(2+1)-Cycloaddition Reactions Give Further Evidence of the Nitrenium

Subscriber access provided by University of Pennsylvania Libraries

Note

(2 + 1)-Cycloaddition Reactions Give Further Evidence of the Nitrenium-like Character of 1-Aza-2-azoniaallene Salts Nezar Al-Bataineh, Kendall N. Houk, Matthias Brewer, and Xin Hong J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00407 • Publication Date (Web): 20 Mar 2017 Downloaded from http://pubs.acs.org on March 25, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

(2 + 1)-Cycloaddition Reactions Give Further Evidence of the Nitrenium-like Character of 1-Aza-2-azoniaallene Salts Nezar Al-Bataineh†,ǂ, Kendall N. Houk§, Matthias Brewer*,† and Xin Hong*,‡ †Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States ‡Department of Chemistry, Zhejiang University, Hangzhou 310027, China §Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States Supporting Information Placeholder

ABSTRACT: Cationic 1-aza-2-azoniaallene salts react with structurally constrained alkenes in intramolecular reactions by C-H insertion at the allylic position, or by (2 + 1)-cycloaddition with the alkene followed by ring opening. The latter reaction gives further evidence of the nitrenium-like character of 1-aza-2-azoniaallene salts. DFT calculations show that alkene addition is intrinsically more favorable, but that predistortion can lead to C-H insertion.

Cationic 1-aza-2-azoniaallene salts (e.g. 2, Scheme 1) react intramolecularly by a variety of mechanistically distinct pathways leading to several different classes of N-containing heterocycles. For example, we have shown that these 1,3monopoles react intramolecularly with pendent alkenes by a (3 + 2) cycloaddition to give bicyclic diazenium salt products (e.g. 3),1-3 or a (4 + 2) cycloaddition to give 1,2,3,4tetrahydrocinnoline products (e.g. 6).4-5 These reactions are concerted cycloadditions and the length of the tether between the heteroallene and the alkene determines the chemoselectivity by controlling the stereoelectronic alignment of the reacting groups.6 In addition to cycloadditions, 1-aza-2-azoniaallene salts containing a pendant aryl ring can react by intramolecular C-H insertion at the benzylic position to generate pyrazoline products (e.g. 9, Scheme 1), or undergo an intramolecular FriedelCrafts reaction.7 Our computational studies have shown that the C-H insertion occurs through a bonding stepwise but energetically concerted hydride-transfer/ring closure process.8 The terminal nitrogen of the heteroallene acts as a nitrenium cation9 and accepts the hydride from the benzylic carbon, at which point C-N bond formation occurs spontaneously to generate the heterocyclic product. Insertion occurs more readily adjacent to electron-rich than electron-poor aryl rings, which is in line with the hydride-transfer mechanism. A similar insertion process should be possible at allylic positions, but computational studies show that the competitive (3 + 2) and (4 + 2) cycloaddition pathways are more facile, which is consistent with our observation that insertion products are not observed when the tether allows proper orbital alignment for (3 + 2) or

(4 + 2) cycloadditions. We reasoned that allylic insertion might become a competitive pathway if the system was constrained so that the cycloaddition pathways were energetically unfavorable due to stereoelectronic issues. In this paper we describe experimental and computational studies on such systems, and the results give further evidence for the nitreniumlike character of 1-aza-2-azoniaallene salts. Scheme 1. Intramolecular Reactions of 1-aza-2azoniaallene salts SbCl6 N N

Cl

N N

SbCl5

SbCl6 N N

[1]

CH2Cl2 1

3, 88%

2

SbCl 6

N N

Cl

N

N N

HN

[2]

N

CH 2Cl2

4

Cl

SbCl6

N

SbCl 5

5

i) AlCl3 CH 2Cl2

N N

6, 87%

[3] AlCl4

N N

ii) Et 3N 7

ACS Paragon Plus Environment

8

9 , 74%


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

To determine if allylic insertion would occur in systems structurally biased against cycloaddition, we prepared the heteroallene salt from cyclopentene derivative 10 (Scheme 2). The orbitals that would be involved in the cycloaddition reactions should not productively overlap in this substrate because the alkene is constrained within the five-membered ring. With the cycloaddition pathways less likely, the heteroallene indeed reacted by C-H insertion at the allylic position to give pyrazoline 11 in 69% yield. Scheme 2. C-H Insertion at an Allylic Position

N N Cl

i) AlCl3 (1.1 equiv) -60 °C, 4h ii) warm to rt iii) Et3N (1.1 equiv) 69% yield

10

N N

11

In hopes of extending this allylic insertion to the synthesis of other bicyclic heterocycles, we prepared the closely related cyclohexene analog 12 (Scheme 3). However, on subjecting this material to the reaction conditions, we were surprised to observe that the heteroallene derived from this species did not undergo allylic insertion, but instead engaged the alkene in an addition reaction to give the chloro substituted tetrahydropyridazine 13 in 84% yield. Heteroatom-stabilized nitrenium ions are known to add to alkenes,10-11 and our result provides further experimental evidence for the nitrenium-like character of 1-aza-2-azoniaallene salts. Scheme 3. Intramolecular Alkene Chloroamination

N N Cl

12

i) AlCl3 (1.1 equiv) -60 °C, 4h ii) warm to rt iii) Et3N (1.1 equiv) 84% yield

N

N

Page 2 of 6

amination transition states (TS15 and TS20, Figure 2), the heteroallene and the reacting C-H bond are nearly coplanar. In this regard, the five-membered ring substrate 14 is more predistorted towards the C-H amination transition state than is the six-membered ring substrate 19. As shown in Figure 2, the highlighted dihedral angle between the reacting C-H bond and the C-C bond bearing the heteroallene is 31.0 degrees. This allows the azoniaallene moiety to approach the C-H bond without significantly distorting the dihedral angle. Increasing the ring size changes this dihedral angel to 44.6 degrees, and this decrease of predistortion makes the C-H amination much more difficult. The transition states for aziridinium formation (TS17 and TS22) have the terminal nitrogen of the azoniaallene interacting with the gamma-carbon of the substituted cycloalkene.15 This distant interaction makes the transition states less sensitive to the conformation of the substrates. As a result, the barriers are almost the same for each substrate (14 and 19) and a ring size-dependence does not exist for the (2+1) cycloaddition pathway. The intrinsic chemoselectivity favors aziridinium formation, but the cyclopentenyl substituent makes the substrate predistorted favoring C-H amination.

Ph

Cl 13

To help establish the mechanism leading to 13, and to better understand why the seemingly insignificant structural change between compounds 10 and 12 resulted in different reaction outcomes, we investigated the allylic insertion and chloroamination reactions computationally. Using density functional theory (DFT) calculations at the M06-2X12/6-311+G(d,p)//B3LYP/6-31G(d) level of theory,13,14 we explored the competing C-H amination and aziridinium formation pathways for heteroallenes 14 and 19 (Figure 1). For cyclopentene derivative 14, the C-H amination pathway, via TS15, has a barrier of 15.3 kcal/mol, and the competing nitrenium (2+1) addition pathway, via TS17, has a barrier of 16.2 kcal/mol. Both transformations are irreversible, and the 0.9 kcal/mol preference leads to the favorable C-H amination, as observed experimentally. For cyclohexene derivative 19, the C-H amination pathway is computed to be less favorable by 4.0 kcal/mol, which is consistent with the experimentally observed ring size-dependent chemoselectivity. Interestingly, while the energy barriers for aziridinium formation are almost identical for the two substrates, the energy barrier for C-H amination depends significantly on ring size. Changing the ring from cyclopentenyl to cyclohexenyl increases the C-H amination energy barrier by 5.1 kcal/mol, which results in the reversed chemoselectivity. The significant ring size-dependence of the C-H amination barrier can be attributed to substrate predistortion. In the C-H

Figure 1. DFT-computed Gibbs free energy barriers for C-H amintion and aziridinium formation of heteroallenes 14 and 19. Energies in kcal/mol.


Page 3 of 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry Table 1. Intramolecular reaction of constrained alkenes with heteroallene salts.

Figure 2. DFT-optimized structures of the heteroallenes 14 and 19, and corresponding C-H amination and (2 + 1) cycloaddition transition states.

With a better understanding of this alkene addition in hand, we extended our experimental studies to several other systems that contain constrained alkenes. The results of these studies are shown in Table 1. To confirm that the intrinsic chemoselectivity favors aziridinium ion formation for rings other than cyclopentane we prepared the cycloheptene-derived heteroallene salt 24. As expected, this material underwent chloroamination to give tetrahydropyridazine 25 in 76% yield. No insertion product was observed in this reaction, which supports the supposition that insertion reactions are typically not the most favorable pathway. We also prepared heteroallenes derived from norbornene (26) and bicyclo[2.2.2]oct-2-ene (28). Because the heteroallene is held in close proximity to the alkene we expected these systems to give good yield of the chloroamination products. However, both of these bicyclic systems failed to react cleanly and each returned a complex product mixture. The complexity of these reactions may be a reflection of the fact that cations of these bicyclic systems tend to rearrange easily. To see if increased steric hindrance about the alkene could promote insertion by making the competitive alkene addition less favorable, we prepared 1,2-dimethyl cyclohexene derivative 30. In this case, the heteroallene added to the alkene and the resulting sterically-congested aziridinium intermediate reacted by elimination rather than capture by chlorine to give tetrahydropyridazine 31 in 72% yield. Clearly, the added steric hindrance did not play a significant role in directing the course of the reaction, which allowed a new nitrogen-substituted quaternary center to be formed.

In our prior work on the insertion of 1-aza-2-azoniaallene salts at benzylic positions we noted that the electronics of the aryl ring impacted the rate of the reaction. Electron withdrawing groups on the aromatic ring slowed the insertion, while electron donating groups promoted it. This is consistent with our computational results that indicate a stepwise hydride transfer mechanism, because hydride migration from a less electron rich position would be disfavored.8 An electron deficient alkene should also react less readily with the cationic 1aza-2-azoniaallene salt. With this in mind, we generated the ester and nitrile substituted cyclohexenes 32 and 34. In each case, the heteroallene failed to react with the electron deficient π-system by addition or allylic insertion pathways; in these cases the ketone derived from hydrolysis of the heteroallenes was isolated upon aqueous workup. An electron rich alkene, on the other hand, would be expected react readily with the heteroallene. Indeed, enoxysilane 36 gave the bicyclic αamino ketone 37 in 83% yield. In this case, the oxygensubstituted aziridinium ion intermediate ring-opened to the ketone product. In summary, 1-aza-2-azoniallene salts can react with alkenes by four divergent pathways. Without imposed constraint, the most energetically favorable pathway is a (3+2) cycloaddition leading to a diazenium salt product. This occurs in all known intermolecular reactions and in intramolecular reaction wherein the tether between the reacting partners is three or four atoms long. Shortening the tether to 2 atoms makes (3+2) cycloaddition unfavorable, and (4+2) cycloaddition occurs instead. In systems constrained to prevent these cycloadditions, two alternative pathways become operative; (2+1) cycloaddition and allylic insertion. These latter reactions give evidence for the nitrenium-like character of 1-aza-2-azoniaallene salts. Of these two options, (2+1) cycloaddition is typically the more energetically favorable process and is 4.0 kcal/mol more favorable than insertion in a cyclohexene based system. However, experimental and computational results show that a cyclopentene system is uniquely reactive toward allylic C-H insertion. In this case the cyclopentenyl system is predistorted for C-H amination because the dihedral angle between the heteroallene and the reactive allylic hydrogen lines these functional groups up well for reaction in the lowest energy conformation.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

EXPERIMENTAL SECTION General Experimental Information. All reactions were performed under an atmosphere of nitrogen in flame-dried glassware. All solvents were removed in vacuo using a rotary evaporator attached to a self-cleaning dry vacuum pump, and further dried under reduced pressure on a high vacuum line. Tetrahydrofuran (THF) and dichloromethane (CH2Cl2) were dried via a solvent dispensing system. Triethylamine was freshly distilled from CaH2 before use. Oxalyl chloride (98%) was freshly distilled before use. Anhydrous aluminum(III)chloride (98.5%) was used as received and stored in a dry glovebox under an atmosphere of nitrogen. Extra dry DMSO stored over molecular sieves was used as received. All hydrazones were freshly prepared before use as these materials could not be stored and underwent facile auto oxidation on standing in air. Molecular sieves (4 Å) were activated by heating overnight at 120 oC in a vacuum oven. Reactions were cooled to –78 °C by immersion in dry-ice acetone baths and were maintained at –60 °C with the aid of an immersion cooler. Silica gel flash column chromatography was performed using silica gel (230-400 mesh) and TLC analysis was carried out using silica on glass plates. Visualization of TLC plates was achieved using ultraviolet light, polyphosphomolybdic acid and cerium sulfate in EtOH with H2SO4, ceric ammonium molybdate, or iodine. 1 H and 13C NMR data was collected at room temperature on a 500 MHz spectrometer in CDCl3. 1H NMR chemical shifts are reported in ppm (δ units) downfield from tetramethylsilane, and 13C NMR spectra are referenced to 77.0 ppm for CDCl3. IR data were collected on a Shimadzu IR Affinity1 FTIR. Samples were analyzed on a Waters Xevo G2-XS QTof LCMS operated in positive ESI. Hydrazone Preparation and Characterization Data: 1-(cyclopent-3-en-1-yl)ethanone phenyl hydrazone (S1): 1-(Cyclopent-3-en-1-yl)ethanone (200 mg, 1.81 mmol) was added to a room temperature mixture of phenyl hydrazine (196 mg, 1.81 mmol) and 4Å molecular sieves in CH2Cl2 (5 mL) under an atmosphere of nitrogen and the mixture was heated to reflux for 3.5 hours. The reaction was cooled to room temperature, filtered through a short plug of basic alumina, and the volatiles were removed in vacuo to give 172 mg (72% yield) of the title compound as a mixture of diastereomers in the form of a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.25-7.18 (m, 2H), 7.08-7.02 (m, 2H), 6.86 (s, 1H), 6.81 (tt, J = 7.4, 1.1 Hz, 1H), 5.71 (m, 2H), 3.24 (tt, J = 9.3, 9.1 Hz, 1H), 2.66-2.56 (m, 2H), 2.54-2.46 (m, 2H), 1.85 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 148.8, 146.0, 129.7, 129.2, 119.6, 113.0, 45.4, 36.5, 12.4. MS (ESI): Calculated for [C13H17N2]+: 201.1392. Found: 201.1396 1-(1-(cyclohex-3-enyl)ethylidene)-2-phenylhydrazine (S2): Prepared as a dark orange oil in 84% yield following the procedure used to make S1; 1H NMR (500 MHz, CDCl3) δ 7.2 (t, J = 8.4 Hz, 2H), 7.05 (d, J = 7.7 Hz, 2H), 6.90 (s, 1H), 6.81 (t, J = 7.3 Hz, 1H), 5.81-5.64 (m, 2H), 2.52-2.43 (m, 1H), 2.23-2.17 (m, 2H), 2.16-2.10 (m, 2H), 1.96-1.91 (m, 1H), 1.85 (s, 3H), 1.61-1.54 (m, 1H); ); 13C NMR (126 MHz, CDCl3) δ 149.3, 146.0, 129.1, 126.7, 126.2, 119.5, 113.0, 42.7, 28.8, 26.5, 25.4, 12.8. MS (ESI): Calculated for [C14H19N2]+: 215.1548. Found: 215.1551. 1-(1-(cyclohept-3-enyl)ethylidene)-2phenylhydrazine (S3): Prepared as a dark orange oil in 98% yield following the procedure used to make S1; 1H NMR (500 MHz, CDCl3) δ 7.25-7.19 (m, 2H), 7.08-7.00 (m, 2H), 6.86-

Page 4 of 6

6.78 (m, 2H), 5.82-5.74 (m, 2H), 2.41-2.35 (m, 1H), 2.34-2.28 (m, 2H), 2.22 (ddd, J = 14.1, 7.3, 2.3 Hz, 1H), 2.16-2.04 (m, 2H), 1.84 (s, 3H), 1.86-1.79 (m, 1H), 1.70 (dddd, J = 13.5, 10.5, 6.7, 3.4 Hz, 1H), 1.43 (ddt, J = 10.7, 5.8, 2.9 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 150.4, 146.0, 132.8, 130.3, 129.1, 119.5, 113.0, 46.8, 35.7, 32.3, 28.6, 26.2, 12.91. MS (ESI): Calculated for [C15H21N2]+: 229.1705. Found: 229.1714. 1-(1-(3,4-dimethylcyclohex-3-enyl)ethylidene)-2phenylhydrazine (S4): Prepared as a yellow oil in 81% yield following the procedure used to make S1; 1H NMR (500 MHz, CDCl3) δ 7.24-720 (m, 2H), 7.08-7.03 (m, 2H), 6.88 (s, 1H), 6.81 (tt, J = 7.4, 1.1 Hz, 1H), 2.49-2.40 (m, 1H), 2.21-2.07 (m, 2H), 2.06-1.99 (m, 2H), 1.94-1.89 (m, 1H), 1.84 (s, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.59-1.49 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 149.5, 146.1, 129.1, 125.2, 124.7, 119.5, 113.0, 112.8, 43.6, 35.3, 31.9, 27.2, 19.2, 18.9, 12.7. MS (ESI): Calculated for [C16H23N2]+: 243.1861. Found: 243.1866. 1-(1-(4-(tert-butyldimethylsilyloxy)cyclohex-3enyl)ethylidene)-2-phenylhydrazine (S5): Prepared as a dark brown oil in 83% yield as a diastereomeric mixture following the procedure used to make S1; 1H NMR (500 MHz, CDCl3) δ 7.25-7.18 (m, 2H), 7.08-7.01 (m, 2H), 6.88 (s, 1H), 6.84-6.77 (m, 1H), 4.94-4.83 (m, 1H), 2.55-2.38 (m, 1H), 2.25-2.18 (m, 2H), 2.14-2.01 (m, 2H), 1.85 (s, 3H), 1.80-1.62 (m, 2H); 0.940.91 (m, 9H), 0.17-0.09 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 150.3, 148.9, 146.0, 129.1, 119.6, 113.0, 112.9, 103.2, 102.3, 47.1, 42.6, 33.4, 29.8, 27.6, 26.8, 25.7, 25.7, 19.7, 18.0, 12.8. MS (ESI): Calculated for [C20H33N2OSi]+: 345.2362. Found: 345.2356. α-Chloroazo Preparation and Characterization Data: 1-(1-chloro-1-(cyclopent-3-enyl)ethyl)-2phenyldiazene (10): Oxalyl chloride (0.38 ml, 2.21 mmol) was added dropwise to a solution of DMSO (0.39 ml, 3.69 mmol) in THF (4 mL) that was maintained between – 55 °C to –65 °C and the resulting solution was stirred until the formation of bubbles ceased (typically 30 min). The reaction mixture was cooled to –78 °C and a solution of the phenyl hydrazone of 1(cyclopent-3-en-1-yl)ethanone (S1; 261 mg, 1.23 mmol) and Et3N (0.45 ml, 1.48 mmol) in THF (2 mL) was added. After 30 min the cold bath was removed. Upon reaching room temperature the mixture was filtered and the filtrate was concentrated. The oily residue was dissolved in pentane to give an orange solution that was filtered to remove a dark red insoluble residue. The pentane was removed in vacuo give 230 mg (80% yield ) of α-chloroazo 10 as an orange-red liquid; 1H NMR (500 MHz, CDCl3) δ 7.79-7.71 (m, 2H), 7.51-7.44 (m, 3H), 5.68 (m, 2H), 3.29-3.20 (tt, 8.7, 8.3 Hz, 1H), 2.62-2.55 (m, 2H), 2.54-2.38 (m, 2H), 1.90 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 151.3, 131.2, 129.6, 129.2, 129.1, 122.9, 99.9, 48.5, 34.9, 34.7, 27.3. (E)-1-(1-chloro-1-(cyclohex-3-enyl)ethyl)-2phenyldiazene (12): Prepared as a dark orange oil in 80% yield following the procedure used to make 10. Characterized as mixture of diastereomers; 1H NMR (500 MHz, CDCl3) δ 7.727.82 (m, 4H), 7.53-7.43 (m, 6H), 5.77-5.70 (m, 2H), 5.77-5.60 (m, 4H), 2.33-2.27 (m, 1H), 2.24-2.06 (m, 8H), 1.91 (s, 3H), 1.87 (s, 3H), 1.84-1.79 (m, 1H), 1.58-1.46 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 151.1, 131.2, 131.2, 129.1, 126.9, 126.7, 125.9, 125.8, 122.9, 99.9, 45.4, 44.8, 27.0, 26.8, 26.5, 26.5, 25.7, 25.6, 23.9, 23.8. (E)-1-(1-chloro-1-(cyclohept-3-enyl)ethyl)-2phenyldiazene (S6): Prepared as a dark orange oil in 92% yield following the procedure used to make 10. Characterized


Page 5 of 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


as mixture of diastereomers; 1H NMR (500 MHz, CDCl3) δ 7.82 – 7.72 (m, 4H), 7.53 – 7.44 (m, 6H), 5.86 – 5.73 (m, 3H), 5.72-5.65 (m, 1H), 2.57 – 2.46 (m, 2H), 2.46 – 2.38 (m, 1H), 2.25-2.09 (m, 8H), 2.04-1.98 (m, 1H), 1.92-1.88 (m, 1H), 1.87 (s, 3H), 1.86-1.84 (m, 1H), 1.83 (s, 3H), 1.75-1.61 (m, 2H), 1.57-1.43 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 151.1, 132.8, 132.5, 131.2, 131.2, 129.5, 129.4, 129.1, 122.1, 100.4, 100.4, 48.7, 48.1, 32.1, 31.7, 29.3, 29.2, 28.4, 26.7, 26.5, 26.5, 25.7, 25.7. (E)-1-(1-chloro-1-(3,4-dimethylcyclohex-3enyl)ethyl)-2-phenyldiazene (S7): Prepared as a orange oil in 72% yield following the procedure used to make 10. Characterized as mixture of diastereomers; 1H NMR (500 MHz, CDCl3) δ 7.88-7.69 (m, 4H), 7.58-7.41 (m, 6H), 2.53-2.43 (m, 2H), 2.15-2.10 (m, 4H), 2.07-1.93 (m, 4H), 1.91 (s, 3H), 1.88 (s, 3H), 1.81-1.74 (m, 2H), 1.63 (s, 6H), 1.61 (s, 6H), 1.521.43 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 151.1, 131.2, 129.1, 125.6, 125.4, 124.4, 122.9, 100.0, 48.3, 46.1, 45.6, 33.2, 32.9, 32.04, 31.98, 26.6, 24.5, 24.4, 19.2, 19.1, 18.8. (E)-1-(1-(4-(tert-butyldimethylsilyloxy)-5chlorocyclohex-3-enyl)-1-chloroethyl)-2-phenyldiazene (S8): Prepared as a dark brown oil in 71% yield following the procedure used to make 10. Characterized as mixture of several diastereomers; 1H NMR (500 MHz, CDCl3) δ 7.80-7.73 (m, 4H), 7.51-7.43 (m, 6H), 5.05-4.86 (m, 2H), 4.58-4.32 (m, 2H), 3.04-2.95 (m, 1H), 2.46-2.40 (m, 2H), 2.39-2.32 (m, 2H), 2.24-2.21 (m, 1H), 2.11-2.09 (m, 1H), 2.05-2.02 (m, 1H), 1.93 (s, 1H), 1.89 (s, 2H), 1.87-1.83 (m, 2H), 0.97-0.92 (m, 18H), 0.20-0.14 (m, 12H); 13C NMR (126 MHz, CDCl3) δ 151.0, 148.8, 131.4, 129.2, 129.1, 123.0, 106.1, 106.0, 105.4, 98.8, 58.1, 58.0, 57.3, 41.0, 39.6, 39.2, 34.1, 27.1, 27.1, 25.7, 25.6, 25.3, 25.2, 25.2, 18.3. Procedures and characterization data for products derived from the reaction of α-chloroazo compounds with AlCl3: 3-methyl-1-phenyl-1,3a,4,6atetrahydrocyclopenta[c]pyrazole (11): A solution of αchloroazo 10 (90 mg, 0.38 mmol) in CH2Cl2 (1.5 mL) was added dropwise to a –78 °C suspension of AlCl3 (61 mg, 0.04 mmol) in CH2Cl2 (4 mL). The reaction was allowed to slowly warm to room temperature in the dry-ice/acetone bath (typically 2 h) at which point a saturated aq. solution of NaHCO3 (2 mL) was added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (10 ml). The organic layers were combined, dried (MgSO4) and concentrated to a dark yellow oil that was purified by silica gel flash column chromatography (9/1; hexanes/ethyl acetate) to give 52 mg (69% yield) of pyrazole 11 as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.25-7.21 (m, 2H), 7.07-7.02 (dd, J = 8.8, 1.1 Hz, 2H), 6.76 (tt, J = 7.3, 1.1 Hz, 1H), 5.95-5.87 (m, 2H), 5.245.19 (d, J = 9.8 Hz, 1H), 3.72 (m, 1H), 2.79-2.71 (m, 1H), 2.62-2.55 (m, 1H), 2.02 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 151.4, 145.3, 132.7, 129.3, 127.7, 118.1, 112.5, 70.4, 51.1, 36.3, 14.5; MS (ESI): Calculated for [C13H15N2]+: 199.1230. Found: 199.1227. Rel-(1R,5R,8R)-8-chloro-4-methyl-2-phenyl-2,3diazabicyclo[3.3.1]non-3-ene (13): Prepared as an oil in 84% yield following the procedure used to make 11; 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J = 8.9 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.84 (t, J = 7.2 Hz, 1H), 4.41-4.36 (m, 1H), 4.28-4.23 (m, 1H), 2.51 (dt, J = 13.0, 2.3 Hz, 1H), 2.42-2.37 (m, 1H), 2.062.01 (m, 1H), 2.03 (s, 3H), 1.88-1.81 (m, 1H), 1.73-1.67 (m, 2H), 1.63-1.56 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 145.8, 145.7, 129.2, 119.2, 112.5, 57.5, 52.3, 31.5, 27.8, 24.5, 22.6,

20.1. MS (ESI): Calculated for [C14H18ClN2]+: 249.1159. Found: 249.1163. Rel-(1R,5R,6R)-5-chloro-9-methyl-7-phenyl-7,8diazabicyclo[4.3.1]dec-8-ene (25): Prepared as a yellow oil in 76% yield following the procedure used to make 11; 1H NMR (500 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.28-7.26 (m, 2H), 6.88-6.83 (tt, J = 13.8, 7.0, 1.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.26-4.30 (m, 1H), 2.41 (t, J = 6.9 Hz, 1H), 2.35 (d, J = 14.4 Hz, 1H), 2.03 (s, 3H), 2.00-1.83 (m, 5H), 1.72-1.66 (m, 1H), 1.39-1.31 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 145.8, 145.0, 129.2, 119.1, 112.7, 62.1, 55.0, 33.7, 31.3, 30.1, 22.5, 20.8, 19.9. MS (ESI): Calculated for [C15H20ClN2]+: 263.1315. Found: 263.1321. Rel-(1R,5R)-1,4,8-trimethyl-2-phenyl-2,3diazabicyclo[3.3.1]nona-3,7-diene (31): Prepared as an oil in 72% yield following the procedure used to make 11; 1H NMR (500 MHz, CDCl3) δ 7.25-7.14 (m, 2H), 7.16-7.12 (m, 2H), 7.12-7.08 (m, 1H), 5.63-5.56 (m, 1H), 2.45-2.38 (m, 1H), 2.29-2.21 (m, 2H), 2.03 (dd, J = 12.2, 4.3 Hz, 1H), 1.96 (s, 3H), 1.64 (dd, J = 12.1, 1.7 Hz, 1H), 1.41, (s, 3H), 1.26-1.20 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 147.9, 147.5, 134.2, 127.8, 127.0, 124.8, 123.6, 54.3, 35.9, 32.2, 31.6, 25.9, 22.3, 20.4. MS (ESI): Calculated for [C16H21N2]+: 241.1705. Found: 241.1712. Rel-(1R,5S,7R)-7-chloro-4-methyl-2-phenyl-2,3diazabicyclo[3.3.1]non-3-en-8-one (37): Prepared as a waxy solid 83% yield following the procedure used to make 11; 1H NMR (500 MHz, CDCl3) δ 7.32-7.21 (m, 4H), 6.90 (tt, J = 6.7, 1.8 Hz, 1H), 4.80-4.66 (m, 1H), 4.34 (dd, J = 12.9, 7.1 Hz, 1H), 2.77 (dtd, J = 10.0, 6.7, 3.1 Hz, 1H), 2.64-2.53 (m, 1H), 2.17 (s, 3H), 2.15 (d, J = 3.9 Hz, 1H), 2.14-2.11 (m, 1H), 2.07 (dt, J = 13.4, 2.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 198.9, 145.9, 143.2, 129.2, 120.6, 113.3, 60.6, 60.1, 42.7, 31.7, 26.6, 22.6. MS (ESI): Calculated for [C14H16ClN2O]+: 263.0951. Found: 263.0957.

ASSOCIATED CONTENT Supporting Information Optimized geometries and energies of all computed species, 1H and 13C NMR spectra (PDF). The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected].

Present Address

ǂ College of Pharmacy, Al Ain University of Science and Technology, P.O. Box: 112612, Abu Dhabi, UAE Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT Financial support from the National Science Foundation of the USA (CHE-1362286 for M.B. and CHE-1361104 for K.N.H.), Zhejiang University (X.H.) and the Chinese “Thousand Youth Talents Plan” (X.H.) is gratefully acknowledged. Mass spectrometry data was acquired by Bruce O’Rourke on instruments purchased through instrumentation grants provided by the Nation-



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

al Institutes of Health (NIH) (S10 OD018126). Calculations were performed on the Hoffman2 cluster at UCLA and the supercomputer cluster at the Department of Chemistry, Zhejiang University.

REFERENCES (1) Al-Bataineh, N. Q.; Brewer, M. Tetrahedron Lett. 2012, 53, 5411. (2) Javed, M. I.; Wyman, J. M.; Brewer, M. Org. Lett. 2009, 11, 2189. (3) Wyman, J.; Javed, M. I.; Al-Bataineh, N.; Brewer, M. J. Org. Chem. 2010, 75, 8078. (4) Bercovici, D. A.; Ogilvie, J. M.; Tsvetkov, N.; Brewer, M. Angew. Chem., Int. Ed. 2013, 52, 13338. (5) Dhakal, R. C.; Brewer, M. Tetrahedron 2016, 72, 3718. (6) Hong, X.; Liang, Y.; Brewer, M.; Houk, K. N. Org. Lett. 2014, 16, 4260. (7) Bercovici, D. A.; Brewer, M. J. Am. Chem. Soc. 2012, 134, 9890. (8) Hong, X.; Bercovici, D. A.; Yang, Z. Y.; Al-Bataineh, N.; Srinivasan, R.; Dhakal, R. C.; Houk, K. N.; Brewer, M. J. Am. Chem. Soc. 2015, 137, 9100. (9) Nitrenes and Nitrenium Ions; Falvey, D.E., Gudmundsdottir, A.D., Eds. John Wiley & Sons: Hoboken, New Jersey, 2013. (10) For examples of the addition of N-stabilized nitrenium ions to alkenes see: (a) Urry, W. H.; Kruse, H. W.; McBride, W. R. J. Am. Chem. Soc. 1957, 79, 6568. (b) Urry, W. H.; Gaibel, Z. L. F.; Duggan, J. C.; Tseng, S. S. J. Am. Chem. Soc. 1973, 95, 4338. (c) Cauquis, G.; Genies, M. Tetrahedron Lett. 1971, 12, 3959. (d) Cauquis, G.; Chabaud, B.; Genies, M. Bull. Soc. Chim. Fr. 1973, 12, 3487. (e) Tsukamoto, M.; Murata, K.; Sakamoto, T.; Saito, S.; Kikugawa, Y. Heterocycles, 2008, 75, 1133. (f) Murata, K.; Tsukamoto, M.; Sakamoto, T.; Saito, S.; Kikugawa, Y. Synthesis 2008, 32. (11) For examples of the addition of O-stabilized nitrenium ions to alkenes see: (a) Hoffman, R. V.; Christophe, N. B. J. Org. Chem. 1988, 53, 4769. (b) Rudchenko, V. F.; Ignatov, S. M.; Kostyanovsky, R. G. J. Chem. Soc., Chem. Commun. 1990, 261. (c) Vedejs, E.; Sano, H. Tetrahedron Lett. 1992, 33, 3261. (d) Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188. (e) Bowen, E. G.; Wardrop, D. J. Org. Lett. 2010, 12, 5330. (f) Wardrop, D. J.; Yermolina, M. V.; Bowen, E. G. Synthesis 2012, 14, 1199. (12) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc., Wallingford, CT, 2009. (14) Extensive conformational searches for the intermediates and transition states have been conducted. The lowest energy conformers are shown in this work. Solvation energies in dichloromethane were evaluated by a self-consistent reaction field (SCRF) using the SMD model. For reference on SMD model, see: Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (15) The regioisomeric (2+1) transition state of cyclohexene derivative is 0.8 kcal/mol less favorable as compared to TS22.


Page 6 of 6

(2+1)-Cycloaddition Reactions Give Further Evidence of the Nitrenium

Recommend Documents