CN113336786B - 一种非对映选择性的多取代环烷基化合物及其制备方法 - Google Patents
一种非对映选择性的多取代环烷基化合物及其制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 11
- 150000001503 aryl iodides Chemical class 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 11
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- 238000000034 method Methods 0.000 claims abstract description 11
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- -1 polysubstituted cycloalkyl compound Chemical class 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 8
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
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- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 3
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- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 claims description 2
- GWQSENYKCGJTRI-UHFFFAOYSA-N 1-chloro-4-iodobenzene Chemical compound ClC1=CC=C(I)C=C1 GWQSENYKCGJTRI-UHFFFAOYSA-N 0.000 claims description 2
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- Organic Chemistry (AREA)
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
本发明公开了一种非对映选择性的多取代环烷基化合物及其制备方法。本发明通过将反应混合物在氮气氛围、55~65℃下剧烈搅拌10~14小时;其中,所述反应混合物包括按摩尔体积比为0.5~1mmol:0.5~1mmol:0.5mmol:1mmol:0.05mmol:0.05mmol:1mL的环烷基碘化物、芳基碘化物、添加剂、锌粉、催化剂、配体、无水溶剂;将反应产物洗涤、萃取和干燥,再通过柱层析分离得到非对映选择性的多取代环烷基化合物。本发明制备方法以立体控制的方式有效地进行,并得到具有高非对映选择性和广泛的官能团兼容性的一系列交叉偶联产物;产物,本发明“一锅法”反应易于操作且经济实惠,无需提前制备对水敏感的有机金属试剂。
Description
技术领域
本发明属于有机合成领域,尤其涉及一种非对映选择性的多取代环烷基化合物及其制备方法。
背景技术
立体选择性的有机分子多取代环烷基化合物在学术界和工业界都具有十分重要的用途。过渡金属催化的非对映选择性交叉偶联反应,可作为立体选择性构建分子结构的有效途径,并且可以同时构建多个立体中心。已报道通过钯或钴催化的环烷基锌试剂与芳基或炔基卤化物的高度非对映选择性交叉偶联反应可以构建带有两个手性中心的二取代环烷基化合物(Nat.Chem.2010,2,125)。此外,这种类型的非对映选择性交叉偶联反应也可以通过环烷基卤化物与芳基(或炔基、烷基)有机金属试剂,在铁、铬、钴或镍催化下的交叉偶联来实现。
然而,现有方法具有一定局限性,因为其采用预先制备的且对水敏感的有机金属试剂(RMX;M=Mg,Zn),既操作复杂又不具有经济性。因此,在不降低产物非对映选择性的情况下实现环烷基卤化物与芳基卤化物的直接交叉偶联方法,将更加简洁和实用。
通过“一锅法”来实现两种不同亲电卤化物的过渡金属催化的还原交叉偶联反应,其优势在于交叉偶联反应可直接在两种不同的有机卤化物之间发生,而无需使用可能不稳定且难以合成的有机金属试剂。但目前只有很少的实例是使用常规的二取代环烷基卤化物作为底物进行交叉偶联反应,其中涉及二取环烷基卤化物的非对映选择性还原交叉偶联就更加稀少,并且没有对这种类型的有机转化进行系统的研究。
发明内容
本发明的首要目的在于提供一种非对映选择性的多取代环烷基化合物的制备方法,旨在解决现有合成技术上的所存在的困难,并取得其它方面的进步。
本发明的再一目的在于提供上述非对映选择性的多取代环烷基化合物。
本发明是这样实现的,一种非对映选择性的多取代环烷基化合物的制备方法,该方法包括以下步骤:
(1)将反应混合物在氮气氛围、55~65℃下剧烈搅拌10~14小时;其中,所述反应混合物包括按摩尔体积比为0.5~1mmol:0.5~1mmol:0.5mmol:1mmol:0.05mmol:0.05mmol:1mL的环烷基碘化物、芳基碘化物、添加剂、锌粉、催化剂、配体、无水溶剂;
(2)将反应产物洗涤、萃取和干燥,再通过柱层析分离得到非对映选择性的多取代环烷基化合物。
优选地,在步骤(1)中,所述环烷基碘化物选自(1R,2R)-1-碘代-2-甲基环己烷、(1R,2R)-1-碘代-2-乙基环己烷、(1R,2R)-1-碘代-2-丙基环己烷、(1R,2R)-1-碘代-2-丁基环己烷、(1R,2R)-1-碘代-2-叔丁基环己烷、叔丁基(((1R,2R)-2-碘代环己基)氧)二甲硅烷、三乙基(((1R,2R)-2-碘代环己基)氧)硅烷、三异丙基(((1R,2R)-2-碘代环己基)氧)硅烷、((1S,2R)-2-碘代环己基)苯中的任意一种;
在步骤(1)中,所述芳基碘化物选自4-氟碘苯、4-氯碘苯、4-氰基碘苯、4-三氟甲基碘苯、4-乙氧羰基碘苯、4-甲基碘苯、4-乙酰氨基碘苯、4-甲氧基碘苯、2-吡啶基碘苯中的任意一种。
优选地,在步骤(1)中,所述添加剂选自四丁基碘化铵、四丁基溴化铵、氯化锂、碘化钠、三甲基氯硅烷、氯化镁中的任意一种;
在步骤(1)中,所述催化剂选自乙酰丙酮镍、二(三苯基膦)氯化镍、氯化镍、溴化钴、三氯化铁中的任意一种;
在步骤(1)中,所述配体选自1,10-菲罗啉、2-联吡啶、4,4'-二甲氧基-2,2'-联吡啶、吡啶、三苯基膦中的任意一种;
在步骤(1)中,所述溶剂选自N,N’-二甲基乙酰胺、二甲亚砜、乙腈、四氢呋喃中的任意一种。
优选地,所述添加剂为四丁基碘化铵;所述催化剂为乙酰丙酮镍;所述配体为4,4'-二甲氧基-2,2'-联吡啶;所述溶剂为N,N’-二甲基乙酰胺。
优选地,在步骤(1)中,所述环烷基碘化物和芳基碘化物的摩尔比为1.5:1;
在步骤(1)中,将反应混合物在氮气氛围、60℃下剧烈搅拌12小时。
本发明进一步公开了上述方法制备得到的非对映选择性的多取代环烷基化合物,该化合物的化学结构如下式(Ⅰ)所示:
式(Ⅰ)中,Ar选自卤素取代苯基、氰基取代苯基、三氟甲基取代苯基、酯基取代苯基、酰基取代苯基、甲基取代苯基、乙酰氨基取代苯基、甲氧基取代苯基和2-吡啶基中的任意一种;
R选自C1~C4烷基、烷氧基、叔丁基二甲基硅氧基、三乙基硅氧基、三异丙基硅氧基、苯基中的任意一种;
Y选自亚甲基、氧或N-对甲苯磺酰胺中的任意一种;
n为0~2的自然数。
优选地,所述卤素取代的苯基包括氟苯基、氯苯基。
优选地,所述C1~C4烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基中的任意一种。
本发明克服现有技术的不足,提供一种非对映选择性的多取代环烷基化合物及其制备方法,本发明研究了镍催化的二取代环烷基碘化物与芳基碘化物的直接还原交叉偶联反应,反应以立体控制的方式进行,得到具有高非对映选择性和高官能团耐受性的交叉偶联产物。
该反应的化学方程式如下所示:
在本发明化合物的制备中,通过调控所选催化剂的种类、配体的种类、添加剂的种类、反应物的比例、反应进行的溶剂、反应温度和反应时间等一系列条件,可高效合成一系列非对映选择性的多取代环烷基化合物。其中,对不同的催化剂,如:乙酰丙酮镍、二(三苯基膦)氯化镍、氯化镍、溴化钴、三氯化铁进行优选,以乙酰丙酮镍效果最优,产率最高;对不同的配体,如:1,10-菲罗啉、2-联吡啶、4,4'-二甲氧基-2,2'-联吡啶、吡啶、三苯基膦进行优选,以4,4'-二甲氧基-2,2'-联吡啶效果最优,产率最高;对不同的添加剂,如:四丁基碘化铵、四丁基溴化铵、氯化锂、碘化钠、三甲基氯硅烷、氯化镁进行优选,以四丁基碘化铵效果最优,产率最高;环烷基碘化物和芳基碘化物之间不同的比例(1~2):(1~2)之间,以1.5:1最优;对不同的溶剂,如:N,N’-二甲基乙酰胺、二甲亚砜、乙腈、四氢呋喃进行优选,以N,N-二甲基乙酰胺效果最优,产率最高;25~90℃范围内的不同温度下均能得到目标产物,60℃最优,产率最高;反应6~24小时均能得到相应产物,以12小时反应时间最优,产率最高。
相比于现有技术的缺点和不足,本发明具有以下有益效果:
(1)本发明提供了一种使用镍盐作为催化剂,2,2'-联吡啶作为配体,锌粉作为还原金属,TBAI作为添加剂,在DMA中实现了二取代的环烷基碘化物与芳基碘化物的直接还原交叉偶联反应;
(2)本发明制备方法以立体控制的方式有效地进行,并得到具有高非对映选择性和广泛的官能团兼容性的一系列交叉偶联产物;
(3)本发明“一锅法”反应易于操作且经济实惠,无需提前制备对水敏感的有机金属试剂。
附图说明
图1是4-((1S,2R)-2-((叔丁基二甲基硅基)氧)环己基)苯腈1的氢谱;
图2是4-((1S,2R)-2-((叔丁基二甲基硅基)氧)环己基)苯腈1的碳谱。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
(1)向预先干燥的10mL Schlenk管中依次添加叔丁基(((1R,2R)-2-碘代环己基)氧)二甲硅烷(0.75mmol),4-氰基碘苯(0.5mmol),四丁基碘化铵(0.5mmol),锌粉(1mmol),乙酰丙酮镍(0.05mmol),4,4'-二甲氧基-2,2'-联吡啶(0.05mmol)和无水N,N-二甲基乙酰胺溶剂(1mL)。将反应混合物在氮气氛围下60℃剧烈搅拌12小时;
(2)在步骤(1)反应结束后,将反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件:固定相为200~300目硅胶粉,流动相为乙酸乙酯(A)和石油醚(B),流动相变化程序(A:B)为1:200→1:100,得到0.116克反应产物4-((1S,2R)-2-((叔丁基二甲基硅基)氧)环己基)苯腈1。
对上述4-((1S,2R)-2-((叔丁基二甲基硅基)氧)环己基)苯腈1进行表征,如图1~2所示,结果为:无色液体;1H NMR(400MHz,CDCl3):δ7.53(d,J=8.2Hz,2H),7.28(d,J=8.2Hz,2H),3.51(td,J=9.7,4.5Hz,1H),2.50(ddd,J=13.0,9.7,3.4Hz,1H),2.03-1.92(m,1H),1.86-1.77(m,2H),1.76-1.70(m,1H),1.53(dq,J=13.0,3.6Hz,1H),1.43-1.21(m,3H),0.62(s,9H),-0.18(s,3H),-0.54(s,3H)ppm.13C NMR(100MHz,CDCl3):δ150.8,131.7,129.0,119.2,109.6,75.4,53.2,36.4,32.2,25.6,25.4,24.9,17.6,-4.5,-5.7ppm.HRMS(ESI,m/z):[M+H]+,calcd.for C19H30NOSi+:316.2091,found:316.2097.FTIR(KBr,neat):ν2931,2857,2227,1608,1250,1095,832,775,564cm-1.
根据表征数据可知,制得的反应产物1为4-((1S,2R)-2-((叔丁基二甲基硅基)氧)环己基)苯腈(纯度>98%);对产品产率进行计算,结果为73%。
实施例2~17
实施例2~17与上述实施例1基本相同,差别之处在于步骤(1)中,环烷基碘化物和芳基碘化物不同,具体如下表1所示:
表1实施例2~17
实施例18~35
实施例18~35与上述实施例1基本相同,差别之处在于步骤(1)中,催化剂、添加剂、配体、溶剂、温度(℃)、时间(h)不同,具体如下表2所示:
表2
实施例36
本实施例与实施例1基本相同,差别之处在于,在步骤(1)中,向预先干燥的10mLSchlenk管中添加的叔丁基(((1R,2R)-2-碘代环己基)氧)二甲硅烷的量为0.5mmol,4-氰基碘苯的量为1.0mmol。
实施例37
本实施例与实施例1基本相同,差别之处在于,在步骤(1)中,向预先干燥的10mLSchlenk管中添加的叔丁基(((1R,2R)-2-碘代环己基)氧)二甲硅烷的量为1.0mmol,4-氰基碘苯的量为0.5mmol。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种非对映选择性的多取代环烷基化合物的制备方法,其特征在于,该方法包括以下步骤:
(1)将反应混合物在氮气氛围、55~65℃下剧烈搅拌10~14小时;其中,所述反应混合物包括按摩尔体积比为0.5~1mmol:0.5~1mmol:0.5mmol:1mmol:0.05mmol:0.05mmol:1mL的环烷基碘化物、芳基碘化物、添加剂、锌粉、催化剂、配体、无水溶剂;
(2)将反应产物洗涤、萃取和干燥,再通过柱层析分离得到非对映选择性的多取代环烷基化合物;
在步骤(1)中,所述环烷基碘化物选自(1R,2R)-1-碘代-2-甲基环己烷、(1R,2R)-1-碘代-2-乙基环己烷、(1R,2R)-1-碘代-2-丙基环己烷、(1R,2R)-1-碘代-2-丁基环己烷、(1R,2R)-1-碘代-2-叔丁基环己烷、叔丁基(((1R,2R)-2-碘代环己基)氧)二甲硅烷、三乙基(((1R,2R)-2-碘代环己基)氧)硅烷、三异丙基(((1R,2R)-2-碘代环己基)氧)硅烷、((1S,2R)-2-碘代环己基)苯中的任意一种;
在步骤(1)中,所述芳基碘化物选自4-氟碘苯、4-氯碘苯、4-氰基碘苯、4-三氟甲基碘苯、4-乙氧羰基碘苯、4-甲基碘苯、4-乙酰氨基碘苯、4-甲氧基碘苯、2-吡啶基碘苯中的任意一种;
在步骤(1)中,所述添加剂选自四丁基碘化铵、四丁基溴化铵、氯化锂、碘化钠、三甲基氯硅烷、氯化镁中的任意一种;
在步骤(1)中,所述催化剂选自乙酰丙酮镍、二(三苯基膦)氯化镍、氯化镍、溴化钴、三氯化铁中的任意一种;
在步骤(1)中,所述配体选自1,10-菲罗啉、2-联吡啶、4,4'-二甲氧基-2,2'-联吡啶、吡啶、三苯基膦中的任意一种;
在步骤(1)中,所述溶剂选自N,N’-二甲基乙酰胺、二甲亚砜、乙腈、四氢呋喃中的任意一种。
2.如权利要求1所述的制备方法,其特征在于,所述添加剂为四丁基碘化铵;所述催化剂为乙酰丙酮镍;所述配体为4,4'-二甲氧基-2,2'-联吡啶;所述溶剂为N,N’-二甲基乙酰胺。
3.如权利要求1所述的制备方法,其特征在于,在步骤(1)中,所述环烷基碘化物和芳基碘化物的摩尔比为1.5:1;
在步骤(1)中,将反应混合物在氮气氛围、60℃下剧烈搅拌12小时。
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