Studies towards a greener diazo transfer methodology

Abstract

A very mild, efficient and green method has been developed for diazo transfer to a range of β-ketoesters using polystyrene-supported benzenesulfonyl azide, water as solvent and a catalytic amount of base. This methodology eliminates the need for a standard work up and purification which is usually required to remove the sulfonamide by-product from the reaction.

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1. Introduction

α-Diazocarbonyl compounds play a key role in organic synthesis due to their ease of preparation and the range of chemical transformations which they can undergo. Most of these transformations involve the initial loss of nitrogen which can be achieved under thermal, photochemical or catalytic conditions generating reactive intermediates such as carbenes, carbenoids and carbonyl ylides which can undergo a wide variety of chemical reactions. There are numerous reviews on these transformations in the literature,¹ and some of the main reactions of α-diazocarbonyl compounds include cyclopropanation, Wolff rearrangement,² α,α-substitution, C–H insertion,³ X–H insertion, ylide generation, dimerisation, aromatic addition,⁴ and dipolar cycloaddition.

There are a number of methods of synthesising α-diazocarbonyl compounds.⁵ While the synthesis of acyclic terminal diazo compounds is commonly achieved via the acylation of an ethereal solution of diazomethane with an acyl chloride to give the α-diazocarbonyl compound,⁶ the most widely used method for the introduction of the diazo group to activated systems is by the diazo transfer reaction developed by Regitz.⁷ This method allows not only the synthesis of cyclic α-diazocarbonyl compounds but also a route to acyclic systems not accessible by the acylation method. Diazo transfer is the process by which a complete diazo group is transferred from a donor to an acceptor. For α-diazocarbonyl products the acceptor is a carboxylic acid, ester or ketone and the diazo donor is generally a sulfonyl azide. Traditionally compounds with an activated methylene group such as β-keto esters, β-diketones β-keto phosphonates and β-keto sulfones are very reactive towards diazo transfer by reaction with tosyl azide in dry acetonitrile using triethylamine or potassium carbonate as a base.⁸ Recent work in our group has shown the successful synthesis of a range of stable, isolable bicyclic and monocyclic α-diazo-β-oxo sulfoxides by diazo transfer to the corresponding sulfinyl lactones, while acyclic systems remain elusive.⁹ For monoactivated carbonyl compounds other methods such as deformylation and debenzoylation have been used successfully.

Diazo transfer reagents have been reviewed, most notably a review of their utility, safety and stability carried out by Bollinger and co-workers.^10,11 The most commonly used diazo transfer reagent is tosyl azide¹² which is easily prepared using sodium azide and purified tosyl chloride.¹³ Tosyl azide is a dangerous transfer reagent and care must be taken when handling it.^10,11 It has a high impact sensitivity and a large heat of decomposition. A major disadvantage of using tosyl azide is that it is very difficult to separate the diazo product from the p-toluenesulfonamide by-product of the reaction. Interest in the development of safer alternatives has seen the development of a range of diazo transfer reagents with improved safety profiles, greater ease of handling, less hazardous and easier isolation of the diazo product. Bollinger and co-workers have extensively reviewed a number of diazo transfer reagents and have found that there are some good alternatives to using tosyl azide in diazo transfer reactions such as naphthalenesulfonyl azide,¹⁴ p-carboxybenzenesulfonyl azide¹⁵ and p-acetamidobenzenesulfonyl azide.^16,17 More recent studies use 2-azido-1,3-dimethylimidazolinium salts in the diazo transfer to 1,3-dicarbonyl compounds in high yields, with the optimised method being the addition of substrate and base in THF and/or acetonitrile and where the reagent is not sulfonyl azide-based, the by-products are highly soluble in water.¹⁸ Polystyrene-supported benzenesulfonyl azide has been used as an efficient and safe diazo transfer reagent, with the polystyrene-bound benzenesulfonamide by product easily removed by filtration.¹⁹ Goddard-Borger and co-workers²⁰ recently developed an inexpensive and shelf-stable alternative diazo transfer reagent in the form of the hydrochloride salt of imidazole-1-sulfonyl azide. This reagent has been shown to equal trifyl azide in its ability to act as a “diazo donor” in the conversion of both primary amines into azides and activated methylene substrates into diazo compounds although moderate yields are reported for the latter. Katritzky and co-workers²¹ report the synthesis of benzotriazol-1-yl-sulfonyl azides as a safe and stable reagent for the synthesis of a range of azides and diazo-compounds including N-(α-azidoacyl)-benzotriazoles. Organo-catalysed diazo transfer reactions in ionic liquids have also been studied with the advantage of green reaction media rather than organic solvents and it was reported that a catalytic quantity of amine base served to accelerate the reaction rate.²² A practical protocol for the large scale preparation of 2-diazo-1,3-dicarbonyl compounds has been described recently using tosyl azide as diazo transfer reagent followed by chromatographic purifications on silica gel and/or alumina.⁸ The use of nonafluorosulfonyl azide (NfN₃) as a diazo-transfer reagent has also been described.²³ Diazo transfer with this reagent is reported as fast and high yielding, and does not require chromatography in most cases, with the sulfonamide by-product efficiently removed by base extraction. NfN₃ has been recently shown to be a non-hazardous compound with a high shelf stability and low sensitivity to hydrolysis.²⁴

With this in mind, it was decided to revisit the synthesis and methodology used to generate α-diazo-β-ketoesters, because despite their versatility in organic synthesis and range of potential reaction pathways, diazo compounds are not widely used in large scale industrial processes. The key objectives of this study were to establish (1) if diazo transfer could be achieved in water as an alternative to organic solvents such as dichloromethane/acetonitrile; (2) if a sub-stoichiometric or catalytic amount of base would be sufficient to effect diazo transfer and (3) if we could use the much safer polymer bound azide in combination with (1) and (2) to overcome the problem of removal of the p-toluenesulfonamide side-product from the reaction, leading to a potentially attractive process for use in industry.

2. Results and discussion

Synthesis of β-ketoester precursors

At the outset of this study a variety of β-ketoester precursors were required, some of which were commercially available (1–3 and 7–8), while other non-commercially available and novel derivatives needed to be synthesised 4–6. While seemingly straightforward using standard Fischer esterification methodology, this did not prove to be the case for long side chain esters, or those that included other groups such as alkenes or carbonyls. A recent publication by Tale and co-workers²⁵ reports successful transesterification of a wide range of esters with various alcohols. The reaction is catalysed by 3-nitrobenzeneboronic acid, which is both an efficient and environmentally friendly catalyst. The scope of this reaction was utilised as an efficient method for the synthesis β-ketoesters 4–6, obtained in high purity or requiring straightforward isolation by chromatography (Table 1).

Table 1 Summary of β-ketoesters synthesised by transesterification

Entry	β-Keto ester	R	R^1	Yield (%)
1	4	Me	2-Ethylbutyl	95
2	5	Me	3,7-Dimethyloct-6-enyl	97
3	6	Me	Undec-10-en-1-yl	97

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Standard Regitz diazo transfer methodology

With a range of β-ketoesters in hand, authentic α-diazo-β-ketoesters samples were prepared using standard Regitz methodology for diazo transfer (Table 2). A review of the literature found a base work-up involving a 9% KOH wash, outlined by Regitz²⁶ to remove the p-toluenesulfonamide by-product. Interestingly, we found that a room temperature addition of the tosyl azide which allows for a slight exothermic reaction, facilitated a faster diazo transfer from the azide to the β-ketoester 1. This could be seen visually by a much more rapid appearance of a yellow coloured solution, which is characteristic of diazo transfer and led to the desired diazocarbonyl product 9 as a bright yellow oil in 95% yield after work-up (Table 2, entry 1). The ¹H NMR spectrum showed the crude product was pure with no p-toluenesulfonamide remaining and 9 could be used without any further purification. We were subsequently able to synthesise the range of α-diazo-β-ketoesters required in this research using this methodology Table 2. All the α-diazocarbonyl compounds were synthesised as bright yellow oils in excellent yields which were stable over prolonged periods of storage in the dark at room temperature. The only observed effect of increasing the alkyl side-chain length on the ketone moiety was that the yields of these compounds were slightly lower.

Table 2 Diazo transfer using tosyl azide, triethylamine in acetonitrile

Entry	β-Keto-ester	R	R^1	Diazo product	Yield (%)
1	1	Me	t-Butyl	9	95
2	2	Me	Et	10	90
3	3	Me	Pentyl	11	94
4	4	Me	2-Ethylbutyl	12	68
5	5	Me	3,7-Dimethyloct-6-enyl	13	90
6	6	Me	Undec-10-en-1-yl	14	88
7	7	n-Propyl	Et	15	81
8	8	n-Butyl	Me	16	72

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Enhanced diazo transfer

Two aspects to improving the diazo transfer were explored – the stoichiometry of base and the solvent used. Firstly, it was decided to investigate briefly base catalysed diazo transfer in acetonitrile. Two diazo transfer reactions were carried out with t-butyl acetoacetate 1, the first using 5 mol% triethylamine and the second using 5 mol% DMAP and both reactions gave 100% conversion to the desired diazo-product 9 with yields of 98% and 70% respectively. This was a very interesting result and allowed successful diazo transfer with a catalytic amount of base with no substantial reduction in yield. This is in contrast to the well-established protocols where it is accepted that at least one equivalent of base is required for these β-keto ester systems. This was the first step in the move towards a greener, more efficient synthesis of diazocarbonyl compounds and as was outlined by Anastas,²⁷ the use of catalytic reagents is much more attractive to stoichiometric reagents in this regard.

The next challenge was to see if the ultimate goal of using water as an alternative to organic solvents such as acetonitrile and dichloromethane for diazo transfer reactions could be achieved an extensive study was then undertaken for diazo transfer in H₂O using a catalytic amount of amine base. As can be seen below in Table 3 we now report successful diazo transfer reactions in water using 5 mol% base for all of our substrates.

Table 3 Diazo transfer using tosyl azide, 5 mol% base in H₂O^a

Entry	R	R^1	Diazo product	Time (h)	Et3N		DMAP
a Notes: % conversion calculated from ^1H NMR spectra of crude reaction mixtures; % yield reflects the yield of analytically pure samples that were obtained after column chromatography on silica gel, additional material collected was >90% pure.
1	Me	t-Butyl	9	20	% conversion	99	% conversion	95
					% yield after KOH wash	81	% yield after KOH wash	80
					% purity	90	% purity	87
					% yield	51	% yield	50
2	Me	Pentyl	11	20	% conversion	98	% conversion	98
					% yield after KOH wash	94	% yield after KOH wash	88
					% purity	95	% purity	89
					% yield	60	% yield	62
3	Me	2-Ethylbutyl	12	20	% conversion	100	% conversion	98
					% yield after KOH wash	73	% yield after KOH wash	86
					% purity	80	% purity	95
					% yield	50	% yield	58
4	Me	3,7-Dimethyloct-6-enyl	13	20	% conversion	93	% conversion	93
					% yield after KOH wash	82	% yield after KOH wash	79
					% purity	88	% purity	93
					% yield	52	% yield	54
5	Me	Undec-10-en-1-yl	14	20	% conversion	91	% conversion	91
					% yield after KOH wash	92	% yield after KOH wash	86
					% purity	73	% purity	91
					% yield	66	% yield	60
6	n-Propyl	Et	15	21	% conversion	84	% conversion	93
					% yield after KOH wash	89	% yield after KOH wash	88
					% purity	88	% purity	90
					% yield	61	% yield	64

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With regard to the reactions conducted in water, the 9% KOH wash removed most of the sulfonamide by-product but ¹H NMR analysis of the crude reaction material showed some residual sulfonamide (>88% purity diazo product in most cases). Analytically pure samples of the diazo compounds from the water reactions could be easily obtained using flash chromatography.

The initial diazo transfer reaction was carried out on β-ketoester 1 at room temperature for 20 h to give 99% conversion to 9 using 5 mol% DMAP as base catalyst. Successful diazo transfer with excellent conversions to the desired products was achieved to a range of β-ketoester derivatives as shown in Table 3.

Overall these were very promising results which indicated that diazo transfer can be achieved in the presence of a catalytic amount of base (5 mol% triethylamine or DMAP) instead of one equivalent. The reaction can also be carried out in the most environmentally friendly solvent, water, which avoids the use of chlorinated solvents or acetonitrile with no substantial decrease in conversion to diazo product. In addition the safety improvement is enormous – using non-flammable water as the reaction solvent is very attractive from an industrial large scale viewpoint. The one aspect that we looked to improve upon was the removal of the sulfonamide by-product as the yields of analytically pure material was compromised. The % conversions from starting material to product listed in Table 3 using a catalytic amount of base and water only as solvent are excellent and very comparable to conversions obtained in Table 2 and also traditional published diazo transfer to these ketoester systems using 1 or more equivalents of base and organic solvents such as dichloromethane or acetonitrile. Indeed, the chemistry and methodology described here is currently being used in ongoing research in the group for developing telescoped diazo processes without the need for isolation of the diazo products. The excellent conversions outlined in this paper for the process are a good indication for the success of this work. In addition, aspects of this work involving diazo transfer in water has been used concurrently with the development of a scalable continuous diazo transfer process using flow chemistry.²⁸

Use of immobilised diazo transfer reagent in H₂O

Having reduced the amount of base required for the reaction from 1 equivalent to 5 mol% and demonstrated the diazo transfer reaction can be conducted successfully in water, the next aim in the move towards greener diazo transfer methodology was to investigate the use of a safer azide. Recently, safer alternatives have been developed as discussed in the introduction; of these we were particularly interested in the polystyrene-supported benzenesulfonyl azide,¹⁹ as the impact sensitivity of the polymer bound azide is substantially reduced when compared to other sulfonyl azides such as tosyl azide. In addition, the use of polymer bound azide would also allow immediate and facile removal of the sulfonamide by-product from the diazo transfer reaction mixture with no requirement for chromatographic purification that could compromise the yields of analytically pure material.

Polystyrene-supported benzenesulfonyl azide was prepared from polystyrene benzenesulfonyl chloride (100–200 mesh with a loading of 1.5–2.0 mmol per gram) following the literature procedure as outlined by Green.¹⁹ Successful diazo transfer was achieved to the β-ketoesters 1 and 2 using freshly prepared resin, in acetonitrile as a comparison reaction giving diazo products 9 and 10 in 97% and 71% yield respectively. The p-toluenesulfonamide is supported on the resin and can be removed by filtration thus negating the need for a base work-up or purification by chromatography which is also especially valuable for labile diazocarbonyl compounds.

The next step in this study was to attempt diazo transfer with the polymer-supported azide in water. Diazo transfer was initially carried out using the same reaction procedure as described above replacing the acetonitrile with water. We are pleased to report, diazo transfer to 1 was achieved with 100% conversion to the desired product 9 in 62% isolated yield (Table 4, entry 1). The resin was re-stirred in ether for a further 2 h to ensure full recovery of diazo product, after filtration, drying and concentration to a pale yellow oil. Using this modified reaction procedure successful diazo transfer was achieved to a range of β-ketoesters as summarised in Table 4.

Table 4 Diazo transfer using polymer-supported benzenesulfonyl azide, 3 equiv. Et₃N in H₂O

Entry	β-Keto ester	R	R^1	Diazo product	Conversion (%)	Yield (%)
1	1	Me	t-Butyl	9	100	62
2	3	Me	Pentyl	11	100	71
3	4	Me	2-Ethylbutyl	12	100	72
4	5	Me	3,7-Dimethyloct-6-enyl	13	100	80
5	6	Me	Undec-10-en-1-yl	14	88	70
6	7	n-Propyl	Et	15	100	74

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The long lipophilic chain of 6 seemed to affect conversion to the desired diazocarbonyl 14 as shown in entry 5. All the other reactions had 100% conversion to the desired diazocarbonyl products.

A key goal in this investigation was to see if a base-catalysed diazo transfer using the polystyrene-supported benzenesulfonyl azide in water could be achieved. Initial reactions were attempted using 5 mol% Et₃N and 5 mol% DMAP with the polymer-bound azide in H₂O, however the conversion to the diazocarbonyl products was poor. Screening reactions were carried out using base loadings of 0.18, 0.20 and 0.25 equivalents of triethylamine and it was subsequently found that 25 mol% of base was the optimum base loading required to furnish the best conversions to diazo product. These results are summarised in Table 5. Similar problems arose as described above with the longer side-chained β-ketoesters (entries 4 and 5) and this is attributed to the long lipophilic side-chain possibly reducing the solubility in water. The use of 25 mol% Et₃N for these diazo transfer reactions is a substantial reduction from three equivalents used for these reactions up until this point. In addition, for applications of this described methodology, % conversion is critical for this research going forward in developing a telescoped diazo process with in situ diazo transfer (monitored by NMR and IR analysis).

Table 5 Diazo transfer using polymer-supported benzenesulfonyl azide, 0.25 equiv. Et₃N in H₂O

Entry	R	R^1	Diazo product	Conversion (%)
1	Me	t-Butyl	9	94
2	Me	Pentyl	11	97
3	Me	2-Ethylbutyl	12	94
4	Me	3,7-Dimethyloct-6-enyl	13	65
5	Me	Undec-10-en-1-yl	14	69
6	n-Propyl	Et	15	91

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3. Conclusions

Overall, we have shown that diazo transfer can be achieved to a range of β-keto esters using safer polymer-supported azide, and with just a catalytic amount of base in water thus moving towards a green, environmentally friendly method for this transformation. This is an improvement over the traditional methods of diazo transfer to these systems which routinely use tosyl azide, 1–2 equivalents of base and organic solvents such as dichloromethane or acetonitrile. The attractiveness of this method also lies in the use of a safer diazo transfer reagent, non-flammable solvent and simplified workup by filtration of resin bound sulfonamide by-product. All these features make this methodology potentially attractive for use in industry routes in the future.

4. Experimental

General experimental procedures

All chemicals were purchased from commercial vendors and used without further purification. ¹H (400 MHz) and ¹³C (100 MHz) spectra were recorded on a Bruker Avance 400 NMR spectrometer. All spectra were recorded at 20 °C in deuterated chloroform (CDCl₃) unless otherwise stated, using tetramethylsilane (TMS) as internal standard. ¹³C NMR spectra were assigned with the aid of DEPT experiments.

General procedure for transesterification using 3-nitrobenzeneboronic acid catalyst

Note: β-keto esters 4–6 can also exist in enol form and it can be seen from the ¹H NMR and ¹³C NMR spectra that there is up to 10% enol form present. Characteristic signals for the enol form are present at 5 ppm in the ¹H NMR spectrum and at 22, 63, 90, 173 and 176 ppm in the ¹³C NMR spectrum for these samples.

3,7-Dimethyloct-6-enyl 3-oxobutanoate 5²⁹. Citronellol (2.39 g, 15.38 mmol, 1 equiv.) was added to a stirring solution of ethyl acetoacetate (2.00 g, 15.38 mmol, 1 equiv.) in toluene (40 mL). 3-Nitrobenzeneboranic acid (63.82 mg, 0.31 mmol, 2.5 mol%) was added as catalyst. The reaction was heated under reflux (150 °C) with the removal of the toluene–ethanol azetrope using Dean–Stark distillation. The reaction was monitored by TLC analysis and after 5 h there was no evidence of any ethyl acetoacetate starting material. The reaction was cooled and the solvent removed under reduced pressure to give 3,7-dimethyloct-6-enyl 3-oxobutanoate 5 as a yellow oil (3.58 g, 97%), which was used without further purification. δ_H (400 MHz, CDCl₃)/ppm: 0.91 (3H, d, J 6.3, CHCH₃), 1.12–1.24 (1H, m, CH), 1.24–1.41 (2H, m, CH₂), 1.42–1.56 (2H, m, CH₂), 1.61 (3H, s, CH₃), 1.68 (3H, s, CH₃), 1.88–2.04 (2H, m, OCH₂CH₂), 2.26 [3H, s, C(O)CH₃], 3.43 [2H, s, C(O)CH₂C(O)], 4.11–4.24 (2H, m, OCH₂), 5.03 [1H, t, J 6.9, CH=C(CH₃)₂,]; δ_C (75.5 MHz, CDCl₃): 17.6 (CH₃), 19.5 (CH₃), 25.3 (CH₂), 25.4 (CH₃), 29.1 (CH₃), 29.4 (CH), 35.3 (CH₂), 36.9 (CH₂), 50.1 [C(O)CH₂C(O)], 62.4 (OCH₂), 124.7 (CH) alkene, 131.9 (C_q) alkene, 167.1 (C=O) ester, 200.9 (C=O) ketone. ν_max (film)/cm⁻¹ 2963, 2925, 1743, 1720, 1649. Found (HRMS, ESI): [M + H]⁺, m/z 241.1814. C₁₄H₂₅O₃ requires [M + H]⁺ 241.1804.

Characterisation data for β-ketoesters

Undec-10-en-1-yl 3-oxobutanoate 6³⁰. From ester 2 (2.00 g, 15.38 mmol); clear oil (3.78 g, 97%); δ_H (300 MHz, CDCl₃)/ppm: 1.24–1.42 (12H, m, 6 × CH₂), 1.59–1.68 (2H, m, CH₂), 2.01–2.07 (2H, m, CH₂), 2.26 [3H, s, C(O)CH₃], 3.45 [2H, s, C(O)CH₂C(O)], 4.13 (2H, t, J 6.7, OCH₂), 4.90–5.02 (2H, m, CH=CH₂), 5.74–5.87 (1H, m, CH=CH₂); δ_C (75.5 MHz, CDCl₃): 25.7 (CH₂), 28.4 (CH₂), 28.8 (CH₂), 29.0 (CH₂), 29.1 (CH₂), 29.3 (CH₂), 29.4 (CH₂), 30.0 (CH₃), 33.8 (CH₂), 50.1 [C(O)CH₂C(O)], 65.5 (OCH₂), 114.1 (CH₂) alkene, 139.1 (CH) alkene, 175.3 (C=O) ester, 200.6 (C=O) ketone; ν_max (film)/cm⁻¹ 2855, 1744, 1720. Found (HRMS, ESI): [M + H]⁺, m/z 255.1963. C₁₅H₂₇O₃ requires [M + H]⁺ 255.1960.

2-Ethylbutyl 3-oxobutanoate 4³¹. From ester 2 (2.00 g, 15.38 mmol); clear oil (2.68 g, 94%); δ_H (300 MHz, CDCl₃)/ppm: 0.89 (6H, t, J 7.5, 2 × CH₃), 1.31–1.41 (4H, m, 2 × CH₂CH₃), 1.47–1.60 (1H, m, CH), 2.27 [3H, s, C(O)CH₃], 3.47 [2H, s, C(O)CH₂C(O)], 4.07 (2H, d, J 6.1, OCH₂); δ_C (75.5 MHz, CDCl₃): 10.8 (2 × CH₃), 22.8 (2 × CH₂), 30.0 (CH₃), 40.2 (CH), 50.2 [C(O)CH₂C(O)], 67.5 (OCH₂), 167.2 (C=O) ester, 200.5 (C=O) ketone; ν_max (film)/cm⁻¹ 2964, 2935, 1744, 1720. Found (HRMS, ESI): M⁺, m/z 186.1301. C₁₀H₁₈O₃ requires M⁺ 186.1256.

General procedure for diazo transfer using tosyl azide, triethylamine in acetonitrile

t-Butyl 2-diazo-3-oxobutanoate 9²⁶. Triethylamine (1.82 mL, 12.64 mmol) was added to a stirring solution of t-butyl acetoacetate 1 (2.00 g, 12.64 mmol) in acetonitrile (25 mL). After 2 min a solution of p-toluenesulfonyl azide (2.51 g, 12.64 mmol) in acetonitrile (25 mL) was added dropwise, at room temperature, over 15 min to give a bright yellow solution. The reaction was stirred overnight under an inert nitrogen atmosphere. After 18 h TLC analysis showed no evidence of any ester starting material present and the reaction mixture was concentrated under reduced pressure. The resulting cream crystals were dissolved in ether (40 mL) and washed with 9% KOH (2 × 50 mL) followed by water (1 × 50 mL). The organic layer was dried (MgSO₄) and concentrated under reduced pressure to give t-butyl 2-diazo-3-oxobutanoate 9 (2.21 g, 95%) as a yellow oil, which was used without further purification. δ_H (400 MHz, CDCl₃)/ppm: 1.55 (9H, s, 3 × CH₃ of t-butyl), 2.51 [3H, s, C(O)CH₃]; δ_C (CDCl₃, 75.5 MHz): 27.9 (CH₃), 28.2 (CH₃ × 3 of t-butyl), 51.5 (C=N₂), 83.1 (C_q), 160.2 (C=O) ester, 190.6 (C=O) ketone; ν_max (film)/cm⁻¹ 2982, 2134, 1715, 1660. Found (HRMS, ESI): [M + H]⁺, m/z 185.0927; C₈H₁₃O₃N₂ requires [M + H]⁺ 185.0926.

Characterisation data for α-diazo-β-ketoesters

Ethyl 2-diazo-3-oxobutanoate 10³². From ester 2 (2.01 g, 15.41 mmol); yellow oil (2.16 g, 90%); δ_H (300 MHz, CDCl₃)/ppm: 1.33 (3H, t, J 7.2, OCH₂CH₃), 2.51 [3H, s, C(O)CH₃], 4.32 (2H, q, J 7.2, OCH₂CH₃); δ_C (75.5 MHz, CDCl₃)/ppm: 14.3 (CH₃), 28.2 (CH₃), 62.4 (OCH₂), 161.4 (C=O) ester, 190.3 (C=O) ketone, no signal observed for (C=N₂); ν_max (film)/cm⁻¹ 2985, 2140, 1720, 1661. Found (HRMS, ESI): [M + H]⁺, m/z 157.0607. C₆H₉O₃N₂ requires [M + H]⁺ 157.0613.

Pentyl 2-diazo-3-oxobutanoate 11. From ester 3 (2.00 g, 11.61 mmol); yellow oil (2.15 g, 94%); δ_H (300 MHz, CDCl₃)/ppm: 0.92 (3H, t, J 6.9, CH₂CH₃), 1.31–1.39 (4H, m, 2 × CH₂), 1.65–1.74 (2H, m, CH₂), 2.51 [3H, s, C(O)CH₃], 4.24 (2H, t, J 6.9, OCH₂CH₂); δ_C (75.5 MHz, CDCl₃)/ppm: 13.9 (CH₃), 22.2, 27.9, 28.3 (CH₂ × 3), 28.3 (CH₃), 65.5 (OCH₂), 161.5 (C=O) ester, 190.3 (C=O) ketone, no signal observed for (C=N₂); ν_max (film)/cm⁻¹ 2934, 2141, 1718, 1661. Found (HRMS, ESI): [M + H]⁺, m/z 199.1083. C₉H₁₅O₃N₂ requires [M + H]⁺ 199.1083.

2-Ethylbutyl 2-diazo-3-oxobutanoate 12. From ester 4 (2.01 g, 10.79 mmol); yellow oil (1.54 g, 68%), which was used without further purification. δ_H (300 MHz, CDCl₃)/ppm: 0.92 (6H, t, J 7.5, 2 × CH₃), 1.34–1.43 (4H, m, 2 × CH₂), 1.51–1.64 (1H, m, CH), 2.48 [3H, s, C(O)CH₃], 4.19 (2H, d, J 6.1, OCH₂); δ_C (75.5 MHz, CDCl₃)/ppm: 10.7 (2 × CH₃), 22.8 (2 × CH₂), 28.1 (CH₃), 40.3 (CH), 61.3 (C=N₂), 67.2 (OCH₂), 171.0 (C=O), 190.0 (C=O); ν_max (film)/cm⁻¹ 2965, 2934, 2140, 1720, 1662. Found (HRMS, ESI): [M + H]⁺, m/z 213.1238. C₁₀H₁₇O₃N₂ requires [M + H]⁺ 213.1239.

3,7-Dimethyloct-6-enyl 2-diazo-3-oxobutanoate 13. From ester 5 (2.01 g, 8.37 mmol); yellow oil (2.02 g, 90%); δ_H (300 MHz, CDCl₃)/ppm: 0.93 (3H, d, J 6.3, CHCH₃), 1.14–1.26 (1H, m, CH₂CH), 1.30–1.42 (2H, m, CH₂), 1.44–1.57 (2H, m, CH₂), 1.61 (3H, s, CH₃), 1.68 (3H, s, CH₃), 1.89–2.08 (2H, m, CH₂), 2.47 [3H, s, C(O)CH₃], 4.02–4.34 (2H, m, OCH₂), 5.07 [1H, t, J 6.9, CH=C(CH₃)₂]; δ_C (75.5 MHz, CDCl₃): 17.6 (CH₃), 19.5 (CH₃), 25.3 (CH₂), 25.7 (CH₃), 28.2 (CH₃), 29.2 (CH), 30.9 (CH₂), 36.9 (CH₂), 50.2 (C=N₂), 63.9 (OCH₂), 124.3 (CH) alkene, 131.5 (C_q) alkene, 161.5 (C=O) ester, 190.2 (C=O) ketone; ν_max (film)/cm⁻¹ 2964, 2925, 2138, 1719, 1662. Found (HRMS, ESI): [M + H]⁺, m/z 267.1719. C₁₄H₂₃O₃N₂ requires [M + H]⁺ 267.1709.

Undec-10-en-1-yl 2-diazo-3-oxobutanoate 14. From ester 6 (2.01 g, 7.87 mmol); yellow oil (1.94 g, 88%); δ_H (300 MHz, CDCl₃)/ppm: 1.22–1.43 (12H, m, 6 × CH₂), 1.64–1.75 (2H, m, CH₂), 1.99–2.09 (2H, m, CH₂), 2.47 [3H, s, C(O)CH₃], 4.23 (2H, t, J 6.6, OCH₂), 4.90–5.01 (2H, m, CH=CH₂), 5.74–5.87 (1H, m, CH=CH₂); δ_C (75.5 MHz, CDCl₃): 25.7 (CH₂), 28.2 (CH₃), 28.6 (CH₂), 28.8 (CH₂), 29.0 (CH₂), 29.1 (CH₂), 29.32 (CH₂), 29.37 (CH₂), 33.7 (CH₂), 50.0 (C=N₂), 65.5 (OCH₂), 114.1 (CH₂) alkene, 139.0 (CH) alkene, 161.4 (C=O) ester, 190.6 (C=O) ketone; ν_max (film)/cm⁻¹ 2927, 2855, 2139, 1720, 1662. Found (HRMS, ESI): [M + H]⁺, m/z 281.1855. C₁₅H₂₅O₃N₂ requires [M + H]⁺ 281.1865.

Ethyl 2-diazo-3-oxohexanoate 15³³. From ester 7 (2.01 g, 12.66 mmol); yellow oil (1.88 g, 81%); δ_H (300 MHz, CDCl₃)/ppm: 0.96 (3H, t, J 7.5, CH₃), 1.34 (3H, t, J 7.2, OCH₂CH₃), 1.62–1.71 [2H, m, C(O)CH₂CH₂], 2.83 [2H, t, J 7.2, C(O)CH₂CH₂], 4.31 (2H, q, J 7.2, OCH₂CH₃); δ_C (75.5 MHz, CDCl₃): 11.9 (CH₃), 12.5 (CH₃), 16.0 (CH₂), 40.7 [C(O)CH₂], 59.5 (OCH₂), 64.0 (C=N₂), 159.6 (C=O) ester, 191.1 (C=O) ketone; ν_max (film)/cm⁻¹ 2966, 2134, 1717, 1658. Found (HRMS, ESI): [M + H]⁺, m/z 185.0918. C₈H₁₃O₃N₂ requires [M + H]⁺ 185.0926.

Methyl 2-diazo-3-oxoheptanoate 16³⁴. From ester 8 (1.04 g, 6.32 mmol); yellow oil (0.84 g, 72%); δ_H (300 MHz, CDCl₃)/ppm: 0.93 (3H, t, J 7.2, CH₂CH₃), 1.33–1.42 (2H, m, CH₂), 1.58–1.65 (2H, m, CH₂), 2.85 [2H, t, J 7.6, C(O)CH₂], 3.84 (3H, s, OCH₃); δ_C (75.5 MHz, CDCl₃): 13.8 (CH₃), 22.3 (CH₂), 26.4 (CH₂), 39.9 [C(O)CH₂], 52.1 (OCH₃), 75.6 (C=N₂), 161.8 (C=O) ester, 192.9 (C=O) ketone; ν_max (film)/cm⁻¹ 2343, 2136, 1724, 1659. Found (HRMS, ESI): M⁺, m/z 184.0982. C₈H₁₂O₃N₂ requires M⁺ 184.0848.

General procedure for diazo transfer using tosyl azide, 5 mol% base in H₂O

t-Butyl 2-diazo-3-oxobutanoate 9. p-Toluenesulfonyl azide (0.098 g, 0.5 mmol, 1 equiv.) was added to a stirring solution of t-butyl acetoacetate (0.080 g, 0.5 mmol, 1 equiv.) and DMAP (3 mg, 25.0 μmol, 5 mol%) in water (1.5 mL). The reaction was stirred under an inert nitrogen atmosphere at room temperature for 20 h until TLC showed no further evidence of starting material. Evidence for successful diazo transfer could be seen from the presence of the white sulfonamide side product in the reaction mixture. The crude reaction mixture was extracted into ethyl acetate (3 × 15 mL) and washed 9% KOH (2 × 30 mL), H₂O (30 mL), dried (MgSO₄) and concentrated to a yellow oil (0.198 g, 80%). Spectral details are consistent with those reported above. 9% KOH wash did not remove all of the sulfonamide by-product from the reactions done in water. Analytically pure samples could be obtained in this case by flash chromatography using ethyl acetate/hexane 30 : 70 as eluent.

Synthesis of polystyrene-supported benzenesulfonyl azide¹⁹

Polystyrene-supported benzenesulfonyl chloride (1.0 g, loading 1.5–2.0 mmol g⁻¹) was ‘swollen’ by stirring in DMF (5 mL) for 5 min. Sodium azide (0.195 g, 3 mmol) was dissolved in H₂O (1 mL), diluted with DMF (7 mL) and added dropwise to produce an orange coloured solution. The reaction was stirred overnight at room temperature. The polystyrene-supported azide product was isolated by gravity filtration using a Hirsch funnel and washed with H₂O (5 × 5 mL), DMF (5 × 5 mL) and DCM (5 × 5 mL). The polymer-bound azide resin was spread on a clock-glass to dry. The product was weighed and stored in a sample vial in the fridge.

General procedure for diazo transfer using polystyrene-supported benzenesulfonyl azide, Et₃N (3 equiv.) in H₂O

t-Butyl 2-diazo-3-oxobutanoate 9. Polystyrene-bound benzenesulfonyl azide (500 mg, 0.75 mmol) was placed in a 15 mL round bottomed flask with 1.5 mL H₂O and stirred at room temperature for 5 min. A mixture of the ester, t-butyl acetoacetate (79 mg, 0.5 mmol) and triethylamine (0.22 mL, 1.5 mmol) in 1.5 mL H₂O was added dropwise. The reaction was stirred at room temperature for 16 h. The resin was removed by gravity filtration and the organic layer was extracted into ether (15 mL). The resin was re-stirred in ether (5.0 mL) for 2 h at room temperature. The resin was isolated by filtration and both ethereal layers were combined, dried (MgSO₄) and concentrated under reduced pressure to give t-butyl 2-diazo-3-oxobutanoate 9 as a yellow oil (56 mg, 62%). Spectral details are consistent with those reported above.

General procedure for diazo transfer using polystyrene-supported benzenesulfonyl azide, Et₃N (0.25 equiv.) in H₂O

t-Butyl 2-diazo-3-oxobutanoate 9. Polystyrene-bound benzenesulfonyl azide (500 mg, 0.75 mmol) was placed in a 15 mL round bottomed flask with 1.5 mL H₂O and stirred at room temperature for 5 min. A mixture of the ester, t-butyl acetoacetate (79 mg, 0.5 mmol) and triethylamine (0.017 mL, 0.125 mmol, 0.25 eq.) in 1.5 mL H₂O was added dropwise. The reaction was stirred at room temperature for 16 h. The resin was removed by gravity filtration and the organic layer was extracted into ether (15 mL). The resin was re-stirred in ether (5.0 mL) for 2 h at room temperature. The resin was isolated by filtration and both ethereal layers were combined, dried (MgSO₄) and concentrated under reduced pressure to give t-butyl 2-diazo-3-oxobutanoate 9 as a yellow oil. Spectral details are consistent with those reported above.

Acknowledgements

This work was supported by IRCSET Enterprise Partnership Scheme with GSK (Elaine Tarrant and Claire O'Brien), and Synthesis and Solid State Pharmaceutical Centre/SFI (Stuart Collins).

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for esters and diazocarbonyl products. See DOI: 10.1039/c6ra03678c

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