Subscriber access provided by Universidad de Alicante Article Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic Acid: Mechanistic Investigations and Synthetic Applications Manel Estruch-Blasco, Diego Felipe-Blanco, Irene Bosque, and José C. González-Gómez J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00795 • Publication Date (Web): 18 May 2020 Downloaded from pubs.acs.org on May 24, 2020
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1 2 3 4 5 6 7 8 9 Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic Acid: Mechanistic 10 11 Investigations and Synthetic Applications 12 13 Manel Estruch-Blasco,† Diego Felipe-Blanco,† Irene Bosque, Jose C. Gonzalez-Gomez* 14 15 16 Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de 17 Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain 18 19 Email: [email protected] 20
21 CO H NH2 2 Ar O O 22 + OH <10 mol % Ar + P P OPh 23 P(OPh)3 SA OPh Ar OPh OPh + CH CN [0.20 M] 24 3 29 examples t-BuONO Ar, 20 ºC, 12 h 25 "Persistent radical effect" up to 94% yield 26 Metal free and additive free Availability of starting materials 27 SA as very convenient catalyst Gram-scale and operationally simple 28 Short reaction times at 20 ºC Unique reactivity of diaryl phosphonates 29 30 31 ABSTRACT: A straightforward and scalable methodology to synthesize diphenyl 32 arylphosphonates at 20 ºC within 1-2 h is reported, using inexpensive SA as the catalytic 33 34 promoter of the reaction. Mechanistic investigations suggest that the reaction proceeds via 35 36 radical-radical coupling, consistent with the so-called Persistent Radical Effect. The reaction 37 tolerated a wide range of functional groups and heteroaromatic moieties. The synthetic 38 39 usefulness and the unique reactivity of the obtained phosphonates were demonstrated in 40 41 different one-step transformations. 42 43 44 45 INTRODUCTION 46 47 Aryl phosphonates are privileged scaffolds among pharmaceuticals, agrochemicals, and 48 49 organic materials; as well as being versatile building blocks in organic synthesis or ligands 50 in transition-metal (TM) catalysis.1 Traditionally, these organophosphorus compounds were 51 52 prepared by reaction of electrophilic dialkyl chlorophosphonates with organolithium2 or 53 3 4 54 Grignard reagents. Since the seminal contribution of Hirao and coworkers, the 55 TM-catalyzed cross-coupling of (pseudo)haloarenes with H-phosphonates or trialkyl 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 2 of 37
1 2 3 phosphites has been one of the most extensively used strategies to prepare aryl 4 5 phosphonates.5-7 Given the recent advancements in visible light photocatalysis,8 the room 6 7 temperature preparation of aryl phosphonates has also been accomplished using this 8 methodology. In this frame, the photoinduced reductive generation of aryl radicals trapped 9 10 by trisubstituted phosphites has been successfully implemented,9 as well as the single- 11 12 electron oxidation of arenes to obtain radical cations that easily add nucleophilic 13 10 14 phosphites. In addition, intensive efforts have been made recently in the development of 15 TM-free synthesis of aryl phosphonates at room temperature. In this context, one successful 16 17 approach relied on the nucleophilic addition of dialkyl phosphites to in situ generated arynes 18 11 19 from 2-(trimethylsilyl)aryl triflates (Kobayashi precursors, Scheme 1a). It has been also 20 recently reported that the combination of diaryliodonium salts with phosphites can form an 21 22 electron donor-acceptor complex, upon irradiation with blue light in the presence of a base, 23 24 leading to the desired aryl phosphonates (Scheme 1b).12 The photoinduced oxidation of 25 26 arylhydrazines to produce aryl radicals that were trapped with trialkyl phosphites was also 27 recently developed,13 using an organic photocatalyst and 1,4-diazabicyclo[2.2.2]octane 28 29 (DABCO) as additive under aerobic conditions (Scheme 1c). The visible light-driven 30 31 generation of aryl radicals from arylazo sulfones in the absence of photocatalyst, which was 32 14 33 trapped with triaryl phosphites, is another elegant approach recently reported (Scheme 1d). 34 Furthermore, a Sandmeyer-type reaction of in situ formed diazonium salts with triaryl 35 36 phosphites promoted by stoichiometric amounts of p-toluene sulfonic acid (TsOH), has also 37 15 38 allowed the efficient preparation of aryl phosphonates (Scheme 1e). Despite these 39 remarkable contributions, a TM-free synthesis of aryl phosphonates at room temperature, 40 41 from readily available starting materials, without stoichiometric additives or excess of 42 43 reagents, is still desired. 44 45 Given the high reactivity and low selectivity of aryl radicals, a sustained catalytic aryl 46 47 radical generation is a more convenient approach for a successful synthetic 48 transformation.16,17 We have recently demonstrated that aryl radicals can be catalytically 49 50 generated from readily available anilines that are in situ transformed into diazonium salts 51 18 52 with tert-butyl nitrite (TBN), by using salicylic acid (SA) as a catalyst at room 53 temperature.19 We do think that SA is a very convenient catalyst because is inexpensive, non- 54 55 toxic, and a renewable feedstock derived from natural salicin. As part of our ongoing 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 37 The Journal of Organic Chemistry
1 2 3 program, we decided to explore these mild and environmentally benign conditions to obtain 4 5 diphenyl arylphosphonates. 6 7 Scheme 1. Context of the TM-free synthesis of diaryl phosphonates 8 9 (a) Chen, Q., et al.: Reference 11 10 OTf CsF (5 equiv) Cs2CO3 (1 equiv) 11 Ar + P(OR)3 12 TMS CH3CN, 25 ºC, 24 h (2 equiv) (1 equiv) 13 14 (b) Lecroq, W., et al.: Reference 12 K CO (1 equiv) 15 2 3 Ar2IOTf + P(OR)3 Blue LEDs, 16 h 16 (1.5 equiv) (1 equiv) CH3CN, 35 ºC 17 (c) Li, R., et al.: Reference 13 18 Eosin B (5 mol%) O 19 + P(OR) DABCO (50 mol%) ArNHNH2 3 P 20 (1 equiv) (2 equiv) white LEDS, 45 ºC Ar OR 21 CH3CN, open air, 6 h OR 22 (d) Qiu, D., et al.: Reference 14 Blue LEDs, 24 h 23 ArN2SO2Me + P(OR)3 24 (1 equiv) (3.5 equiv) CH3CN, 35 ºC 25 (e) Wang, S., et al.: Reference 15 26 TsOH×H2O (1.2 equiv) 27 P(OPh) (3 equiv) ArNH t-BuONO (1.5 equiv) 3 28 2 (1 equiv) CH3CN, 0 ºC, 15 min 0 ºC- 25 ºC, 8 h 29 30 31 RESULTS AND DISCUSSION 32 33 Since at 60 ºC the diazonium salts can react with CH3CN to form acetamides via N- 34 20 35 arenenitrilium salts (Ritter reaction), we carefully controlled the reaction temperature at 20 36 ºC. We were pleased to observe how the addition of 10 mol % of salicylic acid (SA) 37 38 significantly accelerated the formation of phosphonate 2a in CH3CN (Table 1, entries 1-2). 39 40 Importantly, the reaction was complete within 1 h without preforming of the diazonium salt, 41 42 and without requiring an excess of triphenyl phosphite (TPP) or any other additive. We have 43 seen that the presence of minor amounts of H O is not critical for the success of the reaction, 44 2 45 but its addition to the reaction media was not beneficial neither (entry 3). The reaction 46 47 performance was worst under air atmosphere, which is in accordance with the intermediacy 48 49 of radicals, as also suggested by its complete inhibition in the presence of 2,2,6,6- 50 Tetramethylpiperidine 1-oxyl (TEMPO, entries 4-5). Given the precedents in the 51 52 photogeneration of aryl radicals from aryl diazonium salts,21 we carefully checked that the 53 54 ambient light was not promoting the reaction (entry 6). Importantly, no reaction was 55 observed using P(OEt) (entry 7), and the addition of TPP after the formation of the 56 3 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 4 of 37
1 2 3 diazonium salt was detrimental to the reaction yield (entry 8). When stoichiometric amounts 4 5 of the more acidic p-TsOH were used to promote the reaction, in analogy to the conditions 6 15 7 reported by Wang and coworkers but without preforming the diazonium salt, only 38% of 8 2a was obtained (entry 9).22 We have also confirmed that with both hydroxyl groups free in 9 10 the SA, the formation of 2a is more efficient (entries 10-11). Remarkably, the reaction is 11 12 complete after only 30 min under our optimal reaction conditions (entry 12 and Figure S3), 13 14 and only 2 mol % of SA is enough to efficiently promote the reaction (Figure S4) with about 15 1 equivalent of TPP. These conditions represent a significant improvement over the method 16 17 shown in Scheme 1e,15 where 3 equivalents of TPP are required in a sequential procedure 18 19 (preformation of the diazonium salt) that uses stoichiometric amounts of p-TsOH and needs 20 about 8 h for completion. 21 22 Table 1. Reaction optimization and control experiments.a 23 24 O t-BuONO (1.50 equiv) 25 NH2 P SA (10 mol %), Ar OPh 26 + P(OPh)3 OPh CH CN, 20 ºC, 1 h 27 Cl 3 Cl 28 1a (TPP: 1.15 equiv) 2a (Yield) 29 30 Entry Deviation from above Yieldb 31 32 1 Without SA 27% 33 2 none 94% 34
35 3 in 3:1 CH3CN: H2O 88% 36 37 4 Without an Ar atmosphere 64% 38 5 + TEMPO (2.0 equiv) traces 39 40 6 Protected from light 93% 41 7 With P(OEt) as phosphite 0% 42 3 43 8c TPP added to the diazonium salt 45% 44 45 9 p-TsOH•H2O (1.2 equiv) instead of SA 38% 46 10 With Methyl salicylate instead of SA 37% 47 48 11 With O-Acetyl SA instead of SA 48% 49 50 12 After 30 min 93% 51 a Reactions with 0.30 mmol of aniline in 1.5 mL of CH3CN. 52 bDetermined by GC, using adamantane as the internal standard 53 54 (Figure S1). cTPP was added 30 min after the other reactants. 55 56 57 58 59 60 ACS Paragon Plus Environment Page 5 of 37 The Journal of Organic Chemistry
1 2 3 To gather information about our arylation of TPP, we conducted a series of experiments. 4 5 When the isolated pure diazonium salt of 1a reacted with TPP in MeCN at 20 ºC, only 17% 6 7 of 2a was obtained, being improved to 40% in the presence of SA (Scheme 2a). This 8 experiment excludes a direct single-electron transfer (SET) between the diazonium salt and 9 10 TPP as the main pathway under our optimized conditions (Sandmeyer-like reaction),23 as 11 12 proposed by Wang and coworkers under the conditions shown in Scheme 1e.15 The formation 13 24 25 14 of diazo anhydrides (Ar-N=N-O-N=N-Ar) or triazene intermediates (ArN=N-NHAr) and 15 their radical fragmentation could explain the background reaction. The p-nitrophenyl radical 16 17 was trapped by TEMPO (Scheme 2b) and a competitive experiment in the presence of 18 6 ―1 ―1 26 19 2-propanol (kHAT ≈ 10 푀 푠 ) allowed us to estimate the rate constant for the addition 20 of the p-chlorophenyl radical to the TPP (Scheme 2c). This very fast reaction (k ≈ 2.2 푥107 21 22 푀 ―1푠 ―1) indicates that TPP is functioning as a very efficient radical trap under our reaction 23 24 conditions, competing favorably with the other possible radical side-reactions. It has been 25 26 known for a long time that phenyl radicals react very rapidly with trimethyl phosphite to give 27 dimethyl phenylphosphonate, likely through a radical Arbuzov-like mechanism.27 However, 28 29 in a reaction of aryl radical with TPP, this pathway involves the cleavage of a stronger O- 30 31 C(sp2) bond to furnish the desired product and the phenyl radical. More importantly, this 32 33 phenyl radical would eventually be trapped by TPP, and we never observed the formation of 34 2c when we submitted anilines 1a or 1h to our reaction conditions (Scheme 2d). Trying to 35 36 identify the catalytically active species of the process, we put into reacting the diazonium salt 37 38 of 1h with SA. After careful crystallization, we only isolated the azo compound II-h in a 39 rather low yield (Scheme 2e).28 However, this tan azo compound was unreactive with 40 41 stoichiometric amounts of TPP, as well as in THF solution, and resulted catalytically inactive 42 43 in the studied reaction (Scheme 2f). 44 45 Scheme 2. Mechanistic investigations 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 6 of 37
1 2
3 N2BF4 4 O P(OPh)3 (1.15 equiv) - N2 BF4 1 P 5 (a) Ar + P(OPh)3 MeCN, 20 ºC, Ar, 2 h Ar1 OPh 6 OPh Cl Ar1 Sandmeyer-like reaction 7 2a (17%) 8 1a-diazonium salt With 10 mol % of SA (40%) 9 NH2 TEMPO (2 equiv) 10 SA (10 mol %) Me Me O 11 (b) t-BuONO (1.5 equiv) N P(OPh)3 (1.15 equiv) 12 2a + O N Me MeCN, 20 ºC, Ar, 1 h 2 13 NO2 (traces) Me 14 1h 1h-TEMPO (32%) 15 NH2 SA (10 mol %) 16 P(OPh)3 t-BuONO (1.5 equiv) 2a (75%) 17 P(OPh)3 (3.3 equiv) k 2.5 x 107 M-1s-1 (c) ad 18 i-PrOH (3.3 equiv) i-PrOH 19 Cl MeCN, 20 ºC, Ar, 1 h Ar1H (3%) 1a kHAT 20 21 SA (10 mol %) t-BuONO (1.5 equiv) Ph O O 22 P(OPh) (1.15 equiv) P Ar-NH 3 P 23 (d) 2 Ar OPh MeCN, 20 ºC, Ar, 1 h Ar OPh OPh 1a or 1h OPh 2a or 2h 24 Ph O 25 P(OPh)3 26 Radical Arbuzov-like reaction P Ph OPh 27 OPh 2c (0%) 28 N BF 29 2 4 Ar2 CO2H N CO2H 30 40 min, 20 ºC N (e) + 31 OH MeCN:H2O/ 2:1 OH (SA) II-h (18% after recryst.) 32 2 NO2 Ar in THF 33 (0.20 M) P(OPh)3 (1.15 equiv) 1h-diazonium in MeCN (0.20 M) 34 salt 35 C6H5NO2 (0%) 2h (0%) 36 II-h (10 mol %) O 37 NH2 t-BuONO (1.5 equiv) P OPh 38 (f) P(OPh)3 (1.15 equiv) OPh 39 Cl MeCN, 20 ºC, Ar, 1 h Cl 40 1a 2a (29%) 41 42 The redox potentials of TPP, P(OEt)3 and SA were measured by cyclic voltammetry (CV, 43 Figure S5) to examine their different reactivities (entries 2 and 7 of Table 1). Considering the 44 45 • 표푥 experimental values obtained, the salicyloyl radical (SA , 퐸푝/2 =+1.97 V vs SCE) would be 46 표푥 47 able to oxidize TPP (퐸푝/2 = +1.85 V vs SCE) but the oxidation of P(OEt)3 is slightly 48 표푥 49 unfavored (퐸푝/2 = +2.04 V vs SCE). As shown in Figure 1 (left), the onset potential of the 50 51 mixture of SA and TPP was found to be like the one of the SA alone, but higher current 52 density was achieved. This result suggests that after the oxidation of the SA, an electron 53 54 transfer occurs from TPP to SA•. On the contrary, when a similar experiment was conducted 55 56 with P(OEt)3, the onset potential for the oxidation of the mixture started at least 400 mV 57 58 59 60 ACS Paragon Plus Environment Page 7 of 37 The Journal of Organic Chemistry
1 2 3 before than the one of SA alone (Figure 1, right). This significant difference suggests that 4 • 5 P(OEt)3 reacts directly with SA (not with SA ), resulting in the consumption of the SA before 6 29 7 the catalytic cycle starts. 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Figure 1. Cyclic voltammograms. See SI for more details. 25 26 Based on our experimental investigations and literature precedents, we propose the 27 28 mechanism depicted in Scheme 3. The reaction of aniline 1 with TBN in the presence of SA 29 30 would form the diazonium salt I. This intermediate would lead to the azo compound II, which 31 is catalytically inactive, or to the aryl diazobenzoate III.30 Based on literature precedents, 32 33 31,32 acyloxydiazoaryls decompose easily to generate N2 and aryl radicals. The fragmentation 34 35 of III would lead to the aryl radicals and to the salicyloyl radical SA•, likely stabilized by an 36 37 intramolecular H-bond. We have then shown by CV measurements that the SET between 38 TPP and SA• is feasible, enabling the turnover of the SA and producing the phosphoniumyl 39 40 radical cation IV.33 We speculate that hydrolysis of IV would produce phenol (almost 1 equiv 41 42 of phenol in the formation of 2a, see SI) and the phosphanyl radical V, which is stabilized by 43 44 electron-donation from the two phenoxy groups and can be considered a persistent radical. 45 We thus propose that nucleophilic radical V serves as an efficient trap of the aryl radicals, 46 47 which are σ-sp2 radicals and therefore more electrophilic than common π-alkyl radicals 48 34 49 (pathway A). This highly selective cross-coupling is consistent with the reaction between a 50 transient aryl radical and a longer-lived phosphanyl radical, being both generated at equal 51 52 rates within the catalytic cycle (Persistent Radical Effect).35 Alternatively, aryl radical can 53 54 also be trapped by the radical cation IV to obtain the quaternary phosphonium intermediate 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 8 of 37
1 2 3 VI, which after hydrolysis could provide the product 2, with concomitant formation of phenol 4 5 and deprotonation (pathway B).14 6 7 Scheme 3. Plausible mechanism 8 9 O 10 Ar N catalytically N OH inactive O 11 (II) P OH Ar OPh 12 (2) OPh 13 O 14 N N Ar CO O N 2 (III) 15 N 16 OH A (I) OH Ar 17 - N2 Ar
18 t-BuOH Pathway 19 O P 20 t-BuO N Ar O 2 OH O PhO OPh 21 (V) O O H 22 H O 2 SET (SA ) 23 O H t-BuONO P(OPh) + 24 (SA) H+ 3 + H (TBN) P(OPh) (IV) 25 3 H2O PhOH 26 O Ar ArNH2 (1) PhOH OPh 27 P H2O Ar OPh (VI) OPh P 28 (2) Ar OPh 29 Pathway B OPh 30 31 Having identified the optimal conditions for the radical arylation of TPP, we examined 32 33 the scope of the reaction with diversely substituted anilines. As shown in Scheme 4, 34 35 unsubstituted aniline and halogen-containing anilines at the ortho-, metha- or para- position, 36 ready for further functionalization, afforded the phosphonates (2a, 2b, 2c, 2m, 2q, 2x) in 37 38 good-to-excellent yields. Anilines bearing electron-donating groups (methyl, ethynyl, 39 40 phenyl, methoxy, N-acetyl) were also suitable substrates, leading to the expected 41 42 phosphonates (2d-2g, 2p, 2r-2s) in moderate-to-good yields. However, the yield dropped 43 when the electron-rich 2-methoxy aniline (1t) was used to obtain compound 2t. On the other 44 45 hand, a variety of electron-withdrawing groups in the aniline remained intact (NO2, CN, Ac, 46 47 CO2H, CO2Me, CF3), affording the corresponding products in good-to-excellent yields (2h- 48 49 2l, 2n-2o, 2u-2v). Electron-donating- and electron-withdrawing-groups could also be 50 successfully combined in the same aniline, as exemplified by the product 2w. More 51 52 importantly, the reaction was not restricted to anilines since heteroaryl amines were also 53 54 suitable substrates. While 8-aminoquinoline and 2-aminobenzothiazole gave the 55 corresponding phosphonates (2y and 2z) in rather low yields, the thiophene-derived 2aa and 56 57 58 59 60 ACS Paragon Plus Environment Page 9 of 37 The Journal of Organic Chemistry
1 2 3 pyridine-phosphonate 2ab were obtained in moderate-to-good yields. Furthermore, the 4 5 2-(4-aminophenyl)benzothiazole (1ac), which exhibits a potent anti-breast cancer activity,36 6 7 was smoothly transformed into the phosphonate 2ac under our optimized conditions. 8 Scheme 4. Reaction scope 9 10 11 SA (10 mol %) P(OPh)3 (1.15 equiv) O 12 t-BuONO (1.5 equiv) P NH2 P OPh 13 Ar Ar CH3CN [0.20 M] OPh 14 Ar, 20 ºC, 2 h 1 (0.3 mmol) 2 (Yield) 15 16 P P P 17 18 X EDG EWG 19 2a: X = Cl (92%) 2d: EDG = Me (50%) 2h: EWG = NO2 (94%) 2b: X = Br (65%) 2e: EDG = C CH (65%) 2i: EWG = CN (82%) 20 2c: X = H (81%) 2f: EDG = OMe (61%) 2j: EWG = Ac (76%) 21 2g: EDG = NHAc (63%) 2k: EWG = CO2H 56%) 22 2l: EWG = CO2Me (75%) R P P 23 Br NO2 P 24 R P 25 2m: R= Cl (65%) 2q: R = Cl (67%) 2n: R= NO (87%) 2r: R = Me (63%) 26 2 MeO 2o: R= CF3 (66%) 2s: R = Ph (58%) F 27 2p: R= NHAc (48%) 2t: R = OMe (37%) 2w (54%) 2x (72%) 28 2u: R = CN (69%) P MeO C 29 2v: R = NO2 (91%) 2 P P N S 30 S P N Cl 31 N 2aa (50%) 2ab (74%) 32 2y (32%) 2z (27%) standard 33 S S conditions P 34 NH2 35 N N 1ac: potent antitumor agent 2ac (81%) 36 37 38 We further carried out the preparation of phosphonates 2s, 2x and 2ac on the gram scale, 39 40 using only 2 mol % of SA (Scheme 5a). Remarkably, we obtained similar yields of isolated 41 42 pure products than in 0.30 mmol-scale, even after recrystallization (see SI for details). With 43 these diphenyl arylphosphonates in gram-quantities, we explored the underexploited 44 45 reactivity of this family of compounds. To overcome the limitation of this methodology to 46 47 triaryl phosphites we examined the transesterification of diphenyl phosphonates into dialkyl 48 phosphonates (Scheme 5b). This two-step protocol provided a convenient TM-free approach 49 50 to the calcium channel blocker compound 3,37 which is analogous to the pharmaceutical 51 52 fostedil. We also studied the transformation of diaryl phosphonates into phosphine 53 54 derivatives since they can be used as ligands in TM catalysis and their preparation usually 55 requires expensive and multistep procedures. It is known that the reaction of dialkyl 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 10 of 37
1 2 3 phosphonates with Grignard reagents is limited by Arbuzov-like decomposition of the 4 5 starting material,38a and this limitation was recently circumvented by the use of 6 38b 7 stoichiometric amounts of NaOTf as additive. In stark contrast, we have observed that 8 diphenyl phosphonate 2s smoothly reacted with MeMgBr at 0 ºC, in the absence of additives, 9 10 obtaining dimethyl(aryl)phosphine oxide 4 in excellent yield (Scheme 5c). Importantly, 11 12 compound 4 can be easily transformed by one-step reduction into Methyl JohnPhos, a 13 38b 14 Buchwald-type ligand. Under similar conditions but using an excess of PhMgBr and 15 longer reaction time, compound 5 was prepared in excellent yield. It is worthy of mention 16 17 that compound 5 and some derivatives have been used as “platform molecules” for the Pd- 18 2 19 catalyzed R2(O)P-directed C(sp )–H activation, introducing a wide range of functionalities 20 at the adjacent phenyl ring.39 Moreover, by only reducing the amount of PhMgBr and running 21 22 the reaction over 30 min at 0 ºC, we obtained the racemic phosphinate 6 in an unoptimized 23 24 but useful synthetic yield. The reaction of this compound with MeMgBr allowed the efficient 25 26 preparation of chiral, albeit racemic, tertiary phosphine oxide 7. The results shown in 27 Scheme 5c support diaryl phosphonates as convenient synthetic precursors for the 28 29 preparation of tertiary phosphine oxides by reaction with Grignard reagents.40 Finally, we 30 31 explored an intramolecular C-H arylation reaction with diaryl phosphonate 2x (Scheme 5d). 32 33 Using (R)-BINAP as chiral ligand and Pd(OAc)2 we obtained the P-chiral biaryl phosphonate 34 8. Although in an unoptimized yield and enantioselectivity, this reaction demonstrates the 35 36 straightforward access to chiral biaryl phosphonates in only two steps from readily available 37 41 38 starting materials. 39 Scheme 5. Scale-up and follow-up reactions 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 11 of 37 The Journal of Organic Chemistry
1 2 3 (a) Gram-scale preparation (only 2 mol % SA used) 4 O O P 5 P OPh OPh S O OPh OPh P 6 OPh Ph F Br N 7 OPh 2s: 2.30 g (60%) 2x: 2.85 g (70%) 2ac: 1.99 g (75%) 8 9 (b) Transformation into dialkyl phosphonates S O 10 NaOEt (6 equiv) 2ac P 11 EtOH OEt N OEt 20 ºC, 2 h 12 3 (80%, calcium antagonist) 13 14 (c) Transformation into phosphine oxides and phosphinates 15 O O P P 16 Ph PhMgBr (4 equiv) MeMgBr (2.6 equiv) Me Ph 2s Me THF, 0 ºC, 4 h THF, 0 ºC, 30 min 17 Ph Ph 18 5 (80%) 4 (92%) PhMgBr (1.2 equiv) 19 THF, 0 ºC, 1 h Ref. 36b 20 O O P Ph MeMgBr (1.5 equiv) P Ph P Me 21 Me OPh Me THF, 0 ºC, 1 h 22 Ph Ph Ph 23 7 (87%) 6 (62%) Methyl JohnPhos 24 25 (d) Intramolecular C-H arylation H O OPh O OPh 26 Pd(OAc)2 (5 mol %) 27 O P (R)-BINAP (10 mol %) O P AcOK (1.5 equiv.) 28 Br F toluene, 100 ºC, 24 h F 29 30 2x 8 (31%, S:R / 61:39) 31 32 CONCLUSION 33 34 In summary, we have demonstrated that SA efficiently catalyzes the arylation of TPP, 35 36 using readily available anilines as starting materials and TBN for the in situ formation of 37 38 diazonium salts, without thermal or photochemical activation. Our mechanistic studies 39 supported the intermediacy of transient aryl radicals which rapidly coupled with the longer- 40 41 lived phosphanyl radical, being the SA regenerated by SET between the TPP and the SA•. 42 43 The protocol was easily adapted for the gram-scale preparation of three diphenyl 44 45 arylphosphonates and we examined the unique reactivity of these compounds by 46 straightforward transformations into dialkyl phosphonates, phosphinates, phosphine oxides, 47 48 and cyclic P-chiral biaryl phosphonates. 49 50 51 52 EXPERIMENTAL SECTION 53 54 General Remarks. Most commercial chemicals were used as obtained from Sigma- 55 56 Aldrich, TCI Europe or Alfa-Aesar. However, after the long storage of TPP, it became yellow 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 12 of 37
1 2 3 and it was purified by washing its solution in EtOAc with a 1 M solution of NaOH. CH3CN 4 5 (for analysis, ACS) was purchased from Panreac 99.7% pure. The preparation of starting 6 7 materials not obtained from commercial sources is detailed below. TLCs were performed on 8 silica gel 60 F , using aluminum plates and visualized by exposure to ultraviolet light. Flash 9 254 10 chromatographies (FC) were carried out on handpacked- columns of silica gel 60 (230–400 11 12 mesh). Melting points (mp) were measured in a Riecher Thermovar heating stage microscope 13 14 and were not corrected. GC yields were determined by GC-FID (6890 Agilent, HP-5 30 m 15 column), using adamantane as the internal standard. LRMS were obtained using a mass 16 17 spectrometer coupled with a gas chromatographer (GC); the mobile phase was helium (2 18 −1 19 mL·min ); HP-1 column of 12 m was used; temperature program starts at 80 ºC for 3 min, 20 then up to 270 ºC at a rate of 15 ºC·min−1, and 15 min at 300 ºC (unless other conditions are 21 22 indicated). NMR spectra were recorded at 300 or 400 MHz for 1H, at 75 or 101 MHz for 13C, 23 31 1 24 and at 122 or 202 MHz for P, using CDCl3 as solvent (unless otherwise stated). For H 25 31 26 NMR, TMS was used as an internal standard (0.00 ppm) and for P-NMR, H3PO4 was the 27 external standard used (0.00 ppm). The data are reported as (s = singlet, d = doublet, t = 28 29 triplet, m = multiplet or unresolved, brs = broad signal, coupling constant(s) in Hz, 30 31 integration). 13C NMR spectra were recorded with 1H-decoupling {1H} at 101 MHz and 32 33 referenced to CDCl3 at 77.16 ppm. Enantiomeric ratios were determined by chiral HPLC 34 (1100 Series Agilent Hewlett-Packard, G1311A pump, DAD G1315B detector, Chiral 35 36 column AD-H Chiralpack, Particle size: 5 µm; Dimensions: 4.6 mm x 250 mm). Exact 37 38 masses were determined by HRMS (Agilent 7200 de Quadrupole-Time of Flight (Q-TOF)). 39 42 40 Procedure for the synthesis of anilines 1g and 1p: Into an oven-dried pressure tube 41 was added the corresponding N-(nitrophenyl)acetamide (360.0 mg, 2 mmol) capped with a 42 43 rubber septum and the system was evacuated and filled with Ar (3 times), then MeOH 44 45 anhydrous (10 mL) was added, followed by 10% wt Pd/C (100.0 mg, 0.10 mmol) and 46 47 ammonium formate (252.22 mg, 4 mmol). After 24 h at 20 ºC (water bath), the reaction 48 mixture was filtered through a short plug of Celite, dried over MgSO4, filtered and 49 50 concentrated in vacuo. The corresponding pure products were obtained after FC in silica gel 51 52 from (50:50 hexane/EtOAc to 100% EtOAc). 53 N-(4-Aminophenyl)acetamide (1g). Compound 1g was obtained as an off-white solid 54 55 1 (169.1 mg, 1.12 mmol, 57 %): TLC (EtOAc 100%) Rf 0.30; H-NMR (300 MHz, CD3OD) δ 56 57 58 59 60 ACS Paragon Plus Environment Page 13 of 37 The Journal of Organic Chemistry
1 2 3 7.33 – 7.25 (m, 2H), 6.78 – 6.71 (m, 1H), 4.87 (s, 2H), 2.08 (s, 3H) ppm; 13C-NMR {1H} (75 4 5 MHz, CD3OD) δ 171.6 (CO), 143.6 (C-NH2), 132.2 (C-NHAc), 123.4 (2xCH), 117.9 6 7 (2xCH), 23.8 (Me). 8 N-(3-Aminophenyl)acetamide (1p). Compound 1p was obtained as a pale-yellow solid 9 1 10 (145.2 mg, 0.96 mmol, 48%): TLC (EtOAc 100%) Rf 0.42; H-NMR (300 MHz, CD3OD) δ 11 12 7.18 – 6.98 (m, 2H), 6.87 – 6.80 (m, 1H), 6.51 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 4.90 (s, 2H), 13 13 13 1 14 2.12 (s, 3H) ppm; C-NMR (75 MHz, CD3OD) δ C-NMR { H} (75 MHz) δ 171.5 (CO), 15 3 1 5 6 4 2 149.2 (C -NH2), 140.5 (C -NHAc), 130.3 (C -H), 112.6 (C -H), 111.2 (C -H), 108.4 (C -H), 16 17 23.8 (Me). 18 19 4-(Benzo[d]thiazol-2-yl)aniline (1ac). Aniline 1ac was synthesized by minor 20 modifications of a reported procedure.43 Into a pressure tube equipped with a magnetic stirrer 21 22 were added 4-aminobenzoic acid (1.37 g, 10.0 mmol, 1 equiv.) and polyphosphoric acid (4 23 24 g). The reaction mixture was gently heated to obtain a homogeneous mixture, before adding 25 26 2-Aminophenol (1.04 mL, 10.0 mmol, 1 equiv.). The tube was closed with a Teflon cap and 27 heated at 220 ºC into a san bath for 3 h. After cooling at room temperature, the reaction 28 29 mixture was poured into aqueous ammonia (15 mL, 25%v/v). The precipitate was collected 30 31 by filtration and washed with water (50 mL). The solid product was recrystallized from EtOH 32 1 33 (13 mL, 60 ºC to 20 ºC) (1.358 g, 6 mmol, 60%): TLC (hexane/EtOAc 70:30) Rf 0.36; H- 34 NMR (300 MHz, CDCl3) δ 8.05 – 7.79 (m, 2H), 7.38 (dt, J = 38.0, 7.6 Hz, 1H), 6.73 (d, J = 35 13 1 5 10a 1 36 7.9 Hz, 1H) ppm; C-NMR { H} (75 MHz, CDCl3) δ 168.7 (C ), 154.3 (C ), 149.4 (C - 37 6a 3 9 8 4 6 38 NH2), 134.7 (C -S), 129.3 (2xC -H), 126.2 (C -H), 124.66 (C -H), 124.04 (C ), 122.6 (C - 39 H), 121.5 (C10-H), 114.9 (2xC2-H) ppm. 40 41 Procedure for the synthesis of 4-chlorobenzenediazonium tetrafluoroborate (1a- 42 43 diazonium salt) and 4-nitrobenzenediazonium tetrafluoroborate (1h-diazonium salt): The 44 45 corresponding aniline (10.0 mmol) was dissolved in a 50% (w/w aqueous solution) mixture 46 of tetrafluoroboric acid (5 mL, 39.9 mmol, 4 equiv) and water (5 mL). After cooling near to 47 48 0 ºC, a freshly-prepared solution of sodium nitrite (700 mg, 10.1 mmol) in H2O (3 mL), was 49 50 added in portions (0.25 mL each) during 10 min. The mixture was stirred for an additional 51 30 min and the thick precipitate formed was collected by filtration, washed with water, and 52 53 dissolved in the minimal amount of acetone. The diazonium tetrafluoroborate was then 54 55 precipitated by the addition of Et2O. The solid was filtered out and dried under vacuum for 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 14 of 37
1 2 3 several hours. The corresponding diazonium salts were employed directly without further 4 5 purification. 6 7 2-Hydroxy-5-((4-nitrophenyl)diazenyl)benzoic acid (II-h): Into and oven-dried round- 8 bottom flask equipped with a magnetic stirrer, 4-nitrophenyl diazonium tetrafluoroborate 9 10 (1.185 g, 5.0 mmol) and SA (690 mg, 5.0 mmol) were added. The system was evacuated and 11 12 filled with argon (three times), before adding MeCN (13.20 mL) and water (6.80 mL). Then, 13 14 the reaction mixture was protected from the light and was stirred for 45 min at 20 ºC (water 15 bath). After this time, the aqueous solution was extracted with Et2O (3x20 mL), the combined 16 17 organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced 18 19 pressure without heating. The residue was dissolved in Et2O and precipitated by the addition 20 of hexane. The solid was filtered out and dried in vacuo to give the pure product as a brick- 21 22 red solid (287.2 mg, 0.90 mmol, 18 %). The spectral data matched that reported.44 23 1 24 H-NMR (500 MHz, Acetone-d6) δ 8.56 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 9.0 Hz, 2H), 25 26 8.22 (dd, J = 8.9, 2.5 Hz, 1H), 8.13 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 8.9 Hz, 1H), 3.42 – 3.12 27 (m, 1H) ppm; 13C-NMR {1H} (126 MHz, Acetone) δ 172.2, 166.2, 156.7, 149.7, 146.2, 130.0, 28 29 128.7, 125.7, 124.2, 119.5, 113.8 ppm. 30 31 2,2,6,6-Tetramethyl-1-(4-nitrophenoxy)piperidine (1h-TEMPO). p-Nitroaniline (41.4 32 33 mg, 0.30 mmol), TEMPO (93.9 mg, 0.6 mmol), SA (4.14 mg, 0.04 mmol), TPP (90 μL, 0.345 34 mmol) and TBN (60 μL, 0.45 mmol), were put into reacting in acetonitrile (1.5 mL). The 35 36 reaction mixture was then diluted with EtOAc (25 mL), transferred to a round-bottom flask, 37 38 and the solvent was evaporated in-vacuo. The crude mixture was purified by flash column 39 chromatography on silica gel from hexane 100% to 90:10 hexane/EtOAc obtaining the 40 41 TEMPO-adduct as a white amorphous solid (26.7 mg, 0.096 mmol, 32%): TLC 42 1 43 (hexane/EtOAc 90:10) Rf 0.65; H-NMR (300 MHz, CDCl3) δ 8.14 (d, J = 9.5 Hz, 2H), 7.30 44 13 45 (br s, 2H), 1.65 – 1.56 (m, 5H), 1.45 – 1.42 (m, 1H), 1.24 (s, 6H), 0.98 (s, 6H) ppm; C- 46 1 NMR { H} (75 MHz, CDCl3) δ 168.8 (C), 141.2 (C), 125.6 (CH), 114.2 (CH), 61.0 (C), 39.8 47 + 48 (CH2), 32.4 (CH3), 20.6 (CH3), 17.0 (CH2) ppm; LRMS (EI-DIP) m/z (%) 278 (M , 11), 263 49 50 (43), 149 (20), 125 (100), 97 (40). 51 General Procedure (GP) for the synthesis of compounds 2: The corresponding 52 53 aromatic amine (0.30 mmol) and the salicylic acid (SA, 4,14 mg, 0,03 mmol, 10 mol%) were 54 55 added into an oven-dried Schlenck tube. The system was evacuated and filled with argon 56 57 58 59 60 ACS Paragon Plus Environment Page 15 of 37 The Journal of Organic Chemistry
1 2 3 (three times), then acetonitrile (1.5 mL) and the TPP (90.4 μL, 0.35 mmol) were added. The 4 5 reaction mixture was stirred vigorously until a homogeneous solution was obtained. At this 6 7 point, tert-butyl nitrite (TBN, 60 μL, 0.45 mmol) was added (the solution turned orange after 8 some minutes) and the reaction mixture was stirred for 2 h, keeping the temperature at 20 ºC 9 10 with an external water bath. For most substrates, the reaction was complete within 1 h, but 11 12 we ran the reactions over 2 h to use uniform conditions. The mixture was diluted with EtOAc 13 14 (25 mL), concentrated in vacuo, and the residue was purified by FC. 15 Diphenyl (4-chlorophenyl)phosphonate (2a). Following the general procedure, compound 16 17 2a was obtained after FC (from 98:2 hexane/EtOAc to 90:10 hexane/EtOAc) as a yellow 18 15 19 liquid (93.18 mg, 0.27 mmol, 92%). The spectral data matched that reported: TLC 20 (hexane/EtOAc 80:20) R 0.40; 1H NMR (300 MHz, CDCl ) δ 7.90 (dd, J = 13.6, 8.5 Hz, 21 f 3 22 2H), 7.48 (dd, J = 8.4, 3.8 Hz, 2H), 7.33-7.27 (m, 4H), 7.17 (m, 6H) ppm; 13C NMR {1H} 23 2 1’ 4 4 24 (101, CDCl3) δ 150.3 (d, JC-P = 7.6 Hz, 2xC -H), 140.1 (d, JC-P = 4.2 Hz, C -Cl), 133.9 (d, 25 2 2 4 3’ 3 3 26 JC-P = 11.4 Hz, 2xC -H), 130.0 (d, JC-P = 5.6 Hz, 4xC -H), 129.3 (d, JC-P = 16.6 Hz, 2xC - 27 H), 125.48 (d, 1J = 195.8 Hz, C1-P), 125.47 (2xC4’-H), 120.7 (d, 3J = 4.6 Hz, 4xC2’-H) 28 C-P C-P 29 ppm; LRMS (EI) m/z (%) 346 (M++2, 27) 344 (M+, 100), 251 (M+-OPh, 42), 77 (100). For 30 31 the numbering of the skeleton of compounds 2 used to assign the peaks in 13C NMR, see the 32 33 structure shown for compound 2n as example 34 Diphenyl (4-bromophenyl)phosphonate(2b). Following the general procedure, compound 35 36 2b was obtained after FC (from 95:5 hexane/EtOAc to 80:20 hexane/EtOAc) as a brown 37 15 38 liquid (74.98 mg, 0.193 mmol, 65%). The spectral data matched that reported: TLC 39 (hexane/EtOAc 80:20) R 0.32; 1H NMR (300 MHz, CDCl ) δ 7.86–7.76 (m, 2H), 7.67–7.61 40 f 3 13 1 41 (m, 2H), 7.36–7.22 (m, 4H), 7.21–7.12 (m, 6H) ppm; C NMR { H} (75 MHz, CDCl3) δ 42 2 1’ 2 2 3 43 150.3 (d, JC-P= 7.5 Hz, 2xC -H), 133.9 (d, JC-P = 11.2 Hz, 2xC -H), 132.2 (d, JC-P = 16.4 44 3 3’ 4 4 1 1 45 Hz, 2xC -H), 129.9 (4xC -H), 128.7 (d, JC-P = 4.2 Hz, C ), 126.0 (d, JC-P = 195.4 Hz, C - 46 4’ 3 2’ + P), 125.4 (2xC -H), 120.7 (d, JC-P = 4.5 Hz, 4xC -H) ppm; LRMS (EI) m/z (%) 390 (M +2, 47 48 100), 388 (M+, 97), 297 (M++2-OPh, 40) 295 (M+-OPh, 43), 170, (28), 77 (89). 49 50 Diphenyl phenylphosphonate (2c). Following the general procedure, compound 2c was 51 obtained after FC (90:10 hexane/EtOAc) as a dark orange solid (75.18 mg, 0.242 mmol, 52 53 15 81%). The spectral data matched that reported: TLC (hexane/EtOAc 80:20) Rf 0.25; 54 1 55 H NMR (300 MHz, CDCl3) δ 7.97 (dd, J = 14.1, 7.5 Hz, 2H), 7.65–7.55 (m, 1H), 7.49 (td, 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 16 of 37
1 2 3 J = 7.5, 4.7 Hz, 2H), 7.36–7.24 (m, 4H), 7.23–7.10 (m, 6H) ppm; 13C NMR {1H} (101 MHz, 4 2 1’ 4 4 2 5 CDCl3) δ 150.5 (d, JC-P = 7.6 Hz) (2xC ), 133.3 (d, JC-P = 3.3 Hz) (C -H), 132.4 (d, JC-P = 6 2 3’ 3 3 1 7 10.3 Hz) (4xC -H), 129.8 (4xC -H), 128.8 (d, JC-P = 15.7 Hz) (2xC -H), 127.0 (d, JC-P = 8 192.9 Hz) (C-P), 125.3 (2xC4’-H), 120.7 (d, 3J = 4.6 Hz) (4xC2’-H) ppm; LRMS (EI) m/z 9 C-P 10 (%) 310 (M+, 78), 309 (M+-H, 100), 217 (41), 170 (33), 77 (46). 11 12 Diphenyl p-tolylphosphonate (2d). Following the general procedure, compound 2d was 13 14 obtained after FC (from 98:2 hexane/EtOAc to 95:5 hexane/EtOAc) as an orange liquid (49.7 15 mg, 0.15 mmol, 50%). The spectral data matched that reported:15 TLC (hexane/EtOAc 80:20) 16 1 17 Rf 0.50; H NMR (400 MHz, CDCl3) δ 7.91 – 7.77 (dd, J = 13.8, 8.1 Hz, 2H), 7.33 – 7.23 18 13 19 (m, 6H), 7.18 (dq, J = 7.8, 1.3 Hz, 4H), 7.13 (tt, J = 7.2, 1.1 Hz, 2H), 2.40 (s, 3H) ppm; C 20 NMR {1H} (101, CDCl ) δ 150.6 (d, 2J = 7.5 Hz, 2xC1’-H), 144.2 (d, 4J = 3.5 Hz, C4- 21 3 C-P C-P 22 2 2 3’ 3 3 Me), 132.5 (d, JC-P = 10.8 Hz, 2xC -H), 129.9 (4xC -H), 129.6 (d, JC-P = 16.3 Hz, 2xC - 23 4’ 1 1 3 2’ 24 H), 125.2 (2xC -H), 123.7 (d, JC-P = 195.1 Hz, C -P), 120.8 (d, JC-P = 4.6 Hz, 4xC -H), 25 + + + 26 21.9 (Me) ppm; LRMS (EI) m/z (%) 324 (M , 81), 323 (M -H, 100), 231 (M -OPh, 70), 77 27 (45). 28 29 Diphenyl (4-ethynylphenyl)phosphonate (2e). Following the general procedure, 30 31 compound 2e was obtained after FC (from 95:10 hexane/EtOAc to 80:20 hexane/EtOAc) as 32 15 33 a pale brown solid (65.1 mg, 0,192 mmol, 65%). The spectral data matched that reported: 34 1 TLC (hexane/EtOAc/AcOH 80:20) Rf 0.28; H NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 35 36 13.8, 8.5 Hz, 1H), 7.60 (dd, J = 8.3, 4.2 Hz, 2H), 7.33 – 7.25 (m, 4H), 7.21 – 7.11 (m, 6H) 37 13 1 2 1’ 3 38 ppm; C NMR { H} (75 MHz, CDCl3) δ 150.33 (d, JC-P = 7.5 Hz, C ), 132.29 (d, JC-P = 39 16.0 Hz, 2xC3-H), 132.28 (d, 2J = 10.7 Hz, 2xC2-H), 129.9 (4xC3’-H), 127.3 (d, 1J = 40 C-P C-P 1 4 4’ 3 2’ 41 193.8 Hz, C ), 125.4 (d, JC-P = 1.3 Hz, 2xC -H), 120.7 (d, JC-P = 4.5 Hz, 4xC -H), 120.2 42 4 4 5 43 (d, JC-P = 4.8 Hz, C ), 82.5 (d, JC-P = 1.8 Hz, C≡CH), 80.7 (CC-H) ppm; LRMS (EI) m/z 44 + + 45 (%) 334 (M , 96), 333 (M -H, 100), 241 (54), 194 (42), 77 (68). 46 Diphenyl (4-methoxyphenyl)phosphonate (2f). Following the general procedure, 47 48 compound 2f was obtained after FC (from 90:10 hexane/EtOAc to 70:30 hexane/EtOAc) as 49 15 50 a dark orange liquid (62.0 mg, 0.182 mmol, 61%). The spectral data matched that reported: 51 TLC (hexane/EtOAc 80:20) R 0.28; 1H NMR (300 MHz, CDCl ) δ 7.97–7.86 (m, 2H), 7.35– 52 f 3 53 7.27 (m, 4H), 7.24–7.12 (m, 6H), 7.05–6.95 (m, 2H), 3.86 (s, 3H) ppm; 13C NMR {1H} (101 54 4 4 2 1’ 55 MHz, CDCl3) δ 163.6 (d, JC-P = 3.4 Hz, C -OMe), 150.6 (d, JC-P = 7.4 Hz, 2xC ), 134.5 (d, 56 57 58 59 60 ACS Paragon Plus Environment Page 17 of 37 The Journal of Organic Chemistry
1 2 3 2 2 3’ 4’ 3 2’ JC-P = 11.9 Hz, 2xC -H), 129.8 (4xC -H), 125.2 (2xC -H), 120.7 (d, JC-P = 4.6 Hz, 4xC - 4 1 1 3 3 5 H), 117.9 (d, JC-P = 200.5 Hz, C -P), 114.3 (d, JC-P = 16.9 Hz, 2xC -H), 55.5 (OCH3) ppm; 6 + + 7 LRMS (EI) m/z (%) 340 (M , 73), 247 (M -OPh, 100), 200 (17), 77 (39). 8 Diphenyl (4-acetamidophenyl)phosphonate(2g). Following the general procedure, 9 10 compound 2g was obtained after FC (from 50:50 hexane/EtOAc to 100% EtOAc) as an 11 12 orange sticky oil (69.0 mg, 0.19 mmol, 63%). The spectral data matched that reported:14 TLC 13 1 14 (hexane/EtOAc 50:50) Rf 0.32; H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.81 (dd, J = 15 13.4, 8.4 Hz, 2H), 7.67 (dd, J = 8.4, 4.1 Hz, 2H), 7.32 – 7.16 (m, 4H), 7.17 – 7.05 (m, 6H), 16 13 1 2 17 2.07 (s, 3H) ppm; C NMR { H} (101 MHz, CDCl3) δ 169.5 (CO), 150.3 (d, JC-P = 7.5 Hz, 18 1’ 4 4 2 2 3’ 19 C ), 143.3 (d, JC-P = 3.6 Hz, C -NH), 133.4 (d, JC-P = 11.4 Hz, 2xC -H), 129.9 (4xC -H), 20 125.4 (2xC4’-H), 120.73 (d, 3J = 4.5 Hz, C2’-H), 120.61 (d, 1J = 198.6 Hz, C1-P), 119.3 21 C-P C-P 22 3 + (d, J = 16.1 Hz, 2xC -H), 24.6 (NHCOCH3) ppm; LRMS (EI) m/z (%) 367 (M , 100), 325 23 24 (25), 274 (64), 232 (86). 25 26 Diphenyl (4-nitrophenyl)phosphonate (2h). Following the general procedure, compound 27 2h was obtained after FC (from 95:5 hexane/EtOAc to 70:30 hexane/EtOAc) as an orange 28 29 liquid (100.2 mg, 0.28 mmol, 94%). The spectral data matched that reported:15 TLC 30 1 31 (hexane/EtOAc 80:20) Rf 0.20; H NMR (300 MHz, CDCl3) δ 8.37 – 8.32 (m, 2H), 8.21 – 32 13 1 33 8.12 (m, 2H), 7.36 – 7.28 (m, 4H), 7.19 (m, 6H) ppm; C NMR { H} (75 MHz, CDCl3) δ 34 4 4 2 1’ 1 150.8 (d, JC-P = 4.0 Hz, C -NO2), 150.0 (d, JC-P = 7.8 Hz, 2xC ), 133.91 (d, JC-P = 191.8 35 2 2 3’ 4’ 36 Hz, C-P), 133.73 (d, JC-P = 11.1 Hz, 2xC -H), 130.1 (4xC -H), 126.0 (2xC -H), 123.7 (d, 37 3 3 3 2’ 38 JC-P = 16.1 Hz, 2xC -H), 120.6 (d, JC-P = 4.5 Hz, 4xC -H) ppm; LRMS (EI) m/z (%) 355 39 (M+, 90), 354 (M+-H, 100), 308 (M+-NO 17), 262 (M+-OPh, 15), 215 (37), 77 (89). 40 2 41 Diphenyl (4-cyanophenyl)phosphonate (2i). Following the general procedure, compound 42 43 2i was obtained after FC (from 85:15 to 80:20 hexane/EtOAc) as pale brown solid (82.4 mg, 44 15 45 0.25 mmol, 82%). The spectral data matched that reported: TLC (hexane/EtOAc 80:20) Rf 46 1 0.18; H NMR (300 MHz, CDCl3) δ 8.13–8.02 (m, 2H), 7.84–7.76 (m, 2H), 7.36–7.27 (m, 47 13 1 2 48 4H), 7.21–7.14 (m, 6H) ppm; C NMR { H} (75 MHz, CDCl3) δ 150.0 (d, JC-P = 7.8 Hz, 49 1’ 2 2 3 3 50 2xC ), 132.89 (d, JC-P = 10.3 Hz, 2xC -H), 132.33 (d, JC-P = 15.8 Hz, 2xC -H), 132.07 (d, 51 1J = 192.5 Hz, C1-P), 130.1 (4xC3’-H), 125.8 (d, 5J = 1.4 Hz, 2xC4’-H), 120.6 (d, 3J 52 C-P C-P C-P 53 2’ 5 4 4 = 4.6 Hz, 4xC -H), 117.7 (d, JC-P = 1.3 Hz, CN), 117.1 (d, JC-P = 3.7 Hz, C -CN) ppm; 54 55 LRMS (EI) m/z (%) 335 (M+, 79), 334 (M+-1, 90), 242 (M+-OPh, 19), 195 (45), 77 (100). 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 18 of 37
1 2 3 Diphenyl (4-acetylphenyl)phosphonate (2j). Following the general procedure, compound 4 5 2j was obtained after FC (from 85:15 to 7:3 hexane/EtOAc) as an orange liquid (79.80 mg, 6 15 7 0.23 mmol, 76%); The spectral data matched that reported: TLC (hexane/EtOAc 80:20) Rf 8 0.15; 1H NMR (300 MHz, CDCl ) δ 8.10 – 7.99 (m, 4H), 7.34 – 7.26 (m, 4H), 7.22 – 7.14 9 3 13 1 2 10 (m, 6H), 2.63 (s, 3H) ppm; C NMR { H} (75, CDCl3) δ 197.4 (C=O), 150.2 (d, JC-P = 7.7 11 1’ 4 4 2 2 12 Hz, 2xC ), 140.5 (d, JC-P = 3.5 Hz, C -COMe), 132.7 (d, JC-P = 10.6 Hz, 2xC -H), 131.6 13 1 4 3’ 3 3 14 (d, JC-P = 191.1 Hz, C-P), 129.9 (d, JC-P = 1.1 Hz, 2xC -H), 128.3 (d, JC-P = 15.9 Hz, 2xC - 15 5 4’ 3 2’ H), 125.5 (d, JC-P = 1.3 Hz, 2xC -H), 120.6 (d, JC-P = 4.5 Hz, 4xC -H), 26.9 (CH3) ppm; 16 17 LRMS (EI) m/z (%) 352(M+, 100), 259 (M+-OPh, 33), 77 (82). 18 19 4-(Diphenoxyphosphoryl)benzoic acid (2k). Following the general procedure, compound 20 2k was obtained after FC (from 89:10:1 to 69:30:1 hexane/EtOAc/AcOH) as a pale yellow 21 22 1 solid (59.54 mg, 0,17 mmol, 56%): TLC (hexane/EtOAc/AcOH 79:20:1) Rf 0.32; H NMR 23 24 (300 MHz, Acetone-d6) δ 8.25 – 8.09 (m, 4H), 7.42 – 7.32 (m, 4H), 7.29 – 7.15 (m, 6H) ppm; 25 13 1 2 1’ 26 C NMR { H} (75 MHz, Acetone-d6) δ 166.7 (CO2H), 151.24 (d, JC-P= 7.3 Hz, C ), 135.8 27 (d, 4J = 3.3 Hz, C4), 133.4 (d, 2J = 10.7 Hz, 2xC2-H), 132.4 (d, 1J = 189.4 Hz, C1-P), 28 C-P C-P C-P 3’- 3 3 4 4’ 29 130.74 (4xC H), 130.56 (d, JC-P = 15.8 Hz, 2xC -H), 126.22 (d, JC-P = 1.2 Hz, 2xC -H), 30 2’ 31 31 121.42 (d, J = 4.6 Hz, 4xC -H) ppm; P-NMR (202 MHz, Acetone-d6) δ 11.40 ppm; LRMS 32 + 33 (EI) m/z (%) 279 (M -Ph, 18),167 (25), 149 (100); HRMS (EI-TOF) m/z calculated for 34 C19H15O5P 354.0657, found 354.0652. 35 36 Methyl 4-(diphenoxyphosphoryl)benzoate (2l). Following the general procedure, 37 38 compound 2l was obtained after FC (from 90:10 hexane/EtOAc to 80:20 hexane/EtOAc) as 39 an orange solid (83.14 mg, 0.226 mmol, 75%): TLC (hexane/EtOAc 80:20) R 0.18; 1H NMR 40 f 41 (300 MHz, CDCl3) δ 8.20–8.13 (m, 2H), 8.09–7.98 (m, 2H), 7.34–7.24 (m, 4H), 7.21–7.12 42 13 1 2 43 (m, 6H), 3.95 (s, 3H) ppm; C NMR { H} (75 MHz, CDCl3) δ 166.1 (CO), 150.2 (d, JC-P = 44 1’ 4 4 2 2 45 7.8 Hz, 2xC ), 134.5 (d, JC-P = 3.2 Hz, C ), 132.4 (d, JC-P = 10.6 Hz, 2xC -H), 131.5 (d, 46 1 1 3’ 3 3 4’ JC-P = 191.4 Hz, C -P), 130.0 (4xC -H), 129.7 (d, JC-P = 16.0 Hz, 2xC -H), 125.6 (2xC - 47 2 2’ 31 48 H), 120.7 (d, JC-P = 4.6 Hz, C -H), 52.7 (CH3-O) ppm; P-NMR (162 MHz, CDCl3) δ 10.04 49 + + + + 50 ppm; LRMS (EI) m/z (%) 368 (M , 82), 367 (M -H, 100), 337 (M -OMe, 11), 275 (M -OPh, 51 29), 228 (25), 77 (50); HRMS (EI-TOF) m/z calculated for C H O P 368.0814, found 52 20 17 5 53 368.0798. 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 19 of 37 The Journal of Organic Chemistry
1 2 3 Diphenyl (3-chlorophenyl)phosphonate (2m). Following the general procedure compound 4 5 2m was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as an orange solid (66.87 6 1 7 mg, 0.194 mmol, 65%): TLC (hexane/EtOAc 80:20) Rf 0.30; H NMR (300 MHz, CDCl3) δ 8 7.96 (dt, J = 14.5, 1.6 Hz, 1H), 7.84 (ddt, J = 13.6, 7.5, 1.3 Hz, 1H), 7.59–7.54 (m, 1H), 7.44 9 13 1 10 (td, J = 7.8, 5.2 Hz, 1H), 7.35–7.10 (m, 10H) ppm; C NMR { H} (101 MHz, CDCl3) δ 11 2 1’ 3 3 4 12 150.2 (d, JC-P = 7.7 Hz, 2xC ), 135.2 (d, JC-P = 21.4 Hz, C -Cl), 133.5 (d, JC-P = 3.2 Hz, 13 4 2 2 2 6 3 14 C -H), 132.2 (d, J = 11.2 Hz, C -H), 130.41 (d, JC-P = 9.8 Hz, C -H), 130.23 (d, JC-P = 17.3 15 5 3’ 1 1 4’ Hz, C -H), 129.9 (4xC -H), 127.0 (d, JC-P = 254.9 Hz, C -P), 125.5 (2xC -H), 120.7 (d, 16 3 2’ + + 17 JC-P = 4.6 Hz, 4xC -H) ppm; LRMS (EI) m/z (%) 346 (M +2H, 34), 344 (M , 100), 309 18 + + 31 19 (M -Cl, 10), 251 (M -OPh, 32), 77 (72); P-NMR (162 MHz, CDCl3) δ 9.30 ppm; HRMS 20 (EI-TOF) m/z calculated for C H O P (M+-Cl) 309.0681, found 309.0675. 21 18 14 3 22 Diphenyl (3-nitrophenyl)phosphonate (2n). 23 24 Following the general procedure compound 2n was obtained after 2 O OPh 3 25 O2N P 26 1 O FC (from 90:10 to 80:20 hexane/EtOAc) as an orange solid (92.3 27 4 6 1' 14 2' mg, 0.260 mmol, 87%). The spectral data matched that reported: 28 5 29 3' 1 4' TLC (hexane/EtOAc 80:20) Rf 0.15; H NMR (300 MHz, CDCl3) δ 30 31 8.87–8.77 (m, 1H), 8.53–8.41 (m, 1H), 8.29 (ddt, J = 13.1, 7.6, 1.3 Hz, 1H), 7.73 (ddd, J = 32 13 1 33 8.6, 7.6, 4.5 Hz, 1H), 7.36–7.28 (m, 4H), 7.23–7.15 (m, 6H) ppm; C NMR { H} (101 MHz, 34 2 1’ 3 3 2 CDCl3) δ 150.0 (d, JC-P = 7.7 Hz, 2xC ), 148.2 (d, JC-P = 19.2 Hz, C -NO2), 138.0 (d, JC- 35 6 3 5 3’ 1 36 P = 10.3 Hz, C -H), 130.23 (d, J = 16.3 Hz, C -H), 130.08 (4xC -H), 129.6 (d, JC-P = 196.6 37 1 4 4 2 2 4’ 38 Hz, C -P), 127.9 (d, JC-P = 3.0 Hz, C -H), 127.2 (d, JC-P = 12.0 Hz, C -H), 125.8 (2xC -H), 39 120.6 (d, 3J = 4.6 Hz, 4xC2’-H) ppm; LRMS (EI-DIP) m/z (%) 355 (M+, 100), 308 (37), 40 C-P 41 262 (M+-OPh 17), 207 (24), 77 (64). 42 43 Diphenyl (3-(trifluoromethyl)phenyl)phosphonate (2o). Following the general procedure, 44 45 compound 2o was obtained after FC (90:10 hexane/EtOAc) as an orange liquid (75.10 mg, 46 1 0.198/ mmol, 66 %): TLC (hexane/EtOAc 80:20) Rf 0.32; H NMR (300 MHz, CDCl3) δ 47 48 8.23 (d, J = 14.3 Hz 1H), 8.16 (dd, J = 13.6, 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.65 (tdt, 49 13 1 50 J = 7.8, 4.3, 0.8 Hz, 1H), 7.36–7.14 (m, 10H) ppm; C NMR { H} (101 MHz, CDCl3) δ 51 150.2 (d, 2J = 7.8 Hz, 2xC1’), 135.6 (dd, 2J , 5J = 10.0,1 Hz, C6-H), 131.4 (dq, 2J , 52 C-P C-P C-F C-F 53 3 3 3’ 3 4 JC-P = 32, 16.5 Hz, C -CF3), 130.01 (4xC -H), 129.97 (q, JC-F = 3.6 Hz, C -H)129.4 (d, 54 3 5 4 3 2 1 55 JC-P = 15.9 Hz, C -H), 129.3 (dq, JC-P, JC-F = 8.6, 3.8 Hz, C -H), 126.7 (d, J = 186.2 Hz, 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 20 of 37
1 2 3 1 5 4’ 1 4 C -P), 125.6 (d, JC-P = 1.4 Hz ,2xC -H), 123.5 (qd, JC-F, JC-P = 272, 3 Hz, CF3), 120.7 (d, 4 3 2’ 31 5 JC-P = 4.5 Hz, 4xC -H) ppm; P-NMR (122 MHz, CDCl3) δ 8.10 ppm; LRMS (EI) m/z 6 + + 7 (%) 378 (M , 100), 377 (M -H, 98), 285 (28), 238 (45), 77 (85); HRMS (EI-TOF) m/z 8 calculated for C H F O P 378.0633, found 378.0615. 9 19 14 3 3 10 Diphenyl (3-acetamidophenyl)phosphonate (2p). Following the general procedure, 11 12 compound 2p was obtained after FC (from 50:50 hexane/EtOAc to 100% EtOAc) as an 13 15 14 orange sticky oil (53.0 mg, 0.144 mmol, 48 %). The spectral data matched that reported: 15 1 TLC (hexane/EtOAc 50:50): Rf 0.45; H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.42 – 8.35 16 17 (m, 1H), 7.91 (dt, J = 16.0, 1.8 Hz, 1H), 7.60 (ddt, J = 13.4, 7.6, 1.3 Hz, 1H), 7.47 (td, J = 18 13 1 19 7.9, 5.6 Hz, 1H), 7.35 – 7.20 (m, 4H), 7.17 – 7.01 (m, 6H), 1.86 (s, 3H) ppm; C NMR { H} 20 (101 MHz, CDCl ) δ 169.5 (CONHAr), 150.2 (d, 2J = 7.7 Hz, 2xC2’), 139.7 (d, 3J = 21 3 C-P C-P 22 3 3’ 1 1 2 20.2 Hz, C -NHAc), 129.9 (4xC -H), 128.6 (d, JC-P = 227.0 Hz, C -P), 126.5 (d, JC-P = 8.8 23 6 4’ 4 3 5 3 24 Hz, C -H), 125.6 (2xC -H), 124.6 (C -H), 123.3 (d, JC-P = 13.5 Hz, C -H), 120.8 (d, JC-P = 25 2’ + 26 4.3 Hz, 4xC -H), 24.2 (NHCOCH3) ppm; LRMS (EI) m/z (%) 367 (M , 48), 325 (100), 232 27 (15). 28 29 Diphenyl (2-chlorophenyl)phosphonate (2q). Following the general procedure, compound 30 31 2q was obtained after FC (from 95:5 to 80:20 hexane/EtOAc) as an orange liquid (69,1 mg, 32 15 33 0.20 mmol, 67%). The spectral data matched that reported: TLC (hexane/EtOAc 80:20) Rf 34 1 0.28; H NMR (400 MHz, CDCl3) δ 8.20 – 8.09 (m, 1H), 7.57 – 7.47 (m, 2H), 7.41 – 7.32 35 13 1 36 (m, 1H), 7.34 – 7.21 (m, 8H), 7.19 – 7.11 (m, 2H) ppm; C NMR { H} (101 MHz, CDCl3) 37 2 1’ 2 2 3 3 38 δ 150.3 (d, JC-P = 7.6 Hz, C ), 137.1 (d, JC-P = 2.9 Hz, C -Cl), 137.0 (d, JC-P = 8.9 Hz, C - 39 H), 134.7 (d, 4J = 2.7 Hz, C4-H), 131.2 (d, 2J = 10.8 Hz, C6-H), 129.8 (4xC3’-H), 126.8 40 C-P C-P 3 5 1 1 4’ 2 41 (d, JC-P = 14.7 Hz, C -H), 125.9 (d, JC-P = 196.5 Hz, C -P), 125.4 (2xC -H), 120.7 (d, JC- 42 2’ + + + 43 P = 4.7 Hz, 4xC -H) ppm; LRMS (EI-DIP) m/z (%) 346 (M +2, 21), 344 (M , 86), 309 (M - 44 45 Cl, 72), 215 (82), 77 (100). 46 Diphenyl o-tolylphosphonate (2r). Following the general procedure, compound 2r was 47 48 obtained after FC (from 95:5 to 85:15 hexane/EtOAc) as an orange liquid. (60.8 mg, 0.19 49 15 50 mmol, 63%). The spectral data matched that reported: TLC (hexane/EtOAc 80:20) Rf 0.28: 51 1H NMR (300 MHz, CDCl ) δ 8.08 (ddd, J = 15.2, 7.7, 1.3 Hz, 1H), 7.51 – 7.44 (m, 1H), 52 3 53 13 1 7.35 – 7.09 (m, 13H), 2.76 (d, J = 1.8 Hz, 3H) ppm; C NMR { H} (75 MHz, CDCl3) δ 54 2 1’ 2 2 2 55 150.5 (d, JC-P = 7.8 Hz, 2xC ), 142.2 (d, JC-P = 10.6 Hz, C -Me), 134.5 (d, JC-P = 11.1 Hz, 56 57 58 59 60 ACS Paragon Plus Environment Page 21 of 37 The Journal of Organic Chemistry
1 2 3 6 4 4 3 3 3’ C -H), 133.4 (d, JC-P = 3.1 Hz, C -H), 131.6 (d, JC-P = 15.8 Hz, C -H), 129.8 (4xC -H), 4 3 5 1 5 5 125.79 (d, JC-P = 15.8 Hz, C -H), 125.73 (d, JC-P = 188.6 Hz, C-P), 125.1 (d, JC-P = 1.2 6 4’ 3 2’ 3 7 Hz, 2xC -H), 120.5 (d, JC-P = 4.6 Hz, 4xC -H), 21.6 (d, JC-P = 3.6 Hz, CH3) ppm; LRMS 8 (EI) m/z (%) 324 (M+, 100), 288 (18), 231 (25), 212 (30), 77 (54). 9 10 Diphenyl [1,1'-biphenyl]-2-ylphosphonate (2s). Following the general procedure, 11 12 compound 2s was obtained after FC (from 95:5 to 80:20 hexane/EtOAc) and further purified 13 14 by recrystallization from i-PrOH as an orange crystalline solid (67.2 mg, 0.174 mmol, 58%): 15 1 TLC (hexane/EtOAc 80:20) Rf 0.30; mp (i-PrOH) 93-95 ºC; H NMR (300 MHz, CDCl3) δ 16 17 8.36 – 8.27 (m, 1H), 7.65 (tt, J = 7.6, 1.6 Hz, 1H), 7.54 (dtd, J = 7.6, 3.8, 1.4 Hz, 1H), 7.51 18 19 – 7.46 (m, 2H), 7.45 – 7.38 (m, 4H), 7.25 – 7.17 (m, 4H), 7.13 – 7.05 (m, 2H), 6.93 – 6.86 20 (m, 4H); 13C NMR {1H} (75 MHz, CDCl ) δ 150.5 (d, 2J = 8.4 Hz, 2xC1’), 146.6 (d, 2J 21 3 C-P C-P 22 2 3 7 2 6 4 = 10.0 Hz, C ), 141.2 (d, JC-P = 4.2 Hz, C ), 134.6 (d, J = 10.8 Hz, C -H), 133.0 (d, JC-P = 23 4 3 5 9 3’ 10 24 3.1 Hz, C -H), 131.9 (d, JC-P = 14.9 Hz, C -H), 129.7 (2xC -H), 129.6 (4xC -H), 127.8 (C - 25 8 3 3 1 1 26 H), 127.8 (2xC -H), 127.2 (d, JC-P= 15.6 Hz, C -H), 125. 9 (d, JC-P = 192.4 Hz, C -P ), 124.9 27 (d, 5J = 1.2 Hz, 2xC4’-H), 120.5 (d, 2J = 4.8 Hz, 4xC2’-H) ppm; 31P-NMR (122 MHz, 28 C-P C-P + + 29 CDCl3) δ 11.43 ppm; LRMS (EI-DIP) m/z (%) 386 (M , 42), 293 (M -OPh), 199 (100); 30 31 HRMS (ESI-TOF) m/z calculated for C24H19O3P 386.1072, found 386.1071. 32 33 Diphenyl (2-methoxyphenyl)phosphonate (2t). Following the general procedure, 34 compound 2t was obtained after FC (from 75:25 to 65:35 hexane/EtOAc) as a brown liquid 35 36 (37.1 mg, 0.11 mmol, 37%). The spectral data matched that reported:44 TLC (hexane/EtOAc 37 1 38 80:20) Rf 0.13; H NMR (300 MHz, CDCl3) δ 7.96 (ddd, J = 15.7, 7.6, 1.8 Hz, 1H), 7.54 39 (dddd, J = 8.4, 7.4, 1.8, 0.9 Hz, 1H), 7.33 – 7.26 (m, 11H), 7.26 – 7.14 (m, 1H), 7.06 – 6.89 40 13 1 2 2 41 (m, 1H), 3.87 (s, 3H) ppm; C NMR { H} (75 MHz, CDCl3) δ 161.5 (d, JC-P = 2.5 Hz, C - 42 2 1’ 3 3 2 43 OMe), 150.8 (d, JC-P = 7.5 Hz, 2xC ), 135.9 (d, JC-P = 7.9 Hz, C -H), 135.5 (d, JC-P = 2.2 44 6 3 3’ 4 4’ 45 Hz, C -H), 129.7 (d, JC-P = 1.0 Hz, 4xC -H), 125.0 (d, JC-P = 1.3 Hz, 2xC -H), 120.8 (d, 46 2 2’ 4 1 1 3 JC-P = 4.6 Hz, 4xC -H), 120.55 (C -H), 115.0 (d, JC-P = 192.2 Hz, C -P), 111.4 (d, JC-P = 47 5 + + 48 9.9 Hz, C -H), 55.9 (OCH3) ppm; LRMS (EI-DIP) m/z (%) 340 (M , 27), 309 (M -OMe, 11), 49 + 50 247 (M -OPh, 100), 215 (49), 77 (42). 51 Diphenyl (2-cyanophenyl)phosphonate (2u). Following the general procedure, compound 52 53 2u was obtained after FC (80:20 hexane/EtOAc) as a pale orange solid (69.5 mg, 0.207 mmol, 54 55 69%). The spectral data matched that reported:14 TLC (hexane/EtOAc 80:20) Rf 0.15; 1H 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 22 of 37
1 2 3 NMR (300 MHz, CDCl3) δ 8.31–8.21 (m, 1H), 7.91–7.84 (m, 1H), 7.78–7.66 (m, 2H), 7.39– 4 13 1 2 5 7.23 (m, 8H), 7.21–7.09 (m, 2H) ppm; C NMR { H} (101 MHz, CDCl3) δ 150.1 (d, JC-P 6 1’ 2 6 3 3 7 = 8.1 Hz, 2xC ), 135.7 (d, JC-P = 9.5 Hz, C -H), 134.8 (d, JC-P = 11.4 Hz, C -H), 133.5 (d, 8 4J = 2.7 Hz, C4-H), 132.6 (d, 3J = 14.9 Hz, C5-H), 130.0 (d, 1J = 193.1 Hz, C1-P), 9 C-P C-P C-P 3’ 4’ 3 2’ 3 10 129.9 (4xC -H), 125.6 (2xC -H), 120.6 (d, JC-P = 4.6 Hz, 4xC -H), 117.1 (d, JC-P = 5.9 11 2 2 + 12 Hz, CN), 115.0 (d, JC-P = 4.7 Hz, C -CN) ppm; LRMS (EI-DIP) m/z (%) 335 (M , 100), 242 13 + 14 (M -OPh, 33), 195 (55), 170 (17), 77 (51). 15 Diphenyl (2-nitrophenyl)phosphonate (2v). Following the general procedure, compound 16 17 2v was obtained after FC (from 98:2 to 50:50 hexane/EtOAc) as a brown solid (96.9 mg, 18 1 19 0.273 mmol, 91%): TLC (hexane/EtOAc 80:20) Rf 0.18; H NMR (300 MHz, CDCl3) δ 20 8.35–8.23 (m, 1H), 8.02 (ddd, J = 7.5, 6.2, 1.6 Hz, 1H), 7.82–7.68 (m, 2H), 7.35–7.12 (m, 21 22 13 1 2 2 10H) ppm; C NMR { H} (101 MHz, CDCl3) δ 151.9 (C -NO2), 150.3 (d, JC-P = 8.3 Hz, 23 1’ 2 6 4 4 3 24 2xC ), 136.3 (d, JC-P = 6.6 Hz, C -H), 134.3 (d, JC-P = 2.7 Hz, C -H), 132.8 (d, JC-P = 13.9 25 5 3’ 4’ 3 3 1 26 Hz, C -H), 129.9 (4xC -H), 125.6 (2xC -H), 124.9 (d, JC-P = 8.9 Hz, C -H), 121.9 (d, JC-P 27 = 196.9 Hz, C1-P), 120.7 (d, 3J = 4.6 Hz, 4xC2’-H) ppm; 31P-NMR (162 MHz, CDCl ) δ 28 C-P 3 29 4.70 ppm; LRMS (EI-DIP) m/z (%) 355 (M+, 6), 262 (M+-OPh, 100), 232 (64), 207 (36); 30 31 HRMS (EI-TOF) m/z calculated for C18H14NO5P 355.0610, found 355.0619. 32 33 Diphenyl (4-methoxy-2-nitrophenyl)phosphonate (2w). Following the general procedure, 34 compound 2w was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a pale orange 35 1 36 oil (62.4 mg, 0,162 mmol, 54%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.20; H NMR (300 37 38 MHz, CDCl3) δ 8.18 (dd, J = 14.7, 8.7 Hz, 1H), 7.50 (dd, J = 5.3, 2.5 Hz, 1H), 7.33 – 7.25 39 (m, 4H), 7.24 – 7.07 (m, 7H), 3.91 (s, 3H) ppm; 13C NMR {1H} (75 MHz, CDCl ) δ 163.8 40 3 4 4 2 2 2 41 (d, JC-P = 3.0 Hz, C -OMe), 153.3 (d, JC-P = 3.9 Hz, C -NO2), 150.3 (d, JC-P = 8.1 Hz, 42 1’ 3 3 4 3’ 5 43 2xC ), 138.0 (d, JC-P = 7.8 Hz, C -H), 129.8 (d, JC-P = 1.0 Hz, 4xC -H), 125.4 (d, JC-P = 44 4’ 3 2’ 3 5 45 1.4 Hz, 2xC -H), 120.6 (d, JC-P = 4.7 Hz, 4xC -H), 117.4 (d, JC-P = 14.8 Hz, C -H), 112.5 46 1 1 2 6 31 (d, JC-P = 204.3 Hz, C -P), 111.2 (d, JC-P = 9.9 Hz, C -H), 56.3 (OCH3); P-NMR (162 47 + + + 48 MHz, CDCl3) δ 5.55 ppm; LRMS (EI) m/z (%) 385 (M , 3), 355 (M -OMe, 7), 292 (M - 49 50 OPh, 100), 262 (24); HRMS (ESI-TOF) m/z calculated for C19H16NO6P 385.0715, found 51 385.0716. 52 53 Diphenyl (2-bromo-5-fluorophenyl)phosphonate (2x). Following the general procedure, 54 55 compound 2x was obtained after FC (from 90:10 to 80:20 hexane/EtOAc) as a pale orange 56 57 58 59 60 ACS Paragon Plus Environment Page 23 of 37 The Journal of Organic Chemistry
1 2 3 crystalline solid. (87.5 mg, 0.216 mmol, 72%): TLC (hexane/EtOAc 80:20) Rf 0.20; mp (i- 4 1 5 PrOH/hexane 3:1) 64-66 ºC; H NMR (400 MHz, CDCl3) δ 7.89 (ddd, J = 16.1, 8.4, 3.2 Hz, 6 13 7 1H), 7.69 (ddd, J = 8.7, 6.5, 4.7 Hz, 1H), 7.36 – 7.23 (m, 8H), 7.21 – 7.10 (m, 3H); C NMR 8 {1H} (101 MHz, CDCl ) δ 161.4 (dd, J = 250.9, 20.7 Hz, C5-F), 150.2 (d, J = 7.6 Hz, 2xC1’), 9 3 10 136.4 (dd, J = 14.0, 7.3 Hz, C3-H), 130.2 (dd, J = 197.7, 6.2 Hz, C1-P), 129.9 (4xC3’-H), 11 12 125.6 (2xC4’-H), 124.5 (dd, J = 24.6, 9.9 Hz, C6-H), 121.9 (dd, J = 22.2, 3.1 Hz, C4-H), 120.6 13 2’ 2 31 14 (d, J = 4.7 Hz, 4xC -H), 119.6 (t, J = 3.5 Hz, C -Br) ppm; P-NMR (202 MHz, CDCl3) δ 15 6.11 (d, J = 7.1 Hz) ppm; LRMS (EI) m/z (%) 408 (M++2 ,56), 406 (M+, 58), 327 (M+-Br, 16 17 50), 233 (46), 77 (100); HRMS (EI-TOF) m/z calculated for C18H13BrFO3P 405.977, found 18 19 405.9773. 20 Diphenyl quinolin-8-ylphosphonate (2y). Following the general procedure, compound 2y 21 22 was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a dark brown solid (34.7 mg, 23 1 24 0.096 mmol, 32%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.12; H NMR (300 MHz, CDCl3) 25 26 δ 9.15 (dd, J = 4.3, 1.7 Hz, 1H), 8.54 (ddd, J = 16.9, 7.1, 1.5 Hz, 1H), 8.24 (dt, J = 8.3, 2.1 27 Hz, 1H), 8.07 (dt, J = 8.2, 1.5 Hz, 1H), 7.62 (ddd, J = 8.2, 7.1, 3.9 Hz, 1H), 7.53 (dd, J = 8.3, 28 29 4.2 Hz, 1H), 7.25 (d, J = 4.4 Hz, 8H), 7.10 (tdd, J = 6.4, 3.2, 1.8 Hz, 2H) ppm; 13C NMR 30 1 2 2 1’ 31 { H} (75 MHz, CDCl3) δ 151.4 (C -H), 150.9 (d, JC-P = 7.5 Hz, 2xC ), 148.0 (d, J = 1.2 Hz, 32 8a 8 4 5 33 C ), 146.5 (d, J = 205.0 Hz, C ), 138.3 (d, J = 8.5 Hz, C -H), 134.1 (d, J = 3.4 Hz, C -H), 34 3’ 2 7 4a 6 129.6 (C ), 128.4 (d, JC-P = 11.3 Hz, C -H), 127.5 (C ), 125.9 (d, J = 17.1 Hz, C -H), 125.0 35 36 (d, J = 1.4 Hz, C4’-H), 122.1 (C3-H), 121.0 (d, J = 4.6 Hz, C2’-H) ppm; 31P-NMR (122 MHz, 37 + + 38 CDCl3) δ 10.7 ppm; LRMS (EI-DIP) m/z (%) 361 (M , 6), 268 (M -OPh, 100), 192 (12); 39 HRMS (EI-TOF) m/z calculated for C H NO P 361.0868, found 361.0854. 40 21 16 3 41 Diphenyl benzo[d]thiazol-2-ylphosphonate (2z). Following the general procedure, 42 43 compound 2z was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as a pale pale 44 1 45 yellow oil (29.7 mg, 0,081 mmol, 27%): TLC (hexane/EtOAc/AcOH 80:20) Rf 0.21; H 46 NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 8.4, 1.0 Hz, 1H), 8.01 (ddd, J = 7.9, 1.4, 0.8 Hz, 47 48 1H), 7.66 – 7.52 (m, 2H), 7.37 – 7.27 (m, 8H), 7.23 – 7.14 (m, 2H) ppm; 13C NMR {1H} 49 1 2 3 3a 50 (101 MHz, CDCl3) δ 157.9 (d, JC-P = 251.2 Hz, C ), 154.6 (d, JC-P = 30.6 Hz, C -N), 150.0 51 (d, 2J = 7.6 Hz, C1’), 136.9 (C7a), 130.0 (4xC3’-H), 127.6 (C5-H), 127.3 (C6-H), 125.9 (C7- 52 C-P 53 4 5 4’ 4 2’ H), 125.5 (C -H), 122.2 (d, JC-P = 1.9 Hz, 2xC -H), 120.9 (d, JC-P= 4.6 Hz, 4xC -H) ppm; 54 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 24 of 37
1 2 3 31 + P-NMR (122 MHz, CDCl3) δ -10.28 ppm; LRMS (EI-DIP) m/z (%) 367 (M , 8), 303 (21), 4 5 207 (100); HRMS (EI-TOF) m/z calculated for C19H14NO3PS 367.0432, found 367.0407. 6 7 Methyl 3-(diphenoxyphosphoryl)tiophene-2-carboxylate (2aa). Following the general 8 procedure, compound 2aa was obtained after FC (from 90:10 to 70:30 hexane/EtOAc) as an 9 10 orange liquid (56.2 mg, 0.15 mmol, 50%): TLC (hexane/EtOAc 80:20) Rf 0.10; 1H NMR 11 12 (300 MHz, CDCl3) δ 7.66 (t, J = 5.0 Hz, 1H), 7.57 (dd, J = 5.0, 3.4 Hz, 1H), 7.34–7.25 (m, 13 13 1 14 4H), 7.25–7.19 (m, 4H), 7.18–7.10 (m, 2H), 3.90 (s, 3H) ppm; C NMR { H} (75 MHz, 15 2 1’ 2 2 CDCl3) δ 160.8 (CO2Me), 150.6 (d, JC-P = 8.0 Hz, 2xC -H), 140.3 (d, JC-P = 15.0 Hz, C ), 16 2 4 1 2 3 17 134.7 (d, JC-P = 15.4 Hz, C -H), 132.2 (d, JC-P = 201.4 Hz, C -P), 130.9 (d, JC-P = 20.8 Hz, 18 5 3’ 4’ 3 2’ 19 C -H), 129.8 (4xC -H), 125.3 (2xC -H), 120.7 (d, JC-P = 4.7 Hz, 4xC -H), 53.0 (O-CH3) 20 ppm; 31P-NMR (162 MHz, CDCl ) δ 11.40 ppm; LRMS (EI) m/z (%) 374 (M+,1), 343 (M+- 21 3 22 + OMe, 4), 281 (M -OPh, 100), 77 (6); HRMS (EI-TOF) m/z calculated for C17H12O4PS 23 24 343.0194 (M+-OMe), found 343.0164. 25 26 Diphenyl (2-chloropyridin-3-yl)phosphonate (2ab). Following the general procedure, 27 compound 2ab was obtained after FC (from 95:5 to 70:30 hexane/EtOAc) as an orange liquid 28 29 (76.75 mg, 0.22 mmol, 74 %). The spectral data matched that reported:14 TLC 30 1 31 (hexane/EtOAc 80:20) Rf 0.10; H NMR (300 MHz, CDCl3) δ 8.57 (dt, J = 4.6, 2.2 Hz, 1H), 32 13 33 8.44 (ddd, J = 14.7, 7.6, 2.1 Hz, 1H), 7.38 – 7.22 (m, 9H), 7.19 – 7.12 (m, 2H) ppm; C 34 1 6 2 2 2 NMR { H} (75 MHz, CDCl3) δ 153.6 (C ), 153.1 (d, JC-P = 5.8 Hz, C -H), 150.0 (d, JC-P = 35 1’ 2 4 3’ 4 4’ 36 7.7 Hz, C ), 146.1 (d, JC-P = 8.6 Hz, C -H), 129.9 (4xC -H), 125.7 (d, JC-P = 1.4 Hz, 2xC - 37 1 3 3 5 2 38 H), 123.5 (d, JC-P = 186.7 Hz, C -P), 122.2 (d, JC-P = 10.9 Hz, C -H), 120.6 (d, JC-P = 4.7 39 Hz, C2’-H); LRMS (EI-DIP) m/z (%) 347 (M++2, 21), 345 (M+, 82), 310 (M+-Cl, 62), 169 40 41 (100). 42 43 Diphenyl (4-(benzo[d]thiazol-2-yl)phenyl)phosphonate (2ac). Following the general 44 45 procedure, compound 2ac was obtained after FC (from 90:10 to 80:20 hexane/EtOAc) as a 46 crystalline pale yellow solid (107.6 mg, 0.24 mmol, 81 %): TLC (hexane/EtOAc 80:20) Rf 47 1 48 0.36; mp (hexane/EtOAc 4:1) 133-135 ºC; H NMR (300 MHz, CDCl3) δ 8.24 – 8.19 (m, 49 50 2H), 8.14 – 8.04 (m, 3H), 7.92 (dt, J = 7.9, 0.9 Hz, 1H), 7.53 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 51 7.43 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.35 – 7.27 (m, 4H), 7.25 – 7.11 (m, 6H) ppm; 13C NMR 52 53 1 5 10a 2 1’ { H} (75 MHz, CDCl3) δ 166.3 (C ), 154.1 (C -N), 150.3 (d, JC-P = 7.5 Hz, 2xC ), 137.8 54 2 4 6a 2 2 3’ 55 (d, JC-P = 3.5 Hz, C ), 135.3 (C -S), 133.1 (d, JC-P = 10.6 Hz, 2xC -H), 129.93 (4xC -H), 56 57 58 59 60 ACS Paragon Plus Environment Page 25 of 37 The Journal of Organic Chemistry
1 2 3 2 1 2 3 8 9 129.24 (d, JC-P = 192.9 Hz, C ), 127.6 (d, JC-P = 16.0 Hz, 2xC -H), 126.8 (C -H), 126.0 (C - 4 4’ 7 10 2 2’ 5 H), 125.4 (2xC -H), 123.7 (C -H), 121.9 (C -H), 120.7 (d, JC-P = 4.4 Hz, 4xC -H) ppm; 6 31 + + 7 P-NMR (162 MHz, CDCl3) δ 10.32 ppm; LRMS (EI-DIP) m/z (%) 443 (M , 98), 350 (M - 8 OPh, 100), 77; HRMS (EI-TOF) m/z calculated for C H NO PS 443.0745, found 443.074. 9 25 18 3 10 Diethyl (4-(benzo[d]thiazol-2-yl)phenyl)phosphonate (3). The phosphonate 2ac (443.5 11 12 mg, 1.00 mmol) was added into a flame-dried round bottom flask, and the system was 13 14 evacuated and filled with argon (three times). EtOH (3 mL, 99.9 %) was then added and the 15 mixture was stirred until a homogeneous solution was obtained. Then, freshly prepared 16 17 NaOEt (3 mL, 2 M, 6 equiv) was added dropwise, while stirring at 20 ºC (external water 18 19 bath). After 2 h, NaOH (40 mL, 1 M) was added to the reaction mixture and it was extracted 20 with Et O (3x20 mL). The combined organic layers were dried over MgSO , filtered and 21 2 4 22 evaporated in vacuo. The residue was purified by FC on silica gel (from 90:10 to 70:30 23 24 hexane/EtOAc), to obtain the pure product as a pale yellow solid (277.5 mg, 0.80 mmol, 25 45 26 80%). The spectral data matched that reported. 27 1 TLC (hexane/EtOAc 80:20) Rf 0.24; H-NMR (300 MHz, CDCl3) 28 7 3 2 8 6a O S 5 4 1 29 P OEt δ 8.22 – 8.15 (m, 2H), 8.11 (ddd, J = 8.2, 1.3, 0.6 Hz, 1H), 7.98 30 9 10a N OEt 10 31 – 7.88 (m, 3H), 7.52 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.42 (ddd, J 32 13 1 33 = 8.3, 7.3, 1.2 Hz, 1H), 4.26 – 4.01 (m, 4H), 1.34 (td, J = 7.1, 0.6 Hz, 6H); C-NMR { H} 34 5 10a 4 6a 2 (75 MHz, CDCl3) δ 166.7 (C ), 153.9 (C -N), 137.0 (C ), 135.2 (C -S), 132.6 (d, JC-P = 35 2 1 1 3 3 36 10.1 Hz, 2xC -H), 131.1 (d, JC-P = 188.3 Hz, C -P), 127.6 (d, JC-P = 15.2 Hz, 2xC -H), 37 8 9 7 10 2 38 126.8 (C -H), 125.92 (C -H), 123.6 (C -H), 121.9 (C -H), 62.5 (d, JC-P = 5.5 Hz, O-CH2), 39 16.5 (d, 3J = 6.5 Hz, CH ). 40 C-P 3 41 [1,1'-Biphenyl]-2-yldimethylphosphine oxide (4). Phosphonate 2s (115.92 mg, 0.30 42 43 mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer and 44 45 capped with a rubber septum. The system was evacuated and filled with argon (three times), 46 before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once 47 48 the temperature was reached, MeMgBr (400 µL, 2.4 M, 2.6 equiv.) was added dropwise over 49 50 5 min, letting the drop fall down the walls of the flask to cool the MeMgBr solution. The 51 reaction was stirred for an additional 30 min, before being quenched with H SO (0.5 mL, 52 2 4 53 0.10 M), while keeping the cooling bath. The reaction mixture was extracted with CH2Cl2 54 55 (3x10 mL), the combined organic layers were dried over MgSO4, filtered and the solvent was 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 26 of 37
1 2 3 removed in vacuo. The residue was purified by FC on silica gel (from 100% EtOAc to 80:20 4 5 EtOAc/MeOH) giving the pure product as a white solid (63.0 mg, 0.28 mmol, 92 %). The 6 38b 7 spectral data matched that reported. 8 1 10 TLC (EtOAc/MeOH 90:10) Rf 0.18; H-NMR (400 MHz, CDCl3) δ 8.16 – 9 9 10 8.06 (m, 1H), 7.50 (p, J = 7.4 Hz, 2H), 7.42 – 7.37 (m, 3H), 7.35 – 7.31 (m, 8 11 7 O 2 Me 13 1 12 3 P 2H), 7.28 – 7.24 (m, 1H), 1.37 (d, J = 13.1 Hz, 6H) ppm; C-NMR { H} (101 1 Me 13 2 2 3 7 4 6 MHz, CDCl3) δ 144.5 (d, JC-P = 9.9 Hz, C ), 141.2 (d, JC-P = 3.3 Hz, C ), 14 5 15 1 1 6 4 4 132.8 (d, JC-P = 94.7 Hz, C -P), 132.1 (d, J = 8.3 Hz, C -H), 131.3 (d, JC-P = 2.3 Hz, C -H), 16 3 3 9 10 8 17 131.1 (d, JC-P = 9.9 Hz, C -H), 129.7 (2xC -H), 128.2 (C -H), 128.2 (2xC -H), 127.5 (d, 18 3 5 1 31 19 JC-P = 10.7 Hz, C -H), 19.0 (d, JC-P = 71.5 Hz, 2xMe-P) ppm; P-NMR (202 MHz, CDCl3) 20 δ 36.19 ppm; LRMS (EI): m/z (%) 230 (M+, 12), 229 (M+-H, 100), 215 (M+-Me, 8), 152 (10). 21 22 [1,1'-Biphenyl]-2-yldiphenylphosphine oxide (5). Phosphonate 2s (193.2 mg, 0.50 mmol) 23 24 was added into a flame-dried round bottom flask equipped with a magnetic stirrer and capped 25 26 with a rubber septum. The system was evacuated and filled with argon (three times), before 27 adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once the 28 29 temperature was reached, PhMgBr (910 µL, 2.2 M, 4 equiv.) was added dropwise over 5 min, 30 31 letting the drop fall down the walls of the flask to cool the PhMgBr solution. The reaction 32 33 was stirred for an additional 4 h, before being quenched with H2SO4 (0.5 mL, 0.10 M), while 34 keeping the cooling bath. The reaction mixture was extracted with CH2Cl2 (3x10 mL), the 35 36 combined organic layers were dried over MgSO4, filtered and the solvent was removed in 37 38 vacuo. The residue was purified by FC on silica gel (from 50:50 hexane/EtOAc to 100% 39 EtOAc), giving the pure product as a white solid (141.80 mg, 0.40 mmol, 80 %). The spectral 40 41 data matched that reported:46 42 1 43 10 TLC (hexane/EtOAc 50:50) Rf = 0.30; H-NMR (400 MHz, CDCl3) δ 44 9 45 7.61 – 7.50 (m, 5H), 7.45 – 7.24 (m, 9H), 7.23 – 7.19 (m, 2H), 7.08 – 6.99 8 2' 3' 7 O 46 1' 13 1 2 2 1 (m, 3H) ppm; C-NMR { H} (101 MHz, CDCl3) δ 147.6 (d, JC-P = 8.5 47 3 P 4' Ph 2 3 7 3 3 48 4 6 Hz, C ), 140.2 (d, JC-P = 4.1 Hz, C ), 134.0 (d, JC-P = 12.2 Hz, C -H), 49 5 1 1’ 2 6 50 132.9 (d, JC-P = 104.6 Hz, 2xC -P), 131.9 (d, JC-P = 9.8 Hz, C -H), 131.7 51 (d, 4J = 2.5 Hz, C4-H), 131.52 (d, 3J = 9.3 Hz, 4xC3’-H), 131.50 (d, 1J = 96.8 Hz, C1- 52 C-P C-P C-P 53 4 4’ 9 2 2’ P), 131.1 (d, JC-P = 2.8 Hz, C -H), 130.1 (2xC -H), 128.0 (d, JC-P = 12.0 Hz, 4xC -H), 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 27 of 37 The Journal of Organic Chemistry
1 2 3 127.1 (2xC8-H), 127.06 (C10-H), 126.5 (d, J = 12.4 Hz, C5-H) ppm; 31P-NMR (162 MHz, 4 + 5 CDCl3) δ 32.60 ppm; LRMS (EI) m/z (%) 353 (M , 43), 277 (100), 199 (27). 6 7 Phenyl [1,1'-biphenyl]-2-yl(phenyl)phosphinate (6). Phosphonate 2s (193.2 mg, 0.50 8 mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer and 9 10 capped with a rubber septum. The system was evacuated and filled with argon (three times), 11 12 before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water bath. Once 13 14 the temperature was reached, PhMgBr (273 µL, 2.2 M, 1.2 equiv.) was added dropwise over 15 5 min, letting the drop fall down the walls of the flask to cool the PhMgBr solution. The 16 17 reaction was stirred for an additional 1 h, before being quenched with H2SO4 (0.5 mL, 0.10 18 19 M), while keeping the cooling bath. The reaction mixture was extracted with CH2Cl2 (3x10 20 mL), the combined organic layers were dried over MgSO , filtered and the solvent was 21 4 22 removed in vacuo. The residue was purified by FC on silica gel (from 70:30 to 50:50 23 24 hexane/EtOAc) giving the pure product as a white solid (113 mg, 0.31 mmol, 62%). 25 1 26 10 TLC (hexane/EtOAc 50:50) Rf 0.50; H-NMR (400 MHz, CDCl3) δ 9 27 8.25 (ddd, J = 13.2, 7.6, 1.5 Hz, 1H), 7.58 (tt, J = 7.6, 1.5 Hz, 1H), 7.50 28 8 2' 3' 7 O 29 2 1' 1 P 4' (tdd, J = 7.6, 2.9, 1.4 Hz, 1H), 7.42 – 7.32 (m, 3H), 7.30 – 7.10 (m, 10H), 30 3 O 13 1 31 4 6 A 7.02 (tt, J = 6.6, 1.1 Hz, 3H) ppm; C-NMR { H} (101 MHz, CDCl3) δ B 32 5 150.9 (d, 2J = 8.0 Hz, CA), 146.7 (d, 2J = 12.1 Hz, C2), 140.4 (d, 33 C C-P C-P 34 D 3 7 2 6 4 JC-P = 4.4 Hz, C ), 133.0 (d, JC-P = 8.8 Hz, C -H), 132.2 (d, JC-P = 2.7 35 4 3 3’ 4’ 3 36 Hz, C -H), 131.82 (d, JC-P = 10.5 Hz, 2xC -H), 131.80 (C -H), 131.6 (d, JC-P = 12.4 Hz, 37 3 1 1 1 1’ C 38 C -H), 131.5 (d, JC-P = 120.9 Hz, C -P), 131.3 (d, JC-P = 118.7 Hz, C -P), 129.9 (2xC -H), 39 129.5 (C9-H), 128.0 (d, 2J = 13.6 Hz, 2xC2’-H), 127.5 (2xC8-H), 127.40 (C10-H), 127.0 (d, 40 C-P 3 5 D 3 B 31 41 JC-P = 12.6 Hz, C -H), 124.4 (C -H), 120.7 (d, JC-P = 4.8 Hz, 2xC -H) ppm; P-NMR (162 42 + + + 43 MHz, CDCl3) δ 30.87 ppm; LRMS (EI) m/z (%) 370 (M , 49), 293 (M -Ph, 64), 277 (M , 44 45 100), 199 (85); HRMS (EI-TOF) m/z calculated for C24H19O2P 370.1123, found 370.1113. 46 [1,1'-Biphenyl]-2-yl(methyl)(phenyl)phosphine oxide (7). Phosphonate 6 (115.92 mg, 47 48 0.30 mmol) was added into a flame-dried round bottom flask equipped with a magnetic stirrer 49 50 and capped with a rubber septum. The system was evacuated and filled with argon (three 51 times), before adding dry THF (3 mL) and then cooled to 0 ºC with an external ice-water 52 53 bath. Once the temperature was reached, MeMgBr (18 µL, 2.4 M, 1.5 equiv.) was added 54 55 dropwise over 5 min, letting the drop fall down the walls of the flask to cool the MeMgBr 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 28 of 37
1 2 3 solution. The reaction was stirred for an additional 1 h, before being quenched with H2SO4 4 5 (0.5 mL, 0.1 M), while keeping the cooling bath. The reaction mixture was extracted with 6 7 CH2Cl2 (3x10 mL), the combined organic layers were dried over MgSO4, filtered and the 8 solvent was removed in vacuo. The residue was purified by flash FC on silica gel (from 100% 9 10 EtOAc to 95:05 EtOAc/MeOH) giving the pure product as a white solid (76.0 mg, 0.26 mmol, 11 12 87%). 13 TLC (100% EtOAc) R 0.50; 1H-NMR (400 MHz, CDCl ) δ 7.92 14 10 f 3 9 15 (ddd, J = 13.2, 7.7, 1.1 Hz, 1H), 7.55 (tt, J = 7.5, 1.4 Hz, 1H), 7.49 – 16 8 2' 3' 7 O 1' 17 2 1 7.35 (m, 4H), 7.35 – 7.24 (m, 4H), 7.21 (ddd, J = 8.4, 7.1, 1.2 Hz, 2H), 3 P 4' 18 Me 13 1 19 4 6 7.11 (dt, J = 6.9, 1.4 Hz, 2H), 1.59 (d, J = 13.4 Hz, 3H); C-NMR { H} 5 20 (101 MHz, CDCl ) δ 146.1 (d, 2J = 9.5 Hz, C2), 140.7 (d, J = 3.9 Hz, 21 3 C-P 22 C7), 134.7 (d, J = 102.4 Hz (C1’-P), 132.70 (d, J = 9.7 Hz, C6-H), 131.71 (d, J = 2.8 Hz, C- 23 24 H), 131.54 (d, J = 9.9 Hz, C3-H), 131.36 (d, J = 2.8 Hz, C-H), 130.5 (d, J = 9.9 Hz,2xC3’-H), 25 9 2’ 8 10 26 129.9 (2xC -H), 128.4 (d, J = 12.1 Hz, 2xC -H), 127.83 (2xC -H), 127.78 (C -H), 127.17 27 (d, J = 11.5 Hz, C5-H), 16.72 (d, J = 74.1 Hz, CH ); 31P-NMR (162 MHz, CDCl ) δ 28.52 28 3 3 29 ppm; LRMS (EI) m/z (%) 292 (M+, 21), 291 (M+-H, 68), 215 (M+-Ph, 100), 199 (17); HRMS 30 31 (EI-TOF) m/z calculated for C19H17OP 292.1017, found 292.0993. 32 33 8-Fluoro-6-phenoxydibenzo[c,e][1,2]oxaphosphinine 6-oxide (8). Following a previously 34 reported procedure,47 the phosphonate 2x was added into a flame dried pressure tube (81.43, 35 36 0.20 mmol), followed by KOAc (29 mg, 0.30 mmol, 1.5 equiv.), (Ra)-BINAP (12.45 mg, 37 38 0.02 mmol, 10 mol-%) and Pd(OAc)2 (11.25 mg, 0.01 mmol, 5 mol-%). The tube was capped 39 with a rubber septum, and the system was evacuated and filled with argon (three times). Then, 40 41 dry toluene (1 mL) was added under Ar and the pressure tube was finally capped with a 42 43 pressure cap. The resulting mixture was stirred at 100 ºC (sand bath) for 24 h. After this time, 44 45 the tube was cooled to room temperature, and the solvent was removed in vacuo. The residue 46 was directly purified by FC on silica gel (from 70:30 to 60:40 hexane/EtOAc), affording the 47 48 desired product as a white solid (20.0 mg, 0.06 mmol, 31%). The enantiomeric ratio was 49 50 determined by chiral HPLC: Chiralpak AD-H, 25 ºC, flow rate: 1 mL/min, hexane/i-PrOH: 51 60:40, 254 nm, 8.6 min (S), 9.3 min (R). The absolute configuration was assigned by analogy 52 53 with compounds shown in the literature.47 The authentic racemic mixture to determine the 54 55 enantiomeric ratio by HPLC (see the traces in SI) was obtained with similar yield, using 56 57 58 59 60 ACS Paragon Plus Environment Page 29 of 37 The Journal of Organic Chemistry
1 2 3 almost identical conditions, but in the absence of phosphine ligands. The spectral data 4 5 matched that reported:48 6 1 3 TLC (hexane/EtOAc 70:30) Rf 0.24; H-NMR (400 7 2 4 8 4a 1 5 MHz, CDCl3) δ 7.99 (ddd, J = 8.9, 7.4, 4.6 Hz, 1H), 7.90 9 10b O O 6 OPh PhO 10 10a 6a P P 10 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 (ddd, J = 16.0, 7.4, 2.8 Hz, O O 11 7 9 12 8 (R)-8 (S)-8 1H), 7.48 – 7.38 (m, 2H), 7.34 – 7.21 (m, 4H), 7.18 – 7.12 F F 13 13 14 (m, 1H), 7.04 (dt, J = 8.4, 1.3 Hz, 2H) ppm; C-NMR 15 1 1 3 8 2 { H} (101 MHz, CDCl3) δ 162.1 (dd, JC-F = 252.8, JC-P = 22.3 Hz, C -F), 149.6 (2xd, JC-P 16 1’ 4a 2 4 10a 3 3’ 17 = 7.8 Hz, C and C ), 133.5 (dd, JC-P = 6.4, JC-F 3.4 Hz, C ), 130.7 (C -H), 129.9 (2xC - 18 3 3 10 1 2 4’ 19 H), 126.9 (dd, JC-P = 14.6, JC-F 7.6 Hz, C -H), 125.6 (C -H), 125.33 (C -H), 125.29 (C - 20 H), 123.8 (dd, 1J = 182.6, 3J = 6.8 Hz, C6a), 122.1 (d, 3J = 11.8 Hz, C10b), 121.6 (dd, 21 C-P C-F C-P 22 2 4 9 3 2’ 3 JC-F = 22.0, JC-P = 3.0 Hz, C -H), 120.7 (d, JC-P = 4.4 Hz, 2xC -H), 120.4 (d, JC-P = 7.1 23 4 2 2 7 31 24 Hz, C -H), 117.4 (dd, JC-F = 23.1, JC-P = 9.9 Hz, C -H) ppm; P-NMR (162 MHz, CDCl3) 25 4 + 26 δ 5.04 (d, JP-F = 8.0 Hz); LRMS (EI) m/z (%) 326 (M , 78), 233 (100), 186 (45); HRMS (EI- 27 TOF) m/z calculated for C H FO P 326.0508, found 326.0511. 28 18 12 3 29 30 Supporting Information 31 32 The Supporting Information is available free of charge on the ACS Publications website. 33 GC-calibrations, mechanistic experiments, gram-scale preparations, HPLC traces of chiral 34 35 compound 8, and spectroscopy data (PDF). 36 37 AUTHOR INFORMATION 38 39 40 Corresponding Author 41 42 * E-mail: [email protected] 43 44 Author Contributions 45 46 †These authors contributed equally. 47 48 Notes 49 The authors declare no competing financial interest. 50 51 52 ACKNOWLEDGMENT 53 54 This work was generously supported by the Spanish Ministerio de Ciencia, Innovación y 55 Universidades (MICIU; grant no. CTQ2017-88171-P) and the University of Alicante (grant 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 30 of 37
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