,3-dioxane（2g)
18
Tetrahedron
(9H-fluoren-9-yl)methyl(2-methyl-1-(5-(2nitrophenyl)-1,3-dioxan-2-yl)propyl)carbamate(2h)
19