Catalytic Deprotonative Î±-Formylation of Heteroarenes by an Amide

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Catalytic Deprotonative #-Formylation of Heteroarenes by an Amide Base Generated In Situ from TMAF and N(TMS)3 Masanori Shigeno, Yuki Fujii, Akihisa Kajima, Kanako Nozawa-Kumada, and Yoshinori Kondo Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00247 • Publication Date (Web): 29 Oct 2018 Downloaded from http://pubs.acs.org on October 29, 2018

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Organic Process Research & Development

Catalytic Deprotonative -Formylation of Heteroarenes by an Amide Base Generated In Situ from TMAF and N(TMS)3 Masanori Shigeno*, Yuki Fujii, Akihisa Kajima, Kanako Nozawa-Kumada, Yoshinori Kondo* Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai, 980-8578, Japan

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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TOC figure.


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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 N(TMS)3. The reaction proceeds at room temperature in 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

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 the deprotonation of the acidic proton of the heteroarene and the 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


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(LiTMP), is used.3 It is also noteworthy that these steps involve cryogenic conditions (78 °C) that prevent temperature rising of the reaction mixture due to 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 group tolerant 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 1, (A)). 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 2-thiophenecarboxylate 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-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


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

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, 8b Herein, we report that heteroarene formylation proceeds with DMF using the above-mentioned catalytic system at room temperature in an operationally simple one-pot procedure in which a solution of


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the heteroarene in DMF is stirred with a catalytic amount of tetramethylammonium fluoride (TMAF) and a stoichiometric amount of N(TMS)3 (Figure 1, (B)). 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.

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 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 KOMe and KO-t-Bu potassium alkoxide salts provided 3a in high yields of 91 and 90%, respectively (entries 7 and 8). Ammonium salts were next examined; tetramethylammonium fluoride (TMAF) was the most effective, affording 3a in 93% isolated yield (entries 9 and 10). Satisfactory product yields of 88, 85, or 81% respectively, were obtained even when the reaction was conducted for a shorter time (6 h), or with smaller amounts of TMAF (3 mol %) or DMF (46 L, 0.60 mmol) (entries 11–13). 3a was not obtained in the absence of either TMAF or N(TMS)3 (entries 14 and 15).


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Table 1. Optimizing the formylation conditions for 1a.a

a

Entry

Fluoride or alkoxide salt

Yield (%)b

1

KF

0

2

RbF

13

3

CsF

84

4

NaOMe

84

5

NaO-t-Bu

76

6

NaOPh

35

7

KOMe

91

8

KO-t-Bu

90

9

TBAFc

55

10

TMAF

97 (93)d

11

TMAF

88e

12

TMAF

85f

13

TMAF

81g

14

none

0h

15

TMAF

0i

Reactions were conducted on a 0.2 mmol scale.

spectroscopy.

c

b

Yields were determined by 1H-NMR

A 1 M solution of TBAF (tetrabutylammonium fluoride) in THF was used.

d

Isolated yield. e The reaction time was 6 h. f The reaction was conducted on a 1.0 mmol scale with


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TMAF (3 mol %). g The reaction was conducted with DMF (46 L). h The reaction was attempted in the absence of fluoride or alkoxide salt. i The reaction was attempted in the absence of N(TMS)3.

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 5-chlorobenzothiophene (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.a

a

Reactions were conducted on a 0.20 mmol scale. b Isolated yield. c DMF (2 mL) was used. d CsF

(30 mol %) and N(TMS)3 (3 equiv.) were used. e CsF (10 mol %) was used instead of TMAF.


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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 are tolerated. 2-(2-Pyridyl)thiophene (4f), bearing a pyridyl group at the 2-position of the thiophene ring, also provided product 5f in 67% yield. Notably, ester and amide moieties on the thiophene ring were also tolerated to afford 5g and 5h, respectively. The formylations of benzothiazole (4i, pKa = 27.3 at the 2-position10) and its derivatives 4jl possessing methyl, methoxy, and fluoro groups proceeded to furnish 5il in good yields. The reaction could be extended to include 2-phenyloxazole (4m), which gave 5m in 90% yield, while 3-cyano-N-methylindole (4n) afforded 5n in 88% yield.

Figure 3. Formylations of heteroarenes other than benzothiophenes by amide-base catalysis using TMAF and N(TMS)3.a


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a

Reactions were conducted on a 0.20 mmol scale.

b

Isolated yield.

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c

TMAF (20 mol %) and

N(TMS)3 (3 equiv.) were used. d DMF (1.0 mL) was used. e CsF (10 mol %) was used instead of TMAF. f DMF (3.0 mL) was used. g DMF (2.0 mL) was used.

The scalable nature of the present formylation was demonstrated on a 2.7 g scale (20 mmol) of 1a, which afforded 2.4 g of 3a in 74% yield (Scheme 1, eq. 1). As a related 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).

Scheme 1. Scale up of the formylation of 1a and our previously reported deprotonative coupling of 4i with 6.

For comparison with the present catalytic amide-base system, stoichiometric amounts of alkalimetal bis(trimethylsilyl)amides, namely NaHMDS and KHMDS, and 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 alkoxide and fluoride salts, including NaOMe, NaO-t-Bu, KOMe, KO-tBu, CsF, and TMAF, provided 3a in good yields when used with N(TMS)3 (Table1). It should also


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be noted that, when a catalytic amount of NaHMDS or 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.

Table 2. Reaction of 1a with alkali-metal bis(trimethylsilyl)amide and alkali-metal alkoxide.a

a

Entry

Base

Yield of 3a (%)b

Recovery of 1a (%)b

1

NaHMDS

13

39

2

KHMDS

15

32

3

NaOMe

0

86

4

NaO-t-Bu

0

81

5

KOMe

0

81

6

KO-t-Bu

3

63

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

Scheme 2. Reaction of 1a with a catalytic amount of NaHMDS or KHMDS and a stoichiometric amount of N(TMS)3.


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a

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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.), to afford a trace amount of 3a and a 85% yield of 1a (78% H-incorporation at the 2-position) (Scheme 3), which reveals that 1a is reversibly deprotonated and again emphasises that the strong OSi bond formation involved in the current system (Figures 4 and S1) plays an important role for proceeding the reaction.

Scheme 3. Reaction of 1a-d with a catalytic amount of TMAF and N(TMS)3 and a stoichiometric amount of NH(TMS)2.

a

Yields were determined by 1H-NMR analysis.

A plausible formylation mechanism is presented as follows (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 the alkoxide intermediate C, which then reacts with


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N(TMS)3 to provide the silylated product D, regenerating A (path a). As an alternative pathway, silicate species E, formed by the coordination of C to a silicon atom of N(TMS)3, directly deprotonates 1a to give B and D (path b).11 Finally, D is desilylated when quenched with 1 M HCl to afford the formylated product 3a.12

Figure 4. Plausible reaction mechanism.

Conclusions In summary, 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 in 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 an HMDS amide and an alkoxide base. Heteroarenes, such as benzothiophene, thiophene, oxazole, benzofuran, and indole derivatives, can be formylated


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using this protocol. The reaction is also compatible with heteroarenes bearing a variety of functionalities, including methoxy groups, esters, amides, nitriles, halogen, and pyridyl groups.

Experimental section General Information. All reactions were carried out under N2 or Ar atmosphere. Flash column chromatography was performed with Kanto silica gel 60 N (spherical, neutral, 70-230 m). 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 (IR) data were recorded on SensIR ATR (Attenuated Total Reflectance) FT-IR, and absorbance frequencies are reported in reciprocal centimeters (cm-1). NMR data were recorded on a JEOL AL400 spectrometer (395.75 MHz for 1H, 99.50 MHz for

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C). Chemical shifts are

expressed in  (parts per million, ppm) values, and coupling constants are expressed in herts (Hz). 1

H 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 spectra (LRMS and HRMS) were obtained from Mass Spectrometry Resource, Graduate School of Pharmaceutical Sciences, Tohoku University, on a JEOL JMS-DX 303 and JMS-700/JMS-T 100 GC spectrometer, respectively. Materials. 1c13, 1d14, 4a15, 4b15, 4c16, 4d15, 4e16, 4f17, 4h18, 4j19, 4k19, 4l20, 4m21, 4n22, and 1ad23 were prepared according to the literature procedures. DMF was distilled over CaH2 under a reduced pressure. All other commercially available chemical resources were used as received without further purification.


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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). Benzo[b]thiophene-2-carboxaldehyde (3a). In a glove box under an Ar atmosphere, 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) was added 1a (26.8 mg, 0.20 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M 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 x 3), washed with H2O (10 mL x 2) and brine (10 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 5:1) to afford 3a (30.2 mg, 0.186 mmol, 93%) as yellow solid: Mp 3435 °C (AcOEt/hexane) (lit. 3435 °C;24a 3335 °C24b). 1H NMR (400 MHz, CDCl3/TMS)  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)  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 m/z Calcd for C9H6OS: 162.0139. Found: 162.0111. IR (neat): 1666, 1513, 1425, 1320, 1255, 1133, 988, 876, 846, 759, 726 cm-1. The spectra data matched those reported in the literature. 24 5-Methylbenzo[b]thiophene-2-carboxaldehyde (3b). According to the 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 white solid: Mp 100101 °C (AcOEt/hexane) (lit. 94.595 °C25). 1H NMR (400 MHz, CDCl3/TMS)  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).

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C NMR (100 MHz, CDCl3)  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.


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Found: 176.0301. IR (neat): 1669, 1559, 1520, 1441, 1257, 1231, 1155 1132, 895, 850, 774, 718 cm-1. 4-Methoxylbenzo[b]thiophene-2-carboxaldehyde (3c). According to the 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 white solid: Mp 9798 °C (AcOEt/hexane) (lit. 9697 °C26). 1H NMR (400 MHz, CDCl3/TMS)

 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).

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C NMR (100 MHz, CDCl3)  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 glove box under an Ar atmosphere, 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) was added TMAF (2.0 mg, 0.021 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 21 h, 1M 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 x 3), washed with H2O (10 mL x 2) and brine (10 mL), dried over MgSO4, and concentrated. The residue was purified by preparative thin-layer chromatography of silica gel (hexane:AcOEt = 5:1) to afford 3d (34.5 mg, 0.175 mmol, 86%) as yellow solid: Mp 136139 °C (AcOEt/hexane) (lit. 13435 °C;27a 135 °C27b). 1H NMR (400 MHz, CDCl3/TMS)  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)  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,


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1425, 1251, 1134, 1077, 905, 870, 799, 714 cm-1. The spectra data matched those reported in the literature.27 5-Bromo[b]thiophene-2-carboxaldehyde (3e). According to the 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 that the crude material was purified by column chromatography on silica gel (hexane:AcOEt = 10:1), 3e (39.8 mg, 0.165 mmol, 79%) was obtained from 1e (44.6 mg, 0.209 mmol) as white solid: Mp 129130 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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).

13

C NMR (100 MHz,

CDCl3)  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-Bromo[b]thiophene-2-carboxaldehyde (3f). According to the 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 yellow solid: Mp 121122 °C (AcOEt/hexane) (lit. 11819 °C;28a 116117 °C28b). 1H NMR (400 MHz, CDCl3/TMS)  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). 13C NMR (100 MHz, CDCl3)  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 spectra data matched those reported in the literature.28 5-Phenylthiophene-2-carboxaldehyde (5a). According to the 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 pale yellow solid: Mp 9596 °C (AcOEt/hexane) (lit. 92 °C;29a 94.695.1 °C29b). 1H NMR


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(400 MHz, CDCl3/TMS)  7.337.50 (m, 4H), 7.637.70 (m, 2H), 7.72 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H).

13

C NMR (100 MHz, CDCl3)  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 spectra data matched those reported in the literature.29 5-(4-Fluorophenylthiophene)-2-carboxaldehyde (5b). According to the 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 pale yellow solid: Mp 114115 °C (AcOEt/hexane) (lit. 103 °C;30a 114116 °C30b). 1

H NMR (400 MHz, CDCl3/TMS)  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)  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 spectra data matched those reported in the literature.30 5-(4-Chlorophenylthiophene)-2-carboxaldehyde (5c). According to the 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 white solid: Mp 8384 °C (AcOEt/hexane) (lit. 74 °C;30a 8889 °C31). 1H NMR (400 MHz, CDCl3/TMS)  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)  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 spectra data matched those reported in the literature.30a


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5-(4-Methoxyphenylthiophene)-2-carboxaldehyde (5d). According to the 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 that the crude material was purified by column chromatography on silica gel (hexane:AcOEt = 10:1), 5d (28.0 mg, 0.128 mmol, 63%) was obtained from 4d (39.0 mg, 0.205 mmol) as pale yellow solid: Mp 120121 °C (AcOEt/hexane) (lit. 120 °C;30b 110111 °C32). 1H NMR (400 MHz, CDCl3/TMS)  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)  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: 218.3960. IR (neat): 1647, 1602, 1507, 1449, 1436, 1256, 1223, 1181, 1056, 1024, 833, 802 cm-1. The spectra data matched those reported in the literature.30b, 32 5-(4-Cyanophenylthiophene)-2-carboxaldehyde (5e). According to the 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 red solid: Mp 197198 °C (AcOEt/hexane) (lit. 166 °C;30b 208210 °C (decomposition)33). 1H NMR (400 MHz, CDCl3/TMS)  7.50 (d, 1H, J = 3.9 Hz), 7.677.81 (m, 5H), 9.94 (s, 1H). 13C NMR (100 MHz, CDCl3)  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 spectra data matched those reported in the literature.30b 2-(Pyridin-2-yl)-5-thiophene carbaldehyde (5f). According to the 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 white solid: Mp 125126 °C (AcOEt/hexane) (lit. 122 °C;34a 119120 °C34b). 1H NMR (400


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MHz, CDCl3/TMS)  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)  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 spectra data matched those reported in the literature.34 5-Formyl-thiophene-2-carboxylic acid ethyl ester (5g). According to the 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 white solid: Mp 5758 °C (AcOEt/hexane) (lit. 5758 °C5; 56.9 °C6). 1H NMR (400 MHz, CDCl3/TMS)  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)  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 spectra data matched those reported in the literature.5, 6 5-((N-methyl-N-phenyl-amino)carbonyl-2-yl)-thiophenecarboxaldehyde (5h). According to the 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 white solid: Mp 104105 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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).

13

C NMR (100 MHz,

CDCl3)  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.


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Benzo[d]thiazole-2-carboxaldehyde (5i). According to the procedure analogous to that described for 3d, except that the reaction was conducted in DMF (3.0 mL) for 19 h and that the crude material was purified by column chromatography on silica gel (hexane:AcOEt = 6:1), 5i (22.2 mg, 0.136 mmol, 67%) was obtained from 4i (27.4 mg, 0.203 mmol) as yellow solid: Mp 7273 °C (AcOEt/hexane) (lit. 75 °C35a). 1H NMR (400 MHz, CDCl3/TMS)  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)  122.6, 125.8, 127.4, 128.4, 136.4, 153.5, 165.3, 185.4. LRMS (EI) m/z: 162 (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 spectra data matched those reported in the literature.35b, 35c 6-Methylbenzo[d]thiazole-2-carbaldehyde (5j). According to the 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 yellow solid: Mp 7980 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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)  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 the 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 yellow solid: Mp 124125 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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)  55.9, 103.6, 118.2, 126.5, 138.6, 148.2, 160.3, 162.9, 185.1. LRMS (EI) m/z: 193 (M+).


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HRMS: Calcd. for C9H7NO2S: 193.0197. Found: 193.0191. IR (neat): 1683, 1601, 1492, 1452, 1273, 1196, 1118, 1014, 826, 734 cm-1. The spectra data matched those reported in the literature.36 6-Fluorobenzo[d]thiazole-2-carbaldehyde (5l). According to the procedure analogous to that described for 3d, except that the reaction was conducted for 20 h and that the crude material was purified by column chromatography on silica gel (hexane:CH2Cl2 = 1:5), 5l (24.8 mg, 0.137 mmol, 68%) was obtained from 4l (30.9 mg, 0.202 mmol) as yellow solid: Mp 109110 °C (AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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). 13C NMR (100 MHz, CDCl3)  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 the 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 white solid: Mp 6869 °C (AcOEt/hexane) (lit. 74 °C;37a 6970 °C37b). 1H NMR (400 MHz, CDCl3/TMS)  7.487.60 (m, 3H), 7.96 (s, 1H), 8.178.22 (m, 2H), 9.83 (s, 1H).

13

C NMR (100 MHz, CDCl3)  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 spectra data matched those reported in the literature.37 2-Formyl-1-methyl-1H-indole-3-carbonitrile (5n). According to the 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, 0.198 mmol) as white solid: Mp 142144 °C


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(AcOEt/hexane). 1H NMR (400 MHz, CDCl3/TMS)  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)  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, eq. 1). In a glove box under an Ar atmosphere, 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) was added TMAF (186.8 mg, 2.01 mmol) in an oven-dried glass screw tube ( = 2.5 cm, 15 cm) equipped with a stirrer bar. The tube was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 19 h, 1M 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 x 3), washed with brine (40 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 10:1) to afford 3a (2.397 g, 14.8 mmol, 74%). Scale up of the deprotonative coupling of 4i with 68b (Scheme 1, eq. 2). In a glove box under an Ar atmosphere, 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) was added TMAF (115.3 mg, 1.24 mmol) in an oven-dried glass screw tube ( = 2.5 cm, 15 cm) equipped with a stirrer bar. The tube was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 19 h, 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


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x 3), washed with brine (40 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 6:1) to afford 7 (1.969 g, 8.90 mmol, 74%). Reaction of 1a with alkali-metal bis(trimethylsilyl)amide and alkali-metal alkoxide (Table 2). Representative procedure (Table 2, entry 1). In a glove box 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 stirrer bar. The vial was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M 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 x 3), washed with H2O (10 mL x 2) and brine (10 mL), dried over MgSO4, and concentrated. 3a was obtained in 13% NMR yield (based on 1H NMR using 1,1,2-trichloroethane as an internal standard). Reaction of 1a with a catalytic amount of NaHMDS or KHMDS and a stoichiometric amount of N(TMS)3 (Scheme 2). Representative procedure. In a glove box under an Ar atmosphere, 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) was added NaHMDS (4.1 mg, 0.022 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M 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 x 3), washed with H2O (10 mL x 2) and brine (10 mL), dried over MgSO4, and concentrated. 3a was


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obtained in 71% NMR yield (based on 1H NMR using 1,1,2-trichloroethane as an internal standard). Reaction of 1a-d with a catalytic amount of TMAF and N(TMS)3 and a stoichiometric amount of NH(TMS)2 (Scheme 3). In a glove box under an Ar atmosphere, 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) was added TMAF (1.9 mg, 0.020 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M 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 x 3), washed with H2O (10 mL x 2) and brine (10 mL), dried over MgSO4, and concentrated. 1a was obtained in 85% NMR yield (based on 1H NMR using 1,1,2-trichloroethane as an internal standard). After the material was filtered through a pad of silica gel (hexane:CH2Cl2 = 1:1) 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 L, 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 (CDCl3) (Figure S1). The mixture was also analyzed by HRMS: m/z Calcd for C14H21NOSSi: 279.1113; Found: 279.1113.

ASSOCIATED CONTENT Supporting Information. 1H and 13C NMR spectra of silylated product D and all isolated products


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected], Fax: (+81) 22-795-6804. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was financially supported by JSPS KAKENHI Grant no. 23105009 in Advanced Molecular Transformations by Organocatalysis (Y. K.), JSPS KAKENHI Grant no. 16H00997 in Precisely Designed Catalysts with Customized Scaffolding (Y. K.), JSPS KAKENHI Grant no. 17K15419 (M. S.), Grand 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 Japan Agency for Medical Research and Development (AMED) (Y. K., M. S., and K. N.-K.).

REFERENCES (1) For examples of reviews, (a) Schlosser, M. The 2 x 3 Toolbox of Organometallic Methods for Regiochemically Exhaustive Functionalization. Angew. Chem. Int. Ed. 2005, 44, 376-393. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Deprotonative Metalation Using Ate Compounds: Synergy, Synthesis, and Structure Building. Angew. Chem. Int. Ed. 2007, 46, 38023824. (c) Benischke, A. D.; Ellwart, M.; Becker, M. R.; Knochel, P. Polyfunctional Zinc and Magnesium Organometallics for Organic Synthesis: Some Perspectives. Synthesis 2016, 48,


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1101-1107. (d) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. CH Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. (e) Leitch, J. A.; Bhonoah, Y.; Frost, C. G. Beyond C2 and C3: TransitionMetal-Catalyzed CH Functionalization of Indole. ACS Catal. 2017, 7, 5618-5627. (f) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. CH Functionalization of Azines. Chem. Rev. 2017, 117, 9302-9332. (g) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Cross-Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom. Adv. Synth. Catal. 2014, 356, 17-117. (h) Yang, Y.; Lan, J.; You, J. Oxidative C−H/C−H Coupling Reactions between Two (Hetero)arenes. Chem. Rev. 2017, 117, 8787-8863. (2) (a) van Leeuwen, P. W. N. M. Ed. Science of Synthesis: C-1 Building Blocks in Organic Synthesis 2, Thieme Georg Verlag, Stuttgart, 2014. (b) Brückner, R. Ed. Science of Synthesis: Compounds with Two Carbon-Heteroatom Bonds, Aldehydes, Thieme Georg Verlag, Stuttgart, 2007. (3) For examples, see: (a) Britton, T. C.; Spinazze, P. G.; Hipskind, P. A.; Zinuncrman, D. M.; Zardnrnayeh, H.; Schober, D. A.; Gehlert, D. R.; Bruns. R. F. Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: Optimization of the C-2 side chain. Bioorg. Med. Chem. Lett. 1999, 9, 475-480. (b) Hansen, M.; Jacobsen, S. E.; Plunkett, S.; Liebscher, G. E.; McCorvy, J. D.; Brauner-Osborne, H.; Kristensen, J. L. Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists. Bioorg. Med. Chem. 2015, 23, 3933-3937. (c) Li, Z.; Zhang, J.; Zhang, K.; Zhang, W.; Guo, L.; Huang, J.; Yu, G. Wong, M. S. Naphtho[2,1-b:3,4-b′]bisthieno[3,2-b][1]benzothiophene-


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based semiconductors for organic field-effect transistors. J. Mater. Chem. C 2015, 3, 8024-8029. (d) Yang, L.; Zhang, S.; He, C.; Zhang, J.; Yao, H.; Yang, Y.; Zhang, Y.; Zhao, W.; Hou, J. New Wide Band Gap Donor for Efficient Fullerene-Free All-Small-Molecule Organic Solar Cells. J. Am. Chem. Soc. 2017, 139, 1958-1966. (4) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J.; Regioselective Metalation of Pyridinylcarbamates and Pyridinecarboxamides with (2,2,6,6-Tetramethylpiperidino)magnesium Chloride. J. Org. Chem. 1995, 60, 8414-8416. (5) Shilai, M.; Kondo, Y.; Sakamoto, T. Selective metallation of thiophene and thiazole rings with magnesium amide base. J. Chem. Soc., Perkin Trans. 2001, 1, 442-444. (6) Petersen, T. P.; Becker, M. R.; Knochel, P. Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl·LiCl. Angew. Chem. Int. Ed. 2014, 53, 7933-7937. (7) Zhao, H.; Dankwardt, J. W.; Koenig, S. G.; Singh, S. P. Directed metalation and regioselective functionalization of 3-bromofuran and related heterocycles with NaHMDS. Tetrahedron Lett. 2012, 53, 166-169. (8) (a) Inamoto, K.; Okawa, H.; Taneda, H.; Sato, M.; Hirono, Y.; Yonemoto, M.; Kikkawa, S.; Kondo, Y. Organocatalytic deprotonative functionalization of C(sp2)–H and C(sp3)–H bonds using in situ generated onium amide bases. Chem. Commun. 2012, 48, 9771-9773. (b) Inamoto, K.; Okawa, H.; Kikkawa, S.; Kondo, Y. Use of tetramethylammonium fluoride (TMAF) and alkali metal alkoxides as an activator for catalytic deprotonative functionalization of heteroaromatic C(sp2)H bonds. Tetrahedron 2014, 70, 7917-7922. (c) Taneda, H.; Inamoto, K.; Kondo, Y. Direct condensation of functionalized sp3 carbons with formanilides for enamine synthesis using an in


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Page 29 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


situ generated HMDS amide catalyst. Chem. Commun. 2014, 50, 6523-6525. Also see, (d) Shigeno, M.; Kai, Y.; Yamada, T.; Hayashi, K.; Nozawa-Kumada, K.; Denneval, C.; Kondo, Y. Asian J. Org. Chem. 2018, 7, 2082-2086. (9) For examples of deprotonative functionalizations by a one-step protocol, see: Mach, M. H.; Bunnett, J. F. Duality of mechanism in the electrophilic bromination of aromatic compounds. J. Am. Chem. Soc. 1974, 96, 936-938. (b) Krizan, T. D.; Martin, J. C. In situ trapping of ortho lithiated benzenes containing electrophilic directing groups. J. Am. Chem. Soc. 1983, 105, 6155-6157. (c) Taylor, S. L.; Lee, D. Y.; Martin, J. C. Direct, regiospecific 2-lithiation of pyridines and pyridine 1-oxides with in situ electrophilic trapping. J. Org. Chem. 1983, 48, 4156-4158. (d) Black, W. C.; Guay, B.; Scheuermeyer, F. Metalation of Nitroaromatics with in Situ Electrophiles. J. Org. Chem. 1997, 62, 758-760. (e) Schlosser, M.; Guio, L.; Leroux, F. Multiple Hydrogen/Lithium Interconversions at the Same Benzene Nucleus: Two at the Most. J. Am. Chem. Soc. 2001, 123, 3822-3823. (f) Vazquez, E.; Davies, I. W.; Payack, J. F. A Non-cryogenic Method for the Preparation of 2-(Indolyl) Borates, Silanes, and Silanols. J. Org. Chem. 2002, 67, 7551-7552. (g) Luliński, S.; Serwatowski, J. Regiospecific Metalation of Oligobromobenzenes. J. Org. Chem. 2003, 68, 5384-5387. (h) Popov, I.; Do, H.-Q.; Daugulis, O. In Situ Generation and Trapping of Aryllithium and Arylpotassium Species by Halogen, Sulfur, and Carbon Electrophiles. J. Org. Chem. 2009, 74, 8309-8313. (10) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. What are the pKa values of C–H bonds in aromatic heterocyclic compounds in DMSO? Tetrahedron 2007, 63, 1568-1576.


29


Page 30 of 34

(11) Large, S.; Roques, N.; Langlois, B. R. Nucleophilic Trifluoromethylation of Carbonyl Compounds and Disulfides with Trifluoromethane and Silicon-Containing Bases. J. Org. Chem. 2000, 65, 8848-8856. (12) The formation of D was confirmed by 1H NMR and MS analyses (Figure S1 and “Confirmation of silylated product D” in the experimental section). (13) Cerminara, I.; D’Alesssio, L.; D’Auria, M.; Funicello, M.; Guarnaccio, A. 5-Substituted Benzothiophenes: Synthesis, Mechanism, and Kinetic Studies. Helv. Chim. Acta 2016, 99, 384392. (14) Pérez-Silanes, S.; Martínez-Esparza, J.; Oficialdegui, A. M.; Villanueva, H.; Orús, L.; Monge, A. Synthesis of New 5-Substitutedbenzo[b]thiophene Derivatives. J. Heterocyclic Chem. 2001, 38, 1025-1030. (15) Vásquez-Céspedes, S.; Ferry, A.; Candish, L.; Glorius, F. Heterogeneously Catalyzed Direct CH Thiolation of Heteroarenes. Angew. Chem. Int. Ed. 2015, 54, 5772-5776. (16) Reddy, V. P.; Qiu, R.; Iwasaki, T.; Kambe, N. Rhodium-Catalyzed Intermolecular Oxidative Cross-Coupling of (Hetero)Arenes with Chalcogenophenes. Org. Lett. 2013, 15, 12901293. (17) Park, J.; Chang, S. Comparative Catalytic Activity of Group 9 [Cp*MIII] Complexes: Cobalt-Catalyzed CH Amidation of Arenes with Dioxazolones as Amidating Reagents. Angew. Chem. Int. Ed. 2015, 54, 14103-14107.


30

Page 31 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(18) Yamada, S.; Okuda, M.; Yamamoto, N. Tetrabutylammonium-assisted diastereoselective [6π]-photocyclization of acrylanilides. Tetrahedron Lett. 2015, 56, 2098-2101. (19) Li, Z.-L.; Jin, L.-K.; Cai, C. Efficient synthesis of 2-substituted azoles: radical C–H alkylation of azoles with dicumyl peroxide, methylarenes and cycloalkanes under metal-free condition. Org. Chem. Front. 2017, 4, 2039-2043. (20) Taylor, N. J.; Emer, E.; Preshlock, S.; Schedler, M.; Tredwell, M.; Verhoog, S.; Mercier, J.; Genicot, C.; Gouverneur, V. Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands. J. Am. Chem. Soc. 2017, 139, 8267-8276. (21) Besselièvre, F.; Lebrequier, S.; Mahuteau-Betzer, F.; Piguel, S. CH Bond Activation: A Versatile Protocol for the Direct Arylation and Alkenylation of Oxazoles. Synthesis 2009, 20, 3511-3518. (22) Ushijima, S.; Moriyama, K.; Togo, H. Practical one-pot transformation of electron-rich aromatics into aromatic nitriles with molecular iodine and aq NH3 using Vilsmeier–Haack reaction. Tetrahedron 2012, 68, 4588-4595. (23) Ghosh, D.; Lee, H. M. Efficient Pd-Catalyzed Direct Arylations of Heterocycles with Unreactive and Hindered Aryl Chlorides. Org. Lett. 2012, 14, 5534-5537. (24) (a) Iinuma, M.; Moriyama, K.; Togo, H. Oxidation of Alcohols to Aldehydes or Ketones with 1-Acetoxy-1,2-benziodoxole-3(1H)-one Derivatives. Eur. J. Org. Chem. 2014, 772-780. (b) Zhu, Y.; Zhao, B.; Shi, Y. Highly Efficient Cu(I)-Catalyzed Oxidation of Alcohols to Ketones and Aldehydes with Diaziridinone. Org. Lett. 2013, 15, 992-995.


31


Page 32 of 34

(25) Clarke, K.; Hughes, C. G.; Humphries, A. J.; Scrowston, R. M. Some derivatives of [1]benzothieno[2,3-c]pyridine and [1]benzothieno[3,2-c]pyridine. J. Chem. Soc. C 1970, 1013-1016. (26) Campaigne, E.; Rogers, R. B. Benzo[b]thiophene derivatives. XXI. On the proof of structure of the sulfur isostere of psilocin. J. Heterocyclic Chem. 1973, 10, 963-966. (27) (a) Zhu, R.; Liu, Z.; Chen, J.; Xiong, X.; Wang, Y.; Huang, L.; Bai, J.; Dang, Y.; Huang, J. Preparation of Thioanisole Biscarbanion and CH Lithiation/Annulation Reactions for the Access of Five-Membered Heterocycles. Org. Lett. 2018, 20, 3161-3165. (b) Matsunaga, N.; Kaku, T.; Itoh, F.; Tanaka, T.; Hara, T.; Miki, H.; Iwasaki, M.; Aono, T.; Yamaoka, M.; Kusaka, M.; Tasaka, A. C17,20-Lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors. Bioorg. Med. Chem. 2004, 12, 2251-2273. (28) (a) Li, Z.; Zhang, J.; Zhang, K.; Zhang, W.; Guo, L.; Huang, J.; Yu, G.; Wong, M. S. Naphtho[2,1-b:3,4-b′]bisthieno[3,2-b][1]benzothiophene-based semiconductors for organic field-effect transistors. J. Mater. Chem. C 2015, 3, 8024-8029. (b) Lyaskovskyy, V.; Fröhlich, R.; Würthwein, E.-U. Aminobenzoannulated Hetero- and Carbocycles from 2-Azahepta-2,4-dien6-ynyllithium Compounds: Scope and Limitation of a Novel Benzoannulation Reaction. Synthesis 2007, 14, 2135-2144. (29) (a) Yano, J. K.; Denton, T. T.; Cerny, M. A.; Zhang, X.; Johnson, E. F.; Cashman, J. R. Synthetic Inhibitors of Cytochrome P-450 2A6: Inhibitory Activity, Difference Spectra, Mechanism of Inhibition, and Protein Cocrystallization. J. Med. Chem. 2006, 49, 6987-7001. (b) Salamoun, J. M.; McQueeney, K. E.; Patil, K.; Geib, S. J.; Sharlow, E. R.; Lazo, J. S.; Wipf, P. Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor. Org. Biomol. Chem. 2016, 14, 6398-6402.


32

Page 33 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(30) (a) Rao, M. L. N.; Banerjee, D.; Dhanorkar, R. J. Synthesis of Functionalized 2Arylthiophenes with Triarylbismuths as Atom-Efficient Multicoupling Organometallic Nucleophiles under Palladium Catalysis. Synlett 2011, 9, 1324-1330. (b) Ajdačić, V.; Senerovic, L.; Vranić, M.; Pekmezovic, M.; Arsic-Arsnijevic, V.; Veselinovic, A.; Veselinovic, J.; Šolaja, B. A.; Nikodinovic-Runic, J.; Opsenica, I. M. Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates. Bioorg. Med. Chem. 2016, 24, 1277-1291. (31) Obushak, M. D.; Matiychuk, V. S.; Lytvyn, R. Z. Synthesis and reactions of 5-aryl-2thiophenecarbaldehydes. Chem. Heterocycl. Comp. 2008, 44, 936-940. (32) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Copper-Catalyzed Direct C Arylation of Heterocycles with Aryl Bromides: Discovery of Fluorescent Core Frameworks. Angew. Chem. Int. Ed. 2009, 48, 3296-3300. (33) Mallena, S.; Lee, M. P. H.; Bailly, C.; Neidle, S.; Kumar, A.; Boykin, D. W.; Wilson, W. D. Thiophene-Based Diamidine Forms a “Super” AT Binding Minor Groove Agent. J. Am. Chem. Soc. 2004, 126, 13659-13669. (34) (a) Wippich, J.; Schnapperelle, I.; Bach, T. Regioselective oxidative Pd-catalysed coupling of alkylboronic acids with pyridin-2-yl-substituted heterocycles. Chem. Commun. 2015, 51, 3166-3168. (b) Nerenz, H.; Meier, M.; Grahn, W.; Reisner, A.; Schmälzlin, E.; Stadler, S.; Meerholz, K.; Bräuchle, C.; Jones, P. G. Nonlinear optical chromophores with isoquinolines, thieno[2,3-c]pyridines and 2-(2′-thienyl)pyridines as inherently polarized π-electron bridges. J. Chem. Soc., Perkin Trans. 2 1998, 437-448.


33


Page 34 of 34

(35) (a) Gardini, G. P. Homolytic aromatic substitution: A simple route to the aldehydes of heteroaromatic bases. Tetrahedron Lett. 1972, 13, 4113-4116. (b) García-Ortiz, A. L.; DomínguezGonzález, R.; Romero-Ávila, M.; Flores-Pérez, B.; Guillén, L.; Castro, M.; Barba-Behrens, N. The role of weak interactions in self-assembly of supramolecular associations of benzothiazole derivatives and their coordination compounds. Inorganica Chimica Acta 2018, 471, 550-560. (c) Nagasawa, Y.; Tachikawa, Y.; Yamaguchi, E.; Tada, N.; Miura, T.; Itoh, A. Catalytic Aerobic Photo-oxidation of a Methyl Group on a Heterocycle to Produce an Aldehyde via Homolytic CI Bond Cleavage caused by Irradiation with Visible Light. Adv. Synth. Catal. 2016, 358, 178-182. (36) Shaik, T. B.; Hussaini, S. M. A.; Nayak, V. L.; Sucharitha, M. L.; Malik, M. S.; Kamal, A. Rational design and synthesis of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents. Bioorg. Med. Chem. Lett. 2017, 27, 2549-2558. (37) (a) Šagud, I.; Šindler-Kulyk, M.; Vojnović, D.; Marinić, Ž. Versatile Photochemical Reactivity of Diverse Substituted 2-, 4- and 5-(o-Vinylstyryl)oxazoles. Eur. J. Org. Chem. 2018, 515-524. (b) Hu, Y.; Yi, R.; Wang, C.; Xin, X.; Wu, F.; Wan, B. From Propargylamides to Oxazole Derivatives: NIS-Mediated Cyclization and Further Oxidation by Dioxygen. J. Org. Chem. 2014, 79, 3052-3059.


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Catalytic Deprotonative Î±-Formylation of Heteroarenes by an Amide

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