En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole

Article abstract of DOI:10.1021/acs.joc.8b00100

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.

Full text of DOI:10.1021/acs.joc.8b00100

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En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole
Martin Gazvoda, Marko Krivec, Zdenko Casar, and Janez Košmrlj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00100 • Publication Date (Web): 29 Jan 2018
Downloaded from http://pubs.acs.org on January 31, 2018
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En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole
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Martin Gazvoda,*,†,§ Marko Krivec,†,§ Zdenko Časar,‡ and Janez Košmrlj*,†
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† Faculty of Chemistry and Chemical Technology, University of Ljubljana, Veꢀna pot 113,
Ljubljana SI-1000, Slovenia
‡ Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, Verovškova ulica 57,
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SI-1526 Ljubljana, Slovenia.
TOC Graphics
Abstract:
A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-
3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1 is a key impurity of reverse
transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges,
dead ends and detours are discussed.
5-Chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole derivative 1a1 (Chart
1) has been identified as a key impurity of reverse transcriptase inhibitor efavirenz,2 which is
one of the most important anti-HIV/AIDS drugs. In USP monograph for efavirenz drug
substance as well as in the monographs for efavirenz capsules and tablets, compound 1a has
been listed as a “cyclobutenylindole analog” impurity with the specified low acceptance limit
of 0.10% for drug substance.1 The specifications for impurities given in pharmacopeial
monographs represent official quality standards. Thus, in order to assure a complete
regulatory compliance, an adequate testing of drug substance and drug product must be
performed by using high quality analytical standards of efavirenz and its impurities.3 Since
compound 1a represents a strategic molecule for quality compliance testing of efavirenz,
elaboration of its synthesis is of key importance. Surprisingly, there is no scientific or patent
literature for the preparation of compound 1a neither is commercially available. In addition,
to the best of our knowledge, the synthesis of 2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-
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indole scaffold is unprecedented whereas there is only one report describing 2-(cyclobut-1-en-
1-yl)-1H-indole.4
Constructing an enormous body of natural products and finding myriad applications in
pharmaceutical, material and other sciences,5,6 indole, as a privileged class of compounds,7
inspired synthetic organic and pharmaceutical chemists to develop powerful methodologies
for the ring generation as well as functional group introduction and modification
procedures.8,9 Thus, having this pool of knowledge at hand any single desired indole product
appears "accessible à la carte" in timely, controlled and predictable way. At the first glance
the simplicity in the structure of 1 (Chart 1) promised for relatively trivial synthetic approach;
however, by implementing the precedent knowledge at the bench we came across some
unexpected observations. Eventually, we identified the route to the target compound. Along
with disclosing the successful procedure, we believe a brief overview of dead ends and
detours discussed herein will be beneficial to the chemists working in the field.
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In contrast to the synthesis of drug substances, where overall yield, environmental
impact and scalability of reactions play important role in the viability of the overall synthetic
process, the synthesis of key impurities of drug substance is not subjected to these
requirements, since they are usually required in milligram quantities. Conversely, synthetic
approaches to drug substance impurities used in compliance testing should be as concise as
possible, providing reliable access to high purity material. Therefore, the synthesis of 1 could
be tackled by two possible routes as shown in Chart 1. Route a) would start from a
commercially available indole-2-carboxylic acid derivative 2a, which should after couple of
functional group interconversions, including trifluoromethylation, undergo olefination into
methylenecyclopropane derivative and subsequent ring enlargement into cyclobutene product.
Considering a potential lability of these two highly strained rings, trifluoromethyl group
should preferably be introduced in an early synthetic step. If either the trifluoromethyl or the
cyclobutene group introduction in route a) fails, then route b), an indole ‘2,3’ C–C
disconnection, should offer an alternative scenario. Taking into account the commercial
availability of the starting materials and keeping the synthetic steps at minimum we began our
investigation with route a).
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Chart 1. Retrosynthetic considerations.
The group of Shen recently reported a highly efficient tandem C–H
activation/trifluoromethylation procedure for the synthesis of N-Boc protected 3-
(trifluoromethyl)indole.10 By applying this protocol, the borylation of Boc-indole 2b with
bis(pinacolato)diboron (B2pin2) in the presence of [{Ir(cod)(OMe)}2] (cod = 1,5-
cyclooctadiene) and di-tert-butylbipyridine (dtbpy), followed by trifluoromethylation of the
pinacolboronate intermediate with Togni reagent I, we obtained the desired C-3
trifluoromethyl derivative 3 in acceptable 48% yield (Scheme 1). Unfortunately, all attempts
to reduce the ester group in 3 with DIBAL-H failed, returning the unreacted starting material.
Surprisingly, subjecting ester 3 to LiAlH4 reduction and subsequent MnO2 oxidation resulted
in 5-chloro-3-methyl-1H-indole-2-carbaldehyde (4), where the desired ester reduction was
accompanied by Boc-deprotection and “defluorination”.
Scheme 1. Attempted synthesis of 1H-indole-2-carbaldehyde derivative
Having realized that the C-3 trifluoromethyl group (in 3) renders the C-2
ethoxycarbonyl group inert towards DIBAL-H, while it is incompatible with LiAlH4,
prompted us to test an alternative approach where the CF3 group is introduced in a later stage
of the reaction sequence. This pathway begun with LiAlH4 reduction of ester 2a into alcohol
5, and subsequent MnO2 oxidation into aldehyde 6 (Scheme 2).11,12 Exposure of the latter to
cyclopropyl sulfone 7 in the presence of NaHMDS as a base in THF at low temperature, a
variant of the Julia-Kocienski olefination,13 produced methylenecyclopropane derivative 8. A
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palladium-catalyzed ring enlargement of methylenecyclopropane 8 in the next step was
expected to provide cyclobutene derivative 9. This method, developed by Shi et al., has been
documented on a variety of aryl-substituted methylenecyclopropanes to afford 1-
arylcyclobutenes under mild conditions.14 Unfortunately, all attempts to achieve
rearrangement of 8 into 9 failed, consistently returning complex mixtures of decomposition
and polymerization products as judged by TLC, NMR and MS analyses (Scheme 2).
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Scheme 2. Attempted synthesis of cyclobutene derivative 9
Hoping that the installment of the C-2 cyclobutene ring would eventually be possible,
with aldehyde 6 in hands, we were prompted to test the above-mentioned Shen’s
trifluoromethylation procedure. Unfortunately, exposure of Boc protected indole-2-
carbaldehyde 10 to B2pin2/[{Ir(cod)(OMe)}2]/dtbpy and then to Togni reagent I did not give
product 11. It turned out that already the C-3 borylation failed to proceed in this case (Scheme
3).
Scheme 3. Attempted instalment of trifluoromethyl group at 10
The failure in functionalizing the indole core with trifluoromethyl and cyclobutene
groups called for a tactical change. Seeking for the alternative that would allow construction
of the indole skeleton at the appropriate trifluoromethyl and cyclobutene pre-functionalized
substrate led us to route b) from Chart 1.
A low-valent titanium reductive dimerization of aldehydes and ketones to alkenes,
known as McMurry reaction,15 has been developed by Fürstner and co-workers16 to a
convenient and flexible method for the construction of indole scaffold starting form N,2-
diacetylanilines. To assess this idea, the required starting 4-chloro-2-trifluoroacetylaniline
(12) was provided from the commercial 4-chloroaniline by known procedure.17 N-Acylation
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of 12 with ethyl oxalylchloride gave carbamate 13, which, as expected, cyclized into indole
14 on treatment with TiCl4 and zinc dust in refluxing DME (Scheme 4).
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Scheme 4. Transformations of 4-chloro-2-trifluoroacetylaniline (12)
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Thus, the process, successfully tested in the model system of 13 → 14, seemed to be
promising for the synthesis of the target compound 1. Disappointingly, however, all attempts
to assemble 12 either with 1-cyclobutenecarboxylic acid chloride (15a) or with 1-
cyclobutenecarboxylic acid (15b)18 in the presence of DCC or EDC coupling reagents into
amide 16 failed. 1-Cyclobutenecarboxylic acid chloride (15a) is highly unstable and we
carefully prepared and used this compound as described by Parker, Sampson and co-worker.19
Likewise, DCC coupling had previously proved to form esters from 1-cyclobutenecarboxylic
acid (15b).18 In contrast to the above, aniline 12 could only be coupled with
cyclobutanecarbonyl chloride (15c) into the saturated analogue 17. This was deemed as a
valuable detour since reliable procedures for dehydrogenation of cyclobutane into
cyclobutene ring are available (vide infra). Yet, treatment of 17 with TiCl4 and zinc dust in
refluxing DME afforded a complex reaction mixture in which the desired indole product 18
could not be detected.
Another protocol for the indole ring formation from precursor 12 was examined at this
point. Based on a recent patent,20 on heating with methyl bromoacetate and K2CO3 in
refluxing acetonitrile, 2-trifluoroacetylaniline provides methyl 3-(trifluoromethyl)-1H-indole-
2-carboxylate in 56% yield. In our hands, with 4-chloro-2-trifluoroacetylaniline (12), this
procedure returned a mixture of methyl 2-amino-5-chlorobenzoate (19) and bridging dimer of
12, epoxy dibenzo[b,f][1,5]diazocine 20. No methyl 5-chloro-3-(trifluoromethyl)-1H-indole-
2-carboxylate could be detected in the crude reaction mixture. Compound 20 has been
recently reported by Griffiths and Warm as a side product formed by treatment of 12 with
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much stronger bases, such as Grignard reagents or BuLi, in the synthesis of efavirenz.21
N-Acylated o-toluidines are known to undergo lithiation on treatment with
organolithium reagents, which is followed by intramolecular condensation of the resulting
lithio species into 2-substituted indoles in good yields.22 Indeed, N-acylation of commercial 4-
chloro-2-methylaniline (21) with cyclobutanecarbonyl chloride (15c) into amide 22 followed
by treatment with n-BuLi led to indole derivative 23 in 45% yield (Scheme 5).
Out of the methods available for trifluoromethylation10,23 at this point we decided to
test metal-free photocatalytic radical reaction with methylene blue as a photo-catalyst coupled
with Togni hypervalent-iodine compounds, developed by the group of Scaiano.23 Using this
protocol, but employing more easily accessible Togni reagent II24 in place of Togni reagent I,
compound 23 was transformed into desired C-3 trifluoromethyl derivative 18. The latter was
N-protected with diethyl pyrocarbonate into 24.25
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Scheme 5. Synthesis of dibromocyclobutane derivative 26
Dehydrogenation of the cyclobutane ring in 24 should be possible by radical
monobromination with NBS in the presence of AIBN and subsequent elimination of HBr with
KOH as reported by Jung and Deng.18 Interestingly, although working well in the preparation
of 15b, the above NBS/AIBN conditions transformed cyclobutane 24 into a mixture of
monobrominated product 25 and vicinal dibromide 26. Attempted dehydrobromination26 of
25 by KOtBu in dry THF returned complex mixture of decomposition products and no desired
1a or 1. On the other hand, debromination of 26 with sodium sulfide in DMF by the
procedure of Fukunaga27 furnished N-deprotected cyclobutene derivative 1, which could be
re-protected with diethyl pyrocarbonate into 1a in 58% yield over two steps from 26 (Scheme
6). This undesired step was avoided by employing a modified procedure by using buffer (pH
= 7) in the isolation workup, which prevented hydrolysis of the base-sensitive carbamate N-
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protection. Compound 26 was thus transformed into the target 1a in one step, in 73% yield.
Noteworthy, compound 1a is also extremely sensitive to silica gel chromatography
undergoing rapid decomposition into a complex mixture of products unless the eluent consists
of sufficient amount of base like NEt3.
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Scheme 6. Synthesis of target compound 1a
In conclusion, exemplified by compound 1a, we have developed the first synthesis of
2-(cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole scaffold. Our synthetic approach is based
on
lithium-inducted
intramolecular
condensation
of
N-(4-chloro-2-
methylphenyl)cyclobutanecarboxamide (22) into indole 23. The installment of the C-3
trifluoromethy group into 18 was possible through the photocatalytic radical reaction with
methylene blue and Togni reagent II. Finally, the cyclobutane ring was transformed into the
cyclobutene ring by dibromination/debromination reaction sequence. Interestingly, several
well established reactions failed in producing intermediates along the synthetic pathway into
1a.
Experimental Section
General Information
All reactions were performed in oven-dried glassware under argon atmosphere. All reagents
purchased commercially were used without further purification unless noted otherwise.
Toluene and tetrahydrofuran were distilled over sodium wire. Dichloromethane and
acetonitrile were distilled over calcium hydride. Melting points were determined on a micro-
hot-stage apparatus and are uncorrected. Thin-layer chromatography (TLC) analysis was
performed on Fluka Silica gel on TLC Al foils (silica gel matrix, with fluorescent indicator,
60 Å medium pore diameter). Visualization of compounds was done by illumination with a
UV lamp (254 nm) or by using a solution of KMnO4/K2CO3/NaOH in water (prepared by
dissolving 1.5 g of KMnO4, 10 g K2CO3 and 1.25 mL 10% NaOH in 200 mL of water)
followed by heating. Silica gel column chromatography was carried out on silica gel 60N. IR
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spectra were recorded on a FT-IR spectrometer using ATR. H, 13C and 19F spectra were
recorded with a Bruker Avance III 500 MHz NMR (500 MHz, 126 MHz and 471 MHz)
instrument at 300 K. Some 1H and 13C spectra were recorded with a Bruker Avance DPX 300
spectrometer (300 MHz and 76 MHz) at 302 K. Proton spectra were referenced to TMS as an
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internal standard. Carbon chemical shifts were determined relative to the C signal of CDCl3
(77.0 ppm). Assignments of some proton and carbon resonances were performed by 2D NMR
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techniques (1H−1H gs-COSY, H−13C gs-HSQC, H−13C gs-HMBC and H−31P gs-HMBC).
Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet) or br (broadened). HRMS
spectra were recorded on a time-of-flight (TOF) mass spectrometer equipped with a double
orthogonal electrospray source at atmospheric pressure ionization (ESI) coupled to an HPLC
instrument.
1-(tert-Butyl)-5-(cyclopropylsulfonyl)-1H-tetrazole (7) was prepared by the literature
procedure.28 1-(2-Amino-5-chlorophenyl)-2,2,2-trifluoroethan-1-one (12) was prepared as
described in the literature29 (CAUTION: by adding ethyl trifluoroacetate or
trifluoroacetic anhydride into the reaction mixture, the pressure in the reaction vessel
increases severely).
1-(tert-Butyl) 2-ethyl 5-chloro-1H-indole-1,2-dicarboxylate (2b). To a solution of ethyl 5-
chloro-1H-indole-2-carboxylate (2a, 2.24 g, 10.0 mmol) in THF (30 mL) were added di-tert-
butyl dicarbonate (Boc2O, 2.19 g, 10.0 mmol), 4-dimethylaminopyridine (DMAP, 150 mg,
1.2 mmol), and Et3N (1.40 mL, 10.0 mmol) at room temperature. After stirring the reaction
mixture for 12 h at room temperature, the volatiles were removed under reduced pressure, and
the residue was purified by silica gel column chromatography (EtOAc/petroleum ether 1/7) to
afford 2b (3.07 g, 95%) as a pale yellow oil. Rf 0.44 (EtOAc/petroleum ether 1/5). IR (ATR):
1
2981, 1728, 1539, 1444, 1318, 1227, 1188, 1156, 1139, 1067 cm–1. H NMR (500 MHz,
CDCl3): δ 8.01 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.9, 2.1 Hz, 1H),
4.38 (q, J = 7.2 Hz, 2H), 1.62 (s, 9H), 1.39 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 161.5, 148.8, 135.9, 131.9, 128.8, 128.6, 126.8, 121.4, 116.0, 113.3, 85.0, 61.5, 27.7, 14.2.
+
HMRS (ESI+): m/z calcd for C12H11ClNO4 [M – i-C4H8 + H]+ 268.0371, found 268.0367.30
1-(tert-Butyl) 2-ethyl 5-chloro-3-(trifluoromethyl)-1H-indole-1,2-dicarboxylate (3).
Compound 3 was prepared from 2b by a modified literature procedure for the
trifluoromethylation.10
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An Ace pressure tube was charged with [{Ir(cod)(OMe)}2] (21 mg, 0.03 mmol, 1 mol%), 4,4'-
di-tert-butyl-2,2'-bipyridine (18 mg, 0.06 mmol, 2 mol%), and bis(pinacolato)diboron (506
mg, 2.0 mmol) under argon atmosphere. Dry THF (6.0 mL) and 1-(tert-butyl) 2-ethyl 5-
chloro-1H-indole-1,2-dicarboxylate (2b, 957 mg, 3.0 mmol) were added under a flow of
argon gas, and the reaction mixture was stirred at 80 °C for 24 h. After filtration through a
short pad of celite, the volatiles were removed under reduced pressure. The residue was
dissolved in CH2Cl2 (12 mL) and the solution was transferred by a syringe, under argon
atmosphere, into an oven-dried Ace pressure tube, pre-charged with copper(I) thiophene-2-
carboxylate (60 mg, 0.31 mmol), 1,10-phenanthroline (110 mg, 0.61 mmol), LiOH·H2O (250
mg, 6.0 mmol), and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (Togni reagent I, 1.10
g, 3.3 mmol). The reaction mixture was stirred at 45 °C for 7 h. Brine (25 mL) and CH2Cl2
(10 mL) were added and the resulting layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 × 10 mL) and the combined organic layers were dried (Na2SO4), and
concentrated under reduced pressure. The crude material was purified by column
chromatography (EtOAc/petroleum ether 1/10) to give a mixture (1.07 g) of 3 and 2b in the
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1
molar ratio of 1.0:1.1, as determined by H NMR. Compounds 3 and 2b could not be
separated due to the similar chromatographic properties on silica gel. The yield of product 3
1
was calculated to be 564 mg (48%). Rf 0.52 (EtOAc/petroleum ether 1/3). H NMR (500
MHz, CDCl3): δ 8.09 (d, J = 9.0 Hz, 1H), 7.71–7.69 (m, 1H), 7.41 (dd, J = 9.0, 2.1 Hz, 1H),
4.45 (q, J = 7.1 Hz, 2H), 1.65 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H). HMRS (ESI+): m/z calcd for
C13H10ClF3NO4 [M – i-C4H8 + H]+ 336.0245, found 336.0227.30
+
5-Chloro-3-methyl-1H-indole-2-carbaldehyde (4). The reduction was conducted by a
modified literature procedure for the reduction with LiAlH4.12
A solution of the above prepared mixture of 3 and 2b (1.0:1.1 mol ratio, 269 mg; 0.36 mmol
of 3) in dry THF (5 mL) was cooled to 0 °C, and LiAlH4 (1 M in THF, 0.8 mL, 0.8 mmol)
was slowly added. The reaction mixture was stirred for 2 h at room temperature, quenched
with 20% aqueous KOH solution (1 mL) and filtered. The filtrate was concentrated in vacuo.
Activated MnO2 (313 mg) and CH2Cl2 (5 mL) were added to the residue, and the reaction
mixture was stirred at room temperature overnight, filtered, and the filtrate was concentrated
under reduced pressure. Mass-spectral and NMR analyses of the crude product revealed the
presence of compound 4 as the major product, which was not purified.
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4: H NMR (500 MHz, CDCl3): δ 10.04 (s, 1H), 8.82 (br s, 1H), 7.68 (s, 1H), 7.32–7.34 (m,
2H), 2.62 (s, 3H). HMRS (ESI+): m/z calcd for C10H9ClNO+ [M + H]+ 194.0367, found
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5-Chloro-1H-indole-2-carbaldehyde (6). The reduction was conducted by a modified
literature procedure for the reduction with LiAlH4.12
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A solution of indole 2a (2.28 g, 10.2 mmol) in dry THF (20 mL) was cooled to 0 °C under
argon atmosphere, and a solution of LiAlH4 (1 M in THF, 15.6 mL, 15.6 mmol, 1.5 equiv)
was added dropwise. The mixture was allowed to warm to room temperature and the stirring
was continued for 2 h, until the reaction was considered complete as determined by TLC
analysis. Then, THF (20 mL) and 20% of aqueous KOH (1.5 mL) were added sequentially to
the reaction mixture, which was stirred for additional 15 min and filtered. The solid residue
was extracted with hot (refluxing) THF (20 mL) and filtered. The combined filtrates were
washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to
afford crude alcohol 5 (1.67 g), which was used without further purification in the next step as
follows. A suspension of crude 5 (1.67 g) and activated MnO2 (8.70 g, 100 mmol) in CH2Cl2
(100 mL) was stirred at room temperature for 18 h. The reaction mixture was filtered through
a pad of Celite, the filtrate was evaporated in vacuo, and the residue was purified by silica gel
column chromatography (EtOAc/petroleum ether 1/7) to provide product 6 (1.45 g, 79% over
two steps) as a pale brown solid.
1H NMR (500 MHz, CDCl3): δ 9.86 (s, 1H), 9.09 (br s, 1H), 7.74–7.72 (m, 1H), 7.39 (d, J =
8.8 Hz, 1H), 7.35 (dd, J = 8.8, 1.8 Hz, 1H), 7.23–7.21 (m, 1H). Spectroscopic data were in
agreement with the literature report.31
5-Chloro-2-(cyclopropylidenemethyl)-1H-indole (8). To a stirred solution of 1-(tert-butyl)-
5-(cyclopropylsulfonyl)-1H-tetrazole (7, 555 mg, 2.40 mmol) in dry THF (15 mL) was added
dropwise, under argon atmosphere, at –78 °C, sodium bis(trimethylsilyl)amide (1 M in THF,
3.40 mL, 3.40 mmol). Within 10 minutes yellow suspension formed. The reaction mixture
was stirred at –78 °C for 30 minutes, followed by a dropwise addition of a THF solution (4
mL) of 5-chloro-1H-indole-2-carbaldehyde (6, 240 mg, 1.35 mmol) via syringe. The reaction
mixture was stirred at –78 °C for 1 h, quenched with aqueous solution of NH4Cl (15 mL),
allowed to warm to room temperature, and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (Na2SO4), and concentrated under reduced pressure to afford crude
product, which was subjected to silica gel column chromatography (EtOAc/petroleum ether
1/20) purification to afford 8 (65 mg, 24%) as a white solid. Rf 0.45 (EtOAc/petroleum ether
1
1/3). Mp 85–87 °C. IR (ATR): 3465, 2977, 1573, 1455, 1404, 1306 cm–1. H NMR (500
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MHz, CDCl3): δ 8.43 (br s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.09 (dd, J
= 8.6, 2.0 Hz, 1H), 6.82–6.80 (m, 1H), 6.41–6.39 (m, 1H), 1.46–1.42 (m, 2H), 1.35–1.30 (m,
13
2H). C NMR (126 MHz, CDCl3): δ 138.2, 134.7, 129.9, 125.4, 123.6, 122.3, 119.8, 111.4,
7
8
9
109.9, 101.1, 3.2, 1.5. HMRS (ESI+): m/z calcd for C12H11ClN+ [M + H]+ 204.0575, found
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204.0567.
tert-Butyl 5-chloro-2-formyl-1H-indole-1-carboxylate (10). To a solution of carbaldehyde 6
(1.80 g, 10.0 mmol) in THF (100 mL) were added di-tert-butyl dicarbonate (Boc2O, 3.19 g,
14.6 mmol), 4-dimethylaminopyridine (DMAP, 160 mg, 1.3 mmol), and Et3N (1.74 mL, 12.4
mmol). The reaction mixture was stirred at room temperature for 12 h, concentrated in vacuo,
and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether
1/10) to give product 10 (2.57 g, 92%) as a pale yellow solid. Rf 0.39 (EtOAc/petroleum ether
1/7). Mp 91–93 °C (MeOH). IR (ATR): 2978, 2924, 1731, 1664, 1526, 1348, 1159, 1134,
1089, 1068 cm–1. 1H NMR (500 MHz, CDCl3): δ 10.42 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.65
(d, J = 2.1 Hz, 1H), 7.43 (dd, J = 9.0, 2.1 Hz, 1H), 7.35 (s, 1H), 1.71 (s, 9H). 13C NMR (126
MHz, CDCl3): δ 183.9, 149.4, 138.7, 136.0, 129.4, 128.5, 128.4, 122.4, 117.2, 115.1, 86.1,
28.1. HMRS (ESI+): m/z calcd for C9H7ClNO+ [M – Boc + 2H]+ 180.0211, found 180.0208.
Ethyl 2-((4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)amino)-2-oxoacetate (13). To a solution
of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethan-1-one (12, 250 mg, 1.12 mmol) and
pyridine (230 μL, 2.8 mmol) in dry CH2Cl2 (4 mL), ethyl 2-chloro-2-oxoacetate (145 μL, 176
mg, 1.29 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 1 hour at 0
°C and then for 20 h at room temperature. Then, the reaction mixture was diluted with CH2Cl2
(20 mL), washed with aqueous HCl (1 M, 15 mL), saturated aqueous solution of NaHCO3 (15
mL), brine (15 mL), and the organic layer was dried (Na2SO4), and evaporated to dryness to
give product 13 (330 mg, 91%) as a yellow solid. Mp 142–143.5 °C. IR (ATR): 3275, 3142,
2997, 1724, 1688, 1574, 1518, 1397, 1307, 1278, 1203, 1144 cm–1. H NMR (500 MHz,
1
CDCl3): δ 12.28 (br s, 1H), 8.86 (d, J = 9.1 Hz, 1H), 7.99–7.97 (m, 1H), 7.73 (dd, J = 9.1, 2.3
13
Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). C NMR (126 MHz, CDCl3): δ
182.0 (q, J = 35.5 Hz), 159.7, 155.0, 139.6, 137.5, 131.4 (q, J = 4.5 Hz), 129.7, 122.7, 117.4,
116.1 (q, J = 291.0 Hz), 64.1, 14.0. HMRS (ESI+): m/z calcd for C12H10ClF3NO4 [M + H]+
+
324.0245, found 324.0247.
Ethyl 5-chloro-3-(trifluoromethyl)-1H-indole-2-carboxylate (14). To an ice-cold stirred
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suspension of zinc powder (262 mg, 4 mmol) in dimethoxyethane (DME, 5 mL) was slowly
added TiCl4 (221 μL, 2 mmol). The resulting black slurry was heated under reflux for 2 hours.
A solution of ethyl 2-((4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)amino)-2-oxoacetate (14, 323
mg, 1 mmol) in DME (5 mL) was added and the heating was continued for 2 hours. The
reaction mixture was allowed to cool to ambient temperature. The inorganic residues were
removed by filtration through a short pad of silica and the pad was thoroughly rinsed with
EtOAc (5 × 10 mL). The combined filtrates were concentrated to dryness under reduced
pressure. From the residue, the product was isolated by extraction into hot (refluxing) toluene
(10 mL). The supernatant hot was separated by decantation from the oily residues, and
allowed to cool down to room temperature. The precipitate was collected by filtration, washed
with cold hexane (3 × 10 mL) and dried to afford 14 (135 mg, 46%) as a white solid. Mp 149–
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151 °C. IR (ATR): 3296, 3010, 2959, 1686, 1543, 1452, 1386, 1346 cm–1. H NMR (500
MHz, CDCl3): δ 9.54 (br s, 1H), 7.95–92 (m, 1H), 7.44–7.36 (m, 2H), 4.51 (q, J = 7.1 Hz,
2H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 160.0, 132.7, 128.6, 127.1 (q, J
= 3.7 Hz), 126.8, 125.7 (q, J = 1.5 Hz), 123.3 (q, J = 268.2 Hz), 121.2 (q, J = 3.5 Hz), 113.2,
+
109.4 (q, J = 37.9 Hz), 62.4, 13.9. HMRS (ESI+): m/z calcd for C12H10ClF3NO2 [M + H]+
292.0347, found 292.0345.
N-(4-Chloro-2-(2,2,2-trifluoroacetyl)phenyl)cyclobutanecarboxamide (17).
To an ice-cold stirred solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethan-1-one (12,
357 mg, 1.60 mmol), pyridine (139 mg, 142 μL, 1.75 mmol), and CH2Cl2 (12 mL) was slowly
added cyclobutanecarbonyl chloride (15c, 189 mg, 184 μL, 1.60 mmol). After being stirred
for 30 min at 0 °C, the reaction mixture was allowed to warm to room temperature and the
stirring was continued for additional 16 h. The reaction mixture was diluted with CH2Cl2 (20
mL) and was washed with aqueous HCl (1M, 15 mL) and brine (15 mL). The organic layer
was dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by silica gel
column chromatography (EtOAc/petroleum ether 1/5) to give the product 17 (401 mg, 82%).
Rf 0.36 (EtOAc/petroleum ether 1/3). Mp 82–83 °C. IR (ATR): 3346, 2986, 2947, 2869, 1758,
1
1707, 1674, 1572, 1506, 1453, 1337 cm–1. H NMR (500 MHz, CDCl3): δ 10.81 (br s, 1H),
8.89 (d, J = 9.2 Hz, 1H), 7.91–7.89 (m, 1H), 7.65 (dd, J = 9.2, 2.3 Hz, 1H), 3.28 (quint, J =
8.6 Hz, 1H), 2.44–2.28 (m, 4H), 2.11–2.00 (m, 1H), 1.98–1.90 (m, 1H). 13C NMR (126 MHz,
CDCl3): δ 182.3 (q, J = 35.0 Hz), 174.5, 142.3, 137.6, 130.9 (q, J = 4.5 Hz), 127.7, 122.6,
116.3 (q, J = 291.9 Hz), 116.0, 41.6, 25.3, 17.9. HMRS (ESI+): m/z calcd for
+
C13H12ClF3NO2 [M + H]+ 306.0503, found 306.0498.
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Attempted synthesis of methyl 5-chloro-3-(trifluoromethyl)-1H-indole-2-carboxylate
following the patent procedure:20 A mixture of 1-(2-amino-5-chlorophenyl)-2,2,2-
trifluoroethan-1-one (13, 1.76 g, 7.8 mmol), methyl 2-bromoacetate (1.43 g, 890 μL, 9.4
mmol), and K2CO3 (3.23 g, 23.4 mmol) in dry CH3CN (7.5 mL) was heated under reflux in
argon atmosphere for 17 h. The resulting mixture was filtered and evaporated to yield a crude
product which contained methyl 2-amino-5-chlorobenzoate (19) and 2,8-dichloro-6,12-
bis(trifluoromethyl)-5,6,11,12-tetrahydro-6,12-epoxydibenzo[b,f][1,5]diazocine (20) in the
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1:1 ratio as determined by H NMR. The crude product was subjected to column
chromatography (EtOAc/petroleum ether 1/3) to obtain compounds 19 and 20 in pure form.
Methyl 2-amino-5-chlorobenzoate (19). Rf 0.35 (EtOAc/petroleum ether 1/3). 1H NMR (500
MHz, CDCl3): δ 7.82 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 8.8, 2.5 Hz, 1H), 6.60 (d, J = 8.8 Hz,
1H), 5.73 (br s, 2H), 3.87 (s, 3H). Spectroscopic data were consistent with those reported in
the literature.32
2,8-dichloro-6,12-bis(trifluoromethyl)-5,6,11,12-tetrahydro-6,12-
epoxydibenzo[b,f][1,5]diazocine (20). Rf 0.48 (EtOAc/petroleum ether 1/3). Mp 219–220 °C.
1
Mp (lit.21) 222 °C. H NMR (500 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 7.21 (dd, J = 8.7, 2.3
Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.90 (br s, 2H). Spectroscopic data were consistent with
those reported in the literature.21
N-(4-Chloro-2-methylphenyl)cyclobutanecarboxamide (22). To an ice-cold solution of 4-
chloro-2-methylaniline (21, 2.124 g, 15.0 mmol) and pyridine (1.51 mL, 18.8 mmol) in dry
CH2Cl2 (40 mL) was added cyclobutanecarbonyl chloride (15c, 1.956 g, 16.5 mmol)
dropwise. The reaction mixture was stirred for 1 h at 0 °C and then for 16 h at room
temperature. Afterwards, the reaction mixture was washed with aqueous HCl (1M, 30 mL),
saturated aqueous solution of NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4), and
evaporated to dryness to give pure product 22 (3.15 g, 94%) as a white solid. Mp 151–152 °C.
IR (ATR): 3260, 2979, 2943, 2865, 1647, 1521, 1397, 1269, 1191 cm–1. 1H NMR (500 MHz,
CDCl3): δ 7.84 (d, J = 8.5 Hz, 1H), 7.19–7.15 (m, 2H), 6.78 (br s, 1H), 3.19 (quint, J = 8.5
13
Hz, 1H), 2.43–2.33 (m, 2H), 2.30–2.23 (m, 2H), 2.22 (s, 3H), 2.09–1.98 (m, 2H). C NMR
(126 MHz, CDCl3): δ 173.1, 134.3, 130.3, 130.1, 129.7, 126.7, 123.9, 40.7, 25.4, 18.1, 17.5.
HMRS (ESI+): m/z calcd for C12H15ClNO+ [M + H]+ 224.0837, found 224.0839.
5-Chloro-2-cyclobutyl-1H-indole (23). Following literature procedure.33 To a solution of N-
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(4-chloro-2-methylphenyl)cyclobutanecarboxamide (22, 3.345 g, 15.0 mmol) in anhydrous
THF (200 mL), n-butyl lithium (24 mL, 60.0 mmol, 2.5 M in hexanes) was added dropwise at
–40 °C. The reaction mixture was stirred for 1 h at –40 °C, 1 h at 0 °C, and then overnight at
room temperature. The reaction mixture was quenched by slow addition of water (100 mL) at
0 °C, and the product was extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with brine (150 mL), dried (Na2SO4), and evaporated to dryness. The residue
was purified by silica gel column chromatography (EtOAc/petroleum ether 1/10) to afford 2-
cyclobutyl-5-chloro-1H-indole (23, 1.370 g, 45%) of as a brown solid. Rf 0.49
(EtOAc/petroleum ether 1/3). Mp 61–62.5 °C. IR (ATR): 3394, 2941, 2862, 1683, 1614,
1574, 1464, 1445, 1313 cm–1. 1H NMR (500 MHz, CDCl3): δ 7.89 (br s, 1H), 7.49 (d, J = 2.0
Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 8.6, 2.0 Hz, 1H), 6.23–6.21 (m, 1H), 3.62
(quint, J = 8.6 Hz, 1H), 2.44–2.37 (m, 1H), 2.28–2.19 (m, 1H), 2.12–2.03 (m, 1H), 1.99–1.92
(m, 1H). 13C NMR (126 MHz, CDCl3): δ 145.2, 134.2, 129.8, 125.2, 121.2, 119.3, 111.2,
97.9, 33.7, 29.0, 18.7. HMRS (ESI+): m/z calcd for C12H13ClN+ [M + H]+ 206.0731, found
206.0723.
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5-Chloro-2-cyclobutyl-3-(trifluoromethyl)-1H-indole (18). A mixture of 5-chloro-2-
cyclobutyl-1H-indole (23) (0.820 g, 4.0 mmol), 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-
one (Togni Reagent II) (1.893 g, 6.0 mmol) and methylene blue (29.3 mg, 0.09 mmol) in dry
DMF (40 mL) was purged by argon gas for 15 min. Then, N,N,N′,N′-
tetramethylethylenediamine (TMEDA) (1.20 mL, 8.0 mmol) was added and the reaction
mixture was irradiated with a bulb (40 W) for 18 h. After irradiation, the reaction mixture was
diluted with Et2O (150 mL), washed with brine (5 × 50 mL) dried (Na2SO4), and evaporated
to dryness to give an oily residue. Silica gel column chromatography purification
(EtOAc/petroleum ether 1/15) afforded pure 5-chloro-2-cyclobutyl-3-(trifluoromethyl)-1H-
indole (18, 0.36 g, 33%) as a brown solid. Rf 0.37 (EtOAc/petroleum ether 1/3). Mp 72–73
1
°C. IR (ATR): 3465, 2987, 2943, 2867, 1578, 1558, 1449, 1326, 1143 cm–1. H NMR (500
MHz, CDCl3): δ 8.30 (br s, 1H), 7.66–7.64 (m, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.16 (dd, J =
8.6, 2.0 Hz, 1H), 4.03–3.94 (m, 1H), 2.48–2.40 (m, 1H), 2.29–2.09 (m, 3H), 1.97–1.89 (m,
13
1H). C NMR (126 MHz, CDCl3): δ 143.9 (q, J = 3.6 Hz), 132.4, 127.1, 126.4 (q, J = 1.7
Hz), 124.7 (q, J = 267.0 Hz), 122.8, 118.8 (q, J = 1.3 Hz), 111.8, 101.6 (q, J = 36.1 Hz), 32.2,
28.8, 18.5. HMRS (ESI+): m/z calcd for C13H12ClF3N+ [M + H]+ 274.0605, found 274.0606.
Ethyl 5-chloro-2-cyclobutyl-3-(trifluoromethyl)-1H-indole-1-carboxylate (24). Following
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a modified literature procedure.25 To a solution of indole 18 (200 mg, 0.72 mmol), Et3N (1.0
mL, 7.2 mmol), and 4-dimethylaminopyridine (DMAP, 44 mg, 0.36 mmol) in dry DMF (8
mL) was added diethyl pyrocarbonate (584 mg, 3.6 mmol) under argon atmosphere. The
reaction mixture was stirred for 1 h at 50 °C, allowed to cool to room temperature, and diluted
with a mixture of EtOAc/petroleum ether (1/3, 20 mL). The organic layer was washed with
aqueous HCl (1 M, 5 mL), brine (3 × 5 mL), dried (Na2SO4), and evaporated to dryness. The
residue was purified by column chromatography (EtOAc/petroleum ether 1/20) to afford ethyl
5-chloro-2-cyclobutyl-3-(trifluoromethyl)-1H-indole-1-carboxylate (24, 195 mg, 78%) of as a
colorless oil. Rf 0.53 (EtOAc/petroleum ether 1/3). IR (ATR): 2985, 2873, 1749, 1582, 1456,
1372, 1300, 1258, 1188, 1152, 1110 cm–1. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 9.0 Hz,
1H), 7.66–7.64 (m, 1H), 7.26 (dd, J = 9.0, 2.0 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.20–4.11
(m, 1H), 2.52–2.44 (m, 2H), 2.38–2.29 (m, 2H), 2.08–1.98 (m, 1H), 1.49 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3): δ 150.8, 147 (q, J = 4.2 Hz), 133.5, 129.3, 126.6, 124.8, 123.9
(q, J = 268.7 Hz), 119.2 (q, J = 2.6 Hz), 115.3, 108.8 (q, J = 36.4 Hz), 64.4, 34.5, 29.5 (q, J =
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2.2 Hz), 18.3, 14.1. HMRS (ESI+): m/z calcd for C16H16ClF3NO2 [M + H]+ 346.0816, found
346.0815.
Bromination of compound 24. The reaction was conducted following a modified literature
procedure for the bromination.18
A
mixture of ethyl 5-chloro-2-cyclobutyl-3-
(trifluoromethyl)-1H-indole-1-carboxylate (24, 201 mg, 0.58 mmol), N-bromosuccinimide
(620 mg, 3.48 mmol), 2,2′-azobis(2-methylpropionitrile) (AIBN, 40 mg, 0.24 mmol) in dry
CCl4 (2 mL) was stirred in an Ace pressure tube for 4 h at 90 °C under argon atmosphere.
Then, the reaction mixture was allowed to cool to room temperature and diluted with EtOAc
(20 mL). The organic layer was washed with water (10 mL), brine (2 × 10 mL), dried
(Na2SO4), and evaporated to dryness. The residue was purified by column chromatography
(EtOAc/petroleum ether 1/20) to give monobrominated product 25 (47 mg, 19%) of as a pale
oil and dibrominated product 26 (199 mg, 68%) of as a colorless viscous oil.
Ethyl 2-(1-bromocyclobutyl)-5-chloro-3-(trifluoromethyl)-1H-indole-1-carboxylate (25).
1
Rf 0.19 (EtOAc/petroleum ether 1/20). H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 9.0 Hz,
1H), 7.72‒7.70 (m, 1H), 7.35 (dd, J = 9.0, 2.0 Hz, 1H), 4.56–4.49 (m, 2H), 3.02–2.87 (m,
13
4H), 2.65–2.54 (m, 1H), 1.89–1.82 (m, 1H), 1.52 (t, J = 7.2 Hz, 3H). C NMR (126 MHz,
CDCl3): δ 150.3, 145.0 (q, J = 3.8 Hz), 133.4, 129.9, 126.4, 125.9, 123.0 (q, J = 267.1 Hz),
119.8 (q, J = 2.2 Hz), 115.6, 108.8 (q, J = 37.2 Hz), 65.0, 54.0, 41.2, 16.2, 14.1. HMRS
+
(ESI+): m/z calcd for C16H14ClF3NO2 [M – Br]+ 344.0660, found 344.0662.
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Ethyl 5-chloro-2-(1,2-dibromocyclobutyl)-3-(trifluoromethyl)-1H-indole-1-carboxylate
(26). Rf 0.23 (EtOAc/petroleum ether 1/20). IR (ATR): 2984, 1756, 1581, 1553, 1451, 1373,
1256 cm–1. 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 9.0 Hz, 1H), 7.79–7.77 (m, 1H), 7.37
(dd, J = 9.0, 2.1 Hz, 1H), 5.07 (t, J = 5.8 Hz, 1H), 4.67–4.51 (m, 2H), 3.61–3.54 (m, 1H),
3.42–3.34 (m, 1H), 3.09–3.03 (m, 1H), 2.22–2.16 (m, 1H), 1.56 (t, J = 7.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3): δ 150.1, 141.5 (q, J = 4.1 Hz), 132.9, 130.0, 126.7, 125.8 (q, J = 1.6 Hz),
123.2 (q, J = 270.1 Hz), 120.2 (q, J = 3.7 Hz), 116.8, 110.7 (q, J = 37.1 Hz), 64.9, 57.5, 57.1,
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39.6 (q, J = 5.6 Hz), 29.2, 14.2. HMRS (ESI+): m/z calcd for C16H13BrClF3NO2 [M – Br]+
421.9765, found 421.9759.
Ethyl 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole-1-carboxylate (1a)
Method A (via 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1)):
To a stirred solution of indole 26 (127 mg, 0.25 mmol) in DMF (3.5 mL) was added sodium
sulfide nonahydrate (Na2S × 9H2O, 271 mg, 1.12 mmol) in small portions at room
temperature. After being stirred at room temperature for 3 h, the reaction mixture was poured
into ice cold water (10 mL), and the resulting mixture was extracted with Et2O (3 × 10 mL).
The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and
evaporated to dryness to give crude product 1, which was used in the next step without
purification.
1
1: H NMR (500 MHz, CDCl3): δ 8.29 (br s, 1H), 7.73–7.71 (m, 1H), 7.26 (d, J = 8.7 Hz,
1H), 7.20 (dd, J = 8.7, 1.9 Hz, 1H), 6.50 (s, 1H), 2.99–2.96 (m, 2H), 2.67–2.65 (m, 2H).
HMRS (ESI+): m/z calcd for C13H10ClF3N+ [M + H]+ 272.0448, found 272.0442.
5-Chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1)
To a solution of crude 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) from
the above step, Et3N (253 mg, 348 μL, 2.5 mmol), and 4-dimethylaminopyridine (DMAP, 16
mg, 0.13 mmol) in DMF (1.5 mL) was added diethyl pyrocarbonate (162 mg, 147 μL, 1.0
mmol), and the stirred for 1 h at 50 °C. The reaction mixture was allowed to cool to room
temperature, diluted with a mixture of EtOAc/petroleum ether (1/3, 30 mL), and washed with
aqueous HCl (1 M, 10 mL), brine (3 × 10 mL), dried (Na2SO4), and evaporated to dryness.
The residue was subjected to column chromatography purification (EtOAc/petroleum ether
1/20 with 1% Et3N) to afford 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole
(1a, 50 mg, 58% yield over two steps) as a white solid.
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Method B:
Sodium sulfide nonahydrate (Na2S × 9H2O, 270 mg, 1.1 mmol) was added in small portions
to a stirred solution of ethyl 5-chloro-2-(1,2-dibromocyclobutyl)-3-(trifluoromethyl)-1H-
indole-1-carboxylate (26, 131 mg, 0.26 mmol) in dry DMF (3.5 mL) at 0 °C. After being
stirred for 1 h at 0 °C, the reaction mixture was diluted with Et2O (15 mL), followed by a
slow addition of a ice cold Na2HPO4/NaH2PO4 buffer solution (0.5 M, pH 7, 10 mL). The
biphasic system was vigorously stirred for 10 minutes at 0 °C, the layers were separated and
the aqueous layer was extracted with Et2O (2 × 15 mL). Combined organic layers were
washed with brine (20 mL), dried (Na2SO4), and evaporated to dryness. The residue was
purified by column chromatography (EtOAc/petroleum ether 1/20 with 1% of Et3N) to afford
ethyl 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole-1-carboxylate (1a, 65
mg, 73%) as a white solid.
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Rf 0.46 (EtOAc/petroleum ether 1/20 with 1% of Et3N). Mp 53–54 °C. IR (ATR): 2984, 2928,
1756, 1603, 1580, 1452, 1372, 1256 cm–1. 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 9.0 Hz,
1H, H7), 7.73‒7.70 (m 1H, H4), 7.33 (dd, J = 9.0, 2.0 Hz, 1H, H6), 6.32 (s, 1H, H2cyclobutene),
4.51 (q, J = 7.1 Hz, 2H, CH2), 2.94‒2.91 (m, 2H, H4cyclobutene), 2.64‒2.61 (m, 2H, H3cyclobutene),
13
1.48 (t, J = 7.0 Hz, 3H, CH3). C NMR (126 MHz, CDCl3): δ 150.6 (CO), 138.1 (q, J = 2.2
Hz, C2cyclobutene), 136.6 (q, J = 4.0 Hz, C2), 136.2 (C1cyclobutene), 133.5 (C7a), 129.8 (C5), 126.3
(q, J = 1.1 Hz, C3a), 125.8 (C6), 123.5 (q, J = 269.2 Hz, CF3), 119.6 (q, J = 2.5 Hz, C4),
116.5 (C7), 110.3 (q, J = 35.3 Hz, C3), 64.2 (CH2), 34.0 (C4cyclobutene), 28.2 (C3cyclobutene), 14.0
+
(CH3). 19F NMR (CDCl3, 471 MHz): δ ‒54.52. HMRS (ESI+): m/z calcd for C16H14ClF3NO2
[M + H]+ 344.0660, found 344.0664.
Associated Content
Supporting Information: The Supporting Information is available free of charge on the ACS
Publications website at DOI: ___.
Copies of NMR spectra for new products.
Author Information
Corresponding Authors:
* E-mail (MG): martin.gazvoda@fkkt.uni-lj.si
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* E-mail (JK): janez.kosmrlj@fkkt.uni-lj.si
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§ MG and MK contributed equally.
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Notes: The authors declare no competing financial interest.
Acknowledgements
The authors acknowledge the financial support from the Slovenian Research Agency
(Research Core Funding Grant P1-0230, and Project J1-8147) and Lek Pharmaceuticals d.d.
(Contract No.: 16508-2015 and 40449-2015). We thank Dr. D. Urankar (Research
Infrastructure Centre at the Faculty of Chemistry and Chemical Technology, University of
Ljubljana) for HRMS analyses.
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