Next Article in Journal
Synthesis and In Vitro Antiproliferative Activity of 11-Substituted Neocryptolepines with a Branched ω-Aminoalkylamino Chain
Previous Article in Journal
Peptide Nucleic Acid-Based Biosensors for Cancer Diagnosis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 22
Issue 11
10.3390/molecules22111952
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate

by
Qingqiang Tian
,
Suqin Shang
,
Huajun Wang
,
Guoqiang Shi
,
Zhiyao Li
and
Jianyong Yuan
*
Pharmacy College, Chongqing Medical University, Chongqing 400016, China
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(11), 1952; https://doi.org/10.3390/molecules22111952
Submission received: 18 October 2017 / Revised: 2 November 2017 / Accepted: 9 November 2017 / Published: 11 November 2017
(This article belongs to the Section Organometallic Chemistry)
Browse Figures
Versions Notes

Abstract

:
A selective and practical bromine–metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.

Graphical Abstract

1. Introduction

Substituted heterocyclics are an important class of heterocyclic building blocks that are routinely used in the synthesis of medicinal and agrochemical products [1]. Functionalization of heterocyclics via organometallic intermediates has been one of the most frequently used methods for the synthesis of various heterocyclic derivatives. One of the strategies relies on the rapid bromine–lithium exchange reaction on halogenated heterocyclics under cryogenic conditions at low temperature [2]. However, the reactivity and stability of the lithiated species under the reaction conditions usually require cryogenic conditions to minimize undesired side-reactions, such as nucleophilic attack of the heterocyclic ring by alkyl lithium (Scheme 1) [3,4,5,6,7,8,9,10]. The protocol reported by the literature basically allows for the lithiation of bromo-substituted heterocycles in the presence of N–H and O–H acidic protons such as indoles or phenols. Corresponding protocols are known. In these papers, as the authors did more than two equivalents of the organo-lithium reagent (or another strong base such as KH) is employed, and first deprotonation of the acidic protons takes place, followed by the lithiation [11,12,13,14]. Alternatively, the preparation of the Grinard reagent via halogen–magnesium exchange typically uses i-PrMgCl. The subsequent quenching with various electrophiles has been proven to be a highly useful method for the synthesis of heterocyclic derivatives [15,16,17,18,19,20,21]. In this method, the additional functional groups can tolerate the process of halogen–metal exchange, which considerably enhanced its synthetic utility. However, for those substrates that bearing an acidic proton (Compound 1, Scheme 1), i-PrMgCl is generally not reactive enough to affect Br–Mg exchange. Under these circumstances, the use of more reactive alkyl lithium reagents only made limited success because of nucleophilic attack on the pyridine ring by n-BuLi as well as the formation of corresponding protonated products due to intermolecular quenching [22,23,24,25] (Br–Li exchange is usually fast enough to compete with the removal of an acidic proton by n-BuLi).
Therefore, the development of new methodologies that can address these issues is highly desirable. In this paper, we wish to report that halogen–metal exchange on heterocyclic substrates bearing an acidic proton can be performed efficiently through a combined use of i-PrMgCl and n-BuLi under essentially noncryogenic conditions and that high regioselectivity can be achieved on halogen–metal exchange on substrate with two bromo groups via chelation effect.

2. Results and Discussion

We started with bromopyridine 1a that substituted with a Boc-protected amino group to explore the best condition to execute the Br–Mg exchange in the presence of an acidic carbamate proton. When Compound 1a was treated with one to three equivalents of i-PrMgCl at room temperature, no expected Br–Mg exchange took place (Table 1, entries 1–3). In addition, we used three equivalents of i-PrMgCl, lowered the temperature to 0 °C and increased the reaction time, with no expected exchange results, resulting in a list of impurities (Table 1, entry 4). Subsequently, we used the more active lithium reagent to treat Compound 1a with one to three equivalents of n-BuLi at low temperature and did not find the desired target product to obtain unwanted polymers (Table 1, entries 5–7). In this case, we considered the combination of i-PrMgCl and n-BuLi. First, we explored i-PrMgCl:n-BuLi = 1:1 equivalent and found no efficient exchange (Table 1, entry 8). Then, when we increased the amount of i-PrMgCl to i-PrMgCl:n-BuLi = 1:2 equivalents, compound 1a was treated successively with one equivalent of i-PrMgCl at 0 °C and two equivalents of n-BuLi, gratifyingly a clean exchange took place and subsequent quenching of the intermediate with DMF gave a 90% yield of the expected aldehyde product 3a (Table 1, entry 9).
According to Knochel et al. [26], LiCl-mediated Br–Mg exchange reaction was used to prepare functionalized aryl compounds from organic bromides. Then we guessed the role of lithium in the system. We used inorganic lithium carbonate and lithium chloride instead of n-BuLi, and found no target product formated (Table 1, entries 10 and 11). At the same time, we used p-bromophenol as raw material, to further explore the role of inorganic lithium chloride in the system and found no p-hydroxybenzaldehyde but the starting material (Table 1, entry 12). Therefore, n-BuLi plays a pivotal role in the reaction.
We examined the stability of the metalated species and found that the intermediate was stable in THF at −20 °C, give 3a with a yield of 90%, even after aging for 0.5 h before treated with tert-butyl (5-formylpyridin-2-yl) carbamate (Table 2).
Compared with the typical Br–Li exchange with alkyl lithium which requires to be performed under cryogenic condition, the current reaction could be performed at about 0 °C. It was found that two equivalents of n-BuLi were necessary for the exchange to be completed, indicating that the bromine–metal exchange was probably affected by the action of an “ate” complex (2) (Scheme 2) formed from one equivalent of N-magnesium salt and two equivalents of n-BuLi [27,28,29]. Similarly, following the same protocol, bromine–magnesium exchange could be performed successively on other bromopyridines bearing an acidic carbamate proton, then quenching of the organometallic intermediates with DMF and other electrophiles to afford a high yield of the corresponding products (Table 3, entry 1).
The above-mentioned efficient method for performing halogen–metal exchange on substrates bearing carbamate group(s) was established. Then, we sought to extend the same procedure to bromopyridines bearing other phenolic hydroxyl groups. We obtained the same results for the selective functionalization of the p-bromophenol substrate as those reported with the lithium trialkylmagnesiate complex (ref. [30,31], 56% yield). Then, we turned our attention to the effect of the acetyl amino substituent (Table 3, entry 9). The series proceeded here with the same trend as for the bromopyridines bearing an acidic carbamate proton and resulted in moderate to good yields (94%) with high selectivity.
We examined the selectivity of Br–Mg exchange on a series of dibromo-substituted aromatic hydrocarbon derivatives bearing an acidic functional group which would allow us to synthesize aromatic hydrocarbon derivatives substituted with multiple functional groups. As summarized in Table 3, when dibromo substrates 1e and 1o were treated with one equivalent of i-PrMgCl and two equivalents of n-BuLi, only one of the bromo groups was exclusively exchanged. Subsequent reaction of the metallated aromatic hydrocarbons with various electrophiles afforded trisubstituted aromatic hydrocarbon derivatives 3e and 3o with high yield (Table 3, entries 5 and 15).
To further illustrate the efficient method for bromine–metal exchange on bromopyridines and arenes bearing an acidic proton-containing substituent, we selected bromoindole and heteroaromatic substrates that have active hydrogen sensitive moieties (Table 3), such as bromoindole (entries 3, 4 and 6), bromo benzimidazole (entry 7), bromopyrrole (entry 10), bromoimidazole (entries 11 and 12). In a few cases (entries 4 and 7), the isolated yields were poor (e.g., <80%), which can be attributed to a combination of steric and electronic factors or to the volatility of the product (entries 4 and 7).
Based on the above results and the published literature [32,33,34,35], we postulated a tentative mechanism of halogen–metal exchange in Scheme 3. Initially, we used one equiv. of i-PrMgCl to remove the active proton hydrogen from the aromatic hydrocarbon at 0 °C to form the organomagnesium reagent (a), and then added two equivs. of n-BuLi at −20 °C. A half of the n-BuLi combined with the magnesium salt to form an “ate” complex and the rest of n-BuLi exchanged with the halogen to form magnesium compound (b). Next, one equiv. of an electrophilic reagent was coupled to the C–Li bond (c). Finally, water was added to provide proton hydrogen to obtain the desired product (d).

3. Materials and Methods

General remarks: All reagents were obtained from Aladdin Reagent Shanghai Co., Ltd. (Shanghai, China), Lagewell Technology Co., Ltd., Meyer Reagent Shanghai Co., Ltd., Macklin Reagent Shanghai Co., Ltd., Chongqing Chuandong Chemical Co., Ltd. etc. without further purification unless otherwise noted. High resolution mass spectra (South China Agricultural University, Guangzhou) were measured on commercial instruments. NMR spectra were recorded on commercial instruments (Bruker company, Karlsruhe, Germany) and operated at 600 MHz for 1H-NMR and 151 MHz for 13C-NMR. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard ((CD3)2SO, δ = 2.50, δ = 3.33) in 1H-NMR spectra and chemical shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal standard ((CD3)2SO, δ = 39.5) in 13C-NMR spectra. Spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration and assignment.
(5-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3a): To a solution of (5-Bromo-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 3.7 mmol, 1.0 equiv.) in dry THF (12 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (1.85 mL, 3.7 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3 mL, 7.5 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.27 g, 3.7 mmol, 1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3a as white solid, 0.73 g (yield: 90%). 1H-NMR (600 MHz, DMSO) δ 10.42 (s, 1H), 9.94 (s, 1H), 8.93–8.60 (m, 1H), 8.17 (dd, J = 8.8, 2.3 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 1.48 (s, 9H). 13C-NMR (151 MHz, DMSO) δ 191.18, 157.08, 152.82, 152.40, 138.23, 127.30, 112.23, 80.97, 28.37.
1H-Indole-2-carboxylic acid (3b): To a solution of 2-Bromo-1H-indole (1.0 g, 5 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.5 mL, 5 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of nBuLi in hexanes (4 mL, 10 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.22 g, 5 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3b as white solid, 0.7 g (yield: 85%), m.p.: 203–204 °C. 1H-NMR (600 MHz, DMSO) δ 12.94 (s, 1H), 11.76 (s, 1H), 7.79–6.89 (m, 5H). 13C-NMR (151 MHz, DMSO) δ 163.29, 137.71, 128.88, 127.34, 124.73, 122.40, 120.41, 112.95, 107.77.
1H-Indole-3-carboxylic acid (3c): To a solution of 3-Bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.2 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3c as off-white solid, 0.63 g (yield: 89%), m.p.: 193–196 °C. 1H-NMR (600 MHz, DMSO) δ 11.82 (s, 1H), 8.02 (t, J = 5.7 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.32–6.99 (m, 2H). 13C-NMR (151 MHz, DMSO) δ 166.43, 136.89, 132.71, 126.48, 122.58, 121.42, 121.05, 112.65, 107.87.
1H-Indole-5-carboxylic acid (3d): To a solution of 5-Bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.2 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3d as off-white solid, 0.46 g (yield: 65%), m.p.: 210–214 °C. 1H-NMR (600 MHz, DMSO) δ 12.39 (s, 1H), 11.46 (s, 1H), 8.25 (s, 1H), 7.72 (dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 5.7 Hz, 2H), 6.57 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 168.90, 138.80, 127.64, 127.35, 123.28, 122.67, 121.87, 111.57, 102.93.
5-Bromo-1H-indole-3-carbaldehyde (3e): To a solution of 3,5-dibromo-1H-indole (1.2 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of iPrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3e as yellow solid, 0.78 g (yield: 80%), m.p.: 192–194 °C. 1H-NMR (600 MHz, DMSO) δ 12.35 (s, 1H), 9.93 (s, 1H), 8.47–8.05 (m, 2H), 7.57–7.21 (m, 2H). 13C-NMR (151 MHz, DMSO) δ 185.57, 139.67, 136.23, 126.49, 126.36, 123.39, 117.90, 115.27, 115.01.
5-Methoxy-1H-indole-2-carboxylic acid (3f): To a solution of 2-Bromo-5-methoxy-1H-indole (1.0 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3f as brown solid, 0.68 g (yield: 80%), m.p.: 199–201 °C. 1H-NMR (600 MHz, DMSO) δ 7.36 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 23.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 163.25, 154.31, 133.07, 129.10, 127.65, 116.28, 113.83, 107.47, 102.44, 55.61.
1H-Benzoimidazole-5-carboxylic acid (3g): To a solution of 5-Bromo-1H-benzimidazole (0.87 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 1 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 4.4mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl acetate = 3:1) to afford product 3g as brown solid, 0.5 g (yield: 71%). 1H-NMR (600 MHz, DMSO) δ 8.43 (s, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 168.47, 144.83, 125.10, 123.74, 118.13, 115.12.
4-Hydroxy-benzaldehyde (3h): To a solution of 4-Bromo-phenol (1.5 g, 8.7 mmol, 1 equiv.) in dry THF (25 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (4.3 mL, 8.7 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (7.0 mL, 17.4 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.63 g, 8.7 mmol, 1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl acetate = 5:1) to afford product 3h as white solid, 0.94 g (yield: 90%), m.p.: 114–116 °C. 1H-NMR (600 MHz, DMSO) δ 10.59 (s, 1H), 9.78 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H). 13C-NMR (151 MHz, DMSO) δ 191.35, 191.33, 163.76, 132.53, 128.89, 116.29.
N-(4-Formyl-phenyl)-acetamide (3i): To a solution of 4-Bromo-phen N-(4-Formyl -phenyl)-acetamide (1.5 g, 7.0 mmol, 1.0 equiv.) in dry THF (25 mL) at 0 °C was added a 2 M solution of iPrMgCl in THF (3.5 mL, 7.0 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (5.6 mL, 14.0 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.5 g, 1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3i as white solid, 1.0 g (yield: 94%) , m.p.: 157–158 °C. 1H-NMR (600 MHz, DMSO) δ 10.35 (s, 1H), 9.86 (s, 1H), 7.81 (dd, J = 32.9, 8.6 Hz, 4H), 2.10 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 191.92, 169.55, 145.29, 131.56, 131.27, 119.01, 24.68.
1H-Pyrrole-2-carbaldehyde (3j): To a solution of 2-Bromo-1H-pyrrole (0.5 g, 3.4 mmol, 1.0 equiv.) in dry THF (15 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (1.7 mL, 3.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (2.7 mL, 6.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.25 g, 1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl acetate = 10:1) to afford product 3j as white solid, 0.29 g (yield: 89%) , m.p.: 42–44 °C. 1H-NMR (600 MHz, DMSO) δ 12.19 (s, 1H), 11.69 (s, 1H), 7.04–6.85 (m, 1H), 6.72 (dd, J = 4.2, 2.9 Hz, 1H), 6.12 (dd, J = 5.8, 2.4 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 162.31, 123.82, 123.35, 115.11, 109.73.
1H-Imidazole-2-carbaldehyde (3k): To a solution of 2-bromo-1H-imidazole (0.65 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3k as pale yellow solid, 0.38 g (yield: 91%), m.p.: 205–206 °C. 1H-NMR (600 MHz, DMSO) δ 13.60 (s, 1H), 9.64 (s, 1H), 7.42 (s, 2H). 13C-NMR (151 MHz, DMSO) δ 181.66, 146.09.
1H-Imidazole-4-carbaldehyde (3l): To a solution of 4-bromo-1H-imidazole (0.65 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl acetate = 10:1) to afford product 3l as off-white solid, 0.36 g (yield: 85%), m.p.: 175–177 °C. 1H-NMR (600 MHz, DMSO) δ 9.74 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 184.46, 139.44, 134.9, 129.5.
6-Hydroxy-pyridine-2-carboxylic acid (3m): To a solution of 2-bromo-6-hydroxypyridine (0.76 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of -PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3m as off-white solid, 0.56 g (yield: 93%) , m.p.: 275–277 °C. 1H-NMR (600 MHz, DMSO) δ 7.56 (dd, J = 8.9, 7.0 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 163.28, 162.67, 140.51, 137.97, 123.88, 110.42.
2-Hydroxy-nicotinic acid (3n): To a solution of 3-bromo-2-hydroxypyridine (0.76 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3n as off-white solid, 0.48 g (yield: 79%), m.p.: 255–257 °C. 1H-NMR (600 MHz, DMSO) δ 14.76 (s, 1H), 13.38 (s, 1H), 8.38 (dd, J = 7.2, 2.0 Hz, 1H), 7.95 (dd, J = 6.3, 2.0 Hz, 1H), 6.68 (t, J = 6.7 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 165.46, 165.04, 146.61, 141.95, 117.12, 109.09.
5-Bromo-3-hydroxyethynyl-pyridin-2-ol (3o): To a solution of 3,5-dibromo-2-hydroxypyridine (1.1 g, 4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 °C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below −20 °C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 4.4 mmol, 1.0 equiv.) was added to −20 °C. The resulting mixture was warmed to −20 °C in 0.5 h and quenched with water (6 mL). After stirring the mixture below −20 °C for 10 min, the phases were separated and the water phase was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3o as Off-white solid, 1.0 g (yield: 80%), m.p.: 245–247 °C. 1H-NMR (600 MHz, DMSO) δ 13.82 (s, 2H), 8.31 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 164.43, 163.72, 147.95, 142.51, 118.49, 99.96.
Experimental procedures and analytical data of all compounds (1H-and 13C-NMR), copy of the 1H, 13C and data are available in the Supplementary Materials.

4. Conclusions

In summary, we have developed an efficient method for performing bromine–metal exchange process under non-cryogenic conditions on bromopyridines and arenes bearing an acidic proton-containing substituent. The use of a combination of i-PrMgCl and n-BuLi in this method has solved the problem of intermolecular quenching that is often encountered when using alkyl lithium. Moreover, the method is particularly suitable for aryl bromides of poor reactivity.

Supplementary Materials

The following are available online, general procedure for Halogen-metal exchange reaction and 1H and 13C NMR spectra of all products.

Acknowledgments

We are grateful for the generous financial support by the conversion of outstanding achievements in colleges and universities in Chongqing of China (KJZH14204).

Author Contributions

Guoqiang Shi and Jianyong Yuan conceived and designed the experiments; Qingqiang Tian performed the experiments; Qingqiang Tian and Suqin Shang analyzed the data; Huajun Wang and Zhiyao Li contributed reagents/materials/analysis tools; Qingqiang Tian wrote the paper.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Scriven, E. Pyridines: From Lab to Production; Elsevier Ltd.: Amsterdam, The Netherlands, 2013. [Google Scholar]
  2. Schlosser, M.; Ginanneschi, A.; Leroux, F. In Search of Simplicity and Flexibility: A Rational Access to Twelve Fluoroindolecarboxylic Acids. Eur. J. Org. Chem. 2006, 13, 2956–2969. [Google Scholar] [CrossRef]
  3. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V.A. Highly Functionalized Organomagnesium Reagents Prepared Through Halogen—Metal Exchange. Angew. Chem. Int. Ed. 2003, 42, 4302–4320. [Google Scholar] [CrossRef] [PubMed]
  4. Satoshi, K.; Atsushi, A.; Takehiko, I.; Toshiaki, M.; Nobuyoshi, Y. Bromine–magnesium exchange of 5-bromo-2-picoline via an organomagnesium complex nBu2iPrMgLi: A new preparation methodology of functionalized picolines under noncryogenic conditions. Tetrahedron Lett. 2006, 47, 1877–1879. [Google Scholar]
  5. Abarbri, M.; Dehmel, F.; Knochel, P. Bromine-magnesium-exchange as a general tool for the preparation of polyfunctional aryl and heteroaryl magnesium-reagents. Tetrahedron Lett. 1999, 40, 7449–7453. [Google Scholar] [CrossRef]
  6. Hui, X.; Schmid, F.; Frank, X.; Figadère, B. Novel and highly regioselective synthesis of unsymmetrical 2,3-disubstituted quinoxalines. Heterocycles 2007, 72, 353–361. [Google Scholar]
  7. Skillinghaug, B.; Rydfjord, J.; Odell, L.R. Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2. Tetrahedron Lett. 2016, 57, 533–536. [Google Scholar] [CrossRef]
  8. Yang, Y. Expedient Synthesis of Quinazoline Analogues through Direct Nucleophilic Arylation/Alkylation of 2-Chloroquinazoline. Synthesis 2016, 48, 2255–2262. [Google Scholar] [CrossRef]
  9. Gross, S.; Heuser, S.; Ammer, C.; Heckmann, G.; Bach, T. 2,4-Disubstituted Thiazoles by Regioselective Cross-Coupling or Bromine–Magnesium Exchange Reactions of 2,4-Dibromothiazole. Synthesis 2011, 2, 199–206. [Google Scholar] [CrossRef]
  10. Fritzsche, R.; Seidel, F.; Rueffer, T.; Buschbeck, R.; Jakob, A.; Freitag, H.; Zahn, D.R.T.; Lang, H.; Mehring, M. New organosilanes based on N-methylpyrrole–Synthesis, structure and characterization. J. Organomet. Chem. 2014, 755, 86–92. [Google Scholar] [CrossRef]
  11. Kong, W.; Fu, C.; Ma, S. General Au-Catalyzed Benzannulation Towards Naturally Occurring Carbazole Alkaloids from Methoxypropadiene. Chem. Eur. J. 2011, 17, 13134–13137. [Google Scholar] [CrossRef] [PubMed]
  12. Tois, J.; Koskinen, A. Solid-phase lithiation of 5-carboxyindoles. Tetrahedron Lett. 2003, 44, 2093–2095. [Google Scholar] [CrossRef]
  13. Qiu, Y.; Ma, D.; Fu, C.; Ma, S. An efficient Au-catalyzed synthesis of isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V from propadienyl methyl ether. Org. Biomol. Chem. 2013, 11, 1666–1671. [Google Scholar] [CrossRef] [PubMed]
  14. Ragan, J.A.; Jones, P.B.; Meltz, C.N.; Teixeira, J.J., Jr. Process for the preparation of isonicotinic acid derivatives. Synthesis 2002, 4, 483–486. [Google Scholar] [CrossRef]
  15. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G. Pyridylmagnesium chlorides from bromo and dibromopyridines by bromine magnesium exchange: A convenient access to functionalized pyridines. Tetrahedron Lett. 1999, 40, 4339–4342. [Google Scholar] [CrossRef]
  16. Dohle, W.; Staubitz, A.; Knochel, P. Mild Synthesis of Polyfunctional Benzimidazoles and Indoles by the Reduction of Functionalized Nitroarenes with Phenylmagnesium Chloride. Chem. Eur. J. 2003, 9, 5323–5331. [Google Scholar] [CrossRef] [PubMed]
  17. Bergauer, M.; Gmeiner, P. Diethoxymethyl Protected Pyrroles: Synthesis and Regioselective Transformations. Synthesis 2001, 15, 2281–2288. [Google Scholar] [CrossRef]
  18. Kromann, H.; Slok, A.F.; Johansen, N.T.; Krogsgaard-Larsen, P. A convenient synthesis of 4-substituted 3-ethoxy-5-methylisoxazoles by palladium-catalyzed coupling reactions. Tetrahedron 2001, 57, 2195–2201. [Google Scholar] [CrossRef]
  19. Smith, A.B., III; Minbiole, K.P.; Verhoest, P.R.; Schelhaas, M. Total Synthesis of (+)-Phorboxazole A Exploiting the Petasis−Ferrier Rearrangement. J. Am. Chem. Soc. 2001, 123, 10942–10953. [Google Scholar] [CrossRef] [PubMed]
  20. Abarbri, M.; Knochel, P. Preparation and Reactions of Magnesiated Uracil Derivatives. Synlett 1999, 1577–1588. [Google Scholar] [CrossRef]
  21. Jaramillo, C.; Carretero, C.J.; de Diego, E.J.; del Prado, M.; Hamdouchi, C.; Roldán, L.J.; Sánchez-Martínez, C. Regioselective synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines. Tetrahedron Lett. 2002, 43, 9051–9054. [Google Scholar] [CrossRef]
  22. Beak, P.; Musick, T.J.; Chen, C. Does Formal Intramolecular Transfer of an Acidic Deuterium to a Site of Halogen-Lithium Exchange Show That Lithium-Halogen Exchange Is Faster than Loss of the Acidic Deuterium? Evidence in Favor of an Alternative Mechanism. J. Am. Chem. Soc. 1988, 110, 3538–3542. [Google Scholar] [CrossRef]
  23. Parham, W.E.; Bradsher, C.K. Aromatic Organolithium Reagents Bearing Electrophilic Groups. Preparation by Halogen-Lithium Exchange. Acc. Chem. Res. 1982, 15, 300–305. [Google Scholar] [CrossRef]
  24. Bailey, W.F.; Patricia, J. The mechanism of the lithium—halogen Interchange reaction: A review of the literature. J. Organomet. Chem. 1988, 352, 1–46. [Google Scholar] [CrossRef]
  25. Barluenga, J. Preparation and some applications of functionalized organo-lithium compounds in organic synthesis. Pure Appl. Chem. 1990, 62, 595–604. [Google Scholar] [CrossRef]
  26. Arkady, K.; Knochel, P. A LiCl-Mediated Br/Mg Exchange Reaction for the Preparation of Functionalized Aryl- and Heteroarylmagnesium Compounds from Organic Bromides. Angew. Chem. Int. Ed. 2004, 3333–3336. [Google Scholar]
  27. Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. Selective halogen-magnesium exchange reaction via organomagnesium ate complex. J. Org. Chem. 2001, 66, 4333–4339. [Google Scholar] [CrossRef] [PubMed]
  28. Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Halogen–Magnesium Exchange via Trialkylmagnesates for the Preparation of Aryl- and Alkenylmagnesium Reagents. Angew. Chem. Int. Ed. 2000, 39, 2481–2483. [Google Scholar] [CrossRef]
  29. Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tributylmagnesium ate complex-mediated novel bromine–magnesium exchange reaction for selective monosubstitution of dibromoarenes. Tetrahedron Lett. 2001, 42, 4841–4844. [Google Scholar] [CrossRef]
  30. Fabrice, G.; Ruedi, H.; Hans, H.; Wolfgang, M.; Frank, S.; Manuela, S.W. A practical non-cryogenic process for the selective functionalization of bromoaryls. Tetrahedron Lett. 2008, 49, 5024–5027. [Google Scholar]
  31. Kato, S.; Nonoyama, N.; Tomimoto, K.; Mase, T. Non-cryogenic metalation of aryl bromides bearing proton donating groups: formation of a stable magnesio-intermediate. Tetrahedron Lett. 2002, 43, 7315–7317. [Google Scholar] [CrossRef]
  32. Malpass, D.B.; Eastham, J.F. Preparation of organometallic complexes by reduction of magnesium alkyls with alkali metals. J. Org. Chem. 1973, 38, 3718–3723. [Google Scholar] [CrossRef]
  33. Ashby, E.C.; Chao, L.C.; Laemmle, J. Stereoselective organometallic alkylation reactions. III. Ate complex addition to cyclic and bicyclic ketones. J. Org. Chem. 1974, 39, 3258–3263. [Google Scholar] [CrossRef]
  34. Wakefield, B.J.; Laschat, S. Organomagnesium Methods in Organic Synthesis; Academic Press: London, UK, 1996; pp. 21–71. [Google Scholar]
  35. Comins, D.L.; Higuchi, K. Synthesis of the Benzo-fused Indolizidine Alkaloid Mimics. Beilstein J. Org. Chem. 2007, 3, 42. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
Molecules 22 01952 sch001 550
Scheme 1. Metal halogen exchange method.
Scheme 1. Metal halogen exchange method.
Molecules 22 01952 sch001
Molecules 22 01952 sch002 550
Scheme 2. Intermediate “ate” complex.
Scheme 2. Intermediate “ate” complex.
Molecules 22 01952 sch002
Molecules 22 01952 sch003 550
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 22 01952 sch003
Table
Table 1. Tert-butyl (5-formylpyridin-2-yl) carbamate of metalating reagents prepared from 2-(N-BOC-amino)-5-bromopyridine.
Table 1. Tert-butyl (5-formylpyridin-2-yl) carbamate of metalating reagents prepared from 2-(N-BOC-amino)-5-bromopyridine.
Molecules 22 01952 i001
EntryMetalating ReagentReaction ConditionsYield a of 3a (%)
1i-PrMgCl (1.0 equiv.)THF, rt, 24 hTrace
2i-PrMgCl (2.0 equiv.)THF, rt, 24 hTrace
3i-PrMgCl (3.0 equiv.)THF, rt, 24 hTrace
4i-PrMgCl (3.0 equiv.)THF, 0 °C, 36 hTrace
5n-BuLi (1.0 equiv.)THF, −78 °C, 24 hTrace
6n-BuLi (2.0 equiv.)THF, −20 °C, 0.5 hTrace
7n-BuLi (2.0 equiv.)THF, −20 °C, 0.5 hTrace
8 bi-PrMgCl + n-BuLi (1.0:1.0 equiv.)THF, −20 °C, 0.5 hTrace
9 ci-PrMgCl + n-BuLi (1.0:2.0 equiv.)THF, −20 °C, 0.5 h90
10i-PrMgCl + Li2CO3 (1.0:2.0 equiv.)THF, −20 °C, 0.5 hTrace
11i-PrMgCl + LiCl (1.0:2.0 equiv.)THF, −20 °C, 0.5 hTrace
12 di-PrMgCl + LiCl (1.0:2.0 equiv.)THF, −20 °C, 0.5 hTrace e
a Yields were determined by HPLC; b reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 °C, then n-BuLi (2.0 equiv.) at −20 °C; c reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 °C, then n-BuLi (2.0 equiv.) at −20 °C; d raw materials for bromophenol; e starting material only.
Table
Table 2. Stability of metalating reagents prepared from 2-(N-BOC-amino)-5-bromopyridine.
Table 2. Stability of metalating reagents prepared from 2-(N-BOC-amino)-5-bromopyridine.
Molecules 22 01952 i002
Aging Time (h)Yield a
0.2569
0.590
175
240
523
a Yields were determined by HPLC analysis.
Table
Table 3. Br–Mg (Li) exchange on bromopyridines bearing an acidic proton a.
Table 3. Br–Mg (Li) exchange on bromopyridines bearing an acidic proton a.
EntrySubstrateElectrophileProductYield b, %
1 Molecules 22 01952 i003
1a		DMF Molecules 22 01952 i004
3a		90
2 Molecules 22 01952 i005
1b		CO2 Molecules 22 01952 i006
3b		85
3 Molecules 22 01952 i007
1c		CO2 Molecules 22 01952 i008
3c		89
4 Molecules 22 01952 i009
1d		CO2 Molecules 22 01952 i010
3d		65
5 Molecules 22 01952 i011
1e		DMF Molecules 22 01952 i012
3e		80
6 Molecules 22 01952 i013
1f		CO2 Molecules 22 01952 i014
3f		80
7 Molecules 22 01952 i015
1g		CO2 Molecules 22 01952 i016
3g		71
8 Molecules 22 01952 i017
1h		DMF Molecules 22 01952 i018
3h		90
9 Molecules 22 01952 i019
1i		DMF Molecules 22 01952 i020
3i		94
10 Molecules 22 01952 i021
1j		DMF Molecules 22 01952 i022
3j		89
11 Molecules 22 01952 i023
1k		DMF Molecules 22 01952 i024
3k		91
12 Molecules 22 01952 i025
1l		DMF Molecules 22 01952 i026
3l		85
13 Molecules 22 01952 i027
1m		CO2 Molecules 22 01952 i028
3m		93
14 Molecules 22 01952 i029
1n		CO2 Molecules 22 01952 i030
3n		79
15 Molecules 22 01952 i031
1o		CO2 Molecules 22 01952 i032
3o		80
a Reaction conditions: i-PrMgCl (1.0 equiv.), THF, 0 °C, then n-BuLi (2.0 equiv.) −20 °C; b yield of isolated product.

Share and Cite

MDPI and ACS Style

Tian, Q.; Shang, S.; Wang, H.; Shi, G.; Li, Z.; Yuan, J. Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate. Molecules 2017, 22, 1952. https://doi.org/10.3390/molecules22111952

AMA Style

Tian Q, Shang S, Wang H, Shi G, Li Z, Yuan J. Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate. Molecules. 2017; 22(11):1952. https://doi.org/10.3390/molecules22111952

Chicago/Turabian Style

Tian, Qingqiang, Suqin Shang, Huajun Wang, Guoqiang Shi, Zhiyao Li, and Jianyong Yuan. 2017. "Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate" Molecules 22, no. 11: 1952. https://doi.org/10.3390/molecules22111952

APA Style

Tian, Q., Shang, S., Wang, H., Shi, G., Li, Z., & Yuan, J. (2017). Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate. Molecules, 22(11), 1952. https://doi.org/10.3390/molecules22111952

Article Metrics

Back to TopTop