Synthesis of Borylated Hydrazino Acid Derivatives

Key words

hydrazinoboronates - aminoboronic acids - organoboron - borylated heterocycles - BMIDA

Organoboron compounds have found widespread applications in various fields of inquiry.[1] The ability of boron to reversibly bind to heteroatom nucleophiles, combined with boric acid’s low toxicity (main metabolite of organoboron compounds; LD₅₀ comparable to table salt) have allowed the identification of numerous boron-containing molecules as promising candidates in drug discovery.[1d] [2] Among the many boron-containing scaffolds, borylated peptidomimetics derived from α-aminoboronic acids often display potent antitumor properties.[3] As such, the synthesis of α-amino­boronic acids has been a subject of ongoing interest (Scheme [1]).[4]

Compared to α-aminoboronic acids, α-hydrazinoboronic acids have received no attention despite the prevalence of hydrazine building blocks in organic chemistry.[5] The hydrazine motif is frequently employed in the synthesis of heterocyclic scaffolds with biomedical applications.[6] In addition to being versatile synthetic handles, incorporation of the hydrazine functional group in peptidic scaffolds results in aza-β-peptides, which can display new secondary structures when compared to the parental forms.[7] As part of our ongoing efforts in the pursuit of unique boron-containing building blocks,[8] we report the synthesis and utility of α-boryl-α-hydrazinoacetic acid 1.

Scheme 1 Synthesis of α-aminoboronates: (a) Cu-catalyzed borylation of enantiopure sulfinyl imines. (b) Ugi 4C reaction using α-boryl isocy­anides with aldehydes, carboxylic acids, and ammonia. (c) Reductive amination of MIDA acyl boronates and potassium acyltrifluoroborates. (d) Rh-catalyzed amine-directed C(sp³)–H borylation. (e) Synthesis of α-boryl-α-hydrazinoacetic acid 1.

Treatment of readily available α-borylacetaldehyde 2 [8a] with DBAD (di-tert-butyl azodicarboxylate) in the presence of catalytic amount of proline yielded α-boryl-α-hydrazinoacetaldehyde 3 with complete consumption of 2 (Scheme [2]).[9] No side products were generated based on ¹H NMR spectroscopy of the crude reaction mixture. Accordingly, we moved forward with the reaction by carrying out a Pinnick oxidation.[8a] To our delight, highly functionalized MIDA boronate 1 was isolated by filtration in 86% yield over two steps in a one-pot fashion.

Scheme 2 Synthesis of MIDA boronate 1 via a proline-catalyzed α-amination of α-borylacetaldehyde 2 then subsequent Pinnick oxidation in one pot

With 1 in hand, we set out to explore the utility of the hydrazine moiety. Deprotection of the Boc (tert-butoxycarbonyl) group in a DCM/TFA mixture provided the free hydrazine salt 4 in quantitative yield after 30 minutes without any signs of MIDA deprotection or protodeboronation. Upon evaporation of the solvent, reaction with 1,3- or 1,4-electrophiles in MeCN yielded a series of N-heterocycle-substituted α-carboxy MIDA boronates 5 (Scheme [3]). Reaction with acetylacetaldehyde dimethyl acetal produced a 4:1 mixture of 1,5- and 1,3-substituted pyrazole 5a in quantitative yield. Condensation with acetylacetone and dibenzoylmethane gave 5b and 5c, respectively. However, the reaction to give 5c did not go to completion after 20 h, presumably due to reduced reactivity of dibenzoylmethane. Aryl keto-enamines reacted efficiently with 4 to form the corresponding 5-arylpyrazoles in high yields (5d–5f). Cyclization with arylated malondialdehydes successfully gave the corresponding 4-arylpyrazoles (5g and 5h). Pyrazolone 5i was generated when ethyl acetoacetate was used as the bis-electrophile. Similarly, methyl 2-formylbenzoate and 2-formylphenylboronic acid were suitable 1,4-electrophiles under these conditions and the reactions provided phthalazinone 5j and 1,2,3-diazaborinine 5k, respectively. Lastly, condensation with phthalic anhydride afforded a mixture of phthalazinedione 5l and N-aminophthalimide 5l′ which are separable by column chromatography.

We next turned our attention towards the derivatization of the carboxy functional group (Scheme [4]). Methylation of the carboxylic acid with TMSCHN₂ gave the methyl ester in good yield (6a). Activation of the acid with HATU and subsequent reduction of the activated ester with NaBH₄ gave β-hydrazino alcohol 6b. Similarly, borylated oxadiazole 6c could be synthesized using a one-pot HATU-mediated coupling protocol adapted from our previous report.[8e] Activation of the carboxylic acid with DIC in the presence of 4-nitrobenzyl alcohol provided the corresponding 4-nitrobenzyl ester 6d in excellent yield.[10] Additionally, redox-active ester 6e could be synthesized on a 1-g scale in good yield using N-hydroxyphthalimide as the nucleophile. Reaction with DPPA (diphenylphosphoryl azide) under mild heat provided triazolidinone 6f via the Curtius rearrangement. This represents one of the few examples of a boronate that is attached to a carbon atom with the oxidation state of an aldehyde.[11] Subsequent N-alkylation of 6f with 4-nitrobenzyl bromide gave 6g, the structure of which was confirmed by single crystal X-ray diffraction (Figure [1]).

Scheme 3 Scope of N-heterocycle substituted α-carboxy MIDA boronates from the condensation of 4 with a variety of electrophilic acceptors. ^a Reaction was performed on a 1.05 mmol scale. ^b The product was isolated as a TFA salt.

Scheme 4 Functionalization of the carboxy moiety of 1. Reagents and conditions: (i) TMSCHN₂ (2 equiv), THF/MeOH then AcOH, 84%; (ii) HATU (1.2 equiv), DIPEA (3 equiv), MeCN then NaBH₄ (3 equiv), 66%; (iii) HATU (1.1 equiv), DIPEA (3 equiv), PhNHC(S)NHNH₂ (1.1 equiv), MeCN then TsCl (3.2 equiv) and DIPEA (3 equiv), 68%; (iv) DIC (1.1–1.2 equiv), DMAP (10 mol%), ROH (1.1–1.2 equiv), DCM/MeCN, 91% and 64%; (v) DPPA (1.1 equiv), DIPEA (2.2 equiv), MeCN, 64%; (vi) 4-nitrobenzyl bromide (1.2 equiv), K₂CO₃ (2 equiv), TBAB (10 mol%), DMF, 53%. ^a Reaction was performed on a 2.7 mmol scale. ^b Reaction was performed on a 5.4 mmol scale.

Figure 1 X-ray crystal structure of 6g. Thermal ellipsoid probabilities set at 50%. Hydrogen atoms are omitted for clarity.

In conclusion, we have developed a straightforward synthesis of α-carboxy-α-hydrazino MIDA boronate 1 using a column-free protocol from readily available aldehyde 2. The highly functionalized building block was used to access a variety of boro-methylated heterocycles and carboxy derivatives. The resulting borylated compounds 5 and 6 have considerable potential in transition-metal-catalyzed Suzuki–Miyaura cross-coupling and decarboxylative cross-coupling to access value-added products.

All solvents and reagents were purchased from commercial sources and used as received unless otherwise stated. HPLC grade MeCN, hexane, and i-PrOH were purchased from MilliporeSigma and used as received. THF was distilled from Na benzophenone ketyl prior to use. Aryl keto-enamine,[12] malondialdehydes,[13] and 2 [8c] were synthesized according to literature procedures. Flash column chromatography was carried out using Silicycle 230–400 mesh silica gel. Thin-layer chromatography was performed on Merck Aluminum-backed TLC Silica gel 60 F²⁵⁴ and visualized using a UV lamp (254 nm) and curcumin stain. Reverse-phase chromatography was carried out using Biotage SNAP ultra C18 on a Teledyne-Isco Combiflash system. ¹H, ¹¹B, ¹³C, and ¹⁹F NMR spectra were recorded on Bruker 400 MHz and 500 MHz spectrometers at 23 °C unless otherwise stated. ¹H NMR chemical shifts are referenced to residual protonated solvent peak (MeCN-d ₃: δ = 1.94; DMSO-d ₆: δ = 2.50). ¹¹B NMR chemical shifts are referenced to an external standard of BF₃·OEt₂ (δ = 0.0). ¹³C NMR chemical shifts are referenced to the corresponding solvent peaks (MeCN-d ₃: δ = 118.2; DMSO-d ₆: δ = 39.5). Carbon atoms exhibiting significant line broadening brought about by boron substituents were not reported due to quadrupolar relaxation. ¹⁹F NMR chemical shifts are referenced to an external standard of CFCl₃ (δ = 0.0). HRMS were obtained on a VG 70-250S (double focusing) mass spectrometer at 70 eV or on an ABI/Sciex Qstar mass spectrometer with ESI or DART sources, MS/MS and accurate mass capabilities. Low-resolution mass spectra (ESI) were collected on an Agilent Technologies 1200 series HPLC paired to a 6130 Mass Spectrometer. FTIR analysis was carried out on a Bruker Αlpha Platinum ATP spectrometer and peaks below 1500 cm^–1 are not reported. Melting points were measured uncorrected utilizing a Mel-Temp capillary melting point apparatus.

α-Boryl-α-hydrazinoacetic Acid 1

To a stirred suspension of 2 (1.00 g, 5.03 mmol, 1 equiv) in MeCN (50 mL) were added di-tert-butyl azodicarboxylate (1.39 g, 6.03 mmol, 1.2 equiv) and l-proline (145 mg, 1.26 mmol, 25 mol%). The mixture was stirred at rt for 16 h. Cyclohexene (5.1 mL, 50.3 mmol, 10 equiv), NaH₂PO₄·H₂O (6.94 g, 50.3 mmol, 10 equiv), NaClO₂ (1.36 g, 15.1 mmol, 3 equiv), and water (30 mL) were subsequently added. The mixture was stirred at rt for 6 h. Upon completion of reaction as indicated by ¹H NMR spectroscopy, the organic layer was removed from the biphasic mixture in vacuo. MeCN (10 mL) was added, then the mixture was cooled for 1 h in a 4 °C fridge. The mixture was filtered, then the filter cake was washed with water (20 mL) and Et₂O (50 mL) to afford 1 (1.93 g, 4.33 mmol, 86%) as a colorless solid; mp 207–210 °C.

IR (neat): 3173, 2979, 1799, 1773, 1726, 1714, 1662, 1524 cm^–1.

¹H NMR (500 MHz, 333 K, DMSO-d ₆): δ = 8.12 (br s, 1 H), 4.37 (s, 1 H), 4.27 (d, J = 17.5 Hz, 1 H), 4.21 (d, J = 17.0 Hz, 1 H), 4.00 (d, J = 17.5 Hz, 1 H), 3.95 (d, J = 17.0 Hz, 1 H), 3.16 (s, 3 H), 1.43 (s, 9 H), 1.40 (s, 9 H).

¹³C NMR (126 MHz, 333 K, DMSO-d ₆): δ = 173.6, 168.0, 167.7, 80.7, 80.2, 62.7, 46.3, 27.7, 27.5.

¹¹B NMR (160 MHz, 333 K, DMSO-d ₆): δ = 9.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₈BN₃NaO₁₀: 467.1796; found: 467.1795.

α-Boryl-α-hydrazinoacetaldehyde 3

To a stirred suspension of 2 (0.400 g, 2.01 mmol, 1 equiv) in MeCN (10 mL) were added di-tert-butyl azodicarboxylate (0.555 g, 2.41 mmol, 1.2 equiv) and l-proline (58 mg, 0.50 mmol, 25 mol%). The mixture was stirred at rt for 16 h. The mixture was diluted with MeCN (100 mL) and loaded onto Celite. The volatiles were removed in vacuo, then the residue was purified by normal-phase column chromatography (mixture hexanes/acetone) to afford 3 (0.656 g, 1.53 mmol, 76%) as a colorless solid; mp 120–122 °C.

IR (neat): 3274, 2932, 2861, 1772, 1717, 1685, 1500 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 9.73 (s, 1 H), 6.95–7.10 (br, 1 H), 4.63–4.78 (br, 1 H), 3.96–4.09 (m, 4 H), 3.22 (s, 3 H), 1.41 (s, 18 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 203.1, 167.7, 156.2, 156.1, 81.4, 80.7, 63.4, 63.0, 47.0, 27.5, 27.3.

¹¹B NMR (160 MHz, MeCN-d ₃): δ = 10.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₈BN₃NaO₉: 451.1847; found: 451.1851.

Hydrazine Condensation; General Procedure

To a 1-dram vial containing 1 (44.5 mg, 0.1 mmol, 1 equiv) was added DCM (0.5 mL) and TFA (0.5 mL). The mixture was stirred for 30 min at rt. The volatiles were removed in vacuo, then MeCN (1 mL) was added. To the stirring solution was added the appropriate electrophile (1–1.1 equiv), then the mixture was stirred at rt or 50 °C for 16 h. The mixture was loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to reversed-phase column chromatography (gradient of water/MeCN 95:5 to 0:100) to afford the corresponding products upon removal of solvents. Alternatively, if the product precipitated from the mixture, then the mixture was filtered, and the filter cake was washed with MeCN (1 mL) to afford the corresponding products.

2-(5-Methyl-1H-pyrazol-1-yl)-2-(MIDA-boryl)acetic Acid (5a)

The reaction was carried out according to the general procedure using acetylacetaldehyde dimethyl acetal (14.6 mL, 0.11 mmol, 1.1 equiv) at rt and purified by reversed-phase column chromatography to afford 5a (29.2 mg, 0.099 mmol, 99%) as a colorless solid; mp 176–180 °C (decomp.).

IR (neat): 2982, 1771, 1746, 1717, 1527 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.44 (d, J = 2.5 Hz, 1 H), 7.35* (d, J = 1.5 Hz), 6.10 (d, J = 2.0 Hz, 1 H), 6.09* (d, J = 1.0 Hz), 4.98 (s, 1 H), 4.89* (s), 4.30* (d, J = 16.5 Hz), 4.20 (d, J = 16.0 Hz, 1 H), 4.1–4.02 (overlapped, 2 H), 4.08–4.02* (overlapped), 3.12 (s, 3 H), 3.07* (s), 2.23* (s), 2.22 (s, 3 H); * minor 1,3-regioisomer.

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.2, 172.8*, 169.0*, 168.9*, 168.8, 168.6, 148.7, 141.5*, 138.6*, 133.6, 106.1 (major and minor), 65.1*, 65.0*, 64.8, 64.5, 47.9*, 47.9, 13.3, 11.1*; * minor regioisomer.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.4.

HRMS (ESI): m/z [M – H]^– calcd for C₁₁H₁₃BN₃O₆: 293.0939; found: 293.0944.

2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(MIDA-boryl)acetic Acid (5b)

The reaction was carried out according to the general procedure using acetylacetone (11.2 μL, 0.11 mmol, 1.1 equiv) at rt and purified by reversed­-phase column chromatography to afford 5b (27.4 mg, 0.089 mmol, 89%) as a colorless solid ; mp 110–115 °C (decomp.).

IR (neat): 2968, 2551, 1768, 1669, 1586, 1520 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 5.85 (s, 1 H),4.76 (s, 1 H), 4.27 (d, J = 16.5 Hz, 2 H), 4.08–3.99 (m, 3 H), 3.07 (s, 3 H), 2.14 (s, 3 H), 2.12 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.4, 169.1, 168.9, 147.7, 142.3, 105.8, 65.1, 65.0, 48.0, 13.4, 11.1.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₂H₁₅BN₃O₆: 307.1096; found: 307.1097.

2-(3,5-Diphenyl-1H-pyrazol-1-yl)-2-(MIDA-boryl)acetic Acid (5c)

The reaction was carried out according to the general procedure using 1,3-diphenylpropane-1,3-dione (14.6 μL, 0.11 mmol, 1.1 equiv) at 50 °C and purified by reversed-phase column chromatography to afford 5c (10.2 mg, 0.024 mmol, 24%) as a colorless solid; mp 208–213 °C.

IR (neat): 2968, 1772, 1766, 1607, 1557 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.80–7.78 (m, 2 H), 7.51–7.49 (m, 3 H), 7.44–7.42 (m, 4 H), 7.38–7.36 (m, 1 H), 6.77 (s, 1 H), 4.86 (s, 1 H), 4.21 (d, J = 17.0 Hz, 1 H), 4.09–3.99 (m, 3 H), 3.04 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.0, 169.0, 168.8, 146.1, 139.4, 131.3, 129.8, 129.8, 129.8, 107.1, 65.1, 64.9, 47.9.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.6.

HRMS (ESI): m/z [M – H]^– calcd for C₂₂H₁₉BN₃O₆: 431.1409; found: 431.1413.

2-(MIDA-Boryl)-2-(5-phenyl-1H-pyrazol-1-yl)acetic Acid (5d)

The reaction was carried out according to the general procedure using (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (18.4, 0.105 mmol, 1.05 equiv) at rt and purified by reversed-phase column chromatography to afford 5d (33.9 mg, 0.095 mmol, 95%) as a colorless solid; mp 165–168 °C.

IR (neat): 3029, 2799, 2475, 1769, 1670, 1553 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.52 (d, J = 2.0 Hz, 1 H), 7.49–7.46 (m, 3 H), 7.38–7.36 (m, 2 H), 6.36 (d, J = 1.5 Hz, 1 H), 4.86 (s, 1 H), 4.28 (d, J = 17.0 Hz, 1 H), 4.09–3.99 (m, 3 H), 3.04 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.0, 169.0, 168.7, 148.1, 139.4, 131.3, 129.8, 129.8, 129.8, 107.1, 65.1, 64.9, 47.9.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₅BN₃O₆: 355.1096; found: 355.1099.

2-[5-(1H-Pyrrol-2-yl)-1H-pyrazol-1-yl]-2-(MIDA-boryl)acetic Acid (5e)

The reaction was carried out according to the general procedure using (E)-3-(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (18.1 mg, 0.11 mmol, 1.1 equiv) at rt and purified by reversed-phase column chromatography to afford 5e (33.9 mg, 0.098 mmol, 98%) as a brown solid; mp 170–175 °C (decomp.).

IR (neat): 3374, 3146, 2982, 2262, 1748, 1607, 1511 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 9.51 (br s), 7.47 (d, J = 2.0 Hz, 1 H), 6.90–6.89 (m, 1 H), 6.38 (d, J = 2.0 Hz, 1 H), 6.27–6.25 (m, 1 H), 6.24–6.23 (m, 1 H), 5.06 (s, 1 H), 4.29 (d, J = 16.5 Hz, 1 H), 4.10–4.01 (m, 3 H), 3.02 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.0, 169.1, 168.9, 139.3, 138.8, 121.3, 120.7, 110.2, 109.1, 105.1, 65.1, 65.0, 47.9.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₁₄BN₄O₆: 344.1048; found: 344.1052.

2-[5-(Furan-2-yl)-1H-pyrazol-1-yl]-2-(MIDA-boryl)acetic Acid (5f)

The reaction was carried out according to the general procedure using (E)-3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (18.2 mg, 0.11 mmol, 1.1 equiv) at rt and purified by reversed-phase column chromatography to afford 5f (32.6 mg, 0.094 mmol, 94%) as a brown solid; mp 140–142 °C (decomp.).

IR (neat): 2982, 2886, 1746, 1527 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.60 (dd, J = 1.9, 1.0 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 6.67 (dd, J = 3.5, 1.0 Hz, 1 H), 6.56 (dd, J = 3.5, 2.0 Hz, 1 H), 6.55 (d, J = 2.0 Hz, 1 H), 5.26 (s, 1 H), 4.31 (d, J = 16.5 Hz, 1 H), 4.11–4.02 (m, 3 H), 3.05 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 172.9, 169.0, 168.9, 145.2, 144.3, 139.5, 136.3, 112.5, 110.1, 106.0, 65.2, 65.1, 48.0.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.7.

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₁₃BN₃O₇: 345.0888; found: 345.0894.

2-(MIDA-Boryl)-2-(4-phenyl-1H-pyrazol-1-yl)acetic Acid (5g)

The reaction was carried out on a 1-mmol scale according to the general procedure using 2-phenylmalonaldehyde (156 mg, 1.05 mmol, 1.05 equiv) at rt and purified by reversed-phase column chromatography to afford 5g (294 mg, 0.82 mmol, 82%) as a colorless solid; mp 150–152 °C (decomp.).

IR (neat): 3000, 2981, 1757, 1729, 1608, 1570 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.88 (s, 1 H), 7.80 (s, 1 H), 7.55–7.54 (m, 2 H), 7.38–7.35 (m, 2 H), 7.24–7.22 (m, 1 H), 5.04 (s, 1 H), 4.21 (d, J = 17.0 Hz, 1 H), 4.08 (d, J = 17.0 Hz, 1 H), 4.04 (d, J = 17.0 Hz, 1 H), 3.95 (d, J = 17.0 Hz, 1 H), 3.11 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 172.8, 168.8, 168.6, 137.0, 133.4, 129.8, 129.8, 127.3, 126.2, 123.8, 64.8, 64.5, 47.9.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.5.

HRMS (ESI): m/z [M-H]^- calcd for C₁₆H₁₅BN₃O₆: 355.1096; found: 355.1100.

2-[4-(Biphenyl-4-yl)-1H-pyrazol-1-yl]-2-(MIDA-boryl)acetic Acid (5h)

The reaction was carried out according to the general procedure using 2-(biphenyl-4-yl)malonaldehyde (24.7 mg, 0.11 mmol, 1.1 equiv) at rt and purified by reversed-phase column chromatography to afford 5h (27.7 mg, 0.064 mmol, 64%) as a colorless solid; mp 213–215 °C (decomp.).

IR (neat): 3034, 2964, 1769, 1716, 1615, 1575 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.07 (s, 1 H), 7.91 (s, 1 H), 7.70–7.64 (m, 6 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 1 H), 5.09 (s, 1 H), 4.45 (d, J = 17.0 Hz, 1 H), 4.32 (d, J = 17.0 Hz, 1 H), 4.18 (d, J = 17.0 Hz, 1 H), 4.05 (d, J = 17.0 Hz, 1 H), 3.08 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 172.6, 168.8, 168.3, 139.8, 137.5, 135.8, 131.7, 128.8, 127.2, 127.1, 126.3, 125.4, 121.2, 63.5, 63.2, 46.9.

¹¹B NMR (128 MHz, DMSO-d ₆): δ = 11.2.

HRMS (ESI): m/z [M – H]^– calcd for C₂₂H₁₉BN₃O₆: 431.1409; found: 431.1399.

2-(MIDA-Boryl)-2-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)acetic Acid·Trifluoroacetic Acid (5i)

The reaction was carried out according to the general procedure using ethyl acetoacetate (10.8 μL, 0.1 mmol, 1 equiv) at rt and purified by filtration to afford 5i (28.4 mg, 0.067 mmol, 67%) as a colorless solid; mp 158–161 °C.

IR (neat): 3217, 2969, 2541, 1909, 1770. 1736, 1639, 1575 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 5.36 (br s, 1 H), 4.66 (br s, 1 H), 4.44 (d, J = 17.0 Hz, 1 H), 4.27 (d, J = 16.5 Hz, 1 H), 4.16–4.11 (m, 2 H), 3.06 (s, 3 H), 2.10 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 172.8, 172.0, 168.8, 168.4, 158.3 (q, J = 36.6 Hz), 145.7, 115.5 (q, J = 292.8 Hz), 87.1, 63.7, 63.4, 47.1, 13.2.

¹¹B NMR (128 MHz, DMSO-d ₆): δ = 10.9.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –74.7.

HRMS (ESI): m/z [M – CF₃CO₂H₂]^– calcd for C₁₁H₁₃BN₃O₇: 309.0888; found: 309.0891.

2-(MIDA-Boryl)-2-(1-oxophthalazin-2(1H)-yl)acetic Acid (5j)

The reaction was carried out according to the general procedure using methyl 2-formylbenzoate (18.1 mg, 0.11 mmol, 1.1 equiv) at rt and purified by filtration to afford 5j (28.1 mg, 0.078 mmol, 78%) as a colorless solid; mp 235–236 °C (decomp.).

IR (neat): 3072, 3013, 2970, 2908, 1753, 1726, 1624, 1574 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.9 (s, 1 H), 8.45 (s, 1 H), 8.26 (dd, J = 7.8 Hz, 1 H), 7.97–7.96 (m, 2 H), 7.91–7.87 (m, 1 H), 5.39 (s, 1 H), 4.50 (d, J = 17.2 Hz, 1 H), 4.28 (d, J = 16.8 Hz, 1 H), 4.20–4.14 (m, 2 H), 3.13 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 172.7, 169.0, 168.6, 158.8, 137.2, 133.7, 132.1, 129.2, 126.8, 126.8, 125.9, 63.8, 63.5, 47.7.

¹¹B NMR (128 MHz, DMSO-d ₆): δ = 11.3.

HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₃BN₃O₇: 357.0888; found: 357.0891.

2-(1-Hydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)-2-(MIDA-boryl)acetic Acid·Trifluoroacetic Acid (5k)

The reaction was carried out according to the general procedure using 2-formylphenylboronic acid (15.0 mg, 0.1 mmol, 1 equiv) at rt and purified by filtration to afford 5k (23.2 mg, 0.049 mmol, 49%) as a colorless solid; mp >250 °C.

IR (neat): 3312, 2982, 1780, 1754. 1722, 1674, 1524 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ = 8.26 (d, J = 7.5 Hz, 1 H), 7.99 (s, 3 H), 7.72–7.71 (m, 2 H), 7.61–7.58 (m, 1 H), 4.84 (s, 1 H), 4.46 (d, J = 17.5 Hz, 1 H), 4.20–4.11 (m, 3 H), 3.12 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 175.2, 169.2, 168.6, 158.3 (q, J = 38.1 Hz), 136.8, 135.2, 131.2, 130.9, 128.4, 126.6, 115.1 (q, J = 289.9 Hz), 63.7, 63.6, 47.3.

¹¹B NMR (128 MHz, DMSO-d ₆): δ = 29.0, 10.3.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –74.8.

HRMS (ESI): m/z [M – CF₃CO₂H₂]^– calcd for C₁₄H₁₄B₂N₃O₇: 356.1096; found: 356.1102.

2-[1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl]-2-(MIDA-boryl)acetic Acid (5l)

The reaction was carried out according to the general procedure using phthalic anhydride (16.3 mg, 0.11 mmol, 1.1 equiv) at 50 °C and purified by reversed-phase column chromatography to afford 5l (6.6 mg, 0.018 mmol, 18%) as a colorless solid; mp 185–190 °C.

IR (neat): 2983, 1751, 1645, 1571, 1500 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 8.31–8.29 (m, 1 H), 7.96–7.95 (m, 1 H), 7.88–7.85 (m, 2 H), 5.57 (s, 1 H), 4.26 (d, J = 17.0 Hz, 1 H), 4.12 (d, J = 17.5 Hz, 1 H), 4.06 (d, J = 17.0 Hz, 1 H), 4.02 (d, J = 17.5 Hz, 1 H), 3.23 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.5, 169.1, 169.0, 159.6, 150.4, 134.2, 133.5, 129.7, 127.8, 125.2, 125.1, 65.1, 64.5, 48.6.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.9.

HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₃BN₃O₈: 373.0838; found: 373.0837.

2-[(1,3-Dioxoisoindolin-2-yl)amino]-2-(MIDA-boryl)acetic Acid (5l′)

The reaction was carried out according to the general procedure using phthalic anhydride (16.3 mg, 0.11 mmol, 1.1 equiv) at 50 °C and purified by reversed-phase column chromatography to afford 5l′ (13.7 mg, 0.037 mmol, 37%) as a colorless solid; mp >250 °C.

IR (neat): 2972, 1746, 1639, 1544, 1500 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.84–7.79 (m, 4 H), 5.21 (br s, 1 H), 4.23 (d, J = 17.0 Hz, 1 H), 4.10 (d, J = 17.0 Hz, 1 H), 4.05 (d, J = 17.5 Hz, 1 H), 3.94 (d, J = 17.0 Hz, 1 H), 3.69 (br s, 1 H), 3.17 (s, 3 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 175.2, 168.6, 168.4, 167.8, 135.5, 131.2, 124.1, 63.8, 63.5, 47.6.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 9.8.

HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₃BN₃O₈: 373.0838; found: 373.0831.

2-[1,2-Bis(tert-butoxycarbonyl)hydrazinyl]-2-(MIDA-boryl)acetic Acid (6a)

To a stirred suspension of 1 (44.5 mg, 0.1 mmol, 1 equiv) in THF (0.35 mL) and MeOH (0.15 mL) at 0 °C was added TMSCHN₂ (2 M in hexane, 0.1 mL, 0.2 mmol, 2 equiv). The mixture was stirred for 30 min at 0 °C. After addition of AcOH (0.1 mL), the mixture was loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to normal-phase column chromatography to afford 6a (38.5 mg, 0.084 mmol, 84%) as a colorless solid; mp 115–117 °C.

IR (neat): 2983, 1760, 1713 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 6.97 (br s, 1 H), 4.58 (br s, 1 H), 4.02–3.92 (m, 4 H), 3.68 (s, 3 H), 3.19 (s, 3 H), 1.43–1.41 (overlapped, 18 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 174.1, 168.8, 82.7, 81.4, 64.5, 63.9, 52.7, 47.6, 28.4, 28.2.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₃₀BN₃NaO₁₀: 481.1953; found: 481.1952.

Di-tert-butyl 1-[2-Hydroxy-1-(MIDA-boryl)ethyl]hydrazine-1,2-dicarboxylate (6b)

To a stirred suspension of 1 (44.5 mg, 0.1 mmol, 1 equiv) and HATU (45.6 mg, 0.12 mmol, 1.2 equiv) in MeCN (1 mL) was added DIPEA (34.8 μL, 0.2 mmol, 2 equiv). The mixture was stirred at rt for 15 min. NaBH₄ (11.3 mg, 0.3 mmol, 3 equiv) was added to the solution, then the mixture was stirred at rt for 3 h. After addition of MeOH (0.5 mL), the mixture was loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to reversed-phase column chromatography to afford 6b (28.3 mg, 0.066 mmol, 66%) as a colorless solid; mp 148–150 °C.

IR (neat): 3411, 2981, 2962, 2906, 1768, 1705 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.04–6.82 (br, 1 H), 4.12–3.85 (m, 5 H), 3.65–3.53 (br, 2 H), 3.24–2.99 (br, 3 H), 1.43–1.40 (overlapped, 18 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 169.0, 168.7, 82.1, 81.4, 63.9, 63.0, 60.2, 47.9, 46.8, 28.4, 28.4.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₃₀BN₃NaO₉: 453.2004; found: 453.1994.

Di-tert-butyl {(MIDA-boryl)[5-(phenylamino)-1,3,4-oxadiazol-2-yl]methyl}hydrazine-1,2-dicarboxylate (6c)

To a stirred suspension of 1 (44.5 mg, 0.1 mmol, 1 equiv) and HATU (41.8 mg, 0.11 mmol, 1.1 equiv) in MeCN (1 mL) was added DIPEA (52.3 μL, 0.3 mmol, 3 equiv). The mixture was stirred at rt for 15 min. N-Phenylhydrazinecarbothioamide (18.4 mg, 0.11 mmol, 1.1 equiv) was added to the solution, then the mixture was stirred at rt for 30 min. TsCl (41.9 mg, 0.22 mmol, 2.2 equiv) was added, then the mixture was stirred at rt for 4 h. After 4 h, another aliquot of TsCl (19.1 mg, 0.1 mmol, 1 equiv) and DIPEA (52.3 μL, 0.3 mmol, 3 equiv) were added, then the mixture was stirred at rt for 20 h. The mixture was loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to reversed-phase column chromatography to afford 6c (38.2 mg, 0.068 mmol, 68%) as a colorless solid; mp 157–160 °C.

IR (neat): 3328, 2982, 2936, 1778, 1740, 1700, 1515 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.92–7.88 (m, 4 H), 7.17–7.02 (br, 1 H), 5.10 (br s, 1 H), 4.14–3.99 (m, 4 H), 3.28 (s, 3 H), 1.44 (overlapped, 18 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 168.5, 168.4, 163.1, 136.3, 129.6, 124.9, 82.1, 65.0, 64.3, 47.9, 28.4, 28.1.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₃₁BN₄NaO₁₂: 612.1960; found: 612.1959.

Di-tert-butyl 1-[1-(MIDA-boryl)-2-(4-nitrobenzyloxy)-2-oxoethyl]hydrazine-1,2-dicarboxylate (6d)

To a stirred suspension of 1 (44.5 mg, 0.1 mmol, 1 equiv), 4-nitrobenzyl alcohol (18 mg, 0.12 mmol, 1.2 equiv), and DMAP (1.2 mg, 0.01 mmol, 10 mol%) in DCM (0.66 mL) and MeCN (0.33 mL) was added DIC (18.7 μL, 0.12 mmol, 1.2 equiv). The mixture was stirred at rt for 20 h. The mixture was filtered then loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to normal-phase column chromatography to afford 6d (52.7 mg, 0.091 mmol, 91%) as a colorless solid; mp 155–158 °C.

IR (neat): 3314, 2982, 2942, 1779, 1757, 1724, 1675, 1605, 1514 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 8.21–8.19 (m, 2 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.03 (br s, 1 H), 5.33 (second order, 1 H), 5.25 (second order, 1 H), 4.71 (br, 1 H), 4.05–3.93 (m, 4 H), 3.21 (s, 3 H), 1.42 (s, 9 H), 1.39 (s, 9 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 173.5, 168.7, 168.7, 148.6, 144.7, 129.3, 124.5, 81.6, 66.2, 64.6, 63.9, 47.6, 28.4, 28.2.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₃BN₄NaO₁₂: 602.2117; found: 602.2115.

Di-tert-butyl 1-{2-[(1,3-Dioxoisoindolin-2-yl)oxy]-1-(MIDA-boryl­)-2-oxoethyl}hydrazine-1,2-dicarboxylate (6e)

To a stirred suspension of 1 (1.2 g, 2.70 mmol, 1 equiv), N-hydroxy­phthalimide (484 mg, 2.97 mmol, 1.1 equiv), and DMAP (33 mg, 0.27 mmol, 10 mol%) in DCM (20 mL) and MeCN (7 mL) was added DIC (0.464 mL, 2.97 mmol, 1.1 equiv). The mixture was stirred at rt for 14 h. The mixture was filtered then loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to normal-phase column chromatography to afford 6e (1.02 g, 1.73 mmol, 64%) as a colorless solid; mp 155–158 °C.

IR (neat): 3328, 2982, 2936, 1778, 1740, 1700, 1515 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 7.92–7.88 (m, 4 H), 7.17–7.02 (br, 1 H), 5.10 (br s, 1 H), 4.14–3.99 (m, 4 H), 3.28 (s, 3 H), 1.44 (overlapped, 18 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 168.5, 168.4, 163.1, 136.3, 129.6, 124.9, 82.1, 65.0, 64.3, 47.9, 28.4, 28.1.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 10.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₃₁BN₄NaO₁₂: 612.1960; found: 612.1959.

Di-tert-butyl 3-(MIDA-boryl)-5-oxo-1,2,4-triazolidine-1,2-di­carboxylate (6f)

To a stirred suspension of 1 (2.4 g, 5.39 mmol, 1 equiv) in MeCN (36 mL) at rt was added DIPEA (2.07 mL, 11.86 mmol, 2.2 equiv) and DPPA (1.28 mL, 5.93 mmol, 1.1 equiv). The mixture was stirred at 50 °C for 1.5 h. The mixture was cooled and loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to normal-phase column chromatography to afford 6f (1.53 g, 3.46 mmol, 64%) as a colorless solid; mp 172–177 °C (decomp.).

IR (neat): 3328, 2982, 2936, 1778, 1740, 1700, 1515 cm^–1.

¹H NMR (500 MHz, MeCN-d ₃): δ = 6.16 (br s, 1 H), 5.05 (s, 1 H), 4.07–4.03 (m, 2 H), 3.94–3.88 (m, 2 H), 3.07 (s, 3 H), 1.47 (s, 9 H), 1.45 (s, 9 H).

¹³C NMR (126 MHz, MeCN-d ₃): δ = 168.7, 167.9, 158.8, 153.9, 84.6, 83.7, 63.7, 63.4, 47.1, 28.2, 28.1.

¹¹B NMR (128 MHz, MeCN-d ₃): δ = 8.9.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₂₆BN₄O₉: 440.1835; found: 440.1838.

Di-tert-butyl 3-(MIDA-boryl)-4-(4-nitrobenzyl)-5-oxo-1,2,4-triazolidine-1,2-dicarboxylate (6g)

To a stirred suspension of 6f (100 mg, 0.23 mmol, 1 equiv), K₂CO₃ (63.6 mg, 46 mmol, 2 equiv), and TBAB (7.3 mg, 0.023 mmol, 10 mol%) in DMF (2 mL) at rt was added 4-nitrobenzyl bromide (57.8 mg, 0.27 mmol, 1.2 equiv). The mixture was stirred at 60 °C for 20 h. The mixture was cooled and loaded onto Celite, then the volatiles were removed in vacuo. The residue was subjected to normal-phase column chromatography. Upon removal of volatiles and trituration with Et₂O, 6g (70.2 mg, 0.12 mmol, 53%) was afforded as a colorless solid. Crystals suitable for X-ray diffraction were grown in MeCN/Et₂O using the vapor diffusion method; mp 195–200 °C (decomp.).

IR (neat): 3312, 2982, 1780, 1754, 1722, 1674, 1524 cm^–1.

¹H NMR (500 MHz, DMSO-d ₆): δ =8.21 (d, J = 9.0 Hz, 2 H), 7.44 (d, J = 8.5 Hz, 2 H), 5.07 (s, 1 H), 4.84 (d, J = 17.0 Hz, 1 H), 4.40 (d, J = 17.5 Hz, 1 H), 4.34 (d, J = 17.0 Hz, 1 H), 4.26 (d, J = 17.0 Hz, 1 H), 4.08 (d, J = 17.0 Hz, 1 H), 3.92 (d, J = 17.0 Hz, 1 H), 3.03 (s, 3 H), 1.42 (s, 9 H), 1.40 (s, 9 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 168.4, 167.6, 157.4, 150.9, 146.9, 144.8, 128.0, 123.7, 83.5, 82.3, 62.5, 62.4, 46.3, 44.3, 27.6, 27.4.

¹¹B NMR (128 MHz, DMSO-d ₆): δ = 9.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₂BN₅NaO₁₁: 599.2120; found: 599.2109.

• References

• 1a Wu X, Chen X.-X, Fossey JS, James TD, Jiang Y.-B. Chem. Soc. Rev. 2013; 42: 8032
• 1b Dimitrijević E, Taylor MS. ACS Catal. 2013; 3: 945
• 1c Li J, Ballmer SG, Gillis EP, Fujii S, Schmidt MJ, Palazzolo AM. E, Lehmann JW, Morehouse GF, Burke MD. Science 2015; 347: 1221
• 1d Smoum R, Rubinstein A, Dembitsky VM, Srebnik M. Chem. Rev. 2012; 112: 4156
• 2 Diaz DB, Yudin AK. Nat. Chem. 2017; 9: 731
• 3a Chen D, Frezza M, Schmitt S, Kanwar J, Dou D.-P. Curr. Cancer Drug Targets 2011; 11: 239
• 3b Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Wallner BP. Cancer Res. 2004; 64: 5471
• 3c Seavey MM, Lu LD, Stump KL, Wallace NH, Ruggeri BA. Int. Immunopharmacol. 2012; 12: 257
• 3d Zhanel GG, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, Lagacé-Wiens PR. S, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, Lynch JP. III, Karlowsky JA. Drugs 2018; 78: 65
• 3e Milo LJ. Jr, Lai JH, Wu W, Liu Y, Maw H, Li Y, Jin Z, Shu Y, Poplawski SE, Wu D, Sanford DG, Sudmeier JL, Bachovchin WW. J. Med. Chem. 2011; 54: 4365
• 4a Andrés P, Ballano G, Calaza I, Cativiela C. Chem. Soc. Rev. 2016; 45: 2291
• 4b Beenen MA, An C, Ellman JA. J. Am. Chem. Soc. 2008; 130: 6910
• 4c Zajdlik A, Wang Z, Hickey JL, Aman A, Schimmer AD, Yudin AK. Angew. Chem. Int. Ed. 2013; 52: 8411
• 4d Diaz DB, Scully CC. G, Liew SK, Adachi S, Trinchera P, St Denis JD, Yudin AK. Angew. Chem. Int. Ed. 2016; 55: 12659
• 4e Shiro T, Schuhmacher A, Jackl MK, Bode JW. Chem. Sci. 2018; 9: 5191
• 4f Reyes RL, Sato M, Iwai T, Sawamura M. J. Am. Chem. Soc. 2020; 142: 589
• 5 Fustero S, Sánchez-Roselló M, Barrio P, Simón-Fuentes A. Chem. Rev. 2011; 111: 6984
• 6a Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
• 6b Lamberth C. Heterocycles 2007; 71: 1467
• 6c Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P. J. Med. Chem. 2018; 61: 8402
• 7a Salaün A, Potel M, Roisnel T, Gall P, Le Grel P. J. Org. Chem. 2005; 70: 6499
• 7b Acherar S, Salaün A, Le Grel P, Le Grel B, Jamart-Grégnoire B. Eur. J. Org. Chem. 2013; 2013: 5603
• 7c Avan I, Hall CD, Katritzky AR. Chem. Soc. Rev. 2014; 43: 3575
• 7d Suć J, Tumir L.-M, Glavaš-Obrovac L, Jukic M, Piantanida I, Jerić I. Org. Biomol. Chem. 2016; 14: 4865
• 8a He Z, Yudin AK. J. Am. Chem. Soc. 2011; 133: 13770
• 8b He Z, Trinchera P, Adachi S, St Denis JD, Yudin AK. Angew. Chem. Int. Ed. 2012; 51: 11092
• 8c St Denis JD, Zajdlik A, Tan J, Trinchera P, Lee CF, He Z, Adachi S, Yudin AK. J. Am. Chem. Soc. 2014; 136: 17669
• 8d Kaldas SJ, O’Keefe KT, Mendoza-Sanchez R, Yudin AK. Chem. Eur. J. 2017; 23: 9711
• 8e Holownia A, Tien C.-H, Diaz DB, Larson RT, Yudin AK. Angew. Chem. Int. Ed. 2019; 58: 15148
• 9a List B. J. Am. Chem. Soc. 2002; 124: 5656
• 9b Bøgevig A, Kumaragurubaran N, Juhl K, Zhuang W, Jørgensen KA. Angew. Chem. Int. Ed. 2002; 41: 1790
• 10 Based on separation by HPLC on a chiral stationary phase column (see Supporting Information), the e.r. of 6d, and thus 1 by correlation, was determined to be 60:40. Due to the almost racemic nature of 1, e.r. determination of derivatives 5 and 6 were not measured.
• 11 Ivon YM, Mazurenko IV, Kuchkovska YO, Voitenko ZV, Grygorenko OO. Angew. Chem. Int. Ed. 2020; 59: 18016
• 12 Bindal S, Kumar D, Kommi DN, Bhatiya S, Chakraborti AK. Synthesis 2011; 1930
• 13 Hou T.-C, Wu Y.-Y, Chiang P.-Y, Tan K.-T. Chem. Sci. 2015; 6: 4643