doi.org/10.26434/chemrxiv.14135645.v1

Ozone-Mediated Amine Oxidation and Beyond: A Solvent Free,Flow-Chemistry ApproachEric Skrotzki, Jaya Kishore Vandavasi, Stephen Newman

Submitted date: 01/03/2021 • Posted date: 02/03/2021Licence: CC BY-NC-ND 4.0Citation information: Skrotzki, Eric; Vandavasi, Jaya Kishore; Newman, Stephen (2021): Ozone-MediatedAmine Oxidation and Beyond: A Solvent Free, Flow-Chemistry Approach. ChemRxiv. Preprint.https://doi.org/10.26434/chemrxiv.14135645.v1

Ozone is a powerful oxidant, most commonly used for oxidation of alkenes to carbonyls. The synthetic utility ofother ozone-mediated reactions is hindered by its high reactivity and propensity to over-oxidize organicmolecules, including most solvents. This challenge can largely be mitigated by adsorbing both substrate andozone onto silica gel, providing a solvent-free oxidation method. In this manuscript, a flow-based packed bedreactor approach is described that provides exceptional control of reaction temperature and time of thisreaction to achieve improved control and chemoselectivity over this challenging reaction. A powerful methodto oxidize primary amines into nitroalkanes is achieved. Examples of pyridine, C–H bond, and areneoxidations are also demonstrated, confirming the system is generalizable to diverse ozone-mediatedprocesses.

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Ozone-Mediated Amine Oxidation and Beyond: A Solvent Free, Flow-Chemistry Approach

Eric A. Skrotzki, Jaya Kishore Vandavasi, Stephen G. Newman*

Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10

Marie-Curie, Ottawa, Ontario K1N 6N5, Canada.

ABSTRACT: Ozone is a powerful oxidant, most commonly used for oxidation of alkenes to carbonyls. The synthetic utility of other

ozone-mediated reactions is hindered by its high reactivity

and propensity to over-oxidize organic molecules, includ-

ing most solvents. This challenge can largely be mitigated

by adsorbing both substrate and ozone onto silica gel,

providing a solvent-free oxidation method. In this manu-

script, a flow-based packed bed reactor approach is de-

scribed that provides exceptional control of reaction temp

erature and time of this reaction to achieve improved con-

trol and chemoselectivity over this challenging reaction. A

powerful method to oxidize primary amines into nitroal-

kanes is achieved. Examples of pyridine, C–H bond, and

arene oxidations are also demonstrated, confirming the sys-

tem is generalizable to diverse ozone-mediated processes.

□ Introduction Ozone is an extremely powerful oxidizing agent, capable of

reacting with a wide array of organic and inorganic compounds.

This high reactivity allows ozone to act as a powerful disinfect-

ant, and combined with UV irradiation, is a common and effec-

tive method to sterilize drinking water. In organic synthesis, this

ability of ozone to exhaustively oxidize a broad range of func-

tional groups leads to challenges in chemoselectivity. The most

often used application comes from the oxidation of alkenes.1

The popularity of this reaction spawned further investigations

into ozone’s synthetic usefulness, but no other developed

method has thus far enjoyed the wide applicability that was af-

forded to alkene ozonolysis. While many other functional

groups can be oxidized by ozone, these reactions are slower and

are thus more susceptible to chemoselectivity issues. In other

words, the lack of control over ozone’s extreme reactivity often

results in substrate overoxidation and degradation. This is un-

fortunate, since ozone is among the most atom economical oxi-

dizing agents, usually prepared from molecular oxygen and pro-

ducing O2 as the only waste product.

While not nearly as popular or thoroughly explored as ozo-

nolysis, other synthetic applications of ozone have been discov-

ered and used. For instance, tertiary C-H bond hydroxylation,2

synthesis of N-oxides from pyridines,3 and the transformation

of arenes into carboxylic acids4 have been described. One par-

ticularly interesting application of ozone is in the reaction with

amines. While it was previously thought that ozone degrades

primary amines,5,6 later evidence demonstrated that carefully

chosen conditions could give detectable quantities of nitroal-

kane products.7 These substrates can act as versatile intermedi-

ates for further derivatization, and can be readily converted into

Scheme 1: Evolution of amine ozonation strategies over time

most other functional groups in a handful of steps.8 Existing

means of performing this amine oxidation most commonly in-

volve hazardous reagents such as hypoflourous acid9 or Caro’s

acid,10 both of which present a serious threat of explosion and

injury if mishandled in a lab setting. Less hazardous reagents

for amine oxidation include organic peroxides such as m-

CPBA11 or dimethyldioxirane.12 Less reactive hydrogen perox-

ide can be coerced to perform this transformation as well, but

this usually requires metal catalysts such as tungsten or rhe-

nium.13–15 Ozone-mediated amine oxidation has the potential to

be an appealing alternative to these methods, yet .

Initial reports on ozone-mediated amine oxidation in organic

solvents note moderate yields and formation of a wide range of

byproducts resulting from side chain oxidation or decomposi-

tion via radical or carbocation intermediates (Scheme 1a).7,16–18

Furthermore, the authors found that solvent selection played a

key role in byproduct distribution and selectivity of the reaction.

Halogenated solvents such as chloroform gave the best yields

and product selectivity, but also formed phosgene gas when de-

graded by ozone. Less hazardous solvent choices such as meth-

anol or pentane reacted more with ozone and gave a wider range

of byproducts and lower yields.

Towards overcoming issues associated with solvent degra-

dation in challenging ozone-mediated oxidations, Mazur et al.

developed a strategy to adsorb substrates onto silica gel to act

as a solid matrix (Scheme 1b).19 In many ways, silica is an ideal

solvent-replacement: it is inexpensive, reusable, inert to ozone,

and is able to adsorb ozone more efficiently than most organic

solvents, particularly at cryogenic temperatures.20,21 With this

approach, oxidation of C–H bonds to form alcohols or ketones22

and oxidation of amines to nitroalkanes were reported with im-

proved yields and selectivity compared to use of organic sol-

vents.19 While this represented a substantial improvement over

previously reported liquid-phase oxidations, there are still many

limitations that have kept this chemistry from being used. One

such limitation lies in the lack of fine control over the reaction

conditions in this solid/gas biphasic reaction. Given the aggres-

sive nature of ozone, dialing in a specific contact time at a spe-

cific temperature is important but challenging in the batch sys-

tem. For example, the described procedure involves blowing

ozone gas over the cryogenically cooled silica gel for a set

amount of time, then holding for another set of time before

warming to room temperature.

We hypothesized that the inherent lack of control in this

batch oxidation procedure is responsible for the narrow scope

and lack of broader use of this method. Furthermore, the reac-

tion can be challenging to scale in a controlled manner, since

the amount of time required to saturate the silica gel with ozone

will increase in large-scale reactions, increasing the risk of sub-

strate degradation by overoxidation. Flow chemistry is a well-

established technology for improving reproducibility, enhanc-

ing mass/heat transfer, and providing finer control over process

parameters compared to batch. In addition, it has been previ-

ously established that ozone-mediated reactions can be scaled

up in flow while still minimizing associated safety risks.23 For

these reasons, we proposed that a flow system would be ideal

for performing underutilized ozone-mediated oxidation reac-

tions. While several powerful oxidation procedures have been

developed since this field’s inception, ozone remains an appeal-

ing inexpensive and atom economical oxidant. Herein, we pre-

sent a flow reactor platform designed to harness the synthetic

power of ozone and tempering it with fine levels of control to

perform a series of challenging oxidations (Scheme 1c). A fo-

cus is made on the oxidation of amines to nitroalkanes, with

examples of pyridine, C-H bond, and arene oxidation demon-

strating that the system is general and capable of a range of

transformations.

□ Results and Discussion We set out to design a reactor to gain control over the be-

havior and reactivity of ozone. In the batch system, silica gel

and adsorbed substrate are chilled to cryogenic temperatures,

saturated with O3, and allow to age for an appropriate amount

of time before stopping the O3 stream and warming to room

temperature. We proposed that a packed column reactor would

allow more precise control. Controlling temperature, saturating

the system with O3, and terminating the reaction by flushing

with O2 may be achieved more efficiently due to the compact

size of the system and the improved contact between the gas

and solid phases in the column relative to a flask. Given the high

reactivity of ozone and the propensity of organic molecules to

undergo overoxidation, this added aspect of control and preci-

sion could lead to improved chemoselectivity and functional

group tolerance.

In our reactor design, reactant is adsorbed onto silica gel and

packed into a column (Figure 1a). The column is connected to

a Vapourtec cooling module, chilled, and exposed to a stream

of ozone. After around 15 seconds, the silica gel gains a blue

tinge, indicative of saturation (Figure 1b). After the desired re-

action time, the ozone generator is turned off so that only oxy-

gen flows through the column. The blue colour fades within 5

seconds, leaving the newly formed product (often yellow in

color) behind on the silica gel (Figure 1c). The reactor is al-

lowed to warm to room temperature before the silica gel is col-

lected and the product is extracted from the surface.

Figure 1: a) Immobilized amine before reaction. b) Reaction in progress with

adsorbed ozone. c) Product adsorbed onto silica gel after reaction completion.

For the oxidation of amines, optimal reaction conditions were

identified with a reaction temperature of -60 °C and a reaction

time of 15 minutes. Longer reaction times resulted in decompo-

sition of the product, while shorter times resulted in large

amounts of recovered starting material, highlighting the sensi-

tivity of the reaction to over- and under-oxidation (Table S1).

With these optimized conditions, the scope of the reaction of

ozone with various silica-suspended amines was investigated

(Error! Reference source not found.). Amines situated on pri-

mary, secondary, and tertiary alkyl chains were effectively con-

verted to nitroalkanes in moderate to good yields (2a-c).

Amines bearing electron-neutral and electron-deficient aro-

matic rings were cleanly oxidized with no evidence of ring ox-

idation (2d-f). When electron rich aromatic rings were at-

tempted no product was detected, likely due to ring oxidation

and degradation. Esters and acetal groups were both tolerated

admirably under the reaction conditions and products could be

isolated in good to excellent yields (2g-i).

Scheme 2: Amine to Nitro Ozonation Scopea

[a] Reactions performed on a 0.1 mmol scale. Yields calculated as an average over

two runs. [b] Yield determined by 1H NMR due to volatility of the product.

Secondary and tertiary alcohols were also tolerated (2j and 2k)

despite alcohol oxidation being another prominent reaction that

ozone can mediate.24 Trans-4-hydroxycyclohexylamine (1j)

was found to give the corresponding trans product 2j stereospe-

cifically. Finally, protected amines and a tetrahydrofuran ring

were also tolerated, giving modest yields of oxidation products

2l and 2m. Due to multiple equivalents of ozone being used in

this system, selectivity between multiple amines cannot be

achieved with our current flow rate and ozone concentration.

With this amine oxidation method showing tolerance for

arenes, esters, alcohols, ethers, and carbamates, we were curi-

ous if other classes of ozone-mediated oxidation could be

achieved using this reactor design. Pyridine N-oxides are valu-

able molecules, often formed by the treatment of the corre-

sponding pyridine with m-CPBA.25 Without reoptimization, our

conditions could smoothly oxidize pyridines bearing alcohol

(4a), tert-butyl (4b), and oxidizable benzylic C–H bonds (4c) to

form the corresponding N-oxides in 65-92% yield (Scheme 3a).

We next investigated applications to hydroxylation of tertiary

C–H bonds.2,22 This important class of reactions is often

achieved by a mixture of nitric and sulfuric acid,26 or a variety

of transition metal catalysts,27,28 leaving room for improvement

for more atom economical methods. Given the resistance to the

C–H bonds present in the substrates and products discussed thus

far, more aggressive conditions are needed for this transfor-

mation. We found that a reaction temperature of -20 °C and a 1

h reaction time allowed for the formation of oxidized species 6a

Scheme 3: Additional Oxidations Scopea

[a] Reactions performed on a 0.1 mmol scale. Yields calculated as an average

over two runs.

in 46% yield, and 6b formed stereospecifically from cis-decalin

in 39% yield (Scheme 3b). Notably, both of these substrates

bear two tertiary C–H bonds. The acetate group of 6a presuma-

bly deactivates the nearest methine, and the electronegative ox-

ygen atom in alcohol 6b causes the product to be less reactive

than the starting material. Lastly, the oxidation of aromatic rings

was investigated, which is a powerful but seldom used method

to prepare carboxylic acids.4,29 Arenes were left untouched in

with the low temperature and short reaction times described for

amine oxidation, indicating more aggressive conditions would

be needed again. Using the same conditions for C–H bond hy-

droxylation enabled direct conversion of phenyl substituents

into aliphatic acids in modest yields (Scheme 3cError! Refer-

ence source not found.). While these various transformations

were not subjected to rigorous optimization, the diversity of ox-

idations that this packed bed reactor can facilitate highlights the

promise of ozone’s synthetic use beyond classical ozonolysis.

Due to the small size of the Vapourtec cooled column reactor

platform used for this chemistry, the system is not immediately

applicable to larger scale synthesis without acquiring different

equipment. However, the short reaction times employed and the

use of silica gel as the solid support allows the chemistry to be

automatically repeated in series to acquire larger quantities of

material. With this alternative setup for amine oxidation, the

substrate is dissolved in a 10% solution of methanol in DCM

which can be loaded onto the column (Scheme 4a). After the

amine has been loaded, a stream of O2 is passed over the column

to remove the solvents that may interfere with subsequent oxi-

dations (Scheme 4b). At this stage, the process occurs as previ-

ously outlined, with cooling to -60 °C, passing ozone over the

silica gel for 15 minutes, sparging with O2, and warming to

room temperature (Scheme 4c). A solution of 50% MeOH and

DCM is then pushed through the column to extract the product

(Scheme 4d). This process can then be immediately repeated

with no impact on yield, allowing the procedure to be done in

cycles to provide synthetically useful quantities of product (See

Supporting Information Table S2).

Scheme 4: Reactor Cyclinga

[a] All reactions were performed on a 0.1mmol scale. [b] %Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.

□ Conclusion Ozone is a powerful oxidant but is seldom used in organic

synthesis for reactions other than classical ozonolysis. Due to

its ability to oxidize amines, pyridines, C–H bonds, arenes, and

more, ozone-mediated reactions need to be performed carefully

with conditions tuned to achieve the specific sought after trans-

formation. By using a column packed with substrate immobi-

lized onto silica gel, our oxidation platform is capable of har-

nessing the high reactivity of ozone for productive chemistry.

The synthesis of nitroalkanes from alkylamines is highlighted,

along with select examples of pyridine N-oxide, alcohol, and

carboxylic acid synthesis, highlighting the versatility of this

system. While the platform described is limited in scale due to

the size of the equipment used, the reactor can be iteratively

cycled to achieve modest throughput and may be amenable to

automation to access synthetically useful quantities of material.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the ACS

Publications website.

AUTHOR INFORMATION

Corresponding Author Stephen G. Newman − Centre for Catalysis Research and

Innovation, Department of Chemistry and Biomolec-ular Sciences, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5 Email: stephen.newman@uottawa.ca

Authors Eric A. Skrotzki − Centre for Catalysis Research and

Innovation, Department of Chemistry and Biomolec-ular Sciences, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

Jaya K. Vandavasi − Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolec-ular Sciences, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

Notes Any additional relevant notes should be placed here.

ACKNOWLEDGMENT

Financial support for this work was provided by the American Chemical Society Green Chemistry Institute (ACS GCI Advanc-ing Research Grant), the National Science and Engineering Re-search Council of Canada (NSERC), and the Canada Research Chair program. The Canadian Foundation for Innovation (CFI)

and the Ontario Ministry of Research, Innovation, & Science are thanked for essential infrastructure.

REFERENCES

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313–315.

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Commun., 1974, 437–438.

21 G. A. Cook, A. D. Kiffer, C. V. Klumpp, A. H. Malik and

L. A. Spence, in Ozone Chemistry and Technology, Ameri-

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22 Z. Cohen, E. Keinan, Y. Mazur and T. H. Varkony, J. Org.

Chem., 1975, 40, 2141–2142.

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download fileview on ChemRxivManuscript.pdf (1.38 MiB)

S1

Supporting Information for

Ozone-Mediated Amine Oxidation: A Solvent Free, Flow-Chemistry

Approach

Eric A. Skrotzki, Jaya Kishore Vandavasi, and Stephen G. Newman

Centre for Catalysis Research and Innovation

Department of Chemistry and Biomolecular Sciences

University of Ottawa

10 Marie-Curie, Ottawa, Ontario, Canada, K1N 6N5.

*E-mail: stephen.newman@uottawa.ca

Table of Contents

Contents General Experimental Details: .................................................................................................................... S1

Instrumentation and Flow Reactor Details ............................................................................................. S2

General Procedure A: .............................................................................................................................. S2

General Procedure B: .............................................................................................................................. S2

Reaction Optimization: ........................................................................................................................... S2

Failed Scope Examples: ....................................................................................................................... S4

Flow Automation Optimization: ............................................................................................................. S5

Starting Material Synthesis: ........................................................................................................................ S6

Characterization Data for Products: ........................................................................................................... S7

NMR Spectra: ............................................................................................................................................ S13

References: ............................................................................................................................................... S33

General Experimental Details: Unless otherwise indicated, reagents were obtained from Sigma Aldrich, Fisher Scientific or Combi-Blocks

and used as received. Silicycle F60 40-63 µm silica gel was used for amine suspension and column

chromatography. The silica gel was stored at room temperature and dried in a 140 °C oven for ~24 hours

prior to use in the packed bed reactor. Analytical thin layer chromatography (TLC) was conducted using

aluminum-backed EMD Millipore Silica Gel 60. Visualization of developed plates was performed under UV

light (254 nm) and/or using KMnO4 stains.

S2

Instrumentation and Flow Reactor Details 1H NMR and 13C NMR were recorded on a Bruker AVANCE 400 MHz spectrometer and referenced to

residual solvent signals. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s =

singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration. Yields for

optimization were determined by NMR or GC analysis of the crude reaction mixture using 1,3,5-

trimethoxybenzene as an internal standard. FTIR spectra were collected on a Varian 640-IR spectrometer

equipped with an attenuated total reflectance accessory (ATR, Pike MIRacle) in the 4000-400 cm-1 range

with 64 scans per sample. Unless otherwise indicated, continuous flow experiments were performed using

1/16" O.D., 1.0 mm I.D. PFA. PEEK fittings were used for all PFA tubing. PEEK fittings and parts were

purchased from Upchurch Scientific. Vapourtec V3 pumps with blue tubing and built-in Tee joints were

used for pumping and reagent selection.

General Procedure A: To a clean round-bottom flask was added the corresponding amine (0.3 mmol), followed by pentane (20

mL). 3 g of silica gel (stored in a 140 °C oven overnight) was added to form a slurry (0.1 mmol of substrate

per gram of silica). The solvent was slowly evaporated under reduced pressure (no lower than 800 mbar

to avoid silica bumping as it dries) to yield silica gel loaded with starting material. 1 g of this impregnated

silica gel was added to an omnifit column measuring 150 mm long with an I.D of 10 mm (Part number#

006EZ-10-15-AF). The silica plug measured around 3 cm long inside the column. This assembly was

connected to a Vapourtec E-series (easy-Medchem) reactor and cooled down to -60 °C using the with

Vapourtec Cooling Module (#50-1314) under a constant flow of oxygen through the reaction vessel (10

psi). Once the reactor was cooled, the in-line ozone generator (Oxidation Technologies, VMUS-DG1) was

turned on. This was operated at maximum power with an approximate flow rate of 0.12 L/min of oxygen.

This corresponds to an approximate production of 1.75 g/h or 0.6 mmol of O3 per minute. Ozone exit

tubing from the reaction led to a solution of sodium metabisulfite in water to quench any remaining

excess.

After 15 minutes, the ozone generation was turned off while allowing oxygen to continue to flow. After

the remaining ozone is purged from the silica gel (~10 seconds; loss of blue color), the reactor is allowed

to warm to room temperature. Silica gel was harvested from the reactor and the column was cleaned with

acetone before repeating above procedure again. Two combined 1 g reactions were directly dry-loaded

to a column of silica gel for purification following a pentane wash to remove excess grease.

General Procedure B: Identical to General Procedure A, but reactor is cooled to -20 °C and ozone is applied for 60 mins.

Reaction Optimization: We began our exploration into this topic by using dodecylamine as a model substrate using the reactor

setup illustrated in Figure S1 below. With this, various ozonation times and temperatures were screened

to determine optimal conditions (Table S1). It was previously known that these types of oxidations have

taken place at -78 °C, but our system allowed us greater control over specific temperatures than a simple

dry ice bath. It was found that -60 °C gave the best balance between selectivity while still enabling the

desired reaction to proceed quickly. The next variable to be optimized was time, and 15 minutes proved

to be the point at which yield was highest, even though some starting material was still recovered. If the

reaction is left to continue for longer, degradation pathways will begin to outcompete product formation.

S3

Ozone Generator

Cooling Module

Quench Solution

Reaction Column

Figure S1: Photograph of the complete reactor setup

S4

Table S1: Optimization of Ozonation Time and Temperaturea

Entry Temperature (°C) Time (min) Yieldb (%) Amine Recoveryb

1 -40 10 s 11 47

2 -40 15 51 25

3 -40 30 42 0

4 -60 5 50 32

5 -60 15 62 25

6 -60 30 49 13

7 -70 20 29 n/a

[a]Reactions were run on a 0.1 mmol scale. [b]Yields were obtained via crude NMR spectroscopy using 1,3,5 trimethoxybenzene as an internal standard.

Failed Scope Examples: Notably, two classes of attempted substrates did not yield any product: Electron rich aromatic rings, and

substrates containing multiple amines. Our hypothesis for the former is that the increased electron

density of the aromatic ring make it more prone to reaction with the ozone. The latter class of substrates

failing is most likely due to multiple equivalents of ozone being employed in our method. Each nitrogen

can undergo this reaction independently of one another, and so multiple sites of oxidation could increase

chances of molecule degradation. As such, no product, starting material or discernable side product were

observed with either substrate.

Figure S2: Failed Scope Examples

S5

Flow Automation Optimization: The reactor cycling set-up described in manuscript Scheme 4 is outlined in more detail in Figure S3 below.

Figure S3A illustrates the flow path (in red) for normal reactor operation for ozonation. Oxygen flow from

a gas tank flows through the ozone generator to the reactor inlet. Passing through the reactor, it exits and

flows to a solution of aqueous sodium metabisulfite. Figure S3B illustrates the flow paths for loading the

amine solution onto the column (red path), and flushing material off the column (blue to red path). Table

S2 illustrates reproducibility in triplicate (Entry 1 a-c). Alternate loading conditions were tested using

pentane as the solvent (Entry 2), which resulted in a 0% yield due to a lack of even dispersion of the amine

along the silica length. If the column is not allowed to fully dry before reaction is started, a drastically

reduced yield is also observed (Entry 3). Drying the column using either air pressure or heat alone give

reasonable yields (Entry 4 and 5).

Figure S3: Schematic of Complete Flow Reactor Set Up

S6

Table S2: Optimization of Automation Processa

Entry Deviation from Standard Conditions Yield (%)b

1a None – first reproduction 60c

1b None – second reproduction 59c

1c None – third reproduction 62c

2 Loaded amine in pentane 0

3 Column not fully dried 20

4 Column dried using heat only 55

5 Column dried using air pressure only 57 [a] Reactions performed on a 0.1 mmol scale using dodecylamine. [b]Yields obtained via crude NMR spectroscopy using 1,3,5 trimethoxybenzene as an internal standard. [c] Yield 1a, 1b, and 1c are performed using identical conditions in triplicate.

Starting Material Synthesis:

3-Aminoadamantol (1m): Synthesized according to literature precedent.1 Adamantanamine (1 g, 5.33

mmol) was added to a pot of premixed H2SO4 (10.3 mL) and nitric acid (1 mL) at 0 °C and yielded the title

product as a white solid (0.6987 g , 78%). 1H NMR: (400 MHz, CDCl3) δ 2.28-2.19 (m, 4H), 1.68-1.59 (m,

4H), 1.56 (s, 2H), 1.52-1.48 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 69.8, 53.9, 50.4, 44.9, 44.1, 34.8, 31.1.

6-aminohexanoic acid tert-butyl ester (1h): Synthesized according to literature precedent.2 6-

aminohexanoic acid (0.6560 g, 5.0 mmol) was mixed with thionyl chloride (1.63 mL, 22.5 mmol) and t-

BuOH (2.7 mL) to yield the title compound as an off white solid (0.4064 g, 44%). 1H NMR: (400 MHz, CDCl3)

δ 2.63 (t, J= 7.0 Hz, 2H), 2.19 (s, 2H), 2.13 (t, J= 7.4 Hz, 2H), 1.51 (quin, J= 7.4 Hz, 2H), 1.42 (quin, J= 7.4 Hz,

2H), 1.35 (s, 9H), 1.31-1.22 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.9, 79.4, 41.6, 35.3, 32.7, 28.0, 26.2,

24.7.

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3,7-dimethyloctyl acetate (5a): Synthesized according to literature precedent.3 3,7-Dimethyloctanol (0.96

mL, 5.0 mmol) and acetyl chloride (0.43 mL, 6.0 mmol) were mixed to yield the title compound as a

colourless oil (0.7712 g, 77%). 1H NMR: (400 MHz, CDCl3) δ 4.15-4.03 (m, 2H), 2.04 (s, 3H), 1.70-1.60 (m,

1H), 1.57-1.48 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.08 (m, 6H), 0.89 (d, J=6.5 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 171.2, 63.1, 39.1, 37.1, 35.5, 29.8, 27.9, 24.6, 22.7, 22.6, 21.0, 19.5.

Characterization Data for Products:

1-Nitrododecane (2a): The title compound was synthesized according to general procedure A using

dodecylamine (0.0370 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated using

flash chromatography (5% EtOAc/Hexanes, Rf: 0.43). The title compound was isolated as a yellow oil

(0.013 g, 60%). 1H NMR: (400 MHz, CDCl3) δ 4.38 (t, J = 7.1 Hz, 2H), 2.00 (quin, J = 7.1 Hz, 2H), 1.42-1.20

(m, 18H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 75.7, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2, 28.8,

27.4, 26.2, 22.7, 14.1. Spectral data was consistent with literature reports.4

Nitrocyclohexane (2b): The title compound was synthesized according to general procedure A using

cyclohexylamine (0.0298 g, 0.3 mmol) and 3 g of dry silica gel. After reaction, the product was isolated

using flash chromatography (10% EtAOc/Hexanes, Rf: 0.44). The title compound was isolated as a yellow

oil (0.0216 g, 56%). 1H NMR: (400 MHz, CDCl3) δ 4.36 (tt, J= 10.7, 4.0 Hz, 1H), 2.26-2.19 (m, 2H), 1.91-1.82

(m, 4H), 1.69-1.62 (m, 1H), 1.39-1.23 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 84.6, 30.9, 24.7, 24.1. Spectral

data was consistent with literature reports.5

Nitroadamantane (2c): The title compound was synthesized according to general procedure A using

adamantylamine (0.0306 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated

using flash chromatography (5% EtOAc/Hexanes, Rf: 0.44). The title compound was isolated as a yellowish

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solid (0.0290 g, 80%). 1H NMR: (400 MHz, CDCl3) δ 2.23 (s, 3H), 2.21 (s, 6H), 1.77-1.66 (m, 6H). 13C NMR

(100 MHz, CDCl3) δ 84.7, 40.8, 35.5, 29.7. Spectral data was consistent with literature reports.6

(3-Nitropropyl)benzene (2d): The title compound was synthesized according to general procedure A using

3-phenylpropylamine (0.0270 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated

using flash chromatography (5% EtOAc/Hexanes, Rf: 0.26). The title compound was isolated as a pale-

yellow oil (0.0283 g, 85%). 1H NMR: (400 MHz, CDCl3) δ 7.34-7.16 (m, 5H), 4.37 (t, J= 6.9 Hz, 2H), 2.73 (t,

J= 7.4 Hz), 2.37-2.30 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 139.5, 128.7, 128.4, 126.6, 74.7, 32.3, 28.8.

Spectral data was consistent with literature reports.7

6-Nitrohexanoic Acid Tert-Butyl Ester (2e): The title compound was synthesized according to general

procedure A using tert-butyl-6-aminohexanoate (0.0375 g, 0.2 mmol) and 2 g of dry silica gel. After

reaction, the product was isolated using flash chromatography (10% EtOAc/Hexanes, Rf: 0.21). The title

compound was isolated as a white solid (0.0294 g, 70%). 1H NMR: (400 MHz, CDCl3) δ 4.38 (t, J= 7.0 Hz,

2H), 2.23 (t, J= 7.3 Hz, 2H), 2.06-1.99 (m, 2H), 1.67-1.58 (m, 2H), 1.44 (s, 9H), 1.42-1.39 (m, 2H). 13C NMR

(100 MHz, CDCl3) δ 172.6, 80.4, 75.4, 35.0, 28.1, 27.1, 25.7, 24.2. IR: 1722.306, 1554.190, 1264.298,

1151.132, 730.028. HRMS (ESI+): [M+] m/z Calc’d for C10H19NO4Na: 240.1212; Found: 240.1202.

1-(2-Nitroethyl)-4-(Trifluoromethyl)benzene (2f): The title compound was synthesized according to

general procedure A using 2-(4-trifluoromethylphenyl)ethylamine (0.0378 g, 0.2 mmol) using 2 g of dry

silica gel. After reaction the product was isolated using flash chromatography (10% EtOAc/Hexanes, Rf:

0.33). The title compound was isolated as a pale-yellow oil (0.0325 g, 74%). 1H NMR: (400 MHz, CDCl3) δ

7.60 (d, J= 7.9 Hz, 2H), 7.34 (d, J= 7.9 Hz, 2H), 4.64 (t, J= 7.2 Hz, 2H), 3.38 (t, J= 7.2 Hz, 2H). 13C NMR (100

MHz, CDCl3) δ 139.7, 129.0, 125.9 (quart), 122.6, 75.6, 33.0. Spectral data was consistent with literature

reports.8

1-(2-Nitroethyl)-4-Chlorobenzene (2g): The title compound was synthesized according to general

procedure A using 2-(4-Chlorophenyl)ethylamine (0.0311 g, 0.2 mmol) and 2 g of dry silica gel. After

reaction, the product was isolated using flash chromatography (5% EtOAc/Hex, Rf: 0.15). The title

compound was isolated as a colorless oil (0.0271 g, 73%). 1H NMR: (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H),

S9

7.16-7.13 (m, 2H), 4.60 (t, J= 7.13 Hz, 2H), 3.29 (t, J= 7.13 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 134.1,

133.4, 129.9, 129.2, 76.0, 32.7. Spectral data was consistent with literature reports.9

1,1-Diethoxy-4-Nitrobutane (2h): The title compound was synthesized according to general procedure A

using 1,1-Diethoxy-4-Aminobutane (0.0322 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the

product was isolated using flash chromatography (25% EtOAc/Hexanes, Rf: 0.47). The title compound was

isolated as a yellow oil (0.0352g, 92%). 1H NMR: (400 MHz, CDCl3) δ 4.50 (t, J= 5.3 Hz, 1H), 4.42 (t, J= 7.0

Hz, 2H), 3.68-3.60 (dq, J= 9.4, 7.1 Hz, 2H), 3.51-3.44 (dq, J= 9.4, 7.1 Hz, 2H), 2.13-2.06 (m, 2H), 1.73-1.68

(m, 2H), 1.20 (t, J= 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 102.0, 75.4, 61.7, 30.3, 22.6, 15.3. Spectral

data was consistent with literature reports.10

Tert-Butyl Nitrophenylpropanoate (2i): The title compound was synthesized according to general

procedure A using phenylalanine tert-butyl ester (0.0443 g, 0.2 mmol) and 2 g of dry silica gel. After

reaction, the product was isolated used flash chromatography (5% EtOAc/Hexanes, Rf: 0.35). The title

compound was isolated as a white solid (0.0333 g, 66%). 1H NMR: (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H),

5.25 (dd, J= 9.3, 5.9 Hz), 3.55-3.40 (m, 2H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 162.9, 134.3, 128.9,

128.8, 127.7, 89.9, 84.8, 36.2, 27.7. IR: 2982.828, 1742.389, 1560.800, 1455.847, 1370.294, 1148.553.

HRMS (ESI-H): [M-H]- m/z Calc’d for C13H16NO4: 250.1079; Found: 250.1075.

Trans-4-Nitrocyclohexanol (2j): The title compound was synthesized according to general procedure A

using trans-4-aminocyclohexanol (0.0230 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product

was isolated using flash chromatography (50% EtOAc/Hexanes, Rf: 0.31). The title compound was isolated

as white needle-like crystals (0.0167 g, 58% yield). 1H NMR: (400 MHz, CDCl3) δ 4.39 (tt, J=10.8, 4.1 Hz,

1H), 3.76 (tt, J=9.9, 4.1 Hz, 1H), 2.35-2.29 (m, 2H), 2.11-2.05 (m, 2H), 2.02-1.91 (m. 2H), 1.47-1.38 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 83.3, 68.3, 32.3, 28.2. Spectral data was consistent with literature reports.11

1-Nitro-3-Adamantol (2k): The title compound was synthesized according to general procedure A using

3-Aminoadamantol (0.0335 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated

using flash chromatography (30% EtOAc/Hexanes, Rf: 0.20). The title compound was isolated as colorless

needle-like crystals (0.0227 g, 58%). 1H NMR: (400 MHz, CDCl3) δ 2.46-2.41 (m, 2H), 2.19 (s, 2H), 2.15-2.11

S10

(m, 4H), 1.73 (d, J= 3.1 Hz, 4H), 1.61-1.58 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 86.0, 69.7, 48.0, 43.5, 39.7,

34.1, 30.8. Spectral data was consistent with literature reports.12

Tert-Butyl (2-Nitroethyl)carbamate (2l): The title compound was synthesized according to general

procedure A using N-Boc-Ethylenediamine (0.0320 g, 0.2 mmol) and 2 g of dry silica gel. After reaction,

the product was isolated using flash chromatography (20% EtOAc/Hex, Rf: 0.26). The title compound was

isolated as a colorless oil (0.0193 g, 51%). 1H NMR: (400 MHz, CDCl3) δ 5.03 (s, 1H), 4.51 (t, J= 5.4 Hz, 2H),

3.69 (quart, J= 5.4 Hz), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 155.6, 80.3, 74.2, 37.8, 28.3. IR: 3449.654,

2979.477, 2925.307, 1703.860, 1555.827, 1366.561. Spectral data was consistent with literature reports.13

2-(Nitromethyl)tetrahydrofuran (2m): The title compound was synthesized according to general

procedure A using Tetrahydrofurfylamine (0.0202 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the

product was isolated using flash chromatography (20% EtOAc/Hex, Rf: 0.29). The title compound was

isolated as a colourless oil (0.0174 g, 66%). 1H NMR: (400 MHz, CDCl3) δ 4.60-4.52 (m, 1H), 4.47-4.37 (m,

2H), 3.94-3.80 (m, 2H), 2.20-2.10 (m, 1H), 2.00-1.92 (m, 2H), 1.72-1.62 (m, 1H). 13C NMR (100 MHz, CDCl3)

δ 78.9, 75.2, 68.7, 29.0, 25.4. Spectral data was consistent with literature reports.14

3-Pyridinylpropanol N-oxide (4a): The title compound was synthesized according to general procedure A

using 3-pyridinylpropanol (0.0274 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was

isolated using flash chromatography (20% MeOH/EtOAc, Rf: 0.18). The title compound was isolated as a

colorless oil (0.0198 g, 65%). 1H NMR: (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.09-8.05 (m, 1H), 7.23-7.17 (m,

2H), 3.63 (t, J= 6.1 Hz, 2H) 2.70 (t, J= 7.7 Hz, 2H), 1.88-1.81 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 141.4,

139.1, 136.8, 127.5, 125.7, 60.8, 32.9, 28.9. IR: 3350.784, 2929.856, 2855.369, 1744.059, 1157.842. HRMS

(ESI-TOF) m/z: [M+Na]+ Calc’d for C8H11NO2Na 176.0687; Found: 176.0679.

4-Tert-Butylpyridine N-oxide (4b): The title compound was synthesized according to general procedure A

using 4-tertbutylpyridine (0.0270 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was

isolated using flash chromatography (10% MeOH/EtOAc, Rf: 0.16). The title compound was isolated as a

colorless oil (0.3070, 92%). 1H NMR: (400 MHz, CDCl3) 8.11 (d, J= 7.1 Hz, 2H), 7.23 (d, J= 7.1 Hz, 2H), 1.28

S11

(s, 9H). 13C NMR (100 MHz, CDCl3) δ 151.0, 138.5, 123.1, 34.5, 30.5. Spectral data was consistent with

literature reports.15

4-Benzylpyridine N-oxide (4c): The title compound was synthesized according to general procedure A

using 4-benzylpyridine (0.0338 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was

isolated using flash chromatography (10% MeOH/EtoAc, Rf: 0.09). The title compound was isolated as a

yellow oil (0.0316, 85%). 1H NMR: (400 MHz, CDCl3) δ 8.14-8.10 (m, 2H), 7.35-7.30 (m, 2H), 7.29-7.23 (m,

1H), 7.17-7.12 (m, 2H), 7.08-7.04 (m, 2H), 3.95 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 141.0, 139.0, 138.0,

129.0, 129.0, 128.9, 127.1, 126.3, 40.3. Spectral data was consistent with literature reports.16

7-Hydroxy-3,7-Dimethyloctyl Acetate (6a): The title compound was synthesized according to general

procedure B using 3,7-dimethyloctyl acetate (0.0401 g, 0.2 mmol) and 2 g of dry silica gel. After reaction,

the product was isolated using flash chromatography (10% EtOAc/Hex, Rf: 0.31). The title compound was

isolated as a colourless oil (0.0199 g, 46%). 1H NMR: (400 MHz, CDCl3) δ 4.12-4.01 (m, 2H), 2.02 (s, 3H),

1.69-1.24(m, 10H), 1.19 (s, 6H), 1.17-1.09 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 171.23, 71.0, 63.0, 44.1,

37.4, 35.5, 29.8, 29.3, 29.2, 21.6, 21.0, 19.5. Spectral data was consistent with literature reports.6

Cis-9-Decalol (6b): The title compound was synthesized according to general procedure B using cis-decalin

(0.0276 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated using flash

chromatography (10% EtOAc/Hex, Rf: 0.27). The title compound was isolated as a colourless oil (0.0118 g,

39%). 1H NMR: (400 MHz, CDCl3) δ 1.80-1.19 (m, 18H). 13C NMR (100 MHz, CDCl3) δ 71.8, 42.8, 29.7, 28.0.

Spectral data was consistent with literature reports.17

Cyclohexane Carboxylic Acid (8a): The title compound was synthesized according to general procedure B

using Cyclohexylbenzene (0.0320 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was

isolated using flash chromatography (20% EtOAc/Hex, 1% AcOH, Rf: 0.32). The title compound was isolated

as a colourless oil (0.0122 g, 48%). 1H NMR: (400 MHz, CDCl3) δ 11.1 (br, 1H), 2.33 (tt, J= 3.6, 11.2 Hz, 1H),

1.97-1.90 (m, 2H), 1.80-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.51-1.40 (m, 2H), 1.35-1.20 (m, 3H). 13C NMR

(100 MHz, CDCl3) δ 181.6, 42.8, 28.8, 25.7, 25.3. Spectral data was consistent with literature reports.18

S12

Nonanoic Acid (8b): The title compound was synthesized according to general procedure B using

Octylbenzene (0.0381 g, 0.2 mmol) and 2 g of dry silica gel. After reaction, the product was isolated using

flash chromatography (10% EtOAc/Hex, 1% AcOH, Rf: 0.27). The title compound was isolated as a

colourless oil (0.0132 g, 46%). 1H NMR: (400 MHz, CDCl3) δ 2.35 (t, J= 7.5 Hz, 2H), 1.63 (quin, J = 7.5 Hz,

2H), 1.35-1.22 (m, 8H), 0.88 (t, J= 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 179.5, 34.0, 31.8, 29.2, 29.1,

24.7, 22.6, 14.1. Spectral data was consistent with literature reports.19

S13

NMR Spectra:

2a -Nitrododecane

S14

2b - Nitrocyclohexane

S15

2c - Nitroadamantane

S16

2d - (3-Nitropropyl)benzene

S17

2e - 6-Nitrohexanoic Acid Tert-Butyl Ester

S18

2f - 1-(2-Nitroethyl)-4-(Trifluoromethyl)benzene

S19

2g - 1-(2-Nitroethyl)-4-Chlorobenzene

S20

2h - 1,1-Diethoxy-4-Nitrobutane

S21

2i - Tert-Butyl Nitrophenylpropanoate

S22

2j - Trans-4-Nitrocyclohexanol

S23

2k - 1-Nitro-3-Adamantol

S24

2l - Tert-Butyl (2-Nitroethyl)carbamate

S25

2m - 2-(Nitromethyl)tetrahydrofuran

S26

4a - 3-Pyridinylpropanol N-oxide

S27

4b - 4-Tert-Butylpyridine N-oxide

S28

4c - 4-Benzylpyridine N-oxide

S29

6a - 7-Hydroxy-3,7-Dimethyloctyl Acetate

S30

6b - Cis-9-Decalol

S31

8a - Cyclohexane Carboxylic Acid

S32

8b - Nonanoic Acid

S33

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