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Letter
Synthesis of axially chiral C-N scaffolds via asymmetric coupling with enantiopure sulfinyl iodanes James Rae, Johanna Frey, Soufyan Jerhaoui, Sabine Choppin, Joanna Wencel-Delord, and Françoise Colobert ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b04343 • Publication Date (Web): 02 Feb 2018 Downloaded from http://pubs.acs.org on February 5, 2018
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ACS Catalysis
Synthesis of axially chiral C-N scaffolds via asymmetric coupling with enantiopure sulfinyl iodanes James Rae, Johanna Frey, Soufyan Jerhaoui, Sabine Choppin, Joanna Wencel-Delord* and Françoise Colobert* Laboratoire d’Innovation Moléculaire et Applications (UMR CNRS 7042), Université de Strasbourg / Université de haute Alsace, ECPM, 25 Rue Becquerel, 67087, Strasbourg, France ABSTRACT: Axially chiral C-N compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as biologically active scaffolds and chiral ligands. The synthesis of these compounds is extremely challenging and in particular no metal-catalysed asymmetric, intermolecular C-N coupling has been previously reported. Herein we disclose an intermolecular atropselective C-N coupling, occurring with excellent stereoselectivity. This Cucatalysed transformation is based on the use of highly active coupling partners, i.e. chiral iodanes bearing a very cheap and traceless sulfoxide auxiliary. Use of such original ortho-sulfoxide iodanes enables this challenging coupling to occur at room temperature, guaranteeing high atroposelectivity and atropostability of the coupling products under reaction conditions. Due to extensive possible post-modifications of the optically pure products, a panel of C-N axially chiral scaffolds can now be accessed. KEYWORDS: C-N axial chirality, chiral iodanes, atroposelective coupling, Cu-catalyzed coupling, sulfoxide
Axial chirality is an important feature of many natural and biologically active molecules but also privileged chiral ligands such as BINAP.1 In the vast majority of cases, atropisomerism arises from a slow rotation around an Ar-Ar bond. Likewise, if sterically hindered substituents are present around a C-N axis, the molecule can also exhibit axial chirality, as in case of biologically active products like methaqualone or metolachlor and atropisomeric ligands for allylic alkylation (Fig. 1). Despite the growing interest in C-N axially chiral compounds in medicinal chemistry,2 asymmetric catalysis3 and molecular devices,4 their synthesis presents a compelling scientific challenge. Indeed, over the last decade several strategies have been utilized to construct atropisomeric C-N compounds, these include a) asymmetric N-functionalization of anilides,5 b) [2+2+2] cycloadditions of 1,6-dienes,6 c) kinetic resolution of sulfides7 and d) enantioselective desymmetrization of prochiral substrates.8 Whilst acknowledging the synthetic value of these strategies, these approaches are limited to very specific substrates. Therefore, a significantly more general and direct route involving an asymmetric formation of the C-N motif with concomitant chiral induction would be highly appealing.
Following such a challenging goal, Jorgensen developed the organocatalytic amination of 2-naphthols with azadicarboxylates9 and Kamikawa and Uemura reported diastereoselective SNAr reactions between planar chiral arene chromium complexes and indoles (Scheme 1).10 In clear contrast, although transition metal catalyzed C-N couplings such as the Ullmann reaction or Buchwald-Hartwig transformations have established themselves as benchmark approaches to create C-N linkages,11 no asymmetric version of these reactions has been reported. The major difficulty in accessing atropisomerically pure molecules via C-N cross-couplings arises from the clear antagonism between the generally harsh reaction conditions required for these types of hindered couplings and the low atropostability of the C-N bonds (Scheme 1). Accordingly, under such harsh conditions the rotation around the newly created C-N linkage is rapid, thus preventing the formation of an optically enriched product. The synthesis of C-N atropisomerically enriched compounds by direct coupling between an aryl moiety and a N-coupling partner hence requires the design of a novel approach, compatible with mild reaction conditions. Following this goal we surmised that the use of a highly electrophilic coupling partner such as hypervalent iodines could be a hint to perform the Cu-catalyzed C-N Ullmann-type coupling12,13 at low temperature thus ensuring the configurational stability of the formed atropisomer. Besides, the stereoselectivity could be controlled while employing enantiomerically pure, stereogenic iodanes.
Figure 1 C-N atropisomeric compounds of interest.
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ACS Catalysis Previous examples of atroposelective C-N bond formation
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Jørgensen, 2006 organocatalyzed amination O dihydrocupreidine NH2 O 2O NH (20 mol%) R OH R1O2C - 20 °C, DCE NH2 N OR1 N N + OH 2 CO2R Kamikawa & Uemura, 2006
stereoselective SNAr
R2
R1
NaH Toluene 18-crown-6
F +
110 °C
HN
Me
Metal-catalyzed atropisomeric C-N coupling X R2
M* N H
+
R1
N
Me Cr(CO)3
(OC)3Cr
R1
R2
N R1
R2
unprecedented Potential advantages: general approach variety of products Challenges: coupling of congested partners usually high reaction temperature vs. atropostability of the products
Temp.
This work Cu-catalyzed atroposelective C-N coupling Idea: chiral iodane as highly reactive coupling partner for RT coupling
Ar
I X
O S
R1 1
N
Cu
pTol + N H 2
First metal catalyzed atroposelective C-N coupling Mild reaction conditions Non-activated N-H partner Abundant & cheap metal catalyst
N SOpTol RLi
base R1 RT
First challenging part of this work concerned the synthesis of unprecedented sulfoxide iodanes 1 (Scheme 2).17 An interesting strategy to access hypervalent iodines from the nonprefunctionalized arene precursor, such as 4, relates to a ligand exchange reaction, using a derivative of Koser’s reagent: hydroxy(mesityl)-λ3-iodanyl 4-methylbenzenesulfonate (5Mes). Aryl-sulfoxides precursors 4 were thus prepared by reacting the corresponding aryl magnesium with enantiomerically pure, cheap and accessible at large scale menthylsulfinate (accessible in one step at 50g scale using menthol as chiral pool). Subsequent reaction of 4a with 5-Mes, in the presence of TFA, delivered the expected sulfoxide iodane 1aOTs isolated by simple crystallization in quantitative yield. Importantly, the optical purity of the sulfoxide auxiliary is preserved. Finally an anion exchange proceeded smoothly, delivering 1a bearing, amongst other, BF4 and PF6 counter anions. Notably, the reaction is equally high yielding on a multigram scale. Synthesis of 1b and 1c necessitated the use of MesI(OAc)2 in combination with TMSOTf and provided the expected iodanes in moderate to good yields.
E
1 E+ R
3 Use of very cheap sulfoxide as chiral auxiliary Traceless character of the sulfoxide post-diversification of the C-N axially chiral compounds No additional ligand
Scheme 1: Concept of metal-catalyzed atropisomeric Ccoupling. Scheme 2: Synthesis of sulfoxide iodanes 1a-c. Indeed, if a chiral auxiliary is placed in the ortho-position to the iodine substituent, after the rapid oxidative addition of a Cu-catalyst, coordination between the catalyst and auxiliary could be expected to relay stereogenic induction in C-N bond forming event. However, considering the synthetic utility of such a transformation, the precise design of the chiral iodanes was essential. Firstly, due to the selectivity issues in a targeted transformation, steric and electronic properties of the two aryl moieties on the iodane should be distinct, in order to promote the expected Ar-N coupling delivering the axially chiral compound. Secondly, dissymmetric chiral iodanes need to be straightforwardly accessible from simple starting materials; the chiral auxiliary needs therefore to be prepared from inexpensive chiral pool. Finally, post-modifications of this motif are requested in order to convert the newly constructed atropisomeric C-N molecules into a variety of chiral derivatives. Considering the high potential of the sulfoxide moiety as a chiral auxiliary,14 its convenient, large-scale preparation and its traceless character, we hypothesized that sulfoxidesubstituted iodanes 115 would be perfect candidates to achieve an unprecedented atroposelective C-N coupling. Notably, as the sulfoxide moiety can be easily transformed into an array of functional groups (sulfoxide lithium exchange followed by an electrophilic trapping), hence generated C-N axially chiral compounds should be considered as a platform to build up a large panel of such atropisomeric compounds.16 Accordingly, we report herein the synthesis of original enantiomerically pure sulfoxide iodanes 1 and their use in a first stereoselective metal-catalyzed C-N coupling. This unique transformation allows accessing C-N atropisomerically pure scaffolds under mild reaction conditions, using a cheap and abundant Cucatalyst and under ligand-free conditions (Scheme 1).
With the expected sulfoxide iodane 1a in hand, we subsequently focused on the targeted atroposelective C-N coupling, using indoline 2A as a standard substrate (Scheme 3). Encouragingly, a small amount of the desired product was obtained when using 1a-Mes substrate, in combination with Cu(MeCN)4BF4 as catalyst, Cs2CO3 as base and conducting the reaction at room temperature in DMSO. Crude 1H NMR analysis indicated promising chiral induction (d.r. of 76:24). Along with the desired C-N coupling product 3aA, decomposition of 1a was observed (6a) but also reduced, dehalogenated arene 4a and competitive coupling product 7 were formed. Optimization of the reaction conditions imposes: 1) limitation of the substrate’s degradation (formation of 4a) and 2) enhancement of the bond formation step after oxidative addition of Cu into the C-I bond (generation of 3). Acordingly, it was shown that: 1) use of a mixture of toluene with polar DMSO is essential for good solubility of the reactants and catalyst; 2) nature of the iodane counter anion has a minor impact on the transformation; 3) Cu(I) salts perform better than more oxidized precatalysts, with a commercially available (CuOTf)2Toluene complex outcompeting other salts. Finally, the desired product 3aA was isolated in excellent yield and high atropopurity of 90:1018 when using a slight excess of iodane (1.5 equivalent) and shortening the reaction time to 3 hours. The test reaction conducted in absence of the Cu-catalyst was unproductive. Besides, the key importance of the iodane coupling partner was evidenced as no C-N bond formation occurred when using the corresponding iodo-arene 6d as a substrate (for details see SI).
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ACS Catalysis
Mes
I
OTs
R1
SOpTol
(CuOTf)2-Tol (10 mol%) Cs2CO3 (1 equiv)
+ R
N H
N R1
R2
R2
1a-c
N MeO
SOpTol
2A-L
Me MeO
OMe
Scheme 3: Test reaction for the optimization study.
With the optimized reaction conditions in hand we explored the scope of the reaction (Scheme 4). Firstly, in order to increase the atroposelectivity of the coupling, C7-substituted indolines were used. Rewardingly, coupling with 7methylindoline 2B worked well delivering 3aB in 72% yield as single atropisomer. As expected, the presence of the 7-Me substituent on the indoline significantly increased the rotation barrier from 24.8 kcal/mol measured for 3aA up to 27.4 kcal/mol for 3aB.19 Quantitative yield and excellent chiral induction were also achieved using iodane 1b-Mes. Remarkable, both Br and Cl-atoms were well tolerated at the C7 position of the indoline coupling partner; 3aC and 3aD were isolated in excellent yields of 99 and 88% respectively and high diastereopurity (d.r. of 91:9 and 89:11). Interestingly, the less sterically hindering OMe substituent at 7-position also provided atropostability of the coupling product and 3aE was obtained as single atropisomer albeit in decreased yield of 51%. Using benzyl-protected 7-hydroxyindoline 2F, 3aF was delivered with > 95 : 5 diastereomeric ratio, but in moderate yield. An alternative solution to increase the hindrance around the CN linkage consists in replacing OMe-substituent of iodane 1a by a more hindering moiety. Accordingly, iodane 1c was synthesized (for details see SI). As foreseen, the coupling product 3cA was not only isolated in good yield (63%) but also impressively as a single atropisomer. Remarkably, the change from OMe group to Me substituents leads to a drastic change of the rotational barrier from 24.8 kcal/mol to 30.7 kcal/mol. Subsequently, transformations with several indolines 2G-M were explored. 4-Me, 4-Br and 4-Cl substituted Ncoupling partners (2G-I) performed well, delivering 3cG, 3cH and 3cI in 61, 46% and 53% yield, and d.r. > 95 : 5. Equally stereoselective reactions occurred while using 5-Bpin and 5-Br substituted N-coupling partners 2J and 2K delivering optically pure products of interest for further modifications. Relevant for pharmaceutical and agrochemical applications, strongly electron withdrawing and sterically demanding CF3substituent was also relatively well tolerated, affording 3cL in 35% yield. A more productive coupling occurred when Bratom was introduced at 6-position (3cM). Finally, coupling between 5-bromoindoline 2H and 1a was also highly atropselective, but as foreseen, a slow rotation around the ArAr bond occurs at room temperature over prolonged time. The absolute SaR configuration of the adducts was confirmed by single X-ray analysis of adduct 3cK.20
N
Cl MeO
SOpTol
N SOpTol
Me iPrO
MeO MeO
N SOpTol
BnO MeO
OMe
Me
OiPr 3cG: 61% yield > 95 : 5 dr
N SOpTol
Me
OiPr 3cA: 63% yield > 95 : 5 dr
N SOpTol
Me
N
OiPr
OiPr 3cJ: 55% yield > 95 : 5 dr Br
Br
N SOpTol
Me
OiPr 3cK: 45% yield > 95 : 5 dr
SOpTol
OiPr 3cK: SaR
SOpTol
3cI: 53% yield > 95 : 5 dr
F3C
Me
SOpTol
Bpin
Me
OiPr
Br
N
N
3cH: 50% yield > 95 : 5 dr
SOpTol
OMe
Cl
SOpTol
N
3aC: 99% yield 91 : 9 dr
OMe
N SOpTol
Br MeO
3aF: 37% yield > 95 : 5 dr
Br
N
SOpTol
OiPr
3aE: 51% yield > 95 : 5 dr
Me
N
3bB: 98% yield > 95 : 5 dr
3aB: 72% yield > 95 : 5 dr
OMe 3aD: 88% yield 89 : 11 dr
Me
3
OMe
3aA: 87% yielda 90 : 10 dr
SOpTol
Tol:DMSO (2.5 : 1) 19 - 23 °C
3cL: 35% yield > 95 : 5 dr
N
Me
N SOpTol MeO
OiPr 3cM: 56% yield > 95 : 5 dr
SOpTol
OMe 3aH: 62% yield 90 : 10 dr
Scheme 4: Scope of the Cu-catalyzed atroposelective C-N coupling. A proposed mechanism for the copper catalyzed asymmetric coupling is shown in Scheme 5. After an initial formation of Cu(I)-indoline complex II, precoordination of II with iodane occurs via the oxygen atom of the sulfoxide moiety; this coordination mode seems privileged considering geometrical reasons, ie. formation of 5-member metallacyclic intermediate, and hard character (HSAB theory) of both, O- and Cu IIatoms.21 The Cu intermediate II approaches the iodane from the opposite side of the bulky p-tolyl group of the chiral sulfoxide to generate III. The oxidative addition of 1 provides Cu(III) intermediate IV. The chemoselectivity of the oxidative addition is controlled at this step as insertion of the metal into I-Mes bond is strongly disfavored due to the steric reasons. Subsequent N-H deprotonation with Cs2CO3 leads to formation of V. Final reductive elimination yields the coupling product 3 and Cu(I) species are regenerated. The stereochemical outcome of this coupling can be tentatively rationalized on the basis of stabilizing ߨ,ߨ-stacking interactions between the pTol-moiety of the auxiliary and the aromatic part of the indoline when intermediate IV-A is formed.22 This assumption seems in accordance with experimental results and the diastereoselectivities observed for the products 3aB-F. Introduction of an additional substituent at 7-position of indoline increases significantly atropostability of the products. Notably, for electron-rich indolines 2B, 2E and 2F the corresponding products are obtained as sole atropisomers. In contrast, intro-
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duction of electron-withdrawing motifs, such as Cl-or Bratoms in position 7 of the indoline, results in drop of diastereoselectivity (approx. 90:10 for 2C and 2D). Weaker ߨ,stacking interactions could be attributed either to decreased electronrichness of the indoline and/or to important steric hindrance of bulky Cl and Br.
Scheme 5: Proposed mechanism. Besides the unique character of this stereoselective coupling allowing metal-catalyzed, mild and atroposelective C-N bond formation, its synthetic value arises from the possible postmodifications of the newly accessed chiral scaffolds (Scheme 6a). Indeed the use of the sulfoxide moiety as a chiral auxiliary gives also unique perspectives in terms of post-modifications of 3. Actually lithium/sulfoxide exchange conducted at sufficiently low temperature should yield atropisomerically pure lithium intermediates prompt to trap a variety of electrophiles. To illustrate this purpose, 3aB was reacted with tBuLi at - 78 °C followed by addition of ethyl formate as aldehyde precursor. Rewardingly, 8 was delivered in a synthetically useful yield of 50% and the atropisomeric purity was conserved (er > 98:2). An additional advantage of this methodology is its compatibility with halogenated substrates and therefore postmodification of the compounds bearing Br-, Cl- or Bpin motifs via state of the art cross-coupling reactions is possible (Scheme 6b). A Stille coupling of 3cK with tributylvinyl stannane in presence of CuI and CsF23 occurred smoothly at 50 °C giving 9 in high 74% yield and with no loss of the atropopurity (Scheme 6b1). In addition, mild Suzuki-Miyaura coupling with 4-methoxyphenylboronic acid was effective under micellar conditions,24 affording the coupling product 10 in 74% yield (Scheme 6b2). Finally, the C-N axially chiral arylindoline 3 could be easily transformed into the corresponding indole 11 in high 90% yield by simple treatment with DDQ therefore allowing the modular access to atropopure C-N axially chiral indoles (Scheme 6c).25
Scheme 6: Post-modification of 3aB: a) sulfoxide/lithium exchange, b) Stille and Suzuki-Miyaura couplings, c) oxidation of indolines to indoles
In summary, this study demonstrates the first atroposelective Ullmann-type construction of atropopure N-arylated indolines possessing C-N axial chirality. The potential of this system is illustrated by the union of very sterically encumbered coupling partners furnishing efficiently and under mild conditions hindered C-N motifs with high atroposelectivity, This strategy resolves an enduring antagonism between the high temperatures generally required in such challenging transformations and the atropostability of the assembled chiral compounds. Importantly, the traceless character of the sulfoxide auxiliary combined with good tolerance of this protocol towards halogenated substrates ensures straightforward diversification of the atropoisomeric C-N products yet permitting a synthesis of a large panel of original chiral scaffolds. We are confident that this study will have wide implications for the development of an array of novel, axially chiral motifs. Further investigations on this theme with various N-coupling partners are currently underway in our laboratory.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures, chiral HPLC Chromatograms, rotational barriers, X Ray data and spectral data for all new compounds (PDF)
AUTHOR INFORMATION Corresponding Author
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ACS Catalysis * e-mail for F.C.:
[email protected] * e-mail for J.W.-D.:
[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding Sources This research is supported by CIFRC Grant.
ACKNOWLEDGMENT We thank the CNRS (Centre National de la Recherche Scientifique), the “Ministere de l’Education Nationale et de la Recherche“, and IcFRC, Strasbourg (International center of Frontier Research in Chemistry ) France for financial support. J. R. is very grateful to the “IcFRC, Strasbourg” for a post-doctoral grant and J. F. is very grateful to the “Ministere de l’Education Nationale et de la Recherche“, France for a doctoral grant. We are also very grateful to Dr. Lydia Karmazin and Dr. Corinne Bailly for single crystal X-ray diffraction analysis and Dr. Emeric Wasielewski for the determination of rotational barriers through 1H NMR analysis.
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Due to the difficulty in obtention of monocrystals, 3cK was prepared using racemic sulfoxide DG. Accordingly, the relative configuration could be determined yet allowing determination of the absolute configuration of the enantiomerically pure compounds herein reported. (21) Numerous literature precedents indicate privileged O-Cu coordination of the sulfoxides (See Fernandez, I.; Khiar, N. Chem. Rev.
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2003, 103, 3651-3705) and several X Ray crystal structures have been reported showing coordination of the oxygene of the sulfoxide with copper. See Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 36513705. (22) For ߨ,ߨ-stacking interactions with p-tolyl substituent of a sulfinyl group see : Garcıa Ruano, J.-L.; Parra, A.; Marcos, V.; del Pozo, C.; Catalan, S.; Monteagudo, S.; Fustero, S.; Poveda, A. J. Am. Chem. Soc. 2009, 131, 9432-9441.
(23) Mee, S. P. H. ; Lee, V. ; Baldwin, J. E. Angew. Chem. Int. Ed. 2004, 43, 1132 –1132. (24) Lipshutz, B. H. ; Petersen, T. B. ; Abela, A. R. Org. Lett. 2008, 10, 1333-1336. (25) Lu, S-C. ; Wei, S-C. ; Wang, W-X. ; Zhang, W. ; Tu Z-F. Eur. J. Org. Chem. 2011, 5905-5910.
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