Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
H2O‑Regulated Chemoselectivity in Oxa- Versus Aza-Michael Reactions Rong Huang,†,‡ Zhihong Li,† Jianghui Yu,† Hongli Chen,*,† and Biao Jiang*,† †
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China
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S Supporting Information *
ABSTRACT: A H2O-regulated chemoselective addition in oxa- and aza-Michael reactions for aminoalcohols and mixtures of structurally similar alcohols and amines was reported. The oxa-Michael reactions might be kinetically controlled, and the reactions to produce O-selective products were slowed by the addition of water. The electrophilicity of Michael acceptors and the steric hindrance of Michael donors also affect the ratios of O/N products. This method offers novel ideas over conventional metal-catalyzed or ligand-induced strategies.
H
catalytic solid NaOH or KOH was used as a base (Table 1, entries 2−4).
etero-Michael reactions are the most valuable and widely used methods in organic chemistry for the mild formation of C−heteroatom bonds. The oxa-Michael reactions,1 which involve the use of oxygen-centered nucleophiles, are more difficult to achieve, compared to the aza-Michael reactions,2 which grant efficient access to nitrogen-containing conjugation, because amines are innately more nucleophilic, compared to alcohols. The utility of metal reagents and catalysts to drive chemoselectivity for ambident O/N nucleophiles is a general methodology.2,3 Catalyst-controlled chemoselective reactions of oxa- over aza-Michael reactions have also been addressed recently (eq 1).4 The reversed chemoselectivity was conducted based on a metal salt catalyst and a strong organometallic base under anhydrous conditions. Optimized metallic catalyst systems attract more attention, and little is known about the effects of water and electrophiles to the chemoselectivity of hetero-Michael reactions. Herein, we report our findings on the H2O-regulated chemoselective Oand N-Michael addition reactions (eq 2). We also demonstrated that the reactivity of electrophiles and the steric hindrance of substrates have a great influence on the chemoselectivity. Our group is interested in the development of vinylsulfonamides as Michael acceptors to selective probe nucleophiles,5 and we reported that N-methyl-N-phenylvinylsulfonamide (1)-based Michael addition was able to mediate cysteine-selective5a or lysine-selective5c conjugation. In order to expand the application of vinylsulfonamides to siteselectively modify a nucleophile, compound 1 was further employed to react with an ambident nucleophile 3-amino-3phenylpropan-1-ol (2). Preliminary experiments were performed in tetrahydrofuran (THF), which was used as commercially available grade, regarding the effect of different bases (Table 1, entries 1−8). Interestingly, an oxygen-selective product (3) was exclusively formed in good yield, when © XXXX American Chemical Society
To demonstrate the generality of this novel method, we further evaluated the substrate scope of the chemoselective oxa-Michael addition with a variety of aminoalcohols (Scheme 1). The result showed that many α-aminoalcohols provided the corresponding O-adducts with excellent chemoselectivity (5− 10). The length of the alkyl chain had no impact on the chemoselectivity (11 and 12). A change of hydrophilicity or hydrophobicity also did not affect the chemoselectivity (13 and 14). Secondary alcohol retained the selectivity to afford Oadduct (15). This method was then used to modify atenolol, which is a medication of beta blockers. After treatment with compound 1 under the standard condition, atenolol was converted to oxygen-selective product 16 in good yield (see Scheme 2). We further applied the method to investigate the chemoselectivity among the mixtures of structurally similar alcohols (17a−17c) and amines (18a−18c). Similarly, O-adducts (19− Received: April 17, 2019
A
DOI: 10.1021/acs.orglett.9b01342 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Table 2. Chemoselective Addition of Alcohols (17a−17c) over Amines (18a−18c)
entry
base
time (h)
3b (%)
4b (%)
1 2 3 4 5 6 7 8
LiOH (solid) NaOH (solid) KOH (solid) KOH (solid) K2CO3 (solid) Et3N DBU DABCO (solid)
2 2 2 overnight 2 2 2 2
0 82 92 98 0 0 0 0
0 0 0 0 0 0 0 0
a
Reaction conditions: 1 (0.05 mol), 2 (0.06 mol), base (0.025 mol), THF (0.5 mL), rt. bYields were determined by 1H NMR analysis of crude mixture [see Figure s1 in the Supporting Information (SI)].
Scheme 1. Substrate Scope of Amino Alcohols
Figure 1. Effects of water on the chemoselectivity for 5-amino-1pentanol. (Yields were determined by high-performance liquid chromatography (HPLC), and the curves were obtained using a normalization method.)
Scheme 2. Chemoselective Modification of Atenolol
excellent yield to no product along with an increase in the amount of water (Figure 2A). In addition, the yield enhancement of the aza-addition product 25 was driven by the increase of water (Figure 2B).
21) were obtained with a high yield rather than N-adducts (Table 2). On the other hand, we found that when an aqueous solution of KOH replaced solid KOH for the reaction of compounds 1 and 2, the oxa-addition product decreased significantly. We then paid attention to investigate the effect of water on these reactions. The experiments that had compound 1 reacting with 5-amino-1-pentanol, in which the alcohol and amino have similar exposures were conducted under different quantities of water. The result showed that the O-adduct 22 was chemoselectively produced with no extra or a small amount of water and decreased rapidly with the increase of water (see Figure 1). Conversely, the yield of the aza-addition product 23 was increased along with the addition of water. A single Nselective product 23 was obtained in good yield when the water content was more than 14% (70 μL water in 500 μL (THF and H2O) total solution). We also examined the effect of water on the reaction of 1 with pentylalcohol or pentylamine. Consistent with the above results, the amount of oxa-addition product 24 decreased from
Figure 2. Effects of water on the chemoselectivity for (A) pentylalcohol and (B) pentylamine. (Yields were determined by HPLC, and the curves were obtained using a normalization method.) B
DOI: 10.1021/acs.orglett.9b01342 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters On the other hand, we have observed that the reaction rates to produce O-adducts are much faster than those of N-adducts. The 1H NMR spectra showed that the reaction to produce Oproduct 6 was completed within 20 min, whereas the reaction to form N-product 27 lasted for 7 h (see Scheme 3, as well as
Scheme 4. Effects of Electrophiles on the Chemoselectivity
Scheme 3. Reaction Time Needed To Complete the O/N Additions In addition, when the electrophile 28 replaced 1 to react with 26, the 1H NMR spectra showed that the reaction was very fast and completed with 10 min (see Figure s6 in the Supporting Information), which demonstrated that stronger electrophile accelerated the reaction and facilitated to yield Oproduct. Reaction rate can also be influenced by steric hindrance. To get a better understanding of the reaction mechanism, (1S,2R)(−)-cis-1-amino-2-indanol (32), which is a sterically more congested aminoalcohol was examined to react with electrophiles 1 and 28. A mixture of O/N-addition products emerged for 1 and stronger electrophile 28 retained the capability to selectively form O-selective product. On the other hand, when 28 reacted with 32 in a solvent containing water (THF/H2O = 4:1), N-selective product was obtained (Scheme 5). When
Figure s5 in the Supporting Information). Based on this, we speculated that the chemoselectivity might be determined by competing rates and the O-selective reaction was kinetically controlled. If that is the case, water will retard the reaction rate to form O-adducts, which results in the change of the ratios of O/N-products. To prove this point, we examined the effects of water to the reaction rate in the process of forming O-adduct 24. As shown in Figure 3, the rate of oxa-Michael reaction decreased when the amount of water was increased. When the
Scheme 5. Reaction Selectivity Influenced by Steric Hindrance
Figure 3. Water effects on the reaction rates for O-product 24.
molar ratio of water (equivalent to 1) was within 5, a prolonged time was required to complete the reaction with the increase of water. Once more water was present in the reaction, the yield of 24 obviously decreased, as shown in Figure 2A. According to the results above, other factors that influence the reaction rate might also affect the chemoselectivity. This left us to consider that stronger electrophiles will promote the oxa-Michael reaction to happen faster, whereas weaker electrophiles might not be robust enough to make O-products form quickly and they would be likely to weaken the chemoselectivity. To verify this hypothesis, a series of Michael acceptors (28−31) other than compound 1 with different activity were set out to react with L-(+)-alaninol (26) under the identical reaction conditions. As mentioned in the previous section, compound 1 reacted with 26, resulting in a single Oadduct (6 in Table 2 and Scheme 3) in high yield. Phenylvinylsulfone 28 with high electrophilic power also led the formation of a selective O-addition product. Reaction of 26 with (vinylsulfinyl)benzene (29), which has a reduced electrophilicity, a mixture of O/N-addition products were produced. When a weaker electrophile, N-phenylacrylamide (30) was employed to treat with 26, the O-addition product was not detected and an N-addition product was yielded in 18 h. No reaction occurred for the weakest electrophile, acrylonitrile (31) (see Scheme 4).
amino-2-propanol (33), in which the hydroxyl group has a hindered environment compared to the amino group, was employed to react with 1 or 28, only N-product was obtained for the both electrophiles. Given the efficient H2O-regulated chemoselectivity in oxaand aza-Michael addition reactions, we continued to an instructive case achieving high levels of chemoselectivity step by step with no reliance on protecting groups. Under identical conditions, as always, the O-adduct 3 and N-adduct 4 were chemoselectively obtained in high yield when compound 1 reacted with aminoalcohol 2 on condition in THF or 20% H2O solution (THF/H2O = 4:1), respectively. And they further reacted with compound 1 in the presence or absence of water, respectively, producing the same product 34 bothfeyield (Scheme 6). Scheme 6. Application of the Method To Achieve Selective Reaction
C
DOI: 10.1021/acs.orglett.9b01342 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(4) (a) Uesugi, S.; Li, Z.; Yazaki, R.; Ohshima, T. Angew. Chem., Int. Ed. 2014, 53, 1611. (b) Li, Z.; Yazaki, R.; Ohshima, T. Org. Lett. 2016, 18, 3350. (c) Li, Z.; Tamura, M.; Yazaki, R.; Ohshima, T. Chem. Pharm. Bull. 2017, 65, 19. (5) (a) Huang, R.; Li, Z.; Sheng, Y.; Yu, J.; Wu, Y.; Zhan, Y.; Chen, H.; Jiang, B. Org. Lett. 2018, 20, 6526. (b) Li, Z.; Huang, R.; Xu, H.; Chen, J.; Zhan, Y.; Zhou, X.; Chen, H.; Jiang, B. Org. Lett. 2017, 19, 4972. (c) Chen, H.; Huang, R.; Li, Z.; Zhu, W.; Chen, J.; Zhan, Y.; Jiang, B. Org. Biomol. Chem. 2017, 15, 7339. (d) Huang, R.; Li, Z. H.; Ren, P. L.; Chen, W. Z.; Kuang, Y. Y.; Chen, J. K.; Zhan, Y. X.; Chen, H. L.; Jiang, B. Eur. J. Org. Chem. 2018, 2018, 829.
In summary, we have developed a new protocol for chemoselective oxa- and aza-Michael reactions of aminoalcohols and mixtures of structurally similar alcohols and amines. This H2O-regulated chemoselective method offers novel ideas and potential advantages in economic cost and environmental consideration over conventional metal-catalyzed or ligand-induced strategies. We observed that the reaction rates to produce O-adducts were much faster than that of N-adducts; and the reactions to produce O-selective products were slowed by the addition of water. We considered O-selective products were kinetically controlled. Water affects the reaction rate resulting in the influence to the chemoselectivity. We also demonstrated that other factors (the electrophilicity of Michael acceptors and the steric hindrance of Michael donors), which influence the reaction rate of oxaMichael addition also affect the chemoselectivity. Strong electrophiles promote the formation of O-selective product, and aminoalcohols having sterically less congested hydroxyl groups are more prone to yield O-adducts. Future work will focus on this water-regulated chemoselective addition in other applications.
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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.9b01342.
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Experimental details, characterization data, and NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Hongli Chen: 0000-0002-9002-2603 Biao Jiang: 0000-0002-4292-7811 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Peixiang Ma, Dr. Wenzhang Chen, and Dr. Ke Song (ShanghaiTech University, SIAIS, Analytical Chemistry and Bioinformatics platform) for helpful discussions and technical assistance with NMR experiments and mechanical calculations.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b01342 Org. Lett. XXXX, XXX, XXX−XXX
