Microwave-Assisted Rapid One-Pot Synthesis of Fused and Non-Fused Indoles and 5-[18F]Fluoroindoles from Phenylazocarboxylates

Article abstract of DOI:10.1002/chem.201703890

Substituted indoles can be prepared from phenylazocarboxylates through a rapid one-pot sequence featuring a microwave-assisted Fischer indole synthesis as a key step. Considering that the phenylazocarboxylates may beforehand be modified by mild nucleophilic aromatic substitution, including the introduction of [¹⁸F]fluoride, the overall strategy offers an attractive new access to 5-[¹⁸F]fluoroindoles.

Full text of DOI:10.1002/chem.201703890

A Journal of
Accepted Article
Title: Microwave-assisted rapid one-pot synthesis of fused
and non-fused indoles and 5-[18F]fluoroindoles from
phenylazocarboxylates
Authors: Jasmin Krüll, Anja Hubert, Natascha Nebel, Olaf Prante, and
Markus Rolf Heinrich
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201703890
Link to VoR: http://dx.doi.org/10.1002/chem.201703890
Supported by

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COMMUNICATION
Microwave-assisted rapid one-pot synthesis of fused and non-
fused indoles and 5-[18F]fluoroindoles from
phenylazocarboxylates
Jasmin Krüll,[a] Anja Hubert,[a] Natascha Nebel,[b] Olaf Prante,*,[b] Markus R. Heinrich*,[a]
Dedication ((optional))
al.,[16f] 18F-substituted indoles are efficiently accessible via 18F-
Abstract: Substituted indoles can be prepared from phenylazo-
deoxyfluorination[16e] and in lower yields via 18F-fluorination of
spirocyclic iodonium(III) ylides.[16f]
carboxylates through
a rapid one-pot sequence featuring a
microwave-assisted Fischer indole synthesis as key step. As the
phenylazocarboxylates may beforehand be modified by mild
nucleophilic aromatic substitution, including the introduction of
[18F]fluoride, the overall strategy offers an attractive new access to 5-
[18F]fluoroindoles.
Our interest in this challenging task was raised by the recent
finding that tert-butyl 4-[18F]fluorophenylazocarboxylate ([18F]1a)
can be prepared from ammonium salt 2 in just 30 seconds with a
radiochemical yield of 86% (Scheme 1C).[18] If azo ester [18F]1a
and suitable ketones 3 could now be rapidly converted to indoles
[18F]4, such reaction could not only open up an attractive new
route to 5-[18F]fluoroindoles, but it would further underline the
versatility of azocarboxylates as bifunctional reagents,[19],[20] for
example in the field of combinatorial chemistry.
Indoles occur as structural elements in many pharmaceuticals,[1]
natural products[2] and compounds for diverse other appli-
cations.[3] Due to their importance, new synthetic methods are
perpetually developed.[4] Recently published strategies comprise
the assembly of the indole moiety through cobalt-,[5a-c] rhodium-
[5d,e]
or palladium-catalyzed[5f,g,h] reactions of such diverse
starting materials as nitrones,[5a] azo esters,[5d] hydrazides,[5c,e]
nitrosoanilines,[5b] enamines[5g] or imines.[5f] In addition to these
developments, the classical Fischer indole synthesis[6,7] is also
constantly improved[8,9] and remains attractive in medicinal
chemistry[10] and in natural product synthesis.[11]
Against this background, it is surprising to see that only a few
efficient strategies for the preparation of 18F-substituted indoles
are known to date. Such compounds are of high value for
radiopharmaceutical purposes, particularly for imaging by
positron emission tomography (PET),[12] but access via the
classical Fischer cyclization remained unattractive due to the
tedious synthesis of the required 18F-substituted aryl hydra-
zines.[13] In 18F-radiochemistry, preparative routes generally have
to compete with the short half-life of the fluorine-18 isotope (109
minutes),[12] whereat a major advance in direct 18F-fluorination of
aromatics[14] could be made through copper-catalyzed reactions
of aryl boronic acids and boronates.[15] While this reaction type at
first gave only low yields of 18F-substituted indoles[16a-c] and
tryptophans,[17] a remarkable breakthrough for this methodology
could recently be achieved by Zischler et al.[16d] through the
addition of alcohols to the reaction mixture (Scheme 1, A and B).
Alternatively, and as shown by Beyzavi et al.[16e] and Rotstein et
Scheme 1. Synthesis of 5-[18F]fluoroindoles. Decay-corrected radiochemical
yields.
In this communication, we now demonstrate that 18F-substituted
as well as unlabeled indoles can be prepared from phenyl-
azocarboxylates via a one-pot reaction in short overall reaction
time. The tert-butyl phenylazocarboxylates 1 used as starting
materials are readily accessible from commercially available
phenylhydrazines via Boc protection and oxidation.[19a,b]
All experiments on the optimization of the intended reaction
sequence were first carried out with non-radioactive azo ester 1a
(Scheme 2).[21]
[a]
[b]
M.Sc. J. Krüll, A. Hubert, Prof. Dr. M. R. Heinrich
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry
Friedrich-Alexander Universität Erlangen-Nürnberg
Schuhstraße 19, 91052 Erlangen, Germany
E-mail: markus.heinrich@fau.de
Dr. N. Nebel, Prof. Dr. O. Prante
Department of Nuclear Medicine, Molecular Imaging and
Radiochemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Schwabachanlage 6, 91054 Erlangen, Germany
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. Three step conversion of azocarboxylate 1a to indole 4a and
possible side reactions. Yields determined by 1H-NMR spectroscopy.
Scheme 3. Functionalization of phenylazocarboxylates 1a and 1b through
nucleophilic aromatic substitution.
Rapid reduction of 1a to hydrazide 5 and further conversion to 4-
fluorophenylhydrazine hydrochloride (6) could be achieved by
zinc powder followed by the addition of concentrated
hydrochloric acid. Upon the addition of phenylacetone (3a) and
classical heating in an oil bath, this sequence led to an overall
reaction time of 90 minutes and gave indole 4a in a yield of 63%
(see Supporting Information for details). To achieve a much
shorter reaction time for the whole sequence, and to enable
application in 18F-radiosynthesis, the final Fischer indole
cyclization of 6 and 3a was next carried out under microwave
conditions.[22] This particular step required a more extensive
optimization, since the zinc powder remaining from the first
stage could, in combination with the large excess of hydrochloric
acid required in the second stage, as well lead to a reduction of
4-fluorophenylhydrazine 6 to 4-fluoroaniline (7) (Scheme 2).[19e]
On the other hand, and assuming that zinc was fully consumed
during the formation of 6 (e.g. through formation of dihydrogen),
an air-promoted oxidation of 6 to 4-fluorophenyldiazene (8)
might occur, which would ultimately result in the formation of
fluorobenzene (9) via a radical pathway.[19d,23] In addition, a
decomposition of the desired product 4a under the strongly
acidic conditions could not be excluded at this initial stage.
After several variations of reaction time and temperature in the
microwave, as well as changes in the amount of 3a, optimized
conditions were determined (see Supporting Information). These
comprise the use of two equivalents of 3a and microwave
heating at 80°C for 10 minutes, whereby the desired indole 4a
was obtained in 80% yield and in a favorable reaction time of
only 11 minutes. The fact that only indole 4a and remaining
ketone 3a could be found as products during optimization, points
to a competing decomposition of the 4-fluorophenylhydrazine 6
via a radical pathway,[23] from which the resulting fluorobenzene
(9) can not be detected due to volatility (Scheme 2).
All three transformations could be conducted under mild
conditions using the moderately strong base potassium
carbonate at ambient temperature. Substitution of phenylazo-
carboxylate 1a with piperidine (10) gave arylamine 1c in a yield
of 92%.[19a] The diphenyl ethers 1d and 1e were obtained from
4-nitro-phenylazocarboxylate 1b upon reaction with 4-fluoro-
phenol (10) or N-acetyl L-tyrosine (11) in yields of 83% and 82%,
respectively.[19a,f] Using the optimized conditions determined
before, scope and limitations of the indole synthesis from
phenylazocarboxylates were evaluated with seven phenylazo-
carboxylic esters 1a,1c-h and seven ketones 3a-g. Selected
results from this study are shown in Scheme 4 (see Supporting
Information for eleven further examples).
Prior to the investigation of scope and limitations of the indole
synthesis, three representative phenylazocarboxylates 1c-e
were prepared via nucleophilic aromatic substitution of azo-
carboxylates 1a and 1b to underline the general bifunctional
character of these reagents (Scheme 3).
Scheme 4. One-pot synthesis of indoles 4 from phenylazocarboxylates 1 and
ketones 3. Yields after purification by column chromatography.
All seven reactions starting from the fluorinated azo ester 1a
gave the desired indoles 4 in useful yields of 52-70%, thereby
providing a sound basis for the later application in 18F-
radiochemistry. Among the experiments aimed at evaluating the
bifunctional character of azocarboxylates, namely by employing
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Table 1. Radiosynthesis of 18F-labeled indoles from tert-butyl 4-[18F]fluoro-
phenylazocarboxylate ([18F]1a) and various ketones 3.
the previously prepared conjugates 1c-e (Scheme 3), only the
reaction to indole 4i led to a significantly lower yield than 50%.
Notably, 5-amino substituted indoles such as 4h and 4k are
apparently not easy to prepare by known methods as such
reactions rarely appear in literature. An additional experiment on
a larger, nine-fold reaction scale furnished indole 4a in 63% yield
(632 mg), thus demonstrating the preparative applicability of the
indole synthesis.
In the next step, and with regard to a future application in
medicinal chemistry and 18F-radiosynthesis, the microwave-
assisted indole synthesis was applied to the derivatization of a
steroid and an opioid receptor ligand (Figure 1). Indoles derived
from steroid-like, polycyclic triterpenes have recently been found
to have cytotoxic activity thus making them potential drugs for
anti-cancer therapy.[24] Within our study, and under conditions
identical to those described above (Scheme 4), dihydro-
testosterone could be converted to the indoloterpene 13 in 52%
yield under simultaneous acetylation of the hydroxy group.
Moreover, the microwave-assisted indole synthesis enabled the
preparation of the 5’-fluoronaltrindole derivative 14 in 52% yield
from naltrexone,[25] whereat the so far unknown [18F]fluoro-
substituted analogue of 14 would be a valuable compound for
application in PET imaging studies of -opioid receptor
expression in vivo.[26,27] Naltrindole itself is known as a highly
selective -opioid receptor antagonist[28] and has recently been
employed for crystallization and X-ray structure analysis of the
corresponding ligand receptor complex.[29]
ketone
3
indole
RCY
RCY
after 10 min
(%)[a],[b]
entry
after 1 min
(%)[a],[b]
1
2
3
4
5
3a
[
18F]4a
18F]4g
28±1
53±5
64±5
27±5
7.0±4
29±1
54±5
66±3
33±3
11±1
3e
3f
[
[
18F]4j
18F]13
18F]14
dihydrotestosterone
[
naltrexone
[
[a]See experimental section for details. Radiochemical yields (RCY) are decay-
corrected and determined by radio-HPLC through integration of the
radioactivity peaks. [b]Experiments performed in duplicates.
Under the no-carrier-added conditions, the one-pot Fischer
indole synthesis starting from [18F]1a proceeded very rapidly.
Without previous optimization, radiochemical yields (RCY) in the
range of 7 to 64% were obtained after one minute, and 11 to
66% after ten minutes, revealing that the final radiochemical
yield was nearly achieved after only one minute. The relatively
low RCY of 5’-[18F]fluoronaltrindole ([18F]14) is currently due to
the formation of four different, yet unknown radioactive side-
products (Table 1, entry 5). At this point, it should be noted that
the reported RCY (Table 1) were determined from the reaction
solution and therefore cannot be directly compared with the RCY
after HPLC isolation as reported in the literature.16 Nevertheless,
this novel methodology provided radiochemical yields of new 5-
[18F]fluoro-substituted indoles, including the two highly
interesting potential PET radioligands [18F]13 and [18F]14,
sufficient for further preclinical evaluation in animal models.
In summary, it has been shown that indoles can be prepared
from phenylazocarboxylates via a rapid microwave-assisted
one-pot reaction comprising three sub-steps. Compared to
established Fischer indole syntheses starting from phenyl-
hydrazines, the use of tert-butyl phenylazocarboxylates allows
functionalization of the aromatic ring through nucleophilic
substitution prior to assembly of the indole core. Due to the short
overall reaction time and the excellent accessibility of tert-butyl
4-[18F]fluorophenylazocarboxylate,[18] this new strategy offers a
novel route to fused and non-fused 5-[18F]fluoroindoles, which
complements existing direct radiofluorination techniques for
such heterocycles.[16,17] In addition, the initial steps of the
reaction sequence provide, for the first time, a convenient
access to 4-[18F]fluorophenylhydrazine, which is now available
for the synthesis of heterocycles as well as for diverse other
radiolabeling purposes.
Figure 1. Application in the synthesis of fluorinated indoloterpene 13 and
naltrindole derivatives 14 and 15.
The reaction of naltrexone with the tyrosine-conjugate 1e to
indole 15 further emphasizes the versatile bifunctional character
of phenylazocarboxylates, as structurally complex molecules
can be prepared in few steps. Remarkably, the syntheses of
indoles 13-15 also proceeded with high regioselectivity, as
possible regioisomers could not be detected by 1H-NMR
analysis of the crude reaction mixtures.
Finally, the novel methodology for 5-fluoroindole synthesis was
adapted to 18F-radiochemistry. For this purpose, tert-butyl 4-
[18F]fluorophenylazocarboxylate ([18F]1a) was prepared from the
+
corresponding trimethylammonium derivative (2, X = NMe3 , see
Scheme 1) as previously reported, again taking advantage of the
bifunctional character of phenylazocarboxylates.[18] The radio-
labeled azocarboxylate was then reacted with phenylacetone
(3a), 2-indanone (3e), 2-tetralone (3f), dihydrotestosterone and
naltrexone under microwave conditions for one minute and for a
prolonged reaction time of ten minutes (Table 1).
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Zakarian, Angew. Chem. Int. Ed; 2015, 54, 9971-9975; Angew.Chem.
2015, 127,10109-10113.
Experimental Section
[3]
[4]
a) R. A. Irgashev, A. A. Karmatsky, G. L. Rusinov, V. N. Charushin,
Org. Lett. 2016, 18, 804-807; b) S. Kotha, A. K. Chinnam, M. E.
Shirbhate, J. Org. Chem. 2015, 80, 9141-9146.
a) J. Herraiz-Cobo, F. Albericio, M. Alvarez, Adv. Heterocycl. Chem.
2015, 116, 1-35; b) L. L. Anderson, M. A Kroc, T. W. Reidl, J. Son, J.
Org. Chem. 2016, 81, 9521-9529; c) I. Gimenez Sonsona, Synlett
2015, 26, 2325-2326; d) Y. Monguchi, Y. Sawama, H. Sajiki,
Heterocycles 2015, 91, 239-264.
a) H. Wang, M. Moselage, M. J. González, L. Ackermann, ACS Catal.
2016, 6, 2705-2709; b) Y. Liang, N. Jiao, Angew. Chem. Int. Ed.
2016, 55, 4035-4039; Angew.Chem. 2016, 128, 4103-4107; c) A.
Lerchen, S. Vásquez-Céspedes, F. Glorius, Angew.Chem. Int. Ed.
2016, 55, 3208-3211; Angew.Chem. 2016, 128, 3261-3265; d) D.
Zhao, S. Vásquez-Céspedes, F. Glorius, Angew. Chem. Int. Ed. 2015,
54 1657-1661; Angew. Chem. 2015, 127, 1677-1681; e) D. Zhao, Z.
Shi, F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 12426-12429;
Angew. Chem. 2013, 125, 12652 –12656; f) Y. Wei, I. Deb, N.
Yoshikai, J. Am. Chem. Soc. 2012, 134, 9098-9101; g) J. Zoller, D. C.
Fabry, M. A. Ronge, M. Rueping, Angew. Chem. Int. Ed. 2014, 53;
13264-13268; Angew. Chem. 2014, 126, 13480-13484; h) K. V.
Chuang, M. E. Kieffer, Reisman, E. Sarah, Org. Lett. 2016, 18, 4750-
4753.
General procedure for synthesis of indoles 4a-y, 13, 14 and
15: The convenient two-step preparation of azo esters 1 from
phenylhydrazines was described previously.[19a,b] Zinc powder
(98.1 mg, 1.50 mmol) was added to a pre-heated solution of azo
ester 1 (0.50 mmol) in acetic acid (2.50 mL) at 60 °C and the
microwave vessel was removed from the oil bath after 30
seconds. Afterwards, hydrochloric acid (0.5 mL, 11.4 N) and the
ketone 3 (1.0 mmol) were added and the vessel was sealed.
Through heating at 4 W the temperature was initially increased
to 80 °C within 15 seconds. This temperature was then
maintained over 10 minutes through heating at ca. 1 W, as
indicated by the external surface sensor. After cooling to 40 °C
in the microwave, the reaction mixture was diluted with CH2Cl2.
Sodium hydroxide (5 mL, 8 N) was added and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were washed with saturated aqueous sodium chloride (20 mL)
and after drying over anhydrous sodium sulfate, the solvent was
removed under reduced pressure. The crude product was
purified by flash column chromatography after desactivation of
the column with NEt3.
[5]
[6]
[7]
E. Fischer, F. Jourdan, Ber. Dt. Chem. Ges. 1883, 16, 2241-2245.
a) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29-41; b) D. L.
Hughes, Org. Prep. Proc. Int. 1993, 25, 607-632.
General procedure of 5-[18F]fluoroindoles [18F]4a, [18F]4g,
[18F]4j, [18F]13 and [18F]14: tert-Butyl (4-[18F]fluorophenyl)azo-
carboxylate ([18F]1a) was prepared as previously reported.[18]
Zinc (20 mg, 0.31 mmol) was placed in a microwave vial (0.5 –
2 mL) and acetic acid (0.5 mL) was added. Subsequently, 20 µL
of [18F]1a from the stock solution (5 - 10 MBq) were added to the
suspension and the reaction mixture was stirred for 30 s at
60 °C in an oil bath. Thereafter, concentrated hydrochloric acid
(100 µL) and the respective ketone 3e, dihydrostestosterone or
naltrexone (30 µmol) in DMF (50 µL) was added. The liquid
ketones 3a (25 µL) and 3f (22 µL) were added without additional
solvent. The vial was sealed and placed in the microwave
(Biotage Initiator 2.5) for 1 minutes and 10 minutes at 80 °C (10
- 20 W). After the given time intervals, aliquots (20 µL) were
drawn and quenched in acetonitrile/water 1:1 (500 µL) prior to
radio-HPLC analysis. Each experiment was performed in
duplicate from the same stock solution of [18F]1a.
[8]
a) Y.-L. Hu, D. Fang, D.-S. Li, Catal. Lett. 2016, 146, 968-976; b) Y.
Ito, M. Ueda, N. Takeda, O. Miyata, Chem. Eur. J. 2016, 22, 2616-
2619; c) B.-Y. Lim, B.-E. Jung, C.-G. Cho, Org. Lett. 2014, 16, 4492-
4495; d) K. Matcha, A. P. Antonchick, Angew. Chem. 2014, 126,
12154-12158; Angew. Chem. Int. Ed. 2014, 53, 11960-11964.
a) C. de Graaff, L. Bensch, S. J. Boersma, R. C. Cioc, M. J. van Lint,
E. Janssen, N. J. Turner, R. V. A. Orru, E. Ruijter, Angew. Chem. Int.
Ed. 2015, 54, 14133-14136; Angew. Chem. 2015, 127, 14339-14342;
b) T. J. Seguin, T. Lu, S. E. Wheeler, Org. Lett. 2015, 17, 3066-3069.
a) F.-Q. Wang, H. Yang, B. He, Y.-K. Jia, S.-Y. Meng, C. Zhang, H.-
M. Liu, F.-W. Liu, Tetrahedron 2016, 72, 5769-5775; b) S. Lepri, F.
Buonerba, L. Goracci, I. Velilla, R. Ruzziconi, B. D. Schindler, S. M.
Seo, G. W. Kaatz, G. Cruciani, J. Med. Chem. 2016, 59, 867-891; c)
R. A. Duval, J. R. Lever, Green Chem. 2010, 12, 304-309.
[9]
[10]
[11]
[12]
a) J. Park, D.-H. Kim, T. Das, C.-G. Cho, Org. Lett. 2016, 18, 5098-
5101; b) J. Moreno, E. Picazo, L. A. Morrill, J. M. Smith, N. K. Garg, J.
Am. Chem. Soc. 2016, 138, 1162-1165; c) L. M. Blair, J. Sperry,
Chem. Commun. 2016, 52, 800-802; d) J. M. Smith, J. Moreno, B. W.
Boal, N. K. Garg, J. Org. Chem. 2015, 80, 8954-8967.
For review articles, see: a) S. Preshlock, M. Tredwell, V. Gouverneur,
Chem. Rev. 2016, 116, 719-766.; b) L. Cai, S. Lu, V. W. Pike, Eur. J.
Org. Chem. 2008, 2008, 2853-2873; c) R. Littich, P. J. H. Scott,
Angew. Chem. Int. Ed. 2012, 51, 1106-1109; Angew. Chem. 2012,
124, 1132-1135; d) M. G. Campbell, J. Mercier, C. Genicot, V.
Gouverneur, J. M. Hooker, T. Ritter, Nat. Chem. 2017, 9, 1-3.
A. L. Feliu, J. Label. Compd. Radiopharm. 1988, 25, 1245-1254.
a) D. van der Born, A. Pees, A. J. Poot, R. V. A. Orru, A. D.
Windhorst, D. J. Vugts, Chem. Soc. Rev. 2017, 46, 4709-4773. b) E.
Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann, G. B. Boursalian, T.
Furuya, D. C. Choi, J. M. Hooker, T. Ritter, Science 2011, 334, 639;
c) E. Lee, J. M. Hooker, T. Ritter, J. Am. Chem. Soc. 2012, 134,
17456-17458.
Acknowledgements
The authors would like to thank the Deutsche Forschungs-
gemeinschaft (DFG) for financial support of this project (HE
5413/3-3, PR 677/6-3, and GRK1910/B3). We are further
grateful to Aleksandra Janik for the experimental assistance and
to Dr. Christoph Haas (Forchheim) for helpful discussions.
[13]
[14]
[15]
[16]
a) S. Preshlock, S. Calderwood, S. Verhoog, M. Tredwell, M. Huiban,
A. Hienzsch, S. Gruber, T. C. Wilson, N. J. Taylor, T. Cailly, M.
Schedler, T. L. Collier, J. Passchier, R. Smits, J. Mollitor, A.
Hoepping, M. Mueller, C. Genicot, J. Mercier, V. Gouverneur, Chem.
Commun. 2016, 52, 8361-8364. b) V. Gouverneur, M. Tredwell, S.
Preshlock, PCT Int. Appl. 2015, WO 2015140572.
a) A. V. Mossine, A. F. Brooks, K. J. Makaravage, J. M. Miller, N.
Ichiishi, M. S. Sanford, P. J. H. Scott, Org. Lett. 2015, 17, 5780-5783;
b) M. Tredwell, S. M. Preshlock, N. J. Taylor, S. Gruber, M. Huiban, J.
Passchier, J. Mercier, C. Génicot, V. Gouverneur, Angew. Chem. Int.
Ed. 2014, 53, 7751-7755; Angew. Chem. 2014, 126, 7885-7889; c) D.
Schäfer, P. Weis, J. Ermert, J. Castillo Melean, F. Zarrad, B.
Keywords: indole • 18-fluorine • radiochemistry • microwave •
combinatorial synthesis
References and footnotes
[1]
a) S. A. Patil, R. Patil, D. D. Miller, Curr. Med. Chem. 2011, 18, 615-
637; b) T. V. Sravanthi, S. L. Manju, Eur. J. Pharm. Sci. 2016, 91, 1-
10.
[2]
a) E. Stempel, T. Gaich, Acc. Chem. Res. 2016, 49, 2390-2402; b) M.
Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod. Rep. 2015, 32,
1389-1471; c) J. J. Jackson, H. Kobayashi, S. D. Steffens, A.
This article is protected by copyright. All rights reserved.

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Neumaier, Eur. J. Org. Chem. 2016, 4621-4628; d) J. Zischler, N.
Kolks, D. Modemann, B. Neumaier, B. D. Zlatopolskiy, Chem. Eur. J.
2017, 23, 3251-3256; e) M. H. Beyzavi, D. Mandal, M. G. Strebl, C. N.
Neumann, E. M. D’Amato, J. Chen, J. M. Hooker, T. Ritter, ACS Cent.
Sci. 2017, DOI: 10.1021/acscentsci.7b00195; f) B. H. Rotstein, L.
Wang, R. Y. Liu, J. Patteson, E. E. Kwan, N. Vasdev, S. H. Liang,
Chem. Sci. 2016, 7, 4407-4417.
[17]
a) T. Tang, H. S. Gill, A.Ogasawara, J. N. Tinianow, A. N. Vanderbilt,
S.-P. Williams, G. Hatzivassiliou, S. White, W. Sandoval, K. DeMent,
M. Wong, J. Marik, Nucl. Med. Biol. 2017, 51, 10-17; b) B. C. Giglio,
H. Fei, M. Wang, H. Wang, L. He, H. Feng, Z. Wu, H. Lu, Z. Li,
Theranostics 2017, 7, 1524-1530.
[18]
[19]
S. K. Fehler, S. Maschauer, S. B. Höfling, A. L. Bartuschat, N.
Tschammer, H. Hübner, P. Gmeiner, O. Prante, M. R. Heinrich,
Chem. Eur. J. 2014, 20, 370-375.
a) S. B. Höfling, A. L. Bartuschat, M. R. Heinrich, Angew. Chem. Int.
Ed. 2010, 49, 9769-9772; Angew. Chem. 2010, 122, 9963-9966; b) H.
Jasch, S. Höfling, M. R. Heinrich, J. Org. Chem. 2012, 77, 1520-
1532; c) R. Lasch, M. R. Heinrich, Tetrahedron 2015, 71, 4282-4295;
d) S. K. Fehler, G. Pratsch, M. R. Heinrich, Angew. Chem. Int. Ed.
2014, 53, 11361-11365; Angew. Chem. 2014, 126 , 11543-11548; e)
R. Lasch, M. R. Heinrich, J. Org. Chem. 2015, 80, 10412-10420; f) R.
Lasch, S. K. Fehler, M. R. Heinrich, Org. Lett. 2016, 18, 1586-1589.
a) N. Nebel, S. Maschauer, T. Kuwert, C. Hocke, O. Prante,
Molecules 2016, 21, 1144; b) N. Nebel, S. Maschauer, C. Hocke, H.
Hübner, P. Gmeiner, O. Prante, J. Label. Comp. Radiopharm. 2016,
59, 48-53.
[20]
[21]
[22]
For a related synthesis of indoles from hydrazides, see: a) I.-K. Park,
S.-E. Suh, B.-Y. Lim, C.-G. Cho, Org. Lett. 2009, 11, 5454-5456; b) J.
Chae, S. L. Buchwald J. Org. Chem. 2004, 69, 3336-3339.
For microwave-assisted indole synthesis, see: a) M. Desroses, K.
Wieckowski, M. Stevens, L. R. Odell, Tetrahedron Lett. 2011, 52,
4417-4420; b) G. A. Kraus, H. Guo, Org. Lett. 2008, 10, 3061-3063;
c) S. Liang, L. Hammond, B. Xu, G. B. Hammond, Adv. Synth. Catal.
2016, 358, 3313-3318; d) J. Panther, T. J. J. Müller, Synthesis 2016,
48, 974-986; e) See also ref 1a.
[23]
[24]
J. Hofmann, H. Jasch, M. R. Heinrich, J. Org. Chem. 2014, 79, 2314-
2320.
V. Kumar, N. Rani, P. Aggarwal, V. K. Sanna, A. T. Singh, M. Jaggi,
N. Joshi, P. K. Sharma, R. Irchhaiya, A. C. Burman, Bioorg. Med.
Chem. Lett. 2008, 18, 5058.
[25]
[26]
a) P. S. Portoghese, M. Sultana, H. Nagase, A. E. Takemori, J. Med.
Chem. 1988, 31, 281-282; b) P. S. Portoghese, M. Sultana, A. E.
Takemori, J. Med. Chem. 1990, 33, 1714-1720.
For a [18F]fluoroethyl-substituted analogue of naltrindole, see: W. B.
Mathews, C. M. Kinter, J. Palma, R. V. Daniels, H. T. Ravert, R. F.
Dannals, J. R. Lever, J. Label. Cpd. Radiopharm. 1999, 42, 43-54.
For radiolabelled analogues of the naltrexone derivative cyclofoxy,
see: a) C. N. Filer, J. Label. Cpd. Radiopharm. 2013, 56, 639-648.
a) A. Capasso, Med. Chem. 2007, 3, 480-487; b) S. Sakami, M.
Maeda, K. Kawai, T. Aoki, K. Kawamura, H. Fujii, K. Hasebe, M.
Nakajima, T. Endo, S. Ueno, T. Ito, J. Kamei, H. Nagase, J. Med.
Chem. 2008, 51, 4404-4411.
[27]
[28]
[29]
S. Granier, A. Manglik, A. C. Kruse, T. S. Kobilka, F. S. Thian, W. I.
Weis, B. K. Kobilka, Nature 2012, 485, 400-404.
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10.1002/chem.201703890
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jasmin Krüll, Anja Hubert, Natascha
Nebel, Olaf Prante,* Markus R. Heinrich*
Page No. – Page No.
Microwave-assisted rapid one-pot
synthesis of fused and non-fused
indoles and 5-[18F]fluoroindoles from
phenylazocarboxylates
Phenylazocarboxylates can be converted to indoles via a rapid one-pot reaction com-
prising a microwave-assisted Fischer indole cyclization. The advantage that phenylazo-
carboxylates can beforehand be modified by mild nucleophilic aromatic substitution also
enables an application of the strategy for the preparation of 5-[18F]fluoroindoles.
This article is protected by copyright. All rights reserved.