Catalytic Deprotonative Î±-Formylation of Heteroarenes by an Amide

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Catalytic Deprotonative α‑Formylation of Heteroarenes by an Amide Base Generated in Situ from Tetramethylammonium Fluoride and Tris(trimethylsilyl)amine Masanori Shigeno,* Yuki Fujii, Akihisa Kajima, Kanako Nozawa-Kumada, and Yoshinori Kondo* Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan

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ABSTRACT: Heteroarene formylations in DMF solution proceed in the presence of an amide base catalyst generated in situ from tetramethylammonium fluoride (TMAF) and tris(trimethylsilyl)amine (N(TMS)3). The reaction proceeds at room temperature and has an operationally simple procedure. Various heteroarenes, including benzothiophene, thiophene, benzothiazole, oxazole, and indole derivatives, can be formylated with high functional group tolerance. KEYWORDS: formylation, room-temperature deprotonation, amide base catalyst, anions, heteroarenes

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INTRODUCTION Heteroarenes are ubiquitous in natural products, biologically active compounds, and organic functional materials. The ability to directly and efficiently functionalize heteroarenes is crucial for the construction of complex molecules bearing heteroarene scaffolds and for rapid access to diverse molecules.1 Heteroarene formylation is of great importance in synthetic organic chemistry because the introduced formyl group serves as a core motif that can be transformed into a variety of units by olefination, oxidation, reduction, and aldol reactions, among others.2 Deprotonative formylation, which involves a two-step procedure, namely, deprotonation of the acidic proton of the heteroarene and subsequent coupling with a formylating agent, is a representative and reliable method in this regard. In the deprotonation step, a stoichiometric amount of a strong base, such as n-BuLi, lithium diisopropylamide (LDA), or lithium 2,2,6,6-tetramethylpiperidide (LiTMP), is used.3 It is also noteworthy that these steps involve cryogenic conditions (−78 °C) that prevent a rise in the temperature of the reaction mixture because of the exothermic nature of the deprotonation step as well as side reactions involving the nucleophilic carbanion. Such conditions are of particular importance in reactions of nucleophiles bearing electrophilic moieties. Hence, the development of deprotonative heteroarene formylation methodology that is highly functional-grouptolerant under ambient conditions is a very attractive objective. A few deprotonative methods have been used to formylate heteroarenes in the presence of electron-withdrawing substituents at almost-ambient temperatures (Figure 1A). In pioneering work, Mulzer studied the formylation of pyridines bearing amide and carbamate groups at 0 °C and room temperature, respectively, using (2,2,6,6-tetramethylpiperidino)magnesium chloride (TMPMgCl).4 We also reported the formylation of ethyl thiophene-2-carboxylate at room temperature in the presence of i-Pr2NMgCl.5 Recently, Knochel developed a flow procedure that uses TMPMgCl·LiCl at room temperature for the formylation of bromo- and chloro© XXXX American Chemical Society

substituted pyridines as well as thiophenes possessing chlorines and ethoxycarbonyl groups.6 Zhao formylated bromo-substituted furan, benzofuran, thiophene, and benzothiophene at 0 °C using sodium bis(trimethylsilyl)amide (NaHMDS).7 Our group has been engaged in the development of heteroarene deprotonative functionalization methodology using amide base catalysts generated in situ from fluoride or alkoxide salts and aminosilanes.8 Heteroarenes, such as benzothiazole, benzoxazole, triazole, benzothiophene, and benzofuran derivatives, have been coupled with aldehyde and ketone moieties.8a,b Herein we report that heteroarene formylation proceeds in DMF using the above-mentioned catalytic system at room temperature in an operationally simple one-pot procedure in which a solution of the heteroarene in DMF is stirred with a catalytic amount of tetramethylammonium fluoride (TMAF) and a stoichiometric amount of tris(trimethylsilyl)amine (N(TMS)3) (Figure 1B). In other words, this reaction necessitates neither the conventional two-step protocol involving the dropwise addition of reagents nor cryogenic conditions.9 A variety of heteroarenes bearing functional groups, including methoxy, pyridyl, halo, ethoxycarbonyl, (methylphenylamino)carbonyl, and cyano groups can be employed, the details of which are reported below.

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RESULTS AND DISCUSSION A variety of fluoride and alkoxide sources were used to investigate the formylation of benzothiophene (1a) (pKa = 32.0 at the 2-position10) in DMF (Table 1). A solution of 1a (0.20 mmol) in DMF (0.50 mL) was stirred for 24 h at room temperature in the presence of a salt (0.02 mmol) and N(TMS)3 (0.40 mmol). The reaction was then quenched with 1 M HCl. A standard extractive workup provided the crude Special Issue: Japanese Society for Process Chemistry Received: September 3, 2018 Published: October 29, 2018 A

DOI: 10.1021/acs.oprd.8b00247 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Table 1. Optimization of the Formylation Conditions for 1aa

entry

fluoride or alkoxide salt

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

KF RbF CsF NaOMe NaO-t-Bu NaOPh KOMe KO-t-Bu TBAFc TMAF TMAF TMAF TMAF none TMAF

0 13 84 84 76 35 91 90 55 97 (93d) 88e 85f 81g 0h 0i

a

Reactions were conducted on a 0.2 mmol scale. bYields were determined by 1H NMR spectroscopy. cA 1 M solution of TBAF in THF was used. dIsolated yield. eThe reaction time was 6 h. fThe reaction was conducted on a 1.0 mmol scale with TMAF (3 mol %). g The reaction was conducted with DMF (46 μL). hThe reaction was attempted in the absence of fluoride or alkoxide salt. iThe reaction was attempted in the absence of N(TMS)3.

Figure 1. Formylations of heteroarenes possessing electrophilic moieties under almost-ambient conditions.

material, from which the yield of the formylated product 3a was determined by NMR spectroscopy. Among alkali-metal fluoride salts, formylation proceeded smoothly with CsF to afford 3a in 84% yield (entries 1−3). Sodium alkoxide and phenoxide salts, namely, NaOMe, NaO-t-Bu, and NaOPh, furnished 3a in yields of 84, 76, and 35%, respectively (entries 4−6). The potassium alkoxide salts KOMe and KO-t-Bu provided 3a in high yields of 91 and 90%, respectively (entries 7 and 8). Ammonium salts were next examined; TMAF was the most effective, affording 3a in 93% isolated yield (entries 9 and 10). Satisfactory product yields of 88, 85, and 81%, respectively, were obtained even when the reaction was conducted for a shorter time (6 h) or with a smaller amount of TMAF (3 mol %) or DMF (46 μL, 0.60 mmol) (entries 11−13). 3a was not obtained in the absence of either TMAF or N(TMS)3 (entries 14 and 15). The optimized conditions were used to formylate a variety of benzothiophenes (Figure 2). Formylated products 3b and 3c bearing electron-donating methyl and methoxy groups were obtained in yields of 88 and 83%, respectively, while 5chlorobenzothiophene (1d) afforded the corresponding product 3d in 86% yield. Benzothiophenes 1e and 1f bearing bromine atoms at the 5- and 3-positions, respectively, afforded 3e and 3f in good yields when CsF was used as the fluoride source.

Figure 2. Formylations of benzothiophenes catalyzed by the TMAF/ N(TMS)3 amide-base system. Notes: aReactions were conducted on a 0.20 mmol scale. bIsolated yields are shown. cDMF (2 mL) was used. d CsF (30 mol %) and N(TMS)3 (3 equiv) were used. eCsF (10 mol %) was used instead of TMAF.

Heteroarenes other than benzothiophenes were also used in the present formylation system (Figure 3). Thiophenes 4a−e bearing aryl groups at their 2-positions were employed; clearly halogens as well as methoxy and cyano functional groups were tolerated. 2-(2-Pyridyl)thiophene (4f) bearing a pyridyl group at the 2-position of the thiophene ring provided product 5f in 67% yield. Notably, ester and amide moieties on the thiophene ring were also tolerated, as the corresponding products 5g and 5h were obtained. The formylations of benzothiazole (4i) (pKa = 27.3 at the 2-position10) and its derivatives 4j−l possessing B



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alkali-metal alkoxides, namely, NaOMe, NaO-t-Bu, KOMe, and KO-t-Bu, were used in the one-step protocol involving 1a at room temperature, which afforded low yields of 3a (Table 2). On the other hand, catalytic amounts of a variety of Table 2. Reactions of 1a with Alkali-Metal Bis(trimethylsilyl)amides and Alkali-Metal Alkoxidesa

entry

base

yield of 3a (%)b

recovery of 1a (%)b

1 2 3 4 5 6

NaHMDS KHMDS NaOMe NaO-t-Bu KOMe KO-t-Bu

13 15 0 0 0 3

39 32 86 81 81 63

a

Reactions were conducted on a 0.2 mmol scale. determined by 1H NMR analysis.

b

Yields were

alkoxide and fluoride salts, including NaOMe, NaO-t-Bu, KOMe, KO-t-Bu, CsF, and TMAF, provided 3a in good yields when used with N(TMS)3 (Table 1). It should also be noted that when catalytic amounts of NaHMDS and KHMDS was used in the reaction of 1a with a stoichiometric amount of N(TMS)3, 3a was obtained in 71% and 82% yield, respectively (Scheme 2). On the basis of these results, we conclude that the current system is driven by the formation of strong O−Si bonds, as shown in Figures 4 and S1.

Figure 3. Formylations of heteroarenes other than benzothiophenes by amide base catalysis using TMAF and N(TMS)3. Notes: aReactions were conducted on a 0.20 mmol scale. bIsolated yield. cTMAF (20 mol %) and N(TMS)3 (3 equiv) were used. dDMF (1.0 mL) was used. eCsF (10 mol %) was used instead of TMAF. f DMF (3.0 mL) was used. gDMF (2.0 mL) was used.

methyl, methoxy, and fluoro groups proceeded, furnishing 5i−l in good yields. The reaction could be extended to include 2phenyloxazole (4m), which gave 5m in 90% yield, while 3cyano-N-methylindole (4n) afforded 5n in 88% yield. The scalable nature of the present formylation was demonstrated on a 2.7 g (20 mmol) scale of 1a, which afforded 2.4 g of 3a in 74% yield (Scheme 1, eq 1). As a related

Scheme 2. Reaction of 1a with a Catalytic Amount of NaHMDS or KHMDS and a Stoichiometric Amount of N(TMS)3

Scheme 1. Scale-Up of the Formylation of 1a and Our Previously Reported Deprotonative Coupling of 4i with 6 a

Yields were determined by 1H NMR analysis.

2-Deuteriobenzothiophene (1a-d) was subjected to our reaction conditions using TMAF (10 mol %), N(TMS)3 (10 mol %), and HMDS (2 equiv) and afforded a trace amount of 3a and an 85% yield of 1a (78% H incorporation at the 2position) (Scheme 3), which reveals that 1a is reversibly deprotonated and again emphasizes that the strong O−Si bond formation involved in the current system (Figures 4 and S1) plays an important role for the reaction to proceed. A plausible formylation mechanism is presented in Figure 4. Amide base A, generated from TMAF and N(TMS)3, abstracts the acidic proton at the 2-position of 1a.11 The resulting carbanion B couples with DMF to form alkoxide intermediate C, which then reacts with N(TMS)3 to provide silylated product D, regenerating A (path a). As an alternative pathway, silicate species E, formed by coordination of C to a silicon atom of N(TMS)3, directly deprotonates 1a to give B and D

study, the scale-up of our previously reported deprotonative coupling of 4i with pivalaldehyde (6)8b was also herein performed on a 1.6 g scale (12 mmol) to produce 2.0 g of 7 in 74% yield (Scheme 1, eq 2). For comparison with the present catalytic amide base system, stoichiometric amounts of alkali-metal bis(trimethylsilyl)amides, namely, NaHMDS and KHMDS, and C



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centimeters. NMR data were recorded on a JEOL AL400 spectrometer (395.75 MHz for 1H and 99.50 MHz for 13C). Chemical shifts (δ) are expressed in parts per million, and coupling constants are expressed in hertz. 1H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl3, 7.26 ppm). 13C NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl3, 77.0 ppm). Low- and high-resolution mass spectrometry (LRMS and HRMS, respectively) were performed by the Mass Spectrometry Resource, Graduate School of Pharmaceutical Sciences, Tohoku University, on JEOL JMS-DX 303 and JMS-700/JMS-T 100 GC mass spectrometers, respectively. Materials. 1c,13 1d,14 4a,15 4b,15 4c,16 4d,15 4e,16 4f,17 4h,18 4j,19 4k,19 4l,20 4m,21 4n,22 and 1a-d23 were prepared according to the literature procedures. DMF was distilled over CaH2 under reduced pressure. All of the other commercially available chemical resources were used as received without further purification. Representative Procedure for Catalytic Deprotonative Formylation of Heteroarenes by an Amide Base Generated in Situ from TMAF and N(TMS)3 (Table 1, Entry 10). In a glovebox under an Ar atmosphere, 1a (26.8 mg, 0.20 mmol) was added to a mixture of TMAF (1.8 mg, 0.019 mmol) and N(TMS)3 (91.2 mg, 0.39 mmol) in DMF (0.5 mL) in an oven-dried vial equipped with a stir bar. The vial was sealed with a cap containing an inner Teflon film. After 24 h of stirring at room temperature, 1 M HCl aqueous solution (0.5 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1.5 h, and H2O (10 mL) was added. The mixture was extracted with AcOEt (10 mL × 3), washed with H2O (10 mL × 2) and brine (10 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (5:1 hexane/ AcOEt) to afford 3a as a yellow solid. Benzo[b]thiophene-2-carboxaldehyde (3a). Yield: 30.2 mg, 0.186 mmol, 93%. Mp: 34−35 °C (AcOEt/hexane) (lit. 34−35 °C;24a 33−35 °C24b). 1H NMR (400 MHz, CDCl3/ TMS): δ 7.42 (t, 1H, J = 7.9 Hz), 7.48 (t, 1H, J = 7.6 Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.99 (s, 1H), 10.08 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 123.2, 125.2, 126.2, 128.1, 134.4, 138.5, 142.6, 143.3, 184.6. LRMS (EI) m/ z: 162 (M+). HRMS: calcd for C9H6OS, 162.0139; found, 162.0111. IR (neat): 1666, 1513, 1425, 1320, 1255, 1133, 988, 876, 846, 759, 726 cm−1. The spectral data matched those reported in the literature.24 5-Methylbenzo[b]thiophene-2-carboxaldehyde (3b). According to a procedure analogous to that described for 3a, 3b (32.1 mg, 0.182 mmol, 88%) was obtained from 1b (30.6 mg, 0.206 mmol) as a white solid. Mp: 100−101 °C (AcOEt/ hexane) (lit. 94.5−95 °C25). 1H NMR (400 MHz, CDCl3/

Figure 4. Plausible reaction mechanism.

(path b).11 Finally, D is desilylated upon quenching with 1 M HCl to afford the formylated product 3a.12

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CONCLUSIONS We developed a catalytic heteroarene formylation system that involves the amide base generated in situ from TMAF and N(TMS)3; the reaction proceeds at room temperature and has a convenient protocol. It should be noted that the present system, which uses a catalytic amount of a salt and a stoichiometric amount of an aminosilane, facilitates this transformation more effectively than stoichiometric amounts of a bis(trimethylsilyl)amide and an alkoxide base. Heteroarenes, such as benzothiophene, thiophene, oxazole, benzofuran, and indole derivatives, can be formylated using this protocol. The reaction is also compatible with heteroarenes bearing a variety of functionalities, including methoxy, ester, amide, nitrile, halogen, and pyridyl groups.

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EXPERIMENTAL SECTION General Information. All of the reactions were carried out under a N2 or Ar atmosphere. Flash column chromatography was performed with Kanto Silicagel 60N (spherical, neutral, 70−230 μm). Preparative thin-layer chromatography was performed with silica gel (Wakogel B-5F). Melting points (Mp) were determined with a Yazawa micro melting point apparatus without correction. Infrared data were recorded on a SensIR attenuated total reflectance (ATR) FT-IR spectrometer, and absorbance peak positions are reported in reciprocal

Scheme 3. Reaction of 1a-d with Catalytic Amounts of TMAF and N(TMS)3 and a Stoichiometric Amount of NH(TMS)2

a

Yields were determined by 1H NMR analysis. D



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(AcOEt/hexane) (lit. 118−19 °C;28a 116−117 °C28b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.49−7.61 (m, 2H), 7.86 (d, 1H, J = 7.8 Hz), 8.00 (d, 1H, J = 8.1 Hz), 10.27 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 118.8, 123.4, 125.0, 126.0, 129.3, 136.5, 138.0, 140.4, 184.7. LRMS (EI) m/z: 240 (M+). HRMS: calcd for C9H5BrOS, 239.9244; found, 239.9236. IR (neat): 1662, 1501, 1304, 1248, 1196, 919, 809, 759 cm−1. The spectral data matched those reported in the literature.28 5-Phenylthiophene-2-carboxaldehyde (5a). According to a procedure analogous to that described for 3a, 5a (30.0 mg, 0.159 mmol, 77%) was obtained from 4a (33.2 mg, 0.207 mmol) as a pale-yellow solid. Mp: 95−96 °C (AcOEt/hexane) (lit. 92−93 °C;29a 94.6−95.1 °C29b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.33−7.50 (m, 4H), 7.63−7.70 (m, 2H), 7.72 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 124.1, 126.4, 129.2, 129.4, 133.0, 137.4, 142.4, 154.2, 182.8. LRMS (EI) m/z: 188 (M+). HRMS: calcd for C11H8OS, 188.0296; found, 188.0287. IR (neat): 1662, 1501, 1304, 1248, 1196, 919, 809, 759 cm−1. The spectral data matched those reported in the literature.29 5-(4-Fluorophenyl)thiophene-2-carboxaldehyde (5b). According to a procedure analogous to that described for 3a, 5b (36.4 mg, 0.176 mmol, 86%) was obtained from 4b (36.4 mg, 0.204 mmol) as a pale-yellow solid. Mp: 114−115 °C (AcOEt/ hexane) (lit. 103−105 °C;30a 114−116 °C30b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.05−7.20 (m, 2H), 7.33 (d, 1H, J = 3.9 Hz), 7.58−7.69 (m, 2H), 7.73 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 116.3 (d, JF = 22.2 Hz), 124.0 (d, JF = 1.7 Hz), 128.2 (d, JF = 8.2 Hz), 129.3, 137.4, 142.5, 153.0, 163.4 (d, JF = 249.5 Hz), 182.7. LRMS (EI) m/z: 206 (M+). HRMS: calcd for C11H7FOS, 206.0193; found, 206.0202. IR (neat): 1635, 1611, 1506, 1442, 1437, 1386, 1232, 1162, 1058, 833, 808 cm−1. The spectral data matched those reported in the literature.30 5-(4-Chlorophenyl)thiophene-2-carboxaldehyde (5c). According to a procedure analogous to that described for 3a, 5c (41.2 mg, 0.185 mmol, 93%) was obtained from 4c (38.8 mg, 0.199 mmol) as a white solid. Mp: 83−84 °C (AcOEt/hexane) (lit. 74−76 °C;30a 88−89 °C31). 1H NMR (400 MHz, CDCl3/ TMS): δ 7.33−7.48 (m, 3H), 7.55−7.67 (m, 2H), 7.73 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 124.3, 127.5, 129.4, 131.5, 135.4, 137.3, 142.7, 152.6, 182.7. LRMS (EI) m/z: 222 (M+). HRMS: calcd for C11H7ClOS, 221.9906; found, 221.9898. IR (neat): 1653, 1530, 1445, 1402, 1223, 1093, 1057, 1008, 824, 799 cm−1. The spectral data matched those reported in the literature.30a 5-(4-Methoxyphenyl)thiophene-2-carboxaldehyde (5d). According to a procedure analogous to that described for 3d, except that the reaction was conducted with TMAF (3.7 mg, 0.040 mmol) and N(TMS)3 (141.9 mg, 0.608 mmol) in DMF (1.0 mL) for 24 h and the crude material was purified by column chromatography on silica gel (10:1 hexane/AcOEt), 5d (28.0 mg, 0.128 mmol, 63%) was obtained from 4d (39.0 mg, 0.205 mmol) as a pale-yellow solid. Mp: 120−121 °C (AcOEt/hexane) (lit. 120−121 °C;30b 110−111 °C32). 1H NMR (400 MHz, CDCl3/TMS): δ 3.86 (s, 3H), 6.95 (d, 2H, J = 8.8 Hz), 7.30 (d, 1H, J = 4.4 Hz), 7.55−7.63 (m, 2H), 7.71 (d, 1H, J = 3.9 Hz), 9.86 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 55.4, 114.6, 123.0, 125.8, 127.8, 137.7, 141.5, 154.5, 160.7, 182.7. LRMS (EI) m/z: 218 (M+). HRMS: calcd for C12H10O2S, 218.0402; found, 218.0396. IR (neat): 1647, 1602, 1507, 1449, 1436, 1256, 1223, 1181, 1056, 1024, 833, 802

TMS): δ 2.48 (s, 3H), 7.33 (d, 1H, J = 8.3 Hz), 7.72 (s, 1H), 7.77 (d, 1H, J = 8.3 Hz), 7.94 (s, 1H), 10.08 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 21.3, 122.9, 125.9, 130.1, 134.1, 135.1, 138.9, 140.0, 143.5, 184.7. LRMS (EI) m/z: 176 (M+). HRMS: calcd for C10H8OS, 176.0296; found, 176.0301. IR (neat): 1669, 1559, 1520, 1441, 1257, 1231, 1155 1132, 895, 850, 774, 718 cm−1. 4-Methoxybenzo[b]thiophene-2-carboxaldehyde (3c). According to a procedure analogous to that described for 3a, 3c (30.9 mg, 0.161 mmol, 83%) was obtained from 1c (31.8 mg, 0.194 mmol) as a white solid. Mp: 97−98 °C (AcOEt/hexane) (lit. 96−97 °C26). 1H NMR (400 MHz, CDCl3/TMS): δ 3.90 (s, 3H), 7.04 (dd, 1H, J = 9.2 Hz, J = 2.4 Hz), 7.30 (d, 1H, J = 2.0 Hz), 7.79 (d, 1H, J = 8.8 Hz), 7.92 (s, 1H), 10.01 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 55.6, 104.5, 116.4, 127.1, 132.5, 134.6, 141.0, 145.1, 160.4, 184.1. LRMS (EI) m/z: 192 (M+). HRMS: calcd for C10H8O2S, 192.0245; found, 192.0238. IR (neat): 1662, 1600, 1512, 1265, 1217, 1139, 1010, 834, 722 cm−1. 5-Chlorobenzo[b]thiophene-2-carboxaldehyde (3d). In a glovebox under an Ar atmosphere, TMAF (2.0 mg, 0.021 mmol) was added to a mixture of 1d (34.6 mg, 0.205 mmol) and N(TMS)3 (96.2 mg, 0.412 mmol) in DMF (2.0 mL) in an oven-dried vial equipped with a stir bar. The vial was sealed with a cap containing an inner Teflon film. After 21 h of stirring at room temperature, 1 M HCl aqueous solution (0.5 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1.5 h, and H2O (10 mL) was added. The mixture was extracted with AcOEt (10 mL × 3), washed with H2O (10 mL × 2) and brine (10 mL), dried over MgSO4, and concentrated. The residue was purified by preparative thin-layer chromatography of silica gel (5:1 hexane/AcOEt) to afford 3d (34.5 mg, 0.175 mmol, 86%) as a yellow solid. Mp: 136−139 °C (AcOEt/hexane) (lit. 134− 135 °C;27a 135 °C27b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.46 (dd, 1H, J = 8.8 Hz, J = 2.0 Hz), 7.83 (d, 1H, J = 8.8 Hz), 7.92 (d, 1H, J = 2.0 Hz), 7.96 (s, 1H), 10.11 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 124.4, 125.5, 128.6, 131.6, 133.1, 139.6, 140.6, 145.0, 184.4. LRMS (EI) m/z: 196 (M+). HRMS: calcd for C9H5ClOS, 196.9750; found, 196.9724. IR (neat): 1674, 1514, 1425, 1251, 1134, 1077, 905, 870, 799, 714 cm−1. The spectral data matched those reported in the literature.27 5-Bromobenzo[b]thiophene-2-carboxaldehyde (3e). According to a procedure analogous to that described for 3d, except that the reaction was conducted with CsF (9.4 mg, 0.062 mmol) and N(TMS)3 (139.6 mg, 0.598 mmol) in DMF (2.0 mL) for 19 h and the crude material was purified by column chromatography on silica gel (10:1 hexane/AcOEt), 3e (39.8 mg, 0.165 mmol, 79%) was obtained from 1e (44.6 mg, 0.209 mmol) as a white solid. Mp: 129−130 °C (AcOEt/ hexane). 1H NMR (400 MHz, CDCl3/TMS): δ 7.59 (dd, 1H, J = 8.8 Hz, J = 1.9 Hz), 7.76 (d, 1H, J = 8.8 Hz), 7.95 (s, 1H), 8.08 (d, 1H, J = 1.4 Hz), 10.1 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 119.2, 124.6, 128.6, 131.1, 132.9, 140.0, 141.1, 144.8, 184.3. LRMS (EI) m/z: 240 (M+). HRMS: calcd for C9H5BrOS, 239.9244; found, 239.9221. IR (neat): 1668, 1548, 1511, 1423, 1275, 1216, 1134, 1064, 881, 808, 710 cm−1. 3-Bromobenzo[b]thiophene-2-carboxaldehyde (3f). According to a procedure analogous to that described for 3a, except that CsF (3.3 mg, 0.022 mmol) was used instead of TMAF, 3f (35.7 mg, 0.148 mmol, 74%) was obtained from 1f (42.6 mg, 0.200 mmol) as a yellow solid. Mp: 121−122 °C E



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cm−1. The spectral data matched those reported in the literature.30b,32 5-(4-Cyanophenyl)thiophene-2-carboxaldehyde (5e). According to a procedure analogous to that described for 3a, except that CsF (4.1 mg, 0.027 mmol) was used instead of TMAF, 5e (26.9 mg, 0.126 mmol, 62%) was obtained from 4e (37.9 mg, 0.205 mmol) as a red solid. Mp: 197−198 °C (AcOEt/hexane) (lit. 166−176 °C;30b 208−210 °C (decomposition)33). 1H NMR (400 MHz, CDCl3/TMS): δ 7.50 (d, 1H, J = 3.9 Hz), 7.67−7.81 (m, 5H), 9.94 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 112.6, 118.3, 125.8, 126.8, 133.0, 137.0, 137.2, 144.1, 151.0, 182.7. LRMS (EI) m/z: 213 (M+). HRMS: calcd for C12H7NOS, 213.0248; found, 213.0244. IR (neat): 2220, 1666, 1604, 1450, 1413, 1227, 1181, 1063, 839, 802 cm−1. The spectral data matched those reported in the literature.30b 2-(Pyridin-2-yl)thiophene-5-carbaldehyde (5f). According to a procedure analogous to that described for 3a, 5f (25.4 mg, 0.134 mmol, 67%) was obtained from 4f (32.2 mg, 0.200 mmol) as a white solid. Mp: 125−126 °C (AcOEt/hexane) (lit. 122−123 °C;34a 119−120 °C34b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.25−7.30 (m, 1H), 7.64−7.68 (m, 1H), 7.70−7.81 (m, 3H), 8.63 (d, 1H, J = 3.9 Hz), 9.93 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 119.7, 123.6, 125.0, 136.8, 136.9, 144.1, 149.9, 151.1, 153.9, 183.1. LRMS (EI) m/z: 189 (M+). HRMS: calcd for C10H7NOS, 189.0248; found, 189.0273. IR (neat): 1646, 1581, 1528, 1447, 1230, 1157, 993, 819, 779 cm−1. The spectral data matched those reported in the literature.34 Ethyl 5-Formylthiophene-2-carboxylate (5g). According to a procedure analogous to that described for 3a, except that the reaction was conducted in DMF (3.0 mL), 5g (25.6 mg, 0.139 mmol, 63%) was obtained from 4g (34.6 mg, 0.222 mmol) as a white solid. Mp: 57−58 °C (AcOEt/hexane) (lit. 57−58 °C;5 56.9−58.6 °C6). 1H NMR (400 MHz, CDCl3/TMS): δ 1.40 (t, 3H, J = 7.3 Hz), 4.40 (q, 2H, J = 7.2 Hz), 7.73 (d, 1H, J = 3.9 Hz), 7.83 (d, 1H, J = 3.9 Hz), 9.97 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 14.2, 62.0, 133.1, 135.0, 141.5, 147.6, 161.5, 183.3. LRMS (EI) m/z: 184 (M+). HRMS: calcd for C8H8NO3S, 184.0194; found, 184.0196. IR (neat): 1696, 1665, 1525, 1364, 1280, 1194, 1093, 1040, 1010, 822, 750 cm−1. The spectral data matched those reported in the literature.5,6 5-((N-Methyl-N-phenylamino)carbonyl)thiophene-2-carboxaldehyde (5h). According to a procedure analogous to that described for 3a, except that the reaction was conducted in DMF (1.0 mL), 5h (43.4 mg, 0.177 mmol, 86%) was obtained from 4h (44.7 mg, 0.206 mmol) as a white solid. Mp: 104−105 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS): δ 3.47 (s, 3H), 6.92 (d, 1H, J = 2.3 Hz), 7.23 (d, 2H, J = 5.0 Hz), 7.38−7.46 (m, 4H), 9.81 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 39.1, 127.8, 128.7, 130.0, 132.2, 134.3, 143.4, 145.9, 161.8, 183.3. LRMS (EI) m/z: 245 (M+). HRMS: calcd for C13H11NO2S, 245.0510; found, 245.0498. IR (neat): 1673, 1616, 1586, 1491, 1374, 1215, 1070, 828, 703 cm−1. Benzo[d]thiazole-2-carboxaldehyde (5i). According to a procedure analogous to that described for 3d, except that the reaction was conducted in DMF (3.0 mL) for 19 h and the crude material was purified by column chromatography on silica gel (6:1 hexane/AcOEt), 5i (22.2 mg, 0.136 mmol, 67%) was obtained from 4i (27.4 mg, 0.203 mmol) as a yellow solid. Mp: 72−73 °C (AcOEt/hexane) (lit. 75−76 °C35a). 1H NMR (400 MHz, CDCl3/TMS): δ 7.55−7.66 (m, 2H), 7.97−8.05

(m, 1H), 8.22−8.27 (m, 1H), 10.17 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 122.6, 125.8, 127.4, 128.4, 136.4, 153.5, 165.3, 185.4. LRMS (EI) m/z: 163 (M+). HRMS: calcd for C8H5NOS, 163.0092; found, 163.0083. IR (neat): 1693, 1486, 1323, 1204, 1122, 1061, 954, 865, 772, 736 cm−1. The spectral data matched those reported in the literature.35b,c 6-Methylbenzo[d]thiazole-2-carbaldehyde (5j). According to a procedure analogous to that described for 3a, except that the reaction was conducted in DMF (1.0 mL), 5j (26.4 mg, 0.149 mmol, 74%) was obtained from 4j (30.1 mg, 0.202 mmol) as a yellow solid. Mp: 79−80 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS): δ 2.54 (s, 3H), 7.42 (dd, 1H, J = 8.3 Hz, J = 1.5 Hz), 7.78 (s, 1H), 8.11 (d, 1H, J = 8.8 Hz), 10.14 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 21.9, 122.1, 125.2, 129.3, 136.7, 139.3, 151.8, 164.4, 185.5. LRMS (EI) m/ z: 177 (M+). HRMS: calcd for C9H7NOS, 177.0248; found, 177.0234. IR (neat): 1684, 1489, 1318, 1223, 1187, 1131, 1037, 897, 812, 737 cm−1. 6-Methoxybenzo[d]thiazole-2-carbaldehyde (5k). According to a procedure analogous to that described for 3a, except that the reaction was conducted in DMF (1.0 mL), 5k (31.8 mg, 0.165 mmol, 83%) was obtained from 4k (32.7 mg, 0.198 mmol) as a yellow solid. Mp: 124−125 °C (AcOEt/hexane). 1 H NMR (400 MHz, CDCl3/TMS): δ 3.93 (s, 3H), 7.21 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.38 (d, 1H, J = 2.4 Hz), 8.10 (d, 1H, J = 8.8 Hz), 10.10 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 55.9, 103.6, 118.2, 126.5, 138.6, 148.2, 160.3, 162.9, 185.1. LRMS (EI) m/z: 193 (M+). HRMS: calcd for C9H7NO2S, 193.0197; found, 193.0191. IR (neat): 1683, 1601, 1492, 1452, 1273, 1196, 1118, 1014, 826, 734 cm−1. The spectral data matched those reported in the literature.36 6-Fluorobenzo[d]thiazole-2-carbaldehyde (5l). According to a procedure analogous to that described for 3d, except that the reaction was conducted for 20 h and the crude material was purified by column chromatography on silica gel (1:5 hexane/ CH2Cl2), 5l (24.8 mg, 0.137 mmol, 68%) was obtained from 4l (30.9 mg, 0.202 mmol) as a yellow solid. Mp: 109−110 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS): δ 7.37 (dt, 1H, J = 2.4 Hz, J = 9.0 Hz), 7.68 (dd, 1H, J = 7.8 Hz, J = 2.4 Hz), 8.22 (dd, 1H, J = 9.3 Hz, J = 4.9 Hz), 10.13 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 108.6 (d, JF = 26.3 Hz), 116.9 (d, JF = 24.7 Hz), 127.2 (d, JF = 9.9 Hz), 137.73 (d, JF = 11.5 Hz), 150.2, 162.3 (d, JF = 250 Hz), 165.2 (d, JF = 3.3 Hz), 184.9. LRMS (EI) m/z: 181 (M+). HRMS: calcd for C8H4FNOS, 180.9998; found, 181.0000. IR (neat): 1689, 1599, 1490, 1326, 1247, 1183, 1128, 866, 817, 738 cm−1. 2-Phenyloxazole-5-carboxaldehyde (5m). According to a procedure analogous to that described for 3a, except that the reaction was conducted in DMF (2.0 mL), 5m (31.5 mg, 0.182 mmol, 90%) was obtained from 4m (29.3 mg, 0.202 mmol) as a white solid. Mp: 68−69 °C (AcOEt/hexane) (lit. 74−76 °C;37a 69−70 °C37b). 1H NMR (400 MHz, CDCl3/TMS): δ 7.48−7.60 (m, 3H), 7.96 (s, 1H), 8.17−8.22 (m, 2H), 9.83 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 125.8, 127.7, 129.1, 132.3, 139.1, 149.6, 165.5, 176.3. LRMS (EI) m/z: 173 (M+). HRMS: calcd for C9H7NOS, 173.0477; found, 173.0468. IR (neat): 1665, 1529, 1475, 1450, 1347, 1234, 1144, 981, 883, 714 cm−1. The spectral data matched those reported in the literature.37 2-Formyl-1-methyl-1H-indole-3-carbonitrile (5n). According to a procedure analogous to that described for 3a, except that CsF (2.9 mg, 0.019 mmol) was used instead of TMAF, 5n (32.2 mg, 0.175 mmol, 88%) was obtained from 4n (31.0 mg, F



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0.198 mmol) as a white solid. Mp: 142−144 °C (AcOEt/ hexane). 1H NMR (400 MHz, CDCl3/TMS): δ 4.14 (s, 3H), 7.37 (t, 1H, J = 6.8 Hz), 7.45−7.59 (m, 2H), 7.83 (d, 1H, J = 8.3 Hz), 10.15 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 32.2, 97.0, 111.2, 113.4, 121.3, 123.7, 126.7, 128.3, 137.5, 138.9, 180.6. LRMS (EI) m/z: 184 (M+). HRMS: calcd for C11H8N2O: 184.0637; found, 184.0655. IR (neat): 1678, 1513, 1477, 1405, 1202, 1130, 892, 876, 749 cm−1. Scale-Up of the Formylation of 1a and Our Previously Reported Deprotonative Coupling of 4i with 6 (Scheme 1.). Scale-Up of the Formylation of 1a (Scheme 1, Equation 1). In a glovebox under an Ar atmosphere, TMAF (186.8 mg, 2.01 mmol) was added to a mixture of 1a (2.697 g, 20.1 mmol) and N(TMS)3 (7.008 g, 30.0 mmol) in DMF (50 mL) in an oven-dried glass screw tube (ϕ = 2.5 cm, 15 cm) equipped with a stir bar. The tube was sealed with a cap containing an inner Teflon film. After 19 h of stirring at room temperature, 1 M HCl aqueous solution (30 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1.5 h, and saturated Na2CO3 aqueous solution (40 mL) was added. The mixture was extracted with AcOEt (20 mL × 3), washed with brine (40 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (10:1 hexane/ AcOEt) to afford 3a (2.397 g, 14.8 mmol, 74%). Scale-Up of the Deprotonative Coupling of 4i with 68b (Scheme 1, Equation 2). In a glovebox under an Ar atmosphere, TMAF (115.3 mg, 1.24 mmol) was added to a mixture of 4i (1.621 g, 12.0 mmol), 6 (1.554 g, 18.0 mmol), and N(TMS)3 (4.226 g, 18.1 mmol) in DMF (30 mL) in an oven-dried glass screw tube (ϕ = 2.5 cm, 15 cm) equipped with a stir bar. The tube was sealed with a cap containing an inner Teflon film. After 19 h of stirring at room temperature, K2CO3 (1.370 g, 9.91 mmol) and MeOH (20 mL) were added to the reaction mixture. The mixture was stirred at room temperature for 1 h, and H2O (30 mL) was added. The mixture was extracted with AcOEt (20 mL × 3), washed with brine (40 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (6:1 hexane/AcOEt) to afford 7 (1.969 g, 8.90 mmol, 74%). Representative Procedure for the Reaction of 1a with Alkali-Metal Bis(trimethylsilyl)amides and Alkali-Metal Alkoxides (Table 2, Entry 1). In a glovebox under an Ar atmosphere, 1a (29.8 mg, 0.22 mmol) and DMF (0.5 mL) were added to NaHMDS (73.8 mg, 0.40 mmol) in an ovendried vial equipped with a stir bar. The vial was sealed with a cap containing an inner Teflon film. After 24 h of stirring at room temperature, 1 M HCl aqueous solution (0.5 mL) was added. The mixture was stirred at room temperature for 1.5 h, and H2O (10 mL) was added. The mixture was extracted with AcOEt (10 mL × 3), washed with H2O (10 mL × 2) and brine (10 mL), dried over MgSO4, and concentrated. 3a was obtained in 13% yield based on 1H NMR analysis using 1,1,2trichloroethane as an internal standard. Representative Procedure for the Reaction of 1a with a Catalytic Amount of NaHMDS or KHMDS and a Stoichiometric Amount of N(TMS)3 (Scheme 2). In a glovebox under an Ar atmosphere, NaHMDS (4.1 mg, 0.022 mmol) was added to a mixture of 1a (30.1 mg, 0.224 mmol) and N(TMS)3 (97.0 mg, 0.415 mmol) in DMF (0.5 mL) in an oven-dried vial equipped with a stir bar. The vial was sealed with a cap containing an inner Teflon film. After 24 h of stirring at room temperature, 1 M HCl aqueous solution (0.5

mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1.5 h, and H2O (10 mL) was added. The mixture was extracted with AcOEt (10 mL × 3), washed with H2O (10 mL × 2) and brine (10 mL), dried over MgSO4, and concentrated. 3a was obtained in 71% yield based on 1H NMR analysis using 1,1,2-trichloroethane as an internal standard. Reaction of 1a-d with Catalytic Amounts of TMAF and N(TMS)3 and a Stoichiometric Amount of NH(TMS)2 (Scheme 3). In a glovebox under an Ar atmosphere, TMAF (1.9 mg, 0.020 mmol) was added to a mixture of 1a-d (25.8 mg, 0.191 mmol), N(TMS)3 (4.4 mg, 0.019 mmol), and NH(TMS)2 (58.6 mg, 0.363 mmol) in DMF (0.5 mL) in an oven-dried vial equipped with a stir bar. The vial was sealed with a cap containing an inner Teflon film. After 24 h of stirring at room temperature, 1 M HCl aqueous solution (0.5 mL) was added to the reaction mixture. Then saturated Na2CO3 aqueous solution (5.0 mL) was added. The mixture was extracted with AcOEt (10 mL × 3), washed with H2O (10 mL × 2) and brine (10 mL), dried over MgSO4, and concentrated. 1a was obtained in 85% yield based on 1H NMR analysis using 1,1,2-trichloroethane as an internal standard. After the material was filtered through a pad of silica gel (1:1 hexane/CH2Cl2) and concentrated, the ratio of proton and deuterium at the 2-position of 1a was determined by 1H NMR analysis. Confirmation of Silylated Product D. A mixture of 1a (26.6 mg, 0.20 mmol), DMF (46 μL, 0.60 mmol), TMAF (1.9 mg, 0.02 mmol), and N(TMS)3 (96.4 mg, 0.40 mmol) was stirred at room temperature for 24 h. A portion of the mixture was analyzed by 1H NMR spectroscopy (CDCl3) (Figure S1). The mixture was also analyzed by HRMS (calcd for C14H21NOSSi, 279.1113; found, 279.1113).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00247. 1

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H and 13C NMR spectra of silylated product D and all isolated products (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Fax: (+81) 22-795-6804. ORCID

Masanori Shigeno: 0000-0002-9640-8283 Kanako Nozawa-Kumada: 0000-0001-8054-5323 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant 23105009 in Advanced Molecular Transformations by Organocatalysis (Y.K.), JSPS KAKENHI Grant 16H00997 in Precisely Designed Catalysts with Customized Scaffolding (Y.K.), JSPS KAKENHI Grant 17K15419 (M.S.), a Grant for Basic Science Research Projects from The Sumitomo Foundation (M.S.), and also the Platform Project for Supporting Drug Discovery and Life Science Research funded by the Japan Agency for G



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Medical Research and Development (AMED) (Y.K., M.S., and K.N.-K.).

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