CN107848907A - 取代烯烃的环丙烷化 - Google Patents

取代烯烃的环丙烷化 Download PDF

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CN107848907A
CN107848907A CN201680043757.6A CN201680043757A CN107848907A CN 107848907 A CN107848907 A CN 107848907A CN 201680043757 A CN201680043757 A CN 201680043757A CN 107848907 A CN107848907 A CN 107848907A
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process according
cyclopropanation process
cyclopropanation
granular metal
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穆罕默德·加拉
伊加尔·贝克尔
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International Flavors and Fragrances Inc
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Abstract

公开一种环丙烷化方法，所述环丙烷化方法包括使具有至少一个碳‑碳双键的烯烃化合物与至少一种二卤代烷烃反应的步骤。所述反应在(i)颗粒状金属Zn、(ii)催化有效量的颗粒状金属Cu或其盐、(iii)至少一种卤代烷基硅烷和(iv)至少一种溶剂的存在下进行。

Description

取代烯烃的环丙烷化
技术领域
本申请提供具有改善的条件和产率的用于使用二卤代甲烷使取代烯烃环丙烷化的方法。
背景
Simmons和Smith在1958报道了在醚中使用二碘甲烷和锌-铜偶(zinc-coppercouple)的烯烃的首次环丙烷化(Organic Reactions,vol.20,1,1973)。推断反应性的卡宾体(carbenoide)为与Zn(CH2I)2和ZnI2处于舒伦克(Schlenc)平衡的碘甲基碘化锌(ICH2ZnI)。发现反应是立体定向的，即在产物中保持烯烃的构型。反应需要非常长的时间(16-72小时)并且产率为7％到70％。
通过二碘甲烷的二聚化在反应期间稳定地产生乙烯，其量与环丙烷化产物的量成反比。氯碘甲烷反应性差并且发现二溴甲烷(DBM)不反应(Simmons和Smith,J.Am.Chem.Soc.,81(16),4256,1959)。锌-铜偶通过将锌和铜粉末熔化然后粉碎固体来制备。之后的研究通过在乙酸中用铜或银盐原位处理粒状锌或锌粉简化程序(Charette和Beauchemin,Organic Reactions,58,第1章,pp.1-415,2001)。
鉴于Simmons-Smith环丙烷化作为合成工具的重要性，作出持续的努力以用便宜得多的DBM代替昂贵的二碘甲烷并且探索新的条件以提高反应速率。
LeGoff(J.Org.Chem.,29(7),2048,1964)发现通过在乙酸中添加Cu(OAc)2·H2O实现粒状锌的提高的活化。该偶允许DBM在环己烯和环辛烯在二乙醚中的环丙烷化中的使用。反应时间是25-40小时并且产率分别是61％和40％。该产率比利用二碘甲烷时低得多并且不可重现。锌粉-铜偶给出低得多的产率。
Fabisch和Mitchell利用DBM和锌在作为溶剂的四氢呋喃(THF)中使简单烯烃环丙烷化。参见J.Organometal.Chem.,269(3),219,1984。该反应在40℃在不存在铜的条件下进行48小时。产率为35％至52.8％。观察到乙烯形成。在全氘化的THF中的NMR分析与BrZnCH2Br一致。NMR显示静置时BrZnCH2Br转化为Zn(CH2Br)2和ZnBr2。
Friedrich、Domek和Pong通过在回流醚中在10摩尔％CuCl的存在下超声处理锌粉显著改善了简单烯烃的DBM环丙烷化。参见J.Org.Chem.,50(23),464,1985。在诱导期(0.5-1hr)后，反应开始并且在2-4小时后结束。产率为28-50％，其中环己烯和环辛烯分别给出60％和72％产率。
将这些反应条件应用于根据美国专利号5,929,291(Bajgrowicz和Frater,1999,Givaudan Roure Int)的添味剂II的合成。
双环丙烷化的产物II由烯丙醇I在持续超声处理22小时后以41％产率获得。为了省去诱导期，在添加I之前将在醚中含有DBM、锌粉和氯化亚铜的反应混合物超声处理30分钟。产物表现出檀香、果味、奶油/类乳、非常持久的气味。
Friedrich、Lunetta和Lewis报道(J.Org.Chem.,54(10),2388,1989)当通过四氯化钛(1.5-2摩尔％)使锌-铜偶更活泼时超声处理不是必需的。反应时间少于2小时并且产率与超声处理相当。DBM和二碘甲烷给出类似的产率。
Friedrich和Lewis(J.Org.Chem.,55(8),2491,1990)发现将2摩尔％乙酰氯添加到锌-铜偶中的效果甚至比四氯化钛更强。利用DBM在回流醚中在10摩尔％氯化铜的存在下的未活化烯烃的环丙烷化需要1-2小时完成。产率为33％至76％。环己烯和环辛烯分别给出61％和88％产率。三甲基氯化甲硅烷被声称具有类似的促进效果但是没有给出实例。
Frederich程序的主要缺点是二乙醚的使用，二乙醚是可能是爆炸性的极易燃的溶剂(-45℃的闪点)。二乙醚蒸气比空气重，因此在地面上积聚并且移动，并且可能被热表面、静电或其他点火源点燃。由于对光和气体敏感，其倾向于形成爆炸性的过氧化物。考虑到其低沸点(34.6℃)和麻醉性质，其在生产场所的操作需要非常高效的热交换器以完全消除其向环境的释放。
锌助催化剂如三甲基氯硅烷之后被证明抑制痕量的铅在商品化锌粉中的减缓效果。Takai、Kakiuchi和Utimoto.(J.Org.Chem.,59(10),2671,1994,)证明在火法冶金的锌中发现的痕量的铅大幅降低锌针对二碘甲烷和碘烷烃的反应性，并且该副作用可以通过添加催化量的Me3SiCl完全抑制。
因此，当二碘甲烷与环辛烯(III)和不含铅的(电解的)锌粉在沸腾的醚中反应8小时时，获得IV，产率为96％。NMR显示卡宾体ICH2ZnI的存在。然而，当使用包含0.06摩尔％铅的锌粉时，产率下降至2％，并且未检测到ICH2ZnI。将三甲基氯化甲硅烷(2摩尔％)添加到包含0.5摩尔％铅的锌粉中以97％产率生成IV。
将更活泼的Friedrich环丙烷化应用于(E)-2-甲基-4-(2,2,3-三甲基环戊-3-烯基)丁-2-烯-1-醇(V)用于香精成分[1-甲基-2-(1,2,2-三甲基双环[3.1.0]己-3-基甲基)环丙基]甲醇(VI，JavanolTM)的合成。参见US5,929,291。
JavanolTM以48％产率制备。其表现出檀香、非常天然、花香、奶油、粉状、非常强且持久的气味。
V的DBM-锌环丙烷化被显示为(Bajgrowicz、Frank和Frater,Helv.Chim.Acta,81(7),1349,1998)以两步进行，较快的步骤是近端环丙烷化，得到VII，其仅以14％产率分离。VII表现出奶油、内酯酸檀香的气味。
单环丙烷化的醇VII之后通过基于镁卡宾体的改善的方法以93％产率制备。利用甲基氯化镁在THF中使V去质子化之后是利用DBM和叔丁基氯化镁在二乙醚中在10-20℃的反应。参见US8,450,533。提出作为活性环丙烷化试剂的镁卡宾体XMgCH2X的参与(Brunner等,J.Org.Chem.73(19),7543,2008)。
JavanolTM还通过利用DBM作为溶剂的两个连续环丙烷化以高的总产率制备。US7,777,084显示三异丁基-铝-FeCl3在远远过量的作为溶剂的DBM的存在下在室温在4小时内催化V的远端环丙烷化，以定量的产率得到VIII。铝卡宾体(iBu)2AlCH2Br通过NMR检测。在后处理后，将DBM共沸干燥和浓缩至3当量/1当量VIII，应用镁卡宾体近端环丙烷化以得到VI，产率为82％。参见Brunner、Elmer和Eur.J.Org.Chem.,24,4623,2011。
反应表现出高立体定向性和高的总产率。尽管远远过量地使用DBM，但是其是可重复利用的。与先前的方法不同，含水废物不含锌和铜盐。缺点是远远过量的具有相对较低反应性的DBM以及远远过量的昂贵且自燃的三异丁基铝和叔丁基氯化镁的使用。第一步反应器通量仅为4.3％。含水废物含有大量的铝和镁氢氧化物。
Rieke等(J.Org.Chem.,46(21),4323,1981)通过在沸腾的二甲氧基乙烷中用锂还原氯化锌制备纳米锌的高度活性形式。在用二乙醚交换溶剂后，利用DBM通过回流6小时将环己烯环丙烷化以生成双环[4.1.0]庚烷，产率为94％。高腐蚀性锂金属的使用以及其对水的高敏感性结合所需的至二乙醚的溶剂交换使该方法在工业规模上不那么引人关注。
Sibille等(J.Org.Chem.,56(10),3255,1991)描述了使用锌棒阳极和碳纤维阴极的利用DBM的烯丙醇的电化学环丙烷化。在包含通过1,2-二溴乙烷的预电解产生的Bu4NBr/Bu4NI和ZnBr2的混合物的二氯甲烷(DCM)和二甲基甲酰胺(DMF)的混合物中进行电解。产率为52％至75％。在E-巴豆醇、E-肉桂醇和2-环己烯-1-醇的环丙烷化中使用溴氯甲烷(CBM)，产率分别为54％、59％和75％。尽管首次证明利用较廉价的CBM进行环丙烷化，但是对能够控制反应热的专用电化学装置的需求极大地限制了其在工业规模上的应用。
尽管在过去57年对Simmons-Smith环丙烷化方法进行研究和开发，但是仍存在对高产率的烯烃的经济、快速且安全的环丙烷化的需求。
一般描述
本发明描述二卤代烷烃，如溴氯甲烷(CBM)，在用于烯烃的环丙烷化的方法中的首次实际使用。本申请的发明人出人意料地发现作为亚甲基源的二卤代烷烃(如CBM)提供高产率和非常快速的取代烯烃的环丙烷化方法。所述方法的特征在于高选择性和与现有技术相比较高的反应器通量。
因此，本发明提供一种环丙烷化方法，所述环丙烷化方法包括使具有至少一个碳-碳双键的烯烃化合物(例如，烯烃反应物)与至少一种二卤代烷烃(例如，CBM)在以下的存在下反应的步骤：
(i)颗粒状金属Zn；
(ii)催化有效量的颗粒状金属Cu或其盐；
(iii)至少一种卤代烷基硅烷；和
(iv)至少一种溶剂；
由此制备所述烯烃化合物的环丙烷衍生物(例如环丙烷产物)。
术语“环丙烷化”涉及其中通过将亚甲基部分添加到烯烃化合物的至少一个碳-碳双键在所述方法中反应的所述化合物上形成环丙烷环的过程。
作为烯烃反应物的术语“具有至少一个碳-碳双键的烯烃化合物”涵盖为直链、支链、环状(即环烯烃)或多环化合物(稠环、螺环系统或经由化学键连接的环)的任何具有一个或多个碳-碳双键的化合物。当烯烃反应物包含多于一个的双键时，所述至少两个双键可以是共轭的或非共轭的。所述反应物还可以包含任何官能团和其他类型的键(σ键、三键或其他)。在其中所述烯烃被多于一个的与所述至少一个碳-碳双键的碳原子直接键合的官能团取代时，所述烯烃可以具有顺式或反式构型或者(Z)或(E)构型。
上述术语还包括术语“未活化烯烃”，其应被理解为涵盖包含烯基的化合物，其中烯基双键未被吸电子基团(如腈基、羧酸酯基、或本领域众所周知的其他缺电子基团)取代，所述吸电子基团可以活化作为亲二烯体的双(或三)键以在典型的环加成反应中与二烯反应。在本发明的环丙烷化方法中用作反应物的未活化烯烃包含至少一个供电子基团(如例如烷基、烷基芳基、烷氧基烷基、环烷基、环烷基烷基或本领域中众所周知的其他供电子基团)。
术语“二卤代烷烃”应被理解为涵盖任何其上具有两个取代的卤素原子的直链或支链C1–C10烷烃。在一些实施方案中，所述卤素各自独立地是Cl和/或Br。在一些其他实施方案中，所述二卤代烷烃是二卤代-C1-C5烷烃。
在一些实施方案中，所述至少一种二卤代烷烃是二溴甲烷(DBM)、氯溴甲烷(CBM)或其组合。在某些实施方案中，所述至少一种二卤代烷烃是二溴甲烷。在其他实施方案中，所述至少一种二卤代烷烃是氯溴甲烷。
出人意料地发现通过所述二卤代烷烃在本发明的方法期间产生的卡宾体极易反应，这提供了未活化烯烃反应物(即针对亲电子卡宾体较不易反应的烯烃。这种烯烃典型地未被取代或被烷基、羰基等取代)的立即环丙烷化。
当提到“颗粒状金属Zn”(也称作“锌粉”)时，其应被理解为涵盖金属Zn颗粒。在一些实施方案中，颗粒状金属Zn具有小于10μm(例如，5至8μm)的粒度。
在一些实施方案中，颗粒状Zn包含至少97％锌，并且在一些实施方案中，颗粒状Zn中的Pb含量是20ppm以下。
在一些实施方案中，当所述烯烃反应物包含一个碳-碳双键时，相对于所述烯烃反应物，所述颗粒状金属Zn以1-10摩尔当量(例如，1-8、2-8、2-5、和3当量)的量存在。
当提到“催化有效量的颗粒状金属Cu”时，其应被理解为涵盖以催化量(即以显著低于本发明的方法的反应物的化学计算量的量)添加的金属Cu的颗粒。在一些实施方案中，颗粒状Cu是颗粒状Cu盐，如例如CuCl的颗粒。在一些实施方案中，以颗粒状金属Zn的重量计，所述金属Cu颗粒以0.1至1％(例如，0.5％)的量存在。在其他实施方案中，以烯烃反应物的摩尔计，金属Cu颗粒以0.1-20％(例如，0.2-15％、0.5-10％、和1-5％)的量存在。
在一些实施方案中，所述颗粒状金属Cu具有小于50μm的粒度。铜粒度可以是37至105μm(400至140目)，优选的粒度是44μm(325目)。
在一些其他实施方案中，本发明的方法利用催化有效量的颗粒状Cu盐进行。在一些实施方案中，所述Cu盐是CuCl。在一些实施方案中，相对于颗粒状金属Zn的量，催化有效量的颗粒状Cu盐的量是约2重量％。
不受理论限制，Cu可以用于活化颗粒状Zn的表面。也参见Blanchard和Simmons,J.Am.Chem.Soc.86(7),1337-47,1964。Cu盐还可以作为用于从有机锌试剂到烯烃的卡宾转移的催化剂。参见Schuchardt、Nery和Zuiani，J.Braz.Chem.Soc.2(2),61-65,1991以及本文中引用的文献。
术语“卤代烷基硅烷”是指C1-C10烷基SiX(其中X是卤素原子如Cl、Br和I)。在一些实施方案中，所述卤代烷基硅烷是三烷基氯硅烷，其可以是三甲基氯硅烷、三乙基氯硅烷、三丁基氯硅烷、三异丁基氯硅烷、三己基氯硅烷、或其任意组合。三甲基氯硅烷是优选的。
在一些实施方案中，以颗粒状金属Zn的重量计，卤代烷基硅烷以0.5-5％(例如，1-3％和1.5％)的水平存在。
在一些实施方案中，所述至少一种溶剂是醚溶剂。在进一步的实施方案中，至少一种醚溶剂选自二乙醚、1,2-二甲氧基乙烷(DME)、甲基叔丁基醚(MTBE)、四氢呋喃(THF)、环戊基甲醚(CPME)、及其任意组合。在更进一步的实施方案中，所述至少一种溶剂还包含二氯甲烷(DCM)。
在一些实施方案中，溶剂是重量比为1:5至10:1(例如，1:2至2:1，和1:1)的环戊基甲醚和二氯甲烷的混合物。
在一些实施方案中，所述烯烃化合物和所述至少一种溶剂的重量比是1:1至10:1，优选2:1至7:1，并且更优选4:1。
在一些实施方案中，环丙烷化方法在20℃至100℃(例如，35℃至70℃和53℃至58℃)的温度中进行。
在一些实施方案中，本发明的环丙烷化方法提供50％至90％的产率。在其他实施方案中，本发明的环丙烷化方法提供85-95％的产率。
当使包含两个双键的化合物如2-烷基-4-(2,2,3-三甲基环戊-3-烯-1-基)丁-2-烯-1-醇、朱栾倍半萜或D-柠檬烯反应时，它们都以高产率在一个步骤中被环丙烷化。根据现有技术(Friedrich和Niyati-Shirkhodaee,J.Org.Chem.,56(6),2202,1991)，D-柠檬烯(IX)被报道为使用DBM进行单和二-环丙烷化以得到由22％未变化的起始材料、37％环外的环丙烷、12％环环丙烷、和29％所需二环丙烷化的产物X组成的产物混合物。相比之下，当将D-柠檬烯在本发明的方法的条件下环丙烷化时，D-柠檬烯完全转化为二-环丙烷化的产物，产率为63％。
当使用THF或DME作为溶剂时，CBM选择性地将V的近端烯丙醇双键环丙烷化以以高产率得到VII。备选地，在CPME-DCM溶剂和作为卡宾体源的CBM的混合物中使用一半当量量的锌的情况下，快速滴定V的近端双键以以高产率得到VII。
当高烯丙醇如(Z)-3-己烯-1-醇(XI，叶醇)暴露于本发明的环丙烷化方法时，以短时间(3hr)和高产率(70％)形成(1R,2R)-2-乙基-环丙乙醇(XII)。
相比之下，Kiyota等报道了通过使XI与昂贵的二碘甲烷和高度自燃的二乙基锌在沸腾的二乙醚中反应7天以62％产率制备化合物XII。参见Flavour Fragr.J.17(3)227–231(2002)。
典型地，使用本发明的环丙烷化方法制备的具有环丙烷部分的化合物是具有味道和嗅觉性质的前体或成分。因此，本发明还提供成本减少且环境影响降低的使用上述环丙烷化方法制备香料或香精成分的方法。
在本文和在权利要求中提到的所有份、百分比和比例都是以重量计的，除非另外指明。
本文公开的值和尺寸不被理解为严格限于所记载的精确数值。而是，除非另外详细说明，每个这种值都旨在意指所记载的值和在该值附近的功能等同范围两者。例如，作为“50％”公开的值旨在意指“约50％”。
本文中引用的所有出版物通过引用完整地并入。
通过以下非限制性实施例更详细地描述本发明。
详述
实施例1.[1-甲基-2-(1,2,2-三甲基双环[3.1.0]己-3-基甲基)环丙基]甲醇(VI)
在氮下向配备回流冷凝器的反应器装入锌粉(100g，1.48mol)、铜粉(0.5g，7.86mmol)、三甲基氯硅烷(1.5g，0.0136mol)、CPME(100g)和DCM(100g)。将混合物在53-55℃搅拌0.5小时(hr)，然后在2hr期间在和缓的回流下添加(E)-2-甲基-4-(2,2,3-三甲基环戊-3-烯基)丁-2-烯-1-醇(V，53g，纯度92.5％，0.25mol)和CBM(165g，纯度99％，1.27mol)的混合物。不断地形成乙烯。在添加完成后，将得到的反应混合物在58℃搅拌另外的1-1.5hr。
将50重量％氯化铵在水(500g)中的溶液在搅拌下冷却至5℃。在用CPME(100g)稀释后，将反应混合物在5℃缓慢地添加到搅拌的氯化铵水溶液中(放热)。使温度在添加期间升高至25℃。将有机相分离并且用10％碳酸氢钠水溶液洗涤。
向水相添加CPME(150g)并且在室温搅拌15分钟(min)。将有机相收集并且与以上获得的第一有机相合并。在将溶剂和粗产物在190-220℃和0.1mm Hg在1重量％碳酸钠和10％导热油(thermal oil)的存在下蒸馏后，获得43.6g的VI，其纯度为82.5％(异构体1-37.73％；异构体2-44.73％)。重量产率为89％(78％摩尔产率)。
实施例2.[1-甲基-2-(1,2,2-三甲基双环[3.1.0]己-3-基甲基)环丙基]甲醇(VI)
在氮下向配备回流冷凝器的反应器装入锌粉(90g)、铜粉(1g)、三甲基氯硅烷(1.5g)和二乙醚(200g)。将混合物在45℃搅拌0.5hr，然后在2hr期间在和缓的回流下添加(E)-2-甲基-4-(2,2,3-三甲基环戊-3-烯基)丁-2-烯-1-醇(53g，92.5％，0.25mol)和CBM(206g，99％，1.57mol)的混合物。在添加完成后，将得到的混合物在45℃搅拌另外的2hr。
制备50重量％氯化铵在水(500g)中的溶液，将其冷却至5℃并在搅拌下保持。在用二乙醚(200g)稀释后，将反应混合物在5℃缓慢地添加到氯化铵水溶液中(放热)。将有机相分离并且用含有氯化钠的碳酸氢钠水溶液洗涤。将有机相过滤。将二乙醚蒸发以获得粗产物。
然后，将粗产物在190-220℃在0.1mmHg下在1重量％碳酸钠和10％导热油的存在下蒸馏以获得40g产物。纯度为82.5％(异构体1-37.73％；异构体2-44.73％)。重量产率为80％(70％摩尔产率)。
实施例3.[1-甲基-2-(1,2,2-三甲基双环[3.1.0]己-3-基甲基)环丙基]甲醇(VI)
按照实施例1中描述的程序，除了用DBM(275g，99％，1.58mol)替代CBM。重量产率为82％(71.8％摩尔产率)。
实施例4.(1-甲基-2-(((R)-2,2,3-三甲基环戊-3-烯-1基)甲基)环丙基)甲醇(VII)
按照实施例1中描述的程序，使用相同量的(E)-2-甲基-4-(2,2,3-三甲基环戊-3-烯基)丁-2-烯-1-醇(V)，除了使用85g的CBM、35g锌粉、0.25g铜粉末和0.2g三甲基氯硅烷。在1.5hr期间在60℃添加CBM和V的混合物。在反应完成后，将反应混合物缓慢地添加到氯化铵(75g)溶解于水(200g)的溶液中。闪蒸得到45.5g无色粘稠油状物，其由74.8％单环丙烷化产物VII和11.6％VI组成。VII的重量产率为67.4％并且VI的重量产率为10.45％。
(1-甲基-2-(((R)-2,2,3-三甲基环戊-3-烯-1基)甲基)环丙基)甲醇(VII)：1H NR(500Mhz，氯仿-d)：5.17-5.30(m,1H),3.24-3.40(m,2H),2.27-2.44(m,1H),1.62-1.95(m,3H),1.53-1.62(m,3H),1.20-1.52(m,2H),1.14(s,～50％的3H),1.13(s,～50％的3H),0.98(s,～50％的3H),0.97(s,～50％的3H),0.74(s,～50％的3H),0.73(s,～50％的3H),0.38-0.68(m,2H),-0.18-0.11(m,1H)。MS(DIP,EI):m/z 208(M+)。
实施例5.(4S,4aR)-4,4a-二甲基-6-(1-甲基环丙基)十氢环丙并[d]萘
除了使用不同的起始材料(即，(3R,4aR,5S)-4a,5-二甲基-3-(丙-1-烯-2-基)-1,2,3,4,4a,5,6,7-八氢萘)，根据实施例1中描述的程序将朱栾倍半萜(15g，80％)环丙烷化，以得到4,4a-二甲基-6-(1-甲基环丙基)十氢-环丙并[d]萘异构体的两种异构体的混合物(15g)，纯度为56％。
(4S,4aR)-4,4a-二甲基-6-(1-甲基环丙基)十氢环丙并[d]萘：1H NMR(400Mhz，氯仿-d)：0.94(s,3H),0.90(s,3H),0.85(d,J＝7.3Hz,3H),0.10-2.43(m,19H)。MS(DIP,EI):m/z 232(M+)。
实施例6.5-异丙基螺[双环[3.1.0]己烷-2,1'-环丙烷。
根据实施例1中描述的程序将桧烯(25g，74/26比例的两种异构体，次要异构体α-侧柏酮(thujone))环丙烷化。存在完全转化以得到29g包含比例为60/20的两种异构体的产物。
主要异构体被鉴定为5-异丙基螺[双环[3.1.0]己烷-2,1'-环丙烷。1H NMR(400Mhz，氯仿-d)：1.78-1.93(m,1H),1.35-1.70(m,4H),1.03-1.14(m,1H),0.99(d,J＝6.8Hz,3H),0.90(d,J＝6.9Hz,3H),0.22-0.63(m,6H)。MS(DIP,EI):m/z 150(M+)。
桧烯被报道为通过二卤代卡宾然后利用Na/液氨脱卤化进行环丙烷化。参见Graefe、Lam和Muehlstaedt,Zeitschrift fuer Chemie 11(8),304,1971)。
实施例7.4-(1-甲基环丙基)-1-甲基双环[4.1.0]庚烷(X)
按照实施例1的程序将D-柠檬烯(38g，98％纯度)环丙烷化。起始材料完全转化以得到44g的65％纯度的X。根据现有技术(Friedrich和Niyati-Shirkhodaee,J.Org.Chem.,56(6),2202,1991)，二环丙烷化产物的产率被报道为29％。
4-(1-甲基环丙基)-1-甲基双环[4.1.0]庚烷(X)：1H NMR(400Mhz，氯仿-d)：0.63-2.06(m,8H),1.05(s,～50％的3H),1.04(s,～50％的3H),0.90(s,～50％的3H),0.85(s,～50％的3H),0.04-0.55(m,6H)。MS(DIP,EI):m/z 164(M+)。
实施例8.3-甲基-双环并[13.1.0]十六烷-(4/5)-酮
根据实施例1中描述的程序将3-甲基环十五碳-(4/5)-烯-1-酮(25g，纯度95％)(具有Z-3-甲基环十五碳-5-烯-1-酮作为主要异构体的4种异构体的混合物)环丙烷化。起始材料完全转化为25g具有60％纯度的环丙烷化异构体。
主要异构体是3-甲基-双环并[13.1.0]十六烷-5-酮：1H NMR(500Mhz，氯仿-d)：0.49-2.61(m,26H),1.04(d,J＝6.6Hz,3H),-0.29--0.16(m,1H)。MS(DIP,EI):m/z 250(M+)。
如在US7943559(2011)中公开的，3-甲基-双环[13.1.0]十六烷-5-酮通过凭借CH2I2/Et2Zn的3-甲基环十五碳-(5)-烯-1-酮的环丙烷化制备。
实施例9.(1R,2R)-2-乙基-环丙乙醇(XII)
在氮下向配备回流冷凝器的反应器装入锌粉(35g，0.535mol)、铜粉(0.1g，1.57mmol)、三甲基氯硅烷(0.2g，1.85mmol)、CPME(60g)和DCM(60g)。将混合物在50℃搅拌0.5hr，然后在1.5hr期间在50℃添加(Z)-3-己烯-1-醇(XI，25g，0.245摩尔，98％纯度)和CBM(50g，99％纯度)的混合物。将得到的反应混合物搅拌另外的2hr并且然后按照实施例1中描述的程序后处理。闪蒸得到25g包含80％(1R,2R)-2-乙基-环丙乙醇的无色油状物(产率70％)。
1H NMR(500Mhz，氯仿-d)位移：3.73(t,J＝6.7Hz,2H),1.67-1.81(m,1H),1.31-1.48(m,3H),1.23(m,1H),0.99(t,J＝7.3Hz,3H),0.56-0.83(m,3H),-0.29--0.18(m,1H).m/z 114(M+)。

Claims (15)

1.一种环丙烷化方法，所述环丙烷化方法包括使具有至少一个碳-碳双键的烯烃化合物与至少一种二卤代烷烃在(i)颗粒状金属Zn、(ii)催化有效量的颗粒状金属Cu或其盐、(iii)至少一种卤代烷基硅烷和(iv)至少一种溶剂的存在下反应的步骤；由此制备所述化合物的环丙烷衍生物。
2.根据权利要求1所述的环丙烷化方法，其中所述烯烃化合物具有至少两个碳-碳双键。
3.根据权利要求1或2所述的环丙烷化方法，其中所述至少一种二卤代烷烃是二溴甲烷、氯溴甲烷或其组合。
4.根据前述权利要求中任一项所述的环丙烷化方法，其中所述颗粒状金属Zn具有小于10μm的粒度。
5.根据前述权利要求中任一项所述的环丙烷化方法，其中所述颗粒状金属Cu具有小于50μm的粒度。
6.根据前述权利要求中任一项所述的环丙烷化方法，其中所述卤代烷基硅烷是三烷基氯硅烷。
7.根据权利要求6所述的环丙烷化方法，其中所述三烷基氯硅烷选自由三甲基氯硅烷、三乙基氯硅烷、三丁基氯硅烷、三异丁基氯硅烷、三己基氯硅烷及其任意组合组成的组。
8.根据前述权利要求中任一项所述的环丙烷化方法，其中所述至少一种溶剂是醚溶剂。
9.根据权利要求8所述的环丙烷化方法，其中所述至少一种醚溶剂选自二乙醚、1,2-二甲氧基乙烷(DME)、甲基叔丁基醚(MTBE)、四氢呋喃(THF)、环戊基甲醚(CPME)及其任意组合。
10.根据权利要求8或9所述的环丙烷化方法，其中所述至少一种溶剂还包含二氯甲烷。
11.根据权利要求10所述的环丙烷化方法，其中所述溶剂是比例为1:5至10:1的环戊基甲醚和二氯甲烷的混合物。
12.根据前述权利要求中任一项所述的环丙烷化方法，其中当所述烯烃化合物包含一个双键时，相对于所述烯烃化合物，所述颗粒状金属Zn以1-10摩尔当量的量添加。
13.根据前述权利要求中任一项所述的环丙烷化方法，其中所述颗粒状金属Cu以所述颗粒状金属Zn的0.1至1重量％的量存在。
14.根据前述权利要求中任一项所述的环丙烷化方法，所述环丙烷化方法具有约50％至约95％的产率。
15.一种制备香料或香精成分的方法，所述方法包括根据权利要求1所述的环丙烷化方法。
CN201680043757.6A 2015-08-06 2016-08-04 取代烯烃的环丙烷化 Pending CN107848907A (zh)

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