Photoredox IridiumâNickel Dual-Catalyzed Decarboxylative Arylation

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Photoredox Iridium-Nickel Dual Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor Hsiao-Wu Hsieh, Connor W. Coley, Lorenz Baumgartner, Klavs F. Jensen, and Richard I. Robinson Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00018 • Publication Date (Web): 26 Mar 2018 Downloaded from http://pubs.acs.org on March 26, 2018

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Organic Process Research & Development

Photoredox

Iridium-Nickel

Dual

Catalyzed

Decarboxylative

Arylation Cross-Coupling: From Batch to Continuous Flow via SelfOptimizing Segmented Flow Reactor Hsiao-Wu Hsieh,1 Connor W. Coley,2 Lorenz M. Baumgartner,2 Klavs F. Jensen,*,2 Richard I. Robinson*,1 1

Global Discovery Chemistry – Chemical Technology Group, Novartis Institutes for Biomedical

Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States 2

Department of Chemical Engineering, Massachusetts Institute of Technology, 77

Massachusetts Avenue, Cambridge, MA 02139, United States KEYWORDS: Flow chemistry, droplet microfluidics, micro-reactor, photoredox crosscoupling, process development, reaction optimization

ABSTRACT: Photoredox decarboxylative cross-coupling via iridium-nickel dual catalysis has emerged as a valuable method for Csp2-Csp3 bond formation. Herein, we describe the application of a segmented flow (“microslug”) reactor equipped with a newly designed photochemistry module for material-efficient reaction screening and optimization. Through the deployment of a self-optimizing algorithm, optimal flow conditions for the model reaction were rapidly developed, simultaneously accounting for the effects of continuous variables (temperature and time), and discrete variables (base and catalyst). 1

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Temperature was found to be a critical parameter with regard to reaction rates and hence productivity in subsequent scale-up in flow. The optimized conditions identified at microscale were found to directly transfer to Vapourtec UV-150 continuous flow photoreactor, enabling predictable scale-up operation at hundreds of milligrams per hour scale. This optimization approach was then expanded to other halide coupling partners that were low-yielding in batch reactions, highlighting the practical application of this optimization platform when developing conditions for photochemical synthesis in continuous flow.

Table of Content Art

Introduction Ir-Ni dual catalyzed photoredox chemistry has witnessed rapid growth in both academia and industry in the last decade, thanks primarily to newly developed photocataylsts, improved LED technology, and deeper understanding of the single electron transfer mechanism.1-7 Compared to traditional two-electron-based cross-coupling reactions,8,9 photoredox chemistry uses relatively non-hazardous reagents and is often conducted under ambient temperature, providing a milder 2


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alternative method for forging carbon-carbon bonds. Early developments by MacMillan, Doyle, Molander, and others (Figure 1)10,11 in the field of photoredox cross-coupling applying Ir-Ni dual catalysis have demonstrated a range of substrates towards challenging C-C bond formation, including their asymmetric varients.12-14 While the methodology allows the introduction of highly desirable Csp3-Csp2 and Csp3-Csp3 fragments,15-17 the reactions are generally slow in a batch setting (12-72 h), and often prone to substrate-dependent anomalies. Reproducibility can also be a challenge, which can be exacerbated through inefficient light irradiation and lack of both standardized instrumentation and operating procedures.18 Moreover, the effect of temperature on photoredox reactions is seldom addressed and is often a neglected concern. Without proper temperature control, competing side reactions (such as de-halogenation, solvent couplings and homo couplings) have been reported, which can lead poor reaction performance or complicated reaction mixtures.16,19-21

Figure 1. Proposed mechanism of Ir-Ni catalyzed Csp3-Csp2 photoredox cross-coupling15

3



Converting batch reactions to flow has many advantages in terms of improving yield and productivity, particularly in photoredox chemistry.22-23 According to the Beer-Lambert Law, the light intensity (photonic flux) decreases exponentially with the depth in a given reaction medium, which suggests the visible-light photoredox reaction might only take place in the proximal area of the vessel wall (i.e. within 2-3 mm).22b,24 Flow chemistry conducted in transparent 1/16” to 1/8” OD (1.6 mm to 3.2 mm) fluorinated ethylene propylene (FEP) tubing not only ensures the sufficient photonic flux exposure to the reaction mixture but also provides better heat and mass transfer, which can result in improved reaction yield and scale-up robustness. On its merits, this approach has been adapted in both academia and industry research labs in recent years.25-30 In order to bridge the reaction development gap between traditional batch and flow chemistry, Jensen and co-workers have developed a fully automated segmented flow reactor for screening and optimization (Figure 2a).31-32 Segmented flow reactions are akin to miniaturized batch reactions with flow chemistry characteristics, which make the screening platform a useful tool for developing batch-to-flow processes.

While very impressive high-throughput screening

techniques have been introduced by the pharmaceutical industry,33 the flexibility of adjusting both reaction time and temperature for every individual experiment remains challenging. One of the important advantages of this system is, as a complementary method to the traditional platebase screening, is that it provides the ability to explore both continuous (e.g. temperature and residence time) as well as non-continuous variables (e.g. catalyst, base) simultaneously with high material efficiency.

Recent examples highlighting the experimental efficiency of utilizing

automated data feedback loops combined with algorithms for the self-adjustment of experimental conditions (self-optimization), show great potential in the field of reaction optimization and process development.34 4


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Controlled by custom LabVIEW and MATLAB codes, the system integrates a liquid handler, syringe pumps, switching valves, and an oscillatory reactor, with an integrated analytical HPLC unit. The generated droplet “microslug” (total volume of ~ 15 µL) represents a discrete reaction. Those droplets are prepared sequentially for each cycle, using approximately 0.1-0.5 mg material at a time. A recently developed self-optimization algorithm was deployed on the platform to perform real-time optimization of reaction conditions with less human intervention.34a,35-36 In order to demonstrate the system’s capability to a photoredox cross-coupling reaction of interest, a custom photochemistry module was integrated with the previously disclosed oscillatory flow reactor (Figure 2b). The photochemistry module is water-cooled, and is heated with electrical cartridge heaters, resulting in an operating temperature between 20-70 °C within error 1 °C. An additional consideration particularly relevant to photo-catalyzed reactions is that the tubing dimensions (hence the irradiating depth) deployed for the segmented flow reactor is identical to the Vapourtec scale-up system.

Figure 2. (a) Overview of the segmented flow reactor (adapted with permission from Chem. Commun. 2017, 53, 6649-6652. Copyright © 2017 The Royal Society of Chemistry) (b) Photochemistry module to accommodate OFR (designed by Novartis) 5



In this work, building on our previous knowledge of this system, we demonstrate a successful transition from batch to flow as a part of the process development of the photoredox decarboxylative arylation, using the segmented oscillatory flow reactor for reaction screening and optimization. The conditions found at the 15 µL scale are transferred to a Vapourtec E-series equipped with a UV-150 10-mL photoreactor, enabling sub-gram per hour production (Figure 3).

Figure 3. Workflow: (1) Validation; (2) screening and optimization; (3) production and scale-up

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Result and Discussion In order to avoid clogging in the tubular flow reactors and develop a homogenous reaction system, the study began with the investigation of suitable organic bases to replace carbonates (e.g. Cs2CO3) in typical photoredox decarboxylative arylation.10,28 Table 1. Base screening using a standard batch photoreactor

a

Conjugated acid pKa in b H2O (DMSO)

Entry

Base

HPLC Yield

1

Cs2CO3

84%

10.3 (N/A)

2

NEt3

0%

10.7 (9.0)

3

2,6-Lutidine

0%

7 (4.5)

4

DBU

83%

5

TMG

87%

13 (ACN: 23)

6

tBu-TMG

91%

14 (ACN: 24)

7

Me-TBD

78%

13 (ACN: 29)

8

NaOtBu

81%

16.5 (N/A)

a

13.5 (ACN: 24) (DMSO: 12)

0.125 mmol scale reactions. 20 mol% of internal standard (biphenyl) was added to determined HPLC yields. Calibration curves were established under 254 and 280 nm UV absorption. b Croat. Chem. Acta 2014, 87, 385-395; J. Org. Chem. 2005, 70, 1019-1028 7



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N-Benzyloxylcarbonyl-L-proline (1, Cbz-Pro-OH) and 4’-bromoacetophenone (2) were chosen to be the coupling partners, giving the corresponding Csp2-Csp3 coupled benzylic amine compound 3. Triethylamine and 2,6-lutidine were the first two bases to test because of their similarity in conjugate acid pKa values with carbonates.

Although both bases led to

homogenous reaction mixtures, no product was observed after 16 h of irradiation and vigorous stirring (Table 1, entries 2 and 3).

Next, three commonly used strong organic bases: 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG) and 2-tert-butyl1,1,3,3-tetramethylguanidine (tBu-TMG or Barton’s base) were applied. These bases led to yields ranging from 83% to 91% with complete consumption of starting material (Table 1, entries 4-6) . To try to accelerate the reaction further, a stronger and more rigid base, 7-methyl1,5,7-triazabicyclo[4.4.0]dec-5-ene (Me-TMD),37 was also tested.

Me-TMD gave full

consumption of the starting material, but led to slightly lower yields, presumably due to the competing side reactions of de-bromination and/or aldol condensation of the ketone group (Table 1, entry 7). To avoid unwanted metal chelation, sodium tert-butoxide was also tested as a nonnitrogen containing base, which led to full conversion but only 81% final yield (Table 1, entry 8). It is worth noting that the tert-butoxide is highly hygroscopic. Without proper sealing of the reaction vessel, the reaction mixture tends to form gel like precipitates, which introduces a clogging risk for flow reactors over time. The batch reactions were initially conducted as 0.05 M solutions with respect to compound 2 at the 0.125 mmol scale (~25 mg). An initial attempt to scale-up the reaction (4-fold, 0.5 mmol, ~100 mg) was attempted in batch. At this scale, the reactions became sluggish, requiring prolonged reaction time, leading to low yields. This is likely due to inefficient irradiation as a result of using larger reaction vessels (supporting information Figures S9 and S10), confirming 8


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our rationale to develop a flow process. Before committing a larger quantity of material to develop a flow procedure, the segmented flow reactor was used to screen organic bases over a range of residence time and temperature settings.

Figure 4. Using oscillatory segmented flow reactor to obtain reaction profile: (a) Organic base screening; (b) temperature screening, tBu-TMG; (c) temperature screening, DBU

The results of photoredox decarboxylative arylation using five different organic bases are shown in Figure 4. In order to gain insights into the reaction rates with different bases, the automated system was pre-defined with experimental conditions (run in duplicate) to investigate the key parameters of both residence time and temperature. Plotting yield versus residence time, reaction profiles of each base were initially obtained at a fixed temperature of 30 °C (Figure 4a). 9



We found that the two guanidine type bases, Barton’s base and TMG, afforded the highest reaction yield (95%) in 30 min. DBU and sodium tert-butoxide were less efficient at around 70% yield, whereas the Me-TBD plateaued at around 40% due to significant side-product formation. Next, by elevating the temperature from 30 to 50 °C, we observed the acceleration of the reaction in both Barton’s base and DBU cases (Figures 4b and 4c). Generally, all reactions were completed within 20 min. Compared to the initial batch study, the improvement (16 h to 20 min) in reaction rate is ideal for enabling rapid reaction condition screening and optimization.

Figure 5. Using oscillatory segmented flow reactor to obtain reaction profile: (a) Varying Ir-catalyst loading; (b) varying Ni-catalyst loading; (c) replacing Ir-catalyst with organic dye 4CzIPn, and then varying 4CzIPn loading

10


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The system’s capability of changing both continuous and discrete variables was demonstrated by fixing the Ir catalyst and varying Ni catalyst loading, and vice versa, to validate the optimal combination of the dual catalyst system (Figures 5a and 5b).

In Figure 5a, the Ir catalyst was

dosed from 0.5 mol% to 2.0 mol% in the model reaction with fixed 10 mol% of Ni catalyst. The reaction did not exhibit a significant change in reaction profile, suggesting the Ir catalyst was robust enough to generate radicals efficiently, even in a relatively low loading. On the other hand, in Figure 5b, the model reaction’s Ni catalyst loading was varied from 2.5 mol% to 20 mol% with fixed 2 mol% of Ir catalyst. The reaction rates increased significantly with increasing Ni catalyst loading, suggesting involvement of this catalyst in the rate determining step. This is also consistent with literature catalyst ratios typically described in early papers.10,11 An organic dye, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-benzene (4CzIPN), has been shown to be an effective photoredox catalyst in decarboxylative arylation.38,39 It is relatively easy and less expensive to prepare, making it a potential replacement of the expensive metalbased (Ir or Ru) catalysts. The organic dye catalyst (4CzIPN) with 1, 2, 4, and 8 mol% catalyst loadings was applied to the model reaction and the results were shown in Figure 5c. The conditions using organic dye seemed to reach maximal yields faster, but the conversion flattened after 15 min, giving final yields ranging from 60-70%, whereas the standard 2 mol% Ir catalyst could reach 95% yield in 20 min. According to our results so far, the substitution of Ir catalyst with 4CzIPN is feasible. Further cost-effective investigation of the reaction is ongoing within our labs.

11



Figure 6. Summary of self-optimizing base screening results: (a) Visualization of yields and productivities; (b) Self-optimization result (arrows) agrees with manual pre-defined screening (points).

After this preliminary pre-defined screening approach, we sought to utilize a self-optimization algorithm approach to maximize yield and productivity simultaneously. The custom MATLAB code applied was a modified algorithum evolved from previous work into solvent effects in SN2 alkylations and catalyst selection for Suzuki-Miyaura cross-couplings.34-36 By specifying ranges of the continuous variables (i.e. temperature and residence time) and different choices of discrete variables (i.e. different base and catalyst identities), the code initiates a minimal D-optimal set of 12


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experiments and creates response surfaces for each discrete variable using a quadratic response surface model.36,40 Next, these surfaces are iteratively refined to identify the best performing discrete variable, which is expected to lead to the global optimum. During this refinement, the poor-performing discrete variables, accounting for model uncertainty, are removed from consideration. New experiments with the better-performing discrete variables and different continuous variable combinations are chosen using a G-optimal strategy.

In this way, the

model’s confidence in its predicted optimum outcome becomes higher after every experimental iteration.36 It is also worth noting that the objective function (productivity) was defined as the total yield divided by the residence time (to penalize long time reactions). The optimization was constrained to maintain at least 95% of the maximal yield. To test if the self-optimizing algorithm agreed with our manual pre-defined screening results, the decarboxylative arylation model reaction was chosen for validation (Figure 6).

The two

continuous variables, temperature and residence time, were set between 30 to 50 °C and 5 to 30 min respectively. The three organic bases (Barton’s base, DBU and Me-TBD) were set as discrete variable conditions for the system to choose from. The objective was to find the maximal yield and constrained optimum productivity conditions in the defined operating window. After a total 22 experiments and 12 h non-stop operation, the system successfully predicted the condition leading to the maximum of 97% yield using Barton’s base at 43 °C with 21 min of residence time. The maximal productivity condition was found at 91% yield using the same base with slightly higher temperature of 50 °C with just 12 min of residence time. Both conditions were validated twice in microslugs with yields matching both predicted values within 1% yield. With reduced experimental time and fewer experiments, the self-optimizing algorithm pleasingly reached the same ultimate conclusion as the extensive pre-defined screening 13



conditions (Figure 6b), demonstrating the systems capability to successfully identify optimal conditions.

Figure 7. Summary of self-optimizing Ni pre-catalyst screening result

The self-optimization scope was expanded to include the Ni pre-catalysts (Figure 7). The flexibility of choosing discrete variables suggests the system could potentially be a platform for new catalyst development.

Four Ni pre-catalysts commonly found in Ir-Ni dual catalyzed

reactions were chosen and prepared according to the literature procedures, using NiCl2•glyme and corresponding bidentate ligands (A: 4’4’-di-tert-butyl-2,2’-dipyridine, B: 4,4’-dimethoxy2,2’-dipyridine, C: 2-pyridinecarboximidamide and D: 4-methoxy-2-pyridinecarboximidamide) under THF reflux conditions.10,41-44 The pre-catalyst self-optimizing experiment was set up 14


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using

similar

variables

as

disclosed

above

(Supporting

Information):

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), Barton’s base (1.5 equiv.), temperature (30-50 °C) and residence time (5-30 min) as the continuous variables, and four choices of Ni pre-catalysts as discrete variables.

After 25 experiments and 18 h of total experiment time, the predicted

maximal yield condition was found to be 93% using NiCl2(dtbbpy) at 50 °C with around 20 min of residence time, whereas the predicted optimal productivity condition had 91% yield using the same pre-catalyst at 50 °C with around 12 min of residence time (Figure 7). Table 2. Demonstration of transferability: Microslug conditions to Vapourtec UV-150 10-mL flow reactor

a

b

Entry

Base

Batch, HPLC Yield

Microslug, HPLC Yield

Vapourtec UV-150 c Condition (Flow Rate)

Vapourtec UV-150 Isolated Yield & Production Rate

1

NaOtBu

81%

70%

35 °C, 20 min (0.50 mL/min)

71%, 115 mg/20 min = 345 mg/h

2

DBU

83%

75%

35 °C, 20 min (0.50 mL/min)

77%, 124 mg/20min = 372 mg/h

3

tBu-TMG

91%

95%

40 °C, 20 min (0.50 mL/min)

94%, 145 mg/20 min = 435 mg/h

tBu-TMG

N/A

92%

50 °C, 12 min (0.83 mL/min)

88%, 142 mg/20 min = 710 mg/h

4 a

0.125 mmol scale, 0.05 M, rt, 16 h 0.125 mmol sacle, 0.05 M, Entries 1, 2 and 3: 20 min; Entry 4: 12 min c 0.500 mmol scale, 0.05 M, Entries 1, 2 and 3: 20 min; Entry 4: 12 min b

The concept of transferability between systems was demonstrated in Table 2 using standard 0.05 M decarboxylative arylation. First, overnight batch reactions at the 0.125 mmol scale using NaOtBu, DBU, and tBu-TMG were conducted, leading to HPLC yields of 81%, 83% and 91% respectively. Based on the knowledge from the previous optimization results, 40 °C and 20 min residence time were applied to the microslug reactions using NaOtBu, DBU, and tBu-TMG, 15



which gave yields of 70%, 75%, and 95% respectively.

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Next, the same combinations of

temperature and residence time were transferred to the corresponding flow rate on the Vapourtec UV-150 flow reactor, conducting 0.5 mmol scale reactions. Note that the irradiation sources are not identical between the two platforms, but both offer high intensity illumination.

The

continuous flow reactions gave 71%, 77% and 94% isolated yields, which were within error of the HPLC yields obtained in microslug experiments. In terms of the final production rate, the Vapourtec UV-150 flow reactor could generate 345 to 435 mg of product per hour (Table 2, entries 1, 2 and 3). The predicted optimal productivity conditions for 3 (50 °C and 12 min residence time) were applied to the Vapourtec UV-150 flow reactor, which led to an isolation yield of 88% and an improved production rate of 710 mg per hour (Table 2, entry 4). This reaction was also conducted at the 1.5 mmol scale using both maximal yield and optimal productivity conditions (i.e. conditions in Table 2, entries 3 and 4) at least two times. The results led to 95% and 89% isolated yields respectively under steady-state conditions, which demonstrated the transferability from microslug to continuous flow for the chemistry considered. The direct transfer based on conditions (concentrations, temperature, and residence time) works in this case as the light activation is not the rate determining step. Had the reaction been photon flux limited, it would have been necessary to include photon flux intensity differences in selecting operating conditions for the scale-up from the microslug results. At this point, a conceptual workflow of batch-to-flow process development using segmented flow self-optimizing reactor had been successfully established. To ensure the protocol was not limited to the model substrate, 4’-chloroacetophenone (4), 5-acetyl-2-bromopyridine (5), 1bromo-4-ethylbenzene (7), 4-ethyl-1-iodobenzene (9) were selected to validate the process development via microslug approach (Table 3). These aryl halides are less reactive than 4’16


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bromoacetophenone (2) in batch settings, typically exhibiting low yields (< 50%) and long reaction times (16-72 h). Nevertheless, after several parallel batch reactions, the corresponding coupling products (3, 6 and 8) were isolated in sufficient quantities for developing HPLC calibration curves (supporting information), prior to the microslug self-optimizing operation.

Table 3. Optimization workflow: From batch to continuous flow via microslug

Ar-X

Batch Conditiona

Microslug Optimized Conditionb

Vapourtec Flow Conditionc

Vapourtec Flow Reaction Isolated Yield & Production Rate

rt, 72 h (14%)

65 °C, 40 min (75%) 65 °C, 37 min (69%)

65 °C, 0.25 mL/min, 40 min (79%)

78%, 125 mg/40 min = 189 mg/h

rt, 16 h (45%)

40 °C, 30 min (94%) 50 °C, 7 min (89%)

40 °C, 0.33 mL/min, 30 min (89%) 50 °C, 1.42 mL/min, 7 min (73%)

rt, 72 h (24%)

55 °C, 40 min (83%) 55 °C, 33 min (78%)


73%, 114 mg/40 min = 171 mg/h 65%, 100 mg/33 min = 182 mg/h

rt, 72 h (51%)

44 °C, 40 min (77%) 48 °C, 25 min (73%)


65%, 101 mg/40 min = 152 mg/h 62%, 95 mg/33 min = 173 mg/h

Product

83%, 134 mg/30 min = 268 mg/h 66%, 107 mg/7min = 917 mg/h

a

0.05 M, 0.125 mmol (~25 mg) scale; HPLC yields in parentheses 0.05 M, 0.002 mmol (~0.5 mg) scale: Optimizing range: 5-40 min, 30-55 °C or 40-65 °C; Top: Maximal yield condition; Bottom: Optimal productivity condition; HPLC yields in parentheses c 0.05 M, 0.500 mmol (~100 mg) scale.

b

Since these reactions were low-yielding and slow, the self-optimizing screening window was extended to 5-40 min and either 30-55 °C or 40-65 °C. Within these screening ranges, all reactions tended to benefit from elevated temperature conditions. 17


Among them, 4’-


chloroacetophenone (4) coupling was significantly improved at higher temperature. For example, using 65 °C and 40 min residence time, the originally 14% yield batch reaction was improved to a 78% isolated yield in flow, with a production rate around 189 mg per hour (Table 3, entry 1). Using 5-acetyl-2-bromopyridine (5), the 45% yield batch reaction was optimised to 94% yield at 40 °C and 30 min residence time. Optimal productivity (at 89% yield) was found by increasing the temperature to 50 °C with just 7 min residence time. Applying both maximal yield and optimal productivity conditions to the Vapourtec UV-150 flow reactor led to an 83% isolated yield with 268 mg per hour production rate, and a lower than expected 66% isolated yield with 917 mg per hour production rate (Table 3, entry 2). Consistent with literature reports,10,17 aryl halides lacking electron-withdrawing groups or heteroatoms were found to be less reactive in decarboxylative cross-coupling reactions. The p-ethyl substituted compound 8 could be derived from the corresponding bromide (7) and iodide (9) with 24% and 51% yields at rt in batch. After screening the temperature from 30-55 °C and residence time from 5-40 min, optimal conditions could be obtained with good yields ranging from 73-83%. Upon transferring to the conditions to the Vapourtec UV-150 flow reactor, 62%-73% isolated yields were obtained with hourly production rates ranging from 95 mg to 114 mg (Table 3, entries 3 and 4). Conclusion In summary, reaction conditions suitable for continuous flow photoredox Ir-Ni dual catalyzed decarboxylative arylation were developed using the fully automated self-optimizing segmented flow reactor, which can optimize both continuous variables (temperature and residence time) and discrete variables (bases and catalysts) in a relatively short period of time. Of note was the importance of temperature control (dependent on substrate), where we have demonstrated that 18


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elevated temperatures often benefit the reaction rate (and hence productivity) in a flow setting. The “microslug” screening platform has been shown to be robust and readily transferable to our scale-up reactors, hence shows promise as a tool to facilitate process development. The system is intended to work concurrently with existing batch- and plate-based screening techniques. Through utilizing this time- and material-efficient screening alternative, valuable reaction profiles and optimal conditions can be quickly obtained. Extending the platform towards to a broader range of chemistry transformations is an ongoing effort as a holistic approach to flow chemistry development.

Meanwhile, continuing effort on both hardware and software

improvements will render this platform even more user-friendly and autonomous. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS publication website at DOI:10.1021/acs.oprdXXXXXXX. Experiment procedures and full characterization (1H NMR, 13C NMR, HRMS, HPLC retention time) for all compounds. (PDF)

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected]

19



Notes The Authors declare no competing financial interest. ACKNOWLEDGMENT This work is supported by Novartis-MIT Center for Continuous Manufacturing and the Education Office of Novartis Institutes for Biomedical Research (H.-W H.). We would like to thank Dr. Mitchell Keylor and Dr. Kian Tan for the insightful discussions. We are grateful to Mr. Mike Fiorino and Mr. Cosden Leahey for the design and manufacture of the NIBR photochemistry module to enable this study. We also thank Mr. David Dunstan for HPLC set-up and method development. REFERENCES (1)

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