Robust and Scalable Reductive Amination Protocol for Electron-Poor Heterocyclic Amines Using Et₃SiH/TFA as Reducing Agent

Abstract

A facile reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et₃SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH₂Cl₂. The reductive aminations are fast and clean, and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.

The selective monofunctionalization of amines via traditional alkylation chemistry with alkyl halides is challenging due to the innate potential of the amine starting material to overalkylate. One solution for this problem is the use of reductive amination protocols.[1] In reductive aminations, the amine is first converted into an intermediate imine via condensation with an aldehyde or ketone, which plays the role of the ‘alkylating agent’. In a second step, the imine is finally reduced to the alkylated amine by a reducing agent. The reduction step normally proceeds under mild conditions and a wide array of reducing agents can be employed. Among the most popular options are NaBH(OAc)₃ [2] and NaBH₃CN,[3] as these reagents show a higher reducing reactivity towards the intermediate imine than for the ketone/aldehyde precursors. Catalytic hydrogenation of the intermediate imine with H₂ gas is also an attractive option.[4] While reductive aminations work reliably for a broad range of substrates, the use of electron-poor amines in such reactions is still one of the remaining challenges in this field.[5] This is especially true for amines that are directly connected to a heteroaromatic ring system. The problematic step is often the initial imine formation due to the delocalization of the nitrogen lone pair in the electron-poor, heteroaromatic ring system. For a recent project, we faced such a formidable challenge, when the reductive amination of ethyl 3-amino-1H-pyrazole-4-carboxylate (2) with 2-(trifluoromethyl)benzaldehyde (3) needed to be developed on scale (Scheme [1]).[6] Heterocyclic amine 2 can be considered as electron-deficient due to the conjugation of the nitrogen lone pair of the amino group with the heteroaromatic ring system and additionally with the ethyl ester at C4. In addition, the pyrazole ring nitrogen atoms are not protected and could potentially interfere in the reductive amination process. As kilogram amounts of benzylated aminopyrazole intermediate 1 were required in-house, we started with the development of a robust and scalable procedure for the reductive amination of the electron-poor heterocyclic amine 2.

At the outset, initial experiments with NaBH(OAc)₃ and acid additives were disappointing. The reactions were messy and several side products formed. In addition, as the reactions only proceeded slowly at room temperature, reduction of aldehyde 3 to the corresponding benzyl alcohol was observed over time. The best result from these early optimization studies was obtained with NaBH(OAc)₃ (2.5 eq.) and AcOH (1.5 eq.) in CH₂Cl₂ at room temperature. Using these conditions on 20 g scale, the crude product was obtained in quantitative yield, but in low HPLC purity [ca. 50%; purity refers to area/area (a/a) percentage by LC/MS]. Most of the impurities could be removed by a hot heptane slurry, leading to a purity upgrade of 1 to 80% a/a. However, the major N-acetyl impurity 4 was not removed by this slurry (Scheme [2]).

Table 1 Optimization Study with Organosilane Reducing Agents^a

Entry	Silane (eq.)	Additive (eq.)	Solvent	Temp	Conversionb	Overall purityc
1	PMHS (2.0)	Ti(Oi-Pr)4 (1.25)	THF	65 °C	25%	12% a/a
2	PMHS (2.0)	Ti(Oi-Pr)4 (1.25)	toluene	65 °C	37%	16% a/a
3	PMHS (2.0)	Ti(Oi-Pr)4 (1.25)	MeCN	65 °C	35%	26% a/a
4	PMHS (2.6)	TFA (2.0)	CH2Cl2	rt	58%	36% a/a
5	PMHS (2.6)	AcOH (2.0)	CH2Cl2	rt	no reaction	–
6	Et3SiH (2.6)	TFA (2.0)	CH2Cl2	rt	92%	75% a/a
7	Et3SiH (2.6)	AcOH (2.0)	CH2Cl2	rt	no reaction	–
8	Et3SiH (2.6)	TFA (3.0)	CH2Cl2	38 °C	>98%	>90% a/a

^a Reaction conditions: 2 (100 mg, 0.645 mmol), 3 (0.1 mL, 0.773 mmol, 1.2 eq.), silane, additive, solvent (1 mL, 10 vol.), 16 h.

^b Conversion was judged by consumption of 2 relative to the formation of 1 by LC/MS at 210 nm.

^c Overall purity refers to area/area (a/a) percentage of 1 in the final IPC by LC/MS at 210 nm.

As 4 clearly originated from NaBH(OAc)₃,[7] alternative reducing agents were explored. At the same time, we speculated that addition of stronger Brønsted or Lewis acids might increase the rate of the initial imine formation, thereby potentially improving the overall reaction impurity profile. Taking these two considerations into account, we became interested in the use of silyl hydrides in combination with TFA or Ti(Oi-Pr)₄ as reducing systems.[8] The nature of the Si–H bond is such that the hydrogen is only weakly hydridic, which makes organosilanes less reactive and more selective reagents for the reduction of the imine. This has the advantage that the reducing agent can be added prior to completed imine formation. With regard to a scale-up, two of the most attractive organosilane reducing agents are triethylsilane (Et₃SiH; US$8.60 per mole of hydride) and polymethylhydrosiloxane (PMHS; US~$1.00 per mole of hydride).[8a] We started our optimization studies with a combination of PMHS and Ti(Oi-Pr)₄ as Lewis acid in different solvents (Table [1], entries 1–3). The reactions proceeded slowly at 65 °C, but with formation of the desired product 1. Over time, reduction of aldehyde 3 was also observed. When Ti(Oi-Pr)₄ was replaced with TFA and the solvent changed to CH₂Cl₂, the reaction took place at room temperature and without reduction of the aldehyde (entry 4). However, we had difficulties to reproduce these results with different batches of PMHS, leading to drastically varying reaction conversions. This is most likely a consequence of the polymeric nature of PMHS, which makes the precise determination of the actual hydride content of different lots very challenging. This potential inaccuracy worried us even more with regard to a future scale-up. Therefore, we explored the use of Et₃SiH due to its well-defined character and ease of handling as a stable liquid. Using Et₃SiH (2.6 eq.) in combination with TFA (2.0 eq.), the reductive amination worked cleanly in CH₂Cl₂ at room temperature, and 92% conversion was achieved after stirring overnight (entry 6). By increasing the amount of TFA (3.0 eq.) and the temperature (38 °C), full conversion of amine 2 was reproducibly obtained and 1 was formed in >90% a/a purity in the final in-process control (IPC) by LC/MS (entry 8). In strong contrast to TFA, AcOH did not promote the reductive amination and only unreacted 2 and 3 were obtained (entries 5 and 7).

Table 2 Aldehyde Substrate Scope^a

^a Reaction conditions: 2 (2.5 g, 16.1 mmol), 18–30 (19.3 mmol, 1.2 eq.), TFA (3.7 mL, 48.3 mmol, 3.0 eq.), Et₃SiH (6.7 mL, 41.9 mmol, 2.6 eq.), CH₂Cl₂ (25 mL, 10 vol.), rt to 38 °C.

With the optimized conditions in hand, we turned our attention to the development of a robust process and the isolation of 1. In a 50 g experiment, Et₃SiH (2.6 eq.) was dosed to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (2) (1.0 eq.), 2-(trifluoromethyl)benzaldehyde (3) (1.2 eq.) and TFA (3.0 eq.) in CH₂Cl₂ during 40 min at 10–15 °C. Immediately after addition, 16% conversion into 1 was observed. After 3 hours at 20–30 °C conversion proceeded to 96%. Prolonged stirring overnight at 20–30 °C resulted in complete consumption of 2. After aqueous quench and neutralization of TFA with 32% aqueous NaOH to pH 7–9, the layers were separated. After the first layer separation, the organic layer was observed to be the upper layer despite using CH₂Cl₂, most likely a consequence of similar densities of the organic and aqueous phase. In order to isolate pure 1, a solvent exchange from CH₂Cl₂ to heptane was performed at 50–55 °C and 150–300 mbar. During the solvent switch, the product started to crystallize as an off-white solid. The slurry was finally aged at 5–10 °C and the product isolated by filtration. Hexaethyldisiloxane – a byproduct of Et₃SiH – was well soluble in heptane and completely purged into the mother liquor. Product 1 was isolated in 90% yield, and with >99% a/a purity by LC/MS. Further process optimizations focused on reducing the accumulation of 2 during the dosing of Et₃SiH. It was found that accumulation could be successfully reduced by dosing Et₃SiH at reflux temperature [internal temperature (IT) = 38 °C]: after complete addition of Et₃SiH at reflux, 89% conversion of 2 was detected. The reaction was complete after stirring for a further 2 hours at reflux. The optimized procedure was successfully performed on 750 g scale in a 30 L double-jacketed reactor (Scheme [3]). After aqueous workup, solvent exchange to heptane and filtration, 1 was isolated in 93% yield (1.41 kg) and with excellent purity (LC/MS purity >99% a/a).[9] Analysis of 1 by ¹H NMR showed no traces of hexaethyldisiloxane. Comparing the disappointing original result with NaBH(OAc)₃ and AcOH (Scheme [2]) to the now optimized conditions with Et₃SiH and TFA, the difference in yield and purity is simply remarkable.

We were curious to test the generality of the optimized Et₃SiH/TFA conditions and therefore explored the substrate scope. Using ethyl 3-amino-1H-pyrazole-4-carboxylate (2) as model amine, we tested our standard conditions with a wide range of different aldehydes (2.5 g scale of 2, Table [2]). The standard conditions worked well for a wide range of different aldehydes without further substrate-specific optimizations. The process robustness is highlighted by product 5, derived from biphenyl-4-carboxaldehyde (18), which was isolated in nearly quantitative yield. The reaction was finished within 3 hours at 38 °C. After basic workup with 4 M aqueous KOH, a solvent switch from CH₂Cl₂ to heptane directly crystallized the product as a white solid with excellent purity. The standard conditions also worked well for halogenated aldehydes, including heterocyclic ones, and products 6–9 were obtained in high yields. Reductive dehalogenation was not observed, highlighting the mildness of the conditions. Electron-rich aldehydes were also viable substrates for the reductive amination and the corresponding products 10–12 were isolated with high purity after crystallization from heptane. The reaction also tolerated several electron-withdrawing groups such as nitrile (13), nitro (15) and even free carboxylic acid (14). A single test with cyclohexanecarboxaldehyde (29) confirmed that the reaction also works well with aliphatic aldehydes, even though overnight stirring at reflux was necessary to reach full conversion of 2. Unfortunately, our standard conditions in CH₂Cl₂ did not work for acetophenone (30): only 17% conversion of 2 was obtained after 24 hours at reflux. The traces of product 17 were not isolated.

We also explored if the Et₃SiH/TFA conditions work for other electron-poor heterocyclic amines (Table [3]). The reaction worked well on pyrazole substrates bearing different substituents at the 4-position such as a primary amide (31), nitrile (32) or bromide (33). Highly electron-poor 2-aminopyridine derivatives 45 and 46 also nicely reacted with 4-methoxybenzaldehyde (23) and 2-bromobenzaldehyde (19), respectively, under the standard conditions to give the corresponding products 34 and 35 in high yields. The reductive amination conditions also worked well for substituted 3-amino(benzo[d])isoxazole derivatives (products 36–38). Bromo-substituted product 38 provides a nice handle for further synthetic modifications. However, the Et₃SiH/TFA conditions were not without limitation, as the reaction did not work with other heterocyclic amine substrates such as 2-aminooxazole (50), 2-aminothiazole (51) or 4-phenylpyrimidin-2-amine (52).

Table 3 Heterocyclic Amine Substrate Scope^a

^a Reaction conditions: 42–52 (2.5 g, 1.0 eq.), 19 or 23 (1.2 eq.), TFA (3.0 eq.), Et₃SiH (2.6 eq.), CH₂Cl₂ (25 mL, 10 vol.), rt to 38 °C.

To address these limitations, the reductive amination of our standard amine 2 with acetophenone (30), and the reaction between 4-phenylpyrimidin-2-amine (52) and 2-bromobenzaldehyde (19), were re-optimized (Scheme [4]). It became obvious that a solvent with a higher boiling point was needed to push the conversion towards completion. After testing several alternative solvents, we found that the reactions worked well in MeCN. The addition of Et₃SiH was performed at 65–70 °C, followed by stirring at this temperature for 3–16 hours. In both cases, full conversion of the heterocyclic amine was obtained. For the reaction of 2 with acetophenone (30), competing N-trifluoroacetylation of the amine was observed (ca. 25% a/a). Nevertheless, the desired product 17 crystallized after aqueous quench and distillative removal of MeCN and was isolated in 57% yield and with excellent purity. In the pyrimidine case, the reaction was clean and product 41 directly crystallized from the reaction mixture as its TFA salt. After cooling to room temperature, the product was simply collected by filtration and isolated in 80% yield. MeCN could also be an attractive option to replace CH₂Cl₂ in future production campaigns of 1.

In summary, we have developed a robust and scalable reductive amination procedure for electron-poor heterocyclic amines – a substrate class that is known to be notoriously difficult to engage in this transformation. The combination of Et₃SiH and TFA as reducing system proved to be optimal for this challenging substrate class. The reactions are easy to set up, fast, clean, and high-yielding, and work for a wide range of different heterocyclic amines and aldehydes. The robustness and scalability of the process has been demonstrated on up to 750 g scale in a 30 L reactor, leading to the isolation of target product 1 in 93% yield (1.41 kg). The conditions also worked for acetophenone and a highly electron-poor 2-aminopyrimidine derivative after switching from CH₂Cl₂ to the higher boiling MeCN. We expect that our reductive amination conditions for electron-poor heterocyclic amines will find widespread applications in academic and industrial organic chemistry laboratories.

All commercially available materials and solvents were used as received. Gram-scale experiments were performed in standard laboratory glassware with magnetic stirrers and under a N₂ atmosphere. The 750 g scale-up run was performed in a 30 L double-jacketed glass-lined steel reactor flushed with N₂. Reaction temperatures are expressed as ET = external temperature (e.g., reactor jacket, heating block) or IT = internal temperature (temperature of the reaction mixture). OP = organic phase. AP = aqueous phase. In-process control (IPC) analyses by LC/MS were conducted on a Waters Acquity UPLC instrument using an Agilent Zorbax RRHD SB-aq column (2.1 × 50 mm, 1.8 μm). The mobile phase consisted of two eluents: A: H₂O/TFA, 100:0.04 (v/v) and B: MeCN. High-resolution mass spectrometric measurements were performed on a SYNAPT G2 spectrometer from Waters (ESI). ¹H NMR and ¹³C NMR spectra were measured on a Bruker Ultrashield spectrometer at 500 MHz and 125 MHz, respectively. ¹⁹F NMR spectra were measured on a Bruker Ultrashield spectrometer at 375 MHz, recorded with ¹H decoupling referenced to TFA (–76.53 ppm). Chemical shifts are expressed in parts per million (ppm) downfield from residual solvent peaks and coupling constants are reported in hertz (Hz). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; br, broad.

Ethyl 3-((2-(Trifluoromethyl)benzyl)amino)-1H-pyrazole-4-carboxylate (1); Large-Scale Synthesis Procedure

A 30 L double-jacketed glass-lined steel reactor was charged with ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 750 g, 4.83 mol, 1.0 eq.) and CH₂Cl₂ (3.8 L, 5 vol.). 2-(Trifluoromethyl)benzaldehyde (3; 1.01 kg, 5.80 mol, 1.2 eq.) was added at IT = 20–30 °C, followed by the addition of TFA (1.11 L, 14.5 mol, 3.0 eq.) over 20 min at IT = 20–30 °C. The resulting mixture was heated with jacket control (ET = 45 °C) to reflux. Et₃SiH (2.0 L, 12.6 mol, 2.6 eq.) was then added dropwise over 30 min at reflux and the reaction mixture was stirred at ET = 45 °C for 2 h (IPC by LC/MS indicated >98% conversion of 2). The reaction mixture was cooled to IT = 20–30 °C and H₂O (6.0 L, 8 vol.) was added over 15 min at IT = 20–30 °C. The mixture was basified to pH 9 by the addition of 32% aq NaOH (1.2 L, 1.6 vol.). Additional CH₂Cl₂ (3.8 L, 5 vol.) was added, and the phases were separated. The OP was washed once with H₂O (3.8 L, 5 vol.). The AP from the first separation was extracted once with CH₂Cl₂ (3.8 L, 5 vol.). The aqueous phases were discarded. A slight vacuum (600–700 mbar) was applied to the reactor, and the combined organic phases were concentrated at ET = 55 °C until a minimal stirring volume was reached. Then, heptane (total amount used for solvent switch, 10.5 L) was continuously added and the distillation continued at ET = 55 °C under reduced pressure (150–300 mbar). The final heptane content in the reactor after distillation was ca. 5 L (7.5 vol.). During the solvent switch to heptane, the product started to crystallize. The resulting suspension was cooled to IT = 0–10 °C and aged at this temperature for 1 h. The solid was collected by filtration, washed once with heptane (3 L, 4 vol.) and dried at ET = 50 °C under vacuum for 11 h to afford 1 (1.41 kg, 4.49 mol, 93% yield) as a light beige, crystalline solid.

¹H NMR (500 MHz, CD₃OD): δ = 7.80 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 4.69 (s, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 166.2, 156.9, 139.3, 135.8, 133.4, 130.1, 128.8 (q, J = 30.8 Hz), 128.4, 127.0 (q, J = 5.8 Hz), 126.3 (q, J = 273 Hz), 97.9, 60.8, 44.8, 14.8.

¹⁹F NMR (375 MHz, DMSO-d ₆): δ = –59.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅F₃N₃O₂: 314.1111; found: 314.1110.

General Procedure on Gram Scale

Under N₂ atmosphere, a three-necked flask with attached reflux condenser was charged with the heterocyclic amine (2.5 g), the aldehyde (1.2 eq.) and CH₂Cl₂ (25 mL, 10 vol.). TFA (3.0 eq.) was added over 1–2 min at rt and the resulting solution was warmed to ET = 35 °C. Then, Et₃SiH (2.6 eq.) was added dropwise over 15–20 min via syringe pump. The reaction mixture was warmed to ET = 38 °C and stirred until full conversion of the amine was confirmed by LC/MS. The reaction mixture was cooled to rt and additional CH₂Cl₂ (25 mL, 10 vol.) was added. The reaction mixture was placed into an ambient water bath and then 4 M aq KOH (25 mL, 10 vol.) was added dropwise over 5 min. The reaction mixture was stirred for 5 min at rt (pH of AP was 14). The phases were separated (OP was lower phase). The AP was extracted once with CH₂Cl₂ (25 mL, 10 vol.). Combined OPs were washed with 10% aq NaCl (25 mL, 10 vol.), dried over Na₂SO₄ and filtered.

Final product isolation procedure A: The CH₂Cl₂ filtrate was transferred to a round-bottom flask and a solvent switch to heptane was performed at a rotavap by distillative removal of CH₂Cl₂ and continuous addition of heptane (ET = 50 °C, 500 mbar). Final volume of heptane: 25–50 mL, 10–20 vol. During solvent switch, product started to precipitate. The heptane suspension was aged at rt for 1 h. The product was collected by filtration, washed with heptane (2 × 5–10 mL) and dried under reduced pressure (rotavap, 50 °C) for 1–2 h.

Final product isolation procedure B: The CH₂Cl₂ filtrate was transferred to a round-bottom flask and concentrated under reduced pressure (rotavap, ET = 50 °C). The obtained crude material was directly purified by flash column chromatography to obtain the analytical pure product.

Ethyl 3-(([1,1′-Biphenyl]-4-ylmethyl)amino)-1H-pyrazole-4-carboxylate (5)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and biphenyl-4-carboxaldehyde (18; 3.52 g, 19.3 mmol).

White solid; yield: 5.10 g (98%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃OD): δ = 7.74 (s, 1 H), 7.54 (m, 4 H), 7.39 (m, 4 H), 7.29 (t, J = 7.5 Hz, 1 H), 4.49 (s, 2 H), 4.23 (q, J = 7.0 Hz, 2 H), 1.29 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 166.2, 156.4, 142.1 (2 C), 141.4, 139.6, 129.8, 128.7, 128.2, 128.1, 127.9, 97.2, 60.7, 47.8, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀N₃O₂: 322.1550; found: 322.1556.

Ethyl 3-((2-Bromobenzyl)amino)-1H-pyrazole-4-carboxylate (6)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 2-bromobenzaldehyde (19; 2.24 mL, 19.3 mmol).

White solid; yield: 4.62 g (88%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃OD): δ = 7.77–7.16 (m, 5 H), 4.53 (s, 2 H), 4.26 (m, 2 H), 1.32 (m, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 166.2, 156.7, 139.5, 133.8, 129.9 (2 C), 128.7, 124.2, 98.1, 60.8, 14.8; CH₂ carbon under CD₃OD signal.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅BrN₃O₂: 324.0342; found: 324.0349.

Ethyl 3-((2-Iodobenzyl)amino)-1H-pyrazole-4-carboxylate (7)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 2-iodobenzaldehyde (20; 4.49 g, 19.3 mmol).

Off-white solid; yield: 4.72 g (79%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃OD): δ = 7.84–7.62 (m, 2 H), 7.36–7.31 (m, 2 H), 6.97 (s, 1 H), 4.44 (s, 2 H), 4.24 (q, J = 6.3 Hz, 2 H), 1.31 (t, J = 6.3 Hz, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 166.1, 158.2, 153.0, 142.8, 140.5, 133.6, 129.9, 129.4, 99.1, 95.2, 60.8, 53.1, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅IN₃O₂: 372.0203; found: 372.0211.

Ethyl 3-(((5-Bromopyridin-2-yl)methyl)amino)-1H-pyrazole-4-carboxylate (8)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 5-bromo-2-formylpyridine (21; 3.60 g, 19.3 mmol).

Orange oil; yield: 3.50 g (67%). Purified by flash column chromatography (heptane/EtOAc, 75:25 to 25:75) (method B).

¹H NMR (500 MHz, CD₃OD): δ = 8.56 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.72 (s, 1 H), 7.38 (d, J = 8.2 Hz, 1 H), 4.57 (s, 2 H), 4.21 (q, J = 6.4 Hz, 2 H), 1.32 (t, J = 6.7 Hz, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 167.5, 160.0, 159.1, 150.6, 140.8, 140.7, 124.5, 119.7, 96.5, 60.0, 25.3, 15.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₄BrN₄O₂: 325.0295; found: 325.0302.

Ethyl 3-(((2,5-Dichloropyridin-4-yl)methyl)amino)-1H-pyrazole-4-carboxylate (9)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 2,5-dichloro-4-formylpyridine (22; 3.40 g, 19.3 mmol).

Light gray solid; yield: 3.72 g (73%).

Modified isolation procedure: the reaction mixture was cooled to rt and additional CH₂Cl₂ (25 mL, 10 vol.) was added. The reaction mixture was placed into an ambient water bath and then 4 M aq KOH (25 mL, 10 vol.) was added dropwise over 5 min. During this time, a white solid precipitated. The suspension was attached to a rotavap and the CH₂Cl₂ removed under reduced pressure (ET = 50 °C, 500 mbar). i-PrOH (25 mL, 10 vol.) was added to homogenize the resulting aqueous suspension. The i-PrOH/H₂O suspension was aged at rt for 1 h. The product was collected by filtration, washed with H₂O (2 × 5–10 mL) and then i-PrOH (2 × 5–10 mL), and dried under reduced pressure (rotavap, ET = 65 °C) for 1–2 h.

¹H NMR (500 MHz, CD₃OD): δ = 8.33 (s, 1 H), 7.86 (s, 1 H), 7.36 (s, 1 H), 4.59 (s, 2 H), 4.30 (q, J = 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, THF-d ₈): δ = 165.1, 157.0, 151.7, 150.6, 149.0, 133.4, 130.5, 124.1, 98.4, 59.9, 45.1, 14.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₃Cl₂N₄O₂: 315.0410; found: 315.0416.

Ethyl 3-((4-Methoxybenzyl)amino)-1H-pyrazole-4-carboxylate (10)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and p-anisaldehyde (23; 2.35 mL, 19.3 mmol).

Off-white solid; yield: 4.20 g (95%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃CN): δ = 10.36 (s, 1 H), 7.67 (s, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 6.00 (s, 1 H), 4.37 (d, J = 6.5 Hz, 2 H), 4.21 (q, J = 7.3 Hz, 2 H), 3.76 (s, 3 H), 1.27 (t, J = 7.3 Hz, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.4, 159.8, 156.1, 136.3, 129.4, 118.3, 114.8, 97.2, 60.3, 55.9, 47.1, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₈N₃O₃: 276.1343; found: 276.1350.

Ethyl 3-((2,6-Difluoro-4-methoxybenzyl)amino)-1H-pyrazole-4-carboxylate (11)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 2,6-difluoro-4-methoxybenzaldehyde (24; 3.33 g, 19.3 mmol).

Yellow solid; yield: 4.80 g (96%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃CN): δ = 10.56 (s, 1 H), 7.75 (s, 1 H), 6.59 (d, J = 9.8 Hz, 2 H), 5.75 (s, 1 H), 4.46 (d, J = 6.4 Hz, 2 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.79 (s, 3 H), 1.28 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.4, 163.1 (dd, J = 244, 11.5 Hz), 161.6 (t, J = 14.4 Hz), 156.6, 134.3, 108.1 (t, J = 21.2 Hz), 98.9 (dd, J = 23.1, 7.7 Hz), 98.3, 60.4, 56.7, 35.8, 14.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆F₂N₃O₃: 312.1154; found: 312.1159.

Ethyl 3-(((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-1H-pyrazole-4-carboxylate (12)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 1,4-benzodioxan-6-carboxaldehyde (25; 3.17 g, 19.3 mmol).

Off-white solid; yield: 4.40 g (90%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃OD): δ = 7.82–7.61 (m, 1 H), 6.81–6.75 (m, 3 H), 4.31 (s, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.18 (s, 4 H), 1.30 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃OD): δ = 166.2, 158.6, 145.0, 144.3, 141.8, 133.6, 121.1, 118.2, 117.1, 98.8, 65.6, 60.7, 47.6, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₈N₃O₄: 304.1292; found: 304.1298.

Ethyl 3-((4-Cyanobenzyl)amino)-1H-pyrazole-4-carboxylate (13)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 4-cyanobenzaldehyde (26; 2.54 g, 19.3 mmol).

Off-white solid; yield: 4.15 g (95%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃CN): δ = 7.71 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.45 (d, J = 8.5 Hz, 2 H), 6.15 (s, 1 H), 5.15 (s, 1 H), 4.52 (s, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.4, 156.5, 147.3, 135.1, 133.2, 128.6, 118.3, 111.1, 98.0, 60.4, 47.2, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅N₄O₂: 271.1190; found: 271.1197.

2-(((4-(Ethoxycarbonyl)-1H-pyrazol-3-yl)amino)methyl)benzoic Acid Trifluoroacetate Salt (14)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 2-carboxybenzaldehyde (27; 2.90 g, 19.3 mmol).

Off-white solid; yield: 4.57 g (70%).

Modified isolation procedure: the reaction mixture was cooled to rt and additional CH₂Cl₂ (25 mL, 10 vol.) was added. The reaction mixture was placed into an ambient water bath and then H₂O (50 mL, 20 vol.) was added dropwise over 5 min. During this time, a white solid precipitated. The suspension was attached to a rotavap and the CH₂Cl₂ removed under reduced pressure (ET = 50 °C, 500 mbar). The resulting H₂O suspension was aged at rt for 1 h. The product was collected by filtration, washed with H₂O (2 × 5–10 mL) and then heptane (2 × 5–10 mL), and dried under reduced pressure (rotavap, ET = 65 °C) for 1–2 h.

¹H NMR (500 MHz, DMSO-d ₆): δ = 7.90 (dd, J = 7.5, 1.1 Hz, 1 H), 7.71 (s, 1 H), 7.53–7.49 (m, 2 H), 7.37–7.34 (m, 1 H), 6.59 (s, 1 H), 4.70 (s, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 1.23 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 168.4, 163.8, 158.3 (q, J = 36 Hz), 141.1, 136.0, 132.1, 130.8, 129.7, 129.2, 127.1, 116.0 (q, J = 293 Hz), 95.1, 58.8, 45.6, 14.5.

¹⁹F NMR (375 MHz, DMSO-d ₆): δ = –74.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆N₃O₄: 290.1135; found: 290.1138.

Ethyl 3-((3-Nitrobenzyl)amino)-1H-pyrazole-4-carboxylate (15)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and 3-nitrobenzaldehyde (28; 2.92 g, 19.3 mmol).

Light yellow solid; yield: 3.80 g (81%). Crystallized from i-PrOH (modified method A, i-PrOH instead of heptane).

¹H NMR (500 MHz, CD₃CN): δ = 10.51 (s, 1 H), 8.16 (s, 1 H), 8.05 (dd, J = 8.2, 1.5 Hz, 1 H), 7.72 (m, 2 H), 7.52 (t, J = 7.9 Hz, 1 H), 6.18 (s, 1 H), 4.56 (d, J = 6.6 Hz, 2 H), 4.23 (q, J = 7.0 Hz, 2 H), 1.29 (t, J = 7.2 Hz, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.4, 156.7, 149.4, 144.0, 134.4, 130.4, 122.7, 122.7, 98.2, 60.4, 46.8, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅N₄O₄: 291.1088; found: 291.1090.

Ethyl 3-((Cyclohexylmethyl)amino)-1H-pyrazole-4-carboxylate (16)

Synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol) and cyclohexanecarboxaldehyde (29; 2.34 mL, 19.3 mmol).

Colorless oil; yield: 3.20 g (79%). Purified by flash column chromatography (heptane/EtOAc, 90:10 to 70:30) (method B).

¹H NMR (500 MHz, CD₃CN): δ = 10.41 (s, 1 H), 7.61 (s, 1 H), 5.80 (s, 1 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.06–3.04 (m, 2 H), 1.72 (t, J = 11.9 Hz, 4 H), 1.65 (d, J = 11.9 Hz, 1 H), 1.60–1.54 (m, 1 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.23–1.16 (m, 3 H), 0.99–0.90 (m, 2 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.5, 155.7, 137.6, 95.9, 60.1, 50.5, 38.6, 31.5, 27.3, 26.7, 14.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₂₂N₃O₂: 252.1707; found: 252.1707.

Ethyl 3-((1-Phenylethyl)amino)-1H-pyrazole-4-carboxylate (17)

Off-white solid; yield: 2.37 g (57%).

Modified procedure: Under N₂ atmosphere, a three-necked flask with attached reflux condenser was charged with 3-amino-1H-pyrazole-4-carboxylate (2; 2.5 g, 16.1 mmol, 1.0 eq.), acetophenone (30; 2.26 mL, 19.3 mmol, 1.2 eq.) and MeCN (25 mL, 10 vol.). Then, TFA (3.70 mL, 48.3 mmol, 3.0 eq.) was added over 1–2 min at rt and the resulting solution was warmed to ET = 75 °C. Once the IT was >65 °C, Et₃SiH (6.7 mL, 41.9 mmol, 2.6 eq.) was added dropwise over 15–20 min via syringe pump. Stirring of the reaction mixture was continued for 16 h at ET = 75 °C. The reaction mixture was cooled to rt and placed into an ambient water bath. Then, 4 M aq KOH (25 mL, 10 vol.) was added dropwise over 5 min. The reaction mixture was stirred for 5 min at rt (pH of AP was 14). The quenched solution was attached to a rotavap and the MeCN removed under reduced pressure (55 °C, 150 mbar). A suspension was obtained. i-PrOH (5 mL) was added to homogenize the resulting aqueous suspension. The i-PrOH/H₂O suspension was aged at rt for 30 min. The off-white solid was collected by filtration, washed with H₂O/i-PrOH (9:1, 2 × 5–10 mL) and dried under reduced pressure (rotavap, ET = 65 °C) for 1–2 h.

¹H NMR (500 MHz, CD₃CN): δ = 7.68 (s, 1 H), 7.39–7.33 (m, 4 H), 7.26 (t, J = 7.2 Hz, 1 H), 6.06 (d, J = 6.1 Hz, 2 H), 4.76 (quint, J = 7.0 Hz, 1 H), 4.27 (m, J = 7.0 Hz, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.33 (t, J = 7.0 Hz, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 165.6, 155.4, 146.2, 135.9, 129.5, 127.9, 126.8, 97.3, 60.4, 53.8, 24.5, 14.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₈N₃O₂: 260.1394; found: 260.1400.

3-((2-Bromobenzyl)amino)-1H-pyrazole-4-carboxamide (31)

Synthesized from 3-aminopyrazole-4-carboxamide (42; 2.5 g, 19.8 mmol) and 2-bromobenzaldehyde (19; 2.76 mL, 23.8 mmol).

Off-white solid; yield: 5.10 g (87%).

Modified isolation procedure: the reaction mixture was cooled to rt and additional CH₂Cl₂ (25 mL, 10 vol.) was added. The reaction mixture was placed into an ambient water bath and then 4 M aq KOH (25 mL, 10 vol.) was added dropwise over 5 min. During this time, a white solid precipitated. The suspension was attached to a rotavap and the CH₂Cl₂ removed under reduced pressure (ET = 50 °C, 500 mbar). i-PrOH (5 mL, 2 vol.) was added to homogenize the resulting aqueous suspension. The i-PrOH/H₂O suspension was aged at rt for 1 h. The product was collected by filtration, washed with H₂O/i-PrOH (9:1, 2 × 5–10 mL) and dried under reduced pressure (rotavap, ET = 65 °C) for 1–2 h.

¹H NMR (500 MHz, CD₃OD): δ = 7.87 (s, 1 H), 7.53 (d, J = 7.9 Hz, 1 H), 7.39 (d, J = 7.3 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 4.49 (s, 2 H).

¹³C NMR (125 MHz, CD₃OD): δ = 169.5, 156.5, 139.5, 139.0, 133.7, 129.8, 129.8, 128.6, 124.2, 99.2, 48.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₂BrN₄O: 295.0189; found: 295.0190.

3-((2-Bromobenzyl)amino)-1H-pyrazole-4-carbonitrile (32)

Synthesized from 3-amino-4-cyanopyrazole (43; 2.5 g, 23.1 mmol) and 2-bromobenzaldehyde (19; 3.22 mL, 27.8 mmol).

White solid; yield: 4.80 g (75%). Purified by flash column chromatography (CH₂Cl₂/MeOH, 100:0 to 95:5) (method B).

¹H NMR (500 MHz, CD₃OD): δ = 7.92 (s, 1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.39 (d, J = 7.3 Hz, 1 H), 7.29 (t, J = 6.9 Hz, 1 H), 7.14 (m, 1 H), 4.50 (s, 2 H).

¹³C NMR (125 MHz, CD₃OD): δ = 159.1, 143.4, 139.6, 136.2, 133.7, 129.5, 128.5, 124.0, 115.4, 78.0; CH₂ carbon under CD₃OD signal.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₀BrN₄: 277.0083; found: 277.0087.

4-Bromo-N-(2-bromobenzyl)-1H-pyrazol-3-amine (33)

Synthesized from 3-amino-4-bromopyrazole (44; 2.5 g, 15.4 mmol) and 2-bromobenzaldehyde (19; 2.15 mL, 18.5 mmol).

Light gray solid; yield: 4.19 g (82%). Crystallized from heptane (method A).

¹H NMR (500 MHz, CD₃OD): δ = 7.53 (d, J = 7.9 Hz, 1 H), 7.44 (s, 1 H), 7.39 (d, J = 7.5 Hz, 1 H), 7.25 (td, J = 7.6, 0.9 Hz, 1 H), 7.10 (m, J = 7.9, 1.5 Hz, 1 H), 4.47 (s, 2 H).

¹³C NMR (125 MHz, CD₃OD): δ = 154.6, 140.1, 133.5, 130.8, 129.9, 129.5, 128.4, 124.1, 80.6; CH₂ carbon under CD₃OD signal.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₀Br₂N₃: 329.9236; found: 329.9238.

5-Bromo-N-(4-methoxybenzyl)-3-nitropyridin-2-amine (34)

Synthesized from 2-amino-5-bromo-3-nitropyridine (45; 2.5 g, 11.5 mmol) and p-anisaldehyde (23; 1.67 mL, 13.8 mmol).

Bright yellow oil; yield: 2.70 g (70%). Purified by flash column chromatography (heptane/EtOAc, 95:5 to 85:15) (method B).

¹H NMR (500 MHz, CD₃CN): δ = 8.52 (s br, 1 H), 8.52 (d, J = 2.3 Hz, 1 H), 8.43 (d, J = 2.3 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 4.71 (d, J = 6.0 Hz, 2 H), 3.75 (s, 3 H).

¹³C NMR (125 MHz, CD₃CN): δ = 159.9, 157.1, 152.0, 137.7, 131.7, 129.8, 129.4, 114.8, 105.0, 55.9, 44.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₃BrN₃O₃: 338.0135; found: 338.0138.

N-(2-Bromobenzyl)-6-chloropyridin-2-amine (35)

Synthesized from 2-amino-6-chloropyridine (46; 2.5 g, 19.1 mmol) and 2-bromobenzaldehyde (19; 2.79 mL, 22.9 mmol).

White solid; yield: 5.18 g (91%). Crystallized from heptane (method A).

¹H NMR (500 MHz, DMSO-d ₆): δ = 7.62 (d, J = 7.8 Hz, 1 H), 7.50 (t, J = 5.8 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.35 (d, J = 4.5 Hz, 2 H), 7.22 (m, 1 H), 6.55 (d, J = 7.3 Hz, 1 H), 6.51 (d, J = 8.2 Hz, 1 H), 4.46 (d, J = 6.0 Hz, 2 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 158.6, 148.4, 139.7, 138.2, 132.4, 128.9, 128.8, 127.7, 122.6, 110.6, 106.7, 44.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₁BrClN₂: 296.9789; found: 296.9789.

N-(2-Bromobenzyl)isoxazol-3-amine (36)

Synthesized from 3-aminoisoxazole (47; 2.5 g, 29.7 mmol) and 2-bromobenzaldehyde (19; 4.13 mL, 35.6 mmol).

White solid; yield: 7.35 g (98%). Crystallized from heptane (method A).

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.38 (d, J = 1.7 Hz, 1 H), 7.61 (dd, J = 7.8, 0.8 Hz, 1 H), 7.41 (dd, J = 7.5, 1.2 Hz, 1 H), 7.36 (td, J = 7.5, 0.8 Hz, 1 H), 7.21 (td, J = 7.8, 1.7 Hz, 1 H), 6.73 (t, J = 6.0 Hz, 1 H), 6.02 (d, J = 1.7 Hz, 1 H), 4.32 (d, J = 6.1 Hz, 2 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 163.4, 158.5, 138.1, 132.3, 129.0, 128.8, 127.6, 122.6, 96.4, 47.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₀BrN₂O: 252.9971; found: 252.9971.

4-Bromo-N-(2-bromobenzyl)-5-methylisoxazol-3-amine (37)

Synthesized from 4-bromo-5-methylisoxazol-3-amine (48; 2.5 g, 14.1 mmol) and 2-bromobenzaldehyde (19; 1.96 mL, 16.9 mmol).

Light tan solid; yield: 3.39 g (69%). Crystallized from heptane (method A).

¹H NMR (500 MHz, DMSO-d ₆): δ = 7.60 (d, J = 8.0 Hz, 1 H), 7.33 (m, 2 H), 7.20 (td, J = 7.8, 1.8 Hz, 1 H), 6.69 (t, J = 6.0 Hz, 1 H), 4.32 (d, J = 6.0 Hz, 2 H), 2.27 (s, 3 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 165.4, 161.1, 137.6, 132.2, 128.7, 128.3, 127.5, 122.3, 82.7, 46.4, 11.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₁Br₂N₂O: 344.9233; found: 344.9232.

N-(2-Bromobenzyl)benzo[d]isoxazol-3-amine (38)

Synthesized from 1,2-benzisoxazol-3-amine (49; 2.5 g, 18.6 mmol) and 2-bromobenzaldehyde (19; 2.59 mL, 22.3 mmol).

White solid; yield: 5.48 g (97%). Crystallized from heptane (method A).

¹H NMR (500 MHz, DMSO-d ₆): δ = 7.94 (d, J = 7.9 Hz, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 5.6 Hz, 1 H), 7.55 (m, 1 H), 7.48 (m, 2 H), 7.37 (t, J = 7.3 Hz, 1 H), 7.28 (m, 1 H), 7.24 (td, J = 7.8, 1.4 Hz, 1 H), 4.51 (d, J = 5.8 Hz, 2 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 162.0, 158.1, 137.5, 132.4, 130.0, 129.1, 129.0, 127.7, 122.8, 122.2, 121.6, 116.1, 109.4, 46.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₂BrN₂O: 303.0128; found: 303.0126.

N-(2-Bromobenzyl)-4-phenylpyrimidin-2-amine Trifluoroacetate Salt (41)

Gray, fluffy solid; yield: 5.30 g (80%).

Modified procedure: Under N₂ atmosphere, a three-necked flask with attached reflux condenser was charged with 4-phenylpyrimidin-2-amine (52; 2.5 g, 14.6 mmol, 1.0 eq.), 2-bromobenzaldehyde (19; 2.03 mL, 17.5 mmol, 1.2 eq.) and MeCN (25 mL, 10 vol.). Then, TFA (3.35 mL, 43.8 mmol, 3.0 eq.) was added over 1–2 min at rt and the resulting solution was warmed to ET = 75 °C. Once the IT was >65 °C, Et₃SiH (6.06 mL, 38.0 mmol, 2.6 eq.) was added dropwise over 15–20 min via syringe pump. Stirring of the reaction mixture was continued for 3 h at ET = 75 °C. The resulting suspension was cooled to rt and aged for 30 min. The gray, fluffy solid was collected by filtration, washed with MeCN (2 × 5–10 mL) and then heptane (2 × 5–10 mL), and dried under reduced pressure (rotavap, ET = 60 °C) for 1–2 h.

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.41 (s, 1 H), 8.09 (d, J = 4.4 Hz, 2 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.54–7.50 (m, 3 H), 7.39 (s br, 1 H), 7.33 (td, J = 7.3, 1.1 Hz, 1 H), 7.28 (s br, 1 H), 7.19 (td, J = 7.9, 1.7 Hz, 1 H), 4.67 (s, 2 H).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 164.7, 160.0, 158.4 (q, J = 38 Hz), 156.5, 138.3, 136.3, 132.3, 131.2, 128.8, 128.7, 127.7, 127.0, 122.3, 115.4 (q, J = 290 Hz), 106.2, 44.6.

¹⁹F NMR (375 MHz, DMSO-d ₆): δ = –74.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₅BrN₃: 340.0444; found: 340.0449.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Boris Mathys, Marco Calderone and François Le Goff for high-resolution mass spectrometry. The organizing committee of the 55th Bürgenstock Conference and the Swiss Chemical Society are gratefully acknowledged for an industrial JSP fellowship to G.S.

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The N-acetylation is believed to be the result of nucleophilic attack by the amines on the triacetoxyborohydride and has been described in previous publications:
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• 9 Our process has been further scaled up at an external CMO with success: on 44.8 kg scale of 2, product 1 was isolated with identical yield and purity as in our kilolab run in a 30 L reactor (93% yield, HPLC: 99.8% a/a).

Corresponding Author

Publication History

Received: 08 September 2022

Accepted after revision: 17 November 2022

Accepted Manuscript online:
17 November 2022

Article published online:
12 December 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1a Afanasyev OI, Kuchuk K, Usanov DL, Chusov D. Chem. Rev. 2019; 119: 11857
  CrossrefPubMedSearch in Google Scholar
• 1b Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
  CrossrefPubMedSearch in Google Scholar
• 1c Gusak KN, Ignatovich ZV, Koroleva EV. Russ. Chem. Rev. 2015; 84: 288
  CrossrefSearch in Google Scholar
• 1d Podyacheva E, Afanasyev OI, Tsygankov AA, Makarova M, Chusov D. Synthesis 2019; 51: 2667
  Thieme ConnectSearch in Google Scholar
• 1e Tripathi RP, Verma SS, Pandey J, Tiwari V. Curr. Org. Chem. 2008; 12: 1093
  CrossrefSearch in Google Scholar
• 2a Abdel-Magid AF, Mehrman SJ. Org. Process Res. Dev. 2006; 10: 971
  CrossrefSearch in Google Scholar
• 2b Abdel-Magid AF, Maryanoff CA, Carson KG. Tetrahedron Lett. 1990; 31: 5595
  CrossrefSearch in Google Scholar
• 3a Hutchins RO, Natale NR. Org. Prep. Proced. Int. 1979; 11: 201
  CrossrefSearch in Google Scholar
• 3b Lane CF. Synthesis 1975; 135
  Thieme Connect
• 4a Irrgang T, Kempe R. Chem. Rev. 2020; 120: 9583
  CrossrefPubMedSearch in Google Scholar
• 4b Murugesan K, Senthamarai T, Chandrashekhar VG, Natte K, Kamer PC. J, Beller M, Jagadeesh RV. Chem. Soc. Rev. 2020; 49: 6273
  CrossrefPubMedSearch in Google Scholar

For selected examples of reductive aminations with electron-deficient amines, see:
• 5a Pletz J, Berg B, Breinbauer R. Synthesis 2016; 48: 1301
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The N-acetylation is believed to be the result of nucleophilic attack by the amines on the triacetoxyborohydride and has been described in previous publications:
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• 9 Our process has been further scaled up at an external CMO with success: on 44.8 kg scale of 2, product 1 was isolated with identical yield and purity as in our kilolab run in a 30 L reactor (93% yield, HPLC: 99.8% a/a).

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