Multifunctional 2- and 3-Fluoropyrroles

Article abstract of DOI:10.1002/ejoc.201900185

Sequential reaction cascades for the synthesis of polysubstituted 2- and 3-fluoropyrrole derivatives from common polybromopyrrole precursors have been developed. A strategic variation of a combination of regioselective debromolithiation followed by trapping of the corresponding carbanions by electrophilic fluorination and Pd catalysed cross-coupling reactions allows access to polyfunctional fluoropyrrole products by methodology applicable to drug discovery programs, extending the range of five-membered fluoroazaheteroaromatic derivatives potentially available for incorporation into screening libraries.

Full text of DOI:10.1002/ejoc.201900185

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Title: Multifunctional 2- and 3-fluoropyrroles
Authors: Darren Heeran and Graham Sandford
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
Multifunctional 2- and 3-fluoropyrroles
Darren Heeran and Graham Sandford*
Dr Darren Heeran and Prof. Graham Sandford
Department of Chemistry
Durham University
South Road, Durham, DH1 3LE, U.K.
E-mail: Graham.Sandford@durham.ac.uk
https://www.dur.ac.uk/chemistry/staff/profile/?id=199
Supporting information for this article is given via a link at the end of the document. CCDC 1879860-
1879866 contain the supplementary crystallographic data for this paper.
Abstract: Sequential reaction cascades for the synthesis of polysubstituted 2- and 3-fluoropyrrole
derivatives from common polybromopyrrole precursors have been developed. A strategic variation of a
combination of regioselective debromolithiation followed by trapping of the corresponding carbanions by
electrophilic fluorination and Pd catalysed cross coupling reactions allows access to polyfunctional
fluoropyrrole products by methodology applicable to drug discovery programs, extending the range of five-
membered fluoroazaheteroaromatic derivatives potentially available for incorporation into screening
libraries.
Introduction
Since the seminal work by Fried and Sabo concerning the enhanced biological activity of Fludrocortisone,[1]
the introduction of fluorine into organic systems has been shown to effectively modulate lipophilicity,
metabolic stability and pH profiles of many classes of organic systems.[2–6] These factors underpin the
strategic use of fluorine within drug design and many commercially successful life science products contain
fluorinated groups within their structures.[7–9]
In particular, fluorinated six-membered heterocycles are structural units found within a number of
commercially important life science products. Fluoro-pyridine or –pyrimidine motifs have well-established
synthetic protocols at both discovery and industrial scales[10–17] and, as a result, life science products
containing six-membered fluoroheteroaromatic units such as Voriconazole (antifungal, Pfizer), Capecitabine
(anticancer, Roche) and Diclosulam (herbicide, Dow) have now reached the commercial market[18–20] with
many others such as Abemaciclib (anticancer, Eli Lilly), Riociguat (heart failure, Bayer) and Verubecestat
(Alzheimers, Merck) in clinical trials.[21] In contrast, while functionalised five-membered heterocycles such
as pyrroles, thiophenes and furans are prevalent structural units within life science products and many
biologically active compounds,[22] corresponding occurences of fluorinated five-membered heteroaromatic
in life science products are very rare. This is primarily due to the lack of readily available, convenient,
efficient and regioselective synthetic methodologies for the synthesis of wide ranges of, for example,
fluoropyrrole analogues at the drug discovery stage.
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
The most direct method for the synthesis of fluoropyrroles is the transformation of C-H to C-F bonds by
reaction of the parent pyrrole with an electrophilic fluorinating agent. Whilst electrophilic bromination and
chlorination reactions of pyrroles using halogenating agents such as NBS, NCS, Br2 or Cl2 are well
[24,25]
established,[23] related fluorination reactions utilising XeF2
or SelectfluorTM[26,27] often proceed in low
yields. For example, we reported a systematic study on the effect of various substituents on the
fluorination of pyrrole derivatives using SelectfluorTM[28] and, although these procedures provided access to
several novel fluoropyrroles bearing electron withdrawing groups on the pyrrole ring, in general, competing
oxidation and subsequent polymerisation of the pyrrole substrate limits the scope of this strategy.
Other approaches to the synthesis of fluoroyrrole derivatives are restricted to very few examples of
processes such as photochemical modification of the Balz-Schiemann reaction,[29] fluorodecarboxylation of
highly substituted derivatives using Selectfluor[30] and reaction of Grignard[31] or lithiated[32] derivatives with
N-fluorobenzene sulfonamide (NFSI). Additionally, the lack of commercially available multifunctional
pyrroles to act as substrates in fluorination reactions limits the range of fluoropyrrole products accessible
by this approach.
In general, therefore, current methodologies for the preparation of fluoropyrrole derivatives are inefficient,
have a very limited substrate scope and the synthesis of diverse libraries of fluoropyrroles for drug
discovery programmes has not been achieved.[33] Thus, there is not only a requirement for the
development of effective fluorination methods applicable to a range of substrates but also for the synthesis
of multifunctional pyrroles in general.
We envisioned that polybromopyrrole derivatives could act as appropriate substrates where several
bromine atoms could be used as functional groups for fluorination reactions in conjunction with sequences
of cross coupling and debromolithiation/trapping chemistries. By varying the order in which
functionalisations are sequentially applied, access to a diverse library of highly functionalised pyrrole
products, including fluoropyrroles, could be possible (Scheme 1).
Scheme 1. Concept sequential reaction cascades for fluoropyrrole synthesis.
However, despite the potential utility of polybrominated pyrroles, tetra- and tri-brominated pyrroles have
been scarcely utilised in synthesis, with only a limited number of reactions reported, largely concerning
Suzuki,[34–39] Sonogashira,[40] Heck,[41] and more recently, Stille[42] processes for the synthesis of polymeric
systems from 2,5-dibromopyrrole derivatives. Metal halogen exchange reactions of tetra- and tri-
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
brominated pyrrole substrates have received even less attention and, until very recently, metal-halogen
exchange of a tetrabrominated pyrrole substrate had not been reported. In the only example, N-phenyl-
2,3,4,5-tetrabromopyrrole could be selectively lithiated at the 2-position before addition of benzophenone
and acidic work up gave a 2-diphenylmethylene product.[43] Tribrominated pyrrole derivatives, such as N-
TIPS-2,3,4-tribromopyrrole, have also been utilised in a limited number of metal halogen exchange
reactions[44,45] whereby lithiation occurs selectivity at the 2-position to yield 2-substituted-3,4-
dibromopyrrole products.
Here, we describe proof-of-concept syntheses of multi-substituted fluoropyrrole derivatives by fluorination,
debromolithiathion/trapping and Pd catalysed coupling cascades.
Results and Discussion
We began our studies with the perbromination of N-benzylpyrrole (1) using NBS following a literature
procedure.[34] (Scheme 2).
Scheme 2. Synthesis and molecular structure of 2-fluoro-3,4-dibromopyrrole 4.
Tetrabromo-N-benzylpyrrole (2) reacted with n-BuLi in THF and, following quenching with dilute HCl, gave
2,3,4-tribromo-N-benzylpyrrole (3) as the only product (Scheme 2). The regioselectivity follows related
results established by Schlosser which indicate that the bromine atom occupying the most acidic site
selectively undergoes debromolithiation.[47]
Unfortunately, analogous reactions involving quenching the lithiated intermediate formed from 2 with a
solution of electrophilic fluorinating agent NFSI in THF gave a complex mixture of products, including
appreciable quantities of difluorinated products, as observed by GC-MS analysis, despite using only 1 eq. of
n-BuLi. This is likely a result of ‘halogen dance’ type processes previously reported for similar halogenated
heterocyclic systems and facilitated by a slow fluorination reaction step.[48]
In contrast, however, fluorination of tribromopyrrole derivative 3 using NFSI under similar conditions, gave
desired 2-fluoro-3,4-dibromopyrrole (4) which was purified by column chromatography (Scheme 2).
Storage of pure 4 at -18 ºC led to the isolation of crystals of suitable quality for x-ray crystallography
confirming the structure (Scheme 2) and, hence, the regioselectivity of fluorination at the most acidic site
consistent with observations discussed above.
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
Dibromofluoropyrrole 4 is a potentially useful fluorinated building block and so we assessed the
regioselectivity of further debronolithiation reactions (Scheme 3). Hydrodebromination using n-BuLi
1
followed by quenching with aq. HCl was performed and gave a single product 5. Analysis of the H NMR
spectrum of 5 shows a proton-proton coupling of J=2.2 Hz which is consistent with four-bond coupling[49]
for related N-substituted 2,3- and 2,4-dibromopyrrole derivatives. The observed regioselectivity reflects the
ability of the fluorine substituent to increase acidity of ortho-sites.
Scheme 3. Synthesis of 2-fluoro-4-substituted pyrrole derivatives from 5.
Ready access to fluorobromopyrrole 5 allowed us to synthesise a range of 2-fluoropyrrole systems by
trapping corresponding carbanions with a short series of electrophiles. Fluoropyrrole systems bearing ester
(6), aldehyde (7) and ketone (8) functional groups at the 4-position were formed by reaction with ethyl
chloroformate, ethyl formate and benzoyl chloride respectively providing a small series of model 2-fluoro-
4-substituted pyrrole systems (Scheme 3). 19F NMR data of 2-fluoropyrrole derivative 6 (F -140.04 ppm in
CDCl3), was in excellent agreement with that previously reported in the literature (F -140.07 ppm) and
distinct from the shift of regioisomer ethyl 2-fluoro-N-benzylpyrrole-3-carboxylate (F -129.22 ppm).[27]
Fluorination of 5 was also attempted to give access to 2,4-difluoro-N-benzylpyrrole but, when using NFSI in
THF as the electrophile source, the major component of the crude reaction mixture was the
hydrodebrominated product alongside only trace amounts of the desired 2,4-difluoropyrrole derivative.
Competing electron transfer reactions between the intermediate lithiate and NFSI, in agreement with
observations previously reported in the synthesis of 3-fluoro-N-TIPS-pyrrole using NFSI[32] and in reactions
of a range of organometallic nucleophiles with N-F electrophilic fluorinating agents,[50,51] is suggested as a
possible mechanism for this process.
The range of fluoropyrrole products accessible from dibromofluoropyrrole 4 could also be expanded by
varying the substituent at the 3-position. Excellent regioselectivity upon debromolithiation/trapping occurs
and a small range of electrophiles was again used to give the corresponding 3-substituted 2-fluoropyrroles
9-12 in good to excellent yields (Scheme 4). The structure of 11 was confirmed by x-ray crystallography
(Figure 1).
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
Scheme 4. Synthesis of 2-fluoro-3,4-disubstituted pyrrole derivatives from 4.
Using similar reaction conditions with allyl bromide as the quenching electrophile, no alkylation occurs
upon lithiation of 4. However, addition of a CuI salt to the reaction mixture prior to the addition of the
electrophile, forming a much softer organocopper nucleophile,[53] led to the isolation of allylated product
12 (Scheme 4).
Additionally, hydrodebromination reactions of 2-fluoro-3-substituted-4-bromopyrrole compounds provided
access to regioisomeric fluoropyrrole products. Using fluoropyrrole 9 as a model substrate, reaction with n-
BuLi followed by quenching with aq. HCl gave 13 (Scheme 4). Synthesis of a mixture of compounds 6 and 13
has previously been reported.[27]
Additonally, fluoropyrrole derivative 9 was used as the substrate that enabled the synthesis of further 3,4-
disubstituted 2-fluoropyrrole products. Fluoropyrrole derivatives 14, 15 and 16 were obtained in moderate
yields by applying analogous lithiation/trapping protocols (Scheme 4) extending the range of fluoropyrrole
systems available.
Furthermore, we used Pd catalysed cross coupling chemistry to diversify the range of fluoropyrrole
products obtainable by this general strategy. Suzuki-type cross coupling conditions adapted from those
reported by Ghosez[54] allowed us to synthesise a range of aryl substituted products (17 – 20) with the
conditions tolerating substituted arylboronic acids bearing both electron-donating and electron-
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10.1002/ejoc.201900185
European Journal of Organic Chemistry
withdrawing substituents as well as heteroaromatic boronic acids in good to excellent yields (Scheme 4).
The structures of 16 and 19 were confirmed by x-ray crystallography (Figure 1).
Having demonstrated the synthesis of a diverse range of 2-fluoro-N-benzylpyrrole derivatives by sequential
processes, we sought to expand the methodology to provide access to corresponding 3-fluoropyrrole
derivatives and envisioned that this could be achieved by simply delaying the fluorination step in the
reaction sequence (Scheme 1).
Figure 1. Molecular structures of 11, 16 and 19.
Hydrodebromination of tribromopyrrole 3 (Scheme 5) gave 21 and subsequent fluorination of 21 gave 3-
fluoro-4-bromopyrrole derivative 22 in moderate yield. The yield of this reaction was limited by the
formation of debrominated product 23, formed by competing electron transfer reactions discussed above.
Optimisation attempts using excess or sub-stoichiometric amounts of NFSI had no desirable effect on the
yield, whilst the addition of SelectfluorTM, a more powerful oxidant, in a THF/MeCN mixture gave
exclusively 23. The 19F NMR spectrum of isolated 3-fluoro-4-bromopyrrole derivative 22, however,
corresponded well with that reported previously for 3-fluoropyrrole derivatives[32] and the structure of 22
was confirmed by x-ray crystallography.
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European Journal of Organic Chemistry
Scheme 5. Synthesis of 3-fluoro-pyrrole derivatives
Using 3-fluorinated building block 22 we synthesised a representative 3-fluoropyrrole derivative by metal-
halogen exchange using n-BuLi and quenching the intermediate carbanion with ethyl chloroformate to give
the ester substituted 3-fluoropyrrole derivative 24 in moderate yield. Finally, we carried out a Suzuki cross
coupling reaction of 22 under similar conditions to those described above and obtained 3-fluoropyrrole
derivative 25 in good yield.
Conclusions
An efficient sequential polybromination-derivatisation strategy for the synthesis of a variety of 2- and 3-
fluoropyrrole
derivatives
by
strategically
varying
the
order
in
which
debromolithiation/trapping/fluorination and Pd catalyzed cross coupling are applied has been developed
(Scheme 1). Clearly, this proof-of-concept methodology could be expanded to reactions involving many
other electrophiles, Pd catalyzed processes, other 5-membered heterocyclic core scaffolds and different
sequential processes. This strategy, therefore, provides methodology for the synthesis multifunctional
fluoropyrrole derivatives bearing multiple reaction handles for further diversification and expedient access
to a diverse array of polyfunctional fluoropyrrole products that can, in principle, be incorporated into life
science screening libraries.
Acknowledgements
We thank EPSRC (Durham University DTA) for a studentship to D.H. and Dr. D. S. Yufit for X-ray
crystallographic analysis.
Keywords: fluoroheterocycle • selective fluorination • fluoropyrrole • electrophilic fluorination • nitrogen
heterocycle
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European Journal of Organic Chemistry
Darren Heeran, Graham Sandford*
Page No. – Page No.
Multifunctional 2- and 3-
fluoropyrroles
Displacement of bromine atoms from tetrabromopyrrole by strategically varying the
order in which debromolithiation/trapping/fluorination and Pd catalyzed cross
coupling are applied, provides methodology for the synthesis of multifunctional of 2-
and 3-fluoropyrrole derivatives bearing multiple reaction handles for further
diversification.
Key Topic : Organofluorine Chemistry
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