Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enoldiazosulfones for Highly Enantioselective [3 + 3]-Cycloaddition with Nitrones Catalyzed by Copper(I) with Chiral BOX Ligands Frady G. Adly,†,‡ Kostiantyn O. Marichev,† Joseph A. Jensen,† Hadi Arman,† and Michael P. Doyle*,† †
Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States Faculty of Science and Technology, University of Canberra, Canberra, Australian Capital Territory 2601, Australia
‡
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S Supporting Information *
ABSTRACT: Enoldiazosulfones undergo [3 + 3]-cycloaddition with nitrones when catalyzed by copper(I) catalysts, but not with dirhodium(II) catalysts. Under mild reaction conditions with chiral bisoxazoline ligands, copper(I) catalysts produce 1,2-oxazine-sulfone derivatives in high yields and enantioselectivities. Dirhodium(II) catalysts form stable donor−acceptor cyclopropenes that undergo uncatalyzed [3 + 2]-cycloaddition reactions with nitrones.
O
Scheme 1. Metal-Catalyzed [3 + 3]-Cycloaddition Reaction of Enoldiazo Compounds with Stable Dipoles
rganosulfones are a valuable class of sulfur containing molecules owing to their versatility as useful intermediates in organic synthesis.1 They have a wide spectrum of biological properties that are recognized in natural products, pharmaceuticals, and agrochemicals.2 However, despite their availability for more than 50 years,3 diazosulfones have not been widely used in catalytic reactions involving metal carbenes.4 Although the construction of these structures extends from tosyldiazomethanes to β-keto-α-diazosulfones, only two examples of cycloaddition reactions have been reported in which a vinyldiazosulfone has been used for the preparation of
We have successfully employed silyl-protected enoldiazoacetates,7 -acetamides,8 and -ketones9 in [3 + 3]-cycloaddition reactions with a variety of stable dipolar reactants (Scheme 1). These reactions occur with competitive formation of the donor−acceptor cyclopropene generated intramolecularly by dinitrogen extrusion.10 In previous studies the donor−acceptor cyclopropene was found to be a resting state for the vinylcarbene that, once regenerated, undergoes [3 + 3]-cycloaddition.11 High enantioselectivities were achieved using chiral dirhodium(II)11 and, more recently, copper(I)8 catalysts. We were intrigued with the possible application of enoldiazosulfones to [3 + 3]cycloaddition reactions. We expected that they would be conveniently available from β-keto-α-diazosulfones by silyl transfer to the enolate,12 but we were uncertain of their viability for [3 + 3]-cycloaddition because of the anticipated stability of the donor−acceptor cyclopropene.6 We now report that the
sulfonyl-bearing frameworks (eq 1 and 2), and one of them the probable uncatalyzed [4 + 2]-cycloaddition by the donor− acceptor TBSO-cyclopropenesulfone formed from the diazo compound by dinitrogen extrusion.5,6 © XXXX American Chemical Society
Received: October 25, 2018
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DOI: 10.1021/acs.orglett.8b03421 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Metal-Catalyzed Divergent Addition Reactions of Enoldiazosulfone 1a and Nitrone 2a: Catalyst Screeninga
Table 2. Copper(I)-Catalyzed [3 + 3]-Cycloaddition of Enoldiazosulfone 1a and Nitrone 2a: Chiral Ligand Optimizationa
yield (%) entry 1 2 3 4 5 6 7
catalyst (x mol %) Rh2(OAc)4 (2) Rh2(oct)4 (2) [Cu(CH3CN)4]BF4 (5) Cu(OTf)·Tol1/2 (5) [Au(JohnPhos)(CH3CN)]SbF6 (5) AgSbF6 (5) Pd(PhCN)2Cl2 (5)
3a
4
5
b
77c 33b
73 74b trace 14b
15b
41b
37b 92c 76c
a
All reactions were carried out on a 0.20 mmol scale in 4.0 mL of DCM: 2a (0.20 mmol) and 1a (0.30 mmol). bDetermined by 1H NMR analysis using 1,3,5-trimethoxybenzene as the internal standard. c Isolated yield after flash-chromatography.
sulfone group stabilizes the cyclopropene formed by dinitrogen extrusion, rendering dirhodium(II) catalysts ineffective to reform the metal-carbene. Chiral copper(I) catalysts, however, are able to overcome this limitation to effect [3 + 3]cycloaddition in high yields and excellent enantiocontrol. Silyl-protected enoldiazosulfones were prepared in high yields from the corresponding β-ketosulfones by diazo transfer and subsequent enolization/silyl transfer.12 To determine metal catalyst suitability tert-butyldimethylsilyl (TBS)-protected enoldiazosulfone 1a was treated with N,α-diphenylnitrone 2a in dichloromethane (DCM) at room temperature (Table 1). Dirhodium(II) catalysts generated the product from [3 + 2]cycloaddition (4) between the nitrone and the donor−acceptor cyclopropene formed from 1a (entries 1 and 2), whereas copper(I) tetrafluoroborate [Cu(CH3CN)4]BF4 formed the product from [3 + 3]-cycloaddition (3a) in 77% isolated yield (entry 3). Unlike previously documented [3 + 3]-cycloaddition reactions of enoldiazo compounds with nitrones,9,13 where a slight molar excess of nitrone over the diazo compound provided optimum results, reactions with 1a required an excess of the enoldiazosulfone over nitrone to achieve optimum yields. The yield of 3a decreased with increasing the amounts of nitrone [copper(I) catalysis]: 0.7 equiv of 2a (77% 3a), 1.0 equiv of 2a (37% 3a), and 2.0 equiv of 2a (19% 3a). This was due to a facile silyl transfer from the donor−acceptor cyclopropene to the nitrone that was competitive with cycloaddition (see Supporting Information for NMR spectra) and probable subsequent ring opening of cyclopropene.6 Other catalysts that are known to form metal carbenes from diazo compounds, specifically, gold(I) hexafluoroantimonate [Au(JohnPhos)(CH3CN)]SbF614 and silver(I) hexafluoroantimonate,7b completely shifted the reaction chemoselectivity to the formation of the Mukaiyama−Mannich addition product affording 5 in 92% and 76% yields, respectively (entries 5 and 6). Use of copper(I) triflate [Cu(OTf)·Tol1/2] and bis(benzonitrile)palladium(II) chloride [Pd(PhCN)2Cl2], however, resulted in a mixture of 3a,
entry
ligand
3a yield (%)b
3a ee (%)c
4 yield (%)d
1 2 3 4 5 6 7 8 9 10 11
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11
40 42 82 85 83(92)e 84(88)e 80 82 81 85 72
28 32 66 79 96(99)e,f 97(98)e 59 85 72 87 97
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