The Detosylation of Chiral 1,2-Bis(tosylamides)

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Jayden J. Gaston, Andrew J. Tague, Jamie E. Smyth, Nicholas M. Butler, Anthony C. Willis,

Nico van Eikema Hommes, Haibo Yu, Timothy Clark, and Paul A. Keller *

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ABSTRACT: The deprotection of chiral 1,2-bis(tosylamides) to their

corresponding 1,2-diamines is mostly unsuccessful under standard

conditions. In a new methodology, the use of Mg/MeOH with suﬃcient

steric additions allows the facile synthesis of 1,2-diamines in 78−98% yields.

These results are rationalized using density functional theory and the

examination of inner and outer-sphere reduction mechanisms.

Scheme 1. The Synthesis of Tosyl-Protected (R,R)-1 from

(R,R)-Tartaric Acid with (a) Ring Opening to Produce an

Acyclic 1,2-Bis(tosylamide) Scaﬀold and (b) Ring Closing

he p-toluenesulfonyl (tosyl) group is a versatile and

1

T_{robust protection for amines}

with a trivial addition,

involving the reaction of the amine with p-toluenesulfonyl

chloride and a base.¹The corresponding deprotection of the

tosyl group is split into the following two mechanistic types:

electron reductions (single-electron transfer (SET)²⁻⁶and

two-electron transfers⁷) and nucleophilic displacement,⁸with

SET reducing agents being the standard. There are many

general procedures that have published for a range of

monotosylamide deprotections;²⁻⁶however, procedures for

the deprotection of 1,2-bis(tosylamide) substrates are limited

(Figure 1, A−C).^9,10

a

to Produce a Cyclic 1,2-Bis(tosylamide)

a

See ref 11.

Figure 1. Compounds A, B,⁹and C¹⁰are published 1,2-bis-

(tosylamides) that were deprotected to the corresponding 1,2-

diamines by the SET methods shown.

(tosylamide) 2 using the standard SET reductant Mg/

MeOH, which resulted in complete decomposition upon

sonication (45 min). Further attempts at 1,2-(bistosylamide)

deprotection using a variety of conditions commonly employed

for monotosylamides,^2,4,12−17(SmI₂,^2,12−14Na/naphthalene,¹⁵

Mg/MeOH,^4,16and Li/amine;¹⁷see Table S1 in the

Supporting Information for data) also resulted in decom-

position or the return of the starting material and did not allow

for the deprotection of the tosyl moiety regardless of the

substrate scaﬀold (Scheme 2, X = O, N, CH₂). Only 1,2-

In a strategy designed to easily generate libraries of chiral

1,2-diamines from a late-stage chiral intermediate, a recent

report detailed the facile synthesis of a small library of tosyl-

protected chiral 1,2-bis(tosylamides) starting from (R,R)-

biaziridine (R,R)-1 (Scheme 1).¹¹The next step to

demonstrate the wide-ranging applicability of this strategy

was the optimization of the tosyl deprotection as applied

speciﬁcally to 1,2-bis(tosylamide) substrates, which is the

subject of this report.

The biaziridine (R,R)-1, which was synthesized from (R,R)-

tartaric acid,¹¹was ring-opened with phenol, benzylmagnesium

chloride, aniline, piperidine, and hexanol nucleophiles under

newly optimized conditions, generating a small library of chiral

acyclic scaﬀolds 2−6 (Scheme 2) of the type a (Scheme 1).

Initial attempts at deprotection started with 1,2-bis-

Received: February 12, 2021

Published: June 21, 2021

https://doi.org/10.1021/acs.joc.1c00359

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Scheme 2. Attempted N-Tosyl Deprotection of 1,2-

Bis(tosylamides) 2−5 Resulted in Either the Starting

Scheme 3. There Are Two Potential Inner-Sphere SET

Pathways (A and B) Depending on the Amount of Steric

Hindrance at the 1,2-Bis(tosylamide) N-Atoms

a

Material or Decomposition

a

Only (1,2-bistosylamide) 6 underwent reduction to the product

a

Only one potential pathway for an outer-sphere SET pathway (C)

amine-6 in the strong Li/amine Benkenser reducing conditions

without the presence of reducible aromatic moieties. See Table S1 in

the Supporting Information for data.

can occur, which requires a high reduction potential for the SET

reductant due to less interaction between the reductant and the

substrate.

bis(tosylamide) 6 was capable of deprotection (Scheme 2),

with the corresponding diamine isolated in a modest yield

(30%). This example contained no functional groups (e.g.,

aromatic groups) that could undergo reduction in the presence

of the strong Benkenser reducing conditions that utilize Li/

propylamine/ethylenediamine.¹⁷

of radical stabilization (e.g., Boc or benzyl), 1,2-bis-

(tosylamide) 7, which contains bis(N-methyl) substitutions,

was subjected to Mg/MeOH deprotection. This reaction gave

decomposition under the deprotection conditions, while the

Mg/MeOH deprotection using bis(N-ethyl) 8 gave the

deprotected 1,2-diamine in an 80% yield (Table 1). The

presence of N-ethyl or N-methyl substituents is expected to

provide similar degrees of radical stabilization. Therefore, the

variation in outcomes is likely a result of steric diﬀerences

between the two groups. This indicates that the presence of an

N−H (2−6) or N-methyl (7) is not suﬃciently sterically

demanding enough to allow deprotection (Tables 1 and

Scheme 2), leading to decomposition. Substrates that contain

substituents larger than N-methyl (e.g., 8−14 and 16) at the

1,2-bis(tosylamide) core are required in order to undergo facile

deprotection, e.g. 1,2-bis(tosylamides) 8−13 and 16 (Table 1).

An analysis of the results in Table 1 and Scheme 2 suggests

that Mg/MeOH deprotection is likely to operate through an

inner-sphere reduction mechanism (Scheme 3, path A or B).

This mechanism requires the substrate and reductant to either

form a bond or have a direct orbital interaction to allow the

electron transfer to occur,^14,18which could either occur with a

free Mg⁰atom in solution or at the surface of the Mg⁰powder.

A closely bound Mg−1,2-bis(tosylamide) intermediate could

potentially cause decomposition via unwanted secondary

reductions (Scheme 3, path A).

Steric hindrance at the 1,2-bis(tosylamide) core decreases

the interaction between the Mg atom and the 1,2-bis-

(tosylamide) core, promoting deprotection by forcing the

Mg atom away from the 1,2-bis(tosylamide) and facilitating

single-electron transfer (SET) to the sulfonamide aromatic ring

(Scheme 3, path B);²thus, this leads to successful tosyl

deprotection. This hypothesis explains the observed diﬀerences

between the N-methyl 7 and N-ethyl 8 deprotections, with the

presence of steric interactions allowing electron transfer to the

sulfonamide moiety of the 1,2-bis(tosylamide) and thereby

hindering SET elsewhere.

These results indicated that detosylation using SmI₂and

Na/naphthalene as SET reductants did not reduce the tosyl

functionality (Scheme 2) and that decomposition occurs with

Mg/MeOH and Li/propylamine/ethylenediamine, indicating

that secondary reductions lead to the decomposition of the

starting materials or products (Scheme 2). This result has not

generally been observed with functionally similar monotosy-

lamides.^2,3An examination of previous mechanistic insights for

the detosylation of monotosylamides indicates that SET

cleavage results in a radical amine intermediate that leads to

the formation of the protonated product.²Consequently, the

stabilization of the intermediate radical N atom in 1,2-

bis(tosylamides) 2−6 with the correct N-functionalities (e.g.,

benzyl groups) may prevent competing decomposition path-

ways and promote tosyl deprotection (Scheme 3). Therefore,

the tertiary 1,2-bis(tosylamides) 7−15 (Table 1) were

synthesized by the addition of the alkyl halide electrophile to

the 1,2-bis(tosylamides) 2−5, followed by NaH. The hetero-

cycle 16 was synthesized by the cyclization of an o-halogenated

derivative of 2 (1,2-bis(tosylamide) 17) with CuI.

The tosyl deprotections of the 1,4-diether scaﬀold 8−13 and

16 under Mg/MeOH conditions proceeded in excellent yields,

producing the corresponding 1,2-diamines in 78−98% yields

(Table 1), and only small amounts of decomposition were

observed. Under the same reaction conditions, the tertiary 1,4-

dimethylene 14 gave a crude yield of 81% despite

decomposition during deprotection, indicating that the

absence of a heteroatom in the molecule backbone likely

leads to secondary reductions and therefore invokes decom-

position. The tertiary 1,4-diamine scaﬀold 15 also underwent

complete decomposition, indicating it was unable to be

accessed.

To ensure that the reaction success was not the result of

functionalities that were not electron-withdrawing or capable

To conﬁrm this hypothesis, the LUMO and spin density

plots of compounds 2−4, 6, 8, and 16 and selected published

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LUMO. This correlates with a published experimental report

that established the necessity of an aromatic sulfonamide in

SET tosyl deprotection with SmI₂whereby electron transfer

was suspected to occur at the sulfonamide aromatic ring.²

However, the DFT analysis only indicates that reduction

should occur at the tosylamide and does not explain where or

when a secondary SET could occur during detosylation to lead

to decomposition.

Table 1. Deprotection of N-Substituted Chiral 1,2-

Bis(tosylamides)

Vertical electron aﬃnities (VEAs) for the synthesized 1,2-

bis(tosylamides) were also calculated in MeOH (Table S3).

No observable correlations were visible since all substrates had

similar aﬃnities for electrons, indicating that their relative ease

to reduce is not a factor in the success of the reduction. Even

the fully deprotected primary amine of 2 (amine-2) had too

little of an aﬃnity for electrons to allow any further reduction

after the tosyl deprotection. This was expected since the

further exposure of amine-2 or amine-16 to Mg/MeOH

reduction conditions had no eﬀect, and only the starting

material was isolated. A 1,2-bis(tosylamide)−Mg chelate is

then responsible for allowing the secondary reductions to

occur, which is a species that was not analyzed under the DFT

model and the only other species likely to exist in solution

during deprotection. Preventing this unknown chelate is

therefore important for successful tosyl deprotection to occur.

An examination of the VEAs for published monotosyl

amides N-Boc-N-phenyltosylamide and 2-pyridylphenylsulfo-

namide (Figure S78 and Table S3) showed they undergo facile

deprotection in Mg/MeOH, while phenyltosylamide does not

react at all.^3,4Similar to the 1,2-bis(tosylamides) 2−4, 6, 8, and

16, DFT calculations indicated only small diﬀerences in the

VEAs for monotosylamides, indicating that it is not a factor

that aﬀects reduction. The only diﬀerence between the

substrates appears to be their relative ability to chelate to the

Mg atom. This should occur using the Boc or pyridyl moiety,

where the heteroatoms in the N-substituent would chelate to

the Mg atom and increase the likelihood of a SET transfer

occurring (Figure S3). Chelation also appears to be important

for the successful tosyl deprotection of monotosylamides and

1,2-bistosylamides when employing Mg/MeOH.

Chelation during reductive SmI₂tosyl deprotections is likely

an important factor as they also operate through inner-sphere

electron transfer.¹²In this case, weak chelation may lead to a

smaller eﬀective reduction potential for SmI₂compared to that

of Mg/MeOH (Table S4), resulting in the observed starting

material with no tosyl deprotection (Table 1 and Scheme 2).

The small degree of decomposition during the attempted

deprotection of 16 using SmI₂does indicate that a reduction

takes place, although not to the desired 1,2-diamine product. If

a substrate undergoes deprotection with SmI₂, path A will

likely need to be prevented using steric hindrance to stop the

competing decomposition from Sm−1,2-bis(tosylamide)

chelates similar to Me/MeOH reaction conditions since their

SET reduction mechanisms are similar (Scheme 3).

The Na/naphthalene conditions also proved to be trouble-

some for the deprotection of 16 despite the use of elevated

temperatures (30 °C). This is a confusing result as compounds

A and B (Figure 1) have been reported to undergo facile

reduction using Na/naphthalene.⁹However, considering the

outer-sphere reduction mechanism,²⁰it is likely that an outer-

sphere reductant needs to be strong to account for the low

likelihood of electron transfer without the ability to chelate to

the substrate (Scheme 2, path C). The reaction conditions

using Li/propylamine/ethylenediamine also face this issue as it

a

Procedures are reported in the Experimental Section. Napth,

nathalene; Mg, magnesium in methanol with ultrasonication as

described in general procedure 1; Na/Naphthalene, a sodium

naphthalenide solution as described in general procedure 3; SmI₂

was prepared as a solution in THF, and the reaction performed with

H₂O and pyrrolidine as described in general procedure 4; Li/amine, a

modiﬁed Benkenser reduction using Na metal, propylamine, and

ethylenediamine to give a Birch-type reduction as described in general

procedure 5. Values refer to the percent yield isolated. Decomp,

decomposition with no product isolated after puriﬁcation; S.M.,

starting material isolated after puriﬁcation.

b

monotosylamides were calculated using DFT (B3PW91-

D3(BJ)/6-311+G(d,p)//B3PW91-D3(BJ)/6-31G(d)).¹⁹

These results indicated that in all cases the LUMO (neutral

compound) and spin density (radical anion) were centered on

the sulfonamide aromatic ring after a visual inspection of the

data (Figure S79 and ESI). SET should therefore occur at the

sulfonamide aromatic ring where the electron should enter the

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is an outer-sphere reductant;^17,21however, the higher

reduction potential ensures that any substrate interactions

result in a fast electron transfer, leading to reduction and

therefore successful tosyl deprotection (i.e., compound 6,

Scheme 2).

where indicated. When the compound was wet loaded, only the

minimum amount of the indicated solvent was used. When the

compound was dry loaded, the indicated solvent was used to dissolve

the compound, dry silica was added, the mixture evaporated using

rotary evaporation to a slurry, and the silica was further dried under

high vacuum to a free-ﬂowing powder. A syringe ﬁlter (nylon 0.45

μm) was attached to the vacuum line to prevent the bumping of the

silica. TLC (thin-layer chromatography) was performed on aluminum

backed plates (silica gel 60 or neutral aluminum oxide 60, F₂₅₄

indicater, 5.0 cm length and 0.20 mm thickness). A stain was used for

visualization as indicated. Only reactions monitored or puriﬁed by

silica gel chromatography have the TLC R_freported. Where the R_fis

not reported, the reaction was monitored by NMR after workup. PLC

(preparative-layer chromatography, silica gel 60, F₂₅₄, 20 × 20 cm

wide, 0.5 mm thick) plates were purchased from Merck and prepared

by drawing a line 2 cm above the bottom of the plate and then gently

adding the dissolved sample using a pipet to ensure a thin even band

of sample was added. Care was also taken to ensure that all loaded

samples were 2 cm away from the edge of the PLC plate. The PLC

plate was then dried with compressed N₂and eluted in a glass

chamber containing 100 mL of the eluent. After being removed, the

plate was dried with compressed N₂and then placed back into the

chamber if the plate required further elution. Fractions were selected

based upon color (where indicated) or by visualization under UV

light. Fractions were then cut or scraped oﬀ carefully using a steel

knife and a spatula, followed by sonication in the stated eluent and

then vacuum ﬁltration through a pad of Celite 545. It is indicated in

the experimental data after the solvent system for cases where TLC

and PLC plates were eluted multiple times under the same solvent

system. Solvent system mixtures for separation are written with the

polar solvent ﬁrst then the nonpolar solvent, with the percentage in

brackets, e.g., EtOAc/hexanes (20%).

Materials. CaCl₂hydrate was dried in a furnace (300 °C) for 24 h,

cooled in an oven (100 °C), then cooled in a desiccator (rt) before

being ground to a powder and packed into a loose column. Molecular

sieves were dried in a furnace (300 °C), cooled in an oven (100 °C),

and allowed to cool to rt in a conical ﬂask stoppered with a septum

before use. THF was dried over 3 Å molecular sieves for 3 d in a

stoppered conical ﬂask,²²except for Grignard reactions that required

the distillation of THF from Na/benzophenone (purple indicator).

Phenol was dried by the azeotropic removal of water with benzene

and puriﬁed by the fractional distillation of the residual benzene and

then pure phenol.²³Hexanol was purchased from Sigma, dried over

K₂CO₃, fractionally distilled, and stored over 3 Å molecular sieves.²³

Aniline was dried over KOH (24 h), decanted, fractionally distilled

under vacuum, and stored in the dark.²³Propylamine and

ethylenediamine were purchased from Sigma, dried over 3 Å

molecular sieves, and stored in a desiccator at either −20 °C or rt.

NaH was purchased from Sigma and stored in a desiccator in the steel

container it was received in; for reaction consistency, it required a

replacement after 1.5 years. Magnesium powder was purchased from

Sigma-Aldrich and stored in a vacuum sealed desiccator between use;

it was replaced after ∼8 months. All bulk solvents were purchased

from ChemSupply except for EtOAc, which was purchased from

ThermoFisher. All solvents were HPLC grade except for benzene,

THF, diethyl ether (BHT stabilized), CHCl₃(ethanol stabilized),

petroleum spirits (pet. spirit), and cyclohexane. Anhydrous DMF,

DMSO, DME, benzene, and methanol were purchased from Sigma

under a SureSeal and used as received. ^L-(+)-Tartaric acid, citric acid,

pyridine, triethylamine (NEt₃), and Na metal were purchased from

ThermoFisher. SmI₂was purchased from Strem Chemicals. DMAP

and CsOAc were purchased from AKScientiﬁc. NaSO₄, MgSO₄, and

NH₄Cl were purchased from ChemSupply. All other reagents were

purchased from Sigma. 4-Methoxybenzyl chloride was prepared by

known procedures.^54,55

CONCLUSION

■

The developed strategy allows the general synthesis of 1,2-

diamines from 1,2-bis(tosylamides) using Mg/MeOH depro-

tection conditions by sterically tuning the N-substituent in the

substrate. It is now possible to employ 1,2-bis(tosylamides) in

the routine synthesis of 1,2-diamines with the general

deprotection protocol presented here. The mechanism of

these deprotections was examined using standard SET

reductants, which demonstrated that inner-sphere reductants

required a degree of chelation to function. While too much

chelation leads to a decomposition pathway, this can be tuned

with steric hindrance from the N-substituent. Outer-sphere

reductants required higher reduction potentials to facilitate the

reduction of the tosylamide functionality due to their lack of

chelation resulting in only a small possibility of reduction, that

is, they have a low eﬀective reduction potential without

chelation despite their high reduction potential (Table S4).

EXPERIMENTAL SECTION

■

General Information. Compounds with known characterization

data have characterization data and assignments listed in the

Supporting Information. Unless stated otherwise, all reactions were

stirred with a magnetic stirring bar under an atmosphere of N₂.

Nitrogen gas was dried by passing it through a column of silica gel

beads and then a column of dry CaCl₂, which was replaced every

three months. Reaction vessels were ﬁtted with a rubber septum, and

sensitive reagents were introduced through the septa with a syringe

under N₂. The vacuum pump used in all reactions placed the

apparatus at a pressure of <0.01 mbar. “In vacuo” refers to the

evaporation of the solvent by rotary evaporation at 40−45 °C (except

for diethyl ether at 30 °C), followed by high vacuum (>0.1 mbar) for

4−6 h unless otherwise stated. Residues that required evaporation on

high vacuum for longer than 6 h are stated in the method. Reactions

that required heating used a paraﬃn oil bath unless otherwise stated.

¹H and ¹³C NMR spectra in CDCl₃were referenced to TMS (δ = 0),

1

while H NMR (δ = 2.05) and ¹³C NMR (δ = 29.92) spectra in

acetone-d₆were referenced to the residual solvent. All NMR

experiments were performed on Bruker Ascend 400 MHz NMR

spectrometer or a Bruker Avance Neo 500 MHz NMR spectrometer,

1D NOE experiments were performed on a Bruker Avance Neo 500

MHz NMR spectrometer, and ¹⁹F NMR experiments were ¹H

coupled. The resolution of the spectra (MHz) is indicated in the

individual characterization data along with the peaks and their

assignments. For rotameric compounds that have multiple resonances

for an atom, the resonances that were identiﬁed to the assigned H or

C atom are indicated with a ‘/’ between the resonances (e.g., 1.42/

1.43 (s, 3H, H1) for proton H1 with two resonances due to

rotamers). Low-resolution mass spectrometry was performed on a

Shimadzu LCMS-2020 (ESI MS) or Shimadzu QP-5050 spectrometer

in the EI mode (EI MS). Where no low-resolution mass spectrum was

reported, no diagnostic ion was observed. High-resolution mass

spectrometry (HRMS) was performed on a XEVO QToF instrument

with LeuEnk as internal standard. FT-IR analysis was performed on a

Bruker Vertex FT-IR spectrometer in the ATR mode. All compounds

loaded neat, or a small amount of THF or diethyl ether was used.

General Methods for Puriﬁcation. Flash column chromatog-

raphy was performed with compressed air using the following internal

diameter depending on the amount of silica or alumina used: < 10

(0.9 cm), 10−20 (1.1 cm), 21−40 (1.7 cm), and >41 g (3.5 cm).

Either silica gel 60 (230−400 mesh, 40−63 μm) or neutral aluminum

oxide 60 (70−230 mesh, 63−200 μm) was used for chromatography

Crystallographic Data. All crystallographic data can be accessed

free of charge from the Cambridge Crystallography Data Centre

(CCDC) database via www.ccdc.ac.uk/structures (CCDC 1998667−

1998668).²⁴Where a crystal structure was obtained by X-ray

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diﬀraction, the relevant crystallization procedure can be found below

the spectral data of the compound.

calculations were performed in Gaussian 16⁴⁶using the B3PW91

functional and 6-311+G(d,p) basis set with the default implicit

solvent model PCM using default solvent parameters for methanol,

THF, or propylamine where indicated. For the radical anion single

points, the neutral geometry with the appropriate charge and

multiplicity was used as the input with UB3PW91. Despite a previous

benchmark¹⁹recommending the use of the 6-311+G(2df,p) basis set

for single point calculations, we found no signiﬁcant diﬀerence for the

VEA calculation of benzylmesylamide (6-311+G(d,p) = 0.76 eV and

6-311+G(2df,p) = 0.75 eV). Therefore, we used the smaller basis set

to reduce the computational time. LUMOs (lowest unoccupied

molecular orbitals) and spin densities were generated using the

Cubegen utility and viewed in VESTA.^47,48All the optimized

structures (Cartesian coordinates, xyz) were generated from Gaussian

output ﬁles using Open Babel^49,50and can be found in the Supporting

Information. The VEA (vertical electron aﬃnity) was calculated in

solvent as VEA = E(geometry of the neutral compound in solvent) −

E(geometry of the neutral compound as a radical anion in solvent).

For the NMR calculation of amine-6, conformers for amine-6 were

generated by exporting the ChemDraw structure to ChemDraw3D,

then exporting that to Avogadro^30,31and optimizing under MMFF94.

Confab³⁹in Openbabel^49,50(energy cutoﬀ = 7 kcal·mol⁻¹) was used

to generate 16 conformers, which were optimized under B3LYP/6-

31G(d) in Gaussian 09.⁴⁴All the optimized conformers contained

intramolecular hydrogen bonding between the nitrogen atoms with

exception of the highest energy conformer, which contained

intramolecular hydrogen bonding to H2 and H3 from both nitrogens.

The two lowest-energy conformers and the higher energy H2 and H3

hydrogen bonded conformers were subjected to a gas-phase

optimization and NMR calculation with GIAO using the SMD

solvent model with CHCl₃, as described in the CHESIRE database

recommendations^51,52(mPW1PW91/6-311+G(2d,p)/SMD-

(CHCl₃)//B3LYP/6-311+G(2d,p)). The data were corrected using

linear regression and the suggested scaling factors (slope of −1.0933

and intercept of 31.9088). Only the conformer with the highest R²

value is reported, and the ﬁnal optimized structure (xyz) can be found

in the Supporting Information. Where a carbon had rotameric

resonances, the strongest resonance was used for Figure S2 and Table

S1.

X-ray diﬀraction images for compound 2 were collected on an

Agilent Xcalibur diﬀractometer (Mo Kα radiation, graphite

monochromator, λ = 0.71073 Å), and images for compound 21

were collected on an Agilent SuperNova diﬀractometer (Cu Kα

radiation, mirror monochromator, λ= 1.54184 Å). Data for each

structure were extracted using the CrysAlis Pro package.²⁵Structures

were solved by direct methods (SIR92).²⁶The structures were reﬁned

using the CRYSTALS program package.²⁷Note that the numbering

used in the X-ray ORTEP diagrams is diﬀerent from the IUPAC

systematic numbering of the structures.

Conﬁrmation of Enantio- And Diastereo-Purity of All

Synthesized Compounds. As addressed in our initial publications

on the ring opening of biaziridine with nucleophiles,^11,28,29all

compounds synthesized by this methodology are enantiomerically and

diastereomerically pure (ee > 99%), having been synthesized from the

pure ^L-(+)-tartaric acid. No racemization during alkylation or tosyl

deprotection was observed by ¹H and ¹³C NMR analysis of the

reaction mixtures, with the primary evidence being the lack of meso-

diastereoisomers. Compound 9 was analyzed by chiral HPLC after the

base-catalyzed N-alkylation using a Chiracel OD-H column eluted

with iPr−OH/hexanes (conditions previously used for enantiomeric

separation of these products)¹¹and only demonstrated a single peak.

Crystal structures are available to conﬁrm the stereochemistry of some

compounds and can be accessed through the CCDC database.

Previous publications on the Mg/MeOH detosylation have

demonstrated that no loss of chirality occurs during the reaction,

and our observations agree with the literature ﬁndings.⁴

Computational Methods. Data from the computational analysis

are reproduced in the Supporting Information. Using the crystal

structure of 2 (CCDC 1998668),²⁴all synthesized 1,2-bis-

(tosylamides) were able to be constructed and edited in Avogadro^30,31

and optimized with MMFF94 in Avogadro for a conformational

search using the Crest³²tool in the xTB package. The extended

semiempirical tight-binding model GFN2³³⁻³⁵was used with the xTB

and Crest default parameters with the exception of 6, where the Crest

“-loose” setting was used due to the extremely high number of

conformations. No conformational search was performed on

structures with a crystal structure readily available, including 2,

which was acquired in this publication, or for the previously published

structures available in the CCDC database,²⁴including benzylmesy-

lamide (KOYVID, CCDC 1200072)³⁶and benzyltosylamide

(PTSBZA01, CCDC 1010172).³⁷For 16, our recently published

crystal structure for a methoxy-functionalized derivative (TUMBOV,

CCDC 1990559)³⁸was edited in the same way to produce

conformations. The crest_best structure from the Crest conforma-

tional analysis or crystal structures, where available, were then chosen

for further analysis by DFT. For further modiﬁcations (such as the

removal of a tosyl group), the DFT-optimized structure (1,2-

bis(tosylamide) for the generation of monotosylamide products and

monotosylamides for the generation of primary amines) was modiﬁed

in the same way as the crystal structures. A comparison of structures

for mono-2 from Crest and Confab³⁹(after optimization with

B3PW91-D3(BJ)/6-31G(d)) as well as previous benchmarks^40,41

indicated that this methodology does produce low energy

conformations.

For DFT, functional and basis set choices was based on previous

benchmark studies for all calculations,^19,42and all calculations used

the Grimme D3 dispersion correction with Becke−Johnson damping

(D3BJ).⁴³DFT optimizations on all neutral molecules were

performed in Gaussian 09⁴⁴using the B3PW91⁴⁵functional and 6-

31G(d) basis set in the gas phase (except N-benzylmethanesulfona-

mide and N-benzyl-4-methylbenzenesulfonamide, which were also

optimized with the 6-31+G(d) basis set), followed by reoptimization

with the implicit solvent model PCM using default solvent parameters

for methanol, THF, or propylamine where indicated. All structures

were checked to ensure that the default convergence criteria from

both the geometry optimization and frequency calculations were met

and that there were no negative vibrational frequencies. Single point

The Synthesis of (2R,2′R)-1,1′-Ditosyl-2,2′-biaziridine ((R,R)-1).

The experimental procedures to the synthesis of biaziridine 1 are

presented here, as there were amendments to the procedures

compared to those published in ref 11, including the scale-up.

Dimethyl (4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-dicarboxylate

(S1).¹¹A reaction mixture containing (R,R)-tartaric acid (53.1 g,

354 mmol), toluenesulfonic acid (0.2 g, 1 mmol), MeOH (20 mL),

and reagent-grade DMP (94 mL) was stirred under an air atmosphere

with heating at reﬂux using a Vigreux column as an air condenser until

the suspension formed a dark red solution (∼1 h). To the mixture was

added cyclohexane (220 mL). The Vigreux column was wrapped in

aluminum foil, and a short path distillation apparatus was connected

to the top along with a 250 mL receiving ﬂask. The temperature was

slowly increased until a small trickle of solvent was observed to distill

into the 250 mL round-bottom ﬂask, and more DMP (50 mL) was

added at 24 and 36 h (when it was observed that no further solvent

was undergoing distillation). After 48 h, when no further solvent was

collected, the solution was cooled, and DMP (3 mL) and K₂CO₃(0.6

g) were added to the mixture. The mixture was stirred at rt for 30

min, and EtOAc was used to transfer the product to a separatory

funnel. The organic phase was washed with water (5 × 250 mL) and

brine (2 × 250 mL), dried (MgSO₄), ﬁltered, and concentrated in

vacuo (high vacuum for 24 h) to yield the protected product S1 (77.4

g, >99%) as a golden yellow oil.

((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (S2).¹¹

To a 2 L round-bottom ﬂask containing freshly opened undried

THF (139 mL) at 0 °C was added LiAlH₄(16.3 g, 426 mmol) in air

portion-wise over 1 h, and the gray suspension was allowed to stir for

10 min at 0 °C. The pure protected tartaric acid S1 (46.6 g, 213

a

mmol) was then placed in a 250 mL separatory funnel and added

dropwise to the mixture with vigorous stirring such that the gas

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formation dissipated between each drop. After addition, any residual

oil within the separatory funnel was washed into the reaction with

additional THF (10 mL). The solution was then warmed slowly to rt

and stirred overnight to produce a thick yellow-gray slurry. Diethyl

ether (1 L) was carefully added to the mixture. A Fieser quench was

performed (16.26 mL H₂O, 16.26 mL 15% NaOH, 48.78 mL H₂O),

and the solution was stirred for 1 h before being ﬁltered by suction.

The precipitate was washed with EtOAc (∼2 L) until most of the

yellow oil had eluted. The ﬁltrate was dried (MgSO₄), ﬁltered by

gravity, and concentrated in vacuo (high vacuum for 48 h) to give the

diol S2 (34.02 g, 96%) as a viscous yellow oil.

concentration of the organic phase in vacuo (high vacuum for 24 h)

aﬀorded the ditosyl amine S6 (38.6 g, 54% yield over 2 steps) as a

thick red gum that could not be dried further.

Reaction note. Extreme care should be taken during the diazide

addition to ensure that the reaction continuously stirs. If the reaction

becomes diﬃcult to stir, more THF can be slowly added, and the

suspension can be allowed to mix for at least 30 min after all diazide

dissolves. No signiﬁcant increases in heat or gas evolution were

observed during the reduction, even after repeating the reaction four

times.

N,N-((2S,3S)-2,3-Dihydroxybutane-1,4-diyl)bis(4-methoxybenze-

nesulfonamide) (S7).¹¹A suspension of the acetonide-protected tosyl

amine S6 (38.6 g, 82.3 mmol) in MeOH (380 mL) and HCl (95 mL,

1 M) was stirred into a vortex to ensure thorough mixing of the

suspension, and the solution was heated at reﬂux for 2 h in air. After

cooling to rt, the stir bar was removed and washed with CH₂Cl₂.

Then, the solvent was concentrated on a rotary evaporator (to ∼100

mL). To this suspension was added EtOAc (1 L), and the precipitated

gum was dissolved with the aid of an ultrasonicator. The two layers

were separated. The organic layer was washed with H₂O (200 mL),

saturated aq. NaHCO₃(2 × 300 mL), and ﬁnally H₂O (300 mL) and

then dried (Na₂SO₄) and evaporated in vacuo (high vacuum for 48 h)

to give the diol S7 (32.5 g, 92%) as a tan solid that contained EtOAc

and H₂O.

(2R,2′R)-1,1′-Ditosyl-2,2′-biaziridine ((R,R)-1). To a solution of

the diol S7 (15.2 g, 35.5 mmol) in pyridine (65 mL) was added MsCl

(11.8 g, 103 mmol) dropwise at 0 °C, and the mixture was allowed to

warm to rt overnight under nitrogen with magnetic stirring. The

mixture was diluted with 1 M aq. HCl (300 mL) and EtOAc (500

mL). The aqueous phase was separated and extracted with EtOAc (3

× 250 mL). The combined organic fractions were washed with 1 M

aq. HCl (2 × 500 mL), water (8 × 500 mL), and saturated aq.

NaHCO₃(2 × 100 mL). The organic solution was dried (MgSO₄),

and the solvent was removed to aﬀord the dimesylate S8 (19.2 g) as a

dark tan powder, which was used in the next step without further

puriﬁcation.

The crude dimesylate S8 (19.2 g) was suspended in benzene (200

mL), and a 10% KOH solution (100 mL) was added slowly. The

mixture was stirred vigorously at room temperature overnight, then

diluted with EtOAc (400 mL) and water (100 mL). The separated

aqueous phase was extracted with EtOAc (4 × 50 mL). The

combined organic layers were washed with water (100 mL) and

saturated aq. NaHCO₃(4 × 50 mL) and dried (MgSO₄), and the

solvent was removed to aﬀord a crude residue. Flash chromatography

(150 g silica, EtOAc/pet. spirits (30%)) of the residue aﬀorded a

highly crystalline major fraction, which was condensed and recrystal-

lized from CHCl₃/pet. spirits to aﬀord (R,R)-biaziridine (R,R)-1

(9.18 g, 67% over two steps) as ﬂuﬀy white crystals.

(4S,5S)-4,5-Bis(azidomethyl)-2,2-dimethyl-1,3-dioxolane (S4).¹¹

To a 1 L round-bottom ﬂask containing the diol S2 (35.3 g, 218

mmol) in CH₂Cl₂(654 mL) was added NEt₃(68.0 mL, 488 mmol) in

air at 0 °C in one portion, and the solution was stirred for 1 min.

Methanesulfonyl chloride (37.0 mL, 478 mmol) was then added

dropwise such that the temperature of the solution was maintained at

5−10 °C. After addition, the suspension was then stirred at 0 °C for 1

h before aq. citric acid (500 mL, 1 M) was added portion-wise. The

solution was allowed to warm to rt with stirring over 24 h, then the

layers were separated. The organic phase washed with water (3 × 200

mL) and brine (200 mL) and concentrated in vacuo (high vacuum for

48 h) to aﬀord the crude mesylate S3 (59.4 g) as a red solid.

To a solution of the crude mesylate S3 (59.4 g) in anhydrous DMF

(529 mL) was added NaN₃(36.4 g, 560 mmol) portion-wise in air at

rt. The suspension was then placed under N₂and heated to 80 °C for

72 h, cooled to rt, and quenched with H₂O (50 mL). The suspension

was poured into a separatory funnel. To the funnel was added diethyl

ether (1 L) was added, followed by brine (300 mL), and the solution

was left to separate for 30 min. The aqueous layer was separated and

extracted with diethyl ether (2 × 250 mL), and the combined organic

layers were washed with H₂O (14 × 250 mL) and brine (3 × 250

mL). The organic phase was concentrated in vacuo to furnish a red oil,

which was dissolved in EtOAc (400 mL) and further washed with

H₂O (6 × 500 mL) to remove the last remaining DMF. The organic

phase was then concentrated in vacuo (high vacuum 48 h) to yield the

azide S4 (32.0 g, 69%) as a red oil.

N,N′-(((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis-

(methylene))bis(4-methylbenzenesulfonamide) (S6).¹¹To freshly

opened undried THF (245 mL) at 0 °C in air was added LiAlH₄

(11.5 g, 303 mmol) portion-wise with stirring, and the suspension was

allowed to stir for 10 min. The diazide S4 (32.0 g, 151 mmol) was

dissolved in THF (447 mL) and added dropwise to the gray

suspension at 0 °C over 4 h in air using a 500 mL separatory funnel.

Halfway through the addition of the azide S4, the thick reaction slurry

required the careful addition of more reagent-grade THF (∼100 mL)

to keep the reaction stirring freely. After the completion of the

addition, the golden yellow-gray suspension was warmed to rt and left

to stir overnight. The reaction mixture was quenched with a Fieser

quench (11.5 mL H₂O, 11.5 mL 15% NaOH, and 34.5 mL H₂O) and

then ﬁltered by vacuum ﬁltration, and the solids were washed with

THF (∼2 L) until most of the yellow oil had eluted. The ﬁltrate was

dried (Na₂SO₄) and concentrated in vacuo (high vacuum for 24 h) to

give the crude diamine S5 (25.5 g) as a red oil, which contained some

alkyl impurities and residual THF.

General Procedures. General Procedure 1: Detosylation of 1,2-

Bis(tosylamides) Using Mg Powder. A round-bottom ﬂask ﬁtted with

a septum containing the 1,2-bis(tosylamide) and magnesium powder

(50 equiv) was placed under high vacuum for 1 h, then backﬁlled with

b

argon. Anhydrous MeOH (1 mL per 50 mg of Mg) was added under

argon, and the ﬂask was ﬁtted with an argon balloon. The suspension

was placed in an ultrasonicator at rt and sonicated for 45 min, with

the ﬂask being manually shaken every minute for the ﬁrst 5 min to

ensure thorough mixing. At the completion of the reaction, the water

bath temperature was found to be 42−44 °C, and a gray suspension

had formed. The suspension was poured over EtOAc with vigorous

shaking to prevent a thick gel from forming, and the thick cloudy

mixture was ﬁltered through Celite 545 using a water aspirator and

washed with EtOAc. Water was added to the mixture, the layers were

separated, and the aqueous layer was extracted three times with

To a well-stirred solution of the crude amine S5 (25.4 g) in reagent

grade pyridine (308 mL) at 0 °C in air was added p-toluenesulfonyl

chloride (60.4 g, 317 mmol) portion-wise, such that no gas evolution

was observed. The red solution was warmed to rt, stirred for 72 h,

then quenched with cold HCl (200 mL, 1 M aqueous) portion-wise,

followed by brine (500 mL) and EtOAc (500 mL). After 1 h, two

layers had formed and the aqueous layer was separated and extracted

with EtOAc (2 × 250 mL); the combined organic phases were

washed with cold HCl (∼2 L, 1 M aqueous) until a wash with CuSO₄

(saturated aqueous solution) to the mixture remained blue, indicating

the removal of most of the pyridine. The organic phase was then

washed with brine (2 × 200 mL), dried (Na₂SO₄) and concentrated

in a rotary evaporator to a thick red oil. The oil was redissolved in

EtOAc (250 mL), washed with cold HCl (5 × 400 mL), then washed

with brine (300 mL) to remove the last of the pyridine. Finally,

c

EtOAc. The pooled organic fractions were then dried (Na₂SO₄).

After being concentrated in vacuo, the compounds were puriﬁed to

aﬀord the product as described in the individual procedures. All

compounds, with the exception of 16 and 13, were found to be

contaminated with an unknown product (resonances at δ 1.26 ppm in

1

the H NMR and sometimes at δ 29.7 ppm in the ¹³C NMR spectra

of the contaminated compounds). This impurity could not be

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removed by silica gel, alumina (neutral), or C18 silica gel

chromatography; acid or base extractions; MeCN/hexanes extrac-

tions; recrystallization; ﬁltration; or trituration. Puriﬁcation proce-

dures were attempted on both the free amine and HCl salt forms of

were separated, and the organic layer was washed with H₂O and brine,

dried (Na₂SO₄), and evaporated in vacuo. The crude amine products

were then puriﬁed by neutral aluminum oxide chromatography as

identiﬁed in the individual procedures.

d

the products.

Syntheses of 1,2-Bis(tosylamides) and 1,2-Diamines. N,N′-

((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(4-methylbenzenesulfo-

namide) (2). To a solution of phenol (1.57 g, 16.6 mmol) in THF

(15.6 mL) was added KHMDS (16.2 mL, 16.2 mmol, 1.0 M in THF)

dropwise at rt, and the resultant slurry was allowed to stir for 10 min.

(R,R)-Biaziridine (R,R)-1 (1.30 g, 3.31 mmol) in DMF (26.0 mL)

was then added dropwise at rt over 2 h. More DMF (3.0 mL) was

used to transfer the residual biaziridine (added dropwise over 5 min),

then the solution was stirred for 24 h. The reaction was quenched

with NH₄Cl (50 mL), and the mixture was extracted with CH₂Cl₂(3

× 100 mL). The combined organic phases were washed with brine,

dried (Na₂SO₄), ﬁltered, evaporated under a stream of compressed air

overnight, and dried under high vacuum (1 h). The residue was then

subjected to column chromatography (∼35 g silica) with wet loading

using CH₂Cl₂and eluted with EtOAc/hexanes (20%). Fractions

containing just the product and fractions containing the phenol/

product mixture (by TLC analysis) were both separately concentrated

in vacuo. Both fractions were then precipitated from boiling CH₂Cl₂/

hexanes, cooled to −20 °C, ﬁltered, dried in air (1 h), and dried under

high vacuum (24 h) to aﬀord the ring opened product 2 (1.80 g,

94%) as a white solid. The product was found to be unstable to high

concentrations of TFA (50% v/v in CH₂Cl₂). mp 131−132 °C; TLC

(EtOAc/hexanes (20%)) R_f= 0.27; [α²_D⁵] = +30.2 (c = 0.36, CH₂Cl₂);

FTIR υ 3300 (br m), 2932 (w), 1598 (m), 1497 (m), 1460 (m), 1434

(m), 1337 (m), 1322 (m), 1290 (m), 1238 (s), 1149 (s), 1087 (s),

1057 (m), 1020 (w), 996 (w), 965 (w), 812 (m), 756 (s), 707 (s),

672 (s), 509 (m), 418 (w) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.73

(d, J = 8.3 Hz, 4H, H2′, H2″, H6′ and H6″), 7.25−7.19 (m, 8H, H3′,

H3″ H5′, H5″, H3‴, H3⁗, H5‴, and H5‴″), 6.95 (t, J = 7.4 Hz, 2H,

H4‴ and H4⁗), 6.62 (d, J = 7.6 Hz, 4H, H2‴, H2⁗, H6‴, and H6⁗),

5.10 (d, J = 6.1 Hz, 2H, NH), 3.96−3.82 (m, 6H, H1, H2, H3, and

H4), 2.38 (s, 6H, TsCH₃); ¹³C NMR (101 MHz, CDCl₃) δ 157.5

(C1‴ and C1⁗), 143.9 (C4′ and C4″), 136.5 (C1′ and C1″), 129.8

(C5′, C5″, C6′ and C6″ or C5‴, C5⁗, C3⁗, and C3‴), 129.5 (C5′,

C5″, C6′ and C6″ or C5‴, C5⁗, C3⁗, and C3‴), 127.3 (C2′, C2″,

C6′, and C6″), 121.6 (C4‴ and C4⁗), 114.3 (C2‴, C2⁗, C6‴, and

C6⁗), 66.3 (C1 and C4), 53.5 (C2 and C3), 21.6 (TsCH₃); MS

(ESI−) 579 [M − H]⁻; HRMS (ESI+) calcd for C₃₀H₃₃N₂O₆S₂

581.1788, found 581.1780 [M + H]⁺.

General Procedures 2a and 2b: Alkylation of 1,2-bis-

(tosylamides)^e. General Procedure 2a. To a stirred solution of the

1,2-bis(tosylamide), alkyl halide (6.0 equiv), and tetrabutylammo-

nium iodide (0.3 equiv) in DMF (∼11.6 mL per mmol 1,2-

bis(tosylamide)) was added excess NaH (10.0 equiv) portion-wise in

air. The vessel was placed under an atmosphere of N₂, and the the

suspension was heated at 60 °C for the time speciﬁed. Reactions were

carefully monitored by TLC analysis for starting material

consumption. The solution was then cooled, quenched with H₂O,

extracted, evaporated by rotary evaporation and compressed air

(overnight as a gentle stream), and puriﬁed as identiﬁed in the

individual procedures.

General Procedure 2b. To a stirred solution of 1,2-bis-

(tosylamide), alkyl halide (6.0 equiv), and tetrabutylammonium

iodide (0.3 equiv) in DMF (∼11.6 mL per mmol 1,2-bis(tosylamide))

was added fresh NaH (3.5 equiv) portion-wise in air. The vessel was

placed under an atmosphere of N₂, and the suspension was heated at

60 °C for 3.5 h. The solution was immediately quenched with H₂O in

one portion, extracted, evaporated by rotary evaporation and

compressed air (overnight as a gentle stream), and puriﬁed as

identiﬁed in the individual procedures.

General Procedure 3: N-Detosylation of Diamines with Na/

Naphthalide.⁵³To naphthalene (257 mg, 2.01 mmol) was added

anhydrous DME (1.66 mL) under an atmosphere of Ar by ﬁrst

removing the septum and adding the solvent under a gentle Ar stream,

followed by the addition of Na metal (52 mg, 2.3 mmol) in one

portion. The solution was stirred for 2 h. The dark green solution was

then added dropwise to a solution of the 1,2-bis(tosylamide) in DME

(40 mg of 1,2-bis(tosylamide) per mL) at −78 °C until the dark green

color persisted for 3−5 min. The reaction was then quenched with a

few drops of H₂O, and the mixture was warmed to rt with stirring.

Then, more H₂O was added to the mixture. The reaction mixture was

extracted with CH₂Cl₂(×2), and the pooled organic fractions were

dried (Na₂SO₄) and evaporated in vacuo. The crude residue was

1

analyzed by H and ¹³C NMR spectrometry.

General Procedure 4: Detosylation of diamines with SmI₂/H₂O/

Pyrrolidine.²To a ﬂask containing 1,2-diiodoethane (0.912 g, 3.24

mmol) in 25 mL of freshly distilled THF from a sodium/

f

benzophenone still was added Sm metal (0.710 g, 4.72 mmol)

X-ray Crystal Growth. To a 2 mL vial containing ∼5 mg of the

compound was added CH₂Cl₂(1.0 mL), and the product was

sonicated to dissolution. To this mixture was then added MeOH (1.0

mL), and the solution shaken. The vial was then left open until the

solvent had evaporated (∼3 d), yielding clear white rod-like crystals.

N,N′-((2R,3R)-1,4-Bis(2-iodophenoxy)butane-2,3-diyl)bis(4-

under N₂. The reaction mixture was then stirred at rt under N₂until it

turned dark blue (∼5 h), indicating that SmI₂had formed. The

reaction mixture was added in one portion (20 equiv., 0.13 M) at rt to

the neat tosyl amide. Thirty minutes after addition, H₂O (60 equiv)

was added dropwise, followed by the dropwise addition of pyrrolidine

(40 equiv). After stirring for a further 10 min, more H₂O was added

to the brown mixture, and the aqueous phase was extracted with

CH₂Cl₂(×2). The combined organic fractions were dried (Na₂SO₄)

methylbenzenesulfonamide) (17).¹¹To prepare the known 17,¹¹

a

modiﬁed procedure was developed. To a solution of 2-iodophenol

(2.85 g, 13.0 mmol) in THF (10 mL) was added KHMDS (12.2 mL,

1

g

and evaporated in vacuo. The crude residue was analyzed by H and

12.2 mmol, 1.0 M in THF) dropwise at rt, and the slurry allowed to

¹³C NMR spectrometry.

stir for 10 min. (R,R)-Biaziridine (R,R)-1 (1.00 g, 2.56 mmol) in

DMF (20 mL) was then added dropwise at rt, and the solution stirred

for 24 h. The reaction was quenched with NH₄Cl (40 mL), and the

mixture was extracted with EtOAc (3 × 50 mL). The combined

organic phases were washed with brine (30 mL), dried (Na₂SO₄),

ﬁltered, and evaporated in vacuo. The crude solid was subjected to

silica gel chromatography (∼20 g of silica) with wet loading using

CH₂Cl₂and eluted with EtOAc/hexanes (20%) to aﬀord the product

17 (1.48 g, 70%) as a white solid.

General Procedure 5: Deprotection of Diamines with Li/

Ethylenediamine/Propylamine.¹⁷To a two-neck round-bottom

ﬂask, which was equipped with a condenser ﬁtted with an argon

balloon at the top and a rubber septum on the unused second ﬂask

neck, were added the tosyl amide (∼0.084 mmol), n-propylamine (0.5

mL), and ethylenediamine (30 equiv, 2.5 mmol, 0.17 mL). The

septum was removed brieﬂy to purge the ﬂask for 10 s, and the

solution was stirred in an ice bath for 10 min under argon. To the

solution was added Li metal (28 equiv), which was blotted with a

paper towel to remove oil before weighing, in one portion by the

removal and quick replacement of the septum. The reaction mixture

was stirred until the solution turned dark blue and all the lithium was

consumed, after which the reaction mixture was stirred for a further

20 min. The vessel was exposed to air, and the solution was poured

over ice. The ﬂask was rinsed with diethyl ether into the ice. After the

ice had melted, diethyl ether was added to the mixture. The layers

N,N′-((2R,3R)-1,4-Bis(phenylamino)butane-2,3-diyl)bis(4-methyl-

benzenesulfonamide) (4).¹¹To a solution of (R,R)-biaziridine (R,R)-

1 (22 mg, 0.057 mmol) in DMF (0.5 mL) was added 20 equiv of

h

aniline (0.12 mL, 1.3 mmol) in one portion, and then the reaction

mixture was stirred for 24 h. The reaction was quenched with H₂O

(10 mL), and the mixture was extracted with EtOAc (20 mL). The

organic phase was separated; washed with brine (2 × 10 mL), water

(3 × 10 mL), and brine (10 mL); and concentrated in vacuo. The oil

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was evaporated under a stream of N₂(∼3 h). The resultant gum was

dissolved in the minimum amount of CHCl₃(<1.0 mL), precipitated

by addition of hexanes (∼150 mL), left to stand for 30 min, ﬁltered by

vacuum, and washed with hexanes (3 × 25 mL). The ﬂuﬀy white solid

was dissolved using CHCl₃into a clean dry ﬂask and concentrated in

N,N′-((2S,3S)-1,4-Bis(hexyloxy)butane-2,3-diyl)bis(4-methylben-

zenesulfonamide) (6). To a solution of hexanol (0.48 mL, 0.39

mmol) in THF (3.0 mL) was added NaHMDS (3.8 mL, 3.8 mmol, 1

M in THF) dropwise at rt, and the slurry allowed to stir for 10 min.

j

(R,R)-Biaziridine (R,R)-1 (303 mg, 0.772 mmol) in DMF (3.0 mL)

I

was then added dropwise at rt over 30 min. More DMF (0.5 mL) was

used to transfer any residual biaziridine (added dropwise over 1 min).

The solution was stirred for 19 h and then the reaction was quenched

with NH₄Cl (10 mL). The aqueous reaction mixture was extracted

with EtOAc (150 mL). The organic phase was separated and washed

with brine (2 × 50 mL), NaOH (3 × 25 mL, 2.0 M), H₂O (50 mL),

and ﬁnally brine (50 mL). The organic phase was dried (Na₂SO₄),

ﬁltered, and evaporated in vacuo, with the exception that a heat gun

was used to aid in the evaporation of the residual hexanol under high

vacuum, yielding the crude product as a clear amber oil. The residue

was then subjected to silica gel chromatography (10 g of silica) by wet

loading with CH₂Cl₂and elution with acetone/hexanes (10%, 150

mL). The fractions containing the product were collected and

subjected to further silica gel chromatography in the same way (20 g

of silica), eluting with acetone/hexanes (10%, 250 mL) to aﬀord the

product 6 (211 mg, 46%) as a clear colorless oil. TLC (acetone/

hexanes (20%)) R_f= 0.27; [α²_D⁵] = +12.7 (c = 1.1, CH₂Cl₂); FTIR υ

3271 (br, s), 2953 (m), 2928 (m), 2858 (m), 1598 (w), 1495 (w),

1442 (br m), 1377 (w), 1329 (m), 1306 (w), 1290 (w), 1185 (w),

1159 (s), 1116 (m), 1088 (s), 1020 (w), 1002 (w), 966 (w), 909 (w),

814 (m), 707 (w), 669 (s), 610 (w), 655 (s); ¹H NMR (CDCl₃, 400

MHz) δ 7.72 (d, J = 8.3 Hz, 4H, H2′, H2″, H6′, and H6″), 7.29 (d, J

= 8.1 Hz, 4H, H3′, H3″, H5′, and H5″), 5.17 (d, J = 6.7 Hz, 2H,

NH), 3.55−3.44 (m, 2H, H2 and H3), 3.41−3.34 (m, 2H, H1_aand

H4_a), 3.30−3.14 (m, 6H, H1_b, H4_b, H1‴, and H1⁗), 2.43 (s, 6H,

TsCH₃), 1.46−1.16 (m, 16H, H2‴, H3‴, H4‴, H5‴, H2⁗, H3⁗,

H4⁗, and H5⁗), 0.90 (t, 6H, H6‴ and H6⁗); ¹³C NMR (CDCl₃,

126 MHz) δ 143.5 (C4′ and C4″), 137.0 (C1′ and C1″), 129.7 (C3′,

C3″, C5′, and C5″), 127.3 (C2′, C2″, C6′, and C6″), 71.4 (C1‴ and

C1⁗), 69.2 (C1 and C4), 53.7 (C2 and C3), 31.6 (hexyl CH₂), 29.4

(hexyl CH₂), 25.7 (hexyl CH₂), 22.6 (hexyl CH₂), 21.6 (TsCH₃),

14.0 (C6‴ and C6⁗); MS (ESI+) 597 (100%, [M + H]⁺); MS

(ESI−) 595 (100%, [M − H]⁻); HRMS (ESI+) calcd for

C₃₀H₄₉N₂O₆S₂597.3027, found 597.3028 [M + H]⁺.

vacuo to yield the product 4 (24 mg, 72%) as a clear colorless gum.

Dissolving the gum with CHCl₃, precipitation with hexanes, and

1

evaporation in vacuo gave the product as a white solid with H NMR

spectra that were identical to the gum.

Reaction Notes. On larger scale (244 mg), the reaction was

incomplete after 24 h, and stirring for longer did not cause the

reaction to go to completion. In this case, evaporation to a gum under

a stream of N₂, followed by the addition of a second amount of DMF

and aniline, allowed reaction to reach completion. After the above

workup, precipitation was not feasible. Therefore, silica gel column

chromatography (20 g of silica gel) with gradient elution using

CHCl₃/hexanes (50%, 150 mL; 80%, 200 mL; 100%, 150 mL) gave a

single spot by TLC analysis that was dissolved in CHCl₃, precipitated

from hexanes, ﬁltered, and evaporated in vacuo. The remaining

column fractions that contained no aniline by TLC analysis (but

multiple other spots) were subjected to further silica gel

chromatography (30 g of silica gel) with elution using CHCl₃/

hexanes (50%, 400 mL), followed by CHCl₃(100%), until no further

product was eluted. Fractions with a single spot by TLC were

evaporated in vacuo, dissolved in CHCl₃, precipitated with hexanes,

ﬁltered, and evaporated in vacuo, then combined with the previous

pure fractions to give 4 (161 mg, 45%) as a white solid. This reaction

was not repeated on a large scale again due to this being the 10th step

in the synthesis; hence, there was a lack of material to reoptimize the

reaction on such a scale.

N,N′-((3R,4R)-1,6-Diphenylhexane-3,4-diyl)bis(4-methylbenzene-

sulfonamide) (3).¹¹To prepare the known compound 3,¹¹a modiﬁed

procedure was developed. A 50 mL two-neck ﬂask containing

CuBrSMe₂(306 mg, 1.50 mmol) was equipped with an argon balloon

that was attached to a Teﬂon tap and a septum on the spare neck. The

ﬂask was purged with argon for 5 s. Tetrahydrofuran (7.0 mL) was

added to the ﬂask, and the mixture was cooled to −40 °C (MeCN/

N_2(l)). BnMgCl (7.6 mL, 15 mmol, 2.0 M in THF) was then added

through the septum, and the mixture was stirred for 10 min. A

solution of (R,R)-biaziridine (R,R)-1 (398 mg, 1.00 mmol) in THF

(7.0 mL) was added dropwise at −40 °C; any undissolved (R,R)-

biaziridine 1 was dissolved with more THF (1.5 mL) and added to

the reaction mixture dropwise. The ﬂask was purged with argon for 5 s

by removing the pierced septum and replacing it with a fresh septum,

and the solution was stirred for 2 h at −40 °C. The reaction solution

was warmed to rt, stirred overnight, quenched with NH₄Cl (20 mL),

and extracted with EtOAc (150 mL). The organic layer was separated

and further washed with NH₄Cl (4 × 50 mL) until the aqueous layer

was no longer blue. The organic layer was dried (Na₂SO₄), ﬁltered,

and evaporated in vacuo. The residual oily solid was recrystallized

from boiling CHCl₃/hexanes (∼30 mL) with vigorous stirring during

precipitation and cooling (slowly cooled in the oil bath to rt) until a

ﬁne white precipitate had formed (∼2 h). The ﬂask was cooled to 0

°C in a freezer (15 min), and the white solid was ﬁltered by vacuum

ﬁltration. The solid was eluted from the ﬁlter paper using CH₂Cl₂.

The ﬁltrate was evaporated and dried in vacuo to give the ring opened

product 3 (436 mg, 75%) as a white solid.

4-Methyl-N-((R)-2-(phenylamino)-1-((R)-1-tosylaziridin-2-yl)-

ethyl)benzenesulfonamide (18).¹¹Attempts at synthesizing the

above compound 4 using our previously published procedure¹¹with

only 5 equiv of aniline (0.060 mL, 0.66 mmol) and (R,R)-biaziridine

(R,R)-1 (48 mg, 0.12 mmol) in 1.0 mL of DMF yielded a mixture of

k

the di-ring opened product 4 and the mono-ring opened product 18.

These products were unable to be completely separated by silica gel

column chromatography and required PLC separation, eluting with

CHCl₃ﬁve times to yield the crude mono-ring opened product 18

(15 mg of crude). TLC (CHCl₃(100%), two times) R_f= 0.36; PLC

1

(100% CHCl₃, 5 times) R_f= 0.31; H NMR (CDCl₃, 400 MHz)

l

(crude) δ 7.75 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.33 (d,

J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.17−7.10 (m, 2H), 6.74 (t,

J = 7.3 Hz, 1H), 6.44 (dd, J = 8.6, 0.9 Hz, 2H), 4.75−4.67 (m, 1H),

3.31−2.93 (m, 6H), 2.47 (s, 3H), 2.42 (s, 3H); ¹³C NMR (CDCl₃,

m

126 MHz) (crude) δ 146.8, 145.3, 143.9, 136.4, 133.7, 130.0, 129.9,

129.3, 128.2, 127.1, 118.5, 113.2, 43.1, 42.1, 41.1, 40.8, 21.7, 21.6; MS

(ESI+) 508 (100%, [M + Na]⁺), 486 (64%, [M + H]⁺; MS (ESI−)

484 (34%, [M − H]⁻); HRMS (ESI+) calcd for C₂₄H₂₈N₃O₄S₂

486.1521, found 486.1526 [M + H]⁺.

Reaction Note. A second fraction from the PLC plate was found to

contain the di-ring opened product 4 (24 mg, 33%), which was

spectroscopically identical to product 4 from the above procedure.

PLC (100% CHCl₃, 5 times) R_f= 0.19.

N,N′-((2R,3R)-1,4-Di(piperidin-1-yl)butane-2,3-diyl)bis(N-ethyl-4-

methylbenzenesulfonamide) (15). In a similar modiﬁcation as that

for 4, 20 equiv of piperidine (0.13 mL, 1.3 mmol) was added in one

portion to a solution of (R,R)-biaziridine (R,R)-1 (25 mg, 0.064

mmol) in DMF (0.5 mL), and the reaction mixture was stirred for 24

h. The reaction was quenched with H₂O (10 mL), and the mixture

was extracted with EtOAc (20 mL). The organic phase was separated;

4-Methoxybenzyl Chloride. This was synthesized by a modiﬁed

procedure.^54,55To 4-methoxybenzyl alcohol (3.12 g, 22.6 mmol) was

added concentrated HCl (6.0 mL), and the reaction mixture was

stirred at rt for 15 min. The mixture was transferred to a separatory

funnel with the aid of pet. spirit (∼10 mL). The layers were separated,

and the aqueous layer was extracted with pet. spirit (20 mL). The

combined organic fractions were washed with brine (20 mL) and

dried (Na₂SO₄). After ﬁltration and evaporation on a rotary

evaporator, the oil was dried further under high vacuum (5 min) to

give 4-methoxybenzyl chloride (2.93 g, 86%) as a clear oil. The

sample was placed over K₂CO₃and stored in a freezer at −20 °C for

24 h before use.

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washed successively with brine (2 × 10 mL), H₂O (3 × 10 mL), and

brine (10 mL); dried (Na₂SO₄); ﬁltered; and concentrated in vacuo.

The residue was then dissolved in EtOAc (20 mL) and subjected to a

second aqueous washing using H₂O (5 × 5 mL) and brine (3 × 5

mL);. The organic phase was then dried (Na₂SO₄), ﬁltered, and

concentrated in vacuo. Residual silicon grease was removed by

dissolution in MeCN (20 mL) and washing with hexanes (50 × 3

mL). The MeCN layer was dried (Na₂SO₄), ﬁltered, and evaporated

in vacuo to yield product 5 (32 mg crude), which was of suﬃcient

purity for the next step. Spectroscopic data were in agreement with

our previous report of the product.¹¹The published puriﬁcation was

found to be diﬃcult and only small amounts of the material (5−10

mg) could be easily puriﬁed, allowing for 5 to be subjected to Mg/

MeOH reduction conditions. Therefore, in a second step using the

above impure material and following general procedure 2b without

tetrabutylammonium iodide, the ring opened product 5 (32 mg, 0.056

mmol), iodoethane (0.03 mL, 0.4 mmol), and NaH (8.4 mg, 0.21

mmol, 60% w/w) in DMF (0.66 mL) were reacted and subsequently

quenched with H₂O (5 mL). The mixture was extracted with CH₂Cl₂

(3 × 10 mL). The combined organic layers were dried (Na₂SO₄),

ﬁltered, and subjected to silica gel chromatography (5 g of silica) by

wet loading using CH₂Cl₂and elution with EtOAc/hexanes (20%) to

give 15 (10 mg, 26% across two steps) as a clear colorless gum. TLC

(EtOAc/hexanes (20%)) R_f= 0.22; [α²_D⁵] = +65.6 (c = 0.49, CH₂Cl₂);

FTIR υ 2932 (s), 2853 (w), 2790 (w), 1598 (w), 1495 (w), 1468 (w),

1450 (w), 1379 (w), 1334 (s), 1305 (m), 1290 (w), 1261 (w), 1183

(w), 1161 (s), 1106 (m), 1088 (m), 1040 (w), 1019 (w), 998 (w),

987 (w), 962 (w), 932 (w), 902 (w), 865 (w), 814 (w), 800 (w), 781

(w), 756 (w), 733 (w), 708 (w), 696 (w), 667 (w), 619 (m), 515

and H5⁗), 6.93 (t, J = 7.3 Hz, H4‴ and H4⁗), 6.68 (d, J = 7.7 Hz,

4H, H2‴, H6‴, H2⁗, and H6⁗), 5.70 (s, 4H, H2 and H3), 4.41 (s,

2H, H1 and H4), 2.42 (s, 6H, TsCH₃), 1.39 (s, 18H, C(CH₃)₃); ¹³

C

NMR (126 MHz, CDCl₃) δ 158.2 (C1‴ and C1‴″), 150.9 (COOR),

144.1 (C4′ and C4″), 137.4 (C1′ and C″), 129.6 (C3‴, C5‴, C3⁗,

and C5⁗), 129.2 (C2′, C2″, C6′, and C6″ or C3′, C3″, C5′, and

C5″), 129.1 (C2′, C2″, C6′, and C6″ or C3′, C3″, C5′, and C5″),

121.4 (C4‴ and C4⁗), 114.8 (C2‴, C6‴, C2⁗, and C6⁗), 85.3

(C(CH₃)₃), 67.6 (C1 and C4), 57.7 (C2 and C3), 28.1 (C(CH₃)₃),

21.7 (TsCH₃); MS (ESI+) 804 (100%, [M + Na]⁺); HRMS (ESI+)

calcd for C₄₀H₄₈N₂O₁₀NaS₂803.2686, found 803.2648 [M + Na]⁺.

N,N′-((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(N-benzyl-4-

methylbenzenesulfonamide) (9). Following general procedure 2b,

benzyl bromide (0.37 mL, 3.1 mmol), 1,2-bis(tosylamide) 2 (293 mg,

p

0.504 mmol) , tetrabutylammonium iodide (63 mg, 0.17 mmol), and

NaH (72 mg, 1.8 mmol, 60% w/w) were reacted in DMF (6.0 mL).

The reaction was quenched with H₂O (50 mL), and the mixture was

extracted with CH₂Cl₂(3 × 100 mL). The combined organic layers

were dried (Na₂SO₄), evaporated in vacuo, and puriﬁed by silica gel

chromatography (20 g of silica) using gradient elution with EtOAc/

hexanes (10%, 400 mL then 20%, 200 mL) to give the N-benzyl-

protected 1,2-bis(tosylamide) 9 as a white gum. Impure fractions were

subjected to a second round of silica gel chromatography under the

same conditions, and any product containing trace amounts of benzyl

bromide (by TLC analysis) were concentrated in vacuo and heated

under vacuum (heat gun) to remove the residual benzyl bromide. The

combined fractions were dissolved in MeCN (50 mL), washed with

hexanes (3 × 100 mL), ﬁltered, and evaporated in vacuo to yield the

target product 9 (205 mg, 52%) as a clear colorless gum. TLC

(EtOAc/hexanes (20%)) R_f= 0.57; [α²_D⁵] = −31.8 (c = 1.7, CH₂Cl₂);

FTIR υ 3090 (w), 3064 (w), 2951 (br), 1599 (m), 1496 (m), 1454

(w), 1325 (m), 1228 (s), 1090 (m), 1046 (w), 1026 (w), 917 (w),

885 (w), 856 (w), 838 (w), 801 (m), 775 (w), 735 (s), 654 (s), 602

(w), 578 (w), 540 (s), 509 (w), 458 (w) cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 7.76 (d, J = 8.3 Hz, 4H, H2′, H2″, H6′, and H6″), 7.30−

7.22 (m, 8H, H3′, H3″, H5′, H5″, H2‴″, H2‴‴, H6‴″, and H6‴‴),

7.21−7.15 (m, 6H, H3‴″, H3‴‴, H4‴″, H4‴‴, H5‴″, and H5‴‴),

7.15−7.10 (m, 4H, H3‴, H3⁗, H5‴, and H5⁗), 6.88 (t, J = 7.3 Hz,

2H, H4‴ and H4⁗), 6.18 (d, J = 7.7 Hz, 4H, H2‴, H2⁗, H6‴, and

H6⁗), 4.76 (d, J = 15.8 Hz, 2H, benzyl CH₂), 4.70−4.62 (m, 2H, H2

and H3), 4.20 (d, J = 15.8 Hz, 2H, benzyl CH₂), 3.83−3.71 (m, 4H,

H1 and H4), 2.42 (s, 6H, TsCH₃); ¹³C NMR (126 MHz, CDCl₃) δ

157.1 (C1‴ and C1⁗), 143.4 (C4′ and C4″), 137.0 (C1‴″ and

C1‴‴), 136.6 (C1′ and C1″), 129.5 (C3′, C3″, C5′, and C5″), 129.2

(C3‴, C3⁗, C5‴, C5⁗, C2‴″, C2‴‴, C6‴″, and C6‴‴), 128.6

(C3‴″, C3‴‴, C5‴″, and C5‴‴), 127.9 (C2′, C2″, C6′, and C6″),

127.8 (C4‴″ and C4‴‴), 121.0 (C4‴ and C4⁗), 114.0 (C2‴, C2⁗,

C6‴, and C6⁗), 64.1 (C1 and C4), 60.8 (C2 and C3), 50.1 (benzyl

CH₂), 21.6 (TsCH₃); MS (ESI+) 783 (13%, [M + Na]⁺); HRMS

(ESI+) calcd for C₄₄H₄₄N₂NaO₆S₂783.2539, found 783.2538 [M +

Na]⁺.

n

(m); ¹H NMR (CDCl₃, 400 MHz) (mixture of rotamers) δ 7.81 (d,

J = 8.3 Hz, 4H, H2′, H6′, H2″, and H6″), 7.28 (d, J = 8.0 Hz, 4H,

C3′, C5′, C3″, and C5″), 4.24 (dd, J = 10.2, 4.5 Hz, 2H, H2 and H3),

3.76−3.61 (m, 2H, H1a‴″, H1a‴″), 3.52−3.37 (m, 2H, H1_b‴″ and

H1_b‴″), 2.93−2.82 (m, 2H, H1_aand H4_a), 2.42 (s, 6H, TsCH₃),

2.37−2.10 (m, 8H, H2‴, H6‴, H2⁗, and H6⁗), 1.85 (d, J = 9.4 Hz,

2H, H1b and H4b), 1.53−1.23 (m, 12H, H3‴, H4‴, H5‴, H3⁗,

H4⁗, and H5⁗), 1.19 (t, J = 7.1 Hz, 6H, H2‴″ and H2‴‴); ¹³C

o

NMR (CDCl₃, 101 MHz, ¹³C DEPTQ-135) (mixture of rotamers) δ

142.9 (C4′ and C4″), 138.1 (C1′ and C1″), 129.3 (C3′, C5′, C3″,

and C5″), 127.8 (C2′, C6′, C2″, and C6″), 59.0 (C1 and C4), 54.6

(C2, C3, C2‴, C6‴, C2⁗, and C6⁗), 40.3 (br, C1‴″ and C1‴″), 26.3

(C3‴, C5‴, C3⁗, and C5⁗), 24.5 (C4‴ and C4⁗), 21.5 (TsCH₃),

15.9 (C2‴″ and C2‴‴); MS (ESI+) 619 (100%, [M + H]⁺); HRMS

(ESI+) calcd for C₃₂H₅₁N₄O₄S₂619.3352, found 619.3358 [M + H]⁺.

Di-tert-butyl ((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis-

(tosylcarbamate) (13). To a reaction ﬂask containing the 1,2-

bis(tosylamide) 2 (358 mg, 0.617 mmol) and DMAP (82 mg, 0.67

mmol) were added NEt₃(0.43 mL, 3.1 mmol) and CH₂Cl₂(10 mL),

and the mixture was stirred until a solution had formed. To the

reaction mixture was added Boc₂O (0.71 mL, 3.1 mmol, gently

warmed to a liquid) dropwise at rt, and the solution was stirred for 24

h with monitoring by TLC analysis to ensure the consumption of the

1,2-bis(tosylamide) starting material. The solution was then

evaporated on a rotary evaporator, dissolved in EtOAc (50 mL),

and washed with HCl (3 × 20 mL, 0.1 M), brine (20 mL), saturated

aq. NaHCO₃(20 mL), and brine (20 mL). The organic phase was

dried (Na₂SO₄), ﬁltered, and evaporated to a white solid on a rotary

evaporator. The solid was redissolved in MeCN (50 mL) and washed

with hexanes (3 × 200 mL) to remove the residual grease. The

MeCN layer was dried (Na₂SO₄), ﬁltered, evaporated in vacuo to a

gum, dissolved in diethyl ether (∼2.0 mL), and re-evaporated under

high vacuum (3 h) to yield the N,N′-di-Boc-protected 1,2-

bis(tosylamide) 13 (482 mg) as a white solid that contained alkyl

impurities. No further puriﬁcation was required for subsequent

detosylation by Mg/MeOH. mp 45−50 °C; TLC (EtOAc/hexanes

(20%)) R_f= 0.71; [α²_D⁵] = −75.3 (c = 0.29, CH₂Cl₂); FTIR υ 2978

(w), 1721 (w), 1597 (w), 1494 (w), 1350 (m), 1236 (m) 1140 (s),

q

Following general procedure 2a , benzyl bromide (0.36 mL, 3.0

mmol), 1,2-bis(tosylamide) (295 mg, 0.508 mmol), tetrabutylammo-

nium iodide (62 mg, 0.17 mmol), and NaH (216 mg, 5.40 mmol, 60%

w/w) were reacted in DMF (6.0 mL) with heating for 3.5 h. The

compound was puriﬁed using the above method to yield the product

as a clear colorless gum (234 mg, 61%) that was spectroscopically

identical to the product obtained via general procedure 2b.

N,N′-((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(N-(4-methoxy-

benzyl)-4-methylbenzenesulfonamide) (10). Following general

r

procedure 2a, freshly prepared 4-methoxybenzyl chloride (0.42 mL,

3.1 mmol), 1,2-bis(tosylamide) 2 (294 mg, 0.507 mmol),

tetrabutylammonium iodide (62 mg, 0.17 mmol), and NaH (218

mg, 5.44 mmol, 60% w/w) were reacted in DMF (6 mL) for 3.5 h.

The reaction was quenched with H₂O (10 mL), and the mixture was

extracted with CH₂Cl₂(3 × 100 mL), dried (Na₂SO₄), and

evaporated in the usual way with the exception that dry N₂was

used instead of air. The residue was then subjected to silica gel

chromatography (20 g of silica) by wet loading with CH₂Cl₂and

gradient elution with EtOAc/hexanes (10%, 300 mL, then 20% until

1

1085 (w), 882 (w), 810 (m), 668 (m), 572 (s), 545 (s) cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.3 Hz, 4H, H2′, H2″, H6′,

and H6″), 7.36−7.16 (m, 8H, H3′, H3″, H5′, H5″, H3‴, H5‴, H3⁗,

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the product eluted) to yield an impure fraction containing both

decomposition and the product. After being concentrated in vacuo,

this residue was subjected to repeated PLC separation (∼60 mg

crude, ﬁve PLC plates) by loading the compound with CHCl₃and

eluting with CHCl₃/hexanes (70%). Each PLC plate was required to

be eluted six times, after which fractions containing the product were

carefully removed from surrounding impurities and sonicated in

CHCl₃(∼50 mL), then ﬁltered through Celite. The Celite pad was

rinsed with more CHCl₃(∼50 mL). After the evaporation and

concentration of the ﬁltrate in vacuo, a thick yellow gum was obtained.

To the gum was added CHCl₃(1 mL), and the he sample was gently

heated using a heat gun under vacuum to obtain the N,N′-dibenzyl

1,2-bis(tosylamide) 10 (183 mg, 43%) as a white solid. mp 48−54

°C; TLC (EtOAc/hexanes (20%)) R_f= 0.10; PLC (CHCl₃/hexanes

(70%), six times) R_f= 0.37; [α²_D⁵] = −35.4 (c = 1.47, CH₂Cl₂); FTIR

υ 2959 (w), 2835 (w), 1610 (w), 1598 (m), 1587 (w), 1512 (s), 1496

(m), 1478 (w), 1328 (m), 1304 (w), 1244 (s), 1158 (s), 1089 (m),

1032 (m), 863 (m), 813 (m), 753 (s), 691 (m), 657 (m), 573 (w),

550 (s), 509 (w), 407 (w) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.77

(d, J = 8.3 Hz, 4H, H2′, H2″, H6′, and H6″), 7.24 (d, J = 8.2 Hz, 4H,

H3′, H3″, H5′, and H5″), 7.18 (d, J = 8.6 Hz, 4H, H2‴″, H2‴‴,

H6‴″, and H6‴‴), 7.13 (dd, J = 8.6, 7.4 Hz, 4H, H2‴, H2⁗, H6‴,

and H6⁗), 6.88 (t, J = 7.4 Hz, 2H, H4‴ and H4⁗), 6.69 (d, J = 8.7

Hz, 4H, H3‴″, H3‴‴, H5‴″, and H5‴‴), 6.22 (d, J = 7.9 Hz, 4H,

H3‴, H3⁗, H5‴, and H5⁗), 4.72 (d, J = 15.6 Hz, 2H, benzyl CH₂),

4.66−4.59 (m, 2H, H2 and H3), 4.14 (d, J = 15.6 Hz, 2H, benzyl

CH₂), 3.83−3.66 (m, 10H, OCH₃, H1 and H4), 2.41 (s, 6H,

TsCH₃); ¹³C NMR (126 MHz, CDCl₃) δ 159.3 (C4‴″ and C4‴‴),

157.3 (C1‴ and C1⁗), 143.3 (C4′ and C4″), 136.8 (C1′ and C1″),

130.5 (C2‴″, C2‴‴, C6‴″, and C6‴‴), 129.4 (C3′, C3″, C5′, and

C5″), 129.2 (C2‴, C2⁗, C6‴, and C6⁗), 129.0 (C1‴″ and C1‴‴),

127.9 (C2′, C2″, C6′, and C6″), 120.9 (C4‴ and C4⁗), 114.0 (C3‴,

C3⁗, C5‴, and C5⁗), 113.9 (C3‴″, C3‴‴, C5‴″, and C5‴‴), 64.2

(C1 and C4), 60.7 (C2 and C3), 55.1 (OCH₃), 49.5 (benzyl CH₂),

21.5 (TsCH₃); MS (ESI+) 843 (13%, [M + Na]⁺); MS (ESI−) 855

(20%, [M + Cl]⁻); HRMS (ESI+) calcd for C₄₆H₄₈N₂NaO₈S₂

843.2750, found 843.2734 [M + Na]⁺.

and C1‴‴), 130.9 (d, ³J_CF= 8.1 Hz, C2‴″, C2‴‴, C6‴″, and C6‴‴),

129.5 (C3″, C3⁗, C5‴, and C5⁗ or C3′, C3″, C5′, and C5″) 129.4

(C3‴, C3⁗, C5‴, and C5⁗ or C3′, C3″, C5′, and C5″), 127.8 (C2′,

C2″, C6′, and C6″), 121.3 (C4‴ and C4⁗), 115.3 (d, ²J_CF= 21.3 Hz,

C3‴″, C3‴‴, C5‴″, and C5‴‴), 114.0 (C2‴, C2⁗, C6‴, and C6⁗),

64.8 (C1 and C4), 60.8 (C2 and C3), 49.7 (benzyl CH₂), 21.5

(TsCH₃); MS (ESI+) 819 (34%, [M + Na]⁺); HRMS (ESI+) calcd

for C₄₄H₄₃N₂O₆F₂S₂797.2531, found 797.2529.

After the elution of the N,N′-dibenzyl product 11 (see above

procedure), fractions containing a small amount of the monobenzyl

product 19 were collected and evaporated in vacuo to yield the crude

N-benzyl 1,2-bis(tosylamide) 19 (5.6 mg of crude, 5.1 mg of the

t

product , 8% yield,) as a yellow gum that contained a 4-ﬂuorobenzyl

chloride impurity. The isolated N-benzyl 1,2-bis(tosylamide) 19 was

91% pure by mass and was therefore used in the next step without

further puriﬁcation. TLC (EtOAc/hexanes (20%)) R_f= 0.63; ¹H

NMR (CDCl₃, 400 MHz) δ 7.73 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3

Hz, 2H), 7.33 (dd, J = 8.4, 5.5 Hz, 1H), 7.25−7.13 (m, 10H), 7.04 (t,

J = 8.7 Hz, 1H), 6.93−6.88 (m, 2H), 6.83 (t, J = 8.6 Hz), 6.55−6.51

(m, 2H), 6.45−6.40 (m, 2H), 5.29 (br s, 1H, NH), 4.51−4.38 (m,

2H), 4.21 (d, J = 15.6 Hz, 1H), 4.12−3.92 (m, 3H), 3.80−3.69 (m,

2H), 2.42−2.35 (m, 6H, TsCH₃); MS (ESI−) 687 (100%, [M −

H]⁻); HRMS (ESI−) calcd. for C₃₇H₃₆N₂O₆FS₂687.1999, found

687.1996 [M − H]⁻.

N-Benzyl-N-((2S,3S)-3-((N-(4-ﬂuorobenzyl)-4-methylphenyl)-

sulfonamido)-1,4-diphenoxybutan-2-yl)-4-methylbenzenesulfona-

mide (12). Following general procedure 2a, benzyl bromide (0.10 mL,

0.84 mmol), the crude N-benzyl 1,2-bis(tosylamide) 19 (89 mg, 0.13

u

mmol) , tetrabutylammonium iodide (18 mg, 0.050 mmol), and NaH

(59 mg, 1.5 mmol, 60% w/w) in DMF (2.0 mL) were reacted for 3.5

h. The reaction was quenched with H₂O (1.0 mL), and the mixture

was extracted with CH₂Cl₂(3 × 25 mL). The combined organic

layers were dried (Na₂SO₄) and evaporated. The residue was

subjected to silica gel chromatography (18 g of silica) by wet loading

with CH₂Cl₂and gradient elution with CHCl₃/hexanes (10%, 100

mL; 20%, 200 mL; 30%, 200 mL; then 50%, 200 mL) to furnish 1,2-

v

bis(tosylamide) 12 (77 mg, 76%) as a white solid. mp 55−57 °C;

TLC (CHCl₃/hexanes (50%)) R_f= 0.40; [α²_D⁵] = −38.3 (c = 0.26,

CH₂Cl₂); FTIR υ 3064 (w), 3032 (w), 2952 (w), 2925 (w), 1704

(m), 1509 (w), 1496 (m), 1478 (w), 1455 (w), 1329 (m), 1305 (w),

1292 (w), 1238 (m), 1224 (m), 1156 (s), 1111 (w), 1089 (m), 1044

(w), 1031 (w), 1014 (w), 917 (w), 884 (w), 859 (w), 837 (w), 814

(m), 753 (m), 727 (m), 691 (m), 656 (m), 601 (w), 569 (w), 547

(s), 494 (w) cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.73 (dd, J = 12.1,

8.3 Hz, 4H, H2′, H2″, H6′, and H6″), 7.28−7.10 (m, 15H, H3′, H3″,

H5′, H5″, H3‴, H3⁗, H5‴, H5⁗, H2‴″, C6‴″, H2‴‴, H3‴‴, H4‴‴,

H5‴‴, and H6‴‴), 6.93−6.87 (m, 2H, H4‴ and H4⁗), 6.84−6.78

(m, 2H, H3‴″ and H5‴″), 6.30−6.22 (m, 4H, H2‴, H2⁗, H6‴, and

H6⁗), 4.81−4.63 (m, 4H, 4-ﬂuorobenzyl CH₂, benzyl CH₂, H2, and

H3), 4.27 (apr. dd, J = 15.7, 5.1 Hz, 2H, 4-ﬂuorobenzyl CH₂and

benzyl CH₂), 3.91−3.78 (m, 4H, H1 and H4), 2.43−2.39 (m, 6H,

N,N′-((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(N-(4-ﬂuoroben-

zyl)-4-methylbenzenesulfonamide) (11) and N-(4-Fluorobenzyl)-4-

methyl-N-((2S,3S)-3-((4-methylphenyl)sulfonamido)-1,4-diphenox-

ybutan-2-yl)benzenesulfonamide (19). Following general procedure

2a, 4-ﬂuorobenzyl chloride (0.070 mL, 0.58 mmol), 1,2-bis-

(tosylamide) 2 (52 mg, 0.090 mmol), tetrabutylammonium iodide

s

(9.8 mg, 0.026 mmol), and NaH (22 mg, 0.55 mmol, 60% w/w)

were reacted in DMF (1 mL) for 4 h. The reaction was quenched

with H₂O (1 mL), and the mixture was extracted with CH₂Cl₂(3 ×

25 mL). The combined organic layers were dried (Na₂SO₄) and

evaporated. The obtained oil was subjected to silica gel chromatog-

raphy (14 g of silica) by wet loading with CH₂Cl₂and gradient elution

with EtOAc/hexanes (2%, 150 mL; 5%, 100 mL; then 20%, 100 mL).

Fractions containing the N,N′-dibenzyl product 11 by TLC analysis

were combined, evaporated in vacuo, dissolved in MeCN (10 mL),

and washed with hexanes (3 × 100 mL), and the resultant MeCN

fraction was evaporated in vacuo to yield the N,N′-dibenzyl 1,2-

bis(tosylamide) 11 (59 mg, 82%) as a clear colorless gum. TLC

(EtOAc/hexanes (20%)) R_f= 0.69; [α²_D⁵] = −33.5 (c = 2.8, CH₂Cl₂);

FTIR υ 3071 (w), 3041 (w), 2957 (w), 2873 (w), 1601 (m), 1511

(s), 1496 (m), 1478 (w), 1400 (w), 1328 (m), 1305 (w), 1223 (s),

1156 (s), 1090 (m), 1048 (br), 1032 (w), 940 (w), 888 (w), 867 (w),

851 (w), 836 (w), 815 (w), 754 (m), 691 (m), 657 (m), 571 (w), 550

(m), 509 (w), 491 (w) cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 7.71 (d,

J = 8.3 Hz, 4H, H2′, H2″, H6′, and H6″), 7.24−7.12 (m, 12H, H3‴,

H3⁗, H5‴, H5⁗, H3′, H3″, H5′, H5″, H2‴″, H2‴‴, H6‴″, and

H6‴‴), 6.91 (t, J = 7.4 Hz, 2H, H4‴ and H4⁗), 6.81 (t, J = 8.7 Hz,

4H, H3‴″, H3‴‴, H5‴″, and H5‴‴), 6.30 (d, J = 7.8 Hz, 4H, H2‴,

H2⁗, H6‴, and H6⁗) 4.76−4.63 (m, 4H, C2, C3 and benzyl CH₂),

4.29 (d, J = 15.8 Hz, 2H, benzyl CH₂), 3.96−3.82 (m, 4H, H1 and

H4), 2.40 (s, 6H, TsCH₃); ¹³C NMR (CDCl₃, 101 MHz) δ 162.4 (d,

¹J_CF= 247.0 Hz, C4‴″ and C4‴‴), 157.2 (C1‴ and C1⁗), 143.5

(C4′ and C4″), 136.9 (C1′ and C1″), 132.6 (d, ⁴J_CF= 3.0 Hz, C1‴″

1

TsCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 162.4 (d, J_CF= 246.8 Hz,

C4‴″), 157.2 (C1‴ and C1⁗), 143.4 (C4′ and C4″), 136.89 (C1′ or

3

C1″), 136.85 (C1′ or C1″) 132.6 (C1‴″), 130.9 (d, J_CF= 8.2 Hz,

C2‴″ and C6‴″), 129.5 (C3′ and C5′, or C3″ and C5″, or C3‴ and

C5‴, or C3⁗ and C5⁗, or C2‴‴, C4‴‴, and C6‴‴), 129.46 (C3′

and C5′, or C3″ and C5″, or C3‴ and C5‴, or C3⁗ and C5⁗, or

C2‴‴, C4‴‴, and C6‴‴), 129.3 (C3′ and C5′, or C3″ and C5″, or

C3‴ and C5‴, or C3⁗ and C5⁗, or C2‴‴, C4‴‴, and C6‴‴), 129.24

(C3′ and C5′, or C3″ and C5″, or C3‴ and C5‴, or C3⁗ and C5⁗,

or C2‴‴, C4‴‴, and C6‴‴), 129.17 (C3′ and C5′, or C3″ and C5″,

or C3‴ and C5‴, or C3⁗ and C5⁗, or C2‴‴, C4‴‴, and C6‴‴),

128.6 (C3‴‴ and C5‴‴), 127.9 (C2′ and C6′ or C2″ and C6″),

127.8 (C2′ and C6′ or C2″ and C6″), 121.2 (C4‴ or C4⁗), 121.1

2

(C4‴ or C4⁗), 115.3 (d, J_CF= 21.3 Hz, C3‴″ and C5‴″), 114.1

(C2‴ and C6‴ or C2⁗ and C6⁗), 114.0 (C2‴ and C6‴ or C2⁗ and

C6⁗), 64.6 (C1 or C4), 64.5 (C1 or C4), 61.0 (C2 or C3), 60.7 (C2

or C3), 50.3 (benzyl CH₂or 4-ﬂuororobenzyl CH₂), 49.6 (benzyl

CH₂or 4-ﬂuororobenzyl CH₂), 21.5 (TsCH₃); MS (ESI+) 801 (40%,

9172

https://doi.org/10.1021/acs.joc.1c00359

J. Org. Chem. 2021, 86, 9163−9180

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

[M + Na]⁺); HRMS (ESI+) calcd for C₄₄H₄₄FN₂O₆S₂779.2610,

found 779.2625 [M + H]⁺.

N,N′-((3R,4R)-1,6-Diphenylhexane-3,4-diyl)bis(N-ethyl-4-methyl-

benzenesulfonamide) (14). Following general procedure 2b without

tetrabutylammonium iodide and with 9 equiv of the alkyl iodide, 1,2-

bis(tosylamide) 3 (50 mg, 0.079 mmol), iodoethane (0.060 mL, 0.075

mmol), and NaH (13 mg, 0.32 mmol, 60% w/w) were reacted in

DMF (1.0 mL). The reaction was quenched with H₂O (5.0 mL), and

the mixture was extracted with CH₂Cl₂(3 × 20 mL). The combined

organic extracts were dried (Na₂SO₄), ﬁltered, and evaporated in

vacuo to give an oily residue. The residue was dissolved in EtOAc (30

mL), washed with H₂O (4 × 10 mL) and brine (2 × 10 mL), dried

(Na₂SO₄), evaporated in vacuo, dissolved in MeCN (30 mL), washed

with hexanes (5 × 50 mL), and concentrated in vacuo to give the

N,N′-diethyl 1,2-bis(tosylamide) 14 (46 mg, 84%) as a golden yellow

gum. [α²_D⁵] = +23.6 (c = 1.2, CH₂Cl₂); FTIR υ 3085 (w), 3062 (w),

3027 (w), 2938 (w), 2873 (w), 2361 (w), 2335 (w), 1599 (w), 1496

(w), 1454 (w), 1398 (w), 1381 (w), 1336 (s), 1305 (m), 1290 (w),

1154 (s), 1120 (m), 1087 (m), 1019 (w), 1004 (w), 986 (w), 929

(w), 816 (w), 801 (w), 750 (w), 731 (m), 701 (m), 666 (m), 622

N,N′-((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(N-ethyl-4-meth-

ylbenzenesulfonamide) (8). Following general procedure 2b without

tetrabutylammonium iodide, 1,2-bis(tosylamide) 2 (51 mg, 0.088

mmol), iodoethane (0.045 mL, 0.56 mmol), and NaH (13 mg, 0.53

mmol, 60% w/w) were reacted in DMF (1.0 mL). The reaction was

quenched with H₂O (10 mL), and the mixture was extracted with

CH₂Cl₂(3 × 20 mL). The combined organic layers were dried

(Na₂SO₄), ﬁltered, and evaporated. The residue was dissolved in

EtOAc (50 mL), washed with H₂O (5 × 10 mL) and brine (10 mL),

dried (Na₂SO₄), ﬁltered, and evaporated in vacuo. Residual grease was

then removed by dissolving the residue with sonication in MeCN (30

mL) and washing with hexanes (3 × 100 mL). The MeCN layer was

then ﬁltered and evaporated in vacuo to yield N,N′-diethyl 1,2-

bis(tosylamide) 8 (55 mg, 99%) as a clear colorless gum. [α²_D⁵] = +7.6

(c = 1.2, CH₂Cl₂); FTIR υ 3064 (w), 3031 (w), 2977 (w), 2937 (w),

2878 (w), 1599 (m), 1589 (m), 1497 (m), 1478 (w), 1383 (w), 1363

(w), 1335 (s), 1305 (m), 1291 (w), 1240 (s), 1185 (m), 1160 (s),

1088 (m), 1051 (w), 1020 (w), 1003 (w), 982 (w), 930 (w), 839 (w),

815 (w), 775 (m), 755 (m), 719 (m), 692 (m), 650 (m), 554 (m),

x

(m), 589 (m), 552 (m); ¹H NMR (CDCl₃, 400 MHz) δ (mixture of

rotamers) 7.79 (d, J = 8.3 Hz, 4H, H2′, H6′, H2″, and H6″), 7.31 (d,

J = 8.0 Hz, 4H, H3′, H5′, H3″ and H5″), 7.28−7.20 (m, 4H, H3‴″

and H5‴″ and H3‴″ and H5‴″), 7.20−7.13 (m, 2H, H4‴″ and

H4‴‴), 7.05−6.98 (m, 4H, H2‴″ and H6‴″ and H2‴″ and H6‴″),

4.09 (t, J = 5.2 Hz, 2H, H3 and H4), 3.35 (q, J = 7.1 Hz, 4H, H1‴

and H1⁗), 2.51−2.32 (m, 10H, TsCH₃, H1 and H6), 2.10−1.92 (m,

2H, H2_aand H5_a), 1.68 (br s, 2H, H2_band H5_b), 1.24 (t, 6H, H2‴

and H2⁗); ¹³C NMR (CDCl₃, 101 MHz, ¹³C DEPTQ-135)

1

509 (m); H NMR (CDCl₃, 500 MHz) δ 7.81 (d, J = 8.3 Hz, 4H,

H2′, H6′, H2″, and H6″), 7.29−7.16 (m, 8H, H3′, H5′, H3″, H5″,

H3‴, H5‴, H3⁗, and H5⁗), 6.94 (t, J = 7.4 Hz, 2H, H4‴ and H4⁗),

6.65 (dd, J = 8.7, 0.9 Hz, 4H, H2‴, H6‴, H2⁗, and H6⁗), 4.75 (s,

2H, H2 and H3), 4.21−4.08 (m, 4H, H1 and H4), 3.65−3.46 (m, 4H,

H1‴″ and H1‴‴), 2.40 (s, 6H, TsCH₃), 1.11 (t, J = 7.1 Hz, 6H,

H2‴″ and H2‴‴); ¹³C NMR (CDCl₃, 126 MHz) δ (mixture of

y

δ (mixture of rotamers) 143.4 (C4′ and C4″), 141.2 (C1‴″ and

w

C1‴″), 137.7 (br s, C1′ and C1″), 129.6 (C3′, C5′, C3″ and C5″),

128.5 (C3‴″ and C5‴″ and C3‴″ and C5‴″ or C2‴″ and C6‴″ and

C2‴″ and C6‴″), 128.2 (C3‴″ and C5‴″ and C3‴″ and C5‴″ or

C2‴″ and C6‴″ and C2‴″ and C6‴″), 127.6 (C2′, C6′, C2″ and

C6″), 126.1 (C4‴″ and C4‴″), 62.1 (br, C3 and C4), 41.1 (br, C1‴

and C1⁗), 33.9 (C1 and C6), 32.0 (C2 and C5), 21.5 (TsCH₃), 15.8

(C2‴ and C2⁗); MS (ESI+) 655 (100%, [M − Na]⁺); HRMS (ESI

+) calcd for C₃₆H₄₄N₂NaO₄S₂655.2650, found 655.2640 [M + Na]⁺.

(3S,3′S)-4,4′-Ditosyl-3,3′,4,4′-tetrahydro-2H,2′H-3,3′-bibenzo[b]-

[1,4]oxazine (16).¹¹To synthesize the known 16, a modiﬁed

procedure was developed. A screw-cap pressure-sealed vial containing

a magnetic stir bar, ring opened intermediate 17 (0.905 g, 1.09

mmol), CsOAc (2.782 g, 14.49 mmol), and anhydrous CuI (0.824 g,

rotamers) 157.6 (C1‴ and C1⁗), 143.3 (C4′ and C4″), 138.2 (C1′

and C1″), 129.53 (C3′, C5′, C3″, and C5″ or C3‴, C5‴, C3⁗, and

C5⁗), 129.50 (C3′, C5′, C3″, and C5″ or C3‴, C5‴, C3⁗, and

C5⁗), 127.8 (C2′, C6, C2″ and C6″), 121.4 (C4‴ and C4⁗), 114.3

(C2‴, C6‴, C2⁗ and C6⁗), 67.1 (C1 and C4), 57.8 (br s, C2 and

C3), 41.5 (br s, C1‴″ and C1‴‴), 21.5 (TsCH₃), 14.7 (C2‴″ and

C2‴‴); MS (ESI+) 659 (62%, [M + Na]⁺); HRMS (ESI+) calcd for

C₃₄H₄₁N₂O₆S₂637.2400, found 637.2402 [M + H]⁺and calcd for

C₃₄H₄₀N₂NaO₆S₂659.2220, found 659.2223 [M + Na]⁺.

N,N′-((2S,3S)-1,4-Diphenoxybutane-2,3-diyl)bis(N,4-dimethyl-

benzenesulfonamide) (7). Following general procedure 2b without

tetrabutylammonium iodide, 1,2-bis(tosylamide) 2 (51 mg, 0.088

mmol), iodomethane (0.03 mL, 0.5 mmol), and NaH (13 mg, 0.32

mmol, 60% w/w) were reacted in DMF (1.0 mL). The reaction was

quenched with H₂O (10 mL), and the mixture was extracted with

CH₂Cl₂(3 × 20 mL). The combined organic layers were dried

(Na₂SO₄), ﬁltered, and evaporated. The solid was then precipitated

from boiling CH₂Cl₂/hexanes (2.0 mL of CH₂Cl₂), ﬁltered, washed

with hexanes (50 mL), and eluted from the ﬁlter paper using CH₂Cl₂.

The CH₂Cl₂ﬁltrate was evaporated in vacuo to yield the N,N′-

dimethyl 1,2-bis(tosylamide) 7 (189 mg, 90%) as a yellow solid. mp

110−111 °C; [α²_D⁵] = +42.4 (c = 1.0, CH₂Cl₂); FTIR υ 3347 (br s),

3030 (w), 2891 (w), 1597 (m), 1587 (m), 1496 (m), 1466 (m), 1449

(m), 1388 (w), 1362 (w), 1334 (s), 1304 (w), 1290 (w), 1240 (s),

1214 (m), 1167 (s), 1148 (s), 1115 (m), 1083 (m), 1034 (m), 1020

(m), 999 (m), 908 (s), 844 (m), 812 (m), 799 (w), 772 (m), 756 (s),

708 (m), 682 (s), 652 (s), 621 (w), 601 (s), 548 (s), 553 (s), 507 (s),

442 (w), 424 (w); ¹H NMR (CDCl₃, 400 MHz) δ 7.77 (d, J = 8.2 Hz,

4H, H2′, H2″, H6′, and H6″), 7.33 (d, J = 8.1 Hz, 4H, H3′, H3″,

H5′, and H5″), 7.18 (t, J = 8.0 Hz, 4H, H3‴, H5‴, H3⁗, and H5⁗),

6.91 (t, J = 7.4 Hz, 2H, H4‴ and H4⁗), 6.48 (d, J = 7.9 Hz, 4H, H2‴,

H6‴, H2⁗, and H6⁗), 4.63−4.54 (m, 2H, H2 and H3), 4.19 (apr.

dd, J = 10.7, 3.4) 2H, H1_aand H4_a), 4.09 (dd, J = 10.7, 3.4 Hz, 2H,

H1_band H4_b), 2.46 (s, 6H, TsCH₃), 2.97 (s, 6H, NCH₃); ¹³C NMR

(CDCl₃, 101 MHz) δ 157.6 (C1‴ and C1⁗), 143.5 (C4′ and C4″),

135.7 (C1′ and C1″), 129.6 (C3′, C5′, C3″, and C5″), 129.4 (C3‴,

C5‴, C3⁗, and C5⁗), 128.0 (C2′, C6′, C2″, and C6″), 121.3 (C4‴

and C4⁗), 114.3 (C2‴, C6‴, C2⁗, and C6″″), 66.7 (C1 and C4),

55.6 (C2 and C3), 30.8 (NCH₃), 21.5 (TsCH₃); MS (ESI+) 631

(100%, [M + Na]⁺), 609 (9%, [M + H]⁺); HRMS (ESI+) calcd for

C₃₂H₃₆N₂O₆NaS₂631.1907, found 631.1909 [M + Na]⁺.

z

4.33 mmol) was purged with a stream of N₂for 5 min, and DMSO

(7.2 mL) added under a stream of N₂. The vial was sealed and heated

at 110 °C for 3 d and then left to cool to rt. The vial was opened to

the atmosphere, the reaction was quenched with saturated aq. NH₄Cl

solution (50 mL), and the mixture was extracted with EtOAc (3 × 50

mL). The combined organic phases were dried (Na₂SO₄), ﬁltered

through a pad of Celite, and concentrated in vacuo to give the crude

product, which was recrystallized from CH₂Cl₂/hexanes (50%, ∼ 6

mL) by slow evaporation over 3 d at −20 °C. After ﬁltration, drying in

air, and further drying in vacuo, the product 16 (392 mg, 62%) was

isolated as a white solid.

4-Methyl-N-((S)-2-phenoxy-1-((S)-4-tosyl-3,4-dihydro-2H-benzo-

[b][1,4]oxazin-3-yl)ethyl)benzenesulfonamide (20). Following the

above procedure for compound 16 using the ring opened product 17

(0.998 g, 1.20 mmol), anhydrous CuI (0.914 g, 4.80 mmol), CsOAc

(3.36 g, 17.50 mmol), and wet DMSO (7.2 mL) produced a mixture

of monocyclized and dicyclized products by crude ¹H NMR. After the

same aqueous extraction as the above procedure, these products could

be separated with extreme diﬃculty by silica gel chromatography (17

g of silica) by wet loading with CH₂Cl₂and elution with CH₂Cl₂

(100%). Careful TLC analysis with all TLC plates side-by-side

allowed the visualization of both products due to their close R_fvalues.

The dicyclic product 16 (197 mg, 34%) was observed to elute ﬁrst,

with spectra identical to those reported. TLC (CH₂Cl₂(100%), two

a1

times) R_f= 0.94. The monocyclic product 20 (65 mg, 11%) was a

white gum and eluted immediately after the dicyclic product 16. The

product 20 contained EtOAc and acetone that could not be dried

further from the gum. TLC (CH₂Cl₂(100%), two times) R_f= 0.89;

[α²_D⁵] = −89.0 (c = 1.0, CH₂Cl₂); FTIR υ 3313 (br s), 364 (w), 3040

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Note

(w), 2960 (w), 2923 (w), 2888 (w), 1598 (m), 1490 (s), 1454 (w),

1401 (w), 1338 (m), 1305 (w), 1291 (w), 1239 (m), 1186 (w), 1163

(s), 1124 (w), 1089 (m), 1068 (w), 1019 (w), 1009 (w), 985 (w),

964 (w), 909 (m), 890 (m), 862 (w), 813 (m), 755 (m), 729 (m),

707 (m), 691 (m), 663 (m), 614 (w) 571 (m), 563 (m), 546 (m),

510 (w); ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, J = 8.3 Hz, 2H, H2′

and H6′ or H2″ and H6″), 7.42 (d, J = 8.2 Hz, 2H, H2′ and H6′ or

H2″ and H6″), 7.33−7.15 (m, 7H, H3′, H5′, H3″, H5″, H3‴, H5‴,

and H6⁗), 6.99 (t, J = 7.3 Hz, 2H, H4‴ and H7⁗), 6.88 (d, J = 8.0

Hz, 2H, H2‴ and H5 or H6⁗, or H7⁗, or H8⁗), 6.79−6.64 (m, 2H,

H5⁗, H6⁗, H7⁗, or H8⁗), 5.38 (d, J = 6.3 Hz, 1H, NH), 4.40 (d, J

= 9.6 Hz, 1H, H3⁗), 4.28 (dd, J = 10.3, 2.8 Hz, 1H, H2_a), 4.11 (dd, J

= 10.2, 2.4 Hz, 1H, H2_b), 4.02 (d, J = 12.1 Hz, 1H, H2_a⁗), 3.43−3.35

(m, 1H, H1), 2.92 (dd, J = 12.1, 2.6 Hz, 1H, H2_b⁗), 2.44 (s, 3H,

TsCH₃), 2.36 (s, 3H, TsCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 158.0

(C1‴), 145.4 (C8a⁗), 144.8 (C4′ or C4″), 143.3 (C4′ or C4″),

136.5 (C1′ and C1″ or C4a⁗), 134.3 (C1′ and C1″ or C4a⁗), 130.1

(C3′ and C5′, or C3″ and C5″, or C2‴ and C6‴), 129.8 (C3′ and

C5′, or C3″ and C5″, or C2‴ and C6‴), 129.6 (C3′ and C5′, or C3″

and C5″, or C2‴ and C6‴), 127.3 (C2′ and C6′ or C2″ and C6″),

127.1 (C2′ and C6′ or C2″ and C6″), 126.1 (C7⁗), 125.2 (C3‴ and

C5‴), 121.7 (C4‴), 121.33 (C5⁗, C6⁗ or C8⁗), 121.26 (C5⁗, C6⁗

or C8⁗), 117.2 (C5⁗, C6⁗ or C8⁗), 114.7 (C2‴ and C6‴), 67.8

(C2), 61.7 (C2⁗), 53.8 (C3⁗), 52.0 (C1), 21.6 (TsCH₃); MS (ESI

+) 579 (53%, [M + H]⁺); HRMS (ESI+) calcd for C₃₀H₃₀N₂NaO₆S₂

601.1438, found 601.1438 [M + Na]⁺.

X-ray Crystal Growth. The product (∼30 mg) was dissolved in

CH₂Cl₂/hexanes (50%, 50 mL) and allowed to evaporate to dryness

to yield clear colorless cube crystals.

1-Propoxyethan-1-ol. Following general procedure 5, Li metal (17

mg, 2.4 mmol) was added to a solution of 1,2-bis(tosylamide) 2 (44

mg, 0.076 mmol) in ethylenediamine (0.17 mL, 2.5 mmol) and

propylamine (0.5 mL). The solution turned dark blue and was stirred

for a further 20 min, then quenched over ice. The reaction mixture

was diluted with H₂O (10 mL) and extracted with diethyl ether (3 ×

10 mL). The combined organic phases were dried (Na₂SO₄) and

evaporated in vacuo to give 1-propoxyethan-1-ol (7.3 mg crude) as a

crude gum that contained some decomposition, and further

puriﬁcation was not attempted.

Reaction Notes. Attempts at reducing the quantity of Li/

ethylenediamine in the solution resulted in an incomplete reaction,

1

with the major product still being 1-propoxyethan-1-ol by H NMR

analysis. Therefore, no further attempts were made to obtain the

deprotected diamine.

(2S,3S)-1,4-Diphenoxy-2,3-di(N-tert-butoxycarbonylamino)-

butane (amine-13). Following general procedure 1, impure 13 (449

mg, 0.574 mmol) and Mg powder (698 mg, 28.7 mmol) were

sonicated in MeOH (14.0 mL). After the completion of the reaction,

the suspension was poured over EtOAc (100 mL) and ﬁltered

through Celite. The ﬁltrate was washed with H₂O (20 mL), and the

aqueous phase was separated and back-extracted with EtOAc (3 × 50

mL). The combined organic phases were dried (Na₂SO₄) and

concentrated in vacuo. The residue was dissolved in MeCN (20 mL),

washed with hexanes (3 × 100 mL), dried (Na₂SO₄), ﬁltered, and

concentrated in vacuo to an oil. Re-evaporation from diethyl ether (2

× 10 mL), followed by drying on high vacuum (∼1 h), aﬀorded the

deprotected amine-13 (245 mg, 90%) as a white solid. The product

was found to be unstable to silica gel chromatography and mildly

acidic workups. mp 84−86 °C; [α²_D⁵] = −66.7 (c = 0.28, CH₂Cl₂);

FTIR υ 3369 (br s), 2977 (w), 2930 (w), 1684 (s), 1599 (w), 1514

(m), 1498 (m), 1365 (w), 1289 (s), 1237 (s), 751 (s), 690 (s), 559

tert-Butyl ((S)-2-Phenoxy-1-((S)-4-tosyl-3,4-dihydro-2H-benzo-

[b][1,4]oxazin-3-yl)ethyl)(tosyl)carbamate (21). To a solution of

b1

1,2-bis(tosylamide) 20 (36 mg, 0.62 mmol), DMAP (6.9 mg, 0.56

mmol), and NEt₃(0.04 mL, 0.3 mmol) in CH₂Cl₂(1 mL) was added

Boc₂O (0.065 mL, 0.28 mmol, gently heated) dropwise, and the

solution was stirred for 20 h. The reaction was mixture diluted with

EtOAc (30 mL) and washed with NaHCO₃(2 × 10 mL), brine (10

mL), NH₄Cl (2 × 10 mL), and brine again (10 mL). The organic

phase was dried (Na₂SO₄), ﬁltered, and evaporated in vacuo,

redissolved in EtOAc, washed further with HCl (3 × 5 mL, 0.1 M),

dried (Na₂SO₄), ﬁltered, and evaporated in vacuo. The residue was

dissolved in MeCN (20 mL) and washed with hexanes (3 × 100 mL)

to remove residual grease. The MeCN layer was dried (Na₂SO₄),

ﬁltered, and evaporated in vacuo to yield the N-Boc-1,2-bis-

1

(br), 507 (m) cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.32−7.19 (m,

4H, H3‴, H5‴, H3⁗ and H5⁗), 6.96 (t, J = 7.3 Hz, 2H, H4‴ and

H4⁗), 6.68 (d, J = 7.7 Hz, 4H, H2‴, H6‴, H2⁗, and H6⁗), 5.41 (br

s, 2H, NH), 4.35 (br s, 2H, H2 and H3), 4.13−4.02 (m, 2H, H1 and

H4), 1.45 (s, 18H, OtBu); ¹³C NMR (126 MHz, CDCl₃) δ 158.5

(C1‴ and C1⁗), 156.5 (COOR), 129.7 (C3‴, C5‴, C3⁗, and C5⁗),

121.4 (H4‴ and H4⁗), 114.5 (H2‴, H6‴, H2⁗, and H6⁗), 79.9

(C2′ and C2″), 67.5 (C1 and C4), 51.4 (C2 and C3), 28.5 (OtBu);

MS (ESI+) 473 (48%, [M + H]⁺), 495 (11%, [M + Na]⁺); HRMS

(ESI+) calcd for C₂₆H₃₆N₂O₆Na 495.2478, found 495.2471 [M +

Na]⁺.

c1

(tosylamide) 21 (42 mg, 99%) as a gum, which solidiﬁed to a

white solid after repeated evaporation from CHCl₃(3 × 1 mL) under

high vacuum. mp 159−161 °C; [α²_D⁵] = +51.0 (c = 0.71, CH₂Cl₂);

FTIR υ 2985 (w), 2926 (w), 2898 (w), 1725 (m), 1598 (w), 1587

(w), 1490 (m), 1477 (m), 1456 (w), 1395 (s), 1357 (w), 1328 (w),

1291 (m), 1256 (m), 1237 (s), 1169 (s), 1156 (m), 1090 (w), 1061

(w), 1044(w), 1035 (w), 1022 (w), 995 (m), 928 (w), 905 (w), 883

(w), 846 (w), 813 (m), 799 (w), 775 (w), 752 (s), 707 (w), 688 (m),

Attempted N-Boc Deprotection. All subsequent N-Boc depro-

tections produced a mixture of products with the use of TFA, HCl

1

and thermal conditions. These deprotections gave broad H NMR

1

670 (m), 653 (m), 604 (m), 592 (w), 574 (s), 559 (w), 544 (s); H

resonances that were unable to be further puriﬁed, indicating likely

decomposition. HRMS ESI was employed to examine the possible

products, which were assigned to a mixture of the following products:

mono-Boc deprotection, N-t-butylation, urea formation, and sub-

sequent combinations of these. Previously, we have been able to

perform this deprotection with concentrated HCl under microwave

conditions in a joint N-Boc deprotection and urea cleavage reaction;

this is the suggested method to acces primary amines from the N,N′-

di-Boc-protected amine-13 above.²⁸

NMR (CDCl₃, 500 MHz) δ 8.06 (d, J = 8.1 Hz, 1H, H5⁗), 7.93 (d, J

= 8.2 Hz, 2H, H1′ and H6′ or H1″ and H6″), 7.46 (d, J = 8.2 Hz, 2H,

H1′ and H6′ or H1″ and H6″), 7.31−7.18 (m, 6H, H3′, H5′, H3″,

H5″, H3‴, and H5‴), 7.15−7.10 (m, 1H, H7⁗), 7.02 (t, J = 7.5 Hz,

1H, H6⁗), 6.94 (t, J = 7.3 Hz, 1H, H4‴), 6.89−6.82 (m, 3H, H1‴,

H6‴ and H8⁗), 5.13 (d, J = 9.8 Hz, 1H, H3⁗), 4.93−4.84 (m, 1H,

H1), 4.52 (t, J = 8.5 Hz, 1H, H2_a), 4.28 (dd, J = 9.0, 5.9 Hz, 1H,

H2_b), 4.02 (d, J = 12.0 Hz, 1H, H2a⁗), 3.11 (d, J = 11.3 Hz, H2_b⁗),

2.43 (s, 3H, TsCH₃), 2.38 (s, 3H, TsCH₃), 1.36 (s, 9H, OtBu); ¹³C

NMR (CDCl₃, 126 MHz) δ 158.2 (C1‴), 150.8 (COOR), 146.3

(C8a⁗), 144.3 (C4′ or C4″), 143.7 (C4′ or C4″), 137.9 (C1′ or

C1″), 135.1 (C1′ or C1″), 129.9 (C3′ and C5′ or C3″ and C5″),

129.4 (C3′ and C5′, or C3″ and C5″, or C3‴ and C5‴), 128.9 (C3′

and C5′, or C3″ and C5″, or C3‴ and C5‴), 128.5 (C1′ and C6′ or

C1″ and C6″), 127.4 (C1′ and C6′ or C1″ and C6″), 127.1 (C5⁗),

126.7 (C7⁗), 121.8 (C4a⁗), 121.6 (C6⁗), 121.3 (C4‴), 117.3

(C8⁗), 114.8 (C1‴ and C6‴), 85.2 (-C(CH₃)₃), 65.9 (C2), 61.9

(C2⁗), 55.1 (C1), 52.1 (C3⁗), 28.0 (OtBu), 21.6 (2 × TsCH₃); MS

(ESI+) 701 (100%, [M + Na]⁺); HRMS (ESI+) calcd for

C₃₅H₃₈N₂NaO₈S₂701.1967, found 701.1981 [M + Na]⁺.

(2S,3S)-N²,N³-Dibenzyl-1,4-diphenoxybutane-2,3-diamine

(amine-9). Following general procedure 1, N,N′-dibenzyl 1,2-

bis(tosylamide) 9 (234 mg, 0.308 mmol) and Mg powder (379 mg,

15.6 mmol) were sonicated in MeOH (7.5 mL). The reaction mixture

was poured over EtOAc (100 mL) and ﬁltered through Celite. The

ﬁltrate was washed with H₂O (20 mL) and back-extracted with

EtOAc (3 × 50 mL). The combined organic fractions were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo to give the deprotected

amine-9 (126 mg, 90%) as a yellow gum. The product was stable for

more than 3 months in a desiccator, although it was observed to

decompose during acidic workups and completely decompose during

silica gel chromatography. [α²_D⁵] = −27.3 (c = 1.3, CH₂Cl₂); FTIR υ

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Note

3331 (br s), 3062 (w), 3028 (w), 2926 (br s), 2872 (br s), 1599 (m),

1587 (w), 1496 (s), 1454 (w), 1300 (w), 1242 (s), 1172 (w), 1153

(w), 1079 (w), 1034 (w), 882 (w), 817 (w), 753 (s), 692 (s), 510 (w)

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38−7.19 (m, 14H, H3′, H5′,

H3″, H5″, H2‴, H3‴, H4‴, H5‴, H6‴, H2⁗, H3⁗, H4⁗, H5⁗, and

H6⁗), 6.94 (t, J = 7.3 Hz, 2H, H4′ and H4″), 6.87 (d, J = 8.0 Hz, 4H,

H2′, H2″, H6′, and H6″), 4.18 (dd, J = 9.7, 3.8 Hz, 2H, H1_aand

H4_a), 4.04 (dd, J = 9.7, 3.9 Hz, 2H, H1_band H4_b), 3.93 (d, J = 13.1

Hz, 2H, benzyl CH₂), 3.80 (d, J = 13.2 Hz, 2H, benzyl CH₂), 3.20 (s,

2H, H2 and H3), 2.06 (br, 2H, NH); ¹³C NMR (126 MHz, CDCl₃) δ

158.6 (C1′ and C1″), 140.2 (C1‴ and C1⁗), 129.4 (C3′, C3″, C5′

and C5″), 128.4 (benzyl Ar−C), 128.2 (benzyl Ar−C), 127.0 (benzyl

Ar−C), 120.9 (C4′ and C4″), 114.5 (C2′, C2″, C6′, and C6″), 66.7

(C1 and C4), 57.3 (C2 and C3), 51.9 (benzyl CH₂); MS (ESI+) 453

(100%, [M + H]⁺); HRMS (ESI+) calcd for C₃₀H₃₃N₂O₂453.2542,

found 453.2553 [M + H]⁺.

1302 (w), 1243 (s), 1221 (s), 1173 (w), 1155(w), 1095 (w), 1079

(w), 1036 (w), 1016 (w), 834 (w), 825 (br), 754 (m), 692 (m), 510

1

(w) cm⁻¹; H NMR (CDCl₃, 500 MHz) δ 7.32−7.22 (m, 8H, H3′,

H3″, H5′, H5″, H3‴, H3⁗, H5‴, and H5⁗), 6.99−6.91 (m, 6H, H4′,

H4″, H2‴, H2⁗, H6‴, and H6⁗), 6.89−6.82 (m, 4H, H2′, H2″, H6′,

and H6″), 4.15 (dd, J = 9.5, 4.4 Hz, 2H, H1_aand H4_a), 4.03 (dd, J =

9.6, 4.4 Hz, 2H, H1_band H4_b), 3.89 (d, J = 13.1 Hz, 2H, benzyl

CH₂), 3.76 (d, J = 13.2 Hz, 2H, benzyl CH₂), 3.22−3.11 (m, 2H, H2

and H3), 2.04 (br s, 2H, NH); ¹³C NMR (CDCl₃, 126 MHz) δ

1

161.93 (d, J_CF= 244.6 Hz, C1‴ and C1⁗), 158.6 (C1′ and C1″),

4

3

136.08 (d, J_CF= 2.8 Hz, C4‴ and C4⁗), 129.69 (d, J_CF= 8.1 Hz,

C2‴, C2⁗, C6‴, and C6⁗), 129.5 (C3′, C3″, C5′ and C5″), 121.0

2

(C4′ and C4″), 115.15 (d, J_CF= 21.3 Hz, C3‴, C3⁗, C5‴, and

C5⁗), 114.5 (C2′, C2″, C6′ and C6″), 67.0 (C1 and C4), 57.3 (C3

and C4), 51.3 (benzyl CH₂); ¹⁹F NMR (CDCl₃, 377 MHz) δ −

115.80 (s); MS (ESI+) 489 (100%, [M + H]⁺); HRMS (ESI+) calcd

for C₃₀H₃₁F₂N₂O₂489.2354 found 489.2362 [M + H]⁺.

(2S,3S)-N²,N³-Bis(4-methoxybenzyl)-1,4-diphenoxybutane-2,3-

diamine (amine-10). Following general procedure 1, 1,2-bis-

(tosylamide) 10 (183 mg, 0.222 mmol) and Mg powder (273 mg,

11.2 mmol) were sonicated in MeOH (5.4 mL). After the completion

of the reaction, the suspension was poured over EtOAc (100 mL) and

ﬁltered through Celite. The ﬁltrate was washed with H₂O (20 mL),

and the aqueous phase was separated and back-extracted with EtOAc

(3 × 50 mL). The combined organic phases were dried (Na₂SO₄) and

concentrated in vacuo to give amine-10 (108 mg, 94%) as a white

gum. The product was stable to be storaged in a desiccator for >3

months, although it decomposed during mildly acidic workups.

Complete decomposition was observed during attempts to deprotect

the 4-methoxybenzyl with triﬂuoroacetic acid and during puriﬁcation

with silica gel chromatography. [α²_D⁵] = −52.2 (c = 0.72, CH₂Cl₂);

FTIR υ 3335 (br s), 3061 (w), 3030 (w), 2997 (w), 2931 (w), 2834

(w), 1611 (w), 1599 (m), 1586 (w), 1511 (m), 1463 (m), 1301 (w),

1243 (s), 1173 (w), 1107 (w), 1079 (w), 1035 (m), 883 (w), 817 (br

s), 754 (m), 692 (m), 511 (w) cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ

7.29−7.24 (m, 4H, H3′, H3″, H5′, and H5″), 7.23−7.19 (m, 4H,

H1‴, H1⁗, H6‴, and H6⁗), 6.97−6.92 (m, 2H, H4′ and H4″),

6.88−6.84 (m, 4H, H2′, H2″, H6′, and H6″), 6.83−6.79 (m, 4H,

H3‴, H3⁗, H5‴, and H5⁗) 4.19−4.11 (m, 2H, H1_aand H4_a), 4.05−

3.99 (m, 2H, H1_band H4_b), 3.86 (apr. d, J = 12.8 Hz, 2H, benzyl

CH₂), 3.77 (s, 6H, OCH₃), 3.73 (apr. d, J = 12.9 Hz, 2H, benzyl

CH₂), 321−3.13 (m, 2H, H2 and H3), 1.95 (br s, 2H, NH); ¹³C

NMR (CDCl₃, 126 MHz) δ 158.7 (C1′ and C1″ or C4″ and C4‴),

158.6 (C1′ and C1″ or C4″ and C4‴), 132.6 (C1‴ and C1⁗), 129.4

(C3′, C3″, C5′, and C5″ or C1‴, C1⁗, C6‴, and C6⁗), 129.3 (C3′,

C3″, C5′, and C5″ or C1‴, C1⁗, C6‴, and C6⁗), 120.8 (C4′ and

C4″), 114.6 (C2′, C2″, C6′, and C6″), 113.8 (C3‴, C3⁗, C5‴, and

C5⁗), 67.1 (C1 and C4), 57.3 (C2 and C3), 55.2 (OCH₃), 51.5

(benzyl CH₂); MS (ESI+) 513 (100%, [M + H]⁺); HRMS (ESI+)

calcd for C₃₂H₃₇N₂O₄513.2753, found 513.2750 [M + H]⁺.

(2S,3S)-N²-Benzyl-N³-(4-ﬂuorobenzyl)-1,4-diphenoxybutane-2,3-

diamine (amine-12). Following general procedure 1, 1,2-bis-

(tosylamide) 12 (76.7 mg, 0.0985 mmol) and Mg powder (124

mg, 5.10 mmol) were sonicated in MeOH (2.5 mL). After the

completion of the reaction, the suspension was poured over EtOAc

(100 mL) and ﬁltered through Celite. The ﬁltrate was washed with

H₂O (20 mL), and the aqueous phase separated and back-extracted

with EtOAc (3 × 50 mL). The combined organic phases were dried

(Na₂SO₄) and concentrated in vacuo to aﬀord amine-12 (47 mg,

98%) as a white gum. [α²_D⁵] = +126.6 (c = 1.9, CH₂Cl₂); FTIR υ 3063

(w), 3030 (w), 2926 (m), 2871 (w), 2855 (w), 1599 (m), 1587 (w),

1508 (w), 1496 (s), 1463 (w), 1465 (w), 1242 (s), 1222 (w), 1172

(w), 1154 (w), 1079 (w), 1035 (m), 822 (br s), 753 (s), 692 (m),

1

509 (w); H NMR (CDCl₃, 500 MHz) δ 7.33−7.22 (m, 11H, H3′,

H3″, H5′, H5″, H2‴, H6‴, H2⁗, H3⁗, H4⁗, H5⁗, and H6⁗),

6.99−6.92 (m, 4H, H4′, H4″, H3‴, and H5‴), 6.89−6.844 (m, 4H,

H2′, H2″, H6′, and H6″), 4.20−4.13 (m, 2H, H1_aand H4_a), 4.07−

4.00 (m, 2H, H1_band H4_b), 3.96−3.87 (m, 2H, 4-F-PhCH₂and

PhCH₂), 3.83−3.73 (m, 2H, 4-F-PhCH₂and PhCH₂), 3.22−3.14 (m,

2H, H2 and H3) 2.11 (br, 2H, NH); ¹³C NMR (CDCl₃, 126 MHz) δ

161.9 (d, ¹J_CF= 244.7 Hz, C4‴), 158.6 (C1′ and C1″), 140.3 (C1⁗),

4

3

136.0 (d, J_CF= 2.7 Hz, C1‴), 129.7 (d, J_CF= 8.1 Hz, C2‴ and

C6‴), 129.5 (C3′, C3″, C5′ and C5″), 128.4 (benzyl Ar−C), 128.1

(benzyl Ar−C), 127.0 (benzyl Ar−C), 120.9 (C4′ and C4″), 115.1

2

(d, J_CF= 21.2 Hz, C3‴ and C5‴), 114.4 (C2′, C2″, C6′ and C6″),

66.9 (C1 or C4), 66.6 (C1 or C4), 57.4 (C2 or C3), 57.2 (C2 or C3),

52.0 (4-F-PhCH₂or PhCH₂), 51.2 (4-F-PhCH₂or PhCH₂); MS (ESI

+) 471 (100%, [M + H]⁺); HRMS (ESI+) calcd for C₃₀H₃₂FN₂O₂

471.2448, found 471.2449 [M + H]⁺.

(2S,3S)-N²,N³-Diethyl-1,4-diphenoxybutane-2,3-diamine

(amine-8). Following general procedure 1, 1,2-bis(tosylamide) 8 (27

mg, 0.042 mmol) and Mg powder (61 mg, 2.5 mmol) were sonicated

in MeOH (1.2 mL). After the completion of the reaction, the

suspension was poured over EtOAc (50 mL) and ﬁltered through

Celite. The ﬁltrate was washed with H₂O (10 mL), and the aqueous

phase separated and back-extracted with EtOAc (3 × 20 mL). The

combined organic phases were dried (Na₂SO₄) and concentrated in

vacuo to give amine-8 (12 mg, 80%) as a clear gum. The compound

(2S,3S)-N²,N³-Bis(4-ﬂuorobenzyl)-1,4-diphenoxybutane-2,3-dia-

mine (amine-11). Following general procedure 1, 1,2-bis-

(tosylamide) 11 (71 mg, 0.089 mmol) and Mg powder (111 mg,

4.58 mmol) were sonicated in MeOH (2.15 mL). After the

completion of the reaction, the suspension was poured over EtOAc

(100 mL) and ﬁltered with Celite. The ﬁltrate was washed with H₂O

(20 mL), and the aqueous phase separated and back-extracted with

EtOAc (3 × 50 mL). The combined organic phases were dried

(Na₂SO₄) and concentrated in vacuo to give amine-11 (33 mg, 76%)

e1

was found to decompose during acidic workups. [α²_D⁵] = +7.6 (c =

1.2, CH₂Cl₂); FTIR υ 3327 (br s), 3061 (w), 3039 (w), 2964 (m),

2922 (m), 2870 (w), 2850 (w), 1775 (w), 1599 (s), 587 (m), 1516

(s), 1516 (s), 1464 (m), 1382 (w), 1344 (w), 1300 (w), 1242 (s),

1172 (w), 1153 (w), 1123 (w), 1079 (w), 1035 (m), 947 (w), 881

d1

as a white gum, which upon standing for 1 h turned to a white solid.

The product was able to be stored in a desiccator for more than 3

months. Complete decomposition was observed during puriﬁcation

with silica gel chromatography, and partial decomposition observed

only when a high concentration of the hydrochloride salt was

neutralized in acid or base extractions (see the section below for

details). The compound was found to be stable to neutral alumina but

was not able to be puriﬁed by this method, and insolubility in most

solvents suitable for reverse phase (C18) chromatography made this

technique unusable. mp 42−44 °C; [α²_D⁵] = −33.4 (c = 0.52,

CH₂Cl₂); FTIR υ 3281 (br s), 3065 (w), 3040 (w), 2926 (br s), 2850

(w), 2821 (w), 1600 (s), 1586 (w), 1510 (s), 1496 (s), 1417 (w),

1

(w), 816 (w), 753 (s), 691 (m), 509 (w); H NMR (CDCl₃, 400

MHz) δ 7.31−7.23 (m, 4H, ArH), 6.99−6.92 (m, 6H, ArH), 4.16

(dd, J = 9.6, 4.0 Hz, 2H, H1_aand H4_a), 4.02 (dd, J = 9.6, 4.0 Hz, 2H,

H1_band H4_b), 3.11 (s, 4H, H2 and H3), 2.91−2.78 (m, 2H, H1_a‴

and H1_a⁗), 2.74−2.62 (m, H1_b‴ and H1_b⁗), 2.07 (br, 2H, NH),

1.13 (t, J = 7.1 Hz, 6H, H2‴ and H2⁗); ¹³C NMR (CDCl₃, 101

MHz) δ 158.8 (C1′ and C1″), 129.5 (ArC), 120.9 (ArC), 114.6

(ArC), 66.8 (C1 and C4), 58.1 (C2 and C3), 42.3 (C1‴ and C1⁗),

15.6 (C2‴ and C2⁗); MS (ESI+) 329 (100%, [M + H]⁺); HRMS

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Note

(ESI+) calcd for C₂₀H₂₇N₂NaO₂351.2048, found 351.2041 [M +

H]⁺.

into EtOAc (100 mL) with vigorous shaking, then water (10 mL) was

addedwith vigorous shaking. The mixture was ﬁltered through Celite,

the layers were separated, and the aqueous layer was back-extracted

(2S,3S)-1,4-Bis(hexyloxy)butane-2,3-diamine (amine-6). Follow-

ing general procedure 5, Li metal (17.1 mg, 2.46 mmol) was added

portion-wise to a solution of 1,2-bis(tosylamide) 6 (50.0 mg, 0.08375

mmol) in ethylenediamine (0.17 mL, 2.55 mmol) and n-propylamine

(0.5 mL). The dark blue solution was poured over crushed ice

(caution! gas evolution) and allowed to melt, then diethyl ether (20

mL) added to the solution. The diethyl ether was washed with water

(2 × 10 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue

was subjected to neutral aluminum oxide chromatography (16 g of

alumina) by dry loading the product (1 g of alumina) using CHCl₃

and eluting with acetone/hexanes (3%, 100 mL; 5%, 150 mL; and

10%, 200 mL). The product was unable to be visualized by TLC

analysis through UV light or with stains (KMnO₄, CAM, ninhydrin,

and iodine/silica gel). Therefore, all fractions from the column

chromatography were evaporated separately with compressed air over

with ethyl acetate (3 × 50 mL). The combined organic extracts were

h1

washed with brine (50 mL), dried (Na₂SO₄),

ﬁltered, and

concentrated in vacuo. The residue was dissolved in MeCN (20

mL) and washed with hexanes (3 × 100 mL), and the MeCN layer

was dried (Na₂SO₄) and concentrated in vacuo to give the

deprotected amine-16 (56 mg, 78%) as a yellow gum. [α²_D⁵] =

−227.5 (c = 0.10, CH₂Cl₂); FTIR υ 3399 (m), 2881 (w), 1608 (m),

1500 (s), 1275 (m), 1207 (m), 1112 (w), 1044 (w), 743 (m) cm⁻¹;

¹H NMR (CDCl₃, 500 MHz) δ 6.84−6.75 (m, 4H, H6, H6′, H8 and

H8′), 6.70−6.60 (m, 4H, H5, H5′, H7 and H7′), 4.26−4.11 (m, 4H,

H2_a, H2_a′, H2_b, and H2_b′), 3.90 (br s, 2H, NH), 3.51 (s, 2H, H3 and

H3′); ¹³C NMR (CDCl₃, 126 MHz) δ 144.0 (C8a and C8a′), 132.5

(C4a and C4a′), 122.0 (C6 and C6′), 119.1 (C7 and C7′), 117.0 (C8

and C8′) 116.1 (C5 and C5′), 65.6 (C2 and C2′), 50.8 (C3 and

C3′); MS (ESI+) 269 (100%, [M + H]⁺); HRMS (ESI+) calcd for

C₁₆H₁₇N₂O₂269.1301, found 269.1290 [M + H]⁺.

1

3 d. The ﬁrst fractions contained an unknown oil (δ 1.26 by H

NMR), and later fractions contained the product as a clear oil mixture

(∼20 mL after acetone/hexanes (5%) was used). The product was

dissolved in CHCl₃, concentrated in vacuo, redissolved and

evaporated from CHCl₃(2 × 50 mL), and dried under high vacuum

(48 h). CDCl₃was added (2 × 1 mL) to aid in the evaporation of

acetone. This gave amine-6 (7.3 mg, 30% crude) as a clear yellow

gum that still contained trace amounts of acetone and silicon grease

and could not be further puriﬁed. [α²_D⁵] = +6.9 (c = 0.35, CH₂Cl₂);

FTIR υ 3300 (br s), 2958 (s), 2928 (s), 2855 (s), 1744 (w), 1668

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00359.

■

sı

NMR spectra for all synthesized compounds, computa-

tional data, X-ray structure data, general reaction notes,

and supplementary experimental data for modiﬁed

procedures of known compounds (PDF)

1

(w), 1466 (m), 1378 (w), 1262 (w), 111 (s), 799 (w); H NMR

(CDCl₃, 400 MHz) (mixture of rotamers) δ 3.61−3.31 (m, 6H, H1,

H2, H3 and H4), 2.24 (br s, 4H, NH₂), 1.70−1.47 (m, 4H, H1′ and

H1″), 1.45−1.16 (m, 16H, H2′, H2″, H3′, H3′′, H4′, H4′′, H5′, and

H5′′), 0.98−0.76 (m, 6H, H6′ and H6″); ¹³C NMR (CDCl₃, 101

Accession Codes

CCDC 1998667−1998668 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

f1

MHz, ¹³C DEPTQ-135) (mixture of rotamers) δ 71.6 (C1 and C4),

71.5 (C1′ and C1″), 31.7 (C2 and C2″ or C4′ and C4″), 29.7/29.6/

29.5 (C4′ and C4″ or C2 and C2″), 25.0/25.8 (C3′ and C3″), 22.6

(C5′ and C5″), 14.0 (C6′ and C6″); MS (ESI+) 289 (87%, [M +

H]⁺); HRMS (ESI+) calcd for C₁₆H₃₇N₂O₂289.2855, found

289.2861 [M + H]⁺.

(3R,4R)-N³,N⁴-Diethyl-1,6-diphenylhexane-3,4-diamine (amine-

14). Following general procedure 1, 1,2-bis(tosylamide) 14 (46 mg,

0.073 mmol) and Mg powder (87 mg, 3.6 mmol) were sonicated in

MeOH (1.8 mL). After the completion of the reaction, the suspension

was poured over EtOAc (25 mL) and ﬁltered through Celite. The

ﬁltrate was washed with H₂O (10 mL), and the aqueous phase

separated and back-extracted with H₂O (2 × 10 mL). The combined

organic phases were dried (Na₂SO₄) and concentrated in vacuo, and

the residue was dissolved in MeCN (∼50 mL) assisted by sonication

and heat due to its low solubility. The MeCN solution was washed

with hexanes (3 × 50 mL) and concentrated in vacuo to give amine-

14 (19 mg crude, 81% crude) as a white gum that contained an

unknown impurity. [α²_D⁵] = −6.75 (c = 0.62, CH₂Cl₂); FTIR υ 3266

(br s), 3085 (w), 3061 (w), 3026 (w), 2963 (m), 2930 (m), 2862

(br), 1770 (w), 1725 (w), 1688 (w), 1602 (m), 1496 (s), 1454 (w),

1380 (w), 1335 (w), 1287 (s), 1261 (w), 1201 (w), 1155 (br s), 1088

(s), 863 (s), 799 (s), 720 (s), 700 (w); ¹H NMR (CDCl₃, 400 MHz)

δ 7.39−7.13 (m, 10 H, ArH), 3.00−2.60 (m, 8H, alkyl H), 2.12−1.90

(m, 4H, alkyl H), 1.26−1.12 (m, 6H, H1′ and H1″); ¹³C NMR

(CDCl₃, 101 MHz,) δ 140.5 (C4‴ and C4⁗), 128.7 (ArC), 128.4

(ArC), 126.5 (ArC), 58.6 (C3 and C4), 41.1 (alkyl CH₂), 32.2 (alkyl

CH₂), 31.2 (alkyl CH₂), 13.8 (C1′ and C1″); MS (ESI+) 325 (100%,

[M + H]⁺); HRMS (ESI+) calcd for C₂₂H₃₃N₂325.2644, found

325.2646 [M + H]⁺.

AUTHOR INFORMATION

Corresponding Author

■

Paul A. Keller − School of Chemistry and Molecular

Bioscience, Molecular Horizons,, University of Wollongong

and Illawarra Health and Medical Research Institute,

Wollongong, NSW 2522, Australia; orcid.org/0000-

0003-4868-845X; Email: keller@uow.edu.au

Authors

Jayden J. Gaston − School of Chemistry and Molecular

Bioscience, Molecular Horizons,, University of Wollongong

and Illawarra Health and Medical Research Institute,

Wollongong, NSW 2522, Australia; orcid.org/0000-

0002-8107-1841

Andrew J. Tague − School of Chemistry and Molecular

Bioscience, Molecular Horizons,, University of Wollongong

and Illawarra Health and Medical Research Institute,

Wollongong, NSW 2522, Australia; orcid.org/0000-

0003-0561-4629

Jamie E. Smyth − School of Chemistry and Molecular

Bioscience, Molecular Horizons,, University of Wollongong

and Illawarra Health and Medical Research Institute,

Wollongong, NSW 2522, Australia

Nicholas M. Butler − School of Chemistry and Molecular

Bioscience, Molecular Horizons,, University of Wollongong

and Illawarra Health and Medical Research Institute,

Wollongong, NSW 2522, Australia; orcid.org/0000-

0002-6479-7819

(3S,3′S)-3,3′,4,4′-Tetrahydro-2H,2′H-3,3′-bibenzo[b][1,4]oxazine

(amine-16). General procedure 1 was adapted to the following

g1

method: to a ﬂask containing ﬁnely powdered 1,2-bis(tosylamide)

16¹¹(155 mg, 0.268 mmol) waere added Mg powder (649.1 mg,

26.71 mmol) and THF/MeOH (25%, 17.3 mL). The ﬂask was

sonicated with vigorous shaking and rotated by hand every 30 s until

the full dissolution of the white solid was observed. Then, sonication

was continued for a total of 45 min. The reaction mixture was poured

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Note

Anthony C. Willis − School of Chemistry, The Australian

National University, Canberra, ACT 2601, Australia

Nico van Eikema Hommes − Computer Chemistry Center,

Department of Chemistry and Pharmacy, Friedrich-

due to the reaction forming an unstirrable slurry at low

temperatures from the precipitation of the potassium

phenolate. All phenoxide and alkoxide ring openings were

therefore performed at room temperature.

h

Alexander Universität Erlangen-Nu

Germany

̈

rnberg, 91052 Erlangen,

A modiﬁcation to the number of equivalents of aniline from

our previous procedure was made due to formation of the

mono-ring opened product. See the reported procedure for

details.

Haibo Yu − School of Chemistry and Molecular Bioscience,

Molecular Horizons,, University of Wollongong and Illawarra

Health and Medical Research Institute, Wollongong, NSW

2522, Australia; orcid.org/0000-0002-1099-2803

I

The product was unable to be N-alkylated with K₂CO₃at rt,

1

and only decomposition was observed by H NMR analysis

Timothy Clark − Computer Chemistry Center, Department of

(>16 TsCH₃resonances). Attempted tetra-ethylation using

general procedure 2b with 5 equiv of NaH and 12 equiv of

ethyl iodide did not aﬀord the product, and signiﬁcant

Chemistry and Pharmacy, Friedrich-Alexander Universität

Erlangen-Nurnberg, 91052 Erlangen, Germany;

̈

orcid.org/0000-0001-7931-4659

1

decomposition was observed by H NMR analysis.

j

Repeating this procedure using 50 mg of (R,R)-biaziridine 1

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00359

gave the pure product as an amber oil in an 80% yield after

aqueous workup with no chromatography and a purity

1

identical to that of the large-scale reaction as analyzed by H

Notes

NMR spectroscopy.

The authors declare no competing ﬁnancial interest.

k

Stirring the reaction for longer than the time indicated (∼3 d)

did not cause any of 18 to be further consumed, as monitored

ACKNOWLEDGMENTS

1

■

by H NMR analysis.

l

1

We acknowledge the Australian Government for the award of

an Australian Government Research Training Program Award

to J.G. We also thank the University of Wollongong, School of

Chemistry and Molecular Bioscience, the Australian National

University, and the Friedrich-Alexander Universität for their

support.

No H NMR assignments were made from the crude sample

m

No ¹³C NMR assignments were made from the crude

sample.

n

A broad carbon resonance was observed for NCH₂CH₃,

which indicates that rotamers are present as identiﬁed in

compound 8 and previously reported.²⁹This explains why

1

some H NMR resonances appear broad.

o

As identiﬁed in compound 8 and previously reported,²⁹

ADDITIONAL NOTES

■

a

rotamers can be observed by NMR analysis within these

Only a portion of the material from S1 was used due to safety

diamine scaﬀolds. For 15, a broad carbon resonance in the ¹³

C

concerns over the amount of LiAlH₄. It is recommended that

extreme care be taken during addition of the ester to the

LiAlH₄suspension, which causes signiﬁcant hydrogen gas

evolution.

NMR spectra was observed for the NCH₂CH₃, indicating that

15 is rotameric.

p

Following this procedure using only 20 mg of 1,2-

b

bis(tosylamide) and 2.5 equiv of NaH gave a 100% conversion

as analyzed by ¹H NMR spectroscopy and TsCH₃integration.

Following this procedure using 2.2 equiv of NaH with 300 mg

of 1,2-bis(tosylamide) gave a ∼50% conversion as analyzed by

¹H NMR spectroscopy and TsCH₃integration, indicating that

a greater excess of NaH is required on scaleup.

Care must be taken to ensure that fresh and unoxidized

magnesium is used. The use of old magnesium was found to

produce the starting material in the case of 16 and

decomposition in other tosyl protected amines.

c

The use of MgSO₄as a drying agent gave low yields for 16,

possibly due to binding of the product to magnesium.

Considering this result, all further compounds were dried

with Na₂SO₄.

Preliminary results show that amines from this reaction were

suﬃciently pure to be utilized in subsequent transformations.

q

Continued heating under general procedure 2a for 24 h

resulted in complete decomposition, with only N-benzyl-4-

methylbenzenesulfonamide being isolated. Stirring at room

temperature under general procedure 2a gave the starting

material and decomposition. The formation of N-benzyl-4-

methylbenzenesulfonamide is discussed in the section on

decomposition (see Section S7 of the Supporting Informa-

tion).

d

e

General procedure 2a was found to be inferior to general

procedure 2b for alkylation due to the highly inconsistent

yields caused by excess NaH, which promoted decomposition.

The use of fresh NaH with molar equivalents promoted

reaction consistency with smaller amounts of decomposition,

and only general procedure 2b was utilized for subsequent

alkylations after this discovery.

r

4-Methoxybenzyl alcohol was found to form by the hydrolysis

of 4-methoxybenzyl chloride in the presence of H₂O and base.

Furthermore, the benzyl alcohol impurity was inseparable from

the target product by silica gel chromatography and

recrystallization. By preparing fresh 4-methoxybenzyl chloride

and storing crude reaction samples in a vacuum-sealed

desiccator (to exclude water), it is possible to prevent the

slow hydrolysis of the 4-methoxybenzyl chloride and remove

the diﬃculty in puriﬁcation.

f

Signiﬁcant diﬃculties were encountered in this study due to

low-quality Sm that required changing suppliers and

attempting SmI₂generation through various methods, a

diﬃculty which has been previously addressed.¹³The method

that is reported here worked for only one batch of old (years)

Sm metal stored in a desiccator; a second fresh batch

purchased under an argon sealed ampule, and used

immediately, would not generate SmI₂under any reported

method.

s

The use of 10 equiv of NaH (211.6 mg, 5.29 mmol, 60% w/

w), 1,2-bis(tosylamide) (299 mg, 0.514 mmol), tetrabutylam-

monium iodide (59.9 mg, 0.162 mmol), and 4-ﬂuorobenzyl

chloride (0.37 mL, 3.1 mmol) in DMF (6.0 mL) with heating

for 3.5 h provided mostly decomposition. However, the crude

Performing the reaction at −10 °C as previously reported¹¹

g

led to decomposition and trace amounts of product. This was

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Note

monobenzyl that contained 4-ﬂuorobenzyl chloride (112.5 mg

crude, 29%, 101.8 mg of tosylamide) and the pure dibenzyl

product (26%, 106.6 mg) were still isolated using the same

puriﬁcation.

was observed even after standing for a week in CDCl₃in an

NMR tube.

While the resonances for H2 and H3 were observed in the

f1

¹H NMR spectrum, resonances for C2 and C3 were unable to

be observed by an analysis of the ¹³C NMR spectrum, possibly

due to signal broadening from rotamers as experienced with

compound 8 and reported previously in similar compounds.²⁹

All other data were in accordance with the presented structure,

anda calculation of the ¹³C NMR spectra using DFT gavea

good correlation to experimental data (R²= 0.9935). The C2

and C3 resonances were calculated to be at 56.2 and 52.5 ppm,

respectively. The carbon resonance assignments were made

based upon the calculated chemical shifts by DFT (see Figure

S1 and Table S2).

t

1

Mass and molar quantity were corrected based on the H

NMR spectroscopy analysis.

u

Mass of the 1,2-bis(tosylamide) 19 was calculated by the

analysis of the crude NMR spectrum compared with the

spectrum of 4-ﬂuorobenzyl chloride (9.3 mg, 0.065 mmol) that

was present.

v

No alkylation from the residual 4-ﬂuorobenzyl chloride was

1

observed by H NMR analysis in crude reaction mixtures or

after puriﬁcation.

w

As identiﬁed within similar compounds in previous reports,²⁹

g1

An adaptation of general procedure 1 was required due to

rotamers can be observed by an analysis of NMR spectra

within the diamine scaﬀolds. Two broad carbon resonances in

the ¹³C NMR spectrum were observed for the NCH (δ 57.8,

H2 and H3) and N(CH₂)CH₃(δ 41.5, H1‴ and H1⁗),

indicating that the compound is rotameric.

the high insolubility of the cyclic 1,2-bis(tosylamide) 16 in

MeOH. This was solved by using THF as a cosolvent in a 1:3

THF/MeOH ratio,³a twofold dilution of the 1,2-bis-

(tosylamide), using 100 equiv of Mg powder (to maintain

[Mg] = 50 mg mL⁻¹), and regular vigorous shaking of the ﬂask

by hand to ensure thorough mixing.

x

Alkyl proton resonances are broad due to the compound

being rotameric, as identiﬁed in 8 and in previous reports.²⁹

h1

y

The use of MgSO₄as a drying agent was found to give very

All broad carbon resonances are due to the compound being

rotameric, as identiﬁed in 8 and in previous reports.²⁹

low yields, likely due to binding of the product to MgSO₄. It is

not recommended to attempt any of these procedures with the

use of MgSO₄. Therefore, Na₂SO₄should be employed.

z

Care should be taken to use anhydrous DMSO due

incomplete cyclization and decomposition occurring with wet

DMSO. See the reported procedure for details.

a1

REFERENCES

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■

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c1

The attempted removal of the N-tosyl protecting groups

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by chromatography.

d1

Silicon grease could be removed from amine-11 using a very

dilute acid/base extraction process. Amine-11 (11 mg) in

diethyl ether (10 mL) was extracted with 5.0 M HCl (3 × 33

mL). The combined acidic extracts were basiﬁed with 10%

NaOH to pH 12 and then extracted with CH₂Cl₂(3 × 100

mL). The combined extracts were concentrated in vacuo,

dissolved in MeCN (20 mL), which was assisted by heating

and sonication, washed with hexanes (3 × 100 mL), dried

(Na₂SO₄), ﬁltered, and evaporated in vacuo. Careful cleaning

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bis(tosylamide) starting material makes the above procedure

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led to more decomposition during acid/base extraction.

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