Expedited access to thieno[3,2-c]quinolin-4(5H)-ones and benzo[h]-1,6-naphthyridin-5(6H)-ones via a continuous flow photocyclization method

Article abstract of DOI:10.1039/c6ob02279k

A single-step continuous flow method has been developed that gives expedited access to complex heterocycles via an intramolecular photochemical cyclization. Herein we report the first examples of the photochemically-induced generation of thieno[3,2-c]quin

Full text of DOI:10.1039/c6ob02279k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Expedited access to thieno[3,2-c]quinolin-4(5H)-ones and
benzo[h]-1,6-naphthyridin-5(6H)-ones via a continuous flow
photocyclization method
Y. Fanga and G. K. Tranmer*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/obc
A single-step continuous flow method has been developed that integrate and exploit the many benefits of flow chemistry
gives expedited access to complex heterocycles via an through its application in photochemical processes. The total
intramolecular photochemical cyclization. Herein we report the synthesis of Artemisinin stands out as an excellent example of
first examples of the photochemically-induced generation of the many benefits that can be realized when flow chemistry
thieno[3,2-c]quinolin-4(5H)-ones, 16 examples, and benzo[h]-1,6- techniques are applied to
a
key photochemical
naphthyridin-5(6H)-ones, 6 examples. Overall, the continuous flow transformation.16 Primarily, flow photochemistry is superior to
method provides access to complex heterocycles in two steps batch photochemical reactions due to the increased efficiency
from commercially available starting materials in good yields and achieved as a result of the narrow width of the flow reactor
with greater atom efficiency than traditional batch reactions.
tubing, a
direct benefit of the Beer-Lambert law.14
Additionally, continuous flow photochemistry provides for
increased scalability, including enhanced levels of production
from low concentration reactions. Continuous photochemical
processing also offers enhanced control over reaction
conditions and UV irradiation duration that often limits the
side-reactions and product decomposition caused by the
prolonged reaction times that are typical of batch
New methods for the synthesis of complex heterocyclic ring
systems have become increasingly important in recent years
due
to
the
need
to
access
medicinally-active
pharmacophores.1 In particular, heterocyclic ring systems have
become a cornerstone in the discovery and development of
anticancer compounds.2 To this end, both groups in academia
and the pharmaceutical industry are constantly searching to
develop new synthetic methods that give improved access to
heterocycles in terms of yield, diversity,3 synthetic utility and
that possess ‘greener’ properties.4 As part of our groups’
contribution to the field, we have set out to discover and
develop new methods for the synthesis of complex
heterocycles, primarily through the application of flow
chemistry techniques in the field of photochemistry.5
photochemical
reactions.
Overall,
continuous
flow
photochemistry has proven to be a highly useful enabling
synthetic technology that provides rapid access to desired
heterocyclic building blocks in a superior manner to batch
photochemical transformations that typically require long
reaction times, offer lower selectivity’s and possess limited
scalability.17
Herein, we report the application of continuous flow
Flow chemistry has had a transformative effect on the field
of synthetic chemistry6 and has become integral to modern-
day pharmaceutical science.7 Flow chemistry has been used for
the synthesis of natural products,8,9 heterocycles10 and in
multi-step organic synthesis,11,12 including its application in the
synthesis of active pharmaceutical ingredients.13 The field has
continued to develop and evolve, and has recently been
integrated with photochemistry, resulting in considerable
synthetic benefit.14 Continuous flow photochemistry15 seeks to
techniques, in combination with
a novel intramolecular
photochemical cyclization, to give rapid access to complex
heterocycles for use as building blocks for a medicinal
chemistry program. Recently, we published a method for the
production of substituted 6(5H)-phenanthridinones (A) via an
intramolecular photochemical cyclization using a continuous
flow technique for use as poly(ADP-ribose) polymerase (PARP)
inhibitors.5 It was our desire to expand upon this work and
a.College of Pharmacy, Faculty of Health Science, University of Manitoba,
Winnipeg, MB, Canada, R3E 0T5. E-mail: geoffrey.tranmer@umanitoba.ca
b.Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg,
MB, Canada, R3T 2N2.
†Electronic Supplementary Information (ESI) available, including NMR spectra of
starting materials and products: See DOI: 10.1039/x0xx00000x
Fig. 1 Generation of Bioisostere Analogs
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develop novel intramolecular cyclization reactions that would desired tricyclic framework R = CO2H, route 3.22 VTiehweArtriceleaOctniloinne
give access to additional drug candidates by replacing a required multiple purification and work-up DstOeIp: s10, .a10n3d9i/nCv6oOlvBe0d222709K+
benzene ring with other sulfur or nitrogen containing hours of reaction time that would take several days to perform. Due
heterocycles. Figure 1 represents this approach where we to the lack of existing methods to provide rapid access to potential
would replace a phenyl ring of known PARP inhibitors with drug candidates with a thieno[3,2-c]quinolin-4(5H)-one framework
aromatic bioisosteres,18,19 creating complex thiophene and in an efficient manner, we set out to apply the many benefits of
pyridine ring systems. In particular, we chose to develop flow photochemistry to the synthesis of these complex biologically-
continuous flow photochemical methods that would give us active heterocycles. We envisioned a simplified two-step method
rapid access to thieno[3,2-c]quinolin-4(5H)-ones
1,6-naphthyridin-5(6H)-ones (C).
(
B
) and benzo[h]- that involved an amide coupling reaction between readily
commercially available 2-chlorothiophene-3-carboxylic acid and
The literature offers very few methods for direct access to substituted anilines, followed by an intramolecular photocyclization
thieno[3,2-c]quinolin-4(5H)-ones from 2-halothiophene derivatives. that would give rapid and efficient access to thieno[3,2-c]quinolin-
To our knowledge, only a single example exists in the literature of 4(5H)-ones, scheme 1. To accomplish this reaction sequence, we
the direct transformation of a 2-halothiophene (2-bromothiophene- planned to use a Vapourtec R2C+/R4 flow chemistry system
3-carboxamide D) into
a tricyclic ring system using simple equipped with a UV-150 photochemical reactor that possesses a 10
(inactivated) aniline derivatives (i.e. route 1). In this example, a mL fluorinated ethylene propylene (FEP) reactor coil and a medium
radical pathway was utilized to form a new carbon-carbon bond, pressure mercury lamp to mediate the key photochemical reaction.
generating a new tricyclic ring system using potassium tert-butoxide The Vapourtec photochemical flow reactor offers an increased
and a catalytic amount of AIBN.20 This reaction proceeds in 75% safety profile in comparison to batch photochemical reactors as the
isolated yield, however, there exists only one single example and UV-exposure is limited to the reactor and the temperature of the
using this method offers very limited scope, and also requires system is continually monitored and the reactor cooled using the
extended reactions times (14 hours). Other methods have been forced air feature of the R4 unit. Overall, this reduces the fire risk
used to access biologically active thieno[3,2-c]quinolin-4(5H)-ones, from the hot UV lamps operating above the flash point of common
however, these methods typically require cross-coupling reactions solvents, and near the auto-ignition temperatures (acetonitrile 2 ˚C,
and the metal-catalysed activation of aniline boronic acids (route 2) 523 ˚C; Cyclohexane -20 ˚C, 245 ˚C; Benzene, -11 ˚C, 498 ˚C),
or involve time-consuming and inefficient multi-step syntheses respectively. An additional advantage of the flow photochemical
(route 3). Scheme 1 highlights these general approaches where a protocol is the ability to scale-out the reaction through the
highly functionalized aniline boronic acid undergoes a tandem extended pumping of starting material for a longer period of time
Suzuki coupling/intramolecular amide bond formation reaction through the UV-reactor, generating additional quantities when
(route 2) that typically gives product in only moderate yield.21 required for medicinal chemistry purposes, such as additional in
Another strategy that has been employed is a six step synthetic vitro or in vivo testing.
process involving
a
Friedel-Craft, Vilsmeier-Haack, SNAr and
In order to generate a series of 2-chloro-N-phenylthiophene-3-
flow-based
cyclization sequence that provided the key reactions to produce the carboxamides that are suitable for developing
a
photochemical cyclization, two separate methods were used. One
method involved the use of oxalyl chloride to generate an acyl
chloride from the corresponding carboxylic acid, followed by
condensation with aniline, and the other employed an amide
coupling method directly from the carboxylic acid. We found that
the best general method involved the generation of the amides via
the HATU/DIPEA coupling of 2-chlorothiophene-3-carboxylic acids
and anilines in DMF which gave good to excellent isolated yields.
Due to the ease in generating the required amides using
conventional batch methods, we decided not to employ flow
methods, although these products could easily be generated using
existing flow methods employing polymer-supported HOBt.23 In the
future, we envision the possibility of combining the amide coupling
reaction and the photocyclization reaction into a single flow
sequence to rapidly generate desired heterocycles, without the
need for handling or purification of the intermediate amides.
Preliminary studies on the development of a single-flow sequence
that incorporates both the amide coupling and flow
photocyclization into a single continuous flow process have been
initiated and will be reported in due course.
Table 1 summarizes the results of the flow photochemical
synthesis of thieno[3,2-c]quinolin-4(5H)-ones from the precursor
amides. Originally, the reactions were performed at a flow rate of
0.2 mL/min., however, we found that unreacted starting material
Scheme 1 Synthesis of thieno[3,2-c]quinolin-4(5H)-ones
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remained, indicating that the thiophene motif might be less photo- provides quicker access to more complex productsVfierwomArticsleimOpnlliener
reactive than previous phenyl derivatives.5 Once the reaction times and cheaper starting materials than previous methods, (routes 2
DOI: 10.1039/C6OB02279K
were extended to 100 minutes, involving a flow rate of 0.1 mL/min. and 3, scheme 1), and in far fewer steps (route 3). Additionally, the
in acetone, we found that the reaction consumed the majority of scope of the reaction provides access to a much greater number of
starting material. Using this adjusted reaction condition, we were potential products than previous methods that involved direct
able to synthesize a series of substituted thieno[3,2-c]quinolin- access to thieno[3,2-c]quinolin-4(5H)-ones from 2-halothiophenes,
4(5H)-ones in isolated yields up to 77%. The parent compound, route 1, scheme 1.
(entry 1, table 1, R = H) occurred in 64% isolated yield, while the
addition of a single electron withdrawing substituent to the aniline known PARP inhibitors, we wished to replace a phenyl ring
portion (R1 = halogen or CF3, entries 2-5, table 1) gave with a pyridine ring system. A search of the literature indicates
In the next phase of our efforts to generate bioisosteres of
or
3
comparable yields, 54% to 77%. In general, the addition of an that no method has yet been developed for direct access to
electron donating group gave lower yields (R1 = OMe, Me, benzo[h]-1,6-naphthyridin-5(6H)-ones (C) from 2-halo-N-
or
3
entries 6-8, table 1) in yields ranging from 23% to 50%. Following phenylnicotinamides (E). A SciFinder® search provided zero results
other substrates, we were excited to find that the flow when a substructure reaction search was performed for this direct
photocyclization reaction tolerated the addition of sulfonamide transformation using any halogen, scheme 2. The closest examples
functional groups, a key functionality found is some selective PARP from the literature involve the metal-catalyzed cross coupling of
inhibitors in yields ranging from 29 to 43% isolated yield, entries 9, highly-functionalized heteroaryl halides and aryl boronic acids,
10, 15, 16, table 1. Further examples were produced that contained which typically occur in less than 25% isolated yield.24 We set out to
an additional halogen on the thiophene ring system (R4 = Cl, entries apply our flow photocyclization method to generate a series of
11-16), which will provide access to an expanded scope of potential these tricyclic analogs, but first needed to generate a series of the
drug candidates following further derivatization using the halogen required precursor nicotinamides through the condensation of
as the site of functionalization. Despite the reduced yield for some substituted anilines with 2-chloronicotinoyl chloride. Once we
of the examples, we found that sufficient quantities are able to be possessed the 2-chloro-N-phenylnicotinamides (E, Halogen = Cl) in
produced for medicinal chemistry purposes in a single day involving hand using this method that normally occurred in reasonable yields,
the two-step amide bond formation/flow photocyclization method we subjected the starting material to the same reaction conditions
in a manner superior to previous batch methods. Overall, from listed in table 1. Unfortunately, during our initial reaction studies,
readily available commercial starting material, we were able to the rate of conversion was found to be relatively low, even with 100
provide rapid access to thieno[3,2-c]quinolin-4(5H)-ones using a minutes of UV irradiation. We did find, however, that the addition
method that has not yet appeared in the literature. In comparison of a small amount of a ruthenium catalyst (Ru(bpy)3Cl2) to the
to conventional batch methods, the flow photocyclization method reaction increased the rate of conversion to approximately 83%
(determined by HPLC), which also translated to an improved
isolated yield of the desired product. At this point, it is unclear why
the ruthenium photocatalyst is beneficial to the reaction, but we
assume that the catalyst is not acting as a photoredox catalyst, but
instead, potentially via chelation to the pyridine nitrogen or amide
functionalities, leading to improved conversion and yield. There is
also a possibility that the catalyst may limit potential side-reactions
or product decomposition, leading to improved yields. It should be
noted that the addition of ruthenium catalyst (Ru(bpy)3(PF6)2 or
Ru(bpy)3Cl2) only benefits the reaction of the nicotinamides, but
reduces the yields of the products when added into reactions that
produce compounds similar to A and B, figure 1, phenyl or thienyl
analogs. For the reactions in table 2, Ru(bpy)3(PF6)2 was found to
give slightly higher isolated yields than Ru(bpy)3Cl2, although both
gave noticeably higher yields than reactions performed without the
catalyst. Additional potential catalysts were added to the reaction
to try to ascertain the effects of the metal complexes, such as
copper (II) acetate and iron(III) acetylacetonate, both of which gave
reasonable rates of conversion, 77% and 64%, respectively.
Table 1 Flow synthesis of thieno[3,2-c]quinolin-4(5H)-
ones from 2-chlorothiophene-3-carboxamides
Scheme 2 Literature search results
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However, neither gave higher isolated yields than the ruthenium phenylnicotinamides (E). This protocol also represents the most
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DOI: 10.1039/C6OB02279K
complexes, and studies are continuing in order to determine the rapid method published to date that gives access to this class of
importance of, and mechanism by which, the metal complexes medicinally important heterocycle from readily available
improve the yields of these reactions, all of which give higher commercial starting materials. Both 2-chloronicotinyl chloride and
conversions and isolated yields than reactions performed without substituted anilines are readily available from
a number of
any catalyst. Table 2 highlights the final results of this flow commercial vendors, and this flow photocyclization method
photocyclization reaction in the presence of ruthenium catalyst provides rapid access to these complex heterocycles in just two
Ru(bpy)3(PF6)2. In general, the reactions gave high rates of synthetic steps, and in quantities sufficient for medicinal chemistry
conversion (>80% by HPLC), but lower isolated yields due to the purposes, with a higher degree of safety and efficiency (fewer
prevalence of side-reactions and the difficulty in separating the synthetic and purification steps) compared to batch methods, such
products from the starting material using column chromatography as cross-coupling reactions24.
methods. Due to the presence of the pyridine ring systems, we had
Herein we have developed a flow chemistry method that
great difficulty in separating the products from starting material, gives rapid access to biologically important complex
resulting in their co-elution in some fractions during column heterocycles using an intramolecular photocyclization
chromatography. The isolated yields reported are only from clean reaction. Using a single step flow protocol, we were able to
fractions of product, and are free of starting material, and sufficient gain rapid access to substituted thieno[3,2-c]quinolin-4(5H)-ones
for medicinal chemistry purposes. Overall, the actual yields are (16 examples) and benzo[h]-1,6-naphthyridin-5(6H)-ones (6
much higher and we are very confident that greater isolated yields examples). This method represents the first protocol that is capable
could be obtained using other methods of purification that are of synthesizing substituted thieno[3,2-c]quinolin-4(5H)-ones from 2-
common in the pharmaceutical industry, such as preparative HPLC halothiophene-3-carboxamides, and the first method to produce
or mass-directed autopurification. For the parent compound R = H, benzo[h]-1,6-naphthyridin-5(6H)-ones directly from 2-halo-N-
the conversion was found to be relatively high (>80% by HPLC), phenylnicotinamides. The methods also represent the most rapid
however this example proved to be the most difficult to purify using method published to date that gives direct access to these complex
column chromatography, and following our best efforts, the final heterocycles in two steps from readily available commercial starting
product gave approximately 51% isolated yield, but still retained a materials. The reactions proceed in isolated yields up to 77%, and in
small portion of starting material and possessed only moderate quantities sufficient for medicinal chemistry assay analysis.
purity. For the other examples, moderate isolated yields were Additionally, the flow photocyclization methods developed herein
found for examples 18, 21 and 22, table 2, due to an easier ability to offer greater substrate scope and atom efficiency than other
separate the products from starting material in a range from 47% to comparable batch methods and in yields that are superior to, or on
52%. For examples 19 and 20, table 2, their isolation also proved to par with, comparable literature examples. Currently, we are
be difficult; however, the collection of clean purification fractions continuing our efforts into the mechanistic understanding of the
resulted in isolated yields of 24 and 26 %, respectively. It should be photocyclization reaction, and in particular, the role of the metal
noted however, that these lower yields are on par with similar complexes in improving the yields for nitrogen containing
previous examples that occur in the literature24 for cross-coupling heterocycles. We also plan on expanding the applications of this
reactions, but those methods require many more synthetic steps method to include other photocatalysts in an effort to improve the
and require much longer reaction times. Overall, the method photocyclization reaction and give access to alternate nitrogen
developed herein is the first reaction to give direct access to containing heterocycles, such as pyrrole and indole, as well as study
benzo[h]-1,6-naphthyridin-5(6H)-ones
(C)
from
2-halo-N- this reaction on oxygen containing heterocycles, such as furan and
oxazole. In the near future, we plan to initiate studies on our
molecules for their ability to act as inhibitors of poly(ADP-
ribose) polymerase, among other biological targets, that will
include additional substrates.
Notes and references
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5(6H)-ones from 2-chloro-N-phenyl-nicotinamides
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