Microwave-assisted synthesis of ortho-substituted diaryl N-(tert-butylsulfinyl)ketimines

Abstract

A simple and efficient procedure for the synthesis of ortho-substituted diarylketimines has been developed under microwave irradiation, employing the corresponding diarylketones and (R)-(+)-tert-butylsulfinamide in the presence of Ti(OⁱPr)₄. This approach allows the preparation of most final ketimines (3a–g) containing electron-donating groups in good yields in 1 h. For starting materials with strong electron-withdrawing groups, the desired (3h–m) products could also be prepared by increasing microwave energy and extension of the reaction time to 2.5 h.

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1. Introduction

Enantiomerically pure N-(tert-butylsulfinyl)imines have been widely used in asymmetric reactions and the synthesis of chiral primary amines.¹ Recent research suggested that ketimines containing the 2-aminophenyl group have also become important intermediates or key structural units in the construction of chiral 1,3-diamines 1,² 1,2-dihydroquinazolinones DPC-961 (a potent second generation non-nucleoside reverse-transcriptase inhibitor) and (±)SM-15811 (an effective Ca²⁺/Na⁺ ion exchanger inhibitor with potential utility for the management of ischemic heart disease),³ chiral auxiliaries and N-heterocyclic carbene ligands 2,⁴ natural products⁵ and other pharmacologically active compounds⁶ (Fig. 1). The ketimines containing chiral auxiliaries such as (R)-(+)-tert-butylsulfinamide or (S)-(−)-tert-butylsulfinamide can lead to chiral primary amines after reduction and hydrolysis. Therefore, the development of efficient methods for the preparation of N-(tert-butylsulfinyl) protected 2-aminoaryl ketimines is very important.

Fig. 1 Representative structures containing chiral 1,3-diamine moieties.

Most of the reported synthetic methods for these imines are mainly based on the direct condensation of aldehydes or highly reactive ketones with optically pure (R)-(+)-tert-butylsulfinamide in the presence of an activating and dehydrating agent such as copper(II) sulfate,⁷ magnesium sulfate/pyridinium p-toluenesulfonate,⁶ titanium(IV) alkoxides,^7,8 cesium carbonate,⁹ ytterbium(III) triflate,¹⁰ or potassium hydrogensulfate.¹¹ Although the synthesis of aldimines and ketimines has been reported under microwave irradiation,^8a,b,12 examples of diaryl sulfinylketimines with steric hindrance such as ortho-substitutions are rare.

During the past few years, one of our main research lines has been focused on the use of N-(tert-butylsulfinyl)imines in asymmetric synthesis and as chiral auxiliaries.^6,13 Herein we report our studies on developing a fast and efficient procedure for the synthesis of ortho-substituent diaryl N-(tert-butylsulfinyl)ketimines.

2. Results and discussions

At first, we tried to synthesize the desired diaryl sulfinylketimines according to the above mentioned methods.^7–12 After attempts with Lewis acid such as copper(II) sulfate, magnesium sulfate/pyridinium p-toluenesulfonate, titanium(IV) alkoxides, titanium tetrachloride, and ytterbium(III) triflate, we found that stronger Lewis acid TiCl₄ was useful for the formation of imines (Table 1, 1a–g).¹⁴ The desired sulfinimides 3a–g (Table 1) were formed at room temperature, but the yields were low. For other diaryl ketones 1h–m bearing an electron-withdrawing substituent such as a nitro group (Table 1), no condensation product was formed even when using TiCl₄. This result indicated that more harsh conditions were needed to push the condensation reaction forward. We decided to increase the reaction energy by heating or microwave irradiation. However, when the temperature was raised to 40 °C using 2 M TiCl₄ in toluene, the materials were quickly carbonized and turned black, with no desired product being detected. Therefore, another Lewis acid was chosen to allow for increased reaction energy input such as heating or microwave irradiation. According to the literature,^8a,b,12 we reasoned that microwave irradiation could be a more effective way to promote the condensation reaction instead of raising the temperature with conventional heating. In order to find a suitable condensation promoter for the microwave-assisted condition, the above mentioned Lewis acids were examined for the synthesis of product 3h at 125 °C and 175 W by using a Biotage initiator (Model: Initiator EXP EU 355301). The results revealed that the condensation product could only be obtained with Ti(OⁱPr)₄. The yield of product 3h was 20% at 125 °C and 175 W. Then, the reaction conditions of synthesizing compound 3h using Ti(OⁱPr)₄ were further optimized. The results were shown in Table 2. The irradiation energy was critical to the success of the reaction. At 120 °C with 160 W input, no product was formed, while at 140 °C with 210 W input material decomposition was severe. Reaction carried out at 130 °C with 190 W input seemed to have the good balance of starting material conversion and product formation. The optimal condition was achieved with 4 equivalent of Ti(OⁱPr)₄ and 2.5 h of reaction time.

Table 1 Synthesis of N-(tert-butylsulfinyl)ketimines 3a–m using TiCl₄^a at room temperature

Entry	No.	R1, R2	Structure	Isolated yields^b (%)
a The mixture of 1a–m (1 mmol), (R)-t-BuSONH2 (1.1 mmol), and 2 M TiCl4 (1.5 mL, 3 mmol) in toluene were stirred at room temperature for 12 h.b Yield of isolated product after being subjected to silica gel column chromatography. Compounds 3a–g were always ≥95% pure (400 MHz ^1H NMR).
1	3a	2-NH2C6H4, Ph		50
2	3b	p-Cl-NH2C6H3, Ph		38
3	3c	p-Cl-NH2C6H3, 2′-FC6H4		37
4	3d	p-Cl-NH2C6H3, 2′-F,6′-FC6H3		25
5	3e	2-NHC6H5CH2C6H4, Ph		31
6	3f	2-NH2C6H3, C6H4		28
7	3g	2-NH2C5H3N, Ph		20
8	3h	2-NO2C6H4, Ph		0
9	3i	2-NO2C6H4, 1′-naphthyl		0
10	3j	2-NO2C6H4, 2′-CH3C6H4		0
11	3k	2-NO2C6H4, 2′-CH3OC6H4		0
12	3l	2-NO2C6H4, 4′-FC6H4		0
13	3m	2-NO2C6H4, 2′-CF3C6H4		0

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Table 2 Optimization of reaction conditions for 3h^a

Entry	1h/2/Ti(O^iPr)4 (eq.)	Temp. (°C)/energy (W)	Reaction time (h)	Conv.	Isolated yields^b
a The mixture of 1h (1 mmol), (R)-t-BuSONH2 (1.1 mmol), Ti(O^iPr)4 (4 mmol) and 1 mL THF were stirred under microwave irradiation for 1.0–2.5 h.b Yield of isolated product after being subjected to silica gel column chromatography. Compounds 3h were always ≥95% pure (400 MHz ^1H NMR).
1	1/1/2	120/160	1.0	Trace	0
2	1/1/3	120/160	1.0	Trace	0
3	1/1/4	120/160	1.0	Trace	0
4	1/1/2	130/190	1.0	30	21
5	1/1/3	130/190	1.0	32	22
6	1/1/4	130/190	1.0	34	22
7	1/1/4	130/190	1.5	38	26
8	1/1/4	130/190	2.0	50	33
9	1/1/4	130/190	2.5	60	41
10	1/1/4	140/210	0.5	90	Trace
11	1/1/4	140/210	1.0	100	Trace
12	1/1/4	140/210	1.5	100	Trace

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Afterwards, the compounds 3i–m were synthesized using the optimized condition and the results were summarized in Table 3 (entries 8–13). Meanwhile, this procedure was also applied to the synthesis of 3a–g, and the yields were enhanced from 20–50% (Table 1 using TiCl₄) to 70–89% (Table 3). Similar yields were obtained at 10 mmol reaction scales.

Table 3 Microwave-assisted synthesis of N-(tert-butylsulfinyl)ketimines 3a–m^a

Entry	No.	R1, R2,	Structure	M.W (W)/temp. (°C)	Time (h)	Conv. (%)	Yield^b(%)
a The mixture of 1a–m (1 mmol), (R)-t-BuSONH2 (1 mmol), and Ti(O^iPr)4 (4 mmol) and 1 mL THF were stirred under microwave irradiation for 2–2.5 h.b Yield of isolated product after being subjected to silica gel column chromatography. Compounds 3a–m were always ≥95% pure (400 MHz ^1H NMR).
1	3a	2-NH2C6H4, Ph		160/120	2	>95	89
2	3b	p-Cl-NH2C6H3, Ph		160/120	2	>95	86
3	3c	p-Cl-NH2C6H3, 2′-FC6H4		160/120	2	>95	85
4	3d	p-Cl-NH2C6H3, 2′-F,6′-F C6H3		160/120	2	>95	73
5	3e	2-NHC6H4CH2C6H4, Ph		160/120	2	>95	70
6	3f	2-NH2C6H3, C6H4		160/120	2	>95	84
7	3g	2-NH2C5H3N, Ph		160/120	2	>95	83
8	3h	2-NO2C6H4, Ph		190/130	2.5	>60	41
9	3i	2-NO2C6H4, 1′-naphthyl		190/130	2.5	>60	38
10	3j	2-NO2C6H4, 2′-CH3C6H4		190/130	2.5	>60	42
11	3k	2-NO2C6H4, 2′-CH3OC6H4		190/130	2.5	>60	44
12	3l	2-NO2C6H4, 4′-FC6H4		190/130	2.5	>50	30
13	3m	2-NO2C6H4, 2′-CF3C6H4		190/130	2.5	>50	19

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To evaluate whether or not there was any beneficial effect in the use of microwave irradiation, the synthesis of imine 3a and 3h was carried out by conventional heating in an oil bath at 130 °C in the presence of Ti(OⁱPr)₄, and no conversion of the starting materials was observed after a reaction time of 3 h. Only a trace amount of 3a was observed after 24 h while 3h still could not be detected after 24 h. This result indicated that the assistance of microwave is essential to the synthesis of ortho-substituted diarylketimines.

As high temperature may cause racemization during the synthesis of sulfinylketimines, we investigated whether or not there was any loss of optical purity in the imines that we had prepared under microwave-assisted conditions. We chose imines 3a, 3b and 3h as test compounds for this study. The corresponding racemic imines were prepared by condensation of the precursor ketones and racemic tert-butylsulfinamide. The optical purities of imines 3a, 3b and 3h were evaluated by HPLC analyses on a chiral column by comparison with the corresponding racemic samples. In all three cases, the enantiomeric excess were >99%. Thus, there was no racemization of the imine products under our reaction conditions.

3. Conclusions

In conclusion, we have optimized the condensation of ortho-substituted diaryl ketones with (R)-(+)-tert-butylsulfinamide in the presence of titanium(IV) isopropoxide under microwave irradiation. This method allows for the preparation of ortho-substitute diarylsulfinyl ketimines in moderate to good yield.

Acknowledgements

Financial support by the Shanghai Municipal Education Commission (no.14ZZ159), the Shanghai Municipal Science and Technology Commission (no. 12430501300), the Program for Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Education, and Shanghai University of Engineering Science (nhrc-2014-05) are gratefully acknowledged. We also thank Dr Erkang Fan from the University of Washington for helpful discussions.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13759k

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