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8.1 Palladium-Catalyzed Allylic Amination Using Aqueous Ammonia

DOI: 10.1055/sos-SD-206-00612

Kobayashi, S.Science of Synthesis: Water in Organic Synthesis, (20121855.

Palladium-catalyzed allylic amination is a well-established method for the synthesis of allylamines. Indeed, since the 1980s, a variety of nitrogen nucleophiles have been developed for this useful transformation.[‌1‌‌7‌] However, although ammonia is one of the most attractive nitrogen sources from a cost and atom-economical point of view,[‌8‌‌23‌] there are no reports on the use of ammonia for metal-catalyzed allylic amination providing primary amines (one example of iridium-catalyzed allylic amination of methyl cinnamyl carbonate using a dioxane solution of ammonia to give the corresponding secondary amine exclusively has been reported[‌17‌]). Far from that, some authoritative review articles on allylic aminations mention that ammonia does not react[‌2‌] or ammonia fails to act as an effective nucleophile for π-allylpalladium.[‌1‌] Due to the failure of ammonia,[‌24‌] a variety of ammonia surrogates such as 4-toluenesulfonamide,[‌25‌] phthalimide,[‌26‌] iminodicarboxylic acid di-tert-butyl ester,[‌27‌] and sodium azide[‌28‌] have been used in allylic amination to synthesize primary amines.[‌2‌,‌29‌,‌30‌] In general, difficulty in the use of ammonia for metal-catalyzed processes arises because (i) many kinds of transition metals are deactivated by ammonia to give stable amine complexes, and (ii) if a reaction forms a primary amine, this product is more reactive than ammonia and causes problematic over-reactions.

Based on continuous studies using ammonia as a nitrogen source for organic synthesis,[‌10‌,‌22‌,‌23‌] it has been found that the reaction of (E)-1,3-diphenylallyl acetate (1) with aqueous ammonia in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) proceeds with full conversion at room temperature to give a 14% yield of the primary amine 2 along with a 71% yield of the corresponding secondary amine 3 (Table 1, entry 1).[‌31‌] It should be noted that these results are contrary to the common knowledge described in review articles. Moreover, while ammonia gas does not give the product at all, aqueous ammonia does give the product. Thus, ammonia does not react in the absence of water, but does react in the presence of water.[‌31‌]

Because the yield of the desired primary amine 2 was low, a variety of reaction conditions were examined using acetate 1 as a model substrate to improve primary/secondary amine selectivity. Changing the aqueous ammonia/tetrahydrofuran ratio from 1:6 to 1:2 at 0.33M, in order to increase the quantity of ammonia, results in slight improvement in the selectivity (entry 2). Fortunately, the dilution method is found to be effective for improvement of the selectivity (entries 24). Although a combination of aqueous ammonia and nonpolar toluene results in no reaction, a polar aprotic cosolvent such as dimethylformamide or acetonitrile shows similar efficiency to tetrahydrofuran (entries 58). Of the solvents tested, 1,4-dioxane gives the best result at 0.11M. Further dilution in the dioxane/aqueous ammonia system has been examined, and it was found that 0.04M was the critical concentration for this reaction (entries 911). At 0.03M the reaction does not proceed at all probably due to the deactivation of palladium(0) (entry 12). It is assumed that under such high-dilution conditions, liberated triphenylphosphine cannot stabilize the catalytically active palladium(0). Indeed, by addition of 13mol% of external triphenylphosphine, which makes the total concentration of triphenylphosphine the same as that in the reaction at 0.04M, the catalyst completely recovers its catalytic activity, giving the products in good yields (entry 13).

Table 1 Optimization of Reaction Conditions in Allylic Amination Using Gaseous Ammonia and Aqueous Ammonia

Entry Solvent Ratio (NH3/solvent) Concentration (M) Catalyst (mol%) Time (h) Selectivitya (2/3) Yieldb (%) of 2 Yieldb (%) of 3
1 THF 1:6 0.33 5 16 26:74 14 71
2 THF 1:2 0.33 5 6 28:72 20 66
3 THF 1:2 0.17 5 10 47:53 34 55
4c THF 1:2 0.11 5 23 59:41 40 42
5 THF 1:2 0.11 10 12 62:36 44 39
6 toluene 1:2 0.11 10 12 trace trace
7 DMF 1:2 0.11 10 12 68:32 48 37
8 MeCN 1:2 0.11 10 12 58:42 39 46
9 1,4-dioxane 1:2 0.11 10 12 77:23 91 29
10 1,4-dioxane 1:2 0.06 10 18 83:17 66 22
11 1,4-dioxane 1:2 0.04 10 18 89:11 71 16
12 1,4-dioxane 1:2 0.03 10 18 0 0
13d 1,4-dioxane 1:2 0.03 10 18 91:9 73 13

a Molar ratio of 2/3 determined by 1HNMR spectroscopic analysis of crude material.

b Isolated yield after chromatography.

c 12% of 1 was recovered.

d 13mol% Ph3P was added.

Substrate generality of this reaction under the optimized conditions is shown in Table 2. Not only 1,3-diaryl- but also 1,3-dialkylallyl acetates can be applied to give the corresponding primary amine in 79% yield (entry 2). The reaction of cyclic allyl carbonates possessing a variety of substituents at the vinylic positions, such as aryl groups, with both electron-donating and -withdrawing groups, and alkyl groups proceeds with excellent selectivities to afford the corresponding primary amines in yields of around 80% (entries 37). The corresponding allyl acetates are found to be unreactive. Under the same conditions as those in entry 3, the reaction of 2-phenylcyclohex-2-enyl acetate proceeds with 38% conversion to give the amine product in 29% yield. It should be noted that the presence of substituents at the vinylic position is not the reason for high primary amine selectivity. Moreover, the reaction of a less sterically hindered, simple nitrogen-containing cyclic allyl carbonate gives the desired primary amine in high yield with high selectivity (entry 8). Five- and seven-membered cyclic allyl carbonates also react smoothly to afford the primary amines in high yields and with high selectivities (entries 9 and 10).

Table 2 Allylic Amination Using Aqueous Ammonia

Entry Substrate R1 Concentration (M) Time (h) Product Selectivitya Yieldb (%)
1 Ph 0.04 18 89:11 71
2 (CH2)2Ph 0.04 18 93:7 79
3 Ph 0.11 12 96:4 81
4 4-MeOC6H4 0.11 12 94:6 80
5 3-O2NC6H4 0.11 12 95:5 80
6 3,5-(F3C)2C6H3 0.04 18 97:3 82
7 (CH2)3Ph 0.11 12 >99:1 82
8 0.11 12 94:6c 85
9 0.11 12 94:6 82
10 0.11 12 93:7 76

a Molar ratio of primary/secondary amine determined by 1HNMR spectroscopic analysis of crude material.

b Isolated yield after chromatography.

c Calculated based on isolated products.

A preliminary investigation into an asymmetric variant of this reaction has also been conducted. In the presence of catalytic amounts of bis(η3-allyl)dichlorodipalladium(II) [Pd2(η3-C3H5)2Cl2] and (R)-2,2-bis(diphenylphosphino)-1,1-binaphthyl [(R)-BINAP], asymmetric allylic amination using aqueous ammonia proceeds to give the corresponding allylamine in 71% yield with 87% ee (Scheme 1).[‌32‌] The effective chiral induction observed here suggests that no replacement of the bisphosphine ligand by ammonia occurs under these conditions. This is the first example of catalytic asymmetric synthesis using aqueous ammonia as a nitrogen source, although a somewhat large amount of chiral ligand is needed. Using 12mol% of BINAP, the reaction does not proceed at all, probably due to the same reason as discussed for Table 1, entry 12 above. An excess of ligand may play a role for stabilization of catalytically active palladium(0); indeed, by using triphenylphosphine as an additive, the amount of BINAP used can be decreased to an equimolar amount to palladium(0). The absolute configuration of the product amine was assigned to be R by transformation of the product into the literature-known tosylamine.[‌33‌] The sense of stereochemistry in the chiral induction is the same as that in the allylic substitution reaction catalyzed by palladium/BINAP complexes.[‌34‌,‌35‌]

Scheme 1 A Preliminary Investigation into Asymmetric Allylic Amination Using Aqueous Ammonia

Thus, palladium-catalyzed allylic amination using aqueous ammonia for the preparation of primary amines has been developed for the first time. It is noteworthy that the use of aqueous ammonia is essential, and that ammonia gas (without water) does not react at all. The first catalytic asymmetric synthesis using aqueous ammonia as a nitrogen source has also been demonstrated. Further investigations to clarify the role of water in the aqueous ammonia reactions are in progress.