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Synlett 2023; 34(05): 429-432
DOI: 10.1055/a-1946-6522
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Special Edition Thieme Chemistry Journals Awardees 2022

A Facile and Mild Alkylation Protocol of NH-Diphenyl Sulfondiimines

Zeyu Xu
,
Shuaisong Su
,
Xue Li
,
Tiezheng Jia  ∗

This work is supported by Natural Science Foundation of Guangdong Province (2022A1515011770), Guangdong-Joint Foundation of Shenzhen (2021B1515120046), Shenzhen Nobel Prize Scientists Laboratory Project (C17783101), and Guangdong Provincial Key Laboratory of Catalysis (2020B121201002).
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Abstract

As a promising pharmacophore, sulfondiimines have drawn increasing attention in recent years, but their uptake in medicinal chemistry is jeopardized by the scarcity of related transformations. Herein, we report a facile and mild N-alkylation protocol of NH-diphenyl sulfondiimines with alkyl halides to prepare a myriad of N-alkylated diphenyl sulfondiimines. Owing to air atmosphere, room temperature, as well as mild reaction conditions, this protocol has exhibited great potential in organic synthesis and medicinal chemistry by the late-stage functionalization of natural products.


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Key words

sulfondiimines - alkylation - mild - alkyl bromides - functional group tolerance

Sulfondiimines, the diaza analogues of sulfones or the monoaza analogues of sulfoximines, remain one class of the least explored S(VI)-derived scaffolds in organic chemistry.[1] Though discovered more than half a century ago,[2] this class of molecules only finds very limited applications, primarily in the construction of heterocycles.[3] Fascinated by the recent surge of interest in sulfoximines in the field of medicinal chemistry and discovery industry,[4] especially the successful advance of Bayer’s Bay 1000394 to clinic phase II,[5] sulfondiimines draw much attention as a promising pharmacophore, due to their three-dimensional structure, hydrogen-bonding ability, potential sulfur stereogenic center, among other intriguing properties.[6] In particular, N-alkylated sulfondiimines exhibited significant bioactivities, and thus, start to appear in patented compounds (Figure [1]).[4c] [7]

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Figure 1Representative examples of bioactive N-alkyl sulfondiimines

Traditionally, N-alkyl sulfondiimines have been prepared by the imination of sulfiliminium salts with alkyl amines, but the strong oxidative conditions severely jeopardize the functional group tolerance.[1] In sharp contrast, alkylation of NH-sulfondiimines represents a mild and step-economic alternative, obviating the employment of hazardous imination reagents. The first N-alkylation protocol dates back to 1969, when Appel and Ross described a single example of alkylation between dimethyl sulfondiimine potassium and ethyl bromide (Scheme [1a]).[8] Since strong and moisture-sensitive KNH2 was employed as base, the alkylation has to be performed at –20 °C under an N2 atmosphere. In 2014, Bolm and coworkers introduced a general alkylation method enabled by ‘KOH/DMSO’ superbase system, and an array of N-alkyl aryl alkyl sulfondiimines, along with an example of N-alkyl dialkyl sulfondiimine, were prepared in good yields (Scheme [1b]).[9] Our group has also demonstrated that Bolm’s KOH/DMSO superbase system could effectively facilitate the N-alkylation of NH,NPh-diphenyl sulfondiimine with 6-bromo-1-hexene.[10] Unfortunately, solvent DMSO is hazardous,[11] and argon atmosphere has to be used to achieve satisfactory yields. Due to the problematic superbasic conditions of Bolm’s protocol,[9] chiral centers bearing acidic C–H bond may undergo racemization. Herein, we report a facile and mild alkylation protocol of NH-diaryl sulfondiimines in the presence of Cs2CO3 as base and acetone as solvent (Scheme [1c]). Our new method features environmentally recommended solvent, room temperature, open-flask conditions, broad substrate scope, as well as tolerance of chiral reactants.

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Scheme 1 N-Alkylation of NH-sulfondiimines

The conditions optimization commenced by a short survey of four bases (KOH, Cs2CO3, Na2CO3, and K2CO3) while DMSO served as solvent at room temperature in air for 24 h (Table [1], entries 1–4). Cs2CO3 was determined to be superior, leading to the formation of 3aa in 97% yield. Forging ahead with Cs2CO3 as the best base, other three solvents (acetone, MeCN, and DMF) were investigated in the N-alkylation of 1a (Table [1], entries 5–7), and 3aa was produced in similar yields in either acetone or MeCN as in DMSO (compare entries 5, 6 vs 2). To achieve a goal of environmentally benign conditions, acetone as recommended by CHEM 21 selection guide of solvents[11] was determined for the subsequent optimization. We can successfully decrease the amount of solvent used, and at 1.0 M concentration, the yield of 3aa stayed the same (entry 8). Next, the stoichiometry of base was optimized, and the yield of 3aa remained near quantitative while 1.5 equivalents base were used (entry 9). Further decrease of Cs2CO3 to 1.1 equivalents resulted in slight drop of 3aa yield to 92% (entry 10), and thus, the optimal amount of base was determined to 1.5 equivalents. In the end, the reaction time of the alkylation could be shortened to 6 h, and yield of 3aa kept (97% assay yield, 94% isolated yield). The attempt to reduce the reaction time to 2 h failed, since only 89% yield of 3aa was obtained (entry 12). Therefore, the optimal conditions for mild and environmentally benign N-alkylation were determined to be: 1a as the limiting reagent, 2a (1.5 equiv) as the alkylating reagent, Cs2CO3 (1.5 equiv) as base, in acetone (1.0 M) at room temperature in air for 6 h (see the Supporting Information for a complete list of optimization).

Table 1 Optimization of N-Alkylation of NH-Sulfondiimine a

Entry

Base (equiv)

Solvent

Concn (M)

Time (h)

Assay yield (%) b

 1

KOH (2.0)

DMSO

0.1

24

77

 2

Cs2CO3 (2.0)

DMSO

0.1

24

97

 3

Na2CO3 (2.0)

DMSO

0.1

24

 5

 4

K2CO3 (2.0)

DMSO

0.1

24

12

 5

Cs2CO3 (2.0)

acetone

0.1

24

96

 6

Cs2CO3 (2.0)

MeCN

0.1

24

95

 7

Cs2CO3 (2.0)

DMF

0.1

24

87

 8 c

Cs2CO3 (2.0)

acetone

1.0

24

98

 9 c

Cs2CO3 (1.5)

acetone

1.0

24

98

10 c

Cs2CO3 (1.1)

acetone

1.0

24

92

11 c

Cs2CO3 (1.5)

acetone

1.0

 6

97 (94 d )

12 c

Cs2CO3 (1.5)

acetone

1.0

 2

89

a Reaction conditions: 1a (0.1 mmol), 2a (1.5 equiv), base (2.0 equiv), solvent (1.0 mL) at room temperature in air for 24 h.

b Assay yields determined by 1H NMR analysis of unpurified reaction mixtures using 0.1 mmol (7.0 μL) of CH2Br2 as internal standard.

c 1a (0.5 mmol), acetone (0.5 mL).

d Isolated yield.

Having the optimal conditions established, the substrate scope of alkyl halides in N-alkylation of NH-diaryl sulfondiimines was first investigated with 1a (Scheme [2]). Benzyl bromide (2a) or chloride (2a′) could react with 1a to deliver 3aa in 95% and 81% yield, respectively. 4-Methylbenzyl chloride (2b) was also a viable alkylating reagent, and 3ab could be obtained in 75% yield with 2.5 equivalents of 2b and Cs2CO3 used. Sterically demanding 2-methylbenzyl bromide (2c) could be tolerated by our alkylation to afford 2ac in 92% yield. 2-Nitrobenzyl, a photocleavable protecting group, could be introduced on nitrogen atom of 1a in 80% yield. Alkyl iodides were also amendable alkylating reagents, as evidenced by formation of 3ae from methyl iodide (2e) and 1a in 92% yield. n-Butyl bromide (2f) reacted with 1a to furnish 3af in 82% yield under slightly modified conditions. The mild and environmentally benign alkylation conditions allowed the compatibility of an array of functional groups appending on alkyl bromides, including alkene (2g), alkyne (2h), alcohol (2i), and ester (2j). Remarkably, our alkylation strategy displayed excellent chemoselectivity favoring C–N bond formation of 1a over C–C bond (2h) or C–O bond formation (2i). Considering the basic reaction conditions, the alkylation of alkyl bromide bearing ester group (2j) is particularly impressive, successfully overriding the potential aldol condensation. Of note, alkyl bromides possessing heterocycles were also well tolerated by our protocol, generating 3ak and 3al in 84% and 80% yield, respectively. Of note, our alkylation protocol could also be expanded to the arylation reaction via the classic SNAr mechanism. An arylation of 1a was conducted with 1-fluoro-2-nitrobenzene (2p), successfully delivering N-arylated product 3ap in 90% yield under modified conditions.

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Scheme 2 Substrate scope of alkyl halides in N-Alkylation with 1a. Reagents and conditions: 1a (0.5 mmol), 2 (1.5 equiv), Cs2CO3 (1.5 equiv), and acetone (0.5 mL), at rt in air for 6 h. a 2 (2.5 equiv), Cs2CO3 (2.5 equiv), 16 h. b 2 (2.5 equiv), 18 h. c R-Cl as alkylating agent. d MeI as alkylating agent. e DMSO, 100 °C, 3 h.

Next, the substrate generality of NH-diphenyl sulfondiimines in N-alkylation with 2a was examined (Scheme [3]). Gratifyingly, while NH,NH-diphenyl sulfondiimine (1b), namely the free sulfondiimine, was utilized as nucleophile in the alkylation, exclusive monoalkylation was achieved under slightly modified conditions, albeit in modest yield (58%). Interestingly, a sequential alkylation could occur in stepwise manner on the monoalkylated sulfondiimines with another electrophile using Bolm’s KOH/DMSO conditions,[9] to furnish N,N-dialkyl sulfondiimines bearing two kinds of alkyl substituents on nitrogen, as evidenced by formation of 3aq in 81% yield. The alkylation proceeded smoothly with sulfondiimines bearing Boc or Cbz group on the other imine moieties (1c,d) to afford 3ca and 3da in good yields. NH,N(p-Ns)-Diphenyl sulfondiimine (1e), an example with sulfonyl-derived protecting group, was successfully tolerated by the protocol. Acyl-based protecting groups, such as acetyl, benzoyl, and pivalate (1f–h), exerted negligible effect on the outcome of the reaction, delivering 3fa–ha in excellent yields. Notably, sulfondiimine with an electron-donating phenyl group on the other imine moiety could also be alkylated with 2a to produce 3ia in 67% yield while DMF was used as the solvent. The broad compatibility of diverse protecting groups on imines provides flexible pathways to furnish NH,N-alkyl-diaryl sulfondiimines, which is of great value in the synthesis of complex molecules.

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Scheme 3 Substrate scope of NH-sulfondiimines in N-alkylation with 2a. Reagents and conditions: 1 (0.5 mmol), 2a (1.5 equiv), Cs2CO3 (1.5 equiv), and acetone (0.5 mL), at rt in air for 6 h. a 1 (0.1 mmol), 2a (2.5 equiv), Cs2CO3 (2.5 equiv) and MeCN (0.5 mL), 12 h. b 2 (2.5 equiv), Cs2CO3 (2.5 equiv) 12 h. c 1 (0.3 mmol), acetone (0.3 mL). d 2a (3.5 equiv), Cs2CO3 (3.5 equiv) and DMF (0.3 mL), 12 h. e KOH (2.0 equiv), DMSO, 110 °C, 4 h.
Zoom Image
Scheme 4Synthetic applications of N-alkylation of NH-diphenyl sulfondiimines. a 2m (3.5 equiv), Cs2CO3 (3.5 equiv) in DMF (1.5 mL), 24 h. b Cs2CO3 (2.5 equiv), 3 h.

One major impediment of Bolm’s N-alkylation procedure of NH-sulfondiimines using KOH/DMSO superbase system is the incompatibility of chiral centers bearing acidic C–H bond.[9] To exhibit the superiority as well as the potential utility of our alkylation protocol in organic synthesis and medicinal chemistry, diphenyl sulfondiimine motif was successfully introduced to three natural products [((R)-nopol, (E)-geraniol, and (7R,11R,2E)-phytol] in yields ranging from 51% to 90% as a single enantiomer. To further display the advantage of our protocol on tolerance of chiral centers bearing acidic C–H bonds, 2r (from (R)-1-phenylethan-1-amine) and 2t (from d -valine) were selected as substrates to perform alkylation with 1a. Remarkably, 3ar and 3at were prepared in good yields, leaving the chiral centers intact (Scheme [4]).

In conclusion, we have developed a facile and mild N-alkylation protocol of NH-diphenyl sulfondiimines with alkyl halides, which features open-flask conditions, environmentally recommended solvent, room temperature, and tolerance of chiral substrates.[12] Leveraging the mild reaction conditions and the broad functional groups compatibility, the alkylation protocol could be utilized as an efficient tool for late-stage functionalization of natural products.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are very grateful to Dr. Yang Yu (SUSTech) for HRMS. We acknowledge the assistance of SUSTech Core Research Facilities.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1946-6522.
  • Supporting Information

Corresponding Author

Tiezheng Jia
Shenzhen Grubbs Institute, Department of Chemistry, and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology
1088 Xueyuan Blvd., Shenzhen, Guangdong, 518055
P. R. of China   

Publication History

Received: 20 June 2022

Accepted after revision: 18 September 2022

Accepted Manuscript online:
18 September 2022

Article published online:
14 October 2022

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1Representative examples of bioactive N-alkyl sulfondiimines
Zoom Image
Scheme 1 N-Alkylation of NH-sulfondiimines
Zoom Image
Scheme 2 Substrate scope of alkyl halides in N-Alkylation with 1a. Reagents and conditions: 1a (0.5 mmol), 2 (1.5 equiv), Cs2CO3 (1.5 equiv), and acetone (0.5 mL), at rt in air for 6 h. a 2 (2.5 equiv), Cs2CO3 (2.5 equiv), 16 h. b 2 (2.5 equiv), 18 h. c R-Cl as alkylating agent. d MeI as alkylating agent. e DMSO, 100 °C, 3 h.
Zoom Image
Scheme 3 Substrate scope of NH-sulfondiimines in N-alkylation with 2a. Reagents and conditions: 1 (0.5 mmol), 2a (1.5 equiv), Cs2CO3 (1.5 equiv), and acetone (0.5 mL), at rt in air for 6 h. a 1 (0.1 mmol), 2a (2.5 equiv), Cs2CO3 (2.5 equiv) and MeCN (0.5 mL), 12 h. b 2 (2.5 equiv), Cs2CO3 (2.5 equiv) 12 h. c 1 (0.3 mmol), acetone (0.3 mL). d 2a (3.5 equiv), Cs2CO3 (3.5 equiv) and DMF (0.3 mL), 12 h. e KOH (2.0 equiv), DMSO, 110 °C, 4 h.
Zoom Image
Scheme 4Synthetic applications of N-alkylation of NH-diphenyl sulfondiimines. a 2m (3.5 equiv), Cs2CO3 (3.5 equiv) in DMF (1.5 mL), 24 h. b Cs2CO3 (2.5 equiv), 3 h.