Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Organocatalytic Asymmetric Allylic Alkylations of Sulfoximines Zhen Li, Marcus Frings, Hao Yu, Gerhard Raabe, and Carsten Bolm* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
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S Supporting Information *
ABSTRACT: An enantio- and regioselective allylic alkylation of sulfoximines with Morita−Baylis−Hillman carbonates was developed. The asymmetric reaction is directed by a quinidine-derived organocatalyst providing a range of optically active αmethylene β-sulfoximidoyl esters in high yields (up to 93%) with good to excellent enantiomeric excesses (up to 95%) under mild reaction conditions.
S
ulfoximines have been applied in crop protection,1 medicinal chemistry,2 and asymmetric synthesis.3 They bear sulfur-bound basic nitrogen atoms, which provide flexible substitution sites for substrate modifications. A wide range of products can be prepared by N-functionalizations of readily available NH-sulfoximines.4,5 In many of these processes, metal catalysis plays a key role (Scheme 1, a). Although such N-
Allyl amines are central motifs in many bioactive compounds and natural products.7 In addition, they have been used as fundamental building blocks in organic synthesis.8,9 A range of asymmetric amination reactions allow access to allyl amines by stereocontrolled C−N bond-forming processes.10 Notably potent are enantioselective substitutions of Morita−Baylis− Hillman (MBH) carbonates with nitrogen nucleophiles,11 which can be affected by both transition-metal catalysts and organocatalysts.12,13 Considering the potential synthetic value of the expected products, it came as a surprise to us that sulfoximines had never been applied in such reactions. Consequently, we studied the effectiveness of chiral Lewis basesin particular, cinchona alkaloid derivativesas catalysts in allylic substitution reactions of MBH carbonates with sulfoximines as nucleophiles (Scheme 1, c). The results are reported here. We began the investigation by choosing S,S-diphenyl sulfoximine (1a) and MBH carbonate 2a as our standard reactants and bromobenzene as solvent. Delightfully, all tested cinchona alkaloid derivatives were able to catalyze the envisaged substitution reaction. However, while the expected product 3aa was obtained with respectable enantiomeric excesses (ee, up to 98%), the yields of 3aa remained low in all cases (Table 1, entries 1−6). These initial results reveal hydroquinidine 1,4-phthalazinediyl diether [(DHQD)2PHAL] as the most promising catalyst, which we thus used in the subsequent solvent screening (Table 1, entries 7−11). 1,4Dioxane, DCM, THF, and MeOH proved unsuitable, but MeCN greatly shortened the reaction time (from 72 or 96 h to 48 h), while simultaneously the yield of 3aa increased to 84% (Table 1, entry 11). Furthermore, the product ee was high (94%) in this solvent. Lowering the catalyst amount from 20 mol % to 10 mol % noticeably decreased both the yield (67%) and the ee (91%) of 3aa (Table 1, entry 12). Raising the
Scheme 1. N-Functionalizations of Sulfoximines
functionalizations proceed well, it has also to be noted that they often require a precious metal catalyst, which can potentially contaminate the final product. The use of suitable organocatalysts could eventually avoid these disadvantages. Our recently reported organocatalytic kinetic resolution of sulfoximines with enals by chiral N-heterocyclic carbenes (NHC) illustrates this concept (Scheme 1, b).6 Interestingly, N-functionalizations of sulfoximines with Lewis base catalysts have remained unreported until now. © XXXX American Chemical Society
Received: September 19, 2018
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DOI: 10.1021/acs.orglett.8b03003 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Search for the Optimal Reaction Conditionsa
entry 1 2 3 4 5 6
cat.b
temp (°C) rt 50 rt rt rt rt
7
(DHQD)2PHAL (DHQD)2PHAL (DHQD)2PYR (DHQ)2PHAL hydroquinidine hydroquinidine 9phenanthryl ether (DHQD)2PHAL
8 9 10 11 12d 13 14e 15f 16g
(DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL (DHQD)2PHAL
rt rt rt rt rt 50 50 50 50
rt
solvent
time (h)
Scheme 2. Applications of Various Sulfoximines in Reactions with MBH Carbonate 2aa
yield (%)
eec (%)
PhBr PhBr PhBr PhBr PhBr PhBr
72 72 96 96 96 96
24 31 34 20 20 32
98 95 94 −73 67 −29
1,4dioxane THF DCM MeOH MeCN MeCN MeCN MeCN MeCN MeCN
72
8
98
72 72 72 48 48 48 72 72 72
18 15 trace 84 67 92 39 26 72
97 93 94 91 90 93 91 91
a All reactions were carried out with 1 (0.1 mmol), 2a (0.2 mmol), and (DHQD)2PHAL (0.02 mmol) in MeCN (1 mL) at room temperature in air for 48 h. The ee was determined by CSP-HPLC analysis.
a
All reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol), and the catalyst (0.02 mmol) in the given solvent (1 mL) at the indicated temperature in air. b(DHQD)2PHAL = hydroquinidine 1,4phthalazinediyl diether; (DHQD)2PYR = hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether; (DHQ)2PHAL = hydroquinine 1,4phthalazinediyl diether. cDetermined by CSP-HPLC analysis. dWith 0.01 mmol of the catalyst. eUsing t-BuOK as additive. fUsing DBU as additive. gUsing 4 Å MS as additive.
Scheme 3. Applications of Various MBH Carbonates in Reactions with Sulfoximine 1aa
temperature or employing additives did not improve the results (Table 1, entries 13−16). Thus, all subsequent studies involved the use of reactants 1 and 2 in ratios of 1:2 and 20 mol % of (DHQD)2PHAL in MeCN (1 mL) at room temperature in air (Table 1, entry 11). Under the optimized conditions with MBH carbonate 2a as substrate, various sulfoximines 1 were evaluated, and Scheme 2 summarizes these results. Generally, all reactions proceeded smoothly to afford the corresponding products 3 with high enantioselectivities in good yields. The asymmetric allylic alkylation worked well for S,S-diaryl sulfoximines 1a−e bearing methyl, methoxy, and halogen substituents on the 4-position of the phenyl group. Dibenzothiophene sulfoximine 1f was tolerated as well, delivering product 3fa with 86% ee in 87% yield. Unsymmetrical sulfoximine 1g led to a 1.1:1.0 mixture of diastereomers of 3ga in 85% yield. Interestingly, the ee of both isomers varied, being 86% for the major and 91% for the minor diastereomer. Sulfonimidamide 4 reacted analogously, giving a mixture of diastereomers of 5 in a 1.1:1.0 ratio with ee values of 89% and 90% for the major and the minor diastereomer, respectively. The low diastereomeric ratio for 3ga and 5 was disappointing but not unexpected considering that a new carbon stereocenter adjacent to the sulfoximine nitrogen atom is generally difficult to form with high stereocontrol. Next, numerous MBH carbonates were applied in catalyses with S,S-diphenyl sulfoximine (1a) as reaction partner (Scheme 3). Irrespective of the carboxyl moiety at the ester group (compare products 3aa, 3ab, and 3ac) and the structural features of the arene (compare 3ad−ap), the yields of the
a
All reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol), and (DHQD)2PHAL (0.02 mmol) in MeCN (1 mL) at room temperature in air. The ee was determined by CSP-HPLC analysis.
corresponding products were high (73−93%). The ee values varied from 70% to 94%. In the series of aryl-containing substrates (3ad−an), neither steric nor electronic factors of the substituent on the arene appeared to play a significant role. Noteworthy, also MBH carbonates with heteroaryl moieties reacted well, affording products 3ao and 3ap in yields of 92% B
DOI: 10.1021/acs.orglett.8b03003 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
methylene β-sulfoximidoyl esters in high yield and with good enantioselectivity. The approach features a broad substrate scope and mild conditions. Currently, further studies concerning the formation of carbamate 7 are carried out in our laboratories, and the results will be reported soon.
and 93% with 90% and 92% ee, respectively.14 Single-crystal Xray analysis of 3ai revealed the product to have the S configuration, and consequently, all other absolute configurations were assigned accordingly. The synthetic utility of the products was exemplified by converting 3aa into isoxazoline 6 (Scheme 4). Upon treatment
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ASSOCIATED CONTENT
S Supporting Information *
Scheme 4. Conversion of 3aa into Isoxazoline 6
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03003. Experimental procedures, analytical data, copies of 1H as well as 13C{1H} NMR spectra, and HPLC chromatograms of the products (PDF) of 3aa with α-chlorobenzaldoxime, a single regioisomer of 6 was obtained as a 6:1 mixture of diastereomers in 56% yield. During this [3 + 2] cycloaddition reaction the ee was essentially retained. Performing the catalysis on a scale of 1 mmol led to new discoveries (Scheme 5). The first experiment (A) was carried
Accession Codes
CCDC 1868573 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Scheme 5. Reactions on 1 mmol Scale
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Marcus Frings: 0000-0002-6228-1229 Carsten Bolm: 0000-0001-9415-9917 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS H.Y. thanks the China Scholarship Council for a predoctoral stipend. out under argon for 49 h. Almost all of 1a was converted, and product 3aa was isolated with an ee of 93%. However, the yield of 3aa was surprisingly low (34%), and unexpected side product 7 was obtained in 41% yield (2% ee). Apparently, the sulfoximine nitrogen had attacked with very low enantioselectivity at another site in the molecule, namely the carbonyl position of the Boc group, giving carbamate 7 as main product. Next, the reaction was repeated under an atmosphere of air for 66 h (experiment B). Now, almost all 2a was consumed, but a significant amount of 1a was left in the reaction mixture (recovered amount: 26%). Isolated 3aa had almost the same ee as before (92%), but the yield was much higher (67% corresponding to 90% yield based on converted 1a). Carbamate 7 represented the minor product with a yield of 7% (9% yield based on converted 1a). The ee of 7 was very high ee (95%). To investigate why MBH carbonate 2a was almost fully consumed under these conditions, albeit being utilized with 2 equiv with respect to 1a, the other detected side products were isolated. They were chirally resolved MBH substance 8 with 56% ee (7% yield based on 2a) and an inseparable diastereomeric mixture (2:1 dr) of the unassigned chiral and meso-diacrylate 9 (14% yield based on 2a). In summary, we developed a Lewis base catalyzed asymmetric allylic alkylation of sulfoximines with Morita− Baylis−Hillman carbonates. It allows the preparation of α-
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DOI: 10.1021/acs.orglett.8b03003 Org. Lett. XXXX, XXX, XXX−XXX
