Visible Light Photocatalytic Synthesis of Tetrahydroquinolines Under Batch and Flow Conditions

Article abstract of DOI:10.1002/ejoc.202001018

In this work, we describe the use of visible light and a photocatalytic system for the cyclization of iodoaryl vinyl derivatives to tetrahydroquinoline structures. The reaction proceeds under very mild conditions, tolerates different functional groups and more importantly, the method allows the synthesis of N-free tetrahydroquinolines from N-unprotected starting materials. In addition, the reaction can also be performed using flow-chemistry. Finally, a mechanistic proposal based on some mechanistic studies has been described.

Full text of DOI:10.1002/ejoc.202001018

Communication
doi.org/10.1002/ejoc.202001018
EurJOC
European Journal of Organic Chemistry
Photocatalysis
Visible Light Photocatalytic Synthesis of Tetrahydroquinolines
Under Batch and Flow Conditions
Daniel González-Muñoz,[a] José Luis Nova-Fernández,[a,b] Ada Martinelli,[a]
Gustavo Pascual-Coca,[b] Silvia Cabrera,*[c,d] and José Alemán*[a,d]
Abstract: In this work, we describe the use of visible light and of N-free tetrahydroquinolines from N-unprotected starting ma-
a photocatalytic system for the cyclization of iodoaryl vinyl de-
rivatives to tetrahydroquinoline structures. The reaction pro-
ceeds under very mild conditions, tolerates different functional
groups and more importantly, the method allows the synthesis
terials. In addition, the reaction can also be performed using
flow-chemistry. Finally, a mechanistic proposal based on some
mechanistic studies has been described.
ing material is usually needed, making tedious the synthesis of
these derivatives because of the protection and deprotection
protocols at the nitrogen atom. All these characteristics have
limited the expansion and applicability of radical chemistry for
the synthesis of THQs.
The synthesis of tetrahydroquinolines (THQs) is of special in-
terest, since they are heterocyclic structures present in natural
and unnatural compounds with interesting biological proper-
ties (Scheme 1a).[1] For example, tetrahydroquinolines display
anti-HIV activity (I),[2] antifungal properties against Cladospo-
rium cladosporioides, yeasts, hialohyphomycetes and dermato-
phytes (II),[3] and antitumor (III)[4] as well as antidepressant ac-
tivities (IV).[5] Therefore, new approaches and strategies for the
synthesis of this class of molecules are one of the main objec-
tives of the modern synthetic chemistry.[1a] In this regard,
among all the synthetic methods available for preparing THQs,
radical chemistry has proven to be a straightforward methodol-
ogy with a good functional group tolerance. In fact, different
synthesis of THQs have been reported under radical conditions,
most of them using tin sources as hydrogen donor and AIBN
as initiator (Scheme 1b).[6] In these methodologies, given the
energetic reaction conditions (usually 80–100 °C) required, the
control in the regioselectivity of the reaction (6 exo-trig vs 7
endo-trig cyclization) is not very predictable, normally giving a
mixture of products. Moreover, the protection (PG) of the start-
[a] D. González-Muñoz, J. L. Nova-Fernández, A. Martinelli, Prof. Dr. J. Alemán
Organic Chemistry Department, M1, Science Faculty,
Universidad Autónoma de Madrid,
Madrid-28049, Spain
E-mail: jose.aleman@uam.es
http://www.uam.es/jose.aleman
Scheme 1. a) Tetrahydroquinolines with different pharmacological applica-
tions. b) Synthesis mediated by radical intermediates. c) Our present work.
[b] J. L. Nova-Fernández, Dr. G. Pascual-Coca
Synthelia Organics Labs, C/Faraday 7. Labs 2.05 and 0.03,
Parque Científico de Madrid, 28049 Madrid, Spain
[c] Prof. Dr. S. Cabrera
Visible light photoredox catalysis has received significant at-
tention over the last years due to the possibility of achieving
new bond constructions that are not possible using other
methodologies.[7] Thus, photoredox catalysis can be employed
to generate radicals through single electron transfer (SET) reac-
tions, which can substitute the reagents and harsh conditions
of classical radical strategies. These SET reactions can be
achieved using organic dyes[8] or metal complexes as photocat-
alysts.[9] In fact, these developments have paved the way for
Inorganic Chemistry Department, M7, Science Faculty,
Universidad Autónoma de Madrid,
Madrid-28049, Spain
E-mail: silvia.cabrera@uam.es
[d] Prof. Dr. S. Cabrera, Prof. Dr. J. Alemán
Institute for Advanced Research in Chemical Sciences (IAdChem),
Universidad Autónoma de Madrid,
Madrid-28049, Spain
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001018.
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the discovery of new reactivities such as the reduction of aryl-
halides under both type of photocatalysts.[10] In 2012, Lee the challenging and unprotected nitrogen derivative 1a, using
showed the possibility of reducing aromatic halides, which un- MeCN (0.1 ) as solvent, at room temperature and under blue
We initially studied the radical formation and cyclization of
M
derwent cyclization to synthesize five membered ring heterocy- LED irradiation (see S.I. for further details). As photocatalyst, we
cles. Similarly to tin-mediated processes, this protocol requires initially tested the well-known organic photocatalyst 10-phenyl-
the use of protecting groups at any nitrogen atom of the mole- phenothiazine[10] (PTH, 5 mol%) due to its high reduction po-
cule.[11] However, the synthesis of THQs using photocatalytic- tential (E*red = –2.1 V vs. SCE),[10b] which will reduce aromatic
mediated conditions has not been yet reported. Taking into halides such as 1a (for analogous iodobenzene derivatives,
account the aforementioned reported results, we envisaged Ered = –1.59 to –2.24 vs. SCE).[12] To our delight, the tetrahydro-
that the reduction of N-pendant vinyl aryl-iodine derivatives un- quinoline 2a was obtained in 42 % conversion in 24 h (entry 1,
der visible light photocatalysis could form aryl radical interme- Table 1), but hydrodehalogenation of 1a was also observed as
diates, which after intramolecular cyclization through the dou- by-product. Next, another classical photocatalyst able to reduce
ble bond would construct THQs in one-step (Scheme 1c). In aryl-halides, that is Ir(ppy)3 (E*red = –1.7 V vs. SCE),[10b] was also
addition, the usual smooth conditions of photocatalysis would evaluated.[12] Under the same reaction conditions, the use of
permit a more controllable cyclization (only 6-exo-cyclization is the iridium catalyst provided a better conversion (65 %), which
expected), without the use of protecting groups at nitrogen. In raised up to 75 % using more diluted solution (entries 2 and 3,
this work, we present the results in the synthesis of THQs under respectively). Unfortunately, the use of other solvents such as
visible light conditions, starting from aryl iodine derivatives and DMF or DCM did not afford better results (entries 4 and 5),
an Ir(ppy)3 as photocatalyst and smooth reaction conditions. probably due to the high insolubility of the iridium catalyst
Moreover, we have also developed the protocol for the synthe- in those reaction media. Afterwards, the catalyst loading was
sis of different THQs using flow photocatalytic conditions. Fi- evaluated. The reduction to 1 mol% of iridium catalyst had a
nally, a mechanistic proposal is described based on some exper- positive outcome in the conversion, whereas the addition of
imental assays.
only 0.5 mol% of catalyst did not improve the result (entries 6–
Daniel González-Muñoz obtained his degree in Experimental Science at Universidad Rey Juan Carlos (2016). He received his Master′s degree in
Molecular Nanoscience and Nanotechnology at Universidad Autónoma de Madrid (2017). Currently. he is a PhD student under the supervision of
Prof. José Alemán. His work is focuses on the synthesis of nanostructured photocatalyst and their applications in new processes.
Jose Luis Nova obtained his Chemistry degree in 2018 from Universidad Autónoma de Madrid (Spain). In 2019, he received his Master's degree in
Organic Chemistry from the same university. He is now starting his PhD thesis in organic chemistry, searching for new synthetic processes using
flow (photo)chemistry.
Ada Martinelli received her Bachelor's and her Master's Degree in Industrial Chemistry at the University of Bologna in 2015 and 2017, respectively.
Currently, she is a PhD student at the Department of Chemistry “G. Ciamician” at the University of Bologna, where she works under the supervision
of Professor Claudio Trombini. She spent four months as a visiting PhD student in the laboratory of Professor José Alemán at Universidad
Autonóma de Madrid. Her research interests include the development of new catalysts and mechanisms for organocatalyzed and photocatalyzed
transformations.
Gustavo Pascual Coca, Manager Partner and Co-Founder at Synthelia Organics, PhD in Chemistry for the University of Salamanca (Spain). He
developed his career in different pharmaceutical companies, starting in mid-size generic pharmas such as Crystalpharma (Valladolid, Spain) or
Ragactives (Boecillo, Spain) where he leaded R&D groups. Later, he joined Eli Lilly & Co. (Madrid, Spain) in the DCSG group developing and
improving chemistry's routes acting as liaison between MedChem and production plant. In 2011, he became co-founder of Synthelia Organics
where he have co-managed more than 150 R&D projects.
José Alemán obtained his Ph.D. working on sulfur chemistry, under the supervision of Prof. García Ruano in 2005. In 2003, he spent six months
in the laboratory of Prof. Albert Padwa at Emory University, Atlanta. Then, he carried out his postdoctoral studies (2006–2008) at the Center for
Catalysis in Aarhus (Denmark) with Prof. Karl A. Jørgensen. He returned to Spain in 2009 as a Ramón y Cajal Researcher and is currently Professor
at the Universidad Autónoma de Madrid (Spain). His research interests include asymmetric synthesis and catalysis.
Silvia Cabrera obtained his Ph.D. at the Universidad Autónoma de Madrid (UAM) in 2006, under the supervision of Prof. Juan C. Carretero and
Prof. Ramón Gómez-Arrayás. Afterwards, she carried out postdoctoral studies in Prof. Karl A. Jørgensen's group at Aarhus University in Denmark
and at the Medicinal Chemistry Institute (CSIC) in Madrid in Dr. Ma José Camarasa's laboratory. In 2011, she got a Ramón y Cajal Researcher
position in the Inorganic Chemistry Department at Universidad Autónoma de Madrid, and since 2013, she is Professor in the same Department.
Her current research interests are the development of new (photo)catalysts and (photo)catalytic methods.
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Table 1. Optimization of reaction conditions for the synthesis of tetrahydroquinoline 2a.[a]
Entry
Solvent
Photocatalyst
Conversion (Yield)[b]
%
1
2
3
4
5
6
7
8
MeCN (0.1
MeCN (0.1
MeCN (0.05
DMF (0.05
DCM (0.05
MeCN (0.05
MeCN (0.05
M
)
)
PTH (5 mol%)
42
65
75
30
n.r.
78
71
90 (78)
n.r.
n.r.
n.r.
M
Ir(ppy)3 (2 mol%)
Ir(ppy)3 (2 mol%)
Ir(ppy)3 (2 mol%)
Ir(ppy)3 (2 mol%)
Ir(ppy)3 (1 mol%)
Ir(ppy)3 (0.5 mol%)
Ir(ppy)3 (1 mol%)
Ir(ppy)3 (1 mol%)
Ir(ppy)3 (1 mol%)
–
M
)
M)
M
)
M
)
)
M
MeCN (0.025
M
)
9[c]
10[d]
11
MeCN (0.025
MeCN (0.025
MeCN (0.025
M
M
M
)
)
)
[a] Reaction conditions: 1a (0.05 mmol), DIPEA (0.125 mmol) and the corresponding amount of photocatalyst and solvent were irradiated under blue LED
(410 nm, 15 W) for 24 h. [b] Conversions and yields were determined by 1H NMR using CH3NO2 as internal standard. [c] Reaction carried out in the absence
of light. [d] Reaction carried out without DIPEA as additive. n.r.: No reaction.
7). We further diluted the reaction up to 0.025 , obtaining 2a and 2i in 50 and 65 % yield, having bromine at 7- and 6-posi-
M
with the highest conversion (90 %) and in 78 % of yield (entry tion, respectively. It is important to mention that the reduction
8). Finally, the reaction was carried out in the absence of light, of the iodide group was the only pathway observed and the
DIPEA or photocatalyst (entries 9–11). In all those cases, the plausible reduction of the bromine was not detected for those
reaction did not proceed, confirming the key role of each com- cases. Furthermore, we also evaluated the presence of the
ponent and the photocatalytic nature of the reaction.
chlorine atom at ortho-, meta-, and para-positions respect to
the amino group of the aromatic ring in the outcome of the
reductive cyclization reaction. In all cases, the corresponding
heterocycles 2j–l were successfully isolated in good yields (50–
70 %). Unfortunately, the use of the bromo derivative 1o did
not allow the synthesis of 2a (see limitations-below, Table 2),
probably due to its high reduction potential (for analogous
bromo-benzene derivatives, Ered = –2.05 to –2.57 vs. SCE).[12b]
Next, we also performed the reductive cyclization of 1a at
With the optimized conditions in hand (entry 8), we evalu-
ated the scope of the reaction (Table 2). Although the free nitro-
gen THQ 2a was the most interesting product from a synthetic
point of view, we also analyzed the influence of other nitrogen
substituents. Thus, the N-alkyl derivatives 1b or 1c led to the
corresponding THQ 2b or 2c in good yields (63 % and 80 %,
respectively, Table 2). Interestingly, the acetyl group (R2) com-
monly used as protecting group in analogous substrates, pro-
vided a sluggish reaction and yielded 2d in 37 %. On the other 0.2 mmol scale, which is the largest quantity allowed by our
hand, the substitution at the double bond is key for the reac- batch photoreactor. However, the heterocycle 2a was obtained
tion to proceed. While the trans-methyl substitution at the dou- in low yield (36 %, see Table 2, data between brackets). Differ-
ble bond (R3 = Me) afforded the tetrahydroquinoline 2e, the ent well-known reasons such as low concentration of the rea-
heterocycle formation starting from methyl-substituted 1m or gents and low penetrability of light (Lambert–Beer law) among
trans-ethyl-substituted 1n was not possible, probably due to others, provoke that batch conditions are not suitable for scal-
the steric hindrance imposed by those substituents (see below- ing up photocatalytic reactions.[13] Taking into account the im-
limitations, Table 2). Next, we studied the influence of the sub- portance of developing a scalable procedure for the synthesis
stitution at the aromatic ring 1. The introduction of a methyl of THQs, we hypothesized about the use of photocatalytic flow
group (1f), as well as electron withdrawing (CF3) group (1g) in conditions[14] for achieving this goal. Thus, the current of the
meta-position respect to the amino moiety, afforded the corre- reaction media through a fine channel is able to increase the
sponding THQs 2f–g in good yields (50–54 %). The moderate surface/volume ratio as well as the radiation efficiency of the
yield obtained for some examples are due to the detection of light. In addition, the development of the reaction in flow
the dehalogenation product along with the cyclized product 2. chemistry allows to scale up processes even though the con-
On the other hand, THQs having bromine substituents are also centration of the reaction is not very high. For all the aforemen-
interesting compounds in the medicinal chemistry area, as they tioned reasons, we decided to develop the reductive cyclization
can be further functionalized via transition metal coupling reac- procedure under photocatalytic flow conditions. The flow sys-
tions to easily generate derivatives. Thus, bromo-substituted tem consisted of a syringe pump connected to the coil reactor,
anilines 1h and 1i reacted to obtain tetrahydroquinolines 2h which was made of PFA capillary tube with a reactor volume of
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Table 2. Scope of the reductive cyclization for the synthesis of THQs 2.[a]
Table 3. Reductive cyclization of different aryl-iodine derivatives 1 using flow
conditions.[a]
[a] The continuous flow experiments were carried out using the correspond-
ing amine 1, Ir(ppy)3 (1.0 mol%) and DIPEA (2.5 equiv.) in acetonitrile. Yields
determined by 1H-NMR using CH3NO2 as internal standard. [b] Experiment
carried out in 0.5 mmol scale.
[a] Reaction conditions: 1 (0.05 mmol), DIPEA (0.125 mmol) and 1 mol%
Ir(ppy)3, in MeCN (0.025 M), were irradiated under blue LED (410 nm, 15 W)
for 24 h (48 h in the case of compound 2g). [b] Yield determined by 1H NMR
using CH3NO2 as internal standard. [c] The reaction was carried out at
0.2 mmol scale. [d] A 1:1 mixture of the unsaturated and saturated iso-
propenyl moiety was obtained (see S.I. for further details).
18 mL (see Figure 1 and S.I. for further information). To irradiate
the system, a blue LED device (40 W, 420 nm) was assembled
at the top of the coil reactor, together with a fan to maintain
the temperature constant.
Figure 1. a) Graphical representation of the flow system used in the reductive
Scheme 2. a) Proposed photocatalytic cycle. b) Quenching experiments of
cyclization of aryl-iodine 1. b) Picture of the system.
the emission of Ir(ppy)3 with increasing amounts of 1a.
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After some optimization of the reaction conditions (see S.I.),
the best results were achieved using a 0.025 solution of com-
M
pound 1 in acetonitrile, containing 1 mol% of iridium catalyst
and 2.5 equiv. of DIPEA. Under these conditions, the reaction
proceeded faster than in batch conditions and only 1 h of resi-
dence time were needed to achieve similar conversions (see
Table 3). Pleasantly, the optimized flow conditions worked quite
well for most of the substrates 1 studied, obtaining similar
yields than in batch conditions for heterocycles 2a, 2c, 2h and
2j,[15] but higher yields for 2i and 2k, in only 1 hour of residence
time. Besides, flow conditions allowed to obtain compound 2k
not only in better yields compare to batch conditions but also
in 0.5 mmol, obtaining 2k in 80 % conversion.
The mechanistic proposal of this transformation is based on
the mechanism reported by Lee and Stephenson for the photo-
catalytic reductive dehalogenation,[11,12] and also in accordance
to the Stern-Volmer experiments that we have carried out
(Scheme 2 and Figure S3). These experiments indicate that
whereas the DIPEA does not affected the excited state of
[2]
[3]
[4]
[5]
[6]
[7]
[8]
Ir(ppy)3, iodoaniline 1a effectively quenches the emission of the
–1
photocatalyst, with a Stern-Vomer constant of Ksv = 34.6
M
.
Therefore, 1a is reduced by the Ir(ppy)3* to form the radical
species II, after halogen cleavage. Next, a 6-exo-trig radical cycli-
zation forms intermediate III, which suffers a hydrogen atom
transfer process (HAT) from amine IV to generate the final prod-
uct 2a. Finally, the iridium catalyst is regenerated by reduction
[9]
[10]
+
of Ir(ppy)3 with DIPEA.
In conclusion, we have found an effective method for the
cyclization of aryl-iodine derivatives to tetrahydroquinolines.
This methodology constitutes an alternative to the classic meth-
ods that use toxic reagents and more energetic conditions. In
addition, the strategy does not need the use of nitrogen pro-
tecting groups. Although one of the limitations is the 24-hour
reaction times in batch conditions, the use of flow conditions
allows to obtain the products in just one hour.
[11]
[12]
[13]
[14]
Acknowledgments
Financial support was provided by the European Research
Council (ERC-CoG, contract number: 647550), Spanish Govern-
ment (RTI2018-095038-B-I00), “Comunidad Autónoma de Ma-
drid” and European Structural Funds (S2018/NMT-4367). J. L. N.
thanks “Comunidad de Madrid” for his industrial doctorate fel-
lowship (IND2019/AMB-17142).
[15]
We tried to improve these results with 2 hour residence time but no
significant difference in terms of conversions were found.
Keywords: Photocatalysis · Flow chemistry · Aryl-iodine
reduction · Cyclization · Photoredox
Received: July 23, 2020
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Photocatalysis
D. González-Muñoz,
J. L. Nova-Fernández, A. Martinelli,
G. Pascual-Coca, S. Cabrera,*
J. Alemán* ............................................ 1–6
Visible Light Photocatalytic Synthe-
sis of Tetrahydroquinolines Under
Batch and Flow Conditions
In this work, we have found an effec- ing groups. Although one of the limi-
tive method for the cyclization of aryl- tations is the 24-hour reaction times in
iodine derivatives to tetrahydroquin- batch conditions, the use of flow con-
olines. In addition, the strategy does ditions allows to obtain the products
not need the use of nitrogen protect- in just one hour.
doi.org/10.1002/ejoc.202001018
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