Letter pubs.acs.org/OrgLett
Rhodium(II)-Catalyzed Alkyne Amination of Homopropargylic Sulfamate Esters: Stereoselective Synthesis of Functionalized Norcaradienes by Arene Cyclopropanation Ryan A. Brawn, Kaicheng Zhu, and James S. Panek* Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States S Supporting Information *
ABSTRACT: A rhodium(II) catalyzed nitrene−alkyne cycloaddition of stereochemically well-defined homopropargylic ethers is followed by arene cyclopropanation to afford unique tetracyclic norcaradiene products bearing a cyclic sulfamate. Products from the arene cyclopropanation (Buchner reaction) can be converted to fused cycloheptatrienes via a ring enlarging electrocyclization after nucleophilic ring opening of the cyclic sulfamate ester.
M
Scheme 1. Rh(II) Catalyzed Cycloaddition Cascade Reactions
etallonitrenes have recently emerged as reactive materials for the selective formation of C−N bonds.1 These complexes are used for alkyne amidation or alkene aziridination, characterized by a reaction in which an electrophilic rhodium nitrene intermediate is captured by the adjacent π-system. This idea has been advanced by Du Bois with the development of the Rh2(esp)2 catalyst, a highly efficient rhodium dimer used for the formation of metallonitrenes.2 Further work from the Blakey group has demonstrated that metallonitrenes formed from sulfamate esters and substoichiometric amounts of rhodium dimers undergo additions to alkynes (Scheme 1A).3 The resulting organo-rhodium intermediate behaves as either a vinyl cation or an α-imino metallocarbenoid species, and can then be trapped by ethers, aromatic rings, or olefins resulting in formation of polycyclic materials. In a related study Reisman recently described an intramolecular cyclopropanation of diazo-β-ketonitriles accessing norcaradienes with good diastereoselectivity (Scheme 1B).4 Herein we report a method that produces stereochemically well-defined norcaradienes through a rhodium-catalyzed internal delivery of a metallonitrene intermediate, resulting in an arene cyclopropanation. This process is followed by an acid catalyzed electrocyclization to access fused cycloheptatrienes. Although these electrocyclic reactions and related cycloadditions are the fundamental basis for much of contemporary organic chemistry, many variants of these reactions remain underdeveloped. Previously, we have shown that nearly complete transfer of chirality is realized in the propargylation of aryl oxonium ions, rapidly accessing highly stereochemically well-defined homopropargylic ethers.5 These reaction products can be subsequently converted to sulfamate ester 2 by LiAlH4 reduction followed by treatment with sulfamoyl chloride.6 These materials © 2013 American Chemical Society
serve as substrates to investigate the scope of the Rh(II)catalyzed metallonitrene cycloaddition sequence. Interestingly, treatment of 2 with catalytic rhodium(II) in the presence of stoichiometric amounts of oxidant, followed by reductive workup, resulted in the formation of tetracyclic norcaradienes 3 (Table 1). This unique tetracyclic material has contiguous Received: October 23, 2013 Published: December 16, 2013 74
dx.doi.org/10.1021/ol403035g | Org. Lett. 2014, 16, 74−77
Organic Letters
Letter
Table 1. Optimization of the Arene Cyclopropanation
a
Table 2. Norcaradiene Formation by Cycloaddition Cascade
Rh catalystb
solvent
temp
oxidant
yieldc
entry
R1
R2
yieldb
Rh(OAc)2 Rh(OAc)2 Rh(OAc)2 Rh(OAc)2 Rh(esp)2 Rh(esp)2 Rh(esp)2 Rh(esp)2 Rh(esp)2 Rh(esp)2 Rh(esp)2
DCM toluene THF DCM DCM toluene THF ether DCM DCM DCM
rt rt rt 40 °C rt rt rt rt 40 °C 40 °C 40 °C
Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 Phl(OAc)2 chloramine-T DDQ
62 35 34 75 73 64 41 trace 85 trace 0
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j
Me Me Me Me Me Me Me allyl Bn Bn
H 3,5-Me 1-napthyl 4-Br 4-CI 4-CF3 4-Me H H 3,5-Me
85% 80% 65% 50% 58% 43% 73% 55%c 76% 67%
a
All cycloaddition products were formed with a >20:1 dr, based on 1H NMR analysis of crude material. bYield after purification by silica gel chromatography. cReaction was run at room temperature.
1
All cycloaddition products were formed with a >20:1 dr based on H NMR analysis. bAll reactions were run with 2 mol % Rh(II) catalyst. c Yield after purification by silica gel chromatography.
substrates (3h−3j) also gave the norcaradiene, with no evidence of trapping of the carbene by the allylic or benzyl ether, which was previously observed and reported by Blakey.3a The structure and stereochemistry of the products were confirmed by X-ray crystallography.9 A sulfamate ester substrate without the methyl group adjacent to the alkyne was also evaluated in the cycloaddition cascade. When 2l was exposed to the optimized reaction conditions, the reaction failed and decomposed material was observed. However, conducting the reaction at room temperature led to formation of norcaradiene 3l in 32% yield with >20:1 dr (Scheme 2).10 These results support the role of the
quaternary stereocenters, with the relative configuration of the products controlled by the configuration of the starting homopropargylic ether. After cleavage of the cyclic sulfamate, the norcaradienes participated in a ring-opening six-π electrocyclization to afford fused cycloheptatrienes. While the addition of the metallonitrene to the proximal alkyne was anticipated, the reactive metallocarbene formed from the addition was not trapped by the ether moiety or by the aromatic ring in a Friedel−Crafts-type mechanism previously reported by Blakey.3b The metallocarbene instead participated in an arene cyclopropanation (Buchner reaction) of the aromatic ring (Scheme 1C).7 This reaction provided a unique tetracyclic norcaradiene 3 as the major product and is believed to transpire through the illustrated reaction sequence. Reaction optimization showed that the best reaction conditions for this transformation were the use of DuBois’ rhodium catalyst (Rh2(esp)2, 2 mol %) with stoichiometric amounts of the oxidant, diacetoxyiodobenzene, in DCM at 40 °C.2 The rhodium acetate dimer also provided the norcaradiene product in slightly lower yields, while the use of other solvents or oxidants resulted in significantly lower conversion. The reaction sequence was terminated by the stereoselective reduction of the intermediate imine using sodium borohydride in methanol.8 A range of aromatic substrates for arene cyclopropanation was evaluated, using unsubstituted and symmetrical substrates in order to avoid the formation of mixtures of regioisomers. With the exception of the 1-napthyl substrate 3c, which formed the Buchner product as a single regioisomer, other unsymmetrical substrates proved difficult to separate by standard chromatographic techniques (Table 2). The reaction performed well for electron neutral or slightly donating groups (3a−c, g− j) and gave moderate yields for electron withdrawing groups (3d−f). The products of the Buchner reaction illustrated in Table 2 were formed with useful levels of selectivity >20:1 dr, where the new stereocenters created were controlled by the existing stereochemistry of the homopropargylic ether starting material. While methoxy homopropargylic ethers typically showed the highest reactivity, the allyloxy and benzyloxy
Scheme 2. Effect of the Benzylic Ether on Reaction Pathway
benzylic ether substituent in driving the cyclopropanation reaction pathway, presumably through donation from the benzylic C−O bond into the σ* orbital of the cyclopropane ring. The absence of the benzylic ether leads to tricyclic product 3m, originally observed by Blakey.3b The presence of strongly electron donating groups on the aromatic ring in 2k also leads to this tricyclic rearrangement product.10 75
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Literature examples of arene cyclopropanation that occur through a Buchner reaction are typically associated with metallocarbene chemistry.11 It is interesting to note that the product of these reactions is usually the cycloheptatriene, formed through an electrocyclization of the norcaradiene.12 Accordingly, this reaction provided a mechanistically interesting way to trap the reactive intermediate of the cycloaddition cascade. Product 3 was stable to chromatography on silica and could be stored at room temperature for weeks with no noticeable decomposition or rearrangement. Studies have been reported on vinyl cyclopropane rearrangements;13 however, examples of rearrangements of fused norcaradienes without activating groups are rare. Accordingly, we anticipated that the fused norcaradiene 3 would undergo a rearrangement to give the cycloheptatriene 4 (Scheme 3); however initial efforts to
Table 3. Rearrangement of Norcaradiene 5a to Cycloheptatriene 6a
entry
catalysta
solvent
temp (°C)b
% conversion (yield)c
1 2 3 4 5 6 7 8 9 10 11 12
none PtCl2 PtCl2 PtCl2 PtCl2 Pt(MeCN)2Cl2 PdCl2 PtCl4 Sc(OTf)3 CSA p-TsOH HCl
toluene DCM benzene toluene Cl-benzene Cl-benzene Cl-benzene Cl-benzene Cl-benzene Cl-benzene Cl-benzene Cl-benzene
110 40 80 110 110 110 110 110 110 110 110 75d
0(0) 0(0) 40(25) 100(70) 100(73) 90(62) 60(35) 100(72) 100(68) 100(60) 100(52) 100(68)
Scheme 3. Rearrangement of the Norcaradiene to the Cycloheptatriene
a
Catalyst loading was 20 mol %. bReaction time was 12 h. Conversion was determined by 1H NMR analysis of the crude product. Yield was based on isolated material after purification by silica gel chromatography. dReaction time was 24 h. c
showed that the ether moiety adjacent to the norcaradiene was crucial for stabilizing the cyclopropane ring. A variety of norcaradiene amides of type 5 undergo the electrocyclization process, providing the corresponding cycloheptatriene products 6 in good yields (Scheme 4). Scheme 4. Ring Opening Electrocyclization of the Norcaradienesa
promote the electrocyclization under thermal conditions were unsuccessful. DFT calculations using MacroModel14 showed that the ground state conformation of the norcaradiene 3i was 37 kcal/mol lower in energy than that of the proposed cycloheptatriene rearrangement product 4i, making the rearrangement thermodynamically unfavorable for this substrate. Norcaradiene 3i was converted to amide 5i by Nacylation followed by a nucleophilic displacement of sulfur trioxide, releasing the ring strain of the sulfamate ester in the process. This substrate was also stable to rearrangement under thermal conditions. Treatment of amide 5i with catalytic Pt(II) in toluene provided cycloheptatriene product 6a, with concomitant elimination of the benzyl ether. Interestingly, amide 5a, generated from norcaradiene 3a, afforded the same rearrangement product 6a when subjected to similar conditions. Several promoters and conditions were evaluated to facilitate the electrocyclization of 5a to cycloheptatriene 6a (Table 3). It was learned that heating at reflux without the presence of a promoter did not afford the rearrangement product (entry 1), recovering only the starting norcaradiene 5a. Reactions in the presence of the Pd(II) or Pt(II) catalyst gave the rearranged product 6a, but elevated temperatures were necessary to achieve full conversion. Initially a metal-promoted cyclopropane ring-opening pathway15 was proposed for this transformation. However, it was found that, in addition to metal chloride promoters, substoichiometric amounts of a Brønsted acid (entries 10−12) or Lewis acid (entry 9) can facilitate the rearrangement. This result indicated that a cyclopropylcarbinyl cation might be generated as an intermediate during the rearrangement process, which in turn
a
Yield after purification by silica gel chromatography.
In summary, homopropargylic ethers could be converted into sulfamate esters in two steps, which in turn underwent a metallonitrene cycloaddition cascade, terminating in a highly selective Buchner reaction. The reaction resulted in the formation of stable tetracyclic norcaradienes and formed four new stereocenters including contiguous quaternary centers. After nucleophilic opening of the cyclic sulfamate ester, the norcaradienes undergo a transition metal or Brønsted acid catalyzed ring-opening electrocyclization to form stereochemically well-defined cycloheptatrienes. 76
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Letter
(8) This N-sulfonyl imine could be observed spectroscopically if the sodium borohydride was not added, but was unstable to chromatography conditions on silica gel. (9) See Supporting Information for X-ray details. (10) For a proposed mechanism for the rearrangement of the norcaradiene product into tricyclic product 3n, see Supporting Information. (11) (a) Levin, S.; Nani, R. R.; Reisman, S. E. Org. Lett. 2010, 12, 780. (b) Reisman, S. E.; Nani, R. R.; Levin, S. Synlett 2011, 22, 2437. (c) McNamara, O. A.; Maguire, A. R. Tetrahedron 2011, 67, 9. (d) Morris, J. C.; Mander, L. N.; Hockless, D. C. R. Synthesis 1998, 30, 455. (e) Maier, G. Angew. Chem., Int. Ed. 1967, 6, 402. (12) (a) Maier, G. Angew. Chem. 1967, 89, 1454. (b) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (c) O’Sullivan, T. P.; Zhang, H.; Mander, L. N. Org. Biomol. Chem. 2007, 5, 2627. (d) Davies, H. M. L; Hedley, S. J. Chem. Soc. Rev. 2007, 36, 1109. (13) (a) Reissig, H.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Wang, S. C.; Tantillo, D. J. Organomet. Chem. 2006, 4386. (14) Conformational analyses were carried out with MacroModel v9.6 (using OPLS 2005 force field; optimizations were carried out using JAGUAR 7.5, 1998 ed.) and B3LYP/6-13G*, Schrodinger, Inc.; Portland, OR, 2008. (15) Ahmad, M. U.; Backvall, J.; Nordberg, R. E.; Norin, T.; Stromberg, S. J. Chem. Soc. 1982, 321−323.
ASSOCIATED CONTENT
S Supporting Information *
Preparation and characterization of all new compounds are included along with CIF files of X-ray structures. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the NIGMS CMLD initiative (P50-GM067041). We thank Dr. Paul Ralifo, Dr. Norman Lee, and Dr. Jeff Bacon (Boston University) for assistance with NMR spectroscopy, HRMS, and X-ray measurements, respectively.
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REFERENCES
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