A Concise, Catalyst-Free Synthesis of Davis’ Oxaziridines using Sodium Hypochlorite

Key words

oxaziridine - Davis’ oxaziridine - sodium hypochlorite - sodium hypochlorite pentahydrate - N-sulfonylimine - oxidation

Oxaziridines contain a strained three-membered ring consisting of a carbon, nitrogen, and oxygen atom. They are interesting reagents in organic synthetic chemistry because they can be used both as oxidizing and electrophilic amination reagents.[1] Of the oxaziridines, N-sulfonyloxaziridines are the most extensively utilized in organic synthesis because of their stability. In the 1980s, Davis and co-workers developed the chemistry of N-sulfonyloxaziridines extensively, thus such compounds are commonly referred to as ‘Davis’ oxaziridines’.[2] They are generally prepared through oxidation of the corresponding imine, and several oxidants (m-chloroperbenzoic acid,[2a] ^, [3`] [b] [c] [d] Oxone™,[2b] hydrogen peroxide or cumene hydroperoxide (CHP)<sup>3h</sup> with a catalyst[3`] [f] [g]) have been used for this purpose (Scheme [1]).

Scheme 1

Sodium hypochlorite (NaOCl) is an ideal oxidant in organic synthesis,[4] because it produces only non-toxic sodium chloride (NaCl) as a by-product following oxidation, and commercial aqueous NaOCl is non-explosive and inexpensive. Recently, we found that stable, crystalline sodium hypochlorite pentahydrate (NaOCl·5H₂O),[5] which is now commercially available from several companies, is a very useful oxidant for the nitroxy radical-catalyzed oxidation of alcohols,[5b] [5c] as well as the oxidation of organosulfur compounds.[5d,5e] However neither of these practical, environmentally friendly oxidants, aq. NaOCl or NaOCl·5H₂O, have been used for the preparation of Davis’ oxaziridines. In this paper, we report the concise, catalyst-free preparation of Davis’ oxaziridines via reaction of N-sulfonyl imines in aqueous acetonitrile with NaOCl under basic conditions (Scheme [2]).

Scheme 2

In initial optimization studies, N-tosylimine (1a) derived from benzaldehyde (3a) was chosen as a substrate, and treated with conventional 12% aqueous NaOCl in several solvents (Table [1]). The desired oxaziridine 2a was produced efficiently in acetonitrile (entry 1). On the other hand, hydrolysis of the imine 1a predominated in other solvents, regenerating 3a (entries 2–4).

Table 1 Solvent Effect for the reaction of 1a with NaOCl

Entry	Solvent	Time (h)	1H NMR ratio
			1a	2a	3a b
			(SM) (oxaziridine)
1	CH3CN	0.5	0	85	15
2	t-BuOH	5	1	5	94
3	CH2Cl2	24	8	57	35
4	toluene	24	0	3	97

^a Conventional aqueous solution was used.

^b p-Toluenesulfonylamide was produced as the side-product from hydration of 1a.

In our effort to explore the use of environmentally benign oxidants, NaOCl·5H₂O proved to be superior to conventional, commercial aqueous NaOCl in this type of reaction. Therefore, the reaction of 1a with 12% aqueous NaOCl, freshly prepared from crystalline NaOCl·5H₂O, was examined (Table [2]). Contrary to our expectation, the desired oxaziridine 2a was obtained in low yield, accompanied by a large amount of benzaldehyde 3a, produced from the hydration of 1a (entry 2) as with the alternative solvent above.

Table 2 Comparison of Conventional vs. Freshly Prepared 12% aq. NaOCl

Entry	12% NaOCl aq.	pH	1H NMR ratio
			2a	3a
1	conventional aq. solution	13	85	15
2	prepared from NaOCl·5H2O	11	10	90

The main difference between conventional aqueous NaOCl and an aqueous solution prepared from NaOCl·5H₂O crystals is the pH.[5] As shown in Table [2], the pH of the former was 13, and the pH of the latter was 11. In our previous work[5b] [5c] on the nitroxy radical-catalyzed oxidation of alcohols and the catalyst-free oxidation of sulfides to sulfoxides with NaOCl·5H₂O, we observed that the pH of the aqueous NaOCl solutions dramatically influenced oxidation reactivity. Therefore, the reactivity of the 12% NaOCl aqueous solutions prepared from NaOCl·5H₂O was evaluated while altering the pH with HCl or NaOH (Table [3]).

Table 3 Reactivity of aq 12% NaOCl with Varying pH

Entry	pH	12% NaOCl aq.	1H NMR ratio
			2a	3a
1	14a	Prepared from NaOCl·5H2O	68	32
2	14a	Conventional solution	81	19
3	13a	Prepared from NaOCl·5H2O	87	13
4	13a	Conventional solution	85	15
5	12a	Prepared from NaOCl·5H2O	26	74
6	12b	Conventional solution	30	70c
7	10b	Prepared from NaOCl·5H2O	0	100c
8	10b	Conventional solution	0	0c

^a pH was adjusted using 12.5 M aqueous NaOH.

^b pH was adjusted using conc. HCl.

^c Formation of benzoic acid was detected.

As we had proposed, the reactivity of 1a toward NaOCl depended on the pH of the reaction mixture. A pH of 13 optimized the outcome (entries 3 and 4), and 2a was obtained in good isolated yields (71% and 69%) as shown in Scheme [3].

Scheme 3

Further screening of the reaction conditions revealed that 6 equivalents of 12% aqueous NaOCl solution, prepared from NaOCl·5H₂O with commercial pH 13 buffer (KCl-NaOH) in acetonitrile, afforded 1a in 90% isolated yield (Scheme [4]).

Scheme 4

Several sulfonylimines 1 were then treated with aqueous NaOCl under the optimized conditions using CH₃CN as the solvent, including the optically active substrate 1g (Table [4]). In most cases, the corresponding oxadirizine 2 was obtained in moderate to high yield. In the case of 1f, the desired 2f was obtained in only 4% yield accompanied by several unidentified by-products. Since the reaction conditions were basic, the acidic methyl proton of 1f might be removed, and the resulting anion 1f′ converted into several by-products (Scheme [5]).

Table 4 Reaction of 1 with NaOCl in CH₃CN

1	2	Time (min)	Yield (%)
		30	90a
		30	67b
		20	73a
		28	81a
		24	69a
		18	4b
		30	66a

^a Isolated yield.

^{b 1}H NMR yield using an internal standard (dimethyl sulfone).

Scheme 5

A plausible reaction mechanism for the formation of 2 is depicted in Scheme [6]. A hypochlorite anion attacks the imine carbon of 1 to produce intermediate A and then the amide anion attacks the oxygen atom to produce the oxaziridine 2. Strongly basic conditions are required to prevent the hydrolysis of 1 to the corresponding aldehyde.

Scheme 6

Oxaziridines 2, prepared from the reaction of 1 with NaOCl, can be used as oxidants. We confirmed that the α-hydroxylation of 2-methyl-1-tetralone using 2a or 2g as the oxidant provided results that tallied with those reported in the literature.[2]

In conclusion, synthetically useful N-sulfonyloxaziridines (Davis’ oxaziridines) 2 can be synthesized from reaction of the corresponding N-sulfonylimine 1 with aqueous NaOCl in acetonitrile without need for a catalyst. Strongly basic conditions (pH 13) are required to obtain the products in high yields.[6] Although both NaOCl·5H₂O and conventional aq. NaOCl can be used as the oxidant, NaOCl·5H₂O is recommended because, due to the instability of conventional aq. NaOCl, we observed that the target compounds are not always obtained in high yields.

All reagents were purchased from Nacalai Tesque, Wako Pure Chemicals Industries, Kanto Kagaku, Kishida Reagents Chemical Co., Tokyo Chemical Industry, or Aldrich, and used without further purification. Melting points were measured with a Yanaco micro melting point apparatus (MP-J3) and are uncorrected. NMR spectra were recorded with a JEOL (JNM-EX400) spectrometer as solutions in CDCl₃ using TMS or the residual CHCl₃ peak as an internal standard. IR spectra were recorded with a JASCO IR-8300 FT-IR spectrophotometer. Mass spectra were recorded with a Shimadzu GCMS-QP1100EX spectrometer. Specific rotations were measured with a JASCO DIP-370 polarimeter. All of the sulfonyl imines 1 were prepared according to reported methods (1a,[2a] 1b,[3a] 1c,[3a] 1d,[3a] 1e,[3a] 1f,[3a] 1g [2c]). NMR yields were determined using dimethyl sulfone as an internal standard. All of the products 2 and 5 are known compounds, and ¹H and ¹³C NMR data of the products obtained in this study are identical to those reported.

Preparation of 2; Typical Procedure

An aqueous NaOCl solution prepared from NaOCl·5H₂O (987 mg, 6.0 mmol) and pH 13 buffer solution (KCl-NaOH) (50 mL) was added to a stirred solution of 1a (260 mg, 1.0 mmol) in acetonitrile (10 mL) at 0 °C. The resulting mixture was stirred at r.t. for 30 min. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 × 30 mL). The extract was washed with brine, dried with anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica-gel column chromatography using hexane/EtOAc (20:1) as an eluent to obtain pure 2a (250 mg, 90%) as colorless crystals.

3-Phenyl-2-tosyl-1,2-oxaziridine (2a)[2a]

Colorless crystals: mp 87–92 °C (lit.[2a] 87 °C).

¹H NMR (CDCl₃): δ = 7.86 (d, J = 8.4 Hz, 2 H), 7.33–7.42 (m, 7 H ), 5.38 (s, 1 H), 2.43 (s, 3 H).

¹³C NMR (CDCl₃): δ = 145.39, 130.37, 129.51, 129.03, 128.39, 127.70, 127.20, 75.30, 28.68, 20.81.

MS: m/z = 259 (M⁺ – O), 155 (M⁺ – C₇H₆ON), 91 (M⁺ – C₇H₆O₃NS).

IR (neat): 2924, 2856, 1596, 1351, 1170, 1087, 807, 712, 569, 543, 421 cm^–1.

3-(Naphthalene-2-yl)-2-tosyl-1,2-oxaziridine (2b)[3a]

According to the typical procedure, 1b (312.5 mg, 1.01 mmol) was treated with aq. NaOCl to provide a crude product (277.6 mg) containing 2b (67%, ¹H NMR yield using dimethyl sulfone as an internal standard). All the peaks shown below appeared in the ¹H and ¹³C NMR spectra of the crude product.

¹H NMR (CDCl₃): δ = 8.03 (brs, 1 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.89–7.84 (m, 3 H), 7.57–7.52 (m, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.40 (dd, J = 8.8, 2.0 Hz, 1 H), 5.61 (s, 1 H), 2.50 (s, 3 H).

¹³C NMR (CDCl₃): δ = 146.43, 142.20, 134.72, 132.57, 131.50, 130.07, 129.75, 129.45, 128.86, 128.33, 127.92, 127,88, 127.64, 126.82, 123.45, 21.86.

7b-Phenyl-7bH-benzo[d][1,2]oxazireno[2,3-b]isothiazol2-3,3-dioxide (2c)[3a]

According to the representative procedure, 2c (190 mg, 73%) was ­obtained from 1c (242 mg, 1.00 mmol).

Colorless crystals: mp 97–99 °C (lit.[2i] 105–106 °C).

¹H NMR (CDCl₃): δ = 7.88 (dd, J = 6.8, 1.2 Hz, 1 H), 7.79–7.71 (m, 2 H), 7.65–7.50 (m, 6 H).

¹³C NMR (CDCl₃): δ = 134.57, 134.44, 133.84, 132.79, 131.34, 129.00, 128.07, 128.04, 127.87, 124.13, 85.25.

7b-(4-Chlorophenyl)-7bH-benzo[d][1,2]oxazireno[2,3-b]isothiazol2-3,3-dioxide (2d)[3a]

According to the representative procedure, 2d (237 mg, 81%) was ­obtained from 1d (276 mg, 1.00 mmol).

White solid; mp 140–143 °C (lit.[3a] 144–145 °C).

¹H NMR (CDCl₃): δ = 7.88 (dd, J = 6.4, 1.6 Hz, 1 H), 7.81–7.73 (m, 2 H), 7.63–7.61 (dd, J = 6.8, 0.8 Hz, 1 H), 7.57–7.49 (m, 4 H).

¹³C NMR (CDCl₃): δ = 137.75, 134.41, 133.98, 133.95, 133.00, 129.51, 129.36, 127.82, 126.42, 124.24, 84.68.

7b-(3-Chlorophenyl)-7bH-benzo[d][1,2]oxazireno[2,3-b]isothiazol2-3,3-dioxide (2e)[3a]

According to the representative procedure, 2d (237 mg, 81%) was ­obtained from 1d (276 mg, 1.00 mmol).

Pale-orange solid; mp 124–126 °C (lit.[3a] 125–126 °C).

¹H NMR (CDCl₃): δ = 7.90–7.87 (m, 1 H), 7.82–7.74 (m, 2 H), 7.64–7.59 (m, 2 H), 7.56 (td, J = 7.6, 1.6 Hz, 1 H), 7.52–7.45 (m, 2 H).

¹³C NMR (CDCl₃): δ = 135.22, 134.35, 134.06, 133.76, 133.06, 131.61, 130.40, 129.93, 128.15, 127.86, 126.29, 124.24, 84.38.

7b-Methyl-7bH-benzo[d][1,2]oxazireno[2,3-b]isothiazol2-3,3-dioxide (2f)[3a]

According to the representative procedure, 1f (181.5 mg, 1.00 mmol) was treated with aq. NaOCl to provide a crude product (28.0 mg) containing 2f (4%, ¹H NMR yield using dimethyl sulfone as an internal standard). All the peaks shown below appeared in the ¹H and ¹³C NMR spectra of the crude product.

¹H NMR (CDCl₃): δ = 7.80–7.71 (m, 4 H), 2.14 (s, 3 H).

¹³C NMR (CDCl₃): δ = 135.09, 134.06, 133.29, 132.56, 125.57, 123.84, 83.91, 15.57.

(+)-(4aR,7R)-9,9-Dimethyltetrahydro-4H-4a,7-methanobenzo[c][1,2]oxazireno[2,3-b]isothiazole 3,3-Dioxide (2g)[2c]

According to the representative procedure, 2g (151 mg, 66%) was ­obtained from 1g (210 mg, 1.00 mmol).

Colorless crystals; mp 167–172 °C (lit.[2c] 165–167 °C); [α]_D +44.6 (CHCl₃, c 1.9) {lit.[2c] [α]_D +44.6 (CHCl₃, c 1.8)}.

¹H NMR (CDCl₃): δ = 3.10 and 3.27 (AB quartet, J = 14 Hz, 2 H, CH₂-SO₂), 2.64 (m, 1 H), 1.50–2.13 (m, 6 H), 1.18 (s, 3 H), 1.03 (s, 3 H).

¹³C NMR (CDCl₃): δ = 98.77, 54.06, 48.32, 45.80, 33.64, 28.39, 26.56, 20.55, 19.50.

• References and Notes


For recent reviews, see:
• 1a Williamson KS, Michaelis DJ, Yoon TP. Chem. Rev. 2014; 114: 8016
• 1b Sala GD, Lattanzi A. ACS Catal. I 2014; 4: 1234
• 2a Davis FA, Stringer OD. J. Org. Chem. 1982; 47: 1774
• 2b Davis FA, Chattopadhyay S, Towson JC, Lal S, Reddy T. J. Org. Chem. 1988; 53: 2087
• 2c Davis FA, Towson JC, Weismiller MC, Lal S, Carroll PJ. J. Am. Chem. Soc. 1988; 110: 8477
• 2d Davis FA, Sheppard AC, Chen B, Haque MS. J. Am. Chem. Soc. 1990; 112: 6679
• 2e Davis FA, Weismiller MC. J. Org. Chem. 1990; 55: 3715
• 2f Davis FA, Sheppard AC. Tetrahedron 1989; 45: 5703
• 2g Davis FA, Chen BC. Chem. Rev. 1992; 92: 919
• 2h Petrov VA, Resnati G. Chem. Rev. 1996; 96: 1809
• 2i Narasaka K, Ukaji Y, Watanabe K. Bull Chem. Soc. Jpn. 1987; 96: 1457

Asymmetric syntheses of oxaziridines:
• 3a Takizawa S, Kishi K, Abozeid MA, Murai K, Fujioka H, Sasaia H. Org. Biomol. Chem. 2016; 14: 761
• 3b Lykke L, Rodríguez-Escrich C, Jørgensen KA. J. Am. Chem. Soc. 2011; 133: 14932
• 3c Zhang T, He W, Zhao X, Jin Y. Tetrahedron 2013; 69: 7416
• 3d Jin Y, Zhang T, Zhang W, Chang S, Feng B. Chirality 2014; 26: 150
• 3e Uraguchi D, Tsutsumi R, Ooi T. J. Am. Chem. Soc. 2013; 135: 8161
• 3f Tsutsumi R, Kim S, Uraguchi D, Ooi T. Synthesis 2014; 871
• 3g Uraguchi D, Tsutsumi R, Ooi T. Tetrahedron 2014; 70: 1691
• 3h Olivares-Romero JL, Li Z, Yamamoto H. J. Am. Chem. Soc. 2012; 134: 5440
• 4 Galvin JM, Jacobsen EN, Palucki M, Frederick MO. e-EROS 2013; ; and references cited therein
• 5a Kirihara M, Okada T, Sugiyama Y, Akiyoshi M, Matsunaga T, Kimura Y. Org. Process Res. Dev. 2017; 21: 1925
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• 5d Okada T, Matsumuro H, Kitagawa S, Iwai T, Yamazaki K, Kinoshita Y, Kimura Y, Kirihara M. Synlett 2015; 26: 2547
• 5e Okada T, Matsumuro H, Iwai T, Kitagawa S, Yamazaki K, Akiyama T, Asawa T, Sugiyama Y, Kimura Y, Kirihara M. Chem. Lett. 2015; 44: 185
• 6 Given that addition of 10 mol% tetrabutylammonium hydroxide (Bu₄NOH) accelerated the oxidation reaction in a biphasic solvent system using trifluoromethylbenzene (benzotrifluoride, BTF), the reaction might proceed enantioselectively if an optically pure alkylammonium salt was employed. As a preliminary result, the desired product 2a was obtained with 7% ee when the reaction was conducted using N-benzylcinchonidinium chloride.