Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: Novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

Article abstract of DOI:10.3762/bjoc.15.212

We present a short and efficient way of synthesizing two synthetically versatile 4-quinolone-3-carboxylate building blocks by cyclopropanation-ring expansion of 3-chloroindoles with α-halodiazoacetates as the key step. This novel transformation was applied towards the synthesis of the antibiotic drug norfloxacin.

Full text of DOI:10.3762/bjoc.15.212

Cyclopropanation–ring expansion of 3-chloroindoles with
α-halodiazoacetates: novel synthesis of
4-quinolone-3-carboxylic acid and norfloxacin
Sara Peeters1, Linn Neerbye Berntsen1, Pål Rongved2 and Tore Bonge-Hansen*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2156–2160.
1Department of Chemistry, University of Oslo, P.O. Box 1033
Blindern, NO-0315 Oslo, Norway and 2Department of Pharmacy,
University of Oslo, P.O. Box 1068 Blindern, NO-0316, Oslo, Norway
doi:10.3762/bjoc.15.212
Received: 31 May 2019
Accepted: 28 August 2019
Published: 13 September 2019
Email:
Tore Bonge-Hansen* - tore.bonge-hansen@kjemi.uio.no
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2019 Peeters et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
catalysis; cyclopropanation; indole; norfloxacin quinoline; quinolone;
Rh(II); ring expansion
Abstract
We present a short and efficient way of synthesizing two synthetically versatile 4-quinolone-3-carboxylate building blocks by
cyclopropanation-ring expansion of 3-chloroindoles with α-halodiazoacetates as the key step. This novel transformation was
applied towards the synthesis of the antibiotic drug norfloxacin.
Introduction
The development and use of metal carbenes occupy a central N–H/C–H insertion products. The presence of electron-with-
part in the field of the C–H functionalization [1]. Among the drawing groups on the indole nitrogen makes it possible to
metal carbenes, the transient Rh carbenes, usually made by cyclopropanate the indole C2–C3 double bond and isolate indo-
Rh-catalyzed decomposition of diazo compounds, are particu- line cyclopropanes.
larly versatile intermediates in organic synthesis, as they
partake in cyclopropanation and C–H insertion reactions with We recently discovered that Rh carbenes derived from ethyl
high levels of selectivity [2]. This transition-metal-catalyzed α-halodiazoacetates (X-EDA) react readily with unprotected
carbene transfer has emerged as a mild and attractive route to indoles to form ethyl 3-carboxyquinoline structures (Scheme 1)
indole functionalization [3-6]. The metal carbene reactions with [15].
indoles have been studied for the three types of carbenoids:
acceptor–acceptor [7-9], mono-acceptor [10] and donor–accep- The Rh carbenes derived from X-EDAs stand out from the three
tor carbenoids [11-14]. Depending on the metal and the diazo other types of classified carbenoids with respect to chemoselec-
compound, the chemo- and regioselectivity in the metal carbene tivity in reactions with indoles. These halo-acceptor carbenoids
transfer reaction typically give N–H, C–H (at C3) and double undergo cyclopropanation of N–H indoles with high selectivity,
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Scheme 1: The effect of indole substituents on the yields of ethyl quinoline-3-carboxylates [15]. Green = good, orange = medium, red = poor.
R = halogen, Me, MeO, NO2.
and only traces of C–H or N–H insertion products were ob- is particularly well suited for 4-chloroquinolines with electron
served. The yield of ethyl quinoline-3-carboxylate is dependent withdrawing substituents (ester and nitro) in the 3-position.
on the halogen in X-EDA (Cl: 90%, Br: 84%, I: 70%). The Both the initial displacement of the 4-chloro-substituent and the
reaction works well for substituted indoles with R-groups in po- cleavage of the 4-alkoxyquinoline is auto-catalyzed and takes
sitions 3–7. When R at position 8 = Cl, the reaction was slug- place under neutral conditions without the need for external
gish, and when R at position 2 = Me there was no quinoline acid catalysis. These relatively mild reaction conditions should
formed. The overall transformation is formally a cyclopropan- be applicable to a large substrate scope.
ation of the indole C2–C3 double bond followed by a spontane-
ous ring expansion of the indoline cyclopropane intermediate We anticipated that our novel cyclopropanation–ring expansion
and elimination of HX.
reaction would apply to 3-chloroindol derivatives, and de-
signed a simple and straightforward retrosynthetic approach
The 4-quinolone-3-carboxylic acid scaffold (Figure 1) is towards quinolone-3-carboxylates, as outlined in Scheme 2.
regarded as a privileged scaffold in medicinal chemistry, due to
the frequent appearance of this structural subunit in many com-
mercial drugs [16-21], and a large variety of compounds with
biological activities ranging from antitumor, antiviral, antibiot-
ic and antiparasitic to cannabinoid receptor modulating [22-28].
Scheme 2: Retrosynthetic outline for the synthesis of quinolone-3-
carboxlates from indole derivatives.
Despite the attractive features of the quinolone-3-carboxylate
scaffold, there are only four reported routes towards this valu-
able structural unit. The common denominator for three of the
routes (Grohe and Heitzer [29], Gould and Jacobs [30] and Cyclopropanation–ring expansion of 3-chloroindole derivatives
Long [31]) is that they consist of ring-closure reactions to form with X-EDA would give ethyl 4-chloro-quinoline-3-carboxyl-
the quinolone ring system. The fourth one (Reddy) utilizes oxi- ates, which would subsequently undergo alcoholysis to give
dative ring cleavage of the indole ring followed by condensa- 4-quinolone-3-carboxylates.
tion [32]. Some of these routes suffer from harsh reactions
conditions and there is clearly room for novel methods comple- Results and Discussion
mentary to those already present.
We started with the simplest 3-chloroindole available
(Scheme 3).
Heindel and Fine reported back in 1970 that 4-(1H)-quinolones
can be synthesized in a straightforward fashion by simply The choice of reaction conditions for the cyclopropanation–ring
heating 4-chloroquinolines in ethanol [33]. This transformation expansion of 3-chloroindole (3) with X-EDA was based on our
Figure 1: Quinolone 3-carboxylate scaffold, norfloxacin (1) and ciprofloxacin (2).
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one of the most prescribed antibiotics even after 20 years of
clinical use. We elected 1 as a synthetic target for our novel ap-
proach towards FQs (Scheme 4). Chlorination of commercially
available 6,7-difluoroindole gave the required substrate 8.
Scheme 3: Synthesis of ethyl 4-quinolone-3-carboxylate (6) and pro-
posed mechanism. a: Rh2(esp)2 (1 mol %), CH2Cl2, rt, Cs2CO3,
50–52%. b: EtOH, reflux, 24 h, 65%.
previous work (Scheme 1) [15]. During our investigation of the
cyclopropanation–ring expansion of indoles with halodiazo-
acetates, we identified Rh2(esp)2 (1 mol %) as the optimal cata-
lyst. Even though several other dirhodium(II)-catalysts could be
used for this transformation, the yields were inferior compared
to Rh2(esp)2. The choice of solvent was out of convenience.
Scheme 4: Synthesis of norfloxacin. a: Cl-EDA (1.3 equiv), Rh2(esp)2
(1 mol %), toluene, rt, Cs2CO3, 75%. b: EtOH, reflux, 24 h, 90%. c: EtI,
K2CO3, DMF, 90 °C, 24 h, 85%. d: Boc-piperazine, K2CO3, CH3CN,
reflux, 3 d, 70%. e: LiOH, MeOH/H2O, 20 h, 96%. f: TFA, DCM then
1 M HCl, 99%.
α-Halodiazoacetates are synthesized and quickly purified using The cyclopropanation–ring expansion reaction of 8 with
CH2Cl2 as solvent, and solutions of X-EDA in CH2Cl2 are Br-EDA in CH2Cl2 using Rh2(esp)2 as catalyst gave the
stable for hours and conveniently handled at 0 °C. In order to 4-chloroquinoline-derivative 9 in 51% yield. The somewhat
ease the chromatographic purification of the ethyl modest yield of 9 was similar to the yield of 4, but was lower
3-carboxyquinoline products, we found it useful to use a slight compared the general yields of 3-carboxy-quinolines obtained
excess (1.1–1.3 equiv) of X-EDA relative to the indole sub- in our initial study. Two previous observations in our lab, one
strates (1.0 equiv). When we applied these standard conditions made in our cyclopropanation–ring expansion study of indoles,
to the cyclopropanation–ring expansion of 3-chloroindole (3) and one made during our initial reactions of X-EDAs with
with Cl-EDA or Br-EDA, we obtained ethyl 4-chloroquinoline olefins [35], gave us the clues for how to quickly improve the
carboxylate (4) in 50% and 52% yield, respectively. The yield of 9. Cl-EDA gave a small, but significant increase in
presumed mechanism for this transformation is shown in yield compared to Br-EDA in our previous study (90% vs 84%
Scheme 3. It starts with a cyclopropanation of the indole C2–C3 yield, Scheme 1). The cyclopropanations of olefins with
double bond to form an unstable, non-isolatable indoline cyclo- X-EDAs were very sensitive to the choice of solvent, and the
propane carboxylate intermediate. This intermediate is nicely yields increased dramatically on going from CH2Cl2 to toluene.
set up for a spontaneous ring expansion and elimination of HX When we applied the combination of Cl-EDA as the X-EDA
to form 4. After exposing 4 to refluxing ethanol, the desired source and toluene as solvent, we obtained 9 in 75% yield. The
ethyl 4-quinolone-3-carboxylate (6) precipitated in 65% yield. transformation of quinoline 9 to quinolone 10 was very simple
The quinoline 4 to quinolone 6 transformation is a two-step to execute experimentally. The 4-quinolone ethyl ester 10 pre-
process [33]. The 4-chloro substituent is displaced by ethanol cipitated in 90% yield after exposing 9 to refluxing ethanol for
giving ethyl 4-ethoxy-quinoline-3-carboxylate (5, not isolated). 24 h. When working on this transformation, we managed to
Subsequent attack by ethanol or Cl− cleaves off the ethyl group isolate trace quantities of the 4-ethoxy-quinoline derivate (not
and yields quinolone (6) after tautomerization. Standard hydro- shown) of 9, hereby supporting the two-step process proposed
lysis (LiOH, H2O/THF) of ester 6 gave the 4-quinolone-3- by Heindel and Fine [33]. The N-ethyl group was introduced
carboxylic acid (7) in 87% yield (not shown).
with Et-I under weakly basic conditions in 85% yield [36]. We
initially introduced the piperazine unit in a quantitative yield
Quinolones, and fluoroquinolones (FQs) in particular, are with unprotected piperazine (not shown) [37,38]. However,
among the most commonly prescribed antibiotics in the world purification and isolation were problematic and we found it
[34]. Norfloxacin (1) is considered to be the first broad band more convenient to use Boc-piperazine (70% yield) to obtain
antibiotic and its structurally related cousin ciprofloxacin (2) is 11. Hydrolysis of the ethyl ester (96%) with LiOH and acidic
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removal of the Boc group (99%) gave norfloxacin as the hydro- the solid was washed with EtOAc and centrifuged 2–3 times to
chloride salt (12) in an overall 35% yield from 8.
leave a pure off-white solid.
Conclusion
Supporting Information
We have developed a novel and efficient synthetic route
towards two privileged 4-quinolone-3-carboxylate scaffolds
commonly used in medicinal chemistry. The highly attractive
6,7-difluoro-4-quinolone-3-carboxylate building block 10 was
accessed in high yield in only three steps from commercially
available substrates. The nature of the cyclopropanation–ring
expansion makes the 4-chloro-3-carboxy-quinoline structure
with perfect positioning of the carboxylate and chlorine substit-
uents for the subsequent reaction to form the quinolone. The
current work shows that the key cyclopropanation–ring expan-
sion reaction works well with 3-chloroindole and 6,7-difluoro-
3-chloro-indole, consistent with our previous work where sub-
stituents in positions 3–7 are well tolerated.
Supporting Information File 1
Synthetic procedures, spectroscopic data and copies of
NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-212-S1.pdf]
ORCID® iDs
Linn Neerbye Berntsen - https://orcid.org/0000-0002-5338-9668
Tore Bonge-Hansen - https://orcid.org/0000-0002-6254-3372
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