Regioselective Functionalization of 4-Methyl-1H-indole for Scalable Synthesis of 2-Cyano-5-formyl-4-methyl-1H-indole

Article abstract of DOI:10.1021/acs.oprd.7b00370

We report a five-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 regioselectively installed at the 2 and 5 position, respectively. T

Full text of DOI:10.1021/acs.oprd.7b00370

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Full Paper
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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Regio-selective Functionalization of 4-Methyl-1H-indole for Scalable
Synthesis of 2-Cyano-5-formyl-4-methyl-1H-indole
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Jun Zhang§; Yun Hu§; Haiyu Wang§; Aixin Guo§; Jianshe Kong§, Rujian Ma§
Tao Wu†; Yi Wang†; LianꢀSheng Li†; Wanping Mai‡; Pingda Ren‡; Xiaohu Deng‡*
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§ 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: xiaohu@kuraoncology.com
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Abstract: we report a 5ꢀstep synthesis of 2ꢀcyanoꢀ5ꢀformylꢀ4ꢀmethylꢀ1Hꢀindole through
sequential functionalization of readily available 4ꢀmethylꢀ1Hꢀindole. Cyano and aldehyde
functionalities are regioꢀselectively installed at 2 and 5 position, respectively. The sequence is
concise and highꢀyielding, amenable for kilogram scale production.
Keywords: Indole, sequential functionalization, flow chemistry, regioꢀselectivity, formylation
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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 regioꢀchemistry. 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 4ꢀmethyl indole ring, as represented in Scheme 1. Strategy I starts from
functionalized phenyl precursors and builds the indole 5ꢀmember ring. The advantage of this
approach is to have the requisite functional groups appropriately positioned at the beginning,
therefore, eliminating the regioꢀselectivity 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 4ꢀmethylꢀindoles, taking advantages of positionꢀspecific 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 2ꢀcyanoꢀ5ꢀformylꢀ4ꢀ
methylꢀ1Hꢀindole (Scheme 1, compound A), utilizing both strategies. Strategy I was initially
employed and flow chemistry was developed to address the safety and lowꢀyield issues in the
key indole cyclization step. Subsequently, strategy II was successfully applied to the
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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, triꢀsubstituted 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 baseꢀ
mediated transformation of Br to CHO proved to be rather difficult and the yield dropped
precipitously along with the reaction scale. Recognizing the difficulty of lateꢀstage 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.
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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 3ꢀ5), 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.
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Table 1. Optimization of indole formation step
entry
solvent
conditions
HPLC yield
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Batch chemistry
110 oC, 1 h
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2
Toluene
Xylenes
11%
34%
140 oC, 2 h
Flow chemistry*
140 oC, 8 min
140 oC, 15 min
180 oC, 8 min
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Toluene
Toluene
Xylenes
12%
33%
78%
6
Xylenes
180 oC, 8 min
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 bisꢀbrominated product
was observed, with monoꢀbrominated 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 bisꢀbromination, regioꢀselectively
at 3 and 5 positions to afford 12. Taking advantage of the higher reactivity at the 3 position,
monoꢀdebromination 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. Regioꢀselective bromination of indole 11.
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Nevertheless, we were very much encouraged by the feasibility of regioꢀselective
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 orthoꢀlithiation 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. Vilsmeierꢀtype reaction conditions for the direct installation of aldehyde functionality on
18 gave a complex mixture of products. Drawing on prior experience with 11, regioꢀselective
halogenation of 18 was explored. To our pleasant surprise, monoꢀhalogenation 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 electronꢀwithdrawing CN
group.12
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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
nꢀBuLi/DMF conditions13 yielded only trace amounts of the desired product. An extensive
survey of combinations of strong bases such as nꢀBuLi, iPrMgCl, iPrMgCl LiCl 14 and
•
iPrBu2MgLi 15 with formylating reagents such as DMF, PhMeNCHO, morpholineꢀCHO, Nꢀ
formylsaccharin 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 metalꢀcatalyzed crossꢀcoupling reactions. Pd catalyzed
Suzuki crossꢀcoupling 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 iodoꢀsubstrate 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 oneꢀpot fashion to afford an excellent 80% isolated
yield of target compound A.
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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 regioꢀselective
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:
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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 LCꢀMS apparatus with an ESI
detector. HRMS (ESI) was performed on a µTof apparatus.
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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)ꢀ2ꢀazidoꢀ3ꢀ[3ꢀ(1,3ꢀdioxolanꢀ2ꢀ
yl)ꢀ2ꢀmethylꢀphenyl]propꢀ2ꢀenoate ethyl (Z)ꢀ2ꢀazidoꢀ3ꢀ(oꢀtolyl)propꢀ2ꢀenoate (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 reꢀslurried 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 4ꢀmethylꢀ
1Hꢀindoleꢀ2ꢀcarboxylate (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
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concentrated to afford compound 12 (0.6 g, 1.6 mmol, 58% yield) as a white solid. 1H NMR
(400 MHz, DMSOꢀd6) 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). 13C NMR (100 MHz, DMSOꢀd6) 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. HRMSꢀESI
(m/z): [MꢀH]ꢀ calcd for C12H11Br2NO2, 359.9079; found, 359.9057.
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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 Nꢀmethylpyrrole (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
1
2:1) to afford 13 (0.3 g, 1.01 mmol, 73%) as a white solid. H 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). 13C 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. HRMSꢀ
ESI (m/z): [MꢀH]ꢀ calcd for C12H12BrNO2, 279.9973; found 279.9980.
1-(Benzenesulfonyl)-4-methyl-indole (16): To a solution of 4ꢀmethylꢀ1Hꢀindole (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 reꢀdissolved 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
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a white solid. H NMR (400 MHz DMSOꢀd6) 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). 13C NMR (100 MHz DMSOꢀd6) 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.
HRMSꢀESI (m/z): [M+H]+ calcd for C15H13NO2S, 272.0745; found, 272.0740.
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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
2ꢀisocyanatoꢀ2ꢀmethylꢀpropane (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,
1
81% yield, 95% purity) as a white solid. H NMR (400 MHz DMSOꢀd6) 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). 13C NMR (100
MHz DMSOꢀd6) 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. HRMSꢀESI (m/z): [M+H]+ calcd for
C20H22N2O3S, 371.1429; found, 371.1438.
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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 reꢀslurryed in 3:1 MTBE/EtOAc and filtered to afford compound 18
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(308 g, 81% yield, 99% purity) as an offꢀwhite solid. H NMR (400 MHz DMSOꢀd6) 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). 13C NMR (100 MHz, DMSOꢀd6) 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. MSꢀESI
(m/z): [MꢀH]ꢀ 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 reꢀdissolved in EtOAc (800 mL). The
organic layer was washed with brine (200 mL), dried over Na2SO4 and concentrated to afford 19
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(78.0 g, 87% yield, 95% purity) as a yellow solid. H 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). 13C 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. MSꢀESI (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 DMSOꢀd6) 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). 13C 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. MSꢀESI (m/z): [M+NH4]+ calcd for C16H12N2O2S, 439.993; found, 440.0.
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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 1,4ꢀdioxane
(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 = 50:1ꢀ5:1)
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).
13C 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. MSꢀESI (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
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(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), 7.93ꢀ8.00 (m, 3H), 7.58 (t, J =7.2 Hz, 1H), 7.47 (t, J = 8.4 Hz, 3H), 2.75
(s, 3H). 13C 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. MSꢀESI (m/z): [M+H]+calcd for
C16H12N2O2S, 325.0647; found, 325.0
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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 reꢀslurried 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 reꢀdissolved in EtOAc, washed with water, brine, dried over
Na2SO4, and concentrated. The solid was slurryed in petroleum ether and collected by filtration
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to afford compound A (40.8 g, 78% yield, 98% purity) as a gray solid. H NMR (400 MHz
DMSOꢀd6) 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). 13C NMR (100 MHz, DMSOꢀd6) 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. HRMSꢀESI (m/z): [MꢀH]ꢀcalcd for C11H8N2O, 183.0559;
found, 183.0573.
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Acknowledgements:
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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,
13C NMR of 18, 19, 20, 22 and 23.
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