An unprecedented approach to the Gabriel amine synthesis utilizing tosylhydrazones as alkylating agents

Abstract

A new and one-pot version of the Gabriel phthalimide amine synthesis utilizing carbonyl compounds as alkylating agents via their tosylhydrazone surrogates is disclosed. The alkylation involves copper catalysed carbene insertion into the N–H bond of phthalimide. Basically, the protocol also offers a powerful tool for deoxygenative hydroamination of carbonyl compounds.

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Amines constitute a prominent class of compounds found in a wide variety of natural products, pharmaceuticals, agrochemicals and organic materials.¹ Particularly, primary amines are very important precursors of most prevalent biologically relevant structural moieties.² The Gabriel phthalimide amine synthesis is a historically important, straightforward and robust tool for chemists to target the synthesis of structurally diverse primary amines uncontaminated by secondary or tertiary amine by-products.³

The Gabriel amine synthesis involves two main steps: (i) the preparation of N-substituted phthalimides, and (ii) hydrolysis or hydrazinolysis of N-substituted phthalimides to afford primary amines (Scheme 1(a)).⁴ Several improvements in the Gabriel synthesis have been suggested so far, but most of them involve conversion of phthalimide into primary amines starting from alkyl or aryl halides.^5a Additionally, tosylates, epoxides and esters have also been used in place of alkyl halides.^5b However, all of these are based on the same mechanistic theme, i.e. the N-alkylation of phthalimide involving displacement reactions. Thus, we were intrigued to develop a new approach to access N-alkylphthalimides followed by their hydrazinolysis to afford primary amines in a one-pot operation (Scheme 1(b)).

Scheme 1 (a) The Gabriel amine synthesis, and (b) its modification.

Inspired by the utilization of N-tosylhydrazones as efficient carbonyl surrogates in synthetically useful transformations via carbene insertion into various bonds, viz. C–H,^6a,q,s,z O–H,^6v S–H,^6u N–H,^6k,t P–H^6n,p and H–F,^6l we hypothesised that phthalimide could be alkylated by carbene insertion into its N–H bond. Interestingly, the reaction worked well to offer a valuable modification of the Gabriel synthesis. Notably, this is the first report on N-tosylhydrazone generated carbene insertion into the N–H bond of an imide. Furthermore, this method is a superior alternative to the synthesis of primary amines by reductive amination of carbonyl compounds⁷ because it advantageously avoids the over-alkylation of primary amines formed and does not use any other reducing agent making the protocol cost-effective and operationally simple. This new way of access to N-alkylphthalimides is very important owing to their great synthetic potential and pharmaceutical applications as anticonvulsant, anti-inflammatory, analgesic, hypolipidimic and immunodulatory.⁸ Fascinated by the above points and in continuation of our recent research focused on strategic synthetic transformations involving carbonyl functionality,^9,6l we conducted the detailed study presented herein.

To start with, acetophenone (1a) derived N-tosylhydrazone (1a′) was chosen as a model alkylting agent for phthalimide in refluxing solvents under basic condition, and optimized results are compiled in Tables 1 and 2. The key reaction was performed with phthalimide (1.0 mmol), 1a′ (1.0 mmol), K₂CO₃ (3 equiv.) in dioxane at 110 °C to explore transition metal-free access to N-alkylphthalimides, but unfortunately, it did not produce 2a (Table 1, entry 1). The isolated compound was a mixture of cis and trans-2,3-diphenyl-2-butenes in 67% yield, which might be formed by dimerisation of the carbene (PhMeC) generated in situ. Then, we turned our attention to copper catalysed cross coupling reaction of N-tosylhydrazone 1a′ with phthalimide. Thus, a catalytic amount of CuI (10 mol%) was used. To our delight, this worked well and afforded the desired product 2a in 96% yields (Table 1, entry 3). Then, the optimisation of catalyst and catalytic loading was performed, which demonstrated that CuI was the most effective catalyst in comparison to CuCl, CuBr, Cu₂O and Cu(OAc)₂ (Table 1, entry 3 versus 7–10). The effective catalytic amount without affecting yield and time was 10 mol%, because on decrease in amount from 10 mol% to 5 mol% decreased the yield (Table 1, entry 3 versus 5). The yield was not affected on increasing the catalyst loading from 10 mol% to 15 mol% (Table 1, entry 3 versus 6). On decreasing the reaction temperature from 110 °C to 80 °C the yield was considerably decreased (Table 1, entry 4). It is noteworthy that the desired product 2a could not be obtained, when potassium phthalimide was used instead of phthalimide (Table 1, entry 2).

Table 1 Optimisation of reaction conditions^a

Entry	Catalyst (mol%)	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: phthalimide (1.0 mmol), 1a′ (1.0 mmol), catalyst (5–15 mol%), Cs2CO3 (3 equiv.), dioxane (4 mL) under N2 for each entry (for Experimental procedure: see, ESI).b Isolated yield of product 2a.c Reaction was carried out with potassium phthalimide.
1	—	110	2	Trace
2	CuI (10)	110	2	Trace^c
3	CuI (10)	110	2	96
4	CuI (10)	80	4	76
5	CuI (5)	110	2	72
6	CuI (15)	110	2	96
7	CuBr (10)	110	3	82
8	CuCl (10)	110	3	77
9	Cu2O (10)	110	4	67
10	Cu(OAc)2 (10)	110	4	59

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Table 2 Optimisation of base and solvent^a

Entry	Base (equiv.)	Solvent	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: phthalimide (1.0 mmol), 1a′ (1.0 mmol), CuI (10 mol%), base (2–4 equiv.), solvent (4 mL) under N2 for each entry (for Experimental procedure: see, ESI).b Isolated yield of product 2a.
1	K2CO3 (3)	Dioxane	110	2	86
2	Cs2CO3 (3)	Dioxane	110	2	96
3	Na2CO3 (3)	Dioxane	110	2	72
4	KOH (3)	Dioxane	110	2	68
5	^tBuOK (3)	Dioxane	110	3	79
6	Cs2CO3 (3)	Toluene	Reflux	3	76
7	Cs2CO3 (3)	CH3CN	Reflux	4	57
8	Cs2CO3 (3)	THF	Reflux	4	67
9	Cs2CO3 (2)	Dioxane	110	2	74
10	Cs2CO3 (4)	Dioxane	110	2	96

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Next, we examined the influence of bases and solvents on the reaction and Cs₂CO₃ was found to be the most effective among the screened bases K₂CO₃, Na₂CO₃, KOH and ^tBuOK (Table 2, entry 2 versus 1, 3–5) and dioxane as the best medium among the tested solvents viz. toluene, CH₃CN and THF (Table 2, entry 2 versus 6–9).

The usual hydrazinolysis of N-(1-phenylethyl)phthalimide 2a with hydrazine hydrate afforded the corresponding primary amine 3a in 94% yield. Prompted by the easy preparation of N-tosylhydrazones by the reaction of N-tosylhydrazides with carbonyl compounds and mild hydrazinolysis of N-alkylphthalimides to alkyl amines using H₂NNH₂·H₂O,¹⁰ we executed the Gabriel synthesis starting directly from carbonyl compounds in a sequential one-pot procedure as depicted in Scheme 2. To our pleasant surprise, it worked well and afforded the desired primary amine 3a in 92% yield (Scheme 2) without the isolation of tosylhydrazone 1a′ and N-(1-phenylethyl)phthalimide 2a.

Scheme 2 One-pot deoxygenative hydroamination of acetophenone.

The generality of this one-pot protocol was demonstrated across a wide range of aldehydes and ketones, including aromatic, hetrocyclic and aliphatic, which were converted into the corresponding primary amines in good to excellent yields (70–94%) and high purity (Table 3). A variety of substituents such as Me, MeO, Me₂N, F, Cl, Br and NO₂ were tolerated. In general, the substrate bearing an electron-withdrawing group required longer reaction time and afforded lower yields of primary amines as compared to those bearing an electron-donating group (Table 3). Also, the reaction worked well on a gram-scale (Table 3, foot note e).

Table 3 Substrate scope in the one-pot Gabriel synthesis^a

a For the Experimental procedure: see, ESI.b Isolated yield of product 3.c All the products are commercially available were well characterized by authentic sample (see, ESI).d Total time required for the conversion of 1 into 3.e Reaction also works well on a gram scale with 1a (1.20 g, 10 mmol), TsNHNH₂ (1.86 g, 10 mmol), phthalimide (1.47 g, 10 mmol), CuI (10 mol%), Cs₂CO₃ (9.75 g, 3 equiv.), dioxane (35 mL) at 110 °C for 2 h under N₂. After the completion of the reaction (as monitor by TLC), H₂NNH₂·H₂O (80%, 15 mmol) was added and the mixture was stirred at same temperature for 1.5 h. The analytically pure product 3a was isolated in 94% yield (1.14 g) after column chromatography (for detail, see ESI).

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On the basis of the experimental results and the literature reports,⁶ a plausible mechanism for the N-alkylation of phthalimide using N-tosylhydrazones 1′ is depicted in Scheme 3. Thermolysis of N-tosylhydrazones 1′ under basic conditions generates carbene, which in situ forms a carbene copper complex A. Finally, insertion of the carbene in to the N–H bond of phthalimide affords the desired N-alkyl phthalimide 2 through transition state B.

Scheme 3 Plausible mechanistic pathway for insertion of carbene into the N–H bond of phthalimide.

In conclusion, we have demonstrated a significant modification of the Gabriel amine synthesis. The protocol involves copper catalysed reductive coupling of tosylhydrazones with phthalimide followed by hydrazinolysis to afford primary amines in a one-pot operation. Furthermore, the reaction could be carried out in one-pot fashion starting directly from carbonyl compounds without the isolation of their tosylhydrazones. Basically, this method also offers a superior alternative to the reductive amination of carbonyl compounds because it avoids the over-alkylation of primary amines formed and does not require any additional reducing agent.

Acknowledgements

We sincerely thank the SAIF, Punjab University, Chandigarh, for providing spectra. One of us (AKY) is greatful to the CSIR, New Delhi, for award of a Senior Research Fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: For experimental details and characterisation of all compounds. See DOI: 10.1039/c4ra05929h

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