钯催化<i>N</i>, <i>N</i>-二甲基甲酰胺与胺高效合成甲酰胺

引用本文: 李春, 王梦娜, 陆逊花, 杨元勇, 张林. 钯催化N, N-二甲基甲酰胺与胺高效合成甲酰胺[J]. 有机化学, 2019, 39(4): 1109-1115. doi: 10.6023/cjoc201809020 shu

Citation: Li Chun, Wang Mengna, Lu Xunhua, Yang Yuanyong, Zhang Lin. Pd-Catalyzed N-Formylation of Amines with N, N-Dimethylformamide[J]. Chinese Journal of Organic Chemistry, 2019, 39(4): 1109-1115. doi: 10.6023/cjoc201809020 shu

钯催化N, N-二甲基甲酰胺与胺高效合成甲酰胺

李春 ^a,b, ,
王梦娜 ^a, ,
陆逊花 ^a, ,
杨元勇 ^a, ,
张林 ^{a,b,
,}

a.
贵州医科大学药学院贵阳 550025
b.
贵州医科大学天药用植物功效与利用国家重点实验室贵阳 550014

通讯作者: Zhang Lin, E-mail: gmulinzhang@163.com

基金项目:

国家自然科学基金（Nos.21562010，21601039）资助项目

摘要: 报道了一种醋酸钯催化N，N-二甲基甲酰胺（DMF）与各类胺高效合成甲酰胺化合物的方法.该反应体系简单，具有催化效率高，不需要其它溶剂及共催化剂，底物普适范围广的优点，为合成甲酰胺化合物提供了一种快速，实用的方法.

关键词:

English

Pd-Catalyzed N-Formylation of Amines with N, N-Dimethylformamide

a.
School of Pharmacy, Guizhou Medical University, Guiyang 550004
b.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014

Corresponding author: Zhang Lin, gmulinzhang@163.com

Received Date: 15 September 2018
Revised Date: 30 November 2018
Available Online: 01 April 2019
Fund Project:

Project supported by the National Natural Science Foundation of China (Nos. 21562010, 21601039)

Abstract: A highly efficient protocol for the transamidation of N, N-dimethylformamide (DMF) and amines has been developed, utilizing a catalytic amount Pd(OAc)₂. This methodology has a broad substrate scope for aliphatic, aromatic, and heterocyclic amines. And this process is simple and easily performed without solvent and co-catalyst.

Key words:

甲酰胺广泛存在于天然产物中, 常是药物的药效官能团, 其衍生物多具有显著的生物活性^[1].在有机合成反应中, 甲酰基是胺类化合物中氨基最有效的保护基团之一^[2], 形成的甲酰胺也是合成异氰化合物, 甲脒的重要前体^[3].另外, 甲酰胺还可作为Lewis碱催化剂催化烷基化和硅氢加成反应^[4].

早在1955年, Fieser等^[5]就成功利用甲酸为原料实现了苯胺的甲酰化.随后, 各种甲酰化试剂相应被报道, 如三氯乙醛^[6], 甲酸铵^[7], 甲酸酯^[8], 甲酸盐^[9]等.但其中有许多方法存在使用毒性试剂, 反应条件不温和, 底物适应范围小等缺点. N, N-二甲基甲酰胺(DMF)具有低毒、廉价、易分离等优点, 是一种理想的酰化试剂^[10].硼试剂在催化胺与DMF合成甲酰胺化合物中具有很好的活性, 如B(OH)₃^[11], B(OCH₂CF₃)₃^[12], 苯基硼酸^[13]等.另外, 过渡金属催化剂在该反应中的应用研究也取得了新的进展, 例如Jagtap等^[14]报道的镍催化剂以及Guo等^[15]报道的钯催化剂.虽然这些催化剂都能成功催化转化胺与DMF合成甲酰胺化合物, 但这些体系仍存在需要共催化剂, 配体, 反应温度高, 底物普适范围小等问题.因此, 探究一种高效, 简单的催化体系来实现氨基的甲酰化仍具有重要的意义.

以理想的甲酰化试剂DMF为原料, 通过对各种钯催化剂的筛选, 以获得无溶剂, 无共催化剂的简单催化合成甲酰胺的反应体系.研究表明, 该体系以三乙胺为碱, 在Pd(OAc)₂催化下能获得优异的甲酰胺产物收率, 广泛的底物适应范围.

1. 结果与讨论

1.1 钯催化剂对胺甲酰化反应活性的影响

首先以DMF与3-(2-氨乙基)吲哚的反应为模板反应, 考察多种钯化合物在胺甲酰化反应中的催化活性, 实验结果如表 1所示.不难发现, 在没有其它溶剂及活化剂的条件下, 钯化合物都能成功催化3-(2-氨乙基)吲哚与DMF合成甲酰胺, 其中Pd(OAc)₂催化该反应最终能获得54%的产物分离收率, 而Pd(OH)₂, PdCl₂, Pd(NO₃)₂, Pd(dppf)Cl₂, Pd(COD)Cl₂, Pd(acac)₂, (Pd(Allyl)Cl)₂催化3-(2-氨乙基)吲哚与DMF合成甲酰胺的活性都较低.当将催化剂的用量降低至10 mol%时, 产物的收率降低至35%(表 1, Entry 5).因此, 我们选择Pd(OAc)₂为最优催化剂, 催化剂用量为20 mol%, 并对反应条件做了进一步筛选.

表 1

表 1 钯催化剂对胺甲酰化反应活性的影响

Table 1. Pd-catalyzed N-formylation of amine

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Entry	Catalyst	Yield^b/%
1	Pd(NO₃)₂	39
2	Pd(OH)₂	22
3	PdCl₂	33
4	Pd(OAc)₂	54
5^c	Pd(OAc)₂	35
6	Pd(dppf)Cl₂	30
7	Pd(COD)Cl₂	30
8	Pd(acac)₂	20
9	(Pd(Allyl)Cl)₂	37
^a Reagents and conditions: 2-(1H-indol-3-yl)-ethylamine (1 mmol), catalyst (0.2 mmol). ^b Isolated yield. ^c Catalyst (0.1 mmol).

1.2 碱对胺甲酰化反应活性的影响

在钯催化反应体系中, 碱是影响催化活性的重要因素.因此, 我们在该反应体系中考察了多种碱对反应活性的影响, 实验结果如表 2所示.从表 2可见, 碱对Pd(OAc)₂催化胺甲酰化反应活性有较大影响, 其中加入K₂CO₃, Ba(OH)₂, CH₃COOK, 该反应活性降低; 加入Cs₂CO₃, NEt₃, ethylenediamine, pyridine, 反应活性明显提高.尤其是当碱为NEt₃时, 产物分离收率能明显提升到81%.继续考察NEt₃与催化剂的比例对催化活性的影响.实验结果表明, 当碱/催化剂提高到4时, 产物分离收率高达94%, 但继续提高比例时, 催化活性降低.因此, 该催化体系的最佳反应条件为: Pd(OAc)₂ (20 mol%), NEt₃ (碱/催化剂=4).

表 2

表 2 碱对胺甲酰化反应活性的影响

Table 2. Effect of different bases on the N-formylation of amine

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Entry	Base	Base/catal.	Yield^b/%
1	K₂CO₃	2	33
2	Cs₂CO₃	2	60
3	Ba(OH)₂	2	38
4	LiOH	2	41
5	CH₃COOK	2	34
6	NEt₃	0	54
7	NEt₃	2	81
8	NEt₃	4	94
9	NEt₃	6	68
10	Ethylenediamine	2	60
11	Pyridine	2	74
^a Reagents and conditions: 2-(1H-Indol-3-yl)-ethylamine (1 mmol), Pd(OAc)₂ (0.2 mmol). ^b Isolated yield.

1.3 DMF对胺甲酰化反应活性的影响

通过对催化剂、碱进行筛选后, 我们继续对DMF的量进行了考察, 实验结果如表 3所示.从表 3可见, 当向体系中加入1 equiv. DMF时, 发现能够以25%的分离产率得到目标产物, 随着DMF增加到8 equiv.时, 产物的分离收率可达到最高为94%, 继续增加后, 目标产物的产率没有明显变化.综上所述, 得到最优反应条件为Pd(OAc)₂ (20 mol%), NEt₃ (碱/催化剂=4), DMF (8.0 equiv.).

表 3

表 3 DMF对胺甲酰化反应活性的影响

Table 3. Effect of DMF on the N-formylation of amine

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Entry	DMF/equiv.	Yield^b/%
1	1	25
2	2	40
3	4	62
4	6	85
5	8	94
6	10	92
7	12	91
^a Reagents and conditions: 2-(1H-Indol-3-yl)-ethylamine (1 mmol), Pd(OAc)₂ (0.2 mmol), NEt₃ (0.8 mmol). ^b Isolated yield.

1.4 反应底物的普适性研究

在最优化的反应条件下、为了探究该方法的普遍性和适用范围, 考察了各种胺, 例如芳胺、杂环芳胺、烷基胺等, 在无溶剂条件下, 分别与DMF进行反应, 反应结果如表 4所示.从表 4可见, 该体系催化芳香伯胺都具有较好的催化活性(Entries 1~10), 在80 ℃条件下, 能获得60%~93%的分离收率, 对位带有吸电子基团或是供电子基团对反应收率都没有较大影响.但当底物含有邻位取代基时, 由于较大的空间位阻, 使反应收率降低(Entries 8, 9).该体系催化芳香仲胺时需要较高的温度, 在140 ℃条件下, 最高能达75%分离收率, 可见仲胺的活性要明显低于伯胺.随后考察了烷基胺在该体系中的普适性, 从Entries 13~17可见, 在140 ℃条件下, 能获得78%~93%的分离收率.杂环芳胺在该体系催化下也能获得最高87%的分离收率.最后为了考察该催化体系的实际应用价值, 我们做了放大实验, 如Scheme 1所示.当3-(2-氨乙基)吲哚的量增加至10 mol时, 最终能达到80%的产物收率.

图式 1

图式 1. 克级甲酰化反应

Scheme 1. Gram scale N-formylation reaction

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表 4

表 4 醋酸钯催化胺甲酰化反应

Table 4. Pd(OAc)₂-catalyzed N-formylation of amines

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2. 结论

综上所述, 通过对金属钯、碱的筛选, 发现了一种在无溶剂条件下使用Pd(OAc)₂作催化剂, 三乙胺作碱, 催化DMF和各类胺进行氨基甲酰化反应的方法.该方法具有催化体系简单、产率高、适用范围广等优点, 为催化胺甲酰化反应合成甲酰胺化合物提供了一条新的途径.

3. 实验部分

3.1 仪器与试剂

除特别说明外, 所用试剂均为化学纯或分析纯.实验所用试剂均购于Adamas试剂公司.熔点测定使用河南省予华仪器有限公司X-5型显微熔点仪; 核磁共振氢谱采用JEOL NMR 400型核磁共振仪测定, DMSO-d₆为溶剂; 质谱采用LCO Advantage型质谱仪测定.

3.2 实验方法

在10 mL的反应试管中, 加入胺(1.0 mmo1)、醋酸钯(0.2 mmol)、三乙胺(0.8 mmol)、DMF (8.0 mmol), 搅拌使其混合均匀, 继续在设定温度下搅拌一定时间, 用薄层层析色谱法(TLC)监测.反应完全后, 加入10 mL水, 搅拌, 乙酸乙酯(10 mL×3), 萃取, 分液, 收集有机相并用无水硫酸钠干燥, 旋蒸, 除去溶剂得粗产品.然后, 运用柱层层析色谱法进行分离提纯.目标化合物的结构经¹H NMR, ¹³C NMR和HRMS确证.

3.3 产物表征

N-[2-(1H-吲哚基-3)-乙基]-甲酰胺(2a):获得产物有两种构象异构体, 比例为9:1.棕色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.89 (s, 1H), 8.15 (s, 0.9H), 8.07 (s, 0.9H), 7.83 (s, 0.1H), 7.58 (d, J=8.0 Hz, 1H), 7.39 (d, J=4.0 Hz, 1H), 7.21 (s, 1H), 7.09~7.13 (m, 1H), 7.01~7.05 (m, 1H), 5.80 (s, 0.1H), 3.42~3.45 (m, 2H), 2.87~2.91 (m, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.96 (minor), 161.59 (major), 136.77 (major), 136.62 (minor), 127.68 (major), 127.63 (minor), 123.59 (minor), 123.25 (major), 121.47 (major), 121.35 (minor), 118.79 (major), 118.75 (major), 118.59 (minor), 118.47 (minor), 112.09 (major), 111.91 (major), 111.71 (minor), 111.54 (minor), 42.29 (minor), 38.56 (major), 27.75 (minor), 25.65 (major); HRMS calcd for C₁₁H₁₂N₂ONa[M+Na⁺] 211.0847, found 211.0839.

N-苯基甲酰胺(2b):获得产物有两种构象异构体, 比例为3:1.黄色固体, m.p. 47~48 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.18 (s, 1H), 8.80 (d, J=6.0 Hz, 0.25H), 8.30 (s, 0.75H), 7.61 (d, J=4.0 Hz, 1.5H), 7.31~7.34 (m, 2H), 7.21 (d, J=4.0 Hz, 0.5H), 7.06~7.09 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.05 (minor), 160.10 (major), 138.86 (minor), 138.78 (major), 129.91 (minor), 129.38 (major), 124.15 (minor), 124.11 (major), 119.65 (major), 118.02 (minor); HRMS calcd for C₇H₇NO- Na [M+Na⁺] 144.0425, found 144.0424.

N-(4-甲基苯基)甲酰胺(2c):获得产物有两种构象异构体, 比例为3:1.白色固体, m.p. 47~49 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.09 (s, 1H), 8.73 (d, J=6.0 Hz, 0.25H), 8.26 (s, 0.75H), 7.50 (d, J=6.0 Hz, 1.5H), 7.12 (d, J=4.0 Hz, 2H), 7.09 (d, J=4.0 Hz, 0.5H), 2.26 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 162.97 (minor), 159.84 (major), 136.45 (minor), 136.30 (major), 133.22 (minor), 133.04 (major), 130.29 (minor), 129.73 (major), 119.62 (major), 118.20 (minor), 20.96 (major), 20.82 (minor); HRMS calcd for C₈H₉NONa [M+Na⁺] 158.0582, found 158.0580.

N-(4-氟苯基)甲酰胺(2d):获得产物有两种构象异构体, 比例为3:1.白色固体, m.p. 62~64 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.18 (s, 0.75H), 10.09 (d, J=4.0 Hz, 0.25H), 8.65 (d, J=6.0 Hz, 0.25H), 8.22 (s, 0.75H), 7.57 (d, J=8.0 Hz, 1.5H), 7.16~7.19 (m, 0.5H), 7.08~7.13 (m, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.21 (minor), 159.99 (major), 158.08 (minor), 157.45 (major), 135.29 (minor), 135.20 (major), 121.36 (major), 120.04 (minor), 116.63 (minor), 116.04 (major); HRMS calcd for C₇H₆FNONa [M+Na⁺] 162.0331, found 162.0324.

N-(4-氯苯基)甲酰胺(2e):获得产物有两种构象异构体, 比例为4:1.白色固体, m.p. 100~102 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.27 (s, 0.8H), 10.18 (d, J=4.0 Hz, 0.2H), 8.75 (d, J=6.0 Hz, 0.2H), 8.25 (s, 0.8H), 7.58 (d, J=4.0 Hz, 1.6H), 7.32 (d, J=4.0 Hz, 2H), 7.17 (d, J=4.0 Hz, 0.4H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.04 (minor), 160.22 (major), 137.91 (minor), 137.67 (major), 129.73 (minor), 129.26 (major), 127.98 (minor), 127.67 (major), 121.20 (major), 119.47 (minor); HRMS calcd for C₇H₆ClNONa [M+Na⁺] 178.0036, found 178.0036.

N-(4-溴苯基)甲酰胺(2f):获得产物有两种构象异构体, 比例为4:1.白色固体, m.p. 113~115 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.29 (s, 0.8H), 10.19 (d, J=6.0 Hz, 0.2H), 8.79 (d, J=6.0 Hz, 0.2H), 8.30 (s, 0.8H), 7.57 (d, J=4.0 Hz, 1.6H), 7.49 (d, J=6.0 Hz, 2H), 7.16 (d, J=4.0 Hz, 0.4H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 162.98 (minor), 160.25 (major), 138.33 (minor), 138.06 (major), 132.61 (minor), 132.17 (major), 121.58 (major), 119.83 (minor), 115.90 (minor), 115.69 (major); HRMS calcd for C₇H₆BrNONa [M+Na⁺] 221.9530, found 221.9514.

N-(4-甲氧基苯基)甲酰胺(2g):获得产物有两种构象异构体, 比例为3:1.白色固体, m.p. 79~80 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.05 (s, 0.75H), 9.99 (d, J=6.0 Hz, 0.25H), 8.61 (d, J=4.0 Hz, 0.25H), 8.22 (s, 0.75H), 7.53 (d, J=4.0 Hz, 1.5H), 7.13 (d, J=4.0 Hz, 0.5H), 6.90 (d, J=4.0 Hz, 2H), 3.72 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.11 (minor), 159.58 (major), 156.51 (minor), 155.90 (major), 131.98 (major), 131.79 (minor), 121.10 (major), 120.19 (minor), 115.10 (minor), 114.46 (major), 55.74 (minor), 55.65 (major); HRMS calcd for C₈H₉O₂NNa [M+Na⁺] 174.0531, found 174.0528.

N-(4-硝基苯基)甲酰胺(2h):获得产物有两种构象异构体, 比例为3:1.淡黄色固体, m.p. 196~198 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.84 (s, 0.75H), 10.74 (s, 0.25H), 9.09 (s, 0.25H), 8.44 (s, 0.75H), 8.25 (d, J=4.0 Hz, 2H), 7.85 (d, J=4.0 Hz, 1.5H), 7.45 (d, J=4.0 Hz, 0.5H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.31 (minor), 161.01 (major), 145.48 (minor), 144.72 (major), 143.09 (major), 143.00 (minor), 125.98 (minor), 125.59 (major), 119.51 (major), 117.07 (minor); HRMS [M+Na⁺] calcd for C₇H₆O₃N₂Na 189.0276, found 189.0278.

N-(2-甲基苯基)甲酰胺(2i):获得产物有两种构象异构体, 比例为7:3.淡黄色固体, m.p. 56~57 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 9.76 (d, J=6.0 Hz, 0.3H), 9.58 (s, 0.7H), 8.42 (d, J=4.0 Hz, 0.3H), 8.30 (s, 0.7H), 7.75 (d, J=4.0 Hz, 0.7H), 7.20~7.23 (m, 1.3H), 7.15 (m, 1H), 7.07~7.09 (m, 0.3H), 7.03~7.05(m, 0.7H), 2.24 (s, 0.9H), 7.22 (s, 2.1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.17 (minor), 160.33 (major), 136.74 (minor), 136.17 (major), 131.31 (minor), 130.91 (major), 130.81 (minor), 129.74 (major), 127.28 (minor), 126.63 (major), 125.81 (minor), 125.14 (major), 123.30 (major), 122.33 (minor), 18.36 (major), 18.22 (minor); HRMS calcd for C₈H₁₀NO [M+H⁺] 136.0762, found 136.0765.

N-(2, 6-二甲基苯基)甲酰胺(2j):获得产物有两种构象异构体, 比例为5:1.白色固体, m.p. 158~159 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 9.47 (s, 0.83H), 9.30 (d, J=6.0 Hz, 0.17H), 8.25 (s, 0.83H), 7.98 (d, J=6.0 Hz, 0.17H), 7.11~7.12 (m, 0.5H), 7.05~7.08 (m, 2.5H), 2.21 (s, 1H), 2.15 (s, 5H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 165.22 (minor), 159.87 (major), 135.44 (minor), 135.22 (major), 134.99 (major), 134.53 (minor), 128.81 (minor), 128.23 (major), 127.31 (minor), 127.08 (major), 18.93 (minor), 18.82 (major); HRMS calcd for C₉H₁₂NO [M+H⁺] 150.0919, found 150.0918.

N-(3-氯苯基)甲酰胺(2k):获得产物有两种构象异构体, 比例为3:1.淡黄色固体, m.p. 56~58 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.33 (s, 0.75H), 10.21 (d, J=6.0 Hz, 0.25H), 8.80 (d, J=4.0 Hz, 0.25H), 8.27 (s, 0.75H), 7.75 (s, 0.75H), 7.40 (d, J=4.0 Hz, 0.75H), 7.27~7.31 (m, 1H), 7.25~7.26 (m, 0.25H), 7.12 (d, J=4.0 Hz, 0.25H), 7.07 (d, J=4.0 Hz, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.11 (minor), 160.48 (major), 140.57 (minor), 140.12 (major), 134.30 (minor), 133.67 (major), 131.49 (minor), 131.06 (major), 123.84 (major), 123.69 (minor), 119.22 (major), 118.03 (major), 117.38 (major), 116.26 (major); HRMS calcd for C₇H₆ClNONa[M+Na⁺] 178.0036, found 178.0027.

N-甲基-N-苯基甲酰胺(2l):获得产物有两种构象异构体, 比例为9:1.棕色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.53 (s, 0.9H), 8.35 (s, 0.1H), 7.49 (d, J=4.0 Hz, 0.2H), 7.40~7.44 (m, 2H), 7.33 (d, J=4.0 Hz, 1.8H), 7.23~7.27 (m, 1H), 3.21 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.06 (minor), 162.55 (major), 142.56 (major), 140.95 (minor), 129.91 (major), 129.17 (minor), 126.09 (major), 125.89 (minor), 123.53 (minor), 121.99 (major), 36.61 (minor), 31.50 (major); HRMS calcd for C₈H₉NONa [M+Na⁺] 158.0582, found 158.0577.

2, 3-二氢-(1-吲哚基)甲酰胺(2m):获得产物有两种构象异构体, 比例为3:1.淡黄色固体, m.p. 62~64 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 9.07 (s, 0.75H), 8.51 (s, 0.25H), 7.94 (d, J=4.0 Hz, 0.25H), 7.46 (d, J=4.0 Hz, 0.75H), 7.30 (d, J=4.0 Hz, 1H), 7.18~7.22 (m, 1H), 7.03~7.07 (m, 1H), 4.13~4.17 (m, 0.5H), 3.91~3.96 (m, 1.5H), 3.10~3.15 (m, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 160.62 (minor), 158.88 (major), 141.75 (minor), 141.68 (major), 133.15 (minor), 132.23 (major), 127.80 (major), 127.52 (minor), 126.31 (major), 125.63 (minor), 124.56 (major), 124.13 (minor), 115.98 (minor), 110.35 (major), 46.95 (minor), 44.63 (major), 27.67 (minor), 27.08 (major); HRMS calcd for C₉H₉NONa [M+Na⁺] 170.0582, found 170.0582.

N-苯乙基甲酰胺(2n):获得产物有两种构象异构体, 比例为9:1.淡黄色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.06 (s, 1H), δ: 8.01 (s, 0.9H), 7.77 (s, 0.1H), 7.28~7.31 (m, 2H), 7.19~7.23 (m, 3H), 3.31~3.36 (m, 2H), 2.72~2.76 (m, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.93 (minor), 161.56 (major), 139.77 (major), 139.27 (minor), 129.40 (minor), 129.14 (major), 128.85 (major), 128.59 (minor), 126.72 (minor), 126.65 (minor), 43.00 (minor), 39.24 (major), 37.66 (minor), 35.55 (major); HRMS calcd for C₉H₁₁NONa [M+Na⁺] 172.0738, found 172.0736.

N-苄基甲酰胺(2o):获得产物有两种构象异构体, 比例为9:1.淡黄色固体, m.p. 62~63 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.53 (s, 1H), 8.16 (s, 0.9H), 8.14 (d, J=6.0 Hz, 0.1H), 7.26~7.37 (m, 5H), 4.32 (d, J=2.0 Hz, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 165.44 (minor), 161.56 (major), 140.19 (minor), 139.52 (major), 128.97 (minor), 128.86 (major), 127.82 (major), 127.60 (minor), 127.57 (minor), 127.40 (minor), 45.08 (minor), 41.25 (major); HRMS calcd for C₈H₉NONa [M+Na⁺] 158.0582, found 158.0577.

N-(1-苯基乙基)甲酰胺(2p):获得产物有两种构象异构体, 比例为9:1.淡黄色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.53 (s, 0.9H), 8.32 (s, 0.1H), 8.11 (d, J=6.0 Hz, 0.1H), 8.05 (s, 0.9H), 7.33~7.37 (m, 4H), 7.23~7.27 (m, 1H), 4.98~5.05 (m, 0.9H), 4.67~4.74 (m, 0.1H), 1.43 (d, J=6.0 Hz, 0.3H), 1.37 (d, J=4.0 Hz, 2.7H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.48 (minor), 160.58 (major), 145.26 (minor), 144.66 (major), 128.96 (minor), 128.83 (major), 127.43 (minor), 127.27 (major), 126.48 (major), 126.40 (minor), 51.30 (minor), 47.08 (major), 23.95 (minor), 22.97 (major); HRMS calcd for C₉H₁₁NONa [M+Na⁺] 172.0738, found 172.0736.

N-环己基甲酰胺(2q):淡黄色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.95 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 3.52~3.57 (m, 1H), 1.59~1.68 (m, 4H), 1.49 (d, J=4.0 Hz, 1H), 1.08~1.23 (m, 5H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 163.93 (minor), 160.44 (major), 50.68 (minor), 46.54 (major), 34.72 (minor), 32.84 (major), 25.66 (major), 25.35 (minor), 25.09 (minor), 24.88 (major); HRMS calcd for C₇H₁₄NO [M+H⁺] 128.1075, found 128.1078.

N-正己基甲酰胺(2r):淡黄色油状物; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.91~7.99 (m, 2H), 3.04~3.09 (m, 2H), 1.36~1.41 (m, 2H), 1.25~1.30 (m, 6H), 0.86 (m, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.97 (minor), 161.38 (major), 41.38 (minor), 37.58 (major), 31.50 (major), 31.43 (minor), 29.53, 26.60 (major), 26.11 (minor), 22.63, 14.43; HRMS calcd for C₇H₁₆NO [M+H⁺] 130.1232, found 130.1234.

N-(2-吡啶基)甲酰胺(2s):获得产物有两种构象异构体, 比例为1:1.白色固体, m.p. 70~71 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.60 (s, 1H), 9.30 (d, J=4.0 Hz, 0.5H), 8.34 (s, 1H), 8.26 (s, 0.5H), 8.07 (d, J=4.0 Hz, 0.5H), 7.73~7.82 (m, 1H), 7.08~7.13 (m, 1H), 6.94(s, J=4.0 Hz, 0.5H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 162.66, 160.64, 152.16, 151.55, 148.69, 148.58, 139.25, 138.86, 120.30, 119.76, 114.30, 111.85; HRMS calcd for C₆H₆N₂ONa [M+Na⁺] 145.0378, found 145.0379.

N-(2-吡啶甲基)甲酰胺(2t):棕色油状物; 获得产物有两种构象异构体, 比例为9:1. ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.59 (s, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.18 (s, 0.9H), 8.14 (s, 0.1H), 7.75~7.79 (m, 1H), 7.31 (d, J=4.0 Hz, 1H), 7.26~7.29 (m, 1H), 4.40 (d, J=2.0 Hz, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 165.86 (minor), 161.82 (major), 159.23 (minor), 158.46 (major), 149.61 (minor), 149.41 (major), 137.44 (minor), 137.30 (major), 122.94 (minor), 122.73 (major), 121.74 (minor), 121.65 (major), 46.99 (minor), 43.30 (major); HRMS calcd for C₇H₈N₂- ONa [M+Na⁺] 159.0534, found 159.0539.

辅助材料(Supporting Information)甲酰胺化合物的¹H NMR和¹³C NMR谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图式 1 克级甲酰化反应

Scheme 1 Gram scale N-formylation reaction

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表 1 钯催化剂对胺甲酰化反应活性的影响

Table 1. Pd-catalyzed N-formylation of amine


Entry	Catalyst	Yield^b/%
1	Pd(NO₃)₂	39
2	Pd(OH)₂	22
3	PdCl₂	33
4	Pd(OAc)₂	54
5^c	Pd(OAc)₂	35
6	Pd(dppf)Cl₂	30
7	Pd(COD)Cl₂	30
8	Pd(acac)₂	20
9	(Pd(Allyl)Cl)₂	37
^a Reagents and conditions: 2-(1H-indol-3-yl)-ethylamine (1 mmol), catalyst (0.2 mmol). ^b Isolated yield. ^c Catalyst (0.1 mmol).

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表 2 碱对胺甲酰化反应活性的影响

Table 2. Effect of different bases on the N-formylation of amine


Entry	Base	Base/catal.	Yield^b/%
1	K₂CO₃	2	33
2	Cs₂CO₃	2	60
3	Ba(OH)₂	2	38
4	LiOH	2	41
5	CH₃COOK	2	34
6	NEt₃	0	54
7	NEt₃	2	81
8	NEt₃	4	94
9	NEt₃	6	68
10	Ethylenediamine	2	60
11	Pyridine	2	74
^a Reagents and conditions: 2-(1H-Indol-3-yl)-ethylamine (1 mmol), Pd(OAc)₂ (0.2 mmol). ^b Isolated yield.

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表 3 DMF对胺甲酰化反应活性的影响

Table 3. Effect of DMF on the N-formylation of amine

Entry	DMF/equiv.	Yield^b/%
1	1	25
2	2	40
3	4	62
4	6	85
5	8	94
6	10	92
7	12	91
^a Reagents and conditions: 2-(1H-Indol-3-yl)-ethylamine (1 mmol), Pd(OAc)₂ (0.2 mmol), NEt₃ (0.8 mmol). ^b Isolated yield.

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表 4 醋酸钯催化胺甲酰化反应

Table 4. Pd(OAc)₂-catalyzed N-formylation of amines

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沈阳化工大学材料科学与工程学院沈阳 110142