CN111960909B - γ-烯基取代的丁烯内酯或丁烯内酰胺化合物及其不对称合成方法和配体 - Google Patents
γ-烯基取代的丁烯内酯或丁烯内酰胺化合物及其不对称合成方法和配体 Download PDFInfo
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- CN111960909B CN111960909B CN202010798393.0A CN202010798393A CN111960909B CN 111960909 B CN111960909 B CN 111960909B CN 202010798393 A CN202010798393 A CN 202010798393A CN 111960909 B CN111960909 B CN 111960909B
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- butenolide
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- FBMORZZOJSDNRQ-UHFFFAOYSA-N Demethoxy,B,HCl-Adriamycin Natural products C1C2C(=C)CCCC2(C)CC2(O)C1=C(C)C(=O)O2 FBMORZZOJSDNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- JUTMAMXOAOYKHT-UHFFFAOYSA-N karrikinolide Natural products C1=COC=C2OC(=O)C(C)=C21 JUTMAMXOAOYKHT-UHFFFAOYSA-N 0.000 title claims abstract description 29
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- 238000000034 method Methods 0.000 title claims abstract description 17
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Abstract
本发明公开了一种γ‑烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,该方法采用廉价镍催化环丙烯酮化合物与α,β‑不饱和酮或与亚胺的[3+2]不对称环加成反应,首次实现了镍催化的C‑C键活化后的分子间C=X的选择性插入反应,其中,X=O或N,高收率、高对映选择性且手性可控地得到γ‑烯基取代的丁烯内酯或丁烯内酰胺化合物,该合成方法新颖,条件温和,底物适用性好,反应简单高效,催化剂廉价易得,降原子经济性好,合成产物易于衍生化,可广泛应用于全合成设计的合成砌块,以及新的手性药物衍生物中,此外本发明还提供一种配体化合物,该配体化合物能应用于γ‑烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成。
Description
相关申请的交叉引用
本申请主张2019年8月8日提交的中国专利申请CN201910727718.3的优先权,其内容在此并入本申请。
技术领域
本发明涉及γ-烯基取代的丁烯内酯或丁烯内酰胺化合物及其合成方法,属于化学合成技术领域。
背景技术
过渡金属催化的不对称碳-碳(C-C)键活化是实现新型复杂分子构建和转化的有力工具,现有技术中主要采用低价贵金属(TMs,如Rh、Pd、Ir等)实现,镍Ni是丰度更高、更廉价的用于C-C活化的金属催化剂,但报道较少,且主要集中在分子内反应领域,例如,零价镍Ni(0)催化实现基于C-C键活化的分子内非极性不饱和键(如C=C)的插入再还原消除反应已取得一定进展,该反应2012年由Murakami组报道,以不饱和酮为原料,经C-C活化后能被C=C选择性插入,但对极性不饱和键(如C=N or C=O)的插入却不适用,且无论是采用TMs或是Ni,目前均难以实现基于C-C活化的分子间反应,因而对反应底物结构的选择有较为苛刻的要求,极大地限制了C-C键活化反应的适用范围。
γ-烯基-丁烯酸内酯及其衍生物广泛存在于生物活性天然产物中,是实用的天然产物或医药中间体,也是有机合成和精细化工领域的重要原料,目前,催化的γ-烯基-丁烯酸内酯的不对称直接合成尚无有效方法。
因而开拓以廉价金属实现的基于C-C键活化的分子间偶联反应,实现复杂分子的高效高选择性构建具有潜在的应用价值和重要的方法学意义,却也充满挑战。
发明内容
定义
为便于对本发明的理解,除非另外说明的,对本文使用的一些术语、缩写或其它缩略语定义如下。
“烷基”,单用或与其它基团合用时,代表含1~8个碳原子的饱和直链或支链基团,例如:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、正戊基、正己基、异己基、正庚基、正辛基和正癸基等,其可进一步被任选基团取代。
“烯基”,单用或与其它基团合用时,代表含1~8个碳原子且含不饱和双键的直链或支链基团,包括直链或支链的二烯,例如:乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、5-庚烯基、6-庚烯基、1,3-丁二烯、1,3-戊二烯,2-甲基-1,3-丁二烯等,其可进一步被任选基团取代。
“环烷基”,单用或与其它基团合用时,代表3-7元碳环基团,例如:环丙基、环丁基、环戊基、环己基等,其可进一步被任选基团取代。
“芳基”或’“芳族”,单用或与其它基团合用时,指含有1、2或3个环的任选取代的芳香碳环基团,所述环之间以键连或稠合方式连接,例如:苯基、联苯基、萘基、四氢化萘、二氢化茚,其可进一步被其它芳基或含芳基的取代基取代。
“杂芳基”或’“杂芳族”,单用或与其它基团合用时,指含有1或2个环的任选取代的芳香杂环基团,所述杂环上的杂原子为1~3个,相同或不同,选自O、N、S,例如:吡啶、吲哚、呋喃、噻吩、哒嗪、吡嗪、嘧啶、喹啉,其可进一步被其它芳基或含芳基的取代基取代。
“杂环基”或“杂环”,单用或与其它基团合用时,代表含一个以上杂原子的任选取代的3-7元环状基团,杂原子选自N、S和O,包括饱和、部分饱和以及芳香性不饱和杂环基团。饱和杂环基团在本文中相当于术语“杂环烷基”,单用或与其它基团合用,其实例包括:氮杂环丙基、氮杂环丁基、四氢呋喃基、四氢噻吩基、噁唑烷基、噻唑烷基、苯并噻唑基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、噻嗪基、2-氧代哌啶基、4-氧代哌啶基、2-氧代哌嗪基、3-氧代哌嗪基、吗啉基、硫代吗啉基、2-氧代吗啉基、氮杂基、二氮杂基、氧杂基、硫杂基等、1~3氧杂环己烷基等。部分饱和杂环基团在本文中相当于术语“杂环烯基”,单用或与其它基团合用,其实例包括二氢噻吩、二氢吡喃、二氢呋喃、二氢噻唑、噁唑啉等。芳香性不饱和杂环基团在本文中相当于术语“杂芳基”或“杂芳族”,单用或与其它基团合用,可以为单环,也可以是稠双环,其实例包括:噻唑基、噁唑基、咪唑基、异噁唑基、吡咯基、吡唑基、三唑基、四唑基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、喹啉基、异喹啉基、喹喔啉基、联吡啶基、喹唑酮基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并恶唑基、苯并异恶唑基。
“杂烷基”,单用或与其它基团合用时,代表含一个以上杂原子的直链或支链烷基,杂原子选自N、S和O,其实例包括:甲氧基、甲氧基甲基、甲氧基乙基、2-甲氧基丙基、二甲胺基、二甲胺基乙基、甲硫基、2-甲硫基丁基等,其可进一步被任选基团取代。
本文中,如无特别限定,“杂烷基”、“杂环基”中含有的杂原子为一个或多个,优选地,为1~6个,更优选地,为1个、2个或3个,当所述杂原子为多个时,所述的多个杂原子相同或不同。
“卤素”,单用或与其他基团合用,例如“卤代烷基”、“全卤代烷基”等时,是指氟、氯、溴或碘基。术语“卤代烷基”代表定义如上的烷基被一个或多个卤素取代,包括全卤代烷基,例如:氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基、五氟乙基等。
“酰基”,单用或与其他基团合用时,包括以下一些形式:-C(=O)H、-C(=O)-烷基、-C(=O)-芳基、-C(=O)-芳烷基和-C(=O)-杂芳基,例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、己酰基、庚酰基、苯甲酰基等,酰基上的非-C(=O)-部分可被任选地取代基取代,包括但不限于被卤素、低级烷基(C1~C4烷基)、芳基或含芳基的取代基取代。
“酯”为一类羧酸衍生物,单用或与其他基团合用时,代表-COO-基团,包括:烷氧基羰基,例如甲氧基羰基、乙氧基羰基等;芳氧基羰基,例如苯氧基羰基、萘氧基羰基等;芳烷氧基羰基,例如苄氧基羰基、苯乙氧基羰基、萘甲氧基羰基;杂环基氧基羰基,其中杂环基定义如上;酯基上的非-COO-部分可进一步被任选地取代基取代。
如本文使用的描述化合物或化学部分被“取代”指化合物或化学部分的至少一个氢原子被第二个化学部分替代。取代基的非限制性实例为本文公开的示例性化合物和实施方案中所存在的那些,以及氟、氯、溴、碘;氧代;亚胺基、硝基;氰基、异氰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、烯基、环烯基、炔基;低级烷氧基、芳氧基;酰基、硫代羰基、磺酰基;酰胺、磺酰胺;酮;醛;酯、磺酸酯;卤代烷基(例如,二氟甲基、三氟甲基);可以为单环或稠合或非稠合多环的碳环烷基(例如,环丙基、环丁基、环戊基或环己基);或可以为单环或稠合或非稠合多环的杂环烷基(例如,吡咯烷基、哌啶基、哌嗪基、吗啉基或噻嗪基);或可以为单环或稠合芳基(例如,苯基、萘基、噻唑基、噁唑基、咪唑基、异噁唑基、吡咯基、吡唑基、三唑基、四唑基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、喹啉基、异喹啉基、喹喔啉基、喹唑酮基、苯并咪唑基、苯并呋喃基、苯并噻吩基基、苯并噻唑基、苯并恶唑基、苯并异恶唑基);或还可以为:芳基-低级烷基;-CHO;-CO(烷基);-CO(芳基);-CO2(烷基);-CO2(芳基);-CONH2;-SO2NH2;-OCH2CONH2;-OCHF2;-OCF3;-CF3;-N(烷基)(芳基);-N(芳基)2;此外,当取代基为氧时,是指相同或不同碳上的二个氢原子被同一氧原子取代形成羰基或环醚,如酮羰基、醛羰基、酯羰基、酰胺羰基、环氧乙烷等;此外,这些部分也可任选由稠环结构或桥(例如,-OCH2O-)取代。在本发明中,优选一个、两个、三个独立选自卤素、硝基、氰基、烷基、烷氧基的取代基取代或全卤素取代,如三氟甲基、五氟乙基,并且,当取代基含氢时,上述这些取代基可任选地被选自这样基团的取代基进一步取代。本文采用概括的方式,例如“烷基”、“烯基”、“环烷基”、“杂烷基”“烷氧基”、“芳基”、“杂芳基”等对化合物或化学部分进行描述时,如无特别限定,应当理解为上述概括的方式包含被任选取代的情形。
如本文使用的描述化合物或化学部分“独立地为”应当理解为该术语前所限定的多个化合物或化学部分均应当相互无干扰地、等同地享有其后提供的选择范围,而不应当理解为是对各个基团之间的任何空间连接关系的限定;关于空间连接关系在本文中通过“相互独立”、“相连”等术语表示;应当予以区别;并且,在本发明中,“独立地为”与“分别独立地为”、“分别独立选自”具有基本相同的含义。
如本文使用的描述两个“相邻”化学部分相连形成环状结构,应当理解为包括两个化学部分在位置上相邻和空间上相邻两种情形,位置上相邻示例性的包括同一个芳香环上的两基团处于邻位的状态,空间上相邻示例性的包括两基团分别位于相连或稠和的不同芳香环上但是在空间上可以相互接近的状态。
发明详述
针对现有技术的不足,本发明的目的在于提供一种γ-烯基取代的丁烯内酯或丁烯内酰胺化合物及其不对称合成方法。
本发明的方法利用Ni(0)催化的分子间C-C键活化和选择性C=O插入反应,实现环丙酮衍生物与不饱和酮衍生物的不对称[3+2]环加成反应,并且制备得到一类新型的γ-烯基取代的丁烯内酯或丁烯内酰胺化合物,具有催化剂廉价易得、产物手性可控、反应简洁、条件温和、收率和对映选择性高等优点。
在本发明中,实现环丙酮衍生物与不饱和酮衍生物之间的对映选择性环加成反应的挑战在于,(a)环丙酮衍生物在加热条件下容易二聚成螺内酯;(b)现有技术中C=C插入的选择性高于C=O,需要翻转其选择性;(c)实现C=O的对映选择性插入难以预料。
为了实现本发明的目的,本发明一方面提供了一种γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,包括:在零价镍Ni(0)和式L所示配体的存在下,于有机溶剂中,使式1所示的环丙烯酮化合物和式2所示的α,β-不饱和酮化合物反应,得到式3所示的手性γ-烯基取代的丁烯内酯或丁烯内酰胺化合物,
其中,
Ni(0)和所述配体均为催化量的;
R1a、R1b独立地为烷基、芳基;
X为O、NRX,其中,RX为磺酰基、烷基、芳基;
R2为烷基、卤代烷基、环烷基、杂环基、芳基、稠芳基、杂芳基;
R3为全氟烷基、芳基、杂芳基、酯基、烷基酰基、芳基酰基、芳基乙烯基;
R4,R5中择一地具有一个不为H的基团,所述不为氢的基团选自烷基、芳基;
R6,R7独立地为H、烷基、芳基、杂芳基;
Z选自H、烷基、环烷基、杂烷基、烯基、芳基、杂环基,其中,当Z不为H时,Z上的H可以被其相连吡啶环上的邻位取代形成5~6元环。
在一些实施例中,R1a、R1b独立地为C1~C6烷基、取代或未取代的苯基。
在一些实施例中,R1a=R1b。
在一些实施例中,RX为对甲苯磺酰基Ts、对溴苯磺酰基Bs、苯磺酰基、甲磺酰基Ms、三氟甲磺酰基Tf、取代或未取代的苯基。
在一些实施例中,R2为C1~C4卤代烷基、取代或未取代的苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、二茂铁基、C3~C8环烷基、C1~C8烷基。
在一些实施例中,R3为C1~C4全氟烷基、取代或未取代的:苯基、苯基乙烯基、苯甲酰基,吡啶基、嘧啶基、呋喃基、噻吩基、酯基、C1~C6烷基酰基。
在一些实施例中,R4,R3中所述不为H的基团为取代或未取代的苯基。
在一些实施例中,零价镍Ni(0)选自单质镍粉、Ni(cod)2。
在一些实施例中,Ni(0)相对于式1化合物的所述催化量为3%~10%,优选4%~7%。
在一些实施例中,所述配体为下列结构所示化合物。
在一些实施例中,Ni(0)与配体的用量比位于1∶1~1∶2之间。
在一些实施例中,所述配体相对于式1化合物的所述催化量为5%~14%。
在一些优选的实施例中,Ni(0)相对于式1化合物的所述催化量为4%,且所述配体相对于式1化合物的所述催化量为7%。
在一些实施例中,所述不对称合成方法还包括降低所述反应的体系中氧含量的操作,示例性的,所述降低所述反应的体系中氧含量的操作为使所述反应在惰性气氛下进行,和/或,预先对所述有机溶剂进行脱氧处理。
在一些实施例中,所述反应的温度为20~130℃。
在一些实施例中,所述反应的温度为室温rt、60℃、100℃、130℃。
在一些实施例中,所述式1化合物和式2化合物的投料比为1∶1~1∶1.2。
在一些实施例中,所述有机溶剂选自:芳烃溶剂,醚类溶剂、醇类溶剂、酰胺溶剂、卤代烷烃溶剂、腈类溶剂、酯类溶剂中的一种或多种;示例性的,所述所述芳烃溶剂包括但不限于苯、甲苯、氟苯、氯苯、1,2,4-三氯苯;所述醚类溶剂选自1,4-二氧六环、四氢呋喃THF、甲基叔丁基醚、乙醚、甲醚DME;所述醇类溶剂包括但不限于乙醇EtOH、甲醇MeOH、异丙醇iPrOH;所述酰胺溶剂包括但不限于N,N-二甲基甲酰胺DMF、N,N-二甲基乙酰胺DMA;所述卤代烷烃溶剂包括但不限于二氯甲烷DCM、1,2--二氯乙烷DCE、氯仿;所述腈类溶剂包括但不限于乙腈CN。
本发明中,所述取代或未取代的苯基中所述的取代是指被下列基团中的一个或多个,相同或不同的取代基在苯基的任意位点取代:卤素、三氟甲基、硝基、氰基、C1~C4烷基、Ci~C4烷氧基,优选的取代基数目为1个、2个或3个
本发明中,室温是指位于20~30℃之间的任一温度。
一种γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,包括:在零价镍Ni(0)和式L所示配体的存在下,于有机溶剂中,使式1所示的环丙烯酮化合物和式2所示的α,β-不饱和酮化合物反应,得到式3所示的手性γ-烯基取代的丁烯内酯或丁烯内酰胺化合物,
其中,Ni(0)和所述配体均为催化量的;R1a、R1b独立地为烷基、芳基;X为O、NRX,其中,RX为磺酰基、烷基、芳基;R2为烷基、环烷基、杂环基、芳基、杂芳基;R3为全氟烷基、芳基、杂芳基、烯基,所述烯基任选地被芳基、杂芳基、酯基、烷基酰基、芳基酰基取代;R4,R5中择一地具有一个不为H的基团,所述不为H的基团选自烷基、芳基;R6,R7独立地为H、烷基、芳基、杂芳基;Z选自H、烷基、环烷基、烯基、芳基、杂环基、杂烷基、杂芳基、烷氧基,其中,当Z不为H时,Z上的H可以被其相连吡啶环上的邻位取代形成5~6元环。
在一些实施例中,R1a、R1b独立地为C1~C6烷基、取代或未取代的苯基。
在一些实施例中,R1a=R1b。
在一些实施例中,RX为对甲苯磺酰基Ts、对溴苯磺酰基Bs、苯磺酰基、甲磺酰基Ms、三氟甲磺酰基Tf、取代或未取代的苯基。
在一些实施例中,R2为C1~C8烷基、C3~C10环烷基、C3~C10杂环基、单环芳基、稠芳基、C3~C10杂芳基,所述C1~C8烷基、C3~C10环烷基、C3~C10杂环基任选地被一个或多个F、Cl、Br、I、CN、CF3、C1~C4烷氧基、C6~C10芳基或C3~C10杂芳基的基团取代,所述单环芳基、稠芳基、C3~C10杂芳基任选地被一个或多个F、Cl、Br、I、CN、OH、甲氧基的基团取代;
在一些实施例中,R2为C1~C4卤代烷基、取代或未取代的苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、二茂铁基、C3~C8环烷基、C1~C8烷基。
在一些实施例中,R3为C1~C4全氟烷基、C6~C12芳基、C4~C10杂芳基、C2~C6烯基,所述烯基任选地被C6~C12芳基、C4~C10杂芳基、C1~C8酯基、C1~C4烷基酰基、C6~C12芳基酰基取代;
在一些实施例中,R3为C1~C4全氟烷基、取代或未取代的:苯基、苯基乙烯基、苯基丁二烯基、苯甲酰基,苯甲酰乙烯基、C1~C6烷基酰基乙烯基、酯基乙烯基、吡啶基、嘧啶基、呋喃基、噻吩基、酯基、C1~C6烷基酰基。
在一些实施例中,R2为三氟甲基、杂环基;
在一些实施例中,R3为烯基,所述烯基任选地被芳基、杂芳基、酯基、烷基酰基、芳基酰基取代;
在一些实施例中,Z选自H、三氟甲基、杂烷基、杂芳基、烷氧基。
在一些实施例中,R4,R5中所述不为H的基团为取代或未取代的苯基。
在一些实施例中,零价镍Ni(0)选自单质镍粉、Ni(cod)2。
在一些实施例中,Ni(0)相对于式1化合物的所述催化量为3%~10%,优选4%~7%。
在一些实施例中,所述配体为下列结构所示化合物:
在一些实施例中,Ni(0)与配体的用量比位于1∶1~1∶2之间。
在一些实施例中,所述配体相对于式1化合物的所述催化量为5%~14%。
在一些优选的实施例中,Ni(0)相对于式1化合物的所述催化量为4%,且所述配体相对于式1化合物的所述催化量为7%。
在一些实施例中,所述不对称合成方法还包括降低所述反应的体系中氧含量的操作,示例性的,所述降低所述反应的体系中氧含量的操作为使所述反应在惰性气氛下进行,和/或,预先对所述有机溶剂进行脱氧处理。
在一些实施例中,所述反应的温度为20~130℃。
在一些实施例中,所述反应的温度为室温rt、60℃、100℃、130℃。
在一些实施例中,所述式1化合物和式2化合物的投料比为1∶1~1∶1.2。
在一些实施例中,所述有机溶剂选自:芳烃溶剂,醚类溶剂、醇类溶剂、酰胺溶剂、卤代烷烃溶剂、腈类溶剂、酯类溶剂中的一种或多种;示例性的,所述所述芳烃溶剂包括但不限于苯、甲苯、氟苯、氯苯、1,2,4-三氯苯;所述醚类溶剂选自1,4-二氧六环、四氢呋喃THF、甲基叔丁基醚、乙醚、甲醚DME;所述醇类溶剂包括但不限于乙醇EtOH、甲醇MeOH、异丙醇iPrOH;所述酰胺溶剂包括但不限于N,N-二甲基甲酰胺DMF、N,N-二甲基乙酰胺DMA;所述卤代烷烃溶剂包括但不限于二氯甲烷DCM、1,2-二氯乙烷DCE、氯仿;所述腈类溶剂包括但不限于乙腈CN。
在一些实施例中,对R4,R5,R6,R7以及Z的定义如下方提供的式L所示结构的配体化合物中所述,在此不再进行赘述。
在一些实施例中,所述取代或未取代的苯基中所述的取代是指被下列基团中的一个或多个,相同或不同的取代基在苯基的任意位点取代:卤素、三氟甲基、硝基、氰基、C1~C4烷基、C1~C4烷氧基,优选的取代基数目为1个、2个或3个。
在一些实施例中,“烷基”、“烯基”、“环烷基”、“杂烷基”“烷氧基”、“芳基”、“杂芳基”可进一步被任选地基团取代,优选地,任选地被一个或多个独立选自卤素、CN、CF3、C1~C4烷氧基、C6~C10芳基或C3~C10杂芳基的基团取代。
本发明中,室温是指位于20~30℃之间的任一温度。
为了实现本发明的目的,本发明还提供一种具有下式3所示结构的化合物,其特征在于,
对R1a、R1b、X、R2、R3的定义如前面所述。
在一些实施例中,式3化合物为消旋体的混合物。
在一些实施例中,式3化合物的主要对映异构体的手性为R构型。
在一些实施例中,式3化合物的主要对映异构体的手性为S构型。
在一些实施例中,式3化合物具有90%以上的对映选择性。
在一些实施例中,式3化合物由前面所述γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法制备得到。
为了实现本发明的目的,本发明还提供式L所示结构的配体化合物:
其中,对R4、R5、R6、R7和Z的定义如前所述;或者,
R4,R5中择一地具有一个不为H的基团,所述不为氢的基团选自烷基、芳基;
R6,R7独立地为H、烷基、芳基、杂芳基;Z选自H、烷基、环烷基、烯基、芳基、杂环基、杂烷基、杂芳基、烷氧基,其中,当Z不为H时,Z上的H可以被其相连吡啶环上的邻位取代形成5~6元环。
在一些实施例中,R4,R5中所述不为H的基团选自C1~C4烷基、C4~C10芳基,所述C1~C4烷基任选地被一个或多个卤素取代,C4~C10芳基任选地被一个或多个独立选自卤素、氰基、三氟甲基、C1~C4烷基、C1~C4烷氧基的基团取代。
在一些实施例中,R4,R5中所述不为H的基团为甲基、乙基、异丙基、叔丁基、三氟甲基、苯基、萘基,所述苯基、萘基任选地被1个或多个独立选自F、Cl、Br、I、甲基、甲氧基、异丙基、叔丁基的基团取代。
在一些实施例中,R6,R7均为H,或者择一地具有一个不为H的基团。
在一些实施例中,R6,R7中所述不为H的基团与R4,R5中所述不为H的基团为相同基团。
在一些实施例中,Z选自H、C1~C6烷基、C1~C6烯基、C4~C10芳基、C1~C6杂烷基、C4~C10杂芳基、C1~C6烷氧基,或者Z与相连吡啶环上两个相邻碳原子形成与所述吡啶环稠和的5~6元芳香或非芳香的碳环或杂环,其中,所述C1~C6烷基、C1~C6烯基、C4~C10芳基、C1~C6杂烷基、C4~C10杂芳基、C1~C6烷氧基任选地被一个或多个独立选自卤素、氰基、三氟甲基、C1~C4烷基、C1~C4烷氧基的基团取代。
在一些实施例中,Z为甲基、乙基、丙基、异丙基、异丁基、叔丁基、苯甲基、二苯甲基、三苯甲基、二氟甲基、三氯甲基、三氟甲基、甲氧基、苯基、萘基或为与所述相连吡啶环并联的苯环,所述苯基、萘基、与所述相连吡啶环并联的苯环任选地被1个或多个独立选自F、Cl、Br、I、甲基、甲氧基、异丙基、叔丁基的基团取代。
在一些实施例中,所述取代或未取代的苯基中所述的取代是指被下列基团中的一个或多个,相同或不同的取代基在苯基的任意位点取代:卤素、三氟甲基、硝基、氰基、C1~C4烷基、C1~C4烷氧基,优选的取代基数目为1个、2个或3个。
在一些实施例中,“烷基”、“烯基”、“环烷基”、“杂烷基”“烷氧基”、“芳基”、“杂芳基”可进一步被任选地基团取代,优选地,任选被一个或多个独立选自卤素、CN、CF3、C1~C4烷氧基、C6~C10芳基或C3~C10杂芳基的基团取代。
在一些实施例中,提供的配体化合物其为下列结构所示的化合物:
为了实现本发明的目的,本发明还提供式L所示结构的配体化合物:
其中,R4,R6为苯基;R5,R7为H,或者R4,R6为H;R5,R7为苯基;Z为甲基、甲氧基或者与相连吡啶环稠和的苯基或被甲基或甲氧基取代的苯基。
在一些实施例中,提供的配体化合物其为下列结构所示的化合物:
本发明的有益效果包括下列中的至少一项:
本发明提供的γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,在零价镍Ni(0)和配体L的存在下,在较宽温度范围,特别是在室温条件下,首次实现了利用廉价镍催化的C-C键活化和分子间C=O的选择性插入的[3+2]环加成反应,实施例示例的反应基本能以良好至优异的收率和85~98%的对映选择性构建得到目标产物。
本发明提供的不对称合成方法,通过改变配体的结构,特别是通过改变配体上的单一碳位置的手性,即可控制产物的对映选择性,分别得到构型相反的两种高ee值的对映异构产物。
本发明提供的不对称合成方法新颖,条件温和,底物适用性好,反应简单高效,催化剂丰度高,廉价易得,降低了成本,原子经济性好。
γ-烯基取代的丁烯内酯或丁烯内酰胺化合物,其含有一个四取代的手性季碳中心、一个四氢呋喃或四氢吡咯骨架,以及至少一个烯烃官能团,易于衍生化,利于作为合成砌块应用于全合成设计和新的药物衍生物合成中,其能放大规模制备而不损失ee值,可以广泛应用于手性化学中间体或手性医药中间体的工业制备中,为合成化学家们构建复杂分子提供了新的选择思路和基础。
本发明提供的配体化合物结构新颖,与零价镍形成的配体-镍络合物能够催化本发明提供的环丙烯酮化合物与α,β-不饱和酮或与α,β-不饱和亚胺的[3+2]不对称环加成反应,相较于其它现有配体,在确保收率与其它配体基本相同或更优的前提下,能更好地实现手性控制,从而获得高ee值的加成产物。
附图说明
图1为本发明实施13的手性产物3aa的HPLC谱图;
图2为本发明实施13的手性产物3aa的消旋体HPLC谱图;
图3本发明实施例部分化合物X-ray单晶衍射谱图:其中,(a)实施例8的手性产物3am的X-ray单晶衍射谱图,(b)实施例16的衍生化产物8的X-ray单晶衍射谱图。
具体实施方式
为了使本发明易于理解,下面显示了本发明实施例涉及的配体:
实施例1
氩气氛下于25mL反应瓶中加入Ni(cod)2、配体L和溶剂(2.0mL).混合物室温搅拌10min后加入环丙烯酮化合物1a(0.200mmol,1.00当量)和α,β-饱和酮2a(0.200mmol,1.0当量).反应管密封后置于温度T℃油浴中.待反应结束(约1h),反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE:EA=10∶1)分离得到产物3aa,经HPLC拆分测定其ee值,结果如下表1所示:
表1.
L1~L8虽然都能实现二苯基环丙烯酮1a与不饱和酮之间的不对称[3+2]环加成反应,但是L2的对映选择性较弱,其余配体均能实现较好的手性控制,其中,L5显示出更为突出的手性控制,明显高于其它配体,产物ee值突破90%,高达95%,L5’为L5的对映异构体,可用于制备构型相反且收率和对映选择性基本保持的的γ-烯基-丁烯羟酸内酯产物,采用L5的更多底物拓展案例参见实施例5~13。
实施例2
设定Ni(cod)2(0.008mmol)、L(0.014mmol),并将α,β-饱和酮2a替换为2t(0.200mmol,1.0当量),其余制备方法与实施例1相同,得产物3at结果如下表2所示:
表2
实施例3
设定Ni(cod)2(0.008mmol)、L(0.014mmol),并将α,β-饱和酮2a替换为2u(0.200mmol,1.0当量),其余制备方法与实施例1相同,得产物3au,结果如下表3所示:
表3
对于R2为烷基取代的底物,L5和L3的手性控制最好,取得基本相同的对映选择性,但是采用L3收率略优于采用L5。
值得一提的是,L8与L5和L3的差别仅在于如本申请所示出结构式中左侧基团结构的不同,L8左侧为取代的噁唑啉环,而L5左侧为与吡啶稠和的苯环,L3左侧则是甲基取代基,实验结果说明,L5中采用喹啉环或甲基相较于噁唑啉环更利于手性控制,从空间上看配体左侧小位阻基团相较于大位阻或者空间延伸较长的基团更利于本反应中手性的控制。
实施例4
设定Ni(cod)2(0.008mmol)、L(0.014mmol),并将α,β-饱和酮2a替换为2z(0.200mmol,1.0当量),其余制备方法与实施例1相同,得产物3az,结果如下表4所示:
表4
当R2为烷基时,反应活性相对较低,反应缓慢,不易转化完全,收率中等,当适当提高温度,反应收率提高,对映选择性基本不变。
实施例5
设定Ni(cod)2(0.008mmol)、L(0.014mmol),并将环丙烯酮1a替换为1j(0.200mmol,1.0当量),其余制备方法与实施例1相同,结果如下表5所示:
表5
实施例6
设定Ni(cod)2(0.008mmol)、L(0.014mmol),并将α,β-饱和酮2a替换为4a(0.200mmol,1.0当量),其余制备方法与实施例1相同,结果如下表6所示:
表6
实施例7-底物拓展
氩气氛下于25mL反应瓶中加入Ni(cod)2(2.7mg,0.008mmol)、L5(5.1mg,0.014mmol)和甲苯(2.0mL).混合物室温搅拌10min后加入化合物1(0.200mmol,1.0当量)和α,β-不饱和酮2x1(0.200mmol,1.0当量).反应管密封后置于室温油浴中.待反应结束(约1h),反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE:EA=10∶1)t得到目标产品3ax1,结果如下表7所示。
表7
实施例8-底物拓展
氩气氛下于25mL反应瓶中加入Ni(cod)2(2.7mg,0.008mmol)、L5(5.1mg,0.014mmol)和甲苯(2.0mL).混合物室温搅拌10min后加入化合物1a(0.200mmol,1.00当量)和α,β-不饱和酮2x2(0.240mmol,1.2当量).反应管密封后置于加热温度为T℃的油浴中.待反应结束(约1h)冷却至室温,反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE:EA=10:1)t得到目标产品3ax2,结果如下表8所示
表8
实施例9-底物拓展
除反应底物α,β-不饱和酮变化以外,其余制备方法与实施例7基本相同,结果如下表9所示:
表9
实施例10
下表10中序号1、5和7的制备方法参见实施例8,其余制备方法参见实施例7。
表10
实施例11
氩气氛下于25mL反应瓶中加入Ni(cod)2(2.7mg,0.008mmol)、L4(5.1mg,0.014mmol)和甲苯(2.0mL).混合物室温搅拌10min后加入化合物1x1(0.200mmol,1.00当量)和α,β-不饱和酮2a(0.20mmol,1.0当量).反应管密封后置于室温油浴中.待反应结束(约24h),反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE:EA=10:1)t得到3x1a与3x1a’的区域选择性混合物,如下表11所示。
表11
实施例12
除特殊标记或说明的反应条件外,下列产物的制备方法参见实施例9。
除特殊标记或说明的反应条件,下列产物的制备方法参见实施例8。
当R3为吸电子基或被吸电子基取代的芳基(例如三氟甲基取代的苯基)时,反应活性较强,收率较高,但对映选择性基本不受影响,适当提高反应的温度,利于增加反应的活性,从而提高收率。
氩气氛下于25mL反应瓶中加入Ni(cod)2、配体L和溶剂(2.0mL).混合物室温搅拌10min后加入环丙烯酮化合物1a(0.200mmol,1.00当量)和α,β-饱和酮9a(0.200mmol,1.0当量).反应管密封后维持室温反应.待反应结束(约1h),反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE∶EA=10∶1)分离得到产物10aa,经HPLC拆分测定其ee值,结果如下表12所示:
表12
实施例13-放大规模
氮气氛下于100mL反应瓶中加入Ni(cod)2(32mg,0.09mmol,0.04eq)、L5(65mg,0.14mmol,0.07eq.)和甲苯(50.0mL).混合物室温搅拌10min后加入环丙烯酮1a(1.05g,5.0mmol,1.00当量)和α,β-不饱和酮2a(1.05g,5.0mmol,1.0eq).反应管密封后置于室温油浴中.待反应结束(约12h),反应混合物采用乙酸乙酯经硅藻土过滤,浓缩后经硅胶柱层析纯化(PE∶EA=10∶1)t得到3aa 2.03g,收率97%,ee 95%,HPLC谱图参见如附图1所示。
实施例14
氮气保护下,将EtMgBr(1.0M THF溶液,0.63mL,0.63mmol)加入0℃下溶有5an(36.0mg,0.063mmol)的THF(2.0mL)溶液中,混合物80℃下搅拌过夜.冷至室温.加H2O(1.0mL)淬灭后,有机层用EtOAc(50mL X 3)萃取.合并有几层,饱和食盐水洗,无水Na2SO4干燥,减压浓缩.硅胶柱层析纯化得到白色固体16.5mg,收率63%.ee:98%,mp:94-96℃.HPLC条件:OD-H柱(正己烷/异丙醇=80/20,流速1.0mL/min):tR=10.2min (次),tR=12.6min(主).[α]D 29=-46.9(c 0.4,CHCl3).1H NMR(400MHz,CDCl3)δ7.41-7.37(m,2H),7.36-7.21(m,9H),7.21-7.15(m,5H),7.09(t,J=7.6Hz,2H),6.89(d,J=16.0Hz,1H),6.81-6.76(m,2H),6.54(d,J=16.0Hz,1H),6.51(br,1H).
实施例15
向5am(22.2mg,0.05mmol)的甲苯(1.0mL)溶液中加入N-苯基丁烯酰亚胺(26mg,0.15mmol)和ZnCl2(22mg,0.15mmol).氮气保护下反应混合物在120℃下搅拌过夜.冷至室温,减压浓缩,浓缩物经硅胶柱层析在PE/EA溶剂下纯化得到紫色固体7(16.5mg,51%).mp:66-68℃.1H NMR(400MHz,CDCl3)δ7.63-7.53(m,2H),7.42-7.19(m,10H),7.16-7.08(m,3H),7.08-6.98(m,3H),6.98-6.93(m,2H),6.79(dd,J=22.2,9.4Hz,5H),6.65-6.58(m,2H),4.24(d,J=8.2Hz,1H),3.80(d,J=8.2Hz,1H),2.85(d,J=8.7Hz,1H),2.29(d,J=8.7Hz,1H).
实施例16
氮气保护以及0℃下,向5aa(41.4mg,0.1mmol)的THF(4.0mL)溶液中加入LiAlH4(16mg,0.42mmol)室温搅拌过夜.减压浓缩,浓缩物经硅胶柱层析在PE/EA=10∶1条件下过滤得到紫色固体8(30.1mg,71%yield(收率),95ee%).HPLC条件:AS-H柱(正己烷/异丙醇=50/50,流速1.0mL/min):tR=17.1min(次),tR=46.7min(主).[α]D 29=2.8(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ(major diastereomer)7.36(d,J=7.2Hz,2H),7.31-7.24(dd,J=14.0,7.0Hz,4H),7.17-7.06(m,11H),6.89-6.76(m,4H),6.68(d,J=15.9Hz,1H),4.15(d,J=13.4Hz,1H),4.07(d,J=13.4Hz,1H).δ(minor diastereomer)6.25(d,J=16.0Hz,1H),4.29(d,J=13.2Hz,1H),3.96(d,J=13.2Hz,1H).
实施例15-16为本发明提供的γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的一些示例性的衍生化反应,易于构建结构复杂或者官能团丰富的手性化合物,且在衍生化过程中,衍生产物的ee值基本保持不变,这些衍生产物是潜在的重要手性合成砌块。
实施例17-配体的制备方法
L5的制备条件如下式所示
在250M1圆底烧瓶中,将2-喹啉甲腈(2.16g,14mmol)溶于50Ml甲醇中,加甲醇钠(10mg),室温搅拌过夜,减压除去溶剂,用乙酸乙酯50Ml溶解,加饱和食盐水50ml洗,无水硫酸钠干燥后,减压除去溶剂,得到白色固体直接用于下一步反应;将得到的白色固体溶于60mL氯苯中,加(1R,2S)-2-氨基-1,2-二苯基乙醇(2.13g,10mmol),加热100℃反应24小时后,将至室温,出去溶剂后,柱层析纯化,得到配体L5(1.4g,41%yield).1H NMR(600MHz,CDCl3)δ8.33(d,J=8.5Hz,1H),8.26(dt,J=11.7,5.9Hz,2H),7.83(d,J=8.2Hz,1H),7.74-7.70(m,1H),7.61-7.55(m,1H),7.02-6.88(m,10H),6.13(d,J=10.3Hz,1H),5.81(d,J=10.3Hz,1H).
L3的制备方法
在250M1圆底烧瓶中,将6-甲基-2-吡啶甲腈(1.18g,10mmol)溶于50M1甲醇中,加甲醇钠(6.0mg),室温搅拌过夜,减压除去溶剂,用乙酸乙酯50Ml溶解,加饱和食盐水50ml洗,无水硫酸钠干燥后,减压除去溶剂,得到白色固体直接用于下一步反应;将得到的白色固体溶于60mL氯苯中,加(1R,2S)-2-氨基-1,2-二苯基乙醇(1.5g,7mmol),加热100℃反应24小时后,将至室温,出去溶剂后,柱层析纯化,得到配体L3(1.3g,61%yield).。1H NMR(400MHz,CDCl3)δ8.08(d,J=7.7Hz,1H),7.74(t,J=7.8Hz,1H),7.33(t,J=7.8Hz,1H),7.12-6.90(m,10H),6.07(d,J=10.3Hz,1H),5.81(d,J=10.3Hz,1H),2.70(s,3H).
其它配体L4~L12可以通过替换不同的2-吡啶甲腈衍生物并采用与L5或L3相同的制备方法制备得到。
L5,1H NMR(400MHz,CD2Cl2)δ8.68(d,J=4.7Hz,1H),8.15(d,J=7.9Hz,1H),7.77(t,J=7.8Hz,1H),7.39(m,1H),6.93(m,10H),6.01(d,J=10.3Hz,1H),5.71(d,J=10.3Hz,1H).
L3,1H NMR(400MHz,CD2Cl2)δ7.96(d,J=7.7Hz,1H),7.67(t,J=7.8Hz,1H),7.27(d,J=7.7Hz,1H),7.02-6.86(m,10H),5.99(d,J=10.3Hz,1H),5.70(d,J=10.3Hz,1H),2.56(s,3H).
L10,1H NMR(400MHz,CD2Cl2)δ8.39(d,J=7.9Hz,1H),8.00(t,J=7.9Hz,1H),7.80(d,J=7.9Hz,1H),6.95(m,10H),6.07(d,J=10.4Hz,1H),5.76(d,J=10.4Hz,1H).
L11,1H NMR(400MHz,CD2Cl2)δ8.03(d,J=7.8Hz,1H),7.72(d,J=7.8Hz,1H),7.20(ddd,J=17.9,14.7,7.6Hz,11H),6.92(m,10H),6.00(d,J=10.3Hz,1H),5.75(s,1H),5.70(d,J=10.3Hz,1H).
L12,1H NMR(400MHz,CD2Cl2)δ8.10(dt,J=7.9,4.1Hz,1H),8.03(d,J=8.0Hz,2H),7.86(m,2H),7.39(m,3H),6.96(dt,J=16.5,7.0Hz,10H),6.05(d,J=10.3Hz,1H),5.75(d,J=10.3Hz,1H).
实验数据
3aa,黄色油状液体.82.0mg,收率:97%.ee:95%,HPLC条件:OD-H柱(正己烷/异丙醇=98/2,流速0.5mL/min):保留时间tR=11.0min(主),tR=18.7min().[α]D 27=69.4(c0.56,CHCl3).1H NMR(600MHz,CDCl3):δ7.36(dd,J=7.6,1.8Hz,2H),7.29-7.19(m,4H),7.19-7.09(m,6H),6.81(d,J=7.4Hz,2H),6.70(dd,J=15.6,1.9Hz,1H),6.28(m,1H),2.32(s,3H).
3ab,黄色油状液体.81.0mg,收率:99%.ee:95%,HPLC条件:ID-H柱(正己烷/异丙醇=70/30,流速0.8mL/min):tR=4.8min(次),tR=6.2min(主).[α]D 24=33.4(c 0.4,CHCl3).1HNMR(600MHz,CDCl3):δ7.47-7.41(m,5H),7.37-7.28(m,6H),7.23(t,J=7.7Hz,2H),6.88(d,J=7.8Hz,2H),6.82(dd,J=15.6,1.7Hz,1H),6.41-6.34(m,1H).
3ac,无色油状液体,86.3mg,收率:99%.ee:93%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.5mL/min):tR=15.2min(主),tR=17.6min(次).[α]D 27=56.5(c 0.8,CHCl3).1H NMR(600MHz,CDCl3):δ7.38-7.35(m,2H),7.28-7.19(m,6H),7.16(dd,J=13.3,5.2Hz,2H),6.90-6.85(m,2H),6.82(dd,J=8.4,1.1Hz,2H),6.68(dq,J=15.5,1.9Hz,1H),6.29(dq,J=15.6,6.3Hz,1H),3.77(s,3H).
3ad,无色油状液体.90.0mg,收率:95%.ee:92%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=14.5min(主),tR=17.9min(次).[α]D 27=32.1(c 0.7,CHCl3).1HNMR(600MHz,CDCl3):δ7.60(d,J=8.3Hz,2H),7.39-7.33(m,4H),7.32-7.28(m,1H),7.24-7.18(m,5H),6.81-6.74(m,3H),6.29(dq,J=15.6,6.3Hz,1H).
3ae,白色固体.mp:118~120℃.79.0mg,收率:93%.ee:96%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=5.3min(次),tR=6.3min(主).[α]D 25=41.1(c0.9,CHCl3).1H NMR(600MHz,CDCl3):δ7.38-7.33(m,2H),7.28-7.15(m,8H),7.06-7.00(m,2H),6.80(dd,J=8.3,1.1Hz,2H),6.73-6.67(m,1H),6.33-6.25(m,1H).
3af,无色油状液体.87.0mg,收率:99%.ee:95%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=14.4min(主),tR=18.7min(次).[α]D 27=119.8(c0.5,CHCl3).1H NMR(600MHz,CDCl3):δ7.37-7.32(m,4H),7.31-7.27(m,1H),7.25-7.18(m,7H),6.81(dd,J=8.3,1.1Hz,2H),6.73-6.68(m,1H),6.29(dq,J=15.6,6.3Hz,1H).
3ag,无色油状液体.96.0mg,收率:99%.ee:90%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=11.1min(主),tR=13.1min(次).[α]D 27=32.1(c 0.7,CHCl3).1H NMR(400MHz,CDCl3):δ7.56(d,J=8.5Hz,2H),7.46-7.41(m,2H),7.40-7.34(m,1H),7.32-7.24(m,5H),7.23-7.18(m,2H),6.92-6.85(m,2H),6.82-6.74(m,1H),6.36(dq,J=15.5,6.3Hz,1H).
3ah,黄色固体,mp:111~113℃.94.0mg,收率:99%.ee:94%,HPLC条件:OD-H柱(正己烷/异丙醇=70/30,流速0.8mL/min):tR=4.4min(主),tR=4.8min(次).[α]D 24=23.7(c0.7,CHCl3).1H NMR(600MHz,CDCl3):δ7.62(d,J=7.7Hz,1H),7.51-7.42(m,3H),7.37-7.28(m,3H),7.26-7.18(m,5H),6.80-6.74(m,3H),6.34-6.26(m,1H).
3ai,黄色固体,mp:118~120℃.55.0mg,收率:62%.ee:91%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=16.1min(主),tR=17.2min(次).[α]D 25=25.5(c0.5,CHCl3).1H NMR(600MHz,CDCl3):δ7.43(d,J=7.9Hz,1H),7.36-7.33(m,3H),7.26-7.21(m,6H),7.14(t,J=7.8Hz,2H),6.79(dd,J=8.3,1.0Hz,2H),6.72(dq,J=15.6,2.0Hz,1H),6.32(dq,J=15.6,6.3Hz,1H).
3aj,黄色固体,mp:99.0~101℃.80.1mg,收率:94%.ee:95%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=14.3min(主),tR=15.2min(次).[α]D 27=34.9(c0.8,CHCl3).1H NMR(600MHz,CDCl3):δ7.39-7.32(m,3H),7.27-7.19(m,5H),7.18-7.11(m,3H),7.06-7.02(m,1H),6.84-6.81(m,2H),6.78-6.73(m,1H),6.32(dq,J=15.5,6.3Hz,1H).
3ak,无色油状液体.78.7mg,收率:89%.ee:90%,HPLC条件:OD-H柱(正己烷/异丙醇=98/2,流速0.5mL/min):tR=9.5min(主),tR=11.3min(次).[α]D 24=17.7(c 0.4,CHCl3).1HNMR(600MHz,CDCl3):δ7.35-7.32(m,2H),7.31-7.27(m,1H),7.25-7.18(m,6H),6.90-6.81(m,4H),6.75-6.70(m,1H),6.33(dq,J=15.5,6.3Hz,1H).
3am,黄色固体,mp:108~110℃.92.8mg,收率:99%.ee:93%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=10.4min(次),tR=12.3min(主).[α]D 23=65.0(c 1.0,CHCl3).1H NMR(600MHz,CDCl3):δ7.37-7.33(m,2H),7.29-7.20(m,4H),7.19-7.15(m,2H),6.86-6.80(m,4H),6.73-6.65(m,2H),6.32-6.23(m,1H),3.83(s,3H),3.71(s,3H).
3an,无色油状液体.58.4mg,收率:64%.ee:97%,HPLC条件:ID-H柱(正己烷/异丙醇=70/30,流速0.8mL/min):tR=6.1min(主),tR=7.1min(次).[α]D 23=56.3(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.21(d,J=8.4Hz,1H),7.95(dd,J=10.3,8.3Hz,2H),7.54-7.46(m,5H),7.44-7.33(m,4H),7.30-7.24(m,1H),7.14(t,J=7.8Hz,2H),6.97-6.87(m,3H),6.32(dq,J=15.7,6.3Hz,1H).
3ao,无色油状液体.90.3mg,收率:99%.ee:94%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=20.3min(次),tR=21.9min(主).[α]D 27=70.3(c 0.5,CHCl3).1H NMR(600MHz,CDCl3):δ7.86-7.74(m,3H),7.71(s,1H),7.50-7.46(m,2H),7.39(dd,J=5.3,2.4Hz,2H),7.33(dd,J=8.6,1.8Hz,1H),7.27-7.18(m,4H),7.10(t,J=7.9Hz,2H),6.89-6.81(m,1H),6.78(d,J=7.6Hz,2H),6.36(dq,J=15.4,6.3Hz,1H).
3ap,无色油状液体.105.0mg,收率:99%.ee:94%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.1min(次),tR=7.3min(主).[α]D 24=160.8(c 1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.42-7.31(m,3H),7.30-7.20(m,5H),6.87(d,J=8.0Hz,2H),6.64(dd,J=15.6,1.3Hz,1H),6.29(dq,J=21.2,6.2Hz,1H),4.29(s,1H),4.26-4.14(s,6H),4.08(s,1H),3.99(s,1H).
3aq,无色油状液体.78.5mg,收率:99%.ee:95%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=12.4min(主),tR=14.9min(次).[α]D 24=57.5(c 1.0,CHCl3).1H NMR(600MHz,CDCl3):δ7.47(d,J=0.9Hz,1H),7.36(dd,J=7.8,1.7Hz,2H),7.28(t,J=7.5Hz,1H),7.25-7.17(m,5H),6.79-6.74(m,2H),6.52(dq,J=15.6,2.0Hz,1H),6.43-6.36(m,2H),6.31(dq,J=15.6,6.3Hz,1H).
3ar,黄色固体,mp:99~101℃.81.6mg,收率:99%.ee:93%,HPLC条件:AD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=15.3min(主),tR=16.2min(次).[α]D 27=59.4(c0.7,CHCl3).1H NMR(600MHz,CDCl3):δ7.36(dt,J=6.6,1.6Hz,3H),7.30-7.26(m,1H),7.25-7.17(m,5H),6.98-6.90(m,4H),6.68(dq,J=15.5,1.9Hz,1H),6.30(dq,J=15.5,6.3Hz,1H).
3as,无色油状液体.76.6mg,收率:93%.ee:93%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.7min(主),tR=7.3min(次).[α]D 27=43.6(c 0.7,CHCl3).1H NMR(600MHz,CDCl3):δ7.36-7.32(m,3H),7.28(dd,J=10.7,4.3Hz,1H),7.24-7.16(m,6H),6.92(dd,J=5.1,1.0Hz,1H),6.85-6.82(m,2H),6.67(dq,J=15.6,1.9Hz,1H),6.28-6.19(dq,J=15.6,6.2Hz,1H).
3at,白色固体,mp:131~133℃.61.0mg,收率:72%.ee:90%,HPLC条件:OD-H柱(正己烷/异丙醇=98/2,流速0.5mL/min):tR=10.1min(主),tR=13.4min(次).[α]D 27=32.6(c1.0,CHCl3).1H NMR(600MHz,CDCl3):δ7.35(dd,J=5.1,1.9Hz,3H),7.26(dd,J=8.0,1.6Hz,2H),7.19-7.15(m,3H),7.09-7.05(m,2H),6.36(dq,J=15.7,2.0Hz,1H),6.04(dq,J=15.6,6.3Hz,1H),1.84-1.67(m,4H),1.61(t,J=13.8Hz,2H),1.33-1.25(m,1H),1.20-1.08(m,4H).
3au,mp:86-87℃.41.0mg,收率:51%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=5.3min(主),tR=5.8min(次).[α]D 28=4.9(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.40-7.32(m,3H),7.32-7.25(m,2H),7.22-7.11(m,3H),7.12-7.03(m,2H),6.38(dd,J=15.7,2.0Hz,1H),6.03(dd,J=15.7,6.3Hz,1H),1.94-1.74(m,2H),1.36-1.25(m,4H),0.82(t,J=7.1Hz,3H).
3av,参照实施例8的反应条件,130℃,无色油状液体.93.1mg,收率:99%.ee:95%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.5mL/min):tR=9.5min(主),tR=10.4min(次).[α]D 24=53.5(c 0.5,CHCl3).1H NMR(600MHz,CDCl3):δ7.39-7.35(m,2H),7.22(t,J=11.9Hz,4H),7.17-7.12(m,6H),6.82-6.72(m,3H),6.32-6.21(m,1H),2.30(s,3H).
3aw,参照实施例8的反应条件,130℃,无色油状液体.41.8mg,收率:43%.ee:91%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.5min(主),tR=7.8min(次).[α]D 27=-60.5(c 0.6,CHCl3).1H NMR(400MHz,CDCl3):δ7.41-7.34(m,2H),7.27-7.14(m,8H),6.91-6.78(m,4H),6.72(dt,J=15.7,2.0Hz,1H),6.33-6.21(m,1H),3.77(s,3H).
3ax,参照实施例8的反应条件,130℃,黄色固体,mp:98~100℃.53.0mg,收率:54%.ee:88%,HPLC条件:AD-H柱(正己烷/异丙醇=70/30,流速0.5mL/min):tR=7.4min(次),tR=8.4min(主).[α]D 27=-37.6(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.39-7.27(m,5H),7.25-7.17(m,7H),6.83-6.78(m,2H),6.74(dt,J=15.6,2.1Hz,1H),6.38-6.20(m,1H).
3ay,参照实施例7的反应条件,黄色固体,mp:135~137℃.82.0mg,收率:85%.ee:96%,HPLC条件:AD-H柱(正己烷/异丙醇=70/30,流速0.5mL/min):tR=8.4min(主),tR=10.4min(次).[α]D 27=-38.8(c 0.6,CHCl3).1H NMR(400MHz,CDCl3):δ7.65(d,J=8.4Hz,2H),7.39-7.30(m,5H),7.27-7.19(m,5H),6.83-6.73(m,3H),6.29(dt,J=15.6,11.5Hz,1H).
3az,黄色油状液体,61.2mg,收率:65%.ee:90%,HPLC条件:OD-H柱(正己烷/异丙醇=98/2,流速0.5mL/min):tR=9.0min(主),tR=11.6min(次).[α]D 29=25.4(c 1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.39-7.31(m,3H),7.27(dd,J=7.7,1.9Hz,2H),7.20-7.13(m,3H),7.08-7.05(m,2H),6.39(dt,J=15.7,2.1Hz,1H),6.02(dt,J=15.7,11.8Hz,1H),1.86-1.66(m,4H),1.59(d,J=12.1Hz,2H),1.31-1.09(m,5H).
3ba,参照实施例8的反应条件,130℃,白色固体,mp:81~83℃.86.1mg,收率:96%.ee:94%,HPLC条件:AD-H柱(正己烷/异丙醇=80/20,流速0.5mL/min):tR=9.2min(主),tR=11.1min(次).[α]D 27=39.6(c 0.6,CHCl3).1H NMR(600MHz,CDCl3):δ7.27(d,J=8.2Hz,2H),7.18-7.15(m,4H),7.04-6.95(m,4H),6.75-6.66(m,3H),6.26(dq,J=15.6,6.4Hz,1H),2.31(s,3H),2.25(s,3H),2.23(s,3H).
3ca,参照实施例7的反应条件,白色固体,mp:63~65℃.95.6mg,收率:86%.ee:98%,HPLC条件:AD-H柱(正己烷/异丙醇=80/20,流速0.5mL/min):tR=7.1min(主),tR=7.8min(次).1H NMR(600MHz,CDCl3):δ7.48(dt,J=13.8,8.3Hz,6H),7.21-7.13(m,4H),6.90(d,J=8.2Hz,2H),6.69-6.61(m,1H),6.32(dq,J=15.6,6.2Hz,1H),2.35(s,3H).
3da,参照实施例7的反应条件,无色油状液体.59.1mg,收率:58%.ee:95%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=7.7min(主),tR=8.9min(次).[α]D24=77.8(c 0.5,CHCl3).1H NMR(600MHz,CDCl3):δ7.36(d,J=8.3Hz,2H),7.17(dd,J=12.8,8.8Hz,4H),6.80(dd,J=17.0,8.4Hz,4H),6.68(t,J=11.9Hz,3H),6.27(dq,J=12.7,6.3Hz,1H),3.72(d,J=24.7Hz,6H),2.33(s,3H).
3ea,参照实施例7的反应条件,无色油状液体.74.8mg,收率:82%.ee:95%,HPLC条件:AD-H柱(正己烷/异丙醇=80/20,流速0.5mL/min):tR=7.8min(主),tR=8.4min(次).[α]D 25=47.0(c 0.5,CHC13).1H NMR(400MHz,CDCl3):δ7.38-7.32(m,2H),7.20-7.12(m,4H),6.99-6.85(m,4H),6.83-6.76(m,2H),6.70-6.60(m,1H),6.28(dq,J=15.6,6.3Hz,1H),2.33(s,3H).
3ga,参照实施例7的反应条件,无色油状液体.67.5mg,收率:74%.ee:98%,HPLC条件:OD-H柱(正己烷/异丙醇=98/2,流速0.5mL/min):tR=9.9min(主),tR=10.9min(次).[α]D24=47.6(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.25-7.05(m,8H),7.12-6.96(m,2H),6.67(dd,J=15.6,2.0Hz,1H),6.61(d,J=7.8Hz,1H),6.53-6.40(m,1H),6.28(dq,J=15.6,6.3Hz,1H),2.33(s,3H).19F NMR(376MHz,CDCl3):δ-64.08(d,J=7.5Hz,3F),-110.09(td,J=8.7,6.1Hz,1F),-111.78(td,J=9.2,6.5Hz,1F).
3ha,参照实施例8的反应条件,130℃,无色油状液体.64.5mg,收率:66%.ee:90%,HPLC条件:AD-H柱(正己烷/异丙醇=80/20,流速0.5mL/min):tR=8.5min(主),tR=12.3min(次).[α]D 24=51.2(c 0.4,CHCl3).1H NMR(400MHz,CDCl3):δ7.42-7.36(m,1H),7.31-7.23(m,2H),7.21-7.10(m,7H),6.76-6.62(m,3H),6.28(dq,J=15.6,6.3Hz,1H),2.34(s,3H).19F NMR(376MHz,CDCl3):δ-64.07(d,J=4.8Hz).
3ja,参照实施例7的反应条件,EtOH作溶剂,黄色液体,54.1mg,收率:79%.ee:96%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.5min(主),tR=7.9min(次).[α]D 26=1.1(c0.9,CHCl3).1H NMR(600MHz,CDCl3)δ7.11(d,J=7.9Hz,2H),7.03(d,J=7.9Hz,2H),6.81(d,J=15.6Hz,1H),6.11(dd,J=15.5,6.3Hz,1H),2.27(s,3H),2.24(td,J=8.5,5.1Hz,3H),2.18-2.07(m,1H),1.60-1.50(m,2H),1.36-1.15(m,2H),0.90(t,J=7.4Hz,3H),0.80(t,J=7.3Hz,3H).19F NMR(376MHz,CDCl3)δ-63.98--64.26(m).
3ka,无色油状液体.34.4mg,收率:48%.ee:91%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.2min(次),tR=7.7min(主).[α]D 24=-3.1(c 0.2,CHCl3).1H NMR(400MHz,CDCl3):δ7.57-7.31(m,5H),7.26-7.05(m,4H),6.85(dd,J=15.6,2.0Hz,1H),6.23(dd,J=15.5,6.3Hz,1H),2.30(s,3H),2.07(s,3H).19F NMR(376MHz,CDCl3):δ-64.12(d,J=7.6Hz).
3ka′,无色油状液体.17.2mg,收率:24%.ee:91%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=6.3min(次),tR=7.9min(主).[α]D 24=-74.6(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ7.36-7.24(m,3H),7.09(dd,J=23.8,8.2Hz,4H),6.95-6.85(m,2H),6.68(dd,J=15.6,2.0Hz,1H),6.17(dd,J=15.6,6.4Hz,1H),2.31(s,3H),1.96(s,3H).19F NMR(376MHz,CDCl3):δ-64.06(d,J=7.5Hz).
3la,黄色油状液体,57.1mg,收率:70%.ee:90%,HPLC条件:AS-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=5.4min(主),tR=7.8min(次).[α]D 26=-46.6(c 0.9,CHCl3).1HNMR(400MHz,CDCl3)δ7.34-7.21(m,3H),7.08(dd,J=16.8,4.7Hz,2H),7.03-6.95(m,2H),6.79-6.72(m,2H),6.65(dq,J=15.6,2.0Hz,1H),6.25-6.08(m,1H),2.78-2.59(m,1H),2.29(s,3H),1.17(d,J=7.0Hz,3H),1.15(d,J=7.0Hz,3H).19F NMR(376MHz,CDCl3)δ-62.74--65.06(m).
3la′,黄色油状液体,23.1mg,收率:29%.ee:88%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=5.6min(次),tR=6.2min(主).[α]D 29=1.6(c 0.3,CHCl3).1HNMR(400MHz,CDCl3)δ7.41-7.33(m,3H),7.31-7.24(m,2H),7.23-7.20(m,4H),6.99(dd,J=15.6,2.0Hz,1H),6.27(dd,J=15.6,6.3Hz,1H),2.64-2.51(m,1H),2.30(s,3H),0.97(d,J=7.1Hz,3H),0.81(d,J=7.0Hz,3H).19F NMR(376MHz,CDCl3)δ-62.96--65.42(m).
5aa,黄色固体,mp:182-184℃.46.4mg,收率:56%.ee:91%,HPLC条件:AS-H柱(正己烷/异丙醇=70/30,流速1.0mL/min):tR=7.9min(主),tR=18.0min(次).[α]D 27=-13.7(c0.2,CHCl3).1H NMR(600MHz,CDCl3):δ7.41-7.35(m,4H),7.34-7.29(m,5H),7.27-7.19(m,7H),7.15(dd,J=15.1,7.1Hz,2H),6.99(d,J=15.9Hz,1H),6.87(dd,J=8.3,1.1Hz,2H),6.52(d,J=15.9Hz,1H).
5ab,白色固体,mp:69~71℃.44.5mg,收率:52%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=21.3min(主),tR=25.1min(次).[α]D 27=-15.1(c0.3,CHCl3).1H NMR(600MHz,CDCl3):δ7.41-7.35(m,4H),7.34-7.31(m,3H7.24-7.20(m,6H),7.16-7.13(m,2H),7.06(d,J=8.0Hz,2H),6.94(d,J=15.9Hz,1H),6.88(dd,J=8.3,1.1Hz,2H),6.46(d,J=15.9Hz,1H),2.27(s,3H).
5ac,黄色固体,mp:60~62℃.80.1mg,收率:83%.ee:93%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=9.2min(主),tR=14.6min(次).[α]D 25=-11.3(c0.6,CHCl3).1H NMR(400MHz,CDCl3):δ7.47(d,J=8.2Hz,2H),7.41-7.30(m,9H),7.28-7.18(m,4H),7.14(t,J=7.7Hz,2H),7.02(d,J=15.9Hz,1H),6.88-6.82(m,2H),6.60(dd,J=15.9,1.5Hz,1H).19F NMR(376MHz,CDCl3):δ-62.56(s).
5ad,黄色固体,mp:54~56℃.46.7mg,收率:54%.ee:92%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=9.5min(主),tR=11.7min(次).[α]D 25=-10.2(c0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.38-7.32(m,6H),7.28-7.22(m,3H),7.25-7.21(m,3H),7.18-7.14(m,3H),6.98-6.91(m,3H),6.89-6.84(m,2H),6.43(d,J=15.9Hz,1H).19F NMR(376MHz,CDCl3):δ-112.98--113.0(m).
5ae,白色固体,mp:73.0~75℃.49.3mg,收率:55%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=9.9min(主),tR=12.9min(次)[α]D 25=-15.2(c0.7,CHCl3).1H NMR(600MHz,CDCl3):δ7.38-7.32(m,7H),7.26-7.20(m,8H),7.18-7.13(m,2H),6.94(d,J=15.9Hz,1H),6.86(dd,J=8.3,1.1Hz,2H),6.49(d,J=15.9Hz,1H).
5af,黄色固体,mp:63~65℃.71.8mg,收率:73%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=10.4min(主),tR=14.0min(次)[α]D 25=-18.3(c0.7,CHCl3).1H NMR(400MHz,CDCl3):δ7.35(ddd,J=10.7,5.8,2.6Hz,9H),7.23(ddd,J=9.7,6.7,4.3Hz,4H),7.17(d,J=9.0Hz,4H),6.93(d,J=15.9Hz,1H),6.89-6.83(m,2H),6.50(d,J=15.9Hz,1H).
5ag,白色固体,mp:55~58℃.40.3mg,收率:47%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=95/5,流速0.4mL/min):tR=20.5min(主),tR=22.2min(次).[α]D 25=-12.3(c0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.46-7.03(m,18H),6.88(d,J=7.3Hz,2H),6.41(d,J=15.8Hz,1H),2.23(s,3H).
5ah,黄色固体,mp:150~153℃.37.0mg,收率:44%.ee:90%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=9.3min(次),tR=10.6min(主).[α]D 23=-37.4(c0.8,CHCl3).1H NMR(400MHz,CDCl3):δ7.39-7.30(m,7H),7.26-7.19(m,4H),7.19-7.08(m,4H),6.96(d,J=3.4Hz,1H),6.93-6.84(m,3H),6.36(d,J=15.7Hz,1H).
5ai,黄色固体,mp:76~82℃.79.1mg,收率:82%.ee:94%,HPLC条件:AD-H柱(正己烷/异丙醇=80/20,流速1.0mL/min):tR=10.0min(主),tR=15.8min(次).[α]D 25=-11.3(c 0.6,CHCl3).1H NMR(400MHz,CDCl3):δ7.57(d,J=8.5Hz,2H),7.48(d,J=8.3Hz,2H),7.36-7.31(m,4H),7.28-7.16(m,9H),6.96(d,J=15.9Hz,1H),6.88(d,J=7.3Hz,2H),6.52(d,J=15.9Hz,1H).19F NMR(376MHz,CDCl3):δ-62.65(s).
5ai黄色固体,mp:160~162℃.73.0mg,收率:74%.ee:93%,HPLC条件:AS-H柱(正己烷/异丙醇=70/30,流速1.0mL/min):tR=10.8min(主),tR=15.3min(次).[α]D 25=-25.3(c0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.44(d,J=8.6Hz,2H),7.35(dd,J=6.6,3.1Hz,2H),7.33-7.29(m,2H),7.28-7.16(m,11H),6.95(d,J=15.9Hz,1H),6.91-6.85(m,2H),6.47(d,J=15.9Hz,1H).
5ak,室温反应,无色油状液体.61.5mg,收率:75%.ee:92%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=8.6min(次),tR=9.8min(主).[α]D 26=-33.8(c0.6,CHCl3)(L5).1H NMR(400MHz,CDCl3):δ7.37-7.29(m,8H),7.24-7.20(m,4H),7.13(t,J=7.7Hz,2H),6.85-6.78(m,2H),6.42(d,J=15.5Hz,1H),4.14(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).
5al无色油状液体.58.5mg,收率:77%.ee:96%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=12.6min(次),tR=13.4min(主).[α]D 24=-35.7(c 1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.42-7.27(m,7H),7.24-7.07(m,7H),6.81(d,J=7.4Hz,2H),6.71(d,J=15.6Hz,1H),2.22(s,3H).
5al′无色油状液体.8.4mg,收率:11%.ee:92%,HPLC条件:AD-H柱(正己烷/异丙醇=90/10,流速0.8mL/min):tR=9.5min(次),tR=10.8min(主).[α]D 24=62.6(c0.5,CHCl3).1HNMR(600MHz,CDCl3)δ7.95-7.85(m,2H),7.52(t,J=7.4Hz,1H),7.42(t,J=7.8Hz,2H),7.36-7.29(m,5H),7.25(d,J=15.3Hz,1H),7.21-7.10(m,5H),7.05(d,J=15.3Hz,1H),1.69(s,3H).
5am,黄色油状液体,42.8mg,收率:56%.ee:96%,HPLC条件:OD-H柱(正己烷/异丙醇=80/20,流速0.8mL/min):tR=9.1min(主),tR=10.6min(次).[α]D 29=3.2(c 0.6,CHCl3).1H NMR(400MHz,CDCl3)δ7.41-7.30(m,9H),7.25-7.20(m,6H),7.18-7.07(m,3H),6.90-6.83(m。2H),6.82-6.68(m,2H),6.62-6.56(m,1H),6.18-6.03(m,1H).
5an,黄色油状液体,82.3mg,收率:72%.ee:98%,HPLC条件:OD-H柱(正己烷/异丙醇=90/10,流速1.0mL/min):tR=11.5min(次),tR=20.2min(主).[α]D 29=-68.5(c1.0,CHCl3).1H NMR(600MHz,CDCl3)δ7.39(d,J=7.4Hz,2H),7.37-7.32(m,3H),7.30(dd,J=7.4,3.9Hz,4H),7.27-7.22(m,4H),7.22-7.20(m,1H),7.16-7.08(m,4H),7.05-6.88(m,5H),6.78(d,J=16.2Hz,1H),6.64(d,J=7.4Hz,2H),2.24(s,3H).
5ap,31.2mg,收率:31%.ee:93%,HPLC条件:OD-H柱(正己烷/异丙醇=95/5,流速1.0mL/min):tR=9.4min(次),tR=10.5min(主).[α]D 29=-24.9(c 0.3,CHCl3).1H NMR(400MHz,CDCl3)δ7.51(d,J=8.3Hz,2H),7.39(d,J=7.3Hz,2H),7.36-7.24(m,8H),7.05(d,J=16.4Hz,1H),6.97(d,J=8.2Hz,1H),6.47(d,J=16.4Hz,1H),2.24(s,3H),2.17(t,J=7.7Hz,2H),2.08-2.05(m,1H),1.98-1.88(m,1H),1.50-1.42(m,2H),0.87(t,J=7.3Hz,1H),0.83-0.75(m,1H),0.61(t,J=4.9Hz,3H),0.61-0.59(m,1H).
10aa,′HNMR(400MHz,CDCl3)-δ7.41-7.33(m,5H),7.35-7.25(m,5H),7.20-7.17(m,5H),7.08(d,J=16.0Hz,1H),6.35(d,J=16.0Hz,1H).
Claims (2)
1.一种γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,其特征在于,所述不对称合成方法包括:在零价镍Ni(0)和式L所示配体存在下,于有机溶剂中,使式1化合物和式2化合物反应,得到式3所示手性γ-烯基取代的丁烯内酯或丁烯内酰胺化合物,
其中:
Ni(0)和所述配体均为催化量;
L选自如下结构:
R1a、R1b独立地为C1~C6烷基、取代或未取代的苯基;X为O、NPh、NTs;R2为C1~C4卤代烷基、取代或未取代的苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、二茂铁基、C3~C8环烷基、C1~C8烷基;R3为C1~C4全氟烷基取代或未取代的:苯基、苯基乙烯基、苯甲酰基,吡啶基、嘧啶基、呋喃基、噻吩基、酯基、C1~C6烷基酰基。
2.根据权利要求1所述的γ-烯基取代的丁烯内酯或丁烯内酰胺化合物的不对称合成方法,其特征在于,所述式1化合物和式2化合物投料比为1:1~1:1.2;
且/或,Ni(0)相对于式1化合物的所述催化量为3%~10%;
且/或,所述配体相对于式1化合物的所述催化量为5%~14%;
且/或,Ni(0)与配体的用量比位于1:1~1:2之间;
且/或,所述反应的温度为20~130℃;
且/或,所述不对称合成方法还包括降低所述反应的体系中氧含量的操作;
且/或,所述有机溶剂选自苯、甲苯、氟苯、氯苯、1,2,4-三氯苯、1,4-二氧六环、四氢呋喃、甲基叔丁基醚、乙醚、甲醚、乙醇、甲醇、异丙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、1,2--二氯乙烷、氯仿、乙腈中的一种或多种的混合。
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