4:利用酰卤合成酰胺

酰卤(酰氯、酰溴和酰氟)与氨或胺作用是合成酰胺的最简便的方法。通过酰氯、酰溴与脂肪族、芳香族胺均可迅速酰化，以较高的产率生成酰胺。酰氟对水和其他亲核试剂较为稳定。其可通过三氟均三嗪在吡啶的存在下制备(Tetrahedron lett. 1991,32（10)，1303)。并可以通过层析分离出来。一般酰氯、酰溴与胺反应是放热的，有时甚至极为激烈，因此通常在冰冷却下进行反应，亦可使用一定量的溶剂以减缓反应速度。常用溶剂为二氯乙烷、乙醚、四氯化碳、甲苯等。由于反应中生成的卤化氢，因此需要用碱除去卤化氢，以防止其与胺成盐。有机碱和无机碱均可用于此类反应，常用的有机碱有三乙胺、吡啶等，常用的无机碱有 Na2CO3,NaHCO3,  K2CO3,NaOH, KOH等。在研究中我们发现，许多反应用无机碱反应更干净且容易处理。

反应实例

一、酰氯合成酰胺示例（有机碱）

To a solution of 47 (1.09 g, 3.00 mmol) was added pyridine (1.50 g, 18.96 mmol), followed by dropwiseaddition of phenylacetyl chloride (0.93 g, 6.00 mmol) in CH2Cl2 (20 mL).  The solution was stirred for 2h. at 25°C, then it was washed successivelywith 10% HCl, 10% NaHCO3 andwater, dried (MgSO4), filtered andthe solvent was then evaporated to give the impure amide which was recrystallizedfrom ethanol to give N-(α-carboethoxy-β-phenylethyl)-3-phenylacetylamino-4-styryl-2-azetidinone(48, 3.86g,80%)。

二、酰氯合成酰胺示例（无机碱）

A mixture containing 8.21 g of phenylalanine, 5.565 g of Na2CO3 in40 mL of water and 20 mL of tetrahydrofuran (THF) was stirred at roomtemperature.  benzoyl chloride (7.73 g), dissolved in 20 mL of anhydrousTHF, was added gradually over a period of 45 minutes with continued stirring atroom temperature.  Stirring was allowedto continue for an additional hour, at which time the reaction mixture wastransferred to a rotary evaporator at 30℃to remove the THF.  An excess of waterwas then added and the reaction mixture extracted four times with ethylacetate.  The aqueous phase was thentitrated to PH 2 with 3N HCl.  A whitecrystalline precipitate formed which was recovered by filtration, washed threetimes with cold dilute HCl and three times with cold water, and dried in avacuum oven over P2O5 at about 50℃.  The product was recrystallized from aqueousethanol, yielding 8.37 g,m.p. 183℃.-184℃., which migrated as a singlecompound on thin layer chromatography in five separate solvent systems.  In this reaction sequence the racemate isobtained.

If a NaOH solution is used in place of the Na2CO3 in this example and the procedure setforth in Carter, H. E. et al, J. Biol. Chem. 138, 627 (1941) is substantiallyfollowed, optical activity is maintained.  Thus, if L-Phe or D-Phe is the startingmaterial, N-alpha-benzoyl-L-phe, or N-alpha-benzoyl-D-Phe, respectively, isproduced.  Similarly, when benzoylN-hydroxysuccinimide ester is used in place of benzoyl chloride in this exampleand the same procedure is followed, the optical activity of D-Phe or D-Phe ismaintained in the N-alpha-benzoyl derivative.

A solution of 6-nitro-1,2-dihydro-3-spiro-1’-cyclopropyl-1H-indole (1.3 g) in CH2Cl2 (100 mL) was suspendedwith NaHCO3 (5 g), andacetyl chloride (720 mg) was added dropwise with vigorous stirring.  After the addition, the reaction was stirredfor 1 h.  the mixture was filtered andthe filtrate was concentrated in vacuo, and then purified via flashchlomatography on silica (EtOAc:hexanes=3:1 to 4:1) to give the title compound.MS (ESI, pos. ion) m/z: 233 (M + 1).

3.5.3应用酰氟合成酰胺示例

Method A:

The N-protected amino acid fluoride (1 mmol) isreacted with the chlorhydrate of and a-amino ester (1.1 mmol) andN-methylmorpholine (2.2 mmol) in acetonitrile (10 ml) untile the acyl fluorideis consumed (approximately 4 h at 25℃).  The reaction is then worked up as usual.

Method B:

A solution of the acylfluoride (1.2 mmol) in CH2Cl2 (5 ml) and a 10%NaHCO3 aqueous solution (10 ml)are added simultaneously to a stirred solution of the ester (1 mmol) in CH2Cl2(5 ml) at room temperature.  Aftercompletion of the reaction (generally 1 to 2 hours), the mixture is worked upas usual. 

5:利用有机磷类缩合剂制备酰胺

多种磷酸酯和磷酰胺类缩合剂也被广泛应用于酰胺的缩合。如二苯基磷酰氯（DPP-Cl）、氰代磷酸二乙酯（DECP）、叠氮化磷酸二苯酯（DPPA、硫代二甲基磷酰基叠氮（MPTA）、二（2-氧-3-唑烷基）磷酰氯（BOP-Cl）等。

在这些磷酸酯和磷酰胺类缩合剂中，DECP常用于小量的多肽的合成， BOP-Cl特别适合与氨基酸的合成，其收率高、不易消旋，但其缺点是，当胺的反应活性低时，常常得到酰化的唑烷。

另外，BOP-Cl的溶解性较差，导致反应时间较长，有时会长达四五天，常用DMF做反应溶剂。

         以下反应用DCC只有15%的收率, 但用DPP-Cl可以得到94%收率。

反应实例

一、DPPA为缩合剂合成酰胺示例

To some of this free amine 30 (0.270 g, 0.96 mmol) was added DMF (5 mL),(2-phthalimidoethoxy)acetic acid 29 (0.237 g, 0.96 mmol), DPPA (0.25 mL, 1.15mmol) and Et3N (0.29 mL, 2.11 mmol) at 0℃ while stirring. The ice bath was removed after two hoursand the reaction was stirred at R.T. overnight.  EtOAc (70 mL) was added and the solution wasextracted successively with 10% citric acid, H2O, saturated NaHCO3solution, H2O, and saturated NaCl solution (20 mL each), dried(anhydrous MgSO4) and finnaly evaporated in vacuo.  The oily residue was purified by columnchromatography on silica gel, eluting with 7:1 CHCl3-MeOH to givethe desired product 31 as a white solid. Yield: 81% (two steps)。

二、BOP-Cl为缩合剂合成酰胺示例

To a solution of theacid 33 in dry CH2Cl2(5 ml / mmol) was added diisopropyl ethylamine (DIEA, 1 equiv) under nitrogen,and the mixture was stirred for 10 min.  Then,BOP-Cl (1 equiv), amine 32 (1.1 equiv) and again DIPEA (2 equiv) wereadded.  After it was stirred overnight,most of the DCM was removed under reduced pressure and ethyl acetate (100 ml)was added.  The solution was washed threetimes with 5% NaHCO3 solution and once consecutively with water, 2M HCl solution, water and saturatedbrine (50 ml each).  The organic layerwas dried over Na2SO4, and the solvent was evaporated to give the desired amide34.

6：利用鎓盐类缩合剂制备酰胺

近年来，许多盐缩合剂被相继开发出来用于酰胺的缩合反应，从盐的种类来分，主要有两类，一类是碳鎓盐，目前常用的为O-(7-氮杂苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸盐（HATU）、O-（苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸盐（HBTU）、O-(5-氯苯并三氮唑-1-基)-二（二甲胺基）碳鎓六氟磷酸盐（HCTU）、O-（苯并三氮唑-1-基)-二（二甲胺基）碳鎓四氟硼酸盐（TBTU）、O-(N-丁二酰亚胺基)-二（二甲胺基）碳鎓四氟硼酸盐（TSTU）、O-(N-endo-5-降莰烯-2,3-二碳二酰亚胺)-二（二甲胺基）碳鎓四氟硼酸盐（TNTU）等。

这些试剂性能及应用有一些区别：HATU 是活性最高的碳鎓盐类缩合剂，但由于它价格昂贵很少用于工业化生产，而且经常是在其它缩合剂效果不好时才用到它。 HBTU 相对来说要经济的多，而且可以用于大多数缩合反应，然而其利较低的收率是限制用于大量生产的主要原因。HCTU活性较高，可以代替HATU用于工业化生产，其高活性要归功于有更好活性的Cl-HOBt 中间体。TSTU 和 TNTU 可以用于含水溶剂的酰胺化反应。若将HATU和HBTU的二甲胺基变为四氢吡咯基可以得到活性比它们更高的O-(7-氮杂苯并三氮唑-1-基)-二（四氢吡咯基）碳鎓六氟磷酸盐（HAPyU）、O-（苯并三氮唑-1-基)-二（四氢吡咯基）碳鎓六氟磷酸盐（HBPyU）,但这些试剂的价格极其昂贵。

另一类为鏻鎓盐，最早的为苯并三氮唑-1-基氧-三（二甲胺基）鏻鎓六氟磷酸盐（BOP）试剂，该试剂由于产生致癌的六甲基磷酰胺（HMPA）副产物，因而近年来被活性更好的，不产生致癌的副产物的苯并三氮唑-1-基氧-三（四氢吡咯基）鏻鎓六氟磷酸盐（PyBOP）所代替。

在鏻鎓盐类的缩合剂中PyBOP的是一个较为强的缩合剂，一般其他缩合剂缩合不好时常常用PyBOP可以得到更好的结果。比如PyBOP可用于将氨基酸与氯化铵缩合得到相应的氨基酰胺。最近有报道PyAOP的缩合剂具有更强的活性。

使用碳鎓盐缩合剂进行酰胺缩合，主要是通过分子内的转移，一步得到相应的活性酯，以下以HATU的缩合反应为例，说明其反应机理。

吡啶环作为分子内的碱使中间体的活性更高。

1、利用HATU/TBTU为缩合剂合成酰胺示例

The generalprocedure:

The carboxyl acid (10mmol), amine (10.4 mmol)and triethylamine (20 mmol) are dissolved in MeCN (20 mL), and HBTU or HATU (10.4mmol) is added to the solution.  After 15-30min the reaction is completed.  100-200 mL of a saturated NaCl solution isthen added and the product extracted with EtOAc (3×50 mL).  The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O.  The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the amide(90-100% yield).

2 、应用BOP为缩合剂合成酰胺示例

A solution of tert-butyloxycarbonyl threonine 20 (2.19 g,10 mmol) and phenylalanine methyl ester hydrochloride 21 (2.16 g,10 mmol) in 150 mL CH3CN is stirred at R.T. while the BOP-reagent (4.42 g, 10 mmol) is added, followed bythe addition of triethylamine (2.2 g,2.8 mL, 20 mmol).  The reaction isstirred at R.T. for 1.5 hr.  100 mL of asaturated NaCl solution is added and the product extracted with EtOAc.  The combined organics are washed with 2NHCl, H2O, 5% NaHCO3, and then H2O.  The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the dipeptide (3.74g, 98%).

2.3.3应用PyBOP为缩合剂合成酰胺示例一 （常规）

Morpholine(0.17 mL, 0.58 mmol) and PyBOP (0.56 g, 0.32 mmol) were added to the solutionof N-methylmorpholine (0.22 mL, 0.58mmol) and carboxylic acid 23(0.50 g, 0.29 mmol) in dimethylformamide (5mL).  The mixture was stirred at roomtemperature for 3 days.  The mixture was quenchedwith water and the aqueous solution was extracted with dichloromethane.  The organic layer was washed with water, driedover Na2SO4 and concentrated in vacuo.  The crude product was purified by silica gelcolumn chromatography eluting with dichloromethane/ethanol (9/1) to give morpholide24 as a white solid (109 mg, 65%).  Mp 92–94℃. 

2.3.4应用PyBOP为缩合剂合成酰胺示例二（用于合成伯酰胺）

A solution of2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (65mg, 0.17 mmol) in anhydrous DMF (1.2 mL) was treated with PyBOP (125 mg, 0.24mmol) and HOBt (32 mg, 0.24 mmol) followed by DIPEA (60 mL, 0.35 mmol) and NH4Cl(19 mg, 0.35 mmol).  After stirring atroom temperature for 20 min, the mixture was concentrated under vacuum and theresidue partitioned between EtOAc and saturated aq. NaHCO3 solution.  The EtOAc phase was washed with brine, dried(MgSO4) and concentrated in vacuo. The product was purified by flash column chromatography on SiO2 elutingwith 0-8% of MeOH/CH2Cl2 to give the title compound 26 (40 mg, 62percent) as an ambercolored oil. 1H NMR (DMSO-d6) d 8.23 (dd, 1H, J=10.7, 2.5Hz), 8.05 (d, 1H, J=9.2 Hz), 7.93 (d, 1H, J=6.1 Hz), 7.42-7.32 (m, 2H),7.33-7.25 (m, 4H), 6.92 (s, 1H), 6.25 (d, 1H, J=5.6 Hz), 5.64 (s, 2H), 3.36 (s,2H); MS (ESI+): m/z 383.17 (M+H)+.

7：碳二亚胺类缩合剂制备酰胺

利用碳二亚胺类缩合剂缩合制备酰胺在药物合成中应用极为广泛，目前常用的缩合剂主要有三种：二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)和1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)。

使用该类的缩合剂一般需要加入酰化催化剂或活化剂，如4-N,N-二甲基吡啶（DMAP）、1-羟基苯并三氮唑(HOBt)等等，其主要由于在反应的第一阶段酸对碳二亚胺的加成中间体其并不稳定，若不用酰化催化剂转化为相应的活性酯或活性酰胺，其自身会通过重排成相应的稳定的脲的副产物 (Path b).

常用的缩合活化剂有以下几种，目前4-N,N-二甲基吡啶（DMAP）已被广泛应用于催化各种酰化反应。有时在用DMAP催化效果不好时，可采用4-PPY，据相关文献报道其催化能力要比DMAP高千倍左右。

在三个常用的缩合剂DCC、DIC和EDCI中， DCC和DIC的价格较为便宜，一般DCC和DMAP合用，使用DCC有一个最大的缺点就是反应的另一产物二环己基脲在一般的有机相溶解度很小但又都有一些微溶，因此通过一些常用的纯化方法，重结晶，柱层析等等很难将其除得很彻底；由于二环己基脲在乙醚中的溶解度相对要比其他溶剂小，因此处理这类反应一般蒸掉反应溶剂后加入乙醚，滤掉大部分的二环己基脲后再进一步处理。DIC由于其产生的二异丙基脲在有一般的有机溶剂中溶解度较好，因此一般在组合化学的固相合成中用的较多。

目前，在药物化学中用的最多的还是EDCI，其一个主要的特点就是其反应后的生成的脲是水溶性的，很容易被洗掉，一般EDCI与HOBt合用（注意: 这一反应HOBt一般是缺不了的，否则有可能导致缩合产率太低）。有时如果酸的a-位位阻大或者连有吸电子基团，反应会停留在活性酯这一步（这一活性酯的质谱信号较强，可通过MS或LC-MS检测到）。由于HOBt也是水溶性的，其使得反应的处理和纯化相对要容易。一般在这一缩合中要加入碱，特别当用胺或氨基酸的盐酸盐等缩合，常用的是加2-3当量的N-甲基吗啡啉或二异丙基乙胺（DIEA,Hunig base）, 缩合时以二氯甲烷为溶剂，若底物的溶解度不好，可用DMF作反应溶剂，再使用该方法进行。

在使用该方法进行氨基酸缩合时，一般投料必须在零下20~30℃下进行，并在此温度下搅拌近一小时后再室温搅拌，否则其会引起氨基酸的消旋化。

1、DCC缩合法合成酰胺示例

To a solution of compound 11 (4.06 g, 10 mmol) in DMF (150 mL) wasadded N-hydroxybenzotriazole (HOBt, 5.64 g, 42 mmol), followed by dicyclohexylcarbodiimide (DCC; 8.60 g, 42 mmol). After stirring for l h,a solution of di-tert-butyl 4-amino-4-[2-(tert-butoxycarbonyl)ethyl]heptanedioate5 (17.34 g, 41.7 mmol)in DMF (60 mL) was added and the solution stirred at 25℃ for 23 h.  The crystals were filtered and washed on thefilter with DMF (25 mL).  The solvent wasdistilled at 50℃/1mm, and the residual oil was dissolved in ether (600mL).  Crystals were filtered, the ethereal solutionwas washed successively with 10% HCl (2 x100 mL), saturated NaHCO3(2 x 100 mL), and brine (2 x 50 mL), then dried (Na2SO4). The ether solution was filtered throughcelite and solvent was then removed in vacuo to afford 19.0 g of crude product, which waspurified on a silica column eluting with toluene/EtOAc (1:1) to furnish (60%)the white, non-crystalline ester 12:14.0 g; mp 55-60℃.  1HNMR δ 1.43 (s, CH3, 108H), 1.94-2.28 (m, CH2CH2,64H), 5.87 (s, NH, 4H), 6.17 (s, CH=CH, 2H); 13C NMR (DMSO-d6) δ28.3 (CH3), 29.3 (CH2CH2),56.8 (CNH), 69.0 (CSO2), 171.1 (CO), 171.4 (CO).

2、DIC缩合法合成酰胺示例

To a solution of amine 13 (106 mg, 0.3 mmol),Fmoc-Phe-OH (116 mg, 0.3 mmol), and HOBt (44.8 mg, 0.33 mmol) in anhydrous DMF(2 mL) was added DIC (56 µL, 0.36 mmol).  The resulting mixture was stirred at roomtemperature overnight, and DMF was then evaporated under high vacuum.  The residue was dissolved in ethyl acetate (10mL), washed sequentially with saturated aqueous NaHCO3 and brine,and then dried over Na2SO4.  The evaporation of the solvent gave the crudeproduct that was directly submitted for the Fmoc removal without purification.  The crude product was dissolved in DMF (8 mL),piperidine (2.0 mL) was added, and the resulting solution was stirred at roomtemperature for 1 h.  Following thesolvent evaporation, the residue was purified by silica gel chromatography (50%ethyl acetate in hexanes to 10% methanol in chloroform) to provide product 14(128 mg) in 85% yield as a mixture of two diastereomers. 1H NMR (CDCl3, 400MHz) ‰ 8.12-8.00 (2H, m), 7.90-7.80 (2H, m), 7.70-7.54 (2H, m), 7.42(2H, m), 7.35-7.20 (2H, m), 6.97-6.83 (3H, m), 5.32 (1H, m), 4.32 (1H, m),4.20-4.03 (2H, m), 3.96-3.80 (2H, m), 3.60 (1H, m), 2.98 (3H, m), 2.88 (2H, s),2.60 (1H, s), 2.00 (1H, m), 1.85 (2H, m), 1.77-1.55 (3H, m); MS (ES+) m/z) 501.4 (M + 1).

3、应用EDC缩合法合成酰胺示例一（二氯甲烷为溶剂）

To a solution of amine16 (0.284 mg, 1.19 mmol) and 5-hexenoic acid 15(0.136 g,1.19 mmol) in CH2Cl2 (12.0 ml) at 0℃were added HOBt (0.177 g,1.31 mmol) and EDC (0.251 g,1.31 mmol).  The reaction mixture was stirredat room temperature for 10 h, then washed with 5% aqueous HCl (3×15.0 ml), 5% aqueous NaHCO3 (20 .0 ml),H2O (20.0 ml), and brine (20.0 ml), and dried (Na2SO4).  Purification by flash chromatography(CH3Cl/MeOH, 10%, Rf = 0.43) afforded amidoalkene 17 in 99%yield as a brown oil. 

4、应用EDC缩合法合成酰胺示例二（DMF为溶剂）

A DMF solution (10 mL) containing HOBt (103 mg, 0.76mmol), EDC (192 mg, 1.0 mmol), and Boc-D-Ile (172 mg, 0.76 mmol) was stirred atroom temperature for 20 h.  A solution ofthe amino ketal 18 (0.41 g,0.76 mmol) and 4-methylmorpholine (0.17 mL, 1.5 mmol) dissolved in 10 mL of DMFwas then added to the reaction mixture.  After4 h the reaction mixture was partitioned between EtOAc and H2O.  The organic layer was washed with H2O,dried over MgSO4, and concentrated under reduced pressure.  Flash chromatography (4:1 EtOAc/hexanes)afforded the Boc ketal 19 (0.44 g,0.59 mmol, 78%).

8：活性酯法制备酰胺

活性酯法早期主要应用酸与氯甲酸乙酯或异丁酯反应生成混合酸酐，而后再与胺反应得到相应的酰胺，这一反应如果酸的a-位位阻大或者连有吸电子基团，有时会停留在混合酸酐这一步，但加热可以促使其反应；这一反应也可用于无取代酰胺的合成。

 应用羰基二咪唑(CDI)与羧酸反应得到活性较高的酰基咪唑，许多酰基咪唑有一定的稳定性，有时可以分离出来，但一般来说其不用分离，反应液直接与胺一锅反应制备相应的酰胺；有文献报道羰基二咪唑与三氟甲磺酸甲酯反应得到的二甲基化的三氟甲磺酸盐(CBMIT)的缩合性能更好。该类反应由于过量的CDI或CBMIT会和胺反应得到脲的副产物，因此其用量一定要严格控制在1当量。最近我们发现应用CDI合成Weinreb 酰胺是一个较好的方法。

另一类常用的方法是羧酸和磺酰氯生成羧酸-磺酸的混合酸酐，其与胺反应得到相应的酰胺。常用的磺酰氯有甲烷磺酰氯（MsCl），对甲苯磺酰氯（TsCl）和对硝基苯磺酰氯（NsCl）, 对硝基苯磺酰氯由于其吸电子性，其与酸反应生成活性更高的混合酸酐，一般二级胺和三级胺，甚至位阻很大的胺都能顺利反应。

通过酸与Boc酸酐反应得到的混合酸酐与氨反应可得到相应的伯酰胺。

一、氯甲酸异丁酯活性酯法合成酰胺示例

A solution of acid 1 and 4-methylmorpholine(NMM, 0.54 mL, 4.92 mmol) in DMF (10 mL) was treated at room temperature withisobutyl chloroformate (0.64 mL, 4.92 mmol).  After 30 min, pentylamine (0.57 mL, 4.92 mmol)was added.  The reaction mixture wasstirred for 12 h.  The solvent was evaporated,and the residue was partitioned between ethyl acetate (25 mL) and water (25mL).  The ethyl acetate layer was washedwith 5% NaHCO3 (10 mL) and brine (20 mL), dried over Na2SO4,and evaporated.  The residue waschromatographed on silica gel eluting with hexane and ethyl acetate (2:1) togive 0.33 g (33%) of tert-butoxycarbonylatedamino amide (2)

二、羰基二咪唑合成Weinreb酰胺示例

To acid 5 (4.0 g, 14.1 mmol) in CH2Cl2(70 mL) at 23℃ was added 1, 1’-carbonyldiimidazole (3.65 g, 22.5 mmol) in equal portions over15 min.  After the final addition,stirring was continued for 10 min, then N,O-dimethylhydroxylamine • HCl(3.43 g, 35.16 mmol)was added in one portion.  The reactionwas allowed to stir at 23℃ for 3 h. Et2O wasadded (50 mL) and the reaction mixture was filtered.  The filtrate was evaporated, diluted with Et2O(125 mL), washed with 5% aq. citric acid (2 x 50 mL) and brine (50 mL), anddried over MgSO4.  The crudeproduct was purified by flash chromatography (3:1 hexanes: EtOAc) to affordWeinreb amide 6(4.29 g,93% yield) as a colorless oil.  Rf0.42 (2:1 hexanes:EtOAc);  1HNMR (300 MHz, CDCl3): δ 5.43 (m, 1H), 4.72 (s, 1H), 4.17-4.11 (m,1H), 3.71 (s, 3H), 3.22 (s, 3H), 2.59-2.24 (comp. m, 3H), 2.03 (dd, J =14.6 Hz, 4.1 Hz, 1H), 1.75-1.71 (m, 3H), 0.86 (s, 9H), 0.11 (s, 3H), 0.09 (s,3H).

三、磺酰氯合成酰胺示例

A mixture of the benzoicacid (10 mmol), 4-methylbenzene-1-sulfonyl chloride (10 mmol), K2CO3(5.52 g, 40 mmol) andTEBAC (0.23 g, 1mmol) in 60 mLof benzene is stirred at reflux for 40 min. Then ethyl 2-aminoacetate (10 mmol) is added and stirring is continuedfor 10 min at reflux temperature.  Theprecipitate is filtered off, and the filtrate is evaporated under reduced pressure.  The carboxamide 8 thus obtained is crystallized from MeOH to afford the pureproduct (yield 82%).

四、Boc酸酐合成伯酰胺示例

Typicalprocedure:

To a stirred solution of N-protected amino acid 9(10 mmol), pyridine (0.5 ml) and Boc2O (3 g, 13 mmol) in an appropriate solvent (such asdioxane, DMF and CH3CN, 10-15 ml), ammonium hydrogencarbonate (1 g, 12.6 mmol) was added and the mixturewas stirred for 4-16 h.  Ethyl acetatewas added and after washings with water and 5% H2SO4, thesolution was dried, the solvent was evaporated and the product was trituratedwith ether.  In another variant the reactionmixture was diluted with water (30-40 ml), stirred until crystallization was completed,a residue was then collected by filtration, washed by water, dried and recrystallizedas necessary.

9：制备酰胺的非常规方法

制备酰胺有很多方法，一种是酸直接和胺缩合，此类方法有：氯甲酸酯类形成活性酯缩合，DDC和EDC之类的碳二酰亚胺类缩合剂，HATU和BOP等鎓盐类缩合剂，DPP-Cl和DPPA之类的有机磷类缩合剂。第二种是，酰卤和酸酐和胺反应得到酰胺。

除了以上常规方法下面介绍两种非常规方法。

一、酰基叠氮

酰基叠氮也是一个较为温和的酰化试剂，由于在反应时其不会引起光学活性物质的消旋且对水及其他亲核试剂较为稳定，因而常用于肽及化合物库的合成.但酰基叠氮由于反应活性低，对于位阻大且亲核性低的胺是不适用的。

酰基叠氮合成酰胺实例（J. Med. Chem 2004, vol. 47, No. 10 2599-2610）

To a solution of Boc-Tyr-N3(0.65 mmol) in DMF (6 mL) were added 7.3N HCl/dioxane (1.30 mmol) and isopentyl nitite (0.78 mmol) under cooling to –15 ℃; The solution was stirred for 10 min at the same temperature, NMM (1.37 mmol) was added to adjust the pH to 8. This solution was added to a cooled solution of 55 (0.26 mmol) and NMM (0.52 mmol) in DMF (6mL). The reaction mixture was stirred for another 24 h under the same conditions and the pH maintained at 8. After removal of DMF, the residue was dissolved in EA and washed with water, 5% NaHCO3, 10% citric acid, and saturated brine. The organic layer was dried over Na2SO4 and evaporated. The product was crystallized from ether, and the crystals were collected by filtration (Yield 53.6%).

二、3-酰基-2-硫噻唑啉

3-酰基-2-硫噻唑啉也是一个较为温和的酰化试剂(Tetrahedron lett. 1980,21，841； J Org. Chem. 1994, 3506), 其对各类胺的反应选择性较好，同时反应可以用乙醇作溶剂。该反应的一个特点是一般3-酰基-2-硫噻唑啉是黄色的，但反应完2-硫噻唑啉为无色，因此可以通过黄色是否消失来跟踪反应。

1、 3-酰基-2-硫噻唑啉的合成示例（J. Org. Chem., Vol. 57, No. 15,1992. 4243-4249）

A solution of 2-(benzyloxy)propionic acid (2.16 g, 12 mmol) in CH2Cl2(50 mL) were added thiozolidine-2-thione (1.93 g, 12 mmol), followed by EDC. HCl(2.42 g, 12.6 mmol) and DMAP (50 mg, 0.41 mmol). After being stirred at RT overnight, the reaction mixture was washed with water and brine, dried, evaporated in vacuo to give an oil residue. The residue was purified by silica gel column chromatography (elution 5:1hexane-AcOEt) to give the desired amide 58 (3.32 g, 86%) as yellow oil.

2 、3-酰基-2-硫噻唑啉的合成酰胺示例（Genin, Michael J.; Allwine, Debra A. ect.; J. Med. Chem., 2000, 5, 953-970）

p-Anisidine (920 mg, 7.47 mmol) was added to a solution of 59 (3.0 g, 6.24 mmol) in CH2Cl2(20 mL) and the solution was stirred at RT overnight. Evaporation of the solvent in vacuo followed by purification of the residue on a silical gel column with 5:1 of hexane-AcOEt gave amide 60 (2.76 g, quantitatively yield) as colorless needles.

10：氰基合成酰胺

腈加水可以分解为伯酰胺。由于伯酰胺会继续水解为羧酸，一般要控制水解的条件。目前有许多方法报道，有时需要根据底物的特性选择酸性，碱性或中性的水解条件。作为中性的条件，也有文献报道使用镍或钯催化剂的方法。

在酸性条件下与饱和碳相连的氰基，可以在酸中很方便的水解转化为酰胺，并在条件较为剧烈时，很容易进一步水解成酸。但乙烯基或芳基腈的水解条件则要求剧烈得多，一般需要强酸条件，而且一般不会进一步水解。

在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为伯酰胺，这是一个较为可靠的方法。利用NaOH(aq.)-CH2Cl2 相转移催化体系，DMSO-K2CO3 体系，可以用于各种腈水解为伯酰胺。

1、盐酸水解腈为伯酰胺示例（Organic Syntheses, Coll. Vol. 1963, 4, 760）

In a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71moles) of benzyl cyanide and 800 ml. of 35% hydrochloric acid. The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer. At a bath temperature of about 40° the mixture is stirred vigorously. Within a period of 20–40 minutes the benzyl cyanide goes into solution. During this time, the temperature of the reaction mixture risesabout 10° above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20–30 minutes. The warm water in the bath is replaced by tap water at about 15–20°, and the thermometer is replaced by a dropping funnel from which

800 ml. of cold distilled water is added with stirring. After the addition of about 100–150ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes. The cooled mixture is filtered by suction. Crude phenylacetamide remains on the filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50–80°. The yield of crude phenylacetamide is 190–200 g. (82–86%).

2 、浓硫酸水解不饱和腈为伯酰胺示例（Org. Syn., Coll. Vol. 1973,5, 73; 1955,3, 66,88）

To 106 g of 84 % sulfuric acid, was added 50 g of acrylonitrile. After stirring for 30 min at r.t., the resulting mixture was heated to 95 ℃, and stirred for 2 h. After cooling, the solid was collected by suction, and the filter cake was transferred into a beaker. To the ice-cooled solid, was added aq. ammonia with the speed that keep the temperature less than 50℃. The precipitated ammonium sulphate was filtered off, and the filtrate was cooled. The precipitate was collected by filtration, and the filter cake was washed by water, dried in vacuum to give

the desired product.

3、 H2O2-K2CO3-DMSO 体系水解腈为伯酰胺示例（Synthesis 1989, 949）

To a stirred solution of 4-chlorobenzonitrile (1.37 g, 0.01 mol) in DMSO (3 ml), cooled in a ice bath, was added 30% H2O2 (1.2 ml) and K2CO3, the reaction was allowed to warm up to r.t. (strong exothermic effect was observed). After 5 min., distilled water (50 ml) was added, cooling applied, and the product was collected by filtration, yield 85%.

4、NaOH(aq.)-CH2Cl2 相转移催化体系水解腈为伯酰胺（Synthesis, 1980, 243）

To a magnetically stirred dichloromethane solution (1.5 ml) of o-tolunitrile (0.5 g, 4.27 mmol) cooled in an ice bath, are added 30% hydrogen peroxide (2.0 ml), tetrabutylammonium hydrogen sulfate (0.290 g, 0.85 mmol), and a 20% aqueous solution of sodium hydroxide (1.6 ml). The reaction mixture is allowed to warm up to r.t. and maintained under stirring. After 1.6 h,dichloromethane is added, the organic layer is separated, washed with brine, and dried with sodium sulphate. The solvent is removed under reduced pressure to leave a white solid from

which pure o-toluamide is obtained by chromatography on silica gel. Yield 0.485 g (97%).

11：Ritter反应

在强酸环境下醇和腈反应制备酰胺的反应。

Prins/Ritter串联反应。

参考文献

1. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045-4048. (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048-4050.

2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review).

3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78-82.

4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem.1989, 54, 2242-2244.

5. Le Goanvic, D; Lallemond, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001,42, 5175-5176.

6. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69,

5906-5925.

7. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575-1577.

8. Concellón, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6, 4499-4501.

9. Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2007, pp 471-476. (Review).

10. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74,

2207-2209.

11. Yadav, J. S.; Reddy, Y. J.; Reddy, P. A. N.; Reddy, B. V. S. Org. Lett. 2013, 15, 546-549.

编译自：J.J. Li, Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications,  Ritter reaction，page 517-518.

12：Overman重排

通过烯烃的1,3-位置互换将烯丙基三氯乙酰亚胺酯转化为烯丙基三氯乙酰胺进而将烯丙醇转化为烯丙胺的反应。

烯丙胺类化合物是重要的含氮分子（如生物碱，抗生素和非天然氨基酸等）的前体。

反应机理：

脱掉质子的醇进攻三氯乙腈得到三氯乙酰亚胺酯负离子，其作为中间体继续对开始的醇进行脱质子，因此反应只需要催化量的强碱。

生成的亚胺酯会进行热力学的[3,3]-σ迁移，与Claisen 重排类似，中间会通过一个椅式的中间态：

另外，重排可以通过过渡金属催化剂[如Pd(II)或 Hg(II)]引发：

有些手性过渡金属催化剂对底物有手性面选择性，因此可以对一些前手性的原料进行对映选择性反应：

C. E. Anderson, L. E. Overman, J. Am. Chem. Soc., 2003, 125, 12412-12413.

对于此反应机理的详尽解释和有关过渡金属催化剂（早期Pd-催化的手性转变）的立体选择性更多详细内容，请参阅 L. E. Overman近期发表的论文 (J. Org. Chem. 1997, 62, 1449. DOI)。

最新文献：

Catalytic Asymmetric Rearrangement of Allylic Trichloroacetimidates. A Practical Method for Preparing Allylic Amines and Congeners of High Enantiomeric Purity
C. E. Anderson, L. E. Overman, J. Am. Chem. Soc., 2003, 125, 12412-12413.

Catalytic Asymmetric Formation of Secondary Allylic Amines by Aza-Claisen Rearrangement of Trifluoroacetimidates
Z.-q. Xin, D. F. Fischer, R. Peters, Synlett, 2008, 1495-1499.

Improved Conditions for Facile Overman Rearrangement
T. Nishikawa, M. Asai, N. Ohyabu, M. Isobe, J. Org. Chem., 1998, 63, 188-192.

A General, Highly Enantioselective Method for the Synthesis of D and L α-Amino Acids and Allylic Amines
Y. K. Chen. A. E. Lurain, P. J. Walsh, J. Am. Chem. Soc., 2002, 124, 12225-12231.

[(NHC)AuI]-Catalyzed Rearrangement of Allylic Acetates
N. Marion, R. Gealageas, S. P. Nolan, Org. Lett., 2007, 9, 2653-2656.

编译自：有机化学门户

相关介绍

烯丙醇通过三氯乙酰亚胺酯中间体立体选择性的转化为烯丙基三氯乙酰胺的反应。

反应机理

反应实例

参考文献

1. Overman, L. E. Acc. Chem. Res. 1971, 4, 49. (Review).

2. Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597.

3. Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901.

4. Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.; Kawai, T.; Goto, T. Tetrahedron

Lett. 1990, 31, 3327.

5. Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527.

6. Toshio, N.; Masanori, A.; Norio, O.; Minoru, I. J. Org. Chem. 1998, 63, 188.

7. Cho, C.-G.; Lim, Y.-K.; Lee, K.-S.; Jung, I.-H.; Yoon, M.-Y. Synth. Commun. 2000,

30, 1643.

8. Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R. Tetrahedron: Asymmetry 2000, 11,

1585.

9. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863.

10. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151.

11. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927.

12. O’Brien, P.; Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523.

13. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2004, 433.

14. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401.

15. Ramachandran, P. V.; Burghardt, T. E.; Reddy, M. V. R. Tetrahedron Lett. 2005, 46,

2121.

编译自：Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Overman rearrangement，page 436-437.

13：Org.Lett.最新报道:攻克挑战性酸胺缩合

酰胺键广泛存在于天然产物和药物分子中，其合成方法也多种多样如混合酸酐法，酰氯合成法，缩合试剂作为媒介等等。然而对于一些大位阻的酸和亲核性较弱的碱之间的反应目前为止有效的方法不是很多，正是在这样一个背景下，最近来自百时美施贵宝公司的Gregory L. Beutner团队报道了一类非常高效的酸胺缩合体系，可解决该类挑战性的酸胺缩合（图1）。

图1:反应通式。图片来源:Org. Lett.

我们来捋一下本文作者的思路，作者认为酰基咪唑鎓盐长期以来被认为是非常高效的酰基转移试剂，并被用于酰胺的合成，酰基咪唑鎓盐的活性也要高于酰基咪唑的活性。酰基咪唑鎓盐一般需要酰基咪唑与很强的烷基化试剂如Meerwein盐（Me3OBF4）,碘甲烷等，Rapoport等人报道了CDI类似物氮甲基咪唑鎓盐用于挑战性酸胺缩合，然而将该类试剂从高活性的烷基化试剂中分离出来本省就是一个较大的挑战（图2）。

图2:活性排序。图片来源:Org. Lett.

本文的亮点在于不需要分离高活性的酰基咪唑鎓盐，而是利用有效策略将TCFH和NMI有效结合原位生成它，并将其用于挑战性酸胺缩合反应，取得了非常好的效果，并且产物能得到很好的手性保持（图3）。

图3:反应机理。图片来源:Org. Lett.

我们来看一下该反应体系的底物范围，首先是大位阻的酸和缺电子的胺的反应结果直接，图4结果一目了然，无需多言，一般方法很那取得这样的缩合结果（图4）。

图4:底物拓展。图片来源:Org. Lett.

对于手性的酸结果又会怎么样呢？图5给我们答案，产率优秀，手性得到非常好的保持（图5）。

图5:底物拓展。图片来源:Org. Lett.

简单的酸胺缩合表现优秀，那用于肽的合成表现怎么样呢？从图6可以看出，该方法同样适用于肽的合成（图6）。

图6:肽合成。图片来源:Org. Lett.

以下内容来源于本文的Supporting Information:

常用缩合剂结构和缩写如下图所示（图7）。

图7:常用缩合剂。图片来源:Org. Lett.

操作步骤如下（图8）：

图8:操作步骤。图片来源:Org. Lett.

Org. Lett., 2018, DOI:10.1021/acs.orglett.8b01591.

本文链接如下：

https://pubs.acs.org/doi/10.1021/acs.orglett.8b01591

14：Passerini反应

羧酸，C-异氰化合物和羰基化合物三组分缩合得到α-酰氧基酰胺的反应，此反应与 Ugi反应类似。

反应机理

反应实例

参考文献

1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126, 181. Mario Passerini (1891