Handling Hazards Using Continuous Flow Chemistry: Synthesis of N1

Oct 5, 2016 - An automated continuous flow unit controlled by custom software created in-house was used to collect the aryl azide stream and restore i...
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Handling hazards using continuous flow chemistry: synthesis of N1aryl-1,2,3-triazoles from anilines via telescoped three step diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition processes Matthieu Teci, Michael Tilley, Michael A. McGuire, and Michael G. Organ Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00292 • Publication Date (Web): 05 Oct 2016 Downloaded from http://pubs.acs.org on October 5, 2016

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Handling hazards using continuous flow chemistry: synthesis of N1aryl-1,2,3-triazoles from anilines via telescoped three step diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition processes. Matthieu Teci,[a] Michael Tilley,[a] Michael. A. McGuire,*[b] Michael G. Organ*[a,c] [a] M. Teci, M. Tilley, Professor M. G. Organ, Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada) [b] Dr. M. A. McGuire, GlaxoSmithKline Pharmaceuticals Inc., 709 Swedeland Road, PO box 1539, UMW 2810, King of Prussia, PA 19406, (USA) [c] Professor M. G. Organ, Director, Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry, University of Ottawa, Ottawa, Ontario, K1N6N5 (Canada) Email: [email protected] ABSTRACT: The conversion of commercially available anilines into triazole products was realized using a telescoped threereactor flow diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition process. The diazotization / azidodediazotization sequence was accelerated by means of an ultrasonic bath resulting in a degassed, segmented effluent. An automated continuous flow unit controlled by custom software created in-house was used to collect the aryl azide stream and restore it to a continuous column of the reagent. When combined with a variety of dipolarophiles, 1-aryl-[1,2,3]-triazoles were thus assembled by either copper catalyzed alkyne-azide cycloaddition (CuAAC) or Huisgen cycloaddition reactions. ` KEYWORDS: anilines, diazotization, triazoles, click chemistry, dipolar cycloaddition, flow In the past decade, continuous flow organic synthesis has become increasingly popular owing to the considerable benefits afforded over conventional batch-style reaction setups. For example, rather than undergoing tedious reaction scale-up to produce more product on increasing scales, the same flowed process can simply be flowed longer, or in parallel, to produce the desired amount of product, a process known as ‘scaling-out’.1 Further, continuous flow processes also allow a greater control of important reaction parameters, such as mass and temperature transfer, and therefore operate, in theory at least, exclusively at steady state once reached.2 Flow is inherently safer,3 allowing several synthetic steps to be telescoped into one continuous sequence where only small quantities of toxic or unstable intermediates exist momentarily and are immediately quenched upon contact with the subsequent reagent stream.4 Triazoles,5 which have applications in a number of industrial sectors, have received much interest during the development of flow methodologies. The syntheses of benzotriazoles,6 1,2,4-triazoles,7 and in particular 1,2,3triazoles8 have all been reported in a flow setting. 1,2,3Triazoles are traditionally assembled via [3 + 2] dipolar cycloaddition reactions, which have been termed “click reactions” owing to their atom-economy and high efficiency. A plethora of batch methodologies for their preparation have been developed using an organic azide (1,3-dipole) and an alkyne or enolate (dipolarophile). Although the

alkyl / aryl azide component can be synthesized prior to use,8i, 9 more attractive strategies rely on their in situ formation.10 From the aspect of safety, it is not surprising that many of these straightforward methodologies have been successfully adapted in flow. Although there are examples of telescoped flow syntheses of 1-alkyl-[1,2,3]-triazoles reported in the literature,11 1-aryl-substituted analogues are less commonly encountered. To the best of our knowledge, such continuous flow sequences using anilines as the starting material have rarely been reported,12 and more strikingly, we were unable to find any examples of flow syntheses of 1-aryl-4-aryl-[1,2,3]-triazoles using commercially available anilines as the starting material. This limited number of applications may be a result of the difficulties associated with concomitant nitrogen evolution during the formation of the aryl azide from the corresponding aniline precursor.10f, 13 Notably, working in segmented streams represents a major technical challenge in terms of retaining stoichiometric ratios when another reactant stream is introduced. In rare cases where N1arylated [1,2,3]-triazoles were synthesized using continuous flow, the reactive aryl-azide intermediates were obtained as segmented streams by reacting an aniline precursor, azidotrimethylsilane (TMS-N3) and t-butyl nitrite (t-BuONO) in a heated reactor (Scheme 1).12 Rather than restoring a continuous aryl azide stream, Stazi et al. directly combined the segmented flow with [3 + 2] cycloaddition reagent solutions. Applying this strategy a

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nitrogen gas. An intermediate reservoir was introduced to collect the segmented flow stream, which was subsequently directed to either Sonogashira or Suzuki-Miyaura crosscoupling reactors using an automated Continuous Flow Unit (CFU) a device controlled by software developed inhouse designed to accommodate a broad range of fluids at high pressure without pulsation This approach minimized safety issues associated with handling hazardous intermediates, allowed ready modification of reaction conditions to counteract solubility problems as they arose, and allowed each step to be optimized separately, ultimately producing a wide substrate scope with high yields. Building up on this previous work, we felt that such a strategy could rapidly be extended to a telescoped diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition flow sequence, thus offering an attractive alternative for the non-segmented, continuous flow synthesis of 1-arylsubstituted [1,2,3]-triazole products from anilines (Scheme 2, Method (2)). (Het)Ar1 - NH 2 DIAZOTIZATION

chiometric ratios (Scheme 1, Method (1). Alternatively, Ley et al. designed a two-step sequence where the dipolarophile (malonitrile anion) was delivered in an immobilised form. In a first step, the segmented aryl azide stream was directed to a reactor containing a cationic polymeric support previously primed with malonitrile anion. Once the triazole was formed, in the absence of a suitable proton source, it was retained inside the column as its corresponding anion. In a second step, washing the reactor with a malonitrile solution (the proton source) facilitated both the recovery of amino-1-aryl-[1,2,3]-triazol-4-carbonitrile products and regeneration of the supported column (Scheme 1, Method (2)). This stepwise strategy has limited scope due to the necessity of anionic dipolarophiles and as such, cannot be extended to electronically neutral dipolarophiles. Furthermore, retention of the triazole anion onto the polymeric support inherently prevents measuring accurate residence times. The system can also never achieve steady state as the stock supported reagent is consumed in a continuous manner. Finally, plugs due to substrate precipitation inside the column were sometimes encountered.

"H+"

t-BuONO r.t.

Ar - NH 2 TMS-N3

50 - 60 °C

(Het)Ar1 - N 2+ n-Bu 4NI

NaN 3 IODO or AZIDO DEDIAZOTIZATION

AZIDATION

t-BuONO

Ar - N 3

r.t. sonication

20 min. O R

O

+ DBU

20 min.

CN

OEt

CN

STEP 1 react

STEP 2 release

80 °C NMe 3+ NC

CN 60 °C

Ar

N

N

Ar

N O

R

N

H 2N

N

N CN

EtO (Method 1)

(Method 2)

Stazi, 2010

Ley, 2011

(Het)Ar1 - I

(Het)Ar1 - N 3

CFU

CFU

Sonogashira or SuzukiMiyaura reagents

[3 + 2] dipolar cycloaddition reagents 60 - 70°C 20 - 45 min.

(Het)Ar1

(Het)Ar2 or

continuous stream

segmented stream

check valve

(Het)Ar1 or (Het)Ar1

(Het)Ar1 Ar2

N

N

N

N

N

R1

R2

N O

Scheme 1. Reported flowed syntheses of 1-aryl-[1,2,3][1,2,3]triazoles from anilines. anilines. Following our group’s interest in continuous flow processes,14 we have recently designed a telescoped diazotization, iododediazotization, cross-coupling flow process, for the conversion of commercially available anilines into biarylacetylene and biphenyl products (Scheme 2, Method (1)).15 Dealing with a high-energy diazonium salt intermediate was key to this strategy. Generated from the corresponding aniline, the salt was immediately treated with tetra-butylammonium iodide to afford aryliodides and

r.t. - 60°C 20 min.

CROSS-COUPLING or [3 + 2] DIPOLAR CYCLOADDITION

fortiori resulted in imbalanced dipole / dipolarophile stoi-

HUISGEN DIPOLAR CYCLOADDITION

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3 : R 2 = Ar, R 3 = H 4 : R 2 = CN, R 3 = NH 2 (Method 2) This work

(Method 1)

continuous stream

segmented stream

Scheme 2. 2. Flow sequential (telescoped (telescoped) telescoped) strategy for the conversion of anilines into biaryl biaryl / biarylacetylene comcompounds (1) (1) and into triazole products (2).

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RESULTS AND DISCUSSION In our approach to a diazotization / azidodediazotization / Cu(I) catalyzed Alkyne Azide Cycloaddition (CuAAC) sequence to access 1-(hetero)aryl-4-aryl-[1,2,3]-triazoles 3, the model substrates chosen to work with are shown in Table 1. 2-Methoxy-4-nitroaniline (1a 1a) 1a was first treated with equal amounts of t-BuONO (1.1 equiv.) and methanesulfonic acid (CH3SO3H) (1.1 equiv.) in DMSO to later aid in solubilizing the triazole products, which often possess low solubility in organic solvents. The reaction proceeded cleanly and quantitatively in less than one minute at room temperature, and sodium azide (NaN3) was then added to the crude mixture. The azidodediazotization reaction was then performed at room temperature with sonication. Proceeding with gas evolution, complete reaction was reached in under 5 minutes. With these results in hands, we then subjected the crude arylazide mixture to the CuAAC conditions using 1-ethynyl-4-methylbenzene and diisopropylamine (0.7 equiv.) as the catalytic mild base. Table 1. Optimization of the CuAAC reaction in batch.[a]

The flow process consisted of three successive reactors, a fully automated CFU (see supporting information), and syringes containing the reagent solutions was designed as depicted in Scheme 3. Customized software developped by our group was used to control the whole CFU, including its valve, its pumps, the infusing / refilling sequence and the flow rates. Following Method A, 1a was the first aniline evaluated (flowed at 33 µl/min (16.5 µmol/min) and the corresponding triazole (3a 3a) 3a isolated in 79% yield (Table 2, entry 1). With this efficient three-reactor flow diazotization / azidodediazotization / CuAAC process in hand, we then evaluated the scope of this transformation using a variety of anilines. Under Method A conditions, other nitro, (alkylthio)-, trifluoromethyl-, and chloro-substituents were nicely tolerated (Table 2, entries 2 and 3). Aniline 1d was successfully processed into triazole 3d in 85% yield (Table 2, entry 4), which is notable for electron-rich substrates as they often react poorly under such diazotiza-

NO 2 t-BuONO (1.1 equiv.), CH 3SO3H (1.1 equiv.), DMSO, r.t, 1 min.

NO 2

O NH 2

then NaN 3 (1.1 equiv.) DMSO, r.t., Sonication, 5 min.

1a

1-Ethynyl-4-methylbenzene (1.3 equiv.), CuI (x mol%),

NO 2

O N3 2a

1,10-phenanthroline (x mol%), i-Pr2NH (0.7 equiv.)

O N

N N

DMSO, 60°C, 20 min. 3a

Entry

CuI (mol%)

1,10 phenanthroline (mol%)

Temp.

Conv.

1

10

none

60°C

60%

2

10

10

60°C

100%

3

5

5

60°C

100%

4

5

5

rt

46%

5

2.5

2.5

60°C

100%

6

2.5

2.5

rt

12%

[a] General conditions: 2-methoxy-4-nitroaniline (0.5 mmol), t-BuONO (0.55 mmol), CH3SO3H (0.55 mmol) in DMSO (2 mL) stirred for 1 min. at room temperature, then NaN3 (0.55 mmol) in DMSO (1 mL) was added and the reaction sonicated for 5 minutes. A solution of CuI, 1,10-phenanthroline (if applicable), and i-Pr2NH (0.7 equiv.) in DMSO (3 mL) was added, followed by 1-ethynyl-4-methylbenzene (1.3 equiv.), and the solution was heated at 60°C for 20 min. Percentage conversion to 3a was determined by 1H-NMR spectroscopic analysis of the crude mixture.

In the initial experiment, CuI (10 mol%) was examined as a catalyst, and after 20 min. at 60°C, 60% of 3a was formed (Table 1, entry 1). Utilizing 1,10-phenanthroline (10 mol%), a cost-effective and efficient ligand for copper in CuAAC reactions,16 gave quantitative conversion to 3a under the same conditions (Table 1, entry 2). Remarkably, the loadings of CuI and 1,10-phenanthroline could both be lowered to 2.5 mol%, and quantitative conversion of the aryl azide was still observed at 60°C (Table 1, entries 3 and 5). However, running reactions at room temperature resulted in incomplete conversion. (Table 1, entries 4 and 6).

Scheme 3. Optimized Optimized threethree-step flow diazotization / azidodediazotization / CuAAC sequence. tion reactions. Under the same conditions, hindered anilines such as 2,3-dimethyl-6-nitroaniline (1e 1e) 1e and 2,6dimethylaniline (1f 1f) 1f were converted into their respective products in good yields (Table 2, entries 5 and 6, respectively). Good yields were also obtained for 3-chloro-4methoxyaniline (1g 1g) 1h) 1g and 4-toluidine (1h 1h (Table 3, entries 7 and 8, respectively). Ester and sulfonamide groups on the aniline were also well tolerated (Table 2, entries 9 and 10, respectively), however, in order to overcome solubility issues encountered with the products, the aniline solution was diluted down to 0.33 M (Method B). The other solutions (i.e. syringe 2 to 5, Scheme 3) were diluted accordingly and an additional syringe (Syringe 6) infusing neat DMSO was used to further dilute the effluent from reactor 3, thus avoiding triazole precipitation outside the oil bath. The corresponding products 3i and 3j were obtained in

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good yields. Method A was also successfully applied to 3aminopyridine (1k 1k) 1k resulting in triazole 3k in 74% yield (Table 2, entry 11). In larger scale experiments performed with 1l, 1l 1i and 1a (5 – 7 mmol), the process was run for 8 h using ethynylbenzene as the dipolarophile partner resulting in triazoles 3l, 3l, 3m and 3n in 81%, 79% and 80% yield respectively.

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7

A (78%) 1g

3g

8

A (83%) 1h

3h

9

B (78%) 1i

3i

10

B (76%) 1j

Table 2. Scope study for the telescoped diazotization / azidodediazotization / CuAAC flow reaction sequence. sequence.[a]

3j

11

A (74%) 1k

3k

12

A (81%)[b] 1l

Entry

Aniline

Product

1

Method (Yield)

3l B (79%)

13 1i

[b]

3m

A (79%)

2

A (73%) 5b

3

A (81%) 1c

5c

4

A (85%) 1d

3d

5

A (81%) 1e

3e

6

A (78%) 1f

3f

[b]

1a

5a

1b

A (80%)

14

1a

3n

[a] General conditions for the telescoped diazotization / azidodediazotization / CuAAC reaction sequence: Method A: solution 1 (aniline (1 equiv., 0.5 M), and CH3SO3H (1.1 equiv.) in DMSO), solution 2 (t-BuONO, (1.1 equiv.) in DMSO), solution 3 (NaN3 (1.1 equiv.) in DMSO), solution 4 (CuI (2.5 mol%), i-Pr2NH (0.7 equiv.) and 1,10-phenanthroline (2.5 mol%) in DMSO), and solution 5 (1-ethynyl-4-methylbenzene (1.3 equiv.) in DMSO) were placed in their respective syringes (i.e., solution 1 in syringe 1, etc.) and connected to the continuous flow system as described in Scheme 3. Method B: As in Method A except aniline concentration was 0.33 M. Syringe 6 was loaded with pure DMSO and infused a rate of 400 µL/min. Yields are based on the volume of the aniline solution infused over 90 min. (2.97 mL, 1.47 mmol of the aniline infused at 16.5 µmol/min) [b] Ethynylbenzene (1.3 equiv.) was used, Yields based on the volume of the aniline solution infused over 8 hours (15.8 mL, 7.92 mmol of the aniline infused at 16.5 µmol.min).

Following this efficient flow synthesis of arylazides, we began exploring alternative dipolarophiles in an effort to rapidly assemble other triazole derivatives. For that purpose, Syringe 4 was filled with DMSO solutions of malonitrile (2 equiv.) or 1,3-cyclohexanedione (2 equiv.), and syringe 5 was filled with DBU (2 equiv.) in DMSO (see supporting information). 4-Chloro-3(trifluoro)methylaniline (1c 1c) and 3-chloro-41c methoxyaniline (1g 1g) 1g were successfully converted into their corresponding 5-amino-4-cyano-1,2,3-triazoles products (4c 4c and 4g) 4g in good yield (Table 3, entries 1 and 2) at room temperature. Under the same conditions, methyl 4-

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aminobenzoate (1 1i) and 4-amino-N,Ndimethylbenzenesulfonamide (1j 1j) 1j were readily processed and no precipitate was observed throughout the flow sequence (Table 3, entries 3 and 4). Triazoloquinazoline (4l 4l) 4l was obtained from 2-aminoacetophenone (1l) 1l) following a subsequent intramolecular condensation between the amino group and the pendent ketone moiety of the aminotriazole product. Finally, when 1,3-cyclohexanedione was used as the dipolarophile (Table 3, entries 6 and 7), fused 1-aryl-triazoles were obtained in good yields.

Table 3. Scope study for telescoped diazotization / azidodediazotization / Huisgen dipolar cycloaddition flow reaction sequence. sequence.[a]

the continuous flow system (see supporting information). Yields are based on the volume of the aniline solution infused over 90 min (2.97 mL, 1.47 mmol of the aniline infused at 16.5 µmol/min). [b] Solution 4 was comprised of 1,3cyclohexanedione (2 equiv.) in DMSO. [c] Reactor 3 was heated at 60°C.

CONCLUSION In this manuscript, the telescoped synthesis of various triazole products from a variety of commercially available anilines has been achieved using a versatile, high-yielding three-reactor flow process. Following a three steps diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition strategy, the flowed synthesis of aryl azides was promoted by means of an ultrasonic bath and the degassed segmented flow stream was collected into an intermediate reservoir. An automated continuous flow unit controlled by custom software developed by our group was used to continuously infuse the azide solution into both CuAAC and Huisgen dipolar cycloaddition reactors with carefully controlled stoichiometry, resulting in a wide reaction scope and good yields of the 1-aryl-[1,2,3]-triazoles products over the three steps.

EXPERIMENTAL SECTION

Entry

Aniline

Product

1c

4c

1

83%

2

80% 1g

4g

3

74% 1i

4i

4

82% 1j

4j

5

81% 1m

6

7

(Yield)[b]

1n

1o

4m 75%[b] 4n 72%[b] [c] 4o

[a] General conditions for the telescoped diazotization / azidodediazotization / Huisgen dipolar cycloaddition reaction sequence: solution 1 (aniline, 5 mmol, 0.5 M and CH3SO3H (1.1 equiv.) in DMSO), solution 2 (t-BuONO, 1.1 equiv. in DMSO), solution 3 (NaN3 (1.1 equiv.) in DMSO), solution 4 (malonitrile (2 equiv.) in DMSO) and solution 5 (DBU (2 equiv.) in DMSO) were placed in their respective syringes (i.e., solution 1 in syringe 1, etc.) and connected to

All anilines, t-butyl nitrite (t-BuONO), methane sulfonic acid (CH3SO3H), sodium azide (NaN3), copper iodide (CuI), diisopropylamine (i-Pr2NH), 1-ethynyl-4-methylbenzene, ethynylbenzene, malonitrile, 1,3-cyclohexanedione, 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) and dimethylsulfoxide (DMSO) were purchased from Sigma-Aldrich, Fisher Scientific and ACROS and used without further purification. Analytical Thin Layer Chromatography (TLC) was performed on EMD 60 F254 pre-coated glass plates and spots were visualized using UV light (254 nm). Column chromatography purifications were carried out using the flash technique on EMD silica gel 60 (230 - 400 mesh). NMR spectra were recorded on Bruker 300 MHz or 400 MHz AVANCE spectrometers. The chemical shifts for 1HNMR spectra are given in parts per million (ppm) referenced to the residual proton signal of the deuterated solvent; coupling constants are expressed in Hertz (Hz). 13CNMR spectra were referenced to the carbon signals of the deuterated solvent. The following abbreviations are used to describe peak multiplicities: s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of doublets, hex = hextet and m = multiplet. High Resolution Mass Spectrometry (HRMS) analysis was performed by the Mass Spectrometry and Proteomics Unit at Queen’s University in Kingston, Ontario. All continuous flow experiments were infused using a New Era syringe pump (NE-1600 and NE4000). Syringes were purchased from Becton Dickinson and company. Flow system polymer tubing and reactors were purchased from IDEX Health and Science LLC. Standard operating procedure for the synthesis of the CuCuAAC products (Table 2): Method A: The following solutions were prepared: Solution 1: the aniline (5 mmol, 0.5 M) and CH3SO3H (355 μL, 5.5 mmol, 0.55 M) in DMSO. Solution 2: t-BuONO (655 μL, 5.5 mmol, 0.55 M) in DMSO. Solution 3: NaN3 (358 mg, 5.5 mmol, 0.55 M) in DMSO. Solution 4: CuI (24 mg, 0.125 mmol, 0.0083 M), i-Pr2NH (500 µL, 3.5 mmol, 0.23 M) and

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1,10-phenanthroline (23 mg, 0,125 mmol, 0.0083 M) in DMSO. Solution 5: the alkyne (6.5 mmol, 0.43 M) in DMSO. Solution 6: neat DMSO. Each syringe containing their respective solution (i.e., solution 1 in syringe 1, etc.) were connected to the continuous flow system as described above, with reactor R2 submerged in a sonicator maintained at rt and reactor R3 placed in an oil bath at 60°C. Solutions 1, 2, and 3 were infused at a flow rate of 33 μL/min (residence time in R1 = 2.7 min; residence time in R2 = 5 min). Solutions 4 and 5 were infused at a flow rate of 50 μL/min whereas the continuous flow unit infused the crude azide at a flow rate of 99 μL/min (residence time in R3 = 20 min). Solution 6 was not infused. Before collection of the effluent, the crude reaction mixture was analyzed by TLC and 1H-NMR to ensure complete conversion of the aryl azide. After flowing for 90 minutes directly into a vessel containing water, the crude reaction mixture was extracted with ethyl acetate (2x10 mL), and the combined organic layers were dried over anhydrous MgSO4. Following filtration, the solvent was removed under reduced pressure and the residue purified by flash column chromatography using the indicated solvent system. Reaction yields are based on the volume of the aniline solution infused over 90 min (2.97 mL, 1.49 mmol of the aniline were infused following methods A or B (16.5 µmol/min). Method B: This method was similar to Method A except all concentrations were diluted down to half: [aniline] = 0.33 M; [CH3SO3H] = 0.36 M; [t-BuONO] = 0.36 M; [NaN3] = 0.36 M; [Cu] = 0.0054 M; [1,10-phenanthroline] = 0.0054 M, [i-Pr2NH] = 0.15 M, [alkyne] = 0.39 M. The neat DMSO in syringe 6 was infused at 400 µL/min. 1-(2(2-MethoxyMethoxy-4-nitrophenyl)nitrophenyl)-4-phenylphenyl-1H-1,2,31,2,3-triazole (3n) (Table 2, entry 14): Using method A described above O with 2-methoxy-4-nitroaniline N N (1a 1a) 1a and ethynylbenzene. The O 2N N flow process was run for 8 hours. After purification by flash column chromatography (50% AcOEt/hexanes, Rf = 0.36), 1.872 g of 3n (80%) were obtained as a white solid. Mp = 186 °C; 1H-NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.06 (dd, J = 8.7, 2.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 4.10 (s, 3H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ 150.7, 148.1, 148.0, 131.1, 130.1, 129.1, 128.7, 126.0, 125.2, 121.5, 116.9, 108.0, 57.0 ppm; HRMS (EI) calcd. for C15H12N4O3 296.0909 [M+]; found 296.0913. Standard operating procedure for the synthesis of the CuCuAAC products (Table 2): The following solutions were prepared: Solution 1: the aniline (5 mmol, 0.5 M) and CH3SO3H (355 μL, 5.5 mmol, 0.55 M) in DMSO. Solution 2: t-BuONO (655 μL, 5.5 mmol, 0.55 M) in DMSO. Solution 3: NaN3 (358 mg, 5.5 mmol, 0.55 M) in DMSO. Solution 4: 1,5-diazabicyclo(4.3.0)non-5-ene (2 equiv, 0.67 M) in DMSO. Solution 5: malonitrile (2 equiv., 0.67 M), or 1,3-cyclohexane-dione (2 equiv., 0.67 M) in DMSO. Each syringe containing their respective solu-

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tion (i.e., solution 1 in syringe 1, etc.) were connected to the continuous flow system as described above, with reactor R2 submerged in a sonicator maintained at rt and reactor R3 kept at rt. Solutions 1, 2, and 3 were infused at a flow rate of 33 μL/min (residence time in R1 = 2.7 min; residence time in R2 = 5 min). Solutions 4 and 5 were infused at a flow rate of 50 μL/min whereas the continuous flow unit infused the crude azide at a flow rate of 99 μL/min (residence time in R3 = 20 min). Before collection of the effluent, the crude reaction mixture was analyzed by TLC and 1H-NMR to ensure complete conversion of the aryl azide. After flowing for 90 minutes directly into a vessel containing water, the crude reaction mixture was extracted with ethyl acetate (2x10 mL), and the combined organic layers were dried over anhydrous MgSO4. Following filtration, the solvent was removed under reduced pressure and the residue purified by flash column chromatography using the indicated solvent system. Reaction yields are based on the volume of the aniline solution infused over 90 min (2.97 mL, 1.49 mmol of the aniline were infused (16.5 µmol/min). 1-(4(4-Nitrophenyl)Nitrophenyl)-1,5,6,71,5,6,7-tetrahydrotetrahydro-4Hbenzo[d][1,2,3]triazol][1,2,3]triazol-4-one (4n) (Table 3, entry 6): Following the standard operating procedure described above with 4-nitroaniline (1n 1n) and 1,31n cyclohexanedione, after purification by flash column chromatography (75% AcOEt / Hexanes, Rf = 0.40), 287 mg of 4n (75%) were obtained as a white solid. Mp > 190 °C; 1H-NMR (300 MHz, CDCl3) δ 8.46 (d, J = 9.0 Hz, 2H), 7,86 (d, J = 9.0 Hz, 2H), 3.05 (t, J = 6.1 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.27 (q, J = 6.6 Hz, 2H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ 190.2, 144.4, 142.5, 134.7, 133.2, 125.0, 123.9, 38.3, 23.2, 21.9 ppm Spectral data were in accordance with those described in the literature.9 1,2,3-Amino--1-(4 (4--chloro chloro--3-(trifluoromethyl)phenyl) (trifluoromethyl)phenyl)--1H-1,2,3 5-Amino triazoletriazole-4-carbonitrile (4c) (Table 3, entry 1): Following the standard operating procedure described above with 4chloro-3-(trifluoro)methylaniline (1c 1c) 1c and malonitrile, after purification by flash column chromatography (25% AcOEt/hexanes, Rf = 0.32), 353 mg of 4c (83%) were obtained as a white solid. Mp = 150 °C; 1H-NMR (300 MHz, d6-dmso) δ 8.09 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 8.6, 1H), 7.93 (dd, J = 2.5, 8.6 Hz, 1H), 7.38 (s, 2H) ppm; 13C{1H} NMR (100 MHz, d6-dmso) δ 148.4, 133.2, 133.1, 132.0, 131.0, 128.0 (q, J = 32.4 Hz), 125.2 (q, j = 5.6 Hz), 122.2 (q, J = 273.5 Hz), 113.3, 101.3 ppm; HRMS (EI) calcd. for C10H5ClF3N5 287.0186 [M+]; found 287.0178.

ASSOCIATED CONTENT Supporting Information It includes detailed experimental procedures, their optimization, pictures of the flow process, a description of the continuous flow unit, and a full characterization for all compounds prepared.

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Organic Process Research & Development Chem., 2014, 85, 65-76; (n) Solum, E. J.; Vik, A.; Hansen, T. V., Steroids, 2014, 87, 46-53.

AUTHOR INFORMATION Corresponding Author * M. G. Organ, Director, Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry, University of Ottawa, Ottawa, Ontario, K1N6N5 (Canada)

Email: [email protected]

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(a) Price, G. A.; Bogdan, A. R.; Aguirre, A. L.; Iwai, T.; Djuric, S. W.; Organ, M. G., Catal. Sci. Technol., 2016; (b) Tilley, M.; Li, G.; Savel,

Funding Sources This work was supported by NSERC (Canada)

Notes The authors declare no competing financial interest.

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Teci M., Tilley M., M. A. McGuire, M. G. Organ, Chem. Eur. J., 2016, accepted for publication

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