Synthesis of Trialkylhydroxylamines by Stepwise Reduction of O-Acyl

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Synthesis of Trialkylhydroxylamines by Stepwise Reduction of O-Acyl N,N-Disubstituted Hydroxylamines. Substituent Effects on the Reduction of O-(1-Acyloxyalkyl)hydroxylamines and on the Conformational Dynamics of N-Alkoxypiperidines. Sandeep Dhanju, Brendan W Blazejewski, and David Crich J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017 Downloaded from http://pubs.acs.org on May 2, 2017

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The Journal of Organic Chemistry

Synthesis of Trialkylhydroxylamines by Stepwise Reduction of O-Acyl N,N-Disubstituted Hydroxylamines. Substituent Effects on the Reduction of O-(1-Acyloxyalkyl)hydroxylamines and on the Conformational Dynamics of N-Alkoxypiperidines.

Sandeep Dhanju, Brendan W Blazejewski, and David Crich* Department of Chemistry, Wayne State University, Detroit, MI 48202, USA

[email protected] ABSTRACT: The influence of the electron-withdrawing azide group on the reduction of O-(1-acyloxy-ωazido)hydroxylamines by triethylsilane in the presence of boron trifluoride etherate is studied and found to increase with increasing proximity to the reaction site, suggesting that the reaction proceeds by way of aminoxocarbenium ion intermediates. The ability to carry azides through the reaction sequence affords O-(ωazidoalkyl-N,N-dialkylhydroxylamines thereby making such functionality available for use in click chemistry. A series of 4-substituted N-alkoxypiperidines were prepared and studied by variable temperature NMR spectroscopy leading to the conclusion that the rate determining step in the stereomutation of such piperidines is the piperidine ring flip and not nitrogen inversion or rotation about the N-O bond. The process of N-O bond rotation only becomes rate determining when it is subjected to pervasive steric hindrance as is the case with the N-alkoxy-2,2,6,6-tetramethylpiperidines.

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Introduction. Extrapolating from our interest in the use of N-alkoxypiperidines as anomerically convertible analogs of glycosidic bonds (Figure 1),1-3 we have initiated a program on the synthesis of a N,N,O-trisubstituted hydroxylamines as stereochemically adaptable mimics of stereogenic centers in alkanes and ethers (Figure 1).4

Figure 1.

Hydroxylamines as Convertible Mimics of Stereogenic Centers.

a) N-

Alkoxypiperidines as mimics of axial and equatorial glycosides. b) Hydroxylamines as mimics of chirally substituted alkanes and ethers. Toward this end we reported4 recently that trialkyl hydroxylamines can be accessed readily by a modification of the Rychnovsky ether synthesis5-6 in which O-acyl N,N-dialkyl hydroxylamines are reduced first to O-(1-hydroxyalkyl) N,N-dialkyl hydroxylamines, trapped in situ as their acetate esters, followed by a second Lewis acid-mediated triethylsilane reduction or alkylation (Scheme 1). Scheme 1. Two Step Reduction Sequence Affording Trialkylhydroxylamines.


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Numerous examples of this process were reported in which the second step typically proceeded in good to high yield with boron trifluoride etherate as Lewis acid, and triethylsilane, allytributylstannane, silylenol ethers, and furan as nucleophile at temperatures ranging from -78 o

C to room temperature over a period of several hours. The reduction of the O-(1-acetoxy-2-β-

naphthyl)ethyl N,N-dibenzyl system 1, however, was strikingly slower and gave only 38% of the hydroxylamine 2 after seven days at room temperature.4 We reasoned that the lack of reactivity of 1 under the typical conditions was a manifestation of the electron-withdrawing effect of the ether moiety on the presumed intermediate aminoxocarbenium ion and, thus, related to the wellknown strong influence of electron-withdrawing substituents on glycosylation,7-10 and solvolysis reactions in general.11-13

A central tenet in our design of hydroxylamines as convertible surrogates of stereogenic centers is the combination of their low basicity and low barriers to conformational inversion by N-O bond rotation or pyramidal inversion at nitrogen.14-17 Thus, hydroxylamines are not protonated in aqueous media at neutral pH, which enables a single trisubstituted hydroxylamine to sample the conformational space of both anomers of a glycosidic bond (Figure 1, part a), or both enantiomers of a corresponding stereogenic center in an alkane or ether (Figure 1, part b). The question of the nature of the limiting barrier in the conformational exchange of hydroxylamines (bond rotation or nitrogen inversion) and of the inter-relatedness of the two processes has been 3 ACS Paragon Plus Environment


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explored by numerous laboratories, and is complicated in the case of derivatives containing one or both of the two heteroatoms in a cyclic structure as, for example, in the N-alkoxypiperidines and 1,2-oxazines, by the ring inversion process.13-14,23-24 In this Article we report the synthesis of a series of three O-(β-, γ- and δ-azido-1acetoxyalkyl)hydroxylamines and the influence of the proximity of the azido group to the reaction center in their subsequent reduction to the corresponding hydroxylamines. We also report the synthesis and variable temperature NMR studies of a series of 4-substituted Nalkoxypiperidines and pyrrolidines leading to the conclusion that, in the absence of pervading steric effects, the limiting barrier to inversion in such N-alkoxy nitrogenous heterocycles is function of the ring inversion process. Results and Discussion. Synthesis of Hydroxylamines and the Influence of Electron-Withdrawing Groups on the Reduction.

Hydroxylamines 3-5 were prepared as previously discussed by the method of

Scheme 1 in 75, 76, and 77% yield, respectively, for the second reduction step of which they are typical examples.4 A further N-alkoxypiperidine 6 was prepared uneventfully by the same process as presented in Scheme 2. Scheme 2. Preparation of the N-alkoxypiperidine 6.


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In order to assess the influence of electron-withdrawing groups on the sequential reduction reaction azidoacetic 13,18 azidopropanoic 14,18 and azidobutanoic 1519 acids were condensed with the hydroxylamine 1220, itself prepared by the Ganem protocol,4,21 to give the Oacylhydroxylamines 16-18 uneventfully (Scheme 3a). DIBAL reduction of 16-18 at -78 oC with in situ quenching by acetic anhydride at that temperature proceeded uneventfully to give the corresponding O-(1-acetoxy-azidoalkyl)hydroxylamines 19-21 in good yield. The subsequent Lewis acid-mediated reduction by triethylsilane to give the O-(azidoalkyl)hydroxylamines, however, was strongly affected by the proximity of the azido group to the center of reaction. Thus, while the 1-acetoxy-4-azidobutyl system 21 was reduced to the hydroxylamine 24 in 54% yield under the standard conditions of treatment with BF3.OEt2 and triethylsilane at -78 oC in dichloromethane followed by warming to 0 oC and stirring for 3 h, a more modest 48% yield of the lower homolog 23 was obtained from the 1-acetoxy-3-azidopropyl precursor 20 only when the reaction was warmed to room temperature and stirring for 24 h. The reduction of next lower homolog 19 was significantly slower such that 22 was obtained in 17% yield only after stirring for four days at room temperature. The presence of an electron-withdrawing group vicinal to the reaction

center

therefore

very

strongly

retards

reduction

of

the

O-(1-

acetoxyalkyl)hydroxylamines, but the effect falls off rapidly with the insertion of successive methylene groups. 5 ACS Paragon Plus Environment


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Scheme 3.

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a) Synthesis of Azidoalkylhydroxylamines. b) Alternative Synthesis of

Azidoalkylhydroxylamine 22.

The strongly retarding effect of the electron-withdrawing group in the reduction of both 1 and 19 is consistent with that of electron-withdrawing groups in solvolysis reactions,11-13 in the hydrolyses of glycosides,22 and in glycosylation reactions,7-10 and lends support to the intermediacy of an aminoxocarbenium ion intermediate (Figure 2) in these reactions.

An

alternative synthesis of 22 involved alkylation of the sodium salt of N,N-dibenzylhydroxylamine 12 with 2-azidoethyl tosylate23 was complicated by formation of the nitrone N(phenylmethylene)benzylamine N-oxide as determeined by mass spectrometry of the crude reaction mixtureand gave only 25% yield, consistent with literature observations on the difficulties of alkylation of N,N-dialkylhydroxylamines with all but the most potent electrophiles24 (Scheme 3b).


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Figure 2.

Intermediate Aminoxocarbenium Ion Destabilized by the Electron-Withdrawing

Group X. Conformational Dynamics of N-Alkoxypiperidines and Pyrrolidines. The relative energetics of nitrogen inversion and N-O bond rotation and the degree of synchronicity, if any, of the two processes in the stereomutation of hydroxylamines have been extensively studied, computationally and spectroscopically, as described in a series of excellent reviews that cover the extensive literature up to the early 1990s.16-17,25-26 When the hydroxylamine moiety is part of a ring structure the problem is compounded by the additional barrier due to ring inversion. This problem has been extensively discussed for situations in which the N-O bond is enodcyclic to the ring, as in the oxazines,16-17,25-26 but much less so when it is exocyclic as in the Nalkoxypiperidines and the like that we now address with the compounds 3-6 and their precursors. X-ray crystal structures of saturated six-membered nitrogen heterocycles with an exocyclic N-O bond show strongly pyramidalized nitrogen atoms, consistent with the early work on hydroxylamines,16-17,25-26 in chair conformations with the nitrogen substituent occupying equatorial positions.27-31 X-ray crystal structures of similarly substituted five-membered nitrogen heterocycles also show strong pyramidalization of the nitrogen atom.32-36 Consistent with the extensive literature on acyclic and endocyclic hydroxylamines,16-17,25-26 these structures adopt conformations about the N-O bond in the crystal in which the nitrogen lone pair eclipses the oxygen substituent, whether it is a simple alkyl group,27,30-31,36 a trifluoromethyl group,29 a vinyl group,34 a 1-hydroxyalkyl group,28 or an acyl group.35 As such the N-alkoxypiperidines and



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pyrrolidines should exist in solution as a mixture of two equivalent conformers whose interconversion requires ring flip, nitrogen inversion, and rotation about the N-O bond (Figure 3).

Figure 3. Stereomutation of the N-Alkoxypiperidines (n = 2) and Pyrrolidines (n = 1). In an early VT-NMR study Jenkins and coworkers noted that the barrier to stereomutation in a series of 2-alkoxy-1,1,3,3-tetramethylisoindolines 25 increased with increasing steric bulk of the alkoxy group and, for a given alkoxy group, and decreased with increasing solvent polarity leading them to conclude that nitrogen inversion and N-O bond rotation occur simultaneously in this series.37

Later, Anderson and coworkers studied a series of 1-alkoxy-2,2,6,6-

tetramethylpiperidines 26 by VT NMR and also noted that the measured barrier to stereomutation varies as a function of the bulk of the alkoxy group, albeit not in a linear fashion.27

Anderson and coworkers further considered that a priori, as each of the three

individual processes of ring flip, nitrogen inversion, N-O rotation have substantial individual barriers stepwise processes are more likely than composites ones. Overall, they concluded that N-O bond rotation is the rate determining step in 26.27 NMR inversion barriers to a series of Nhydroxy and N-acyloxy 2,2,6,6-tetramethylpiperidines substituted at the 4-position have also been determined.38 However, to the best of our knowledge, no such barriers have been reported for 4-substituted N-alkoxypiperidines.


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The availability of the simple N-alkoxypiperidine 3, its 4-methyl homolog 4 and the Nalkoxypyrrolidine 5 presented the opportunity to study the stereomutation of such hydroxylamines in the absence of the extreme steric buttressing common to 25 and 26. The Nalkoxy-4-chloropiperidine 6 was prepared to assess the influence of a substituent of intermediate steric bulk on the stereomutation process. Inspection of the 1H NMR spectra of the N-hydroxypiperidines 9, 27, and 28 at room temperature in CDCl3 reveals the influence of the substituent at the 4-position on the configurational and conformational equilibria of these systems (Figure 4). Thus, the spectrum of the unsubstituted system 27 reveals two sets of two non-equivalent hydrogens geminal to the ring nitrogen suggestive of a predominantly chair-like conformation in which the axial and equatorial protons at the 2- and 6-positions are distinct. The spectrum of the 4-chloro system, however, is more complex and two entities are clearly present in 1:1 ratio. One of these, 9a, is a chair-like system in which the chloride group is equatorial and whose spectrum is otherwise consistent with that of 27. The spectrum of 9b is characterized by the presence of a narrower multiplet for H4, the co-incidence of all methylene protons at the 2- and 6-positions, and the coincidence of all signals at the 3- and 5-positions into a single resonance. For the 4-methyl system 28 two isomers are again apparent but in a ratio of approximately 8.5:1. The spectrum of the major isomer 28a, aside from differences due to the differing substituents at the 4-position, resembles that of the unsubstituted system 27 and isomer 9a. The minor isomer 28b resembles the second isomer of the 4-chloro system 9b in so far as all four hydrogens 9 ACS Paragon Plus Environment


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germinal to the ring nitrogen are equivalent and grouped into a single multiplet, as are all four hydrogens at the 3- and 5-positions.

3

a)

2

1

N OH

4

3', 5', 4

2', 6'

2, 6

3, 5

6

5

4'

27

3

b)

2 1

Cl

4

3b, 5b

6

5

2a, 6a

9 4b

3

c)

2b, 6b

N OH

2a', 6a'

4a

3a, 5a

3a', 5a'

2

7a

1

7

N OH

4

6

5

3b, 5b 2a', 6a'

2a, 6a

3a, 5a

28 2b, 6b

3a', 5a' 4a

7b

Figure 4. Partial 1H-NMR Spectra of the N-Hydroxypiperidines 27 (a), 9 (b), and 28 (c) For the unsubstituted system 27 all four protons geminal to nitrogen become equivalent on heating above the coalescence temperature (90 oC) leading us to conclude that at least one of the processes of ring flip, nitrogen inversion, and N-O bond rotation is slow on the NMR timescale at room temperature in this substance. When substitution is introduced at the 4-position (9 and 28) two diastereomers (cis and trans) are observed when nitrogen inversion is slow on the NMR timescale. The relative proportions of these diastereomers is a function of the size of the 10 ACS Paragon Plus Environment

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substituent introduced, being approximately 1:1 in the case of the smaller chlorine atom (steric A value = 0.53 – 0.64 kcal.mol-1)39 and approximately 8.5:1 for the larger methyl group (steric A value = 1.74 kcal.mol-1).39 Overall, the conformational dynamics of these N-hydroxypiperidines can be described as a series of equilibria as set out in Figure 5.

Figure 5.

Conformational Dynamics of the N-Hydroxypiperidines (R = H) and N-

Alkoxypiperidines (R = alkyl). Thus, one isomer 9a of the chloro-substituted system, the major isomer 28a of the methyl substituted system, and the unsubstituted system 27 of the N-hydroxypiperidines very predominantly take up chair conformations with both substituents equatorial (Figure 1, transmanifold), whereas the second isomer 9b of the chloro-substituted system and the minor isomer 28b of the 4-methyl N-hydroxypiperidine have the cis-configuration and populate a rapidly exchanging set of conformers resulting in the co-incidence of the four hydrogens germinal to nitrogen and the four hydrogens vicinal to nitrogen. For both 9b and 28b these chemical shift equivalences are best explained by a set of interconverting twist boats, some of which are illustrated in the cis-manifold of Figure 5.



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A comparable situation is observed for the N-alkoxypiperidines 3, 4, and 6 whose room 1

temperature

H NMR spectra are presented in Figure 6 along with that of the N-

alkoxypyrrolidine 5.

3 a)

4

2

5

N

1

6

O

Ph

, , 3, 5, 4 2, 6

3

b)

3

Cl

4' 3'a, 5'a

2

4

3b, 5b

1

N

5

2', 6'

6

O

Ph 4b

,

3a, 5a 4a

2b, 6b

2a, 6a

2'a, 6'a

6 7 c)

3 4

, , 3a, 5a

1

N

5

3b,5b

2b,6b 2

6

O

Ph

2a, 6a

2'a, 6'a

7 3'a, 5'a

4 3

d)

2 2, 5

1

4

N 5

O

Ph

3, 4

,

5

Figure 6. Partial 1H-NMR Spectra of the N-Alkoxypiperidines 3 (a), 6 (b), and 4 (c), and the NAlkoxypyrrolidine 5 (d). Several features of the 1H-NMR spectra of these N-alkoxy systems are immediately apparent and instructive: i) In each case all resonances from the 4-phenylbutyl group are sharp suggesting full conformational equilibration of the alkoxy moiety on the NMR timescale at room temperature. ii) The piperidine resonances, while still clearly showing cis and trans-isomers for 4 and 6 are broader than for the corresponding N-hydroxypiperidines, with the corresponding phenomenon also observed for the unsubstituted system 3. This broader line shapes in the spectra of the N-


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alkoxypiperidines as compared to the N-hydroxypiperidines indicates that the former are closer to the coalescence temperature for interconversion between the cis and trans-manifolds than the latter and suggests that the barrier to nitrogen inversion is lower for the N-alkoxy series than for the N-hydroxy series. This observation is consistent with greater relief from steric interactions in the planar transition state for nitrogen inversion in the N-alkoxy series. iii) In the case of the Nalkoxypyrrolidine 5 the entire 1H-NMR spectrum is sharp at room temperature implying full conformational equilibration on the NMR time scale.

To probe the situation further we

determined barriers to stereomutation of N-hydroxypiperidine 27 and of the N-alkoxy amines 36, by the usual variable temperature NMR methods, in both perdeuteriotoluene and DMF, with the results displayed in Table 1 in order of increasing barrier. A number of literature comparators are also presented in Table 1, entries 6-11. Table 1.

Barriers to Stereomutation in 3-6 and 27 and Literature2,40-41 Comparators as

Determined by VT 1H-NMR Entry Hydroxylamine

Inversion barrier

References

(∆GC≠), kcalmol-1 1

13.3 (toluene-d8)

-a

12.3 (DMF-d7) 2

15.3 (toluene d8)

-a

15.4 (DMF-d7)



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

3

15.9 (toluene d8)

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-a

15.9 (DMF-d7) 4

-b

-a

5

16.4 (toluene d8)

-a

16.4 (DMF-d7) 6

15.3 (DMF-d7)

2

7

14.6 (DMF-d7)

2

8

14.5 (DMF-d7)

2

9

11.5 (THF-d8)

40

10

17.0 (CCl4)

40


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12.0 (DMF-d7)

11

41

N OH 34

a

: this work. b : no coalescence below 120 oC.

The inversion barrier for the N-alkoxypyrrolidine 5 (Table 1, entry 1) is substantially lower than that for the three N-alkoxypiperidines 6, 3, and 4 (Table 1, entries 2-4) and for a series of literature N-alkoxypiperidines (Table 1, entries 6-8). This observation is consistent with i) the pseudorotation of five-membered rings being an easier process than ring flip of the sixmembered rings, and ii) with the greater ease of accommodation of a sp2-hybridized atom in a saturated five as opposed to six-membered ring. Among the alkoxy piperidines the 4-methyl system 4 (Table 1, entry 4) has a substantially higher barrier than the 4-unsubstituted and 4chloro analogs 6 and 3 and the literature comparators (Table 1, entries 6-8) as we were not able to reach a coalescence temperature below 120 oC. Evidently, The presence of the bulky group at the 4-position substantially raises the barrier to inversion and this, together with reduced barrier for the pyrrolidine, is best rationalized in terms of the main component of the barrier being due to the ring flip. The barrier to stereomutation of the N-alkoxypiperidines 3 and 6 (Table 1, entries 2 and 3) and indeed for the literature comparators (Table 1, entries 6-8) is lower than that recorded in the literature for N-methoxy-2,2,6,6-tetramethylpiperidine (Table 1, entry 10) suggesting a change in barrier type from the N-O rotation suggested by Anderson and coworkers for the latter system,27 to one of ring flip in the present series.

This conclusion is also supported by

consideration of the inversion barriers in the N-hydroxypiperidine series. Thus, the simple Nhydroxypiperidine 27 (Table 1, entry 5) is little different from that of the corresponding Nalkoxypiperidine 3 (Table 1, entry 3) suggesting a common mechanism of stereomutation that is



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little affected by oxygen substitution, whereas N-methoxy-2,2,6,6-tetramethylpiperidine (Table 1, entry 10) has a barrier of 4.5 kcal.mol-1 higher than that of its N-hydroxy analog (Table 1, entry 9) as a result of the greater steric hindrance to rotation about the N-O bond. The lower barrier to stereomutation in the tetra-alkyl system 32 (Table 1, entry 9) as compared to the simple Nalkoxy and hydroxy piperidines 3 and 27 (Table 1, entries 3 and 5) is consistent with the pattern observed in the N-alkyl piperidines (Figure 7), whereby the more substituted 2,2,6,6-tetramethyl 35 has a lower barriers to inversion than the 2,2,6,6-unsubstituted system 36.40,42-43 A similar effect was also observed in the N-diazenyl piperidine 37 and its 2,2,6,6-tetramethyl congenor 38 (Figure 7) with latter having the lower barrier.44-45 Such phenomena, which are also found in the cyclohexane series, reflect the lowering of the chair/twist boat energy gap in systems that are disubstituted at both the 1- and 3-positions and reflect the destabilization of the chair conformer by the

repulsive

syn

1,3-diaxial

interaction

between

the

alkyl

groups.43,46

Figure 7. Unsubstituted and 2,2,6,6-Tetramethyl Substituted Systems of N-alkyl piperidine and N-diazenyl piperidine. Conclusion. The reduction of O-(1-acetoxyalkyl)hydroxylamines by triethylsilane in the presence of the Lewis acid BF3.OEt2 is strongly retarded by the presence of an electron-withdrawing group in the alkyl chain in a manner that diminishes with increasing separation of the electron16 ACS Paragon Plus Environment

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withdrawing group from the reaction site, which is strongly suggestive of a mechanism proceeding via an intermediate aminoxocarbenium ion. The ability to carry azides through the reaction sequence for the preparation of trisubstituted hydrazines provides the ability to incorporate simple hydroxylamines into larger chemical libraries through click chemistry.47-48 Study of substituent effects at the 4-position of N-alkoxypiperidines leads to the conclusion that the main component of the barrier to stereomutation in such systems is the barrier to ring flip, from which it follows the individual barriers to N-O bond rotation and nitrogen-inversion in these systems are necessarily lower. The process of N-O bond rotation only becomes rate determining in the case of severe steric crowding as with the N-alkoxy-2,2,6,6tetramethylpiperidines. Experimental Part. General Experimental. All reactions were carried out in oven dried glassware and dry solvents under an inert atmosphere. All reagents and solvents were purchased from commercial suppliers and were used without further purification. All purifications were carried out by flash column chromatography using silica gel (230-400 mesh) as stationary phase. Thin layer chromatography was performed with silica gel pre-coated glass backed plates (w/UV 254) and visualized by UV irradiation (254 nm) or by charring with cerium ammonium molybdate (CAM) or ninhydrin solution. 1H NMR spectra of all compounds were recorded using 400, 500, or 600 MHz instruments. 13C NMR spectra of all compounds were recorded at 100, 125, or 150 MHz. All variable temperature (VT) NMR spectroscopy experiments were performed with a 500 MHz instrument. High resolution mass spectra were recorded under electrospray conditions with a time of flight (TOF) mass analyzer using a Waters LCT Premier XE instrument. Melting points were determined using an electrothermal melting point apparatus and are uncorrected. 17 ACS Paragon Plus Environment


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4-Chloropiperidin-1-oxyl Benzoate (8). To a stirred suspension of benzoyl peroxide (3.99 g, 50% w/w blended with dicyclohexyl phthalate, 16.5 mmol) and K2HPO4 (3.92 g, 22.5 mmol) in dry DMF (38 mL) was added 4-chloropiperidine (1.79 g, 15.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h, quenched by addition of water (150 mL), and stirred vigorously for 1 h at room temperature. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aq NaHCO3, water, and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel (eluent: 0 – 10% of ethyl acetate in toluene) to afford 8 (2.92 g, 81%) as a white solid. M.p. 63 – 65 oC; IR (neat, cm1

) √ 1738; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 6.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43

(t, J = 7.7 Hz, 2H), 4.35 (br s, 0.6H), 4.07 (br s, 0.4H), 3.58 (br s, 0.8H), 3.34 (s, 2.4H), 2.97 (br s, 0.8H), 2.37 – 2.24 (m, 2H), 2.20 – 2.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 164.6, 133.1, 129.4, 129.2, 128.4, 55.1, 54.4, 52.8, 51.7, 33.0; ESIHRMS calculated for C12H14NO2ClNa [M+Na]+, 262.0611; found, 262.0613. 4-Chloropiperidin-1-ol (9). To a stirred solution of 8 (2.68 g, 11.2 mmol) in dry CH2Cl2 (67 mL) was added DIBAL (28.0 mL 1 M solution in hexane, 28.0 mmol) slowly via syringe under nitrogen at 0 oC. The reaction mixture was stirred for 0.25 h and quenched by addition of saturated aq NH4Cl (110 mL) and saturated aq sodium potassium tartrate (90 mL) at 0 oC. The resultant mixture was warmed to room temperature and stirred vigorously for 1 h and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel (eluent: diethyl ether) to afford desired product 9 (1.29 g, 85%) as a mixture of two stereoisomers (9a and 9b) in 1:1 ratio in the form of a white solid. M.p. 97 – 99 18 ACS Paragon Plus Environment

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o

C; NMR of isomer 9a: 1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H), 3.91 (s, 1H), 3.32 – 3.22

(m, 2H), 2.62 (t, J = 10.7 Hz, 2H), 2.24 (d, J = 12.8 Hz, 2H), 1.93 – 1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 56.5, 55.5, 34.4; NMR of isomer 9b: 1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H), 4.26 (s, 1H), 3.09 – 2.98 (m, 4H), 2.11 – 1.97 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 54.9, 53.0, 33.0; ESIHRMS calculated for C5H11NOCl [M+H]+, 136.0529; found, 136.0534. 4-Chloro-1-piperidinyloxy

4-Phenylbutanoate

(10).

A

solution

of

N,N'-

dicyclohexylcarbodiimide (951 mg, 4.61 mmol) was added to a stirred solution of 9 (500 mg, 3.69 mmol), 4-phenylbutanoic acid (757 mg, 4.61 mmol) and DMAP (90 mg, 0.74 mmol) in dry CH2Cl2 (37 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h then was filtered through a pad of Celite®. The filtrate was washed with saturated aq NaHCO3, and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent: 10 – 30% of ethyl acetate in hexane) to afford 10 (827 mg, 80%) as a colorless oil. IR (neat, cm-1) √ 1757; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m, 2H), 7.23 – 7.14 (m, 3H), 4.30 (s, 0.6H), 3.97 (br s, 0.4H), 3.42 (br s 0.8H), 3.18 (s, 2.4H), 2.77 (br s, 0.8H), 2.66 (t, J = 7.6 Hz, 2H), 2.35 – 2.18 (m, 4H), 2.11 – 1.91 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.4, 141.2, 128.5, 128.4, 126.1, 55.0, 51.5, 35.0, 32.9, 32.3, 26.6; ESIHRMS calculated for C15H20NO2ClNa [M+Na]+, 304.1080; found, 304.1077. 1-(4-Chloro-1-piperidinyloxy)-4-phenylbutyl acetate (11). To a stirred solution of 10 (100 mg, 0.35 mmol) at –78 oC under nitrogen in dry CH2Cl2 (2.1 mL) were added sequentially, dropwise DIBAL (0.62 mL 1 M in hexane, 0.62 mmol), pyridine (85 µL, 1.06 mmol), a solution of DMAP (87 mg, 0.71 mmol) in dry CH2Cl2 (1 mL), and finally Ac2O (201 µL, 2.13 mmol). The reaction mixture was stirred for 12 h at –78 oC, warmed slowly to 0 oC, and quenched by 19 ACS Paragon Plus Environment


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Page 20 of 29

addition of saturated aq NH4Cl (4 mL) and saturated aq. sodium potassium tartrate (3 mL) at 0 o

C. The resultant mixture was warmed to room temperature and stirred vigorously for 1 h and

extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent: 0 – 20% of ethyl acetate in hexane) to afford desired product 11 (98 mg, 85%) as a colorless oil. IR (neat, cm-1) √ 1738; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m, 2H), 7.23 – 7.13 (m, 3H), 6.05 (s, 1H), 4.21 (br s, 0.5H), 3.92 (s, 0.5H), 3.28 (br s, 1H), 3.05 (br s, 2H), 2.63 (s, 3H), 2.26 – 1.78 (m, 7H), 1.69 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 170.3, 141.9, 128.4, 128.4, 125.9, 99.6, 55.9, 55.5, 52.4, 51.3, 35.5, 34.1, 33.0, 32.5, 26.0, 21.4; ESIHRMS calculated for C17H24NO3ClNa [M+Na]+, 348.1342; found, 348.1346. 4-Chloro-1-(4-phenylbutoxy)piperidine (6). To a stirred solution of 11 (85 mg, 0.26 mmol) in dry CH2Cl2 (5.2 mL) were added dropwise and sequentially under nitrogen Et3SiH (104 µL, 0.65 mmol) and BF3.OEt2 (81 µL, 0.65 mmol) at 0 oC. The reaction mixture was stirred for 2 h at 0 o

C, warmed slowly to room temperature, and stirred for 2 h at room temperature. The reaction

mixture was partitioned between pentane and saturated aq. NaHCO3 and the aqueous layer was extracted with pentane.

The combined organic layer was dried over anhydrous Na2SO4,

concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluent: 0 – 10% of ethyl acetate in hexane) to give 6 (52 mg, 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m, 2H), 7.22 – 7.15 (m, 3H), 4.25 (br s, 0.45H), 3.89 (br s, 0.55H), 3.69 (t, J = 6.3 Hz, 2H), 3.26 (br s, 1H), 3.01 (br s, 1.8H), 2.63 (t, J = 7.5 Hz, 2H), 2.51 (br s, 1H), 2.27 – 1.80 (m, 4H), 1.76 – 1.54 (m, 4H);

13

C NMR (100 MHz, CDCl3) δ 142.4,

128.4, 128.3, 125.7, 71.5, 56.1, 55.8, 54.4, 51.0, 35.8, 34.7, 33.1, 28.5, 28.1; ESIHRMS calculated for C15H23NOCl [M+H]+, 268.1468; found, 268.1470. 20 ACS Paragon Plus Environment

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General procedure (A) for the Synthesis of N,N-Dibenzyl-O-azidoacyl hydroxylamines from

N,N-Dibenzyl

hydroxylamine.

N,N-Dibenzylhydroxylamine

12

(1

mmol),

azidocarboxylic acid (1.5 mmol), and DMAP (0.2 mmol) were dissolved in dry CH2Cl2 (10 mL) and treated with a solution of N,N’-dicyclohexylcarbodiimide (1.5 mmol) in dry CH2Cl2 (1 mL) at room temperature. The reaction mixture was stirred until completion and then filtered through a pad of Celite©. The filtrate was washed with saturated aq NaHCO3 solution, and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue that was purified by flash column chromatography on silica gel to yield the requisite N,N-dibenzyl-Oazidoacyl hydroxylamine. N,N-Dibenzyl-O-(2-azidoacetyl)hydroxylamine (16).

The title compound was prepared

according to general procedure A from 12 (1.53 g, 7.17 mmol), 2-azidoacetic acid 13 (1.45 g, 14.35 mmol), and N,N’-dicyclohexylcarbodiimide (2.97 g, 14.35 mmol) with stirring for 2 h. It was isolated (eluent: 0 – 5% of ethyl acetate in hexane) as a yellow oil (1.38 g, 65%). IR (neat, cm-1) √ 2108, 1765; 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.22 (m, 10H), 4.10 (s, 4H), 3.47 (s, 2H);

13

C NMR (100 MHz, CDCl3) δ 167.6, 135.3, 129.5, 128.5, 128.1, 63.0, 49.5; ESIHRMS

calculated for C16H16N4O2Na [M+Na]+, 319.1171; found 319.1169. N,N-Dibenzyl-O-(3-azidopropionyl)hydroxylamine (17). The title compound was prepared according to general procedure A from 12 (1.74 g, 8.15 mmol), 3-azidopropionic acid 14 (1.41 g, 12.23 mmol), and N,N’-dicyclohexylcarbodiimide (2.52 g, 12.23 mmol) with stirring for 2 h. It was isolated (eluent: 0 – 10% ethyl acetate in hexane) as a yellow oil (1.30 g, 52%). IR (neat, cm-1) √ 2098, 1756; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 6.8 Hz, 4H), 7.37 – 7.25 (m, 6H), 4.08 (s, 4H), 3.26 (t, J = 6.7 Hz, 2H), 2.26 (t, J = 6.7 Hz, 2H);

13

C NMR (100 MHz, CDCl3) δ



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Page 22 of 29

169.6, 135.7, 129.4, 128.4, 127.8, 62.6, 46.4, 32.4; ESIHRMS calculated for C17H19N4O2 [M+H]+, 311.1508; found 311.1518. N,N-Dibenzyl-O-(4-azidobutanoyl)hydroxylamine (18).


according to general procedure A from 12 (687 mg, 3.22 mmol), 4-azidobutyric acid 15 (624 mg, 4.83 mmol), and N,N’-dicyclohexylcarbodiimide (996 mg, 4.83 mmol) with stirring for 2 h. It was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a colorless oil (813 mg, 72%). IR (neat, cm-1) √ 2096, 1756; 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.37 (m, 4H), 7.30 (m, 6H), 4.07 (s, 4H), 2.93 (t, J = 6.8 Hz, 2H), 2.09 (t, J = 7.1 Hz, 2H), 1.57 (m, 2H);

13

C NMR (100 MHz,

CDCl3) δ 171.2, 135.9, 129.5, 128.3, 127.7, 62.7, 50.0, 29.5, 24.1; ESIHRMS calculated for C18H21N4O2 [M+H]+, 325.1665; found 325.1673. General Procedure B for the Synthesis of O-(1-Acetoxy-ω-azidoalkyl)hydroxylamines.4 The N,N-dibenzyl-O-azidoacyl hydroxylamine (0.5 mmol) was dissolved in dry CH2Cl2 (3 mL) with stirring and chilled to –78 oC under nitrogen atmosphere. In sequential order DIBAL (1M in hexane, 0.86 mmol), pyridine (1.5 mmol), a solution of DMAP (1 mmol) in dry CH2Cl2 (1.5 mL), and finally acetic anhydride (3 mmol) were added dropwise while maintaining the temperature at –78 oC. The reaction mixture was stirred for 12 h and then was brought to 0 oC. The reaction was quenched by addition of saturated aq NH4Cl (5 mL) and saturated aq sodium potassium tartrate (4 mL) at 0 oC.

The resulting mixture was stirred vigorously at room

temperature for 1 h and then extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification was by flash column chromatography over silica gel gave the desired hydroxylamine.


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N,N-Dibenzyl-O-(1-acetoxy-2-azidoethyl)hydroxylamine (19).

The title compound was

prepared according to general procedure B from 16 (300 mg, 1.01 mmol) and was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a colorless oil (298 mg, 86%). IR (neat, cm-1) √ 2102, 1751; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.22 (m, 10H), 5.89 (ap t, J = 4.9 Hz, 1H), 4.01 (br d, J = 13.1 Hz, 2H), 3.87 (d, J = 13.1 Hz, 2H), 2.96 (m, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 136.8, 129.6, 128.4, 127.6, 97.4, 63.1, 51.2, 21.0; ESIHRMS calculated for C18H20N4O3Na [M+Na]+, 363.1433; found 363.1434. N,N-Dibenzyl-O-(1-acetoxy-3-azidopropyl)hydroxylamine (20).


prepared according to general procedure B from 17 (300 mg, 0.97 mmol) and was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a colorless oil (210 mg, 61 %). IR (neat, cm-1) √ 2098, 1743; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.12 (m, 10H), 5.87 (ap t, J = 5.4 Hz, 1H), 4.04 (br m, 2H), 3.79 (d, J = 13.0 Hz, 2H), 3.00 (dt, J= 12.5, 7.2 Hz 1H), 2.89 (dt, J = 12.5, 7.2 Hz, 1H), 1.87 (s, 3H), 1.72 – 1.53 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ 169.9, 136.9, 129.5, 128.4,

127.5, 98.1, 62.9, 46.1, 32.3, 21.1; ESIHRMS calculated for C19H22N4O3Na [M+Na]+, 377.1590; found 377.1603. N,N-Dibenzyl-O-(1-acetoxy-4-azidobutyl)hydroxylamine (21).


prepared according to general procedure B from 18 (700 mg, 2.16 mmol) and was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a colorless oil (693 mg, 87 %). IR (neat, cm-1) √ 2097, 1741; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.16 (m, 10H), 5.80 (dd, J= 6.0, 5.3 Hz, 1H), 4.05 (br m, 2H), 3.77 (d, J = 13.6 Hz, 2H), 3.00 (t, J = 6.6 Hz, 2H), 1.88 (s, 3H), 1.49 – 1.41 (m, 2H), 1.37 – 1.16 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ 170.2, 137.0, 129.4, 128.3, 127.5, 100.0,

63.0, 50.7, 29.9, 23.2, 21.2; ESIHRMS calculated for C20H24N4O3Na [M+Na]+, 391.1746; found 391.1748. 23 ACS Paragon Plus Environment


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Page 24 of 29

N,N-Dibenzyl-O-(2-azidoethyl)hydroxylamine (22) by reduction of 19. Compound 19 (50 mg, 0.15 mmol) was dissolved in dry CH2Cl2 (3 mL) and chilled to 0 oC in an ice bath. Et3SiH (59 µL, 0.37 mmol) was added dropwise followed by dropwise addition of BF3 . OEt2 (45 µL, 0.37 mmol). The reaction mixture was allowed to stir for 1 h after which further Et3SiH (59 µL, 0.37 mmol) and BF3.OEt2 (45 µL, 0.37 mmol) were added dropwise in sequence to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 4 days until completion. The mixture was partitioned between saturated aq. NaHCO3 (10 mL) and pentane (10 mL). The aqueous layer was extracted with pentane, and the combined organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure.

Purification was

performed by flash column chromatography on silica gel to afford 22 (7 mg, 17 %) as a yellow oil (eluent: 0 – 5% ethyl acetate in hexane). IR (neat, cm-1) √ 2102; 1H NMR (600 MHz, CDCl3) δ 7.43 – 7.21 (m, 10H), 3.88 (s, 4H), 3.38 (t, J = 5.2 Hz, 2H), 2.96 (t, J = 5.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 137.5, 129.7, 128.2, 127.4, 71.6, 62.8, 49.7; ESIHRMS calculated for C16H19N4O [M+H]+, 283.1559; found 283.1567. N,N-Dibenzyl-O-(2-azidoethyl)hydroxylamine (22) by alkylation of 12.

To a stirred

suspension of NaH (14 mg 60% dispersion in mineral oil, 0.35 mmol) in dry DMF (200 µL) was added N,N-dibenzyl hydroxylamine (50 mg, 0.23 mmol) portion wise at room temperature. The mixture was stirred for 0.5 h and was treated with 2-azidoethyl tosylate (85 mg, 0.35 mmol) in dry DMF (200 µL) dropwise. The resulting reaction mixture was stirred for 14 h at room temperature and was quenched by the addition of saturated aq NH4Cl (1 mL). The mixture was extracted with EtOAc and the organic phase was sequentially washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column


Page 25 of 29

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chromatography on silica gel afforded 22 (16 mg, 25%) as a yellow oil (eluent: 0–5% ethyl acetate in hexane), whose spectral data were identical to those of the above sample. General Procedure C for the Synthesis of N,N-dibenzyl-O-(azidoalkyl)hydroxylamines 23 and 24.4 The α-acetoxy hydroxylamine (0.5 mmol) was dissolved in dry CH2Cl2 (10 mL) and chilled to –78 oC. Sequentially Et3SiH (1.25 mmol) and BF3.OEt2 (1.25 mmol) were added dropwise while maintaining the temperature at –78 oC. The reaction mixtures were warmed to 0 o

C or room temperature and stirred until completion. The reaction mixture was then partitioned

between saturated aq NaHCO3 (30 mL) and pentane (30 mL). The aqueous layer was extracted with pentane, and the combined organic layers were dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Purification by flash column chromatography over silica gel gave the desired hydroxylamine. N,N-Dibenzyl-O-(3-azidopropyl)hydroxylamine (23).


according to general procedure C from 20 (50 mg, 0.14 mmol) with stirring at room temperature for 24 h. It was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a yellow oil (20 mg, 48%). IR (neat, cm-1) √ 2096; 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.20 (m, 10H), 3.85 (s, 4H), 3.34 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H), 1.51 – 1.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 137.7, 129.6, 128.2, 127.3, 69.7, 62.7, 48.4, 28.0; ESIHRMS calculated for C17H21N4O [M+H]+, 297.1715; found 297.1716. N,N-Dibenzyl-O-(4-azidobutyl)hydroxylamine (24).


according to general procedure C from 21 (100 mg, 0.27 mmol) with stirring at 0 oC for 3 h. It was isolated (eluent: 0 – 5% ethyl acetate in hexane) as a yellow oil (45 mg, 54 %). IR (neat,cm1

) √ 2095; 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m, 4H), 7.36 – 7.24 (m, 6H), 3.85 (s, 4H),



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Page 26 of 29

3.28 (t, J = 5.7 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 1.30 – 1.25 (m, 4H);

13

C NMR (100 MHz,

CDCl3) δ 137.8, 129.6, 128.1, 127.2, 72.0, 62.7, 50.9, 25.6, 25.5; ESIHRMS calculated for C18H23N4O [M+H]+, 311.1872; found 311.1885. Dynamic NMR study of nitrogen inversion in hydroxylamines. The inversion barriers for the compounds 3, 4, 5, and 6 were determined by using variable temperature (VT) NMR spectroscopy in 500 MHz instrument. The 1H NMR spectra for each compound were recorded over the temperature range of 223 K to 363 K in Toluene-d8 and 233 K to 363 K in DMF-d7 (233 K to 393 K for 4). The inversion barriers were calculated by applying Eyring equation (1). ∆GC≠ = 4.575 x 10-3 TC[9.972 + log (TC/∆v)] Supporting Information Available.

(1)

Copies of the 1H and

13

C NMR spectra of all new

compounds, and VT NMR spectra. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.****** (1)

Malik, G.; Guinchard, X.; Crich, D. Org. Lett. 2012, 14, 596-599.

(2)

Malik, G.; Ferry, A.; Guinchard, X.; Cresteil, T.; Crich, D. Chem. Eur. J. 2013, 19, 2168-

2179. (3)

Ferry, A.; Malik, G.; Guinchard, X.; Vetvicka, V.; Crich, D. J. Am. Chem. Soc. 2014, 136,

14852-14857. (4)

Dhanju, S.; Crich, D. Org. Lett. 2016, 18, 1820-1823.

(5)

Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191-198.

(6)

Vo, C.-V. T.; Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2011, 133, 14082-14089.

(7)

Fraser-Reid, B.; Lopez, C. Top. Curr. Chem. 2011, 301, 1-29.

(8)

Premathilake, H. D.; Demchenko, A. V. Top. Curr. Chem. 2011, 301, 189-222. 26 ACS Paragon Plus Environment

Page 27 of 29

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(9)

Wu, C.-Y.; Wong, C.-H. Top. Curr. Chem. 2011, 301, 223-252.

(10)

Gomez, A. M. Top. Curr. Chem. 2011, 301, 31-68.

(11)

Lambert, J. B.; Mark, H. W. J. Am. Chem. Soc. 1978, 100, 2501-2505.

(12)

Kirmse, W.; Mrotzeck, U. Chem. Ber. 1988, 121, 485-492.

(13)

Gassman, P. G.; Saito, K.; Talley, J. J. J. Am. Chem. Soc. 1980, 102, 7613-7615.

(14)

Mollin, J.; Kasparek, F.; Lasovsky, J. Chem. Zvesti 1975, 29, 39-43.

(15)

Bartmess, J. E. In Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids;

Rappoport, Z., Liebman, J. F., Eds.; Wiley: Chichester, 2011; Vol. 2, p 115-143. (16)

Raban, M.; Kost, D. Tetrahedron 1984, 40, 3345-3381.

(17)

Raban, M.; Kost, D. In Acyclic Organonitrogen Sterodynamics; Lambert, J. B., Takeuchi,

Y., Eds.; VCH: New York, 1992, p 57-88. (18)

Schmitz, J.; Li, T.; Bartz, U.; Gütschow, M. ACS Med. Chem. Lett. 2016, 7, 211-216.

(19)

Gryder, B. E.; Akbashev, M. J.; Rood, M. K.; Meyers, W. M.; Dillard, P.; Khan, S.;

Oyelere, A. K. ACS Chem. Biol. 2013, 8, 2550-2560. (20)

Fernandes, L.; Fischer, F. L.; Ribeiro, C. W.; Silveira, G. P.; Sá, M. M.; Nome, F.;

Terenzi, H. Bioorg. Med. Chem. Lett. 2008, 18, 4499-4502. (21)

Biloski, A. J.; Ganem, B. Synthesis 1983, 537-538.

(22)

Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.; Withers, S. G. J. Am. Chem.

Soc. 2000, 122, 1270-1277. (23)

Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091-4094.

(24)

Melman, A. In The Chemistry of Hydroxylamines, Oximes, and Hydroxamic Acids, Part

1; Rappoport, Z., Liebman, J. F., Eds.; Wiley: Chichester, 2009, p 117-161. (25)

Riddell, F. G.; Turner, E. S. J. Chem. Soc., Perkin Trans. 2 1978, 707-708.



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

(26)

Page 28 of 29

Bach, R. D.; Raban, M. In Acyclic Organonitrogen Sterodynamics; Lambert, J. B.,

Takeuchi, Y., Eds.; VCH: New York, 1992, p 63-103. (27)

Anderson, J. E.; Tocher, D. A.; Corrie, J. E. T.; Lunazzi, L. J. Am. Chem. Soc. 1993, 115,

3494-3498. (28)

Kliegel, W.; Riebe, U.; Patrick, B. O.; Rettig, S. J.; Trotter, J. Acta Cryst. Sect. E 2001,

E57, o1173-o1174. (29)

Matousˇek, V.; Pietrasiak, E.; Sigrist, L.; Czarniecki, B.; Togni, A. Eur. J. Org. Chem.

2014, 3087-3092. (30)

Barnes, K. L.; Chen, K.; Catalano, V. J.; Jeffrey, C. S. Org. Chem. Front. 2015, 2, 497-

501. (31)

Liew, S. K.; Kaldas, S. J.; Yudin, A. K. Org. Lett. 2016, 18, 6268-6271.

(32)

Busfield, W. K.; Englelhardt, L. M.; Healy, P. C.; Jenkins, I. D.; Thang, S. H.; White, A.

H. Aus. J. Chem. 1986, 39, 357-365. (33)

Busfield, W. K.; Byriel, K. A.; Grice, D.; Jenkins, I. D.; Lynch, D. E. J. Chem. Soc.,

Perkin Trans. 2 2000, 757-760. (34)

Grice, I. D.; Jenkins, I. D.; Busfield, W. K.; Byrield, K. A.; Kennarde, C. H. L. Acta

Cryst, E. 2004, E60, o2386-2387. (35)

Liu, Y.-P.; Zhang, X.-F.; Liu, K.-J.; Liu, Y. Acta Cryst. E. 2006, 62, o3672-o3673.

(36)

Morozov, D. A.; Kirilyuk, I. A.; Komarov, D. A.; Goti, A.; Bagryanskaya, I. Y.;

Kuratieva, N. V.; Grigor’ev, I. A. J. Org. Chem. 2012, 77, 10688-10698. (37)

Busfield, W. K.; Jenkins, I. D.; Thang, S. H.; Moad, G.; Rizzardo, E.; Solomon, D. H. J.

Chem. Soc., Chem Commun. 1985, 1249-1250. (38)

Anderson, J. E.; Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 2 1992, 1027-1031.


Page 29 of 29

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


(39)

Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York,

1994. (40)

Anderson, J. E.; Casarini, D.; Corrie, J. E. T.; Lunazzi, L. J. Chem. Soc., Perkin Trans. 2

1993, 1299-1304. (41)

Perrin, C. L.; Thoburn, J. D.; Elsheimer, S. J. Org. Chem. 1991, 56, 7034-7038.

(42)

Tafazzoli, M.; Suarez, C.; True, N. S.; LeMaster, C. B.; LeMaster, C. L. J. Phys. Chem.

1992, 96, 10201-10205. (43)

Belostotskii, A. M.; Gottlieb, H. E.; Aped, P.; Hassner, A. Chem. Eur. J. 1999, 5, 449-455.

(44)

Lunazzi, L.; Cerioni, G.; Foresti, E.; Macciantelli, D. J. Chem. Soc, Perkin Trans. 2 1978,

686-691. (45)

Fu, J.; Lau, K.; Barra, M. J. Org. Chem. 2009, 74, 1770-1773.

(46)

Weiser, j.; Golan, O.; Fitjer, L.; Biali, S. E. J. Org. Chem. 1996, 61, 8277-8284.

(47)

Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.

(48)

Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952-3015.


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