Study of a Competing Hydrodefluorination Reaction During the

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Study of a Competing Hydrodefluorination Reaction During the Directed ortho-Lithiation/Borylation of 2‑Fluorobenzaldehyde ́ y Angelaud, and Francis Gosselin Fred́ eŕ ic St-Jean,* Katarzyna A. Piechowicz, Lauren E. Sirois, Rem Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States

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S Supporting Information *

ABSTRACT: A single-flask ortho-lithiation/borylation of 2fluorobenzaldehyde, using a “traceless” amino alkoxide directing group, is described. Reaction conditions were explored in detail to identify the effects on and to minimize the formation of a problematic desfluoro impurity observed in the course of development. The mechanism of hydrodefluorination was probed to lend support to a benzyne pathway and interrogate the source of a postulated hydride nucleophile. Process analytical technology (PAT), in the form of ReactIR, was utilized to define the operating conditions for the ortho-metalation and borylation steps, and following this optimization, 3-fluoro-2-formylphenylboronic acid was prepared in an efficient throughprocess in high quality as a building block toward an active pharmaceutical ingredient.

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been utilized previously,3 and an adapted approach was also successful in our laboratories. However, in addition to necessitating cryogenic conditions, the strategy requires at least three steps (including protecting group manipulation) and relies on “pre-oxidation” of the starting material as the aryl bromide. The latter would also be true for Miyaura borylation5 or other metal-catalyzed approaches from aryl halides and similarly oxidized substrates. A more direct installation of boronic acid or ester functionality could in theory be performed from the even more economical6 2-fluorobenzaldehyde, via a transition metal catalyzed C−H borylation.7 However, this method would still likely involve either protection of the aldehyde or preinstallation of a directing group in a separate step to achieve high regioselectivity, and, moreover, can require precious metals or expensive ligands. Even methods that feature impressive catalyst/reagent regiocontrol or leverage imine formation as the protecting/directing functionality may still be complementary to desired selectivity,8 and/or reaction efficiency may not meet the high bar required for large-scale pharmaceutical manufacturing. Inspired by the seminal work of Comins9 and more recent applications10 thereof using other ligands, we were particularly intrigued by the alternative possibility of generating an αamino alkoxide in situ, thereby protecting the aldehyde from nucleophilic attack11 and simultaneously directing a subsequent ortho-deprotonation/metalation (Scheme 1).12,13 Following borate quench, an acidic workup could easily reveal the aldehyde while furnishing the desired phenylboronic acid in a

INTRODUCTION The incorporation of carbon−fluorine bonds into active pharmaceutical ingredients (APIs) has become a widespread strategy to enhance in vivo metabolic stability, modulate protein−ligand interactions, or otherwise improve the pharmacokinetic properties of therapeutic small molecules.1 In some cases, particularly during drug discovery efforts, fluorine can be introduced at a late stage in the synthesis via a number of recent methods developed for increasingly selective and mild fluorination.2 However, as manufacturing routes evolve during development of a lead therapeutic candidate, it may be more practical to incorporate the carbon−fluorine bond of interest by building an advanced synthetic intermediate from a fluorinated commodity chemical. We found this to be the case during the process development of an API in our portfolio, for which 3-fluoro-2-formylphenylboronic acid (1) was required in large quantities as a key building block.3 Starting from a synthon such as 3-fluorobromobenzene (2), compound 1 can be accessed in a sequence featuring metal amide-mediated formylation; then, after suitable protection of the aldehyde moiety (as the dialkylacetal), a halogen−metal exchange4 using n-butyllithium (n-BuLi) can be followed by a trialkylborate quench and hydrolysis (Figure 1). This route has

Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Figure 1. Retrosynthetic approaches to 3-fluoro-2-formylphenylboronic acid (1). © XXXX American Chemical Society

Received: October 8, 2018

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DOI: 10.1021/acs.organomet.8b00730 Organometallics XXXX, XXX, XXX−XXX

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defluorination reaction occurring during the DoM/borylation sequence (Scheme 2). Sources of boronic acid 1 (such as resulting from a halogen−metal exchange preparation) that previously had been taken forward in the large-scale synthesis of an API did not contain detectable levels of 5, and thus the purging of the latter, and its derivatives, throughout the sequence was unknown. The tracking and removal of structurally related and/or similarly reactive desfluoro impurities down to levels appropriate for use in a drug product can pose a significant challenge for pharmaceutical manufacturing.17 This challenge was confirmed by initial efforts to purify 1 using scalable isolation methods such as (re)crystallization, which in many circumstances would be adequate for removal of low-level impurities. However, guided by solubility data for both 1 and 5 (see the Supporting Information), examination of a small subset of solvent mixtures in recrystallization and reslurry experiments with 1 demonstrated that any reasonable purging of desfluoro impurity 5 (for example, from 1.5 down to 0.5 A%, Table 1, entry 4) was generally accompanied by

Scheme 1. Tandem Amino Alkoxide Formation/orthoMetalation/Borylation Strategy To Access 3-Fluoro-2formylphenylboronic Acid (1)

single-vessel operation. Attack of aryllithium species generated from α-amino alkoxides to a number of electrophiles has been well-described, although applied only in limited cases for borylation.14 During the optimization to develop this tandem directed ortho-metalation (DoM)/borylation process on 2fluorobenzaldehyde, a competing hydrodefluorination reaction was observed, which consistently resulted in low but problematic levels of a difficult-to-purge desfluoro impurity. Studies to understand and mitigate this undesired pathway are described herein.

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Table 1. Recrystallization and Reslurry Experiments to Purify Boronic Acid 1 and Remove Desfluoro Impurity 5

RESULTS AND DISCUSSION In an early attempt to effect the single-vessel ortho-borylation of 2-fluorobenzaldehyde (4), we evaluated conditions from the literature10 that made use of the deprotonated bis(2methoxyethyl)amine (BMEA) ligand to form an α-amino alkoxide.15 In our case, following 1,2-addition to the aldehyde in a THF/heptane mixture (1:4, v/v) and aryl C−H lithiation by an additional portion of n-BuLi (2.5 M in hexanes), trimethyl borate16 was employed as the electrophile (Scheme 2). In this way, a high conversion (>95% by HPLC analysis) of

entry

solvent(s) (mL/g)

1 2a 3 4 5 6

toluene (10) DCM (10) amyl acetate (6) IPAc (10)/heptane (3) MTBE (10)/heptane (4) EtOAc (5)/heptane (5)

Scheme 2. Initial Example of the ortho-Borylation of 2Fluorobenzaldehyde Using Bis(2-methoxyethyl)amine (BMEA) as Directing Group

temp. ramp (°C) 95 40 65 80 55 65

to to to to to to

22 22 0 22 22 22

recovery of 1b

5 (A%)c

40% 96% 85% 56% 68% 72%

0.3 1.5 1.4 0.5 0.8 1.5

a

Reslurry experiment; material did not fully dissolve. bIsolated yield of 1 after filtration and drying. cDetermined by HPLC analysis (210 nm).

unacceptably low recovery (85% conversion), neither evidence of desfluoro 9 was observed during the formation of 8 after borate quench/ saponification nor was 3-methylbenzaldehyde (from defluorination of 7) found in quenched reaction aliquots prior to Stage III, thus providing support for a well-precedented benzynebased mechanism as the dominant side reaction.26 Having

a

Stage I: BMEA (1.1 equiv), n-BuLi (1.1 equiv, 2.5 M in hexanes), THF/heptane (1:4, v/v). bStage I: BMEA (1.05 equiv), n-BuLi (1.05 equiv, 2.5 M in hexanes), THF/heptane (1:4, v/v). cStage II: n-BuLi (1.2 equiv), 2−3 h total. dStage II: n-BuLi (1.1 equiv), 3 h total. e Relative conversion of 2-fluorobenzaldehyde at Stage III, determined by HPLC analysis (254 nm) after borate quench. fRelative A% of desfluoro 5 versus 1 in aqueous layer (HPLC, 210 nm) following hydrolysis at Stage IV. gBorate quench (Stage III) performed at −40 to 0 °C.

defluorination (Table 3). Relatively little change in the final amount of desfluoro 5 was observed across these conditions, even at lower, carefully controlled internal temperature and lower overall conversion (Table 3, entry 2) or when n-BuLi was added across the duration of Stage II by action of a syringe pump (entries 3−4). Because this transformation was being developed to compete with and improve upon processes requiring cryogenic conditions (e.g., halogen−metal exchange), temperatures below −40 °C were not investigated. In fact, the lower temperature (entry 2) significantly slowed the desired ortho-lithiation relative to the undesired pathway leading to impurity 5. C

DOI: 10.1021/acs.organomet.8b00730 Organometallics XXXX, XXX, XXX−XXX

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deuterio-2-fluorobenzaldehyde27 (deuterio-4, Scheme 5) and subjected it to DoM/borylation conditions.28 In this instance,

Table 5. Screen of Organolithium Bases for DoM/ Borylation of 2-Fluorobenzaldehyde

Scheme 5. Amino Alkoxide Directed ortho-Lithiation of Deuterated Benzaldehyde 4 and Analysis of Deuterated Desfluoro 5 entrya

base source (stage II)

1b 2b 3b,c 4d

n-BuLi 2.5 M in hexanes n-BuLi 2.5 M in hexanes n-BuLi 2.5 M in hexanes sec-BuLi 1.4 M in cyclohexane PhLi 1.9 M in Bu2O MeLi 1.6 M in Et2O MeLi 1.6 M in Et2O MeLi 3.1 M in (EtO)2CH2

5d 6b 7d 8d

equiv, timee

conv. (%)f

yield (%)g

5 (A%)h

84

1.5 1.5 1.2 14

1.2, 1.5, 1.1, 1.2,

3 3 3 3

h h h h

98 97 97 98

1.2, 1.2, 1.2, 1.5,

6h 6h 6h 16 h

51 75 78 95

38 48 72 80

sec-BuLi was used in place of n-BuLi during Stage II to increase the amount of desfluoro side-product (vide infra, Table 5), and the peak corresponding to this species was isolated separately by preparative HPLC, analyzed by 1H NMR spectroscopy, and identified as deuterio-5 (Scheme 5). In this desfluoro material (deuterio-5), neither was evidence of deuterium transfer to the aryl ring observed nor were we able to find evidence of the corresponding 2-fluoro-bis(2-methoxyethyl)benzamides (byproducts of intermolecular Cannizzaro hydride transfer) in the reaction mixture.29 Alternative sources of inter- or intramolecular hydride transfer in the reaction include LiBMEA or the α-amino alkoxide BMEA moiety;30 this pathway would lead to the formation of their corresponding Schiff bases and derivatives thereof. Tentative evidence for this was found in a reaction of 4 with sec-BuLi (see below, Table 5, entry 4), in which a potential sec-Bu-BMEA adduct was observed.31 We additionally attempted to ascertain whether the α-amino alkoxide moiety specifically was influencing meta deprotonation and/or the formation of a benzyne intermediate.32 Performing a bromide-lithium exchange on the BMEA αamino alkoxide of 2-bromo-6-fluorobenzaldehyde (10, Scheme 6a) confirmed that halogen−metal exchange is indeed much

1.4 0.6 0.6 1.4

a

Stage I: 4 (1.0 equiv), BMEA (1.1 equiv), organolithium base (1.1 equiv). bSolvent for Stage I: THF/heptane (1:4, v/v). cStage I: BMEA (1.3 equiv), n-BuLi (1.3 equiv). dSolvent for Stage I: toluene. e Stage II, equivalents of organolithium base and time at 0 °C. f Relative conversion of 2-fluorobenzaldehyde at Stage III, measured by HPLC analysis (254 nm) after borate quench. gSolution assay yield of 1 in aqueous layer after Stage IV quench. hRelative A% of desfluoro 5 versus 1 in aqueous layer (HPLC, 210 nm) following hydrolysis at Stage IV.

Scheme 3. Proposals for Hydrodefluorination/Reduction of 4 in Pathway to Boronic Acid 1 and Desfluoro Impurity 5

Scheme 6. Bromide−Lithium Exchange Reactions on BMEA α-Amino Alkoxides of Bromo-fluoro-benzaldehydes

Scheme 4. Study of Amino Alkoxide Directed Lithiation/ Borylation Reaction in which Metalation ortho to Fluorine Is Blocked

faster than meta-deprotonation/elimination to benzyne at −20 °C ( 10). Varying the amount of n-BuLi (Stage II) in the range of 1.1−1.5 equiv had little effect on the level of desfluoro 5 at full conversion (>97% after 3 h hold, entries 1−3). We further hypothesized that the relative basicity of the organolithium, as well as the steric factors and solvent effects involved in its (de)aggregation, could play significant roles in the net selectivity of ortho- versus meta-deprotonation. For instance, treatment with sec-BuLi (entry 4) led to 14 A% of desfluoro side product 5, and a larger discrepancy between assay yield of 1 versus conversion of 4 (38% vs 98%, respectively). A number of other products were observed by HPLC, GC-MS, and CAD-MS analysis (presumably from addition of nucleophiles to benzyne, among other pathways), but attempts to isolate these were unsuccessful.31 The use of lithium amide bases (such as excess Li-BMEA or LDA) or Grignard reagent (iPrMgCl·LiCl) for the Stage II ortho-functionalization did not yield the desired product under the conditions investigated. Interestingly, PhLi (Table 5, entry 5) yielded a similar level (1.4 A%) of 5 to n-BuLi, even at lower yield/conversion (48% assay). In contrast, MeLi (in THF/heptane as bulk solvent, entry 6, or toluene, entry 7) provided only 0.6 A% desfluoro 5 at 75−78% conversion (6 h, Stage II), showing a slightly stronger correlation of hydrodefluorination with productive reaction progress. The level of 5 climbed to 1.4 A% at >95% conversion; however, the reaction could be held for 16 h in Stage II to good result (80% assay yield, entry 8) even with an excess of MeLi (1.5 equiv in Stage II). Toluene provided a more homogeneous reaction overall (vs THF/heptane) and was selected as the solvent for further work using MeLi (3.1 M in (EtO)2CH2). Because the DoM reaction appeared to be slower with MeLi versus n-BuLi (Table 5, entry 1 vs 6), we sought to more closely define the reaction time for the Stage II lithiation to complete. Earlier efforts to track reaction progress during the ortho-lithiation stage by quenching aliquots with a variety of reagents (e.g., I2, Br2, MeOD, D2O) and then performing either HPLC or NMR analysis proved to be cumbersome and in many cases not reproducible. We therefore turned to ReactIR as a more appropriate process analytical technology (PAT)34 to follow evidence of the ortho-lithiation event in situ and to monitor Stages I−III in real time. By tracking and plotting changes in the intensity of infrared stretching bands unique to each reaction component, the rapid deprotonation of BMEA (assigned to 1242 cm−1 for tracking) by MeLi addition could be visualized (Figure 2). This was followed empirically by the subsequent, inferred 1,2-attack of the lithium amide (Li-BMEA, assigned to 1272 cm−1 for tracking) upon 2-fluorobenzaldehyde (4, added to the stirring mixture of BMEA and MeLi in toluene) to form α-amino alkoxide int-1 (assigned to the IR peak at 808 cm−1) (see also

Figure 2. Monitoring of apparent Stage I BMEA deprotonation and α-amino alkoxide formation in situ using ReactIR data for visualization. See the Supporting Information for details.

the Supporting Information). No accumulation of aldehyde 4 was noted. After addition of a second portion of MeLi (1.2 equiv) in Stage II (Figure 3), the IR peaks corresponding to putative int1 (followed at 762 cm−1) disappeared, along with the slow formation of a new species, attributed to ortho-lithiated int-2 (monitored by measuring appearance of a new peak at 1543 cm−1) over ca. 8 h as the reaction mixture was allowed to warm to 0 °C (Figure 3).35 IR peaks corresponding to this new species stabilized over ca. 18 h, until the addition of B(OMe)3

Figure 3. Monitoring of inferred ortho-lithiation of α-amino alkoxide int-1 to aryllithium int-2 during Stage II as visualized using ReactIR data. See the Supporting Information for details. E

DOI: 10.1021/acs.organomet.8b00730 Organometallics XXXX, XXX, XXX−XXX

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These various reaction data suggested that it would be difficult to further suppress the formation of desfluoro 5 at otherwise high yields/conversions to 1. Nonetheless, the enhanced reaction understanding and consistent product/ impurity levels achieved prompted us to demonstrate a scaleup DoM/borylation of 2-fluorobenzaldehyde (4, 50 g, conditions shown in Scheme 7) such that a robust isolation of 1 could be developed, and the purging of downstream derivatives of desfluoro 5 investigated.

during the Stage III quench (Figure 4). During this event, the consumption of int-2 was observed, along with the appearance

Scheme 7. DoM/Borylation Reaction of 2Fluorobenzaldehyde (4) and Isolation of 3-Fluoro-2formylphenylboronic Acid (1)

Figure 4. Monitoring the quenching of inferred ortho-lithiated int-2 with B(OMe)3 to arylboronic ester int-3 during Stage III, as monitored using ReactIR data. See the Supporting Information for details.

of a species inferred to be int-3 (assigned to 983 cm−1), showing that conversion to the borate was rapid as expected. As had been performed for the DoM/borylation of 4 using n-BuLi, sample aliquots from the MeLi mediated reaction represented by the ReactIR data (above) were also quenched periodically and tested for the appearance of benzaldehyde (6) relative to 2-fluorobenzaldehyde (4) (Table 6, Stages I−II).

In the event, the Stage I formation of amino alkoxide from BMEA/MeLi proceeded as expected, and the Stage III borate quench was performed after the reaction mixture had stirred for 16 h at 0 °C in the Stage II ortho-lithiation; 88% conversion of 4 was observed. While the reaction can indeed be performed in a single-flask operation, we found it more practical to conduct an inverse quench of the reaction solution into water in a second vessel to effect borate hydrolysis. After separation of the aqueous (pH >9) and organic (primarily toluene) layers, the solution yield of 1 was assayed in the former (80%, with 9% of remaining 4 found in the latter). Desfluoro impurity 5 was observed at 1.5 A% at this stage. A multistage workup sequence was developed, during which the aqueous layer was acidified, and compound 1 was extracted into MTBE and further precipitated from a toluene/water36 mixture (see the Experimental Section for details). As we had noted previously, evidence from periodic 19F NMR analysis of these mixtures suggested that boroxines and similar oligomers of 1 were being formed during solution concentration (see the Supporting Information). Due to this unrelated complication, an unoptimized isolation of 1 from the process stream provided 48% recovery from a first crop of filtered solids (99.1 A%, with 0.9 A% desfluoro 5 in the isolated material due to concomitant loss). Additional product/multimeric aggregates evident in the mother liquor could partially be recovered in a second crop.37 Further efforts to improve the isolation of 1, in conjunction with related API process development, will be reported in due course. This additional work also demonstrated the successful purging of impurity 5 (up to ∼1.5 A%) and associated derivatives in downstream chemistry, made possible in part by the control and understanding of its formation in this optimized ortho-lithiation/borylation process.

Table 6. Investigation of Hydrodefluorination Event during the Directed ortho-Lithiation of 4 using BMEA/MeLi entrya

stage

time (h)b

temp. (°C)

6 (A%)c

1 2 3 4

I II II II

1 0.1 3 18

−20 −20 0 0 to −20

0 0 0.7 2.7

a

Stage I: 4 (1.0 equiv), BMEA (1.1 equiv), MeLi (1.1 equiv, 3.1 M in (EtO)2CH2), toluene, −20 °C; Stage II: MeLi (1.1 equiv), −20 to 0 °C, 18 h. bTime held at each reaction stage. cRelative A% of benzaldehyde (6) versus 2-fluorobenzaldehyde (4) in aliquots quenched with 1:1 MeCN:H2O, determined by HPLC integration at 254 nm.

We again observed that a defluorination event, and pathways leading to desfluoro impurity 5 are first occurring in Stage II and stabilizing upon stirring of the mixture at 0 °C before it is recooled to −20 °C for borate quench (Table 6, entry 4). Although the initial formation of benzaldehyde 6 appears to be reduced at −20 °C in the MeLi example (Table 6, entry 2 as compared to n-BuLi, Table 2, entry 3), an extended time at 0 °C is required to achieve acceptable conversion for the ortholithiation (see Table 5 and Figure 3). F

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8.2 Hz), 165.6 (d, JC−F = 257 Hz), 136.6 (d, JC−F = 9.4 Hz), 129.7 (d, JC−F = 4.4 Hz), 127.7 (d, JC−F = 5.8 Hz), 116.9 (d, JC−F = 21.0 Hz). 19 1 F{ H} NMR (376 MHz, acetone-d6) δ − 123.5 (s, 1F); consistent with data for the known compound (see the Supporting Information).3c

CONCLUSIONS In summary, the borylation of 2-fluorobenzaldehyde (4) has been studied, based on a Comins-inspired, α-amino alkoxide directed deprotonation/lithiation. A number of reaction conditions were studied (particularly looking at solvent, organolithium, and operational parameters) in an attempt to reduce the level of an undesired desfluoro analog (5) generated during the transformation. The hydrodefluorination event was further investigated using time course studies and model systems, providing tentative evidence in support of a benzyne-based pathway from competitive meta deprotonation, with the BMEA moiety as a plausible source of hydride. Although its isolation procedure on multigram scale remains unoptimized for this process, 3-fluoro-2-formylphenylboronic acid (1) was thus synthesized in at least 80% assay yield from a tandem amino alkoxide formation/ortho-lithiation/borylation/ hydrolysis sequence using BMEA as directing ligand and either n-BuLi or MeLi as organolithium bases. This approach provided access to 1 directly from 2-fluorobenzaldehyde in a synthetically economical manner to support long-term API project goals. Future undertakings may also include the development of this chemistry in flow38 to further improve stability, reproducibility, and quench/workup conditions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00730. Relevant experimental procedures and characterization data for the associated compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Frédéric St-Jean: 0000-0001-8818-0218 Lauren E. Sirois: 0000-0002-1948-3749 Francis Gosselin: 0000-0001-9812-4180 Notes

The authors declare no competing financial interest.

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EXPERIMENTAL SECTION

ACKNOWLEDGMENTS We thank Dr. David Russell and Dr. Kenji Kurita for assistance with NMR analysis, Dr. Kenji Kurita, Dr. Sarah Robinson and Tristan Maschmeyer for high-resolution mass spectrometry, Dr. Joseph Lubach and Rebecca Rowe for solid-state characterization, and Tina Nguyen for gas chromatography (all of Genentech, Inc.). We also thank Professor David B. Collum (Cornell University) and Dr. Stephan Bachmann (F. Hoffmann-La Roche, Inc.) for helpful discussions.

3-Fluoro-2-formylphenylboronic Acid (1). An inerted jacketed cylindrical glass reactor was charged with bis(2-methoxyethyl)amine (1.10 equiv, 443 mmol, 65.5 mL) and toluene (8 mL/g, 400 mL), and the resulting solution was cooled to −25 °C. Then, MeLi (3.1 M in diethoxymethane, 1.10 equiv, 443 mmol, 143 mL) was added dropwise over 30 min. The mixture was stirred for 15 min at −20 °C. A solution of 2-fluorobenzaldehyde (1.00 equiv, 402 mmol, 50.0 g) in toluene (2 mL/g, 100 mL) was added dropwise to the reaction vessel over 35 min, and the reaction mixture was then stirred at −20 °C for an additional 45 min. Next, a second portion of MeLi (3.1 M in diethoxymethane, 1.20 equiv, 483 mmol, 156 mL) was added dropwise to the reactor over 30 min, and the mixture was warmed to 0 °C and stirred for 16 h. It was then cooled to −20 °C and B(OMe)3 (3.00 equiv, 1210 mmol, 138 mL) was added over 1 h. The solution was then warmed to 0 °C and stirred for 2.5 h. In a second glass vessel, deionized water (10 mL/g, 500 mL) was cooled to 10 °C before the reaction solution was added over 15 min. The resulting biphasic slurry was stirred for 30 min at 10 °C. Then, the solids were filtered off, and the cake was washed with water (4 mg/L, 200 mL). The biphasic filtrate was poured back into a cylindrical reactor, and the layers were allowed to separate. The organic layer was discarded, and the aqueous layer was washed with MTBE (5 mL/g, 250 mL). Next, H2SO4 (50 wt % aqueous solution, 4 mL/g, 200 mL) was added to adjust the pH from 9 to 2. This acidic mixture was extracted 3 times with MTBE (5 mL/g, 250 mL each). The combined MTBE extracts were washed with water (2 mL/g, 100 mL) and then concentrated to ca. 5 mL/g (250 mL) under reduced pressure (45 °C bath temperature). Toluene (10 mL/g, 500 mL) was added and the solution was again concentrated under reduced pressure, with periodic readdition of toluene, until most of the MTBE had been removed (90% recovery. (37) It is likely that crystallization is further complicated not only by dehydrative trimerization/oligomerization, but also by previously reported solution tautomerization of 1 and similar fluoro-substituted I

DOI: 10.1021/acs.organomet.8b00730 Organometallics XXXX, XXX, XXX−XXX

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Organometallics 2-formylphenylboronic acids (see ref 3). In our hands, solid-state NMR of isolated 1 suggested a single form, in contrast with a mixture of open (1) and closed (taut-1) forms in various NMR solvents (see the Supporting Information).

(38) For relevant case studies, see, for example, (a) Hafner, A.; Filipponi, P.; Piccioni, L.; Meisenbach, M.; Schenkel, B.; Venturoni, F.; Sedelmeier, J. A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities. Org. Process Res. Dev. 2016, 20, 1833−1837. and references therein. (b) Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Pastre, J. C.; Zacharova, M. K.; Ley, S. V.; Browne, D. L. Design and Application of a Low-Temperature Continuous Flow Chemistry Platform. Org. Process Res. Dev. 2014, 18, 1211−1220.

J

DOI: 10.1021/acs.organomet.8b00730 Organometallics XXXX, XXX, XXX−XXX