Extending the versatility of the Hemetsberger-Knittel indole synthesis through microwave and flow chemistry

Article abstract of DOI:10.1016/j.bmcl.2013.01.066

Microwave, flow and combination methodologies have been applied to the synthesis of a number of substituted indoles. Based on the Hemetsberger-Knittel (HK) process, modifications allow formation of products rapidly and in high yield. Adapting the methodology allows formation of 2-unsubstituted indoles and derivatives, and a route to analogs of the antitumor agent PLX-4032 is demonstrated. The utility of the HK substrates is further demonstrated through bioconjugation and subsequent ring closure and via Huisgen type [3+2] cycloaddition chemistry, allowing formation of peptide adducts which can be subsequently labeled with fluorine tags.

Full text of DOI:10.1016/j.bmcl.2013.01.066

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1740–1742
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Bioorganic & Medicinal Chemistry Letters
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Extending the versatility of the Hemetsberger–Knittel indole
synthesis through microwave and flow chemistry
⇑
Nadeesha Ranasinghe, Graham B. Jones
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave, flow and combination methodologies have been applied to the synthesis of a number of
substituted indoles. Based on the Hemetsberger–Knittel (HK) process, modifications allow formation of
products rapidly and in high yield. Adapting the methodology allows formation of 2-unsubstituted
indoles and derivatives, and a route to analogs of the antitumor agent PLX-4032 is demonstrated. The
utility of the HK substrates is further demonstrated through bioconjugation and subsequent ring closure
and via Huisgen type [3+2] cycloaddition chemistry, allowing formation of peptide adducts which can be
subsequently labeled with fluorine tags.
Received 12 October 2012
Revised 4 January 2013
Accepted 16 January 2013
Available online 26 January 2013
Keywords:
Flow
Microwave
Indoles
Ó 2013 Elsevier Ltd. All rights reserved.
Nitrene insertion
Decarboxylation
PLX-4032
Click chemistry
Fluorine labeling
Indoles remain key building blocks in contemporary medici-
nal chemistry due to their ease of functionalization and desirable
pharmacokinetic/pharmacodynamic properties.1 Myriad proce-
dures for their synthesis are available recognizing their
importance as targets over the past 100 years.2 Stimulated by
its elegant use in the preparation of complex indole based
natural products,3 we have studied refinements of the Hemets-
berger–Knittel process, which produces indole-2-carboxyl esters
via nitrene insertion of azidocinnamates (viz. 2 to >3, Scheme 1).4
Specifically, use of microwave irradiation greatly accelerates the
process,5 and can also be used to promote decarboxylation of
(hydrolyzed) product (5).6 Recently a renaissance in interest
has surfaced, with applications of microwave,7 flow,8 and transi-
tion metal catalyzed methods9 to optimize the process, under-
scoring the importance of indole substrates and their
heterocyclic variants in drug discovery. Based on experience
using contemporary microwave, flow, and flow-microwave com-
bination reactors, we assembled a series of substrates 2 and
investigated comparative conversion to the corresponding in-
dole-2-carboxylates 3 under a variety of conditions (Table 1).10
The conventional thermolysis (xylene, 140 °C, 2 h) gives moder-
ate to good yields across a range of substrates, yields falling
off in the case of R = I, F (entries 3, 6). Conversely, use of micro-
waves gave consistently good yields in all cases examined at the
optimal temperature of 200 °C for 10 min (entries 1–12).7 Adap-
tation in a flow based microreactor (165 °C) gave comparable re-
sults save for additional reduction in reaction times to ꢀ1 min.8
The time savings using MW and flow based thermolysis are con-
siderable, and the procedures were also amenable to a Rh cata-
lyzed process, reducing reaction times from >12 h to <30 min
(entries 9–12).9b Having earlier demonstrated that the corre-
sponding carboxylates 5 (derived from hydrolysis of 3) are effec-
tive substrates for MW induced decarboxylation,6 we wished to
investigate the potential for a tandem HK-decarboxylation se-
quence. Accordingly, a series of azidoesters 2 were converted
to the corresponding azidoacids 4 and subjected to MW irradia-
tion in the presence of various catalysts. Under optimal condi-
tions moderate conversion to 6 is observed (entries 13–15),
through presumed intermediate 5 which is not isolable, except
when using the Rh based catalyst (entry 16). Other substrates
were less effective, often resulting in formation of 2-linked
dimer and oligomers/polymers.
To further demonstrate the utility of the HK and decarboxyla-
tive methodology and explore application to aza-indoles, we
elected to prepare analogs of the agent PLX-4032, a recently
approved (as Zelboraf) anti-melanoma agent.11 For this, the cor-
responding pyridyl azidocinnamate
pyridine
9
was prepared from
⇑
Corresponding author. Fax: +1 617 373 8795.
E-mail address: gr.jones@neu.edu (G.B. Jones).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.066

N. Ranasinghe, G. B. Jones / Bioorg. Med. Chem. Lett. 23 (2013) 1740–1742
1741
Scheme 1. Hemetsberger–Knittel route to 2-substituted and 2-unsubstituted indoles.
HN SO2nPr
F
O
Cl
Table 1
Thermal, MW and flow mediated routes to substituted indoles
Entry Substrate
Solvent
Product
%
Da MWb (min)
Flowc
F
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2 R = 3-Cl
2 R = 3-Br
2 R = 3-I
2 R = 3-NO2
2 R = 3-OMe
2 R = 3-F
2 R = 2-Br
2 R = 4-NO2
2 R = 4-OMe
2 R = 2-Cl
2 R = 4-Cl
2 R = 4-F
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
3
3
3
3
3
3
3
3
3
3
3
3
6
6
6
5
87
66
54
78
72
42
70
62
78
67
75
72
—
86 (10)
90 (10)
88 (10)
86 (10)
96 (10)
84 (10)
94 (10)
83 (10)
80
92
—
—
95
—
85
—
—
—
—
N
N
PLX4032
H
8 (Scheme 2). MW accelerated thermolysis of the azidoester gave
10 which could be hydrolyzed and decarboxylated to give 2-
unsubstituted aza-indole 11. Alternatively, hydrolysis to the
corresponding azidoacid and subsequent thermolysis gave 11
directly (Scheme 2). Modified Friedel–Crafts acylation gave
PLX-4032 analog 12 in good yield,12 and paves the way for
substituted derivatives of this agent.
Finally, in a proof of principle study we wished to further inves-
tigate the synthetic utility of the HK substrates in peptide tagging.
Given the emerging importance of protein based biopharmaceuti-
cals, methods to tag and monitor biodistribution of candidates will
be of general utility. We had earlier demonstrated that MW meth-
ods can be used to convert nitro indoles to the corresponding flu-
oro indoles efficiently, potentially allowing introduction of 18F
labels to permit positron emission tomography [PET] imaging.13
Accordingly, a 4-nitro substituted azidoacid was prepared and its
use in bioconjugations investigated (Scheme 3). Conversion to an
activated succinate allowed facile coupling with a glycine ester
to produce 13. Microwave mediated thermolysis to the
corresponding nitro-indole 14 was indeed effective, paving the
way forward for use of the HK reaction in peptide and protein con-
93 (10)/99d (20)
89 (10)/95d (25)
93 (10)/98d (30)
96 (10)/92d (30)
43 (12)
70 (12)
56 (12)
35 (15)
—
—
—
—
4e R = 4-OMe Quinoline
4f R = 4-OMe Quinoline
4g R = 4-OMe Quinoline
4h R = 4-OMe Toluene
—
—
—
—
a
b
c
=140 °C, xylene 2 h.
=MW 200 °C, toluene.
=165 °C, 60 s, xylene at 5 ll/min.
=MW, 95 °C, 7 mol % Rh2(O2CC3F7)4.
=MW 220 °C, 12 min, 30 mol % Cu chromite.
=MW, 30 mol % 5/Cu, 220 °C, 12 min.
=30 mol % 4/Cu, 220 °C, 12 min.
d
e
f
g
h
=MW, 100 °C, 15 min 7 mol % Rh2(O2CC3F7)4.
Scheme 2. HK mediated routes to PLX-4032 analogs.

1742
N. Ranasinghe, G. B. Jones / Bioorg. Med. Chem. Lett. 23 (2013) 1740–1742
Scheme 3. Use of HK substrates for introduction of peptide conjugates.
jugates.13 This strategy opens the possibility of using peptide and
protein based congeners of 13 and thus 14, for late stage introduc-
tion of 18F labels through the [latent] nitro group.13 Conversely, in
an effort to assess the versatility of the azido group of 13 in non-HK
chemistries, Huisgen type click chemistry was successfully per-
formed using protected propargyl glycine 15, giving the expected
adduct 16 in good yield (Scheme 3).14 This bodes well for use of
such substrates for 18F labeling of protein chimeras for use in PET
imaging, a subject of active investigation in these laboratories.15
In summary, microwave mediated HK cylizations and tandem
cyclization–decarboxylation gives efficient access to a range of
substituted and unsubstituted indoles and heterocyclic variants.
The substrates can also be used in peptide coupling reactions and
click chemistries, allowing installation of fluorine based tags for
potential use as image contrast agents.
References and notes
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Acknowledgment
We thank the DoE [DE-SC0001781] for financial support of this
work.
Supplementary data
14. Arksey, N.; Valdivia, A.; Collins, J.; Hadizad, T.; Beanlands, R.; DaSilva, J. J. Nucl.
Med. 2011, 52, 1490.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013. 01.066.
15. Berkowitz, S. A.; Engen, J. R.; Mazzeo, J. R.; Jones, G. B. Nat. Rev. Drug Disc. 2012,
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