Regioselective Functionalization of 4-Methyl-1H-indole for Scalable

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Regio-selective Functionalization of 4-Methyl-1H-indole for Scalable Synthesis of 2-Cyano-5-formyl-4-methyl-1H-indole Jun Zhang, Yun Hu, Haiyu Wang, Aixin Guo, Jianshe Kong, Rujian Ma, Tao Wu, Yi Wang, Liansheng Li, Wanping Mai, Pingda Ren, and Xiaohu Deng Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00370 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on December 27, 2017

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Organic Process Research & Development

Regio-selective Functionalization of 4-Methyl-1H-indole for Scalable Synthesis of 2-Cyano-5-formyl-4-methyl-1H-indole Jun Zhang§; Yun Hu§; Haiyu Wang§; Aixin Guo§; Jianshe Kong§, Rujian Ma§ Tao Wu†; Yi Wang†; Lian-Sheng Li†; Wanping Mai‡; Pingda Ren‡; Xiaohu Deng‡*

§ †

WuXi AppTec Co., Ltd., 168 Nanhai Road, TEDA, Tianjin 300457, China

Wellspring Biosciences Inc., 3033 Science Park Rd. Ste. 220, San Diego, CA 92121, USA ‡

Kura Oncology Inc., 3033 Science Park Rd. Ste. 220, San Diego, CA 92121, USA Email: [email protected]

ACS Paragon Plus Environment

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

Graphic for use in Table of Contents


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Abstract: we report a 5-step synthesis of 2-cyano-5-formyl-4-methyl-1H-indole through sequential functionalization of readily available 4-methyl-1H-indole. Cyano and aldehyde functionalities are regio-selectively installed at 2 and 5 position, respectively. The sequence is concise and high-yielding, amenable for kilogram scale production. Keywords: Indole, sequential functionalization, flow chemistry, regio-selectivity, formylation



Indole is a “privileged” structural motif widely found in biologically active natural products and synthetic drug candidates.1 Construction of the indole ring has been extensively researched and almost all conceivable disconnections have been explored.2 However, decorated indoles with reactive functional groups appropriately installed at the requisite positions are often hard to synthesize, primarily due to the difficulty of controlling the regio-chemistry. Therefore, development of economical, scalable syntheses of highly functionalized indoles is still in high demand. Two general strategies are often considered for the introduction of functional groups in positions 2 and 5 of the 4-methyl indole ring, as represented in Scheme 1. Strategy I starts from functionalized phenyl precursors and builds the indole 5-member ring. The advantage of this approach is to have the requisite functional groups appropriately positioned at the beginning, therefore, eliminating the regio-selectivity issue. However, suitable starting materials are not always readily available and functional group manipulations are frequently involved, which lead to lengthy synthetic sequences. Alternatively, strategy II utilizes sequential functionalization of simple 4-methyl-indoles, taking advantages of position-specific reactivity of the indole ring. While deceivingly straightforward, this strategy is scarce in the literature because it requires deep understanding of the reactivity differences and careful design of reaction sequence. Herein we report our efforts towards the scalable syntheses of highly functionalized 2-cyano-5-formyl-4methyl-1H-indole (Scheme 1, compound A), utilizing both strategies. Strategy I was initially employed and flow chemistry was developed to address the safety and low-yield issues in the key indole cyclization step. Subsequently, strategy II was successfully applied to the development of a concise route for the kilogram production of compound A. We envision utilization of strategy II on syntheses of other structurally related indole compounds as well.

Scheme 1. Two general strategies for the synthesis of functionalized indoles.

In an effort to find a scalable synthesis of compound A, we first employed strategy I using the two discovery routes shown in Scheme 2.3 Both routes go through common intermediate 2, which is prepared in two steps from expensive, tri-substituted phenyl derivative 1. In the original route 1, Hemetsberger–Knittel reaction4 of substrate 2 with potentially explosive azido reagent (N3CH2COOEt) was utilized to construct the indole core to provide compound 3.


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Multiple functional group manipulations afforded precursor 4 in decent yield. Strong basemediated transformation of Br to CHO proved to be rather difficult and the yield dropped precipitously along with the reaction scale. Recognizing the difficulty of late-stage installation of the aldehyde functionality, a modified route 2 was developed. Aldehyde protection of compound 2 followed by lithium mediated formylation afforded differentiatedly protected precursor 5. A Hemetsberger–Knittel indole formation reaction yielded compound 6. Subsequent deprotection followed by necessary functional group transformations afforded compound A on gram scales. Compared with the original route, the modified route is scalable to >100 grams, but the drawbacks are still rather obvious. First, the length and low overall yield makes the sequence economically prohibitive on larger scale. Second, involvement of potentially explosive azido reagent (N3CH2COOEt) poses a significant safety concern.

Scheme 2. Original discovery syntheses of compound A To address these issues, the low yielding indole formation step needed to be improved. For Hemetsberger–Knittel cyclization reactions, harsh conditions are usually compulsory in order to generate the reactive yet unstable azirine intermediate, which undergoes facile decomposition to cause low yielding reactions.5 Flow chemistry6, which limits the exposure of reaction substrates to short residence time, usually in minutes, seems to be particularly suitable for addressing this type of situation. We first used substrate 10 for a model study. Under conventional heating conditions, batch reactions afforded low yields of indole product 11 (Table 1, entries 1, 2). The main byproduct was a dimer, presumably derived from the azirine intermediate.7 Switching to flow conditions, by increasing the reaction temperature while limiting the residence time (entries 3-5), excellent yield (78%) of indole product 11 was obtained. With the more elaborate substrate 8, a similar isolated yield (72%) of indole 6 was also achieved on a 500 gram scale run (entry 6). The flow conditions significantly improved the original route, addressing the main issues of the indole formation step. However, the overall long sequence still makes it economically unappealing for large scale production.



Table 1. Optimization of indole formation step entry solvent conditions

1 2

Toluene Xylenes

3 4 5

Toluene Toluene Xylenes

Batch chemistry 110 oC, 1 h 140 oC, 2 h Flow chemistry* 140 oC, 8 min 140 oC, 15 min 180 oC, 8 min

6

Xylenes

180 oC, 8 min

HPLC yield

11% 34% 12% 33% 78%

72%, 500 g scale, isolated yield

*1g scale, 0.2 M, pressure=1.3 Mpa.

Examining the original syntheses, it is obvious that functional group manipulations make up a majority of the reaction sequence. In an attempt to shorten the route, functionalization of indole 11 (strategy II) was investigated. After largely unsuccessful efforts to directly install formyl group on the 5 position under Vilsmeier conditions8, attention was switched to the bromination reaction. With 1 equivalent of NBS, a mixture of mono and bis-brominated product was observed, with mono-brominated product at the 3 position as the major product. This result did not come as a surprise since the 3 position of indole is known to be the more electrophilic site.9 Increasing the equivalence of NBS yielded the complete bis-bromination, regio-selectively at 3 and 5 positions to afford 12. Taking advantage of the higher reactivity at the 3 position, mono-debromination was achieved to afford 13 in good yield.10 Unfortunately, formylation of 13 under a number of typical conditions produced only low yields of 14. Considering that conversion of 14 to A in the presence of reactive aldehyde functional group might not be a trivial task, we decided not to pursue this route further.

Scheme 3. Regio-selective bromination of indole 11.


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Nevertheless, we were very much encouraged by the feasibility of regio-selective functionalization of the indole core and turned our attention to inexpensive indole 15 that is commercially available on kilogram scale (Scheme 4). To streamline the overall synthesis, we first introduced a CN group at the 2 position. Protecting group directed ortho-lithiation trapping with an appropriate electrophile proved to be a powerful method11 to afford 17 in good yield. Conversion of the amide to a CN group was easily achieved with POCl3 to afford 18 in excellent yield. Vilsmeier-type reaction conditions for the direct installation of aldehyde functionality on 18 gave a complex mixture of products. Drawing on prior experience with 11, regio-selective halogenation of 18 was explored. To our pleasant surprise, mono-halogenation took place exclusively at the 5 position to afford 19 and 20 in high yields, likely due to the deactivation of the usually favored 3 position in the presence of the neighboring electron-withdrawing CN group.12

Scheme 4. Sequential functionalization of 15 at 2 and 5 positions. With compound 19 and 20 in hand, the remaining step involved the conversion of the halides to the requisite aldehyde, which proved to be more difficult than anticipated. The classic n-BuLi/DMF conditions13 yielded only trace amounts of the desired product. An extensive survey of combinations of strong bases such as n-BuLi, iPrMgCl, iPrMgCl•LiCl 14 and i PrBu2MgLi 15 with formylating reagents such as DMF, PhMeNCHO, morpholine-CHO, Nformylsaccharin etc. failed to provide satisfactory results. Careful examination of reaction mixtures revealed two competing side reactions: deprotection of PhSO2 group under basic conditions and nucleophilic addition of bases to the CN group, even at -78 oC. With these insights, we turned our attention to metal-catalyzed cross-coupling reactions. Pd catalyzed Suzuki cross-coupling of 19 with vinyl boronate 21 worked well to afford 22. Oxidative cleavage of the vinyl group exposed the aldehyde followed by deprotection to provide desired product A in decent yields. However, the transformation still required 3 steps, and vinyl boronic ester 21 is quite expensive. Finally, a Pd catalyzed formylation reaction16 worked beautifully with the more reactive iodo-substrate 20 whereas the same conditions afforded only trace amount of A with bromide 19. Furthermore, the mild base (Na2CO3) used in the reaction effectively removed the PhSO2 protecting group concurrently in an one-pot fashion to afford an excellent 80% isolated yield of target compound A.



Scheme 5. Formylation approaches towards compound A In summary, the original synthesis of compound A was optimized by employing flow chemistry in the key step to address the safety concern while significantly increasing the yield. A new, concise route was subsequently developed featuring the sequential regio-selective functionalization strategy than the original route. The new route is much shorter, higher yielding and more economical for kilogram scale production. We expect broader application of this strategy with the synthesis of other structurally related indoles.

Scheme 6. Overall synthetic sequence of compound A


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Experimental Section: Proton and carbon NMR spectra were recorded at a 400 MHz NMR spectrometers. Flash column chromatography was performed using silica gel. The reactions were monitored with TLC and reverse phase analytical HPLC. MS was obtained on a LC-MS apparatus with an ESI detector. HRMS (ESI) was performed on a µTof apparatus. All the reagents and solvents were purchased from commercial sources and used without further purification.

Ethyl 5-(1,3-dioxolan-2-yl)-4-methyl-1H-indole-2-carboxylate (6): Flow chemistry conditions: A 0.2 M stock solution of Ethyl (Z)-2-azido-3-[3-(1,3-dioxolan-2yl)-2-methyl-phenyl]prop-2-enoate ethyl (Z)-2-azido-3-(o-tolyl)prop-2-enoate (8, 0.2 M) in xylene was prepared at room temperature. The solution was pumped through a flow reactor with system pressure maintained at 1.3 MPa. The flow reactor parameters are as following: flow rate: 4 mL/min; PFA tube length: 10 m; residence time (Rt): 7.85 min; back pressure: 0.01 MPa; temperature: 180 °C; running time: 25 min. HPLC analysis was used to monitor the reaction. The product was collected and re-slurried in a mixture of IPA/Hexanes to afford 6 as a yellow solid. The characterization data is consistent to the literature precedent.

Ethyl 3,5-dibromo-4-methyl-1H-indole-2-carboxylate (12): To a solution of ethyl 4-methyl1H-indole-2-carboxylate (0.6 g, 2.8 mmol, 1 equiv.) in CHCl3 (10 mL) was added NBS (1.05 g, 5.61 mmol, 95% purity, 2 equiv.) at 0 °C. After stirred at 10 °C for 1 h, the reaction solution was quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with DCM (20 mL x 2). The organic layers was combined, washed with brine (20 mL), dried with Na2SO4 and



concentrated to afford compound 12 (0.6 g, 1.6 mmol, 58% yield) as a white solid.

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1

H NMR

(400 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.84 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).

13

C NMR (100 MHz, DMSO-d6) δ 160.32,

135.52, 130.79, 129.89, 125.33, 125.28, 117.38, 113.27, 95.13, 61.37, 18.85, 14.68. HRMS-ESI (m/z): [M-H]- calcd for C12H11Br2NO2, 359.9079; found, 359.9057.

Ethyl 5-bromo-4-methyl-1H-indole-2-carboxylate (13): To a solution of H2SO4 (162 mg, 1.66 mmol, 1.2 equiv.) and LiBr (131 mg, 1.52 mmol, 1.1 equiv.) in AcOH (5 mL) was added compound 12 (0.5 g, 1.38 mmol, 1 equiv.) and N-methylpyrrole (223 mg, 2.76 mmol, 2 equiv.) at 0 °C. After stirring at 60 °C for 2 hours, the reaction solution was quenched with aqueous Na2CO3 solution. The aqueous layer was extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (20 mL), and dried with Na2SO4 and concentrated. The residue was purified via column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20/1 to 2:1) to afford 13 (0.3 g, 1.01 mmol, 73%) as a white solid. 1H NMR (100 MHz CDCl3) δ 9.07 (br s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.28 (br d, J=7.2 Hz, 1H), 7.16 (br d, J=8.7 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).

13

C NMR (100 MHz CDCl3) δ 161.71,

135.33, 131.53, 129.43, 129.01, 127.76, 115.87, 110.80, 107.51, 61.21, 18.98, 14.40. HRMSESI (m/z): [M-H]- calcd for C12H12BrNO2, 279.9973; found 279.9980.

1-(Benzenesulfonyl)-4-methyl-indole (16): To a solution of 4-methyl-1H-indole (15, 460 g, 3.4 mol, 1.0 equiv.) in THF (2300 mL), NaH (150 g, 3.74 mol, 60% in mineral oil, 1.1 equiv.) and PhSO2Cl (696 g, 3.74 mol, 1.1 equiv.) was sequentially added at 0 °C. After stirring at 25 °C for 1 hour, the reaction solution was poured into ice water (1.0 L). The precipitated solid was collected by filtration and re-dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1.0 L), brine (1.0 L), dried over Na2SO4 and concentrated. The solid


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was then slurried in petroleum ether (2.0 L) and filtered to afford 16 (767 g, 82%, 99% purity) as a white solid. 1H NMR (400 MHz DMSO-d6) δ 7.94 - 7.99 (m, 2H), 7.80 (d, J = 3.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 - 7.72 (m, 1H), 7.56 - 7.62 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.90 (m, 1H), 2.43 (s, 3H).

13

C NMR (100 MHz DMSO-d6) δ 137.07,

134.54, 133.89, 130.84, 130.03, 129.77, 126.60, 126.27, 124.73, 123.74, 110.54, 108.09, 18.03. HRMS-ESI (m/z): [M+H]+ calcd for C15H13NO2S, 272.0745; found, 272.0740.

1-(Benzenesulfonyl)-N-tert-butyl-4-methyl-indole-2-carboxamide (17): To the solution of 16 (500 g, 1.84 mol, 1.0 equiv.) in THF (2000 mL), LDA (2 M, 1.38 L, 1.5 equiv.) was added dropwise at -60 °C under N2. The reaction mixture was stirred at -60°C for 30 minutes, warmed to 25 °C and stirred for another 30 minutes. The reaction mixture was cooled back to -60 °C and 2-isocyanato-2-methyl-propane (288 g, 2.76 mol, 1.5 equiv.) was added dropwise and allowed to warm to 25 °C. After stirred at 25 °C for 4 hours, the reaction mixture was poured into saturated ammonium chloride solution (1.0 L) and the aqueous layer was extracted with EtOAc (2.0 L x 2). The organic layers were combined, washed with brine (1.0 L), dried over Na2SO4, and concentrated. The solid was slurried in petroleum ether (2.0 L) and filtered to afford 17 (580 g, 81% yield, 95% purity) as a white solid. 1H NMR (400 MHz DMSO-d6) δ 8.36 (s, 1H), 8.15 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.65 - 7.71 (m, 1H), 7.56 - 7.63 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.94 (s, 1H), 2.41 (s, 3H), 1.40 (s, 9H).

13

C NMR (100

MHz DMSO-d6) δ 160.75, 137.65, 136.22, 134.82, 134.34, 131.16, 129.33, 128.02, 127.30, 125.46, 124.01, 111.62, 108.82, 51.06, 28.29, 17.93. HRMS-ESI (m/z): [M+H]+ calcd for C20H22N2O3S, 371.1429; found, 371.1438.



1-(Benzenesulfonyl)-4-methyl-indole-2-carbonitrile (18): To the solution of 17 (470 g, 1.27 mol, 1.0 equiv.) in ACN (2500 mL), SOCl2 (397 g, 3.17 mol, 2.5 equiv.) was added slowly. The reaction solution was degassed with N2 and stirred at 80 °C for 12 hours under N2. The reaction mixture was concentrated and the residue was dissolved in EtOAc (4.0 L). The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over Na2SO4, and concentrated. The collected solid was re-slurryed in 3:1 MTBE/EtOAc and filtered to afford compound 18 (308 g, 81% yield, 99% purity) as an off-white solid. 1H NMR (400 MHz DMSO-d6) δ 8.09 (s, 1H), 7.89 - 7.98 (m, 3H), 7.70 - 7.77 (m, 1H), 7.60 - 7.66 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 2.43 (s, 3H).

13

C NMR (100 MHz, DMSO-d6) δ 136.01, 135.98, 135.52,

133.01, 130.26, 129.29, 127.38, 126.62, 125.18, 123.91, 112.17, 111.59, 107.49, 17.82. MS-ESI (m/z): [M-H]- calcd for C16H12N2O2S, 295.0541; found, 295.0.

1-(Benzenesulfonyl)-5-bromo-4-methyl-indole-2-carbonitrile (19): To the solution of 18 (60 g, 202 mmol, 1 equiv.) in AcOH (600 mL), Br2 (68.1 g, 405 mmol, 2 equiv.) was added slowly at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. The precipitated solid was collected by filtration, washed with H2O (400 mL), and re-dissolved in EtOAc (800 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4 and concentrated to afford 19 (78.0 g, 87% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz CDCl3) δ 8.02 (br d, J = 7.6 Hz, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.61 - 7.70 (m, 2H), 7.50 - 7.56 (m, 2H), 7.40 (s, 1H), 2.52 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 137.19, 135.40, 134.94, 132.65, 131.97, 129.73, 128.73,

127.13, 121.54, 120.39, 113.39, 111.76, 109.40, 18.92. MS-ESI (m/z): [M+NH4]+calcd for C16H12N2O2S, 392.0069; found, 392.1.


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1-(Benzenesulfonyl)-5-iodo-4-methyl-indole-2-carbonitrile (20): To a solution of 18 (400 g, 1.35 mol, 1.0 equiv.) in AcOH (3500 mL) was added NIS (799 g, 3.37 mol, 2.5 equiv.) in portions. The reaction mixture was stirred at 80°C for 12 hours and cooled to 25 °C. The precipitated solid was collected by filtration, washed with water, and dried to afford 20 (475 g, 79% yield, 95% purity) as a white solid. 1H NMR (400 MHz DMSO-d6) δ 8.18 (s, 1H), 7.94 - 8.0 (m, 3H), 7.72 - 7.78 (m, 2H), 7.62 - 7.67 (m, 2H), 2.48 (s, 3H).

13

C NMR (400 MHz, CDCl3) δ

138.80, 137.17, 136.24, 135.83, 134.94, 129.73, 127.94, 127.12, 121.80, 113.75, 111.72, 109.04, 95.89, 24.21. MS-ESI (m/z): [M+NH4]+ calcd for C16H12N2O2S, 439.993; found, 440.0.

1-(Benzenesulfonyl)-4-methyl-5-vinyl-indole-2-carbonitrile (22): To a solution of compound 19 (4.0 g, 10.7 mmol, 1 equiv.) and compound 21 (2.46 g, 16.0 mmol, 1.5 equiv.) in 1,4-dioxane (30 mL), K2CO3 (2.95 g, 21.3 mmol, 2 equiv.), H2O (6 mL) and Pd(dppf)Cl2 (800 mg, 1.07 mmol, 0.1 equiv.) were sequentially added under N2. The reaction mixture was stirred at 80 °C for 24 hours and cooled to 25 °C. The organic layer was separated and concentrated. The residue was purified via column chromatography on silica gel (petroleum ether: ethyl acetate = 50:1-5:1) to afford compound 22 (2.5 g, 60% yield) as a yellow solid. 1H NMR (400 MHz CDCl3) δ 8.00 8.05 (m, 3H), 7.68 (d, J = 8.8 Hz, 1H), 7.58 - 7.64 (m, 1H), 7.47 - 7.53 (m, 2H), 7.43 (s, 1H), 6.99 (d, J = 17.6, 11.0 Hz, 1H), 5.67 (d, J = 17.6 Hz, 1H), 5.36 (d, J = 17.6 Hz, 1H), 2.45 (s, 3H). 13

C NMR (100 MHz CDCl3) δ 137.40, 136.00, 134.71, 133.51, 132.92, 129.62, 129.21, 128.19,

127.12, 126.92, 122.22, 116.31, 112.20, 108.64, 15.04. MS-ESI (m/z): [M+NH4]+calcd for C16H12N2O2S, 340.1120; found, 340.1

1-(Benzenesulfonyl)-5-formyl-4-methyl-indole-2-carbonitrile (23): The reaction mixture of compound 22 (1 g, 3.10 mmol, 1.0 equiv.), RuCl3 (67 mg, 0.31 mmol, 0.1 equiv.), and PhI(OAc)2



(2.6 g, 7.75 mmol, 2.5 eq) in DCM (16 mL) and H2O (4 mL) was degassed with N2 and stirred at 30 °C under N2 for 5 hours. The aqueous layer was extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified via column chromatography (SiO2, petroleum ether/ethyl acetate=100/1 to 10:1) to afford compound 23 (0.55 g, 51% yield) as white solid. 1H NMR (400 MHz CDCl3) δ 8.13 (d, J =8.8 Hz, 1H), 7.93-8.00 (m, 3H), 7.58 (t, J =7.2 Hz, 1H), 7.47 (t, J = 8.4 Hz, 3H), 2.75 (s, 3H).

13

C NMR (100 MHz CDCl3) δ 191.02, 138.79, 137.11, 136.67, 135.17, 131.00, 130.19,

129.85, 128.62, 127.25, 121.74, 112.47, 111.56, 109.97, 14.67. MS-ESI (m/z): [M+H]+calcd for C16H12N2O2S, 325.0647; found, 325.0

5-Formyl-4-methyl-1H-indole-2-carbonitrile (A): To a solution of compound 23 (0.55 g, 1.70 mmol, 1 equiv.) in THF (10 mL) was added TBAF (1 M, 2.1 mL, 1.2 equiv.). The mixture was stirred at 25 °C for 5 hours and then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was re-slurried in ethyl acetate (5 mL). The solid was collected by filtration to afford compound A (0.2 g, 64% yield, 95% purity) as a yellow solid. 5-Formyl-4-methyl-1H-indole-2-carbonitrile (A): To a solution of compound 20 (120 g, 284 mmol, 1.0 equiv.) in DMF (1000 mL), P(Cy)3 (8.39 g, 28.4 mmol, 0.1 equiv.), Et3SiH (87.0 g, 710 mmol, 2.5 equiv.), Pd(OAc)2 (3.36 g, 14.2 mmol, 0.05 equiv.) and Na2CO3 (63.4 g, 568 mmol, 2.0 equiv.) were added sequentially under N2. The reaction suspension was degassed and purged with CO several times and then stirred under CO (50 psi) at 80 °C for 48 hours and then cooled to 25 °C. The solid was filtered off and the filtrate solution was concentrated under reduced pressure. The residue was re-dissolved in EtOAc, washed with water, brine, dried over Na2SO4, and concentrated. The solid was slurryed in petroleum ether and collected by filtration to afford compound A (40.8 g, 78% yield, 98% purity) as a gray solid. 1H NMR (400 MHz DMSO-d6) δ 12.77 (br s, 1H), 10.36 (s, 1H), 7.74 - 7.80 (m, 2H), 7.43 (d, J = 8.6 Hz, 1H), 2.86 (s, 3H).

13

C NMR (100 MHz, DMSO-d6) δ 192.27, 139.64, 137.89, 127.59, 127.38, 126.91,


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114.63, 114.54, 110.96, 107.55, 14.73. HRMS-ESI (m/z): [M-H]-calcd for C11H8N2O, 183.0559; found, 183.0573.

Acknowledgements: The authors thank Dr. Brandon Seal for proofreading the manuscript. Supporting Information Available: 1H, 13C NMR and MS spectra of 12, 13, 16, 17 and A; 1H, 13

C NMR of 18, 19, 20, 22 and 23.

References: 1

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Regioselective Functionalization of 4-Methyl-1H-indole for Scalable

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