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4-aza-aryl alkanol compound and synthetic method thereof

A technology for azaarylalkane and alcohol compounds, which is applied in the field of synthesis of 4-azaarylalkanol compounds, can solve the problem of not being able to meet the needs for the diverse synthesis of complex alcohol derivatives in synthetic chemistry, difficulty in selectivity, and uniform splitting. Difficulty responding

Active Publication Date: 2018-10-16
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0002] sp3 carbon-hydrogen bond (C(sp3)-H) activation and functionalization reaction is the research frontier and hotspot of synthetic chemistry at present, which has the advantages of high efficiency and atom economy, but due to the low activity and difficult selectivity of C(sp3)-H , still faces great challenges
The hydrogen atom transfer reaction (HAT) induced by free radicals is an effective means to activate C(sp3)-H and achieve functionalization. First, under the conditions of heating and ultraviolet irradiation, alkoxy radicals are generated, and then through Hydrogen migration, cleavage of C(sp3)-H, and subsequent substitution reaction to obtain functionalized alcohol compounds, but under harsh conditions, direct use of alkanol as a substrate is prone to β-position C-C fragmentation, while O-H homolysis The reaction is difficult, and it is not easy to generate alkoxy radicals, so it is rarely used, and other substrates are often used instead to generate alkoxy radicals, such as: nitrite, peroxide, sulfonate, alkoxy lead salt , alkoxy hypohalite, etc., but these compounds are often difficult to prepare or handle, and the atom economy is not high; in addition, because the carbon-hydrogen bond energy on the carbon far from the hydroxyl group in the alkanol is much higher than that of the adjacent Therefore, it is more difficult to selectively activate the carbon-hydrogen bond on the farther carbon. For example, the alkylation reaction on the heteroaryl ring is often added to the heteroaryl ring by the activated alkyl group of C(sp3)-H Realization, the method of direct alkylation is very limited, the typical one is the Minisci reaction, but the activation of C(sp3)-H and the formation of alkyl groups are mainly determined by the bond energy of the carbon-hydrogen bond in the molecule BDEs, rarely involving regioselectivity , and metal-containing reagents such as silver nitrate are required
[0003] The existing regioselective long-range carbon-hydrogen bond activation method is mainly realized through the hydrogen atom transfer reaction induced by alkoxyl radicals, but transition metals must be used as catalysts, and the scope of substrate application is narrow, which is far from meeting the complex requirements in synthetic chemistry. Requirements for Diversified Synthesis of Alcohol Derivatives

Method used

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  • 4-aza-aryl alkanol compound and synthetic method thereof
  • 4-aza-aryl alkanol compound and synthetic method thereof
  • 4-aza-aryl alkanol compound and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088]

[0089] Under nitrogen protection, add heteroaryl compound 1a (0.4mmol), alcohol 2a (x mmol) and organic solvent (2.0mL) into the reaction flask, stir to dissolve, then add hypervalent aryl iodide compound Ar-I to the mixed solution III (y mmol), irradiate the reaction vial with light of specific power and wavelength (hv) and keep it at room temperature, or place the reaction vial in a dark room to heat. After the reaction is complete, add aq.KOH until pH>8 to quench the reaction , extracted with ethyl acetate (3x 10mL), combined the organic phases, washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by ethyl acetate / petroleum ether silica gel column chromatography to obtain compound 3a.

[0090]

[0091] 3a: yellow or colorless oily liquid, 1 H NMR (400MHz, CDCl 3 )δ8.03(d,J=8.4Hz,1H),7.92(dd,J=8.0,0.8Hz,1H),7.64(ddd,J=8.0,6.8,1.2Hz,1H)...

Embodiment 2

[0095]

[0096] Under the protection of inert gas, add heteroaryl compound 1b (0.4mmol), alcohol 2a (2.0mmol) and dichloromethane DCM (2.0mL) into the reaction flask, stir to dissolve, then add PIFA (0.92mmol) to the mixed solution , place the reaction bottle under 100W blue LED light, and use a fan to maintain room temperature. After the reaction is complete, add aq.KOH until pH>8 to quench the reaction, extract with ethyl acetate (3x 10mL), combine the organic phases, and saturate Washed with brine, dried and filtered over anhydrous sodium sulfate, concentrated under reduced pressure, separated and purified by ethyl acetate / petroleum ether silica gel column chromatography to obtain compound 3b.

[0097] 3b: yellow oily liquid, 1 H NMR (400MHz, CDCl 3 )δ8.12(dd, J=8.4,0.8Hz,1H),8.01(d,J=8.4Hz,1H),7.67(ddd,J=8.4,6.8,1.2Hz,1H),7.52(ddd,J =8.0,6.8,0.8Hz,1H),7.36(s,1H),3.59(t,J=6.4Hz,2H),3.33(s,1H),3.11-3.01(m,1H),1.92-1.82( m,1H),1.77-1.67(m,1H),1.64-1.53(m,1H),1.50-1.39(m...

Embodiment 3

[0099]

[0100] The difference between this example and Example 2 is that 1b in Example 2 was replaced by 1c, and the rest of the operation was basically the same as that of Example 2, and compound 3c was obtained after reaction and purification.

[0101] 3c: yellow oily liquid, 1 H NMR (400MHz, CDCl 3 )δ8.01-7.95(m,2H),7.58(ddd,J=8.4,6.8,1.2Hz,1H),7.41(ddd,J=8.0,6.8,0.8Hz,1H),7.11(s,1H) ,3.68(br,1H),3.60(t,J=6.4Hz,2H),3.57-3.46(m,1H),2.63(s,3H),1.88-1.66(m,2H),1.64-1.43(m ,2H),1.30(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl 3 )δ158.1,153.2,147.4,128.6,128.5,125.0,122.3,118.0,61.7,33.0,32.6,30.2,24.7,20.7.FT-IR:ν(cm -1 ) 2963, 2934, 2862, 1598, 1562, 1509, 1458, 1415. HRMS [ESI] calcd for C 15 h 20 NO[M+H] + 230.1539, found 230.1536.

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Abstract

The invention discloses a 4-aza-aryl alkanol compound and a synthetic method thereof. The synthetic method comprises the following steps: reacting an aza-aryl compound as shown in formula I with alcohol as shown in formula II under the condition of thermal energy and / or light energy and / or microwave in an organic solvent in an anaerobic atmosphere and in the presence of a hypervalent iodine aryl compound Ar-IIII to obtain the 4-aza-aryl alkanol compound as shown in formula III. By the synthetic method of the 4-aza-aryl alkanol compound, alkanol can be directly used as a substrate, 4-position C(sp3)-H is activated in a regioselective manner and is subjected to functionalization, and the synthetic method has the advantages of simplicity in reaction, gentle condition, zero metal, high atom economy and the like; and the synthesized 4-position aza-aryl substituted alcohol compound can be widely applied to synthesized building blocks designed by total synthesis and new drug derivatives.

Description

technical field [0001] The invention relates to a synthesis method of a 4-azaryl alkanol compound, which belongs to the technical field of chemical synthesis. Background technique [0002] sp3 carbon-hydrogen bond (C(sp3)-H) activation and functionalization reaction is the research frontier and hotspot of synthetic chemistry at present, which has the advantages of high efficiency and atom economy, but due to the low activity and difficult selectivity of C(sp3)-H , still faces enormous challenges. The hydrogen atom transfer reaction (HAT) induced by free radicals is an effective means to activate C(sp3)-H and achieve functionalization. First, under the conditions of heating and ultraviolet irradiation, alkoxy radicals are generated, and then through Hydrogen migration, cleavage of C(sp3)-H, and subsequent substitution reaction to obtain functionalized alcohol compounds, but under harsh conditions, direct use of alkanol as a substrate is prone to β-position C-C fragmentation,...

Claims

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Application Information

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IPC IPC(8): C07D215/14C07D215/18C07D215/48C07D219/02C07D221/12C07D213/30C07D241/12C07D241/24C07D241/42C07D239/30C07D239/90C07D403/06C07D487/04
CPCC07D213/30C07D215/14C07D215/18C07D215/48C07D219/02C07D221/12C07D239/30C07D239/90C07D241/12C07D241/24C07D241/42C07D403/06C07D487/04
Inventor 朱晨吴新鑫
Owner SUZHOU UNIV
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