Unprotected Indazoles Are Resilient to Ring-Opening Isomerization: A Case Study on Catalytic C-S Couplings in the Presence of Strong Base

Article abstract of DOI:10.1021/acs.joc.7b02712

Indazoles represent a privileged scaffold in medicinal chemistry. In the presence of strong base, however, N-protected indazoles are prone to an undesirable ring-opening reaction to liberate o-aminobenzonitriles. By employing unprotected indazoles with a free N-H bond, isomerization is averted because the heterocycle is deprotonated in situ. We herein report functional group-tolerant and robust C-S couplings of bromoindazoles with thiols of varying electronic nature in the presence of lithium bis(trimethylsilyl)amide at elevated temperatures.

Full text of DOI:10.1021/acs.joc.7b02712

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Article
Unprotected Indazoles are Resilient to Ring-opening Isomerization: A
Case Study on Catalytic C–S Couplings in the Presence of Strong Base
Jacob M. Ganley, and Charles S. Yeung
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02712 • Publication Date (Web): 27 Nov 2017
Downloaded from http://pubs.acs.org on November 28, 2017
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Unprotected Indazoles are Resilient to Ring-opening Isomerization:
A Case Study on Catalytic C–S Couplings in the Presence of Strong Base
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Jacob M. Ganley, Charles S. Yeung*
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Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, MA 02115
charles.yeung@merck.com
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Abstract
Indazoles represent a privileged scaffold in medicinal chemistry. In the presence of strong base, however, Nꢀprotected
indazoles are prone to an undesirable ringꢀopening reaction to liberate orthoꢀaminobenzonitriles. By employing
unprotected indazoles with a free N–H bond, isomerization is averted since the heterocycle is deprotonated in situ. We
herein report a functional group tolerant and robust C–S couplings of bromoꢀindazoles with thiols of varying electronic
nature in the presence of lithium bis(trimethylsilyl)amide at elevated temperatures.
Introduction
Indazoles are an important heterocyclic scaffold in drug discovery, and these motifs often exhibit potent biological
activities across a number of targets and therapeutic disease areas.1,2,3 Due to their ubiquity in bioactive molecules and
natural products, the synthesis of functionalized indazoles is an active area of research,4,5 and indazoles bearing
substitution on N1 are common amongst this family of compounds.6,7,8 One common strategy to promote productive bond
1
For a review of biologically active indazole derivatives, see: Cerecetto, H.; Gerpe, A.; González, M.; Arán, V.; Ochoa de Ocáriz, C. Mini-Rev.
Med. Chem. 2005, 5, 869ꢀ878 and references cited therein.
Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa, M.; Nakano, S.; Morimoto, A.; Kasahara, K.; Tanaka, E.; Takada, Y.; Ohashi, S.; Mori, M.;
2
Shuto, S. J. Med. Chem. 2015, 58, 6048ꢀ6057.
Tzvetkov, N.; Hinz, S.; Küppers, P.; Gatreich, M.; Müller, C. J. Med. Chem. 2014, 57, 6679ꢀ6703.
Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 4073ꢀ4095.
Gaikwad, D.; Chapolikar, A.; Devkate, C.; Warad, K.; Tayade, A.; Pawar, R.; Domb, A. Eur. J. Med. Chem. 2015, 90, 707ꢀ731.
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Lien, J.ꢀC.; Lee, F.ꢀY.; Huang, L.ꢀJ.; Pan, S.ꢀL.; Guh, J.ꢀH.; Teng, C.ꢀM.; Kuo, S.ꢀC. J. Med. Chem. 2002, 45, 4947ꢀ4949.
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forming transformations on heterocycles is to introduce protecting groups, since unprotected heterocycles can often
compromise synthetic routes, particularly in transition metal catalysis, due to unproductive reactivity of N–H bonds and/or
catalyst deactivation.9,10
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Figure 1. Kemp-type elimination of C3-unsubstituted indazoles.
In the case of indazoles, substitution of the acidic nitrogen can be detrimental to the success of certain reactions
depending on the nature of the protecting group or functional group on N1.11 During the course of an ongoing medicinal
chemistry program, we observed an undesirable ringꢀopening isomerization reaction of N1ꢀsubstituted indazoles.
Presumably, basic organometallic reagents can rapidly deprotonate an acidic C–H bond at the C3 position,12,13,14 and
owing to the thermodynamic favorability of nitrile formation, these anions rapidly undergo Kempꢀtype eliminations to
afford their corresponding ringꢀopened orthoꢀaminobenzonitrile byꢀproducts (Figure 1).15,16 This reactivity is sparsely
documented in the literature, particularly in the context of modern transition metal catalysis wherein strong bases are
frequently used and is underappreciated as a parasitic side-reaction. Given the need to access indazoles bearing diverse
functional groups, a synthetic approach that could circumvent ringꢀopening of the heterocyclic core would be of high
utility to medicinal chemists.
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Jones, P.; Altamura, S.; Boueres, J.; Ferrigno, F.; Fonsi, M. Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J. Orsale, M.; Palumbi, M.
Pesci, S.; Roscili, G.; Scarpelli, R.; ShultzꢀFademrecht, C.; Toniatti, C.; Rowley, M. J. Med. Chem. 2009, 52, 7170ꢀ7185.
De Moor, O.; Dorgan, C.; Johnson, P.; Lambert, A.; Lecci, C.; Maillol, C.; Nugent, G.; Poignant, S.; Price, P.; Pye, R.; Storer, R.; Tinsley, J.;
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Vickers, R.; van Well, R.; Wilkes, F.; Wilson, F.; Wren, S.; Wynne, G. Bioorg. Med. Chem. Lett. 2011, 21, 4828ꢀ4831.
Slade, D.; Pelz, N.; Bodnar, W.; Lampe, J.; Watson, P. J. Org. Chem. 2009, 74, 6331ꢀ6334.
Düfert, M. A.; Billingley, K.; Buchwald, S. J. Am. Chem. Soc. 2013, 135, 12877ꢀ12885.
In comparison, N2ꢀsubstituted indazoles are resilient to basic media: Bunnell, A.; O’Yang, C.; Petrica, A.; Soth, M. Synth. Comm. 2006, 36, 285ꢀ
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293.
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Stone, T.; Eustace, E.; Pickering, M.; Daves, G. D. J. Org. Chem. 1979, 44, 505ꢀ509.
Tertov, B.; Onishchenko, P.; Koshchienko, Y.; Suvorove, G.; Malysheva, E. Chem. Heterocycl. Compd. 1982, 18, 823ꢀ826
For a related photolytic ringꢀopening of indazoles to orthoꢀaminonitriles, see: Tiefenthaler, H.; Dörscheln, W.; Göth, H.; Schmid, H. Helv. Chim.
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Acta 1967, 50, 2244–2258.
Casey, M.; Kemp, D.S.; Paul, K.; Cox, D. J. Org. Chem. 1973, 38, 2294ꢀ2301.
For a recent solution using a tempered zinc base, TMP2Zn, see: Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680ꢀ2682.
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H
N
Br
N
H
M X
H
tBuO2C
M
N
[Pd]
[Pd]
N
H
N
R1
N
R2
ref. 20
ref. 21, 22
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Br
N
N
CO2tBu
H
R1R2N
H
H
NC
N
H
CN
H
N
>20 examples
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not isolated
one example
this work
[Pd], RS
H
H
R
S
N
N
20 examples
up to 97% yield
R = aryl and alkyl
tolerates nitrile, ester, amide, carboxylic acid, alcohol, ...
Figure 2. Palladium-catalyzed couplings of unprotected indazoles in the presence of strong base.
Figure 3. Therapeutic agents bearing aromatic thioethers.
Using unprotected indazoles provides a pathway for transient protection of the azole nucleus.17 The indazole N–H
bond can be readily deprotonated, and as a consequence, productive chemical transformations can take place,
outcompeting the otherwise facile Kempꢀtype elimination and hence minimizing the formation of orthoꢀ
aminobenzonitriles. Indeed, HornerꢀWadsworthꢀEmmons olefinations18 and amide alkylations19 have been documented
using compounds containing an unprotected indazole. Additionally, catalytic C–N couplings20 and the αꢀarylation of
17
The terminology of “in situ protection” was first coined by Buchwald: Su, Mingjuan; Hoshiya, N.; Buchwald, S.L. Org. Lett. 2014, 16, 832ꢀ835.
Kim, B.ꢀK.; Kim, J.ꢀH.; Kim, N.ꢀR.; Lee, W.ꢀG.; Lee, S.ꢀD.; Yun, S.ꢀH.; Jeon, E.ꢀY.; Kim, Y.ꢀC. Bioorg. Med. Chem. Lett. 2012, 22, 6952ꢀ6956.
Wenthur, C.; Morrison, R.; Daniels, J. S.; Conn, P. J.; Lindsley, C. Bioorg. Med. Chem. Lett. 2014, 24, 2693ꢀ2698.
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Henderson, J.; Buchwald, S. Org. Lett. 2010, 12, 4442ꢀ4445.
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aliphatic nitriles21 and esters22 are known. We selected aryl thioethers as a case study to illustrate the robustness of
indazoles to ringꢀopening (Figure 2). Aryl thioethers are commonly found in biologically active, pharmaceutically
relevant compounds (Figure 3),23 and Pdꢀcatalyzed crossꢀcoupling of aryl halides with thiols can be achieved using
strong bases such as lithium bis(trimethylsilyl)amide (LiHMDS).24,25 Given the relevance of compounds such as axitinib
and a dearth of general methods for thioetherifications using unprotected indazoles, we sought to identify a robust
protocol for crossꢀcoupling a diverse range of thiols and demonstrate functional group compatibility in the context of
medicinal chemistry structureꢀactivity relationship (SAR) support. In this manuscript, we highlight the resistance of
unprotected indazoles to ringꢀopening reactions, and successfully achieve a broadly applicable palladiumꢀcatalyzed C–S
coupling. Importantly, we demonstrate that the presence of free N–H bonds does not impede the success of the catalytic
thioetherifications in a strongly basic medium and is, in fact, crucial to reaction success.
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Results and Discussion
Table 1. Reaction optimization. Conditions: bromoindazole (0.5 mmol), thiol (0.6 mmol), J009-Pd-G3 (x mol%), LiHMDS (1.2 mmol, 1.0 M in solvent), 16 h. a
Determined by LCMS.
Palladiumꢀcatalyzed thioetherifications, in general, have not been extensively studied as their corresponding C–C, C–
N, and C–O coupling counterparts.24,25,26 We began our investigation using thiophenol and 5ꢀbromoindazole as coupling
partners with the goal of identifying a robust set of reaction conditions for rapid SAR evaluation on medicinal chemistry
21
McCabe Dunn, J.; Kuethe, J.; Orr, R.; Tudge, M.; Campeau, L.ꢀC. Org. Lett.2014, 16, 6314ꢀ6317.
Laufer, R.; Ng, G.; Liu, Y.; Patel, N.; Edwards, L.; Lang, Y.; Li, S.ꢀW.; Feher, M.; Awrey, D.; Leung, G.; Beletskaya, I.; Plotnikova, O.; Mason,
22
J.; Hodgson, R.; Wei, X.; Mao, G.; Luo, X.; Huang, P.; Green, E.; Kiarash, R.; Lin, D.; HarrisꢀBrandts, M.; Ban, F.; Nadeem, V.; Mak, T.; Pan,
G.; Qiu, W.; Chirgadze, N.; Pauls, H. Bioorg Med. Chem. 2014, 22, 4968ꢀ4997.
Feng, M.; Tang, B.; Liang, S.; Jiang, X. Curr. Top. Med. Chem. 2016, 16, 1200ꢀ1216.
FernándezꢀRodríguez, M.; Shen, Q.; Hartwig, J. Chem. Eur. J. 2006, 12, 7782ꢀ7796.
FernándezꢀRodríguez, M.; Hartwig, J. J. Org. Chem. 2009, 74, 1663ꢀ1672.
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For a complementary Nꢀheterocyclic carbene based catalyst, see: Farmer, J. L.; Pompeo, M.; Lough, A. J.; Organ, M. G. Chem. Eur. J. 2014, 20,
15790ꢀ15798.
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programs (Table 1). Inspired by Hartwig’s earlier accounts, we opted to use commercially available 3rd generation
Buchwald precatalyst JosiphosꢀSLꢀJ009ꢀ1ꢀPdꢀG3 (J009-Pd-G3, 2 mol%).24, 25 In the presence of 2.4 equiv of LiHMDS, a
modest 54% conversion was observed at 100 °C after 16 h as determined by chromatography (i.e., LCMS). The known
properties of J009-Pd-G3 as a strongly electron donating and bulky ligand presumably prevent the formation of parasitic
Pd complexes that lie off the catalytic cycle. We were pleased to find that changing the solvent from toluene to
tetrahydrofuran (THF) under otherwise identical conditions resulted in >99% conversion. A preliminary assessment of
substrate scope identified that thiols containing trialkylamine functionalities were less reactive, and required a higher
temperature of 120 °C. Of note, given the reactions scales on which we are operating, we opted to use pressureꢀresistant
vials to minimize solvent evaporation since each vessel is designed to operate beyond 30 bar of pressure as set by the
manufacturer’s (Biotage) standard.
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Table 2. Palladium-catalyzed thioetherification of unprotected indazoles with aromatic thiols. Conditions: bromoindazole (0.5 mmol), thiol (0.6 mmol), J009-
Pd-G3 (2 mol%), LiHMDS (1.2 mmol, 1.0 M in THF), 120 °C, 16 h. a Isolated yield. b Not determined. ~3:1 product/byproduct as determined by LCMS. c 0.25 mmol
scale. d 5 mmol scale (~1 g).
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Next, we subjected a number of thiol coupling partners to arylation with unprotected indazoles under palladium
catalysis (Tables 2–4). Aromatic thiols of varying acidity underwent C–S coupling smoothly (Table 2). In the coupling
between 7ꢀbromoindazole and paraꢀmethoxythiophenol (entry 2), we observed complete consumption of the aryl bromide
but a ~3:1 ratio of product to bisꢀindazole thioether dimer as indicated by LCMS. The observation of an “arylꢀaryl
scrambling” was previously reported by Hartwig in which large amounts of symmetrical bisꢀaryl thioethers were formed
particularly when using electronꢀrich aromatic thiols.24 Notably, ringꢀopening isomerization was not observed in our
hands. Using paraꢀcyanothiophenol (entry 3), we demonstrated scalability of this protocol to a 1 g scale (5 mmol) without
significant changes in isolated yield (68% versus 65%).
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Table 3. Palladium-catalyzed thioetherification of unprotected indazoles with aliphatic thiols. Conditions: bromoindazole (0.5 mmol), thiol (0.6 mmol), J009-
Pd-G3 (2 mol%), LiHMDS (1.2 mmol, 1.0 M in THF), 120 °C, 16 h. a Isolated yield. b 100 °C. c LiHMDS (1.7 mmol).
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Aliphatic thiols were likewise competent coupling partners in catalytic C–S crossꢀcouplings (Table 3). Although
harsh basic conditions were used for these thioetherifications, the reaction exhibits broad functional group compatibility.
Lewisꢀbasic functional groups, including pyridine and alkylamines were tolerated (entries 5ꢀ6). Additionally, 3ꢀ
mercaptopropanꢀ1ꢀol gave the C–S coupling product exclusively, even in the presence of an unprotected alcohol (entry 7).
Likewise, carboxylic acid (entry 8) and amide (entry 9) containing thiols generated the desired aryl thioether product in
good yields. In all cases, no ringꢀopening to the orthoꢀaminobenzonitriles was observed, highlighting the robustness of
this protocol and the use of indazoles directly for functionalization without the need for a protecting group at N1.
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H
N
H
N
R SH
2 mol% J009-Pd-G3
R'
R'
R
X
N
S
N
N
N
LiHMDS
THF
H
H
Entry Bromoindazole
Thiol
Product
Yielda
NHAc
Br
H
S
H
SH
N
1
2
48%
77%
N
NHAc
N
N
3a
NHAc
Br
S
H
N
H
SH
MeO
MeO
N
NHAc
N
N
3b
NHAc
Br
Cl
S
H
H
N
N
SH
3
4
66%
52%
N
N
NHAc
Cl 3c
NHAc
Br
S
H
N
H
N
SH
N
NHAc
N
N
Cl
Cl
3d
H
N
H
N
NC
NC
SH
N
5
54%
NHAc
3e
S
Br
NHAc
Table 4. Palladium-catalyzed thioetherification of substituted unprotected indazoles with aliphatic thiols. Conditions: bromoindazole (0.5 mmol), thiol (0.6
mmol), J009-Pd-G3 (2 mol%), LiHMDS (1.7 mmol, 1.0 M in THF), 120 °C, 16 h. a Isolated yield.
With an excellent general scope of thiols and functional group compatibility for our C–S crossꢀcouplings, we next
evaluated a range of bromoindazoles (Table 4). Bromoindazoles bearing additional substitution on the ring underwent
thioetherification in good yields. Methyl (entry 1), methoxy (entry 2), chloro (entries 3ꢀ4), and cyano (entry 5) functional
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groups were all well tolerated. In the coupling of 4ꢀchloroꢀ7ꢀbromoindazole and 5ꢀchloroꢀ7ꢀbromoindazole, we observed
thioetherification of both the C–Br and C–Cl bonds (~15–20% of the bisꢀthioether as determined by LCMS).
5
6
H
N
N
7
8
9
H
tBuO2C
3f
N
SH
N
+
S
tBuO2C
LiHMDS
THF
N
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Br
N
2 mol% J009-Pd-G3: 69%
J009-Pd-G3
0 mol%
: 76%
H
N
N
N
H
N
N
N
SH
N
+
S
N
LiHMDS
THF
N
3g
Cl
N
2 mol% J009-Pd-G3: 38%
0 mol% J009-Pd-G3: 37%
Figure 4. A SNAr thioetherification of electron-deficient unprotected indazoles with aliphatic thiols. Conditions: bromoindazole (0.5 mmol), thiol (0.6 mmol),
J009-Pd-G3 (2 mol%), LiHMDS (1.2 mmol, 1.0 M in THF), 120 °C, 16 h.
In the course of our scope examination, we attempted to crossꢀcouple electronꢀdeficient indazole substrates such as
tertꢀbutyl 4ꢀbromoꢀ5ꢀcarboxylate and 4ꢀchloroꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine with a thiol (Figure 4). Surprisingly, the
reaction produced similar quantities of desired product in the absence of palladium, indicating that a facile SNAr reaction
may take place in specific instances provided that a suitable halide leaving group is present. It is significant that the
deprotonation of the azole N–H does not impede the SNAr reaction from proceeding. Importantly, this background activity
is unique to electronꢀdeficient indazoles, as electronꢀneutral and electronꢀrich substrates are unreactive (see Table 1).
Conclusion
We have demonstrated a robust protocol for functionalizing indazoles utilizing strongly basic reaction conditions. The
Pdꢀcatalyzed C–S coupling with thiols using unprotected indazoles as substrates proceeds with good to excellent yields,
and these reactions exhibit a high degree of functional group tolerance. Together with the known C–N couplings, as
reported by Buchwald,20 and C–C couplings, as reported by the Merck Process21 and University Health Network22 groups,
we anticipate that the guidance delineated in this manuscript will enable future medicinal chemistry efforts on bioactive
indazoles.
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Experimental Section
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General Methods. All reactions were performed in scintillation or microwave vials under an atmosphere of nitrogen.
All reagents and solvents were purchased from commercial sources and used without further purification. Reactions were
monitored by LCMS or thin layer chromatography (TLC) on silica gel and visualized with UV light (254 nm). LCMS
samples were run on an Agilent 1100 or 1200 system. Flash chromatography was performed using preꢀpacked RediSep Rf
silica gel columns on a Teledyne Isco CombiFlash Rf automated chromatography system. Organic solutions were
concentrated under reduced pressure on a Heidolph rotary evaporator. Reversedꢀphase highꢀperformance liquid
chromatography was carried out using an Agilent 1100 HPLCꢀMSD system consisting of a 6130B single quadrupole
massꢀselective detector (MSD), G1315B diode array detector, G2258A autosampler, two G1361A preparative pumps, one
G1379A quaternary pump with degasser, one G1312A binary pump, and three G1364B fraction collectors from Agilent
Technologies. System control and data analysis was performed using Agilent’s ChemStation software, revision B.03.01ꢀ
SR.1. A Waters XBridge C18 OBD Prep Column, 100Å, 5 µm, 19 mm X 150 mm column was used as the stationary
phase (Waters Corporation). Gradient elution was carried out using water and acetonitrile as the mobile phase. An
aqueous 10% ammonium hydroxide solution was teed into the mobile phase as a modifier using a static mixer prior to the
column, pumped at 1% of the total mobile phase flow rate. ESI massꢀtriggered fraction collected was employed using
positive ion polarity scanning to monitor for the target mass.
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Proton nuclear magnetic resonance (1H NMR) spectra and protonꢀdecoupled carbon nuclear magnetic resonance
(13C{1H} NMR) spectra were recorded on a Varian 500 (500 MHz) spectrometer at ambient temperature. All chemical
shifts (δ) are reported in parts per million (ppm) and referenced to residual protium or the carbon resonance of the NMR
solvent, respectively. Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration. Highꢀresolution mass spectrometry
(HRMS) data were recorded on a Waters Xevo G2 QTof instrument in either ESI+ or ESI– (electrospray) ionization
mode.
General Procedure. To a 5 mL microwave vial was added bromoindazole (0.5 mmol), JosiphosꢀSLꢀJ009ꢀ1 PdꢀG3
(9.2 mg, 0.05 mmol, 2 mol%), and thiol (0.6 mmol, 1.2 equiv.). Following a dropwise addition of LiHMDS (1.0 M in
THF, 1.2 mL, 1.2 mmol, 2.4 equiv.), the resulting mixture was heated to 100–120°C for 16 h. After cooling to rt, the
reaction mixture was quenched by the addition of 3 mL of MeOH, filtered through a bed of celite, and washed with
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MeOH. The filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel or
massꢀdirected reversedꢀphase HPLC to give analytically pure product. Note: caution should be taken due to the elevated
internal pressure of each reaction vessel; we opted to use pressure-resistant vials to minimize solvent evaporation since
each vessel is designed to operate beyond 30 bar of pressure as set by the manufacturer’s (Biotage) standard.
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7-(Phenylthio)-1H-indazole (1a): 98.1 mg, 87%, 0–30% EtOAc/hexanes. Pale brown solid. H NMR (500 MHz,
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MeOD) δ 8.12 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.27–7.12 (m, 6H). C{1H} NMR (125 MHz,
CDCl3) δ 141.2, 135.7, 135.2, 133.0, 129.3 (2C), 128.3 (2C), 126.5, 123.9, 122.0, 121.8, 114.3. HRMS (ESI) m/z calc’d
for C13H11N2S (M+H): 227.0643, found: 227.0647.
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7-((4-Methoxyphenyl)thio)-1H-indazole (1b): 78.5 mg, 61%, 0–25% EtOAc/hexanes. Brown solid. H NMR (500
MHz, CDCl3) δ 8.12 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 7.7
Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 3.79 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 159.4, 140.5, 135.6, 132.4 (2C),
130.5, 124.3, 123.9, 121.8, 120.8, 117.3, 115.2 (2C), 55.4. HRMS (ESI) m/z calc’d for C14H13N2OS (M+H): 257.0748,
found: 257.0752.
4-((1H-Indazol-7-yl)thio)-N,N-dimethylaniline (1c): 54.8 mg (0.25 mmol scale), 81%, 0–25% EtOAc/DCM. Brown
solid. 1H NMR (500 MHz, CDCl3) δ 10.35 (br s, 1H), 7.97 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.06
(s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.3 Hz, 2H), 3.02 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 150.8, 140.8,
140.4, 136.5 (2C), 134.7, 121.1, 120.8, 120.8, 116.8, 113.1 (2C), 106.7, 40.3 (2C). HRMS (ESI) m/z calc’d for C15H16N3S
(M+H): 270.1065, found: 270.1060.
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4-((1H-Indazol-5-yl)thio)benzonitrile (1d): 85.6 mg, 68%, 0–20% EtOAc/DCM. Pale brown solid. H NMR (500
MHz, MeOD) δ 8.12 (s, 1H), 8.08 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H),
7.14 (d, J = 8.2 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 146.8, 140.3, 135.2, 133.5, 132.3 (2C), 129.0, 126.5 (2C),
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124.6, 122.1, 118.9, 111.6, 108.4. HRMS (ESI) m/z calc’d for C14H10N3S (M+H): 252.0595, found: 252.0594.
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7-(Octylthio)-1H-indazole (2a): 122.1 mg, 93%, 0–25% EtOAc/hexanes. Pale brown solid. H NMR (600 MHz,
CDCl3) δ 8.16 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.17 (t, J = 7.6 Hz, 1H), 2.95 (t, J =
7.4 Hz, 2H), 1.63 (quin, J = 7.6 Hz, 2H), 1.41 (quin, J = 7.3 Hz, 2H), 1.35–1.19 (m, 8H), 0.87 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 141.4, 135.5, 130.3, 123.3, 121.5, 120.1, 117.4, 34.8, 31.8, 29.7, 29.2, 29.1, 28.7, 22.7, 14.1.
HRMS (ESI) m/z calc’d for C15H23N2S (M+H): 263.1582, found: 263.1583.
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7-(Cyclohexylthio)-1H-indazole (2b): 110.3 mg, 95%, 0–25% EtOAc/hexanes. White solid. H NMR (500 MHz,
CDCl3) δ 8.18 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 3.09 (t, J = 10.7 Hz,
1H), 1.94 (d, J = 11.7 Hz, 2H), 1.75 (d, J = 10.4 Hz, 2H), 1.67–1.51 (m, 1H), 1.39 (q, J = 11.0 Hz, 2H), 1.32–1.14 (m,
3H). 13C{1H} NMR (125 MHz, CDCl3) δ 142.7, 135.7 133.4, 123.3, 121.5, 121.0, 115.1, 47.8, 33.7 (2C), 26.1 (2C), 25.6.
HRMS (ESI) m/z calc’d for C13H17N2S (M+H): 233.1112, found: 233.1114.
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7-(tert-Butylthio)-1H-indazole (2c): 91.7 mg, 89%, 0–25% EtOAc/hexanes. White solid. H NMR (500 MHz,
CDCl3) δ 8.19 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 1.33 (s, 9H). C{1H}
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NMR (125 MHz, CDCl3) δ 144.0, 136.6, 135.6, 123.3, 122.1, 121.3, 113.9, 48.1, 31.2 (3 C). HRMS (ESI) m/z calc’d for
C11H15N2S (M+H): 207.0956, found: 207.0952.
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7-((4-Fluorobenzyl)thio)-1H-indazole (2d): 88.6 mg, 69%, 0–20% EtOAc/hexanes. Pale brown oil. H NMR (500
MHz, CDCl3) δ 8.13 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 8.3
Hz, 2H), 6.90 (t, J = 8.4 Hz, 2H), 4.04 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 163.0, 161.1, 142.0, 135.6, 133.6,
132.8, 130.3, 130.3, 123.3, 121.8, 121.4, 115.5, 115.3, 39.6. HRMS (ESI) m/z calc’d for C14H12FN2S (M+H): 259.0705,
found: 259.0702.
7-((Pyridin-3-ylmethyl)thio)-1H-indazole (2e): 88.6 mg, 73.4%, 5–95% MeCN/H2O with 0.1% NH4OH. Pale brown
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oil. H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.00 (s, 1H), 7.65–7.56 (m, 2H), 7.34 (s, 1H),
7.17 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.07 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 149.0, 147.6, 140.6,
137.1, 134.3, 134.0, 133.4, 123.8, 123.6, 122.2, 121.3, 111.7, 36.5. HRMS (ESI) m/z calc’d for C13H12N3S (M+H):
242.0752, found: 242.0742.
3-((1H-Indazol-5-yl)thio)-N,N-dimethylpropan-1-amine (2f): 114.3 mg, 97%, 0–15% MeOH/DCM with 1% Et3N.
Brown solid. 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.78 (s, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H),
2.93 (t, J = 7.3 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H), 2.28 (s, 6H), 1.82 (quin, J = 7.3 Hz, 2H). 13C{1H} NMR (125 MHz,
CDCl3) δ 139.3, 134.0, 130.4, 127.0, 123.9, 123.7, 110.2, 58.3, 45.3, 33.6, 27.2. HRMS (ESI) m/z calc’d for C12H18N3S
(M+H): 236.1221, found: 236.1225.
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3-((1H-Indazol-7-yl)thio)propan-1-ol (2g): 76.1 mg, 73.1%, 0–5% MeOH/DCM. Pale brown solid. H NMR (500
MHz, CDCl3) δ 8.15 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 3.92 (t, J = 5.8
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Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.88 (quin, J = 6.4 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 141.4, 135.2, 131.3,
123.3, 121.5, 120.8, 116.9, 60.4, 31.4, 31.4. HRMS (ESI) m/z calc’d for C10H13N2OS (M+H): 209.0748, found: 209.0745.
6-((1H-Indazol-4-yl)thio)hexanoic acid (2h): 100.7 mg, 76%, 5–95% MeCN/H2O with 0.1% NH4OH. White
solid.1H NMR (500 MHz, MeOD) δ 8.07 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 6.9 Hz,
1H), 3.08 (t, J = 7.3 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.70 (quin, J = 7.4 Hz, 2H), 1.62 (quin, J = 7.3 Hz, 2H), 1.52 (quin,
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J = 6.8 Hz, 2H). C{1H} NMR (125 MHz, MeOD) δ 176.4, 140.2, 132.1, 129.8, 126.8, 123.0, 119.7, 107.5, 33.7, 32.2,
28.6, 27.9, 24.3. HRMS (ESI) m/z calc’d for C13H17N2O2S (M+H): 265.1010, found: 265.1013.
N-(2-((1H-Indazol-4-yl)thio)ethyl)acetamide (2i): 85.8 mg, 73%, 5–95% MeCN/H2O with 0.1% NH4OH. Pale
brown solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.1
Hz, 1H), 5.94 (br s, 1H), 3.51 (q, J = 6.2 Hz, 2H), 3.21 (t, J = 6.3 Hz, 2H), 1.95 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3)
δ 170.3, 140.1, 133.7, 128.2, 127.2, 123.8, 121.2, 108.3, 38.8, 33.0, 23.2. HRMS (ESI) m/z calc’d for C11H14N3OS (M+H):
236.0857, found: 236.0863.
N-(2-((6-Methyl-1H-indazol-7-yl)thio)ethyl)acetamide (3a): 59.8 mg, 48%, 5–95% MeCN/H2O with 0.1% NH4OH.
White solid. 1H NMR (500 MHz, MeOD) δ 8.03 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.24 (t, J = 7.0
Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H), 2.66 (s, 3H), 1.87 (s, 3H). 13C{1H} NMR (125 MHz, MeOD) δ 172.0, 143.4, 141.7,
134.4, 123.9, 121.8, 120.9, 113.3, 39.4, 33.8, 21.0, 19.1. HRMS (ESI) m/z calc’d for C12H16N3OS (M+H): 250.1014,
found: 250.1007.
N-(2-((6-Methoxy-1H-indazol-7-yl)thio)ethyl)acetamide (3b): 102.7 mg, 77%, 5–95% MeCN/H2O with 0.1%
NH4OH. White solid. 1H NMR (500 MHz, MeOD) δ 7.98 (s, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 3.85
(s, 3H), 3.36 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H), 1.89 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.7, 154.9,
137.7, 134.9, 123.6, 122.9, 110.0, 100.4, 55.9, 39.4, 35.6, 23.2. HRMS (ESI) m/z calc’d for C12H16N3O2S (M+H):
266.0963, found: 266.0962.
N-(2-((4-Chloro-1H-indazol-7-yl)thio)ethyl)acetamide (3c): 85.8 mg, 66%, 5–95% MeCN/H2O with 0.1% NH4OH.
Pale brown solid. 1H NMR (500 MHz, MeOD) δ 8.11 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 3.94 (s,
3H), 3.23 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 1.83 (s, 3H). 13C{1H} NMR (125 MHz, MeOD) δ 172.0, 141.8,
132.7, 131.1, 125.7, 122.2, 120.6, 115.5, 38.9, 33.2, 21.1. HRMS (ESI) m/z calc’d for C11H13ClN3OS (M+H): 270.0468,
found: 270.0465.
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N-(2-((5-Chloro-1H-indazol-7-yl)thio)ethyl)acetamide (3d): 70.1 mg, 52%, 5–95% MeCN/H2O with 0.1% NH4OH.
Pale brown solid. 1H NMR (500 MHz, MeOD) δ 8.07 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 3.38 (t, J = 6.8 Hz, 2H), 3.13 (t, J
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= 7.0 Hz, 2H), 1.89 (s, 3H). C{1H} NMR (125 MHz, MeOD) δ 172.1, 139.3, 133.9, 128.9, 126.1, 123.9, 118.8, 118.7,
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38.8, 32.7, 21.0. HRMS (ESI) m/z calc’d for C11H13ClN3OS (M+H): 270.0468, found: 270.0464.
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N-(2-((6-Cyano-1H-indazol-4-yl)thio)ethyl)acetamide (3e): 70.7 mg, 54%, 5–95% MeCN/H2O with 0.1% NH4OH.
Brown solid. 1H NMR (500 MHz, MeOD) δ 8.21 (s, 1H), 7.84 (s, 1H), 7.40 (s, 1H), 3.46 (t, J = 7.0 Hz, 2H), 3.28 (d, J =
6.7 Hz, 3H), 1.91 (s, 3H). 13C{1H} NMR (125 MHz, MeOD) δ 172.1, 132.5, 132.0, 124.5, 119.6, 118.5, 113.1, 110.0,
109.9, 38.5, 30.9, 21.0. HRMS (ESI) m/z calc’d for C12H13N4OS (M+H): 261.0810, found: 261.0807.
tert-Butyl 4-((pyridin-3-ylmethyl)thio)-1H-indazole-5-carboxylate (3f): 129.7 mg, 76%, 0–25% EtOAc/DCM.
White solid. 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 8.07 (d, J = 9.6 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.0
Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.13 (t, J = 8.7 Hz, 1H), 4.17 (s, 2H), 1.61 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ
167.0, 149.1, 147.9, 140.4, 136.7, 135.5, 134.2, 131.5, 127.8, 127.1, 126.8, 123.5, 110.2, 82.1, 38.2, 28.3 (3 C). HRMS
(ESI) m/z calc’d for C18H20N3O2S (M+H): 342.1276, found: 342.1275.
4-((Pyridin-3-ylmethyl)thio)-1H-pyrazolo[3,4-d]pyrimidine (3g): 45.5 mg, 37%, 5–95% MeCN/H2O with 0.1%
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NH4OH. Yellow solid. H NMR (500 MHz, MeOD) δ 8.72 (s, 1H), 8.68 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.14 (s, 1H),
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7.98 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.0, 4.9 Hz, 1H), 4.69 (s, 2H). C{1H} NMR (125 MHz, CDCl3) δ 164.2, 154.1,
152.5, 150.1, 148.5, 136.9, 133.5, 132.7, 123.6, 111.7, 30.1. HRMS (ESI) m/z calc’d for C11H10N5S (M+H): 244.0657,
found: 244.0650.
Acknowledgements
We thank Lisa M. Nogle, David A. Smith, and Mark Pietrafitta for reversedꢀphase purifications. We thank Rosina
Ayore and Wilfredo Pinto for collecting HRMS data. We thank Jamie McCabe Dunn, Nunzio Sciammetta, and Pamela
Tadross for helpful discussions. We are grateful to the Merck 2016 Chemistry Internship Program, David Witter, Phieng
Siliphaivanh, and Johnny Bennett for support of J. M. G.
Supporting Information Statement
The Supporting Information is available free of charge on the ACS Publications website.
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Copies of 1H and 13C{1H} spectra of isolated compounds (PDF).
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References
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(1) For a review of biologically active indazole derivatives, see: Cerecetto, H.; Gerpe, A.; González, M.; Arán, V.; Ochoa de Ocáriz, C. Mini-
Rev. Med. Chem. 2005, 5, 869ꢀ878 and references cited therein.
(2) Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa, M.; Nakano, S.; Morimoto, A.; Kasahara, K.; Tanaka, E.; Takada, Y.; Ohashi, S.; Mori,
M.; Shuto, S. J. Med. Chem. 2015, 58, 6048ꢀ6057.
(3) Tzvetkov, N.; Hinz, S.; Küppers, P.; Gatreich, M.; Müller, C. J. Med. Chem. 2014, 57, 6679ꢀ6703.
(4) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 4073ꢀ4095.
(5) Gaikwad, D.; Chapolikar, A.; Devkate, C.; Warad, K.; Tayade, A.; Pawar, R.; Domb, A. Eur. J. Med. Chem. 2015, 90, 707ꢀ731.
(6) Lien, J.ꢀC.; Lee, F.ꢀY.; Huang, L.ꢀJ.; Pan, S.ꢀL.; Guh, J.ꢀH.; Teng, C.ꢀM.; Kuo, S.ꢀC. J. Med. Chem. 2002, 45, 4947ꢀ4949.
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