"It's a (Kinetic) Trap!" – Selectively Differentiating Allylic Azide Isomers

SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2018, 29, 1537–1542 synpacts 1537 en

Syn lett J. J. Topczewski, M. R. Porter Synpacts

"It’s a (Kinetic) Trap!" – Selectively Differentiating Allylic Azide Isomers

Me N3

Joseph J. Topczewski* 0000-0029-9215-102 R X Matthew R. Porter HN O Me N3 R X AgSbF6 R X (10 mol%) Department of Chemistry, University of Minnesota - Twin Cities, CCl3 HN O N 207 Pleasant St. SE, Minneapolis MN 55455, USA CHCl3 3 [email protected] Me Me R X HN CCl CCl3 3 up to 94% >25:1 dr O X = CH2, O, NPG >25 Examples N3

Received: 14.02.2018 Accepted after revision: 16.03.2018 Published online: 12.04.2018 DOI: 10.1055/s-0037-1609479; Art ID: st-2018-p0106-sp

Abstract Allylic azides are known to undergo the Winstein rearrangement and are often isolated as an equilibrating mixture of isomers. While this process has been known for almost 60 years, very few synthetic applications of this process have been reported. The absence of methods exploiting these intermediates likely stems from a paucity of approaches for gaining the required selectivity to differentiate the isomers. Our lab has made some progress in leveraging this unusual reaction into practical synthetic methodology. Presented herein is a summary of our lab’s recent accomplishments in selectively trapping allylic Joseph Topczewski (left) grew up in Racine, Wisconsin and received azides. his BSc degree from the University of Wisconsin at Parkside in 2007. 1 Introduction After completing his PhD at the University of Iowa with Prof. David 2 Background: Allylic Azides Wiemer in 2011, he conducted postdoctoral studies at Iowa with Prof. 3 Dynamic Cyclization of Imidates Hien Nguyen and Prof. Daniel Quinn until 2013. He then moved to the 4 Summary and Outlook University of Michigan where he carried out postdoctoral studies with Prof. Melanie Sanford. He started his independent research career at Key words azides, stereoselective, dynamic kinetic resolution, the University of Minnesota in the summer of 2015. cyclization, synthesis, allylic Matthew Porter (right) was born in Portland, Oregon and received his BSc degree from Case Western Reserve University in 2014. In the fall of 2015, he joined the Topczewski lab to focus on organic synthesis with allylic azides.

1 Introduction ates, phosphates, and imidates are employed in transition- metal-catalyzed substitution reactions, such as the Tsuji– Organic azides are key synthetic intermediates with a Trost reaction.5–8 Allyl-vinyl ethers are substrates for the This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. storied history.1–3 Azides are most generally recognized as Claisen rearrangement.9 Furthermore, allyl or crotyl metal protected primary amine equivalents and are typically in- reagents are central to many synthetic sequences.10–13 stalled by straightforward nucleophilic displacement using These reagents have received as much attention as allylic

NaN3, a commodity reagent. Many classic reactions utilize electrophiles because they are functional equivalents to the organic azides including the Staudinger reaction, aza-Wittig aldol reaction. In light of the advantageous properties of reaction, Huisgen cycloaddition, Curtius rearrangement, allylic systems and the plethora of applications of azides, it and Schmidt reaction. The combined utility of these trans- is somewhat surprising that allylic azides are scarcely re- formations places organic azides in a unique arena of signif- ported as synthetic intermediates. icance for synthesis. One explanation for the noticeable underutilization of Likewise, allylic systems are cherished in synthesis. allylic azides is their spontaneous rearrangement (Scheme Allylic electrophiles display enhanced reactivity, which is 1). This phenomenon was first fully documented noted in most sophomore texts.4 Allylic acetates, carbon- by Winstein,14 although others had speculated that the

Syn lett J. J. Topczewski, M. R. Porter Synpacts

or trans and the absolute stereochemistry of the azide bear- N3 ing carbon can be R or S. The complexity of this mixture R N R N 3 R 3 necessitates exceptional selectivity in any reaction focused 1.1 1.2 1.3 on resolving the azide isomers. A few strategies have been Scheme 1 Equilibration of allylic azides by the Winstein rearrangement developed to accomplish this.

N3 N3 15,16 trans rearrangement may exist. In the first account of this R R' R R' process, Winstein thoroughly documented the rearrange- 3.1 3.2 ment of crotyl and prenyl azide. The rate of this rearrange- R N ment is relatively slow at room temperature; however, it is N3 R' 3 cis facile enough that a mixture of azide isomers is commonly R R' isolated.17–20 Due to this complication, many authors have 3.3 3.4 viewed the Winstein rearrangement as a nuisance. Several proximal to R distal to R authors report immediate azide reduction to prevent isom- Scheme 3 General equilibrium for an allylic azide erization.21,22 However, a few promising reports demonstrate that allylic azides may be used in a dynamic process. An initial success by Craig and co-workers was predicat- ed on coupling the allylic azide rearrangement to an intra- 2 Background molecular [3,3] rearrangement (Scheme 4).25 The authors recognized that only one isomer in the azide equilibrium In a seminal study, Sharpless and co-workers reported was poised to undergo an irreversible second rearrange- that simple allylic azides could be used in click reactions or ment. This insight enabled a high-yielding Johnson–Claisen epoxidations (Scheme 2).23 The mixture of crotyl or prenyl rearrangement. While the yield of this process was general- azide isomers could selectively afford a single product un- ly high, it did suffer from minimal diastereoselectivity and a der appropriate conditions. In the mixture of prenyl azides mixture of syn and anti azides was reported. This was the (2.1 and 2.2), the primary azide 2.2 preferentially under- first example of using proximal functionality to lay a kinetic went copper-catalyzed click cycloaddition instead of the trap for the rearrangement. tertiary azide isomer 2.1. The same azide isomer reacted preferentially with m-CPBA to afford the more substituted OEt OEt epoxide 2.3. The selectivity is due to the known preference O ~1:3 O of m-CPBA to react with the more nucleophilic alkene.24 For R R both reactions, the selectivity was not as high for crotyl 4.2 4.1 N3 N3 azide. In both example reactions the predominant azide R = n-pentyl 145 °C isomer was functionalized. Nevertheless, these results 99% showed that it is possible to utilize the dynamic nature of CO2Et CO2Et allylic azides. R + R

N3 N3 Me Me 4.4 4.3 3:7 1:1 syn to anti N3 Me N Me 3 Scheme 4 Double rearrangement of allylic azides 2.1 2.2 PhCCH This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. m-CPBA CuSO4 95% 85% The Aubé lab contributed to the area of allylic azide dif- Me Me ferentiation by recognizing that the azide isomers could be Me N Me N3 Ph O resolved through a cyclization reaction. The azido-Schmidt N 2.4 N 2.3 reaction has been a central theme to the Aubé lab’s research Scheme 2 Seminal contribution by Sharpless and co-workers program and this reaction was extended to allylic azides (Scheme 5).26–28 A mixture of allylic azide isomers was reported and the azide proximal to the ketone (branched) re- For a generic internal allylic azide, the system is more acted preferentially. The tether controls the ring size of the complex than for prenyl azide (Scheme 3). Prenyl azide ex- intermediate adduct and subsequently controls the relative ists as a mixture of only two azide isomers (Scheme 2). rate of ring closure. The five-membered ring forms prefer- However, in a general sense, up to eight isomers are possi- entially over the seven-membered ring, which could arise ble (Scheme 3, enantiomers not shown). The azide can be from the cis isomer. Several examples of this process were proximal or distal to a specific group. The alkene can be cis reported as was a full discussion of the stereochemical out-

Syn lett J. J. Topczewski, M. R. Porter Synpacts comes (not shown). This process was used to complete a 3 Dynamic Cyclization of Imidates formal synthesis of pinnaic acid. In a second study, the Aubé lab reinforced these findings and showed that allylic We turned our attention to more complex systems fea- azides with a pendent alkyne could selectively undergo an turing proximal functionality.20,35 We designed a system intramolecular Huisgen cycloaddition (Scheme 6).28 These that could take advantage of the lessons learned from the examples were the first instances where a minor azide iso- studies of Craig and Aubé with an additional twist. It is mer (ca. 20% at equilibrium) preferentially formed the well-known that allylic electrophiles react faster in substi- major product. tution reactions.36 We hypothesized that this difference in rate could be exploited to differentiate the azide isomers if a specific nucleophile and electrophile combination was O O N3 identified (Scheme 8). An additional element of complexity Ph N3 Ph must be noted. A substitution reaction could occur by an Me Me Me Me 5.1 trans5.3 branched SN2 or SN2′ pathway and this could result in a mixture of SnCl4 products (Scheme 8, linear, syn and anti). If the substitution 54% O reaction provided the linear product, the azide would still O Ph be allylic and would likely form a new mixture of isomers. Me Me Ph N 5.2 cis N3 N N Me 3 3 5.4 51:13:36 trans:cis:branched X X Me R R 8.1 8.2 Scheme 5 Intramolecular azido-Schmidt reaction X is not allylic X is allylic faster reaction?

N3 N3 N3 Nuc 83:17 R R R N3 O Nuc Nuc N3 O 8.3linear 8.4syn 8.5 anti 6.1 6.2 Scheme 8 Allylic leaving group and possible products. X = generic PhMe, reflux 72% leaving group; R = generic carbon group; Nuc = generic nucleophile

N O N Allylic trichloroacetimidates were investigated because N prior experience indicated that these groups are quite ver- N3 O 6.3 6.4 satile and can be activated under electrophilic conditions.37,38 A classic nucleophile to intercept the putative Scheme 6 Intramolecular Huisgen cycloaddition of allylic azides allylic electrophile could be an arene by a Friedel–Crafts reaction. Borrowing from Aubé’s cyclization strategy, tether- Our lab became interested in allylic azides because we ing the arene to the allylic system would provide control for envisioned that the Winstein rearrangement could be used the site of nucleophilic capture. Therefore, we focused our as the racemization pathway in a dynamic kinetic resolu- initial attention on azides such as 9.1 (Scheme 9). After tion (DKR). Dynamic kinetic resolution is a well-established screening a variety of catalysts, it was found that cationic area in enantioselective synthesis.29–33 However, only a few silver salts were effective at promoting the desired cycliza-

mechanisms of racemization are widely used. We achieved tion in high yield and diastereoselectivity. Control experi- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. a DKR by coupling the Sharpless asymmetric dihydroxyl- ments and several qualitative observations indicate that ation to the Winstein rearrangement (Scheme 7).34 Key to general acid catalysis likely facilitates the cyclization.39 the success of this process was using azides that provide the enantiomer upon rearrangement. The process achieved ex- Nucleophile Me N3 cellent stereoselectivity (up to 99:1 er). Of the eight possi- electrophilic ble stereoisomers that could arise from this reaction, one activator N3 was predominantly formed. HN O Me 9.1 9.2 Leaving group CCl3 Me N Me N3 Me 3 Me OH AD-mix Scheme 9 Initial substrate for dynamic cyclization Ar Ar Ar Ar racemic HO H 7.1 7.2 up to 99:1 er The scope of this reaction was explored, and the cyclization was facile with a wide range of substrates (Scheme 10). Scheme 7 First enantioselective allylic azide DKR Several 3-azido-tetralins could be obtained. The possibility

Syn lett J. J. Topczewski, M. R. Porter Synpacts of incorporating a heteroatom into the substrate’s backbone that the geminal dimethyl motif causes a significant syn- was particularly interesting. These substrates afforded pentane interaction in the branched isomer, shifting the chromanes or tetrahydroquinolines after cyclization. Grati- equilibrium to the other isomers. Even though the reactive fyingly, the dynamic cyclization was generalizable and af- isomer is not easily detectible, the cyclization still proceeds forded a wide variety of these building blocks. This reaction in 72% yield and >25:1 dr. This example clearly demon- is amenable to a variety of substituents on the arene as well strates the dynamic nature of this reaction. Based on these as varied linkers. Qualitatively, the cyclization’s rate was de- combined observations, we propose that the system follows pendent on the aryl ring’s substituents. As would be ex- the Curtin–Hammett principle and that aromatic substitu- pected for an electrophilic aromatic substitution, donating tion is rate limiting. groups accelerated the reaction. The rate of cyclization was To demonstrate potential synthetic applications of the decreased with strong withdrawing groups, representing a dynamic cyclization, we performed a concise synthesis of limitation of this reaction. hasubanan (Scheme 12). This scaffold represents the core of One interesting facet of this reaction is that the reactive a natural product family that has been extensively stud- azide isomer was less than 40% of the equilibrium mixture ied.40–46 The vicinal tetrasubstituted carbon stereocenters for almost all substrates. The percentage of the reactive iso- are a key challenge in the synthesis of these molecules. The mer was highly dependent on the substrate’s structure. At allylic trichloroacetimidate precursor was synthesized in the extreme, the reactive isomer of substrate 11.3 was not only a few steps from commercial materials. The allylic detectable by 1H NMR analysis (Scheme 11). We speculate

R' N 3 R' N3 R R R X X X AgSbF6 (10 mol%) N HN O HN O CHCl , 24–48 h 3 3 R' 40–60 °C 10.3 10.1CCl3 10.2 CCl3

Tetralins Me Me

N3 N3 N3 N3 MeO Cl Br N N3 Me Me Me Me 3 Me 10.4 87% 10.5 77% 10.6 81% 10.7 83% 10.8 88% 10.9 72% >25:1 dr 11:1 dr 19:1 dr 20:1 dr 12:1 dr >25:1 dr

N3 N3 10.10 58% Me 10.11 80% Ph 10.7 1.7:1 dr 21:1 dr Chromanes

O O O O O O

N3 N3 N3 N3 N3 N3 Me MeO Br Cl F Me Me Me Me Me Me 10.12 91% 10.13 94% 10.14 89% 10.15 93% 10.16 70% 10.17 83% >25:1 dr 21:1 dr 22:1 dr >25:1 dr 20:1 dr >25:1 dr This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Ph Cl O MeO O Me O O Me O Cl O

N3 N3 N3 N3 N3 N3 F C Me Me Me Me 3 Me Me Me OMe Me 10.18 80% 10.19 76% 10.20 84% 10.21 37% 10.22 82% 10.23 73% >25:1 dr >25:1 dr 25:1 dr 18:1 dr 21:1 dr, 1.4:1 mix 14:1 dr

Tetrahydroquinonines Ph 4-MeC6H4 4-BrC6H4 Ts Ts Ts N N N N N N

N3 N3 N3 N3 N3 N3 MeO Me Me Br Me Me Me Me Me Me 10.24 75% 10.25 80% 10.26 76% 10.27 72% 10.28 81% 10.29 57% >25:1 dr 23:1 dr >25:1 dr >25:1 dr 16:1 dr >25:1 dr Scheme 10 Substrate scope of dynamic cyclization reaction

Syn lett J. J. Topczewski, M. R. Porter Synpacts

syn-pentane Acknowledgment interaction

Me Me Me N3 Me Me Me N3 We thank the continued dedication of students in the University of Minnesota Department of Chemistry who make this research possible. HN O HN O 11.1 not observed CCl3 11.3 CCl3 4:1 E:Z by 1H NMR AgSbF6 References

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