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One-pot synthesis of 9-aminomethylanthracene

Paulina C. Glowacka
G. Richard Stephenson*
School of Chemistry, University of East Anglia
Norwich Research Park, Norwich, Norfolk NR4 7TJ, United Kingdom /
Scheme 1

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AbstractA novel method for the preparation of 9-aminomethylanthracene 1 has been developed by the use of ammonium salts in the reductive amination of the 9-formyl anthracene derivative 2, a reaction which has been examined with a variety ofreducing agents, ammonium ion sources and solvents. The optimized reaction conditions allowed the isolation of fluorophore 1 in good yields.

Key wordsfluorophore, one-pot, reductive amination, ammonium chloride, 9-aminomethylathracene

Many disciplines require sensing systems, including chemistry, biology, clinical biology and environmental sciences, for example, to study the cell chemistry and to understand the mechanisms by which cells work.1 Consequently an enormous demand for chemical sensors for many areas and disciplines has been shown to be necessary. High sensitivity and ease of operation are two main issues for sensor development. Fluorescence techniques can easily fulfill these requirements and therefore fluorescent-based sensors appear as one of the most promising candidates for chemical sensing.2

9-Aminomethylanthracene 13 is an important example of an organic fluorophore which is widely used as a scaffold to build up sensor molecules.4 Additionally, it is also a versatile building block in organic synthesis since the amino group can be converted into a number of derivatives. In this way, 9-aminomethylanthracene can be easily elaborated into more advanced structures in which recognition features are combined with the fluorescence properties. Specifically, this class of fluorophores are important as nitrogen-containing PET-based biosensors.5 Additional advantages of the anthracene sensors are that they have moderate absorption cross-sections in the near-UV region and good fluorescence quantum yields, which are useful, for example, in the monitoring of ligands binding to DNA by spectroscopic methods.6 The chemical reactivity of the 9-aminomethylanthracene core also leads to important applications and allows these anthracene derivatives to serve as fluorescent dye photosensitizers.7 They are capable of light-reliant chemical reactions that result in damage to biological systems.8 Anthracenes are good photosensitizers because of their low polarizability, strong fluorescence, good absorption in the near UV region, and a long-lived excited triplet state.7b,9 Certain anthracene derivatives are also known to be active against specific types of cancers. For example, anthracene-based drugs such as Pseudourea (bis-(2-thio(2,2′-(9,10-anthrylenedimethylene) dihydrochloride) dihydrate) have been tested in clinical trials which showed that the anthracene itself is effective against specific forms of skin cancer.10

For all these reasons, 9-aminomethylanthracene has become a highly sought-after chemical intermediate. Indeed, anthracene is one of the favorite ‘‘core structures” in fluorophore construction due to its availability and tailorisability and thus its derived systems have widely been used in molecular recognition in both inorganic and biological systems.

In view of the importance of 9-aminomethylanthracene it is highly surprising that although commercially available, it is very expensive (2 g costs $1250, at Betapharmascientific®), and many methods of preparation of this compound that have been reported in the literature are indirect and convoluted, even in recent papers. For example, in 2012, Lu, Lei, Tian, Wang and Zhang describe11 a three-step route from the 9-hydroxymethylanthracene via the azide by chlorination, reaction with NaN3, and reduction.12 Other nucleophiles, such as phthalimide13 and hexamethylenetetramine14 have also been used, but in the case ofphthalimide, deprotection requires the use of hydrazine which is an unpleasant reagent because of its carcinogenic properties. Preparation by reduction of 9-cyanoanthracene15has been described,16 but is low-yielding (only 7%). Other variations employ bromination rather than chlorination to install the leaving group, but with no clear improvement.13,17 With these short-comings in mind, for our work to prepare a fluorophore-equipped organometalcarbonyl-based sensor,18 we required 9-aminomethylanthracene as a plentiful starting material, so it was important to find a short and easy way to prepare it.19 We describe here a ‘green’, simple and effective short (one-pot) synthesis of this significant fluorophore starting from the 9-anthracenecarbaldehyde. The use of a reductive amination approach to prepare 9-aminomethylanthracene has been described previously as a two-step procedure via the oxime, but both reports20 of the reduction step employ lithium aluminium hydride which is a significant fire hazard and is notorious for showing exotherms when reactions are used in scale-up procedures. In contrast, our method employs ammonium chloride21 as the nitrogen source and mild borohydride-based reducing agents.

Reductive amination of aldehydes and ketones is a well-known method to prepare secondary amines. In this type of reaction, the amine will react with the carbonyl group to produce an imine 5 (reversible), which involves the loss of one molecule of water. The equilibrium between the imine 5 and aldehyde or ketone 3 (Scheme 1) can be moved to favour imine formation by removal of the water. It is possible to isolate and reduce the imine 5 (an intermediate) with a suitable reducing agent: this is called indirect reductive amination. It is also possible to perform both steps in one pot, with the imine formation and reduction occurring in sequence, which is known as direct reductive amination. In this case, the initial equilibrium can be driven by the irreversible reduction step. These methods use reducing agents which are more reactive towards imines than ketones, for example sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride [NaBH(OCOCH3)3].2122 Another interesting and significant transformation of the imine intermediate uses catalytic hydrogenation. The disadvantage of this method, however, is that the hydrogenation conditions for the reaction are not suitable for many other reducible functional groups, for instance nitro, cyano, double, triple bond. To avoid those extra reductions, sodium cyanoborohydride is preferable.22

Scheme 1Representation of reductive amination.

The reductive amination reaction: Our study of the reductive amination of 9-anthracenecarbaldehyde using ammonium chloride and sodium triacetoxyborohydride began with a comparison of different solvents, EtOH, MeOH, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), or acetonitrile (MeCN), Table 1. The first attempt was performed in EtOH by using the NaBH(OAc)3 to obtain fluorophore 1. Sodium triacetoxyborohydride is presented in the literature as a general reducing agent for the reductive amination of aldehydes and ketones.23 Procedures for using this mild and selective reagent have been developed for a wide variety of solvents. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran (THF), acetonitrile (MeCN).

Table 1 Reductive Amination with NaBH(OAc)3

Entry Methods Time Solvent Yield
(h) (%)
1 / a, b, c / 24 / EtOH / 0a,b,c
2 / a, b, c / 24 / MeOH / 0a,b,c
3 / a, b, c / 18 / DCE / 15a,b, 0c
4 / a, b, c / 24 / THF / 6a,b, 0c
5 / a, b, c / 24 / MeCN / 0a,b,c

Methods: a) without AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent; b) with AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent; c) without AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent, reflux.

The results indicates that DCE is the best solvent and that THF can be used but the yield is lower, Table 1, entries 3 vs 4). The addition of AcOH, did not improve yield of the reaction (Table 1, Method a vs b). When reaction was carried out under reflux no product was formed (Table 1, Method b). We also examined the use of a large excess (10 eq.) of ammonium chloride in EtOH, MeOH, DCE, or CH3CN, which did not improve the yield of the product.

We turned next to the use of sodium cyanoborohydride as this reducing agent is also widely reported for eductive amination in the literature.24 Limitations are that the reaction may require up to a fivefold excess of the amine and the reagent is highly toxic, producing toxic byproducts such as HCN and NaCN upon workup. The results (Method a, Table 2) show that the use of a wider range of solvents was possible with sodium cyanoborohydride as the reducing agent. Our experiments also confirmed the need for an excess of the nitrogen source; the best yields were obtained for sixfold excess of ammonium chloride in all solvents. The reaction was slower than in case of sodium triacetoxyborohydride; but the isolated yield of the purified reductive amination product increased for all solvents apart from EtOH (Table 2).

Direct comparisons were made between reactions with or without added acetic acid, Table 2, method a vs b. The results show that addition of AcOH did not improve the yield. With sodium triacetoxyborohydride, longer reaction times are required and higher yields are observed when compared to reactions using sodium triacetoxyborohydride, Table 1 vs Table 2).

Table 2 Reductive Amination with NaBH3CN

Entry Methods Time (h) Solvent Yield (%)
1 / a, b, c / 36 / EtOH / 0a,b,c
2 / a, b, c / 36 / MeOH / 27a,b, 0c
3 / a, b, c / 24 / DCE / 60a,b, 0c
4 / a, b, c / 36 / THF / 13a,b, 0c
5 / a, b, c / 36 / MeCN / 7a,b, 0c

Methods: a) without AcOH, 1eq. of aldehyde, 6-10 eq. of NH4Cl, 4 eq. of reducing
agent; b) with AcOH, 1eq. of aldehyde, 6-10 eq. of NH4Cl, 4 eq. of reducing agent; c) without AcOH, 1eq. of aldehyde, 6-10 eq. of NH4Cl, 4 eq. of reducing agent, reflux.

As the results indicated that NaBH3CN improved the yield of the product, we decided to assess the use of the more reactive reducing agent, sodium borohydride. Sodium borohydride (NaBH4) is a versatile reducing agent which widely used even in industrial processes.22,25 Reductive amination of carbonyl compounds with primary amines can be complicated. In these cases, formation and isolation of the imine followed by reduction can be useful alternative. Methanol is a favourite solvent because it allows rapid (< 3h) and nearly quantitative imine formation from aldehydes without the need for dehydrating reagents.

Results obtained with sodium borohydride are shown in Table 3. The best reaction conditions were found when using NaBH4 (4 eq.), DCE as a solvent and ammonium chloride (2.5 eq.) for 12 h at room temperature to obtain the product in 80% yield. The results show that addition of AcOH, longer reaction times or heating to reflux did not improve the yield of the reaction, Table 1, methods a vs b. The use of a large excess (10 eq.) of ammonium chloride and reducing agent in all the solvents was examined but did also not improve the yield of the product, Table 3, method a. The same results were obtained for NaBH4 when compared to NaBH(OAc)3 and NaBH3CN when reaction was carried out under reflux, for all reagents no product was formed, Table 1, Table 2, Table 3, method c.

Table 3 Reductive Amination with NaBH4

Entry Methods Time (h) Solvent Yield (%)
1 / a, b, c / 24 / EtOH / 33a,b, 0c
2 / a, b, c / 24 / MeOH / 40a,b, 0c
3 / a, b, c / 12 / DCE / 80a,b, 0c
4 / a, b, c / 24 / THF / 23a,b, 0c
5 / a, b, c / 24 / MeCN / 12a,b, 0c

Methods: a) without AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent; b)with AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent; c) without AcOH, 1eq. of aldehyde, 2.5-10 eq. of NH4Cl, 4 eq. of reducing agent, reflux

Results and Discussion

Comparison of Reducing Agents: Our standard reaction conditions26 for reductive amination start from the preparation of a mixture of the carbonyl compound and ammonium chloride (0-5% molar excess) in the desired solvent and stirred with 1.3-10 eq. of reducing agent under a nitrogen atmosphere at room temperature. In some cases, acetic acid (1-2 mol eq.) was then added to the mixture to initiate imine formation. The progress of the reaction was followed by TLC (diethyl ether / hexanes [1:1]). Solvents such as water are not recommended. Reactions in water resulted in decomposition of the reducing reagent. Reductive amination is relatively slow and some literature indicates that reaction times can be shortened if AcOH is added.27 However, in our case the addition of AcOH did not improve yield of the reaction (Table 1, 2, 3 Method a vs b). When reaction was carried out under reflux, no product was formed (Table 1, 2, 3 Method c). The use of a large excess (10 eq.) of ammonium chloride and reducing agent in all the solvents was examined but did not improve the yield of the product, Table 1, 2, 3, method a.

In general, the results of reductive amination employing sodium borohydride were better thansodium triacetoxyborohydride and sodium cyanoborohydride. For example, we compared the reductive amination using NaBH3CN vs NaBH(OAc)3. The reaction at room temperature with NaBH(OAc)3 (6 eq.) in all solvents and in the absence of AcOH was completed after 18-24 h with the formation of the corresponding product (Table 1 vs Table 2). The conversion did not improve when adding AcOH (1 eq.). The reaction using the standard NaBH3CN conditions was complete in 24-36 h (longer time) but with improved yield (Table 1: entry 5). An impressive result was obtained in the reductive amination with NaBH4 in DCE which give the best yields for all solvents when compared to other reducing agent (Table 1, Table 2, and Table 3).

Generally, reactions in DCE were noticeably faster than those carried out in EtOH, MeOH, THF or CH3CN for all reducing agents (e.g., Table 1: entry 3, Table 2: entries 3, Table 3: entry 3).However, the yields were improved from 0% to 27% and 40%, respectively, when the reactions were carried out with reducing agents in anhydrous MeOH (Table 1: entry 2, Table 2: entry 2 and Table 3: entry 2).

Overall, the best conditions were achieved by using NH4Cl as a source of nucleophile and NaBH4 as the reducing agent in dry DCE, at room temperature.

Summary and conclusions

The results presented here indicate that sodium borohydride is a synthetically useful reagent for reductive amination of 9-aldehydeanthracene with ammonium chloride. It is a mild, inexpensive, non-hazardous and commercially available reagent, and it is a reagent of choice for reductive amination of many carbonyl compounds. Additionally it is ‘greener’ choice of reducing agent when compared to NaBH3CN. In representative comparisons with other commonly used reducing reductive amination reagents, sodium borohydride reacted consistently faster, gave better yields, and produced fewer side products. DCE allows a rapid formation of imines from aldehyde and amine to isolate the target molecule in 80%.

Acknowledgment

We thank the EU Interreg IV Trans Manche / Channel cross-border project ‘Innovative Synthesis: Chemistry and Entrepreneurship’ (IS:CE chem: ref. 4061) for financial support.

References and Notes

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(26)General procedure for the preparation fluorophore 1: To a solution of 9-anthracenealdehyde 2 (1 eq., 1 mmol) in dry solvent (20 mL) under nitrogen, was added ammonium chloride (2.5-10 eq.). The resulting solution was stirred for 2 h at rt, after which, the reducing agent (4 eq., 4 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was quenched by adding aqueous saturated NaHCO3. The aqueous phase was extracted with DCM (3 x 15 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated. Crude material was then purified by silica gel column chromatography (diethyl ether / hexanes [1:1]) affording the desired amine, See Tables 1, 2, 3.

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