Photo-induced sp3 C?H bond arylation, cyanation and nitroalkylation of tetrahydroisoquinolines (THIQs) under visible light irradiation using a combination of NHPI and Rose Bengal

Article abstract of DOI:10.1002/asia.202000999

This work reports a sustainable protocol for α-arylation of tetrahydroisoquinolines (THIQs) with aryl diazonium salts using a combination of a cheap and stable oxidant, N-hydroxyphthalimide (NHPI), and an inexpensive dye photosensitizer, Rose Bengal (RB),

Full text of DOI:10.1002/asia.202000999

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Photo-induced sp3C–H bond arylation, cyanation and
nitroalkylation of tetrahydroisoquinolines (THIQs) under visible
light irradiation using a combination of NHPI and Rose Bengal
Authors: Mahendra Patil, Jagrut Shah, A. Vijay Kumar, and anant kapdi
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10.1002/asia.202000999
Chemistry - An Asian Journal
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Photo-induced
sp3C–H bond arylation, cyanation and
nitroalkylation of tetrahydroisoquinolines (THIQs) under visible
light irradiation using a combination of NHPI and Rose Bengal
Mahendra R. Patila+, Jagrut Shaha+A.Vijay Kumara* and Anant R. Kapdia*
Abstract:. This work reports a sustainable protocol for α-arylation of
tetrahydroisoquinolines (THIQ’s) with aryl diazonium salts using a
combination of a cheap and stable oxidant,N-hydroxyphthalimide
(NHPI) and an inexpensive dye photosensitizer Rose Bengal (RB)
for the first time. The reaction was performed at ambient
temperature using green LED light irradiation underan oxygen
atmosphere. The developed α-arylation protocol shows a diverse
substrate scope for various THIQ’s and aryl diazonium salts. The
work also explores nitroalkylationand cyanation under the
developedreaction conditions. The work shows a possible SET
mechanism involved which was confirmed by ESI-MS analysis of the
reaction mixture.
arylboronic acids at high temperature.[9]
The α-substituted nitrogen heterocycles are an important
structural motif in chemistry, biology, and medicine.[1]In particular,
tetrahydroisoquinoline core with α-functional groups constitutes
a large family of natural and synthetic products with interesting
biological activities (Figure 1). For example, (S)-cryptostyline (I),
cryptostyline (II) have anti-convulsant activity and are used as
Figure 1: Representative biologically important α-substituted
tetrahydroisoquinoline moieties.
anti-fertile
agent,[2]whereas,lactamderivative
of
1-phenyl
isoquinoline alkaloid exhibit enhanced anti-convulsant activity[3]
than cryptostylines. The amide derivative of 1-phenyl
isoquinoline alkaloid is a potential AMPA receptor antagonist
and is useful as a neuroprotective agent in the treatment of
neurological diseases such as epilepsy, Parkinson’s disease,
and multiple sclerosis.[4]Solifenacin is another example of anti-
spasmodic drug commonly used in the treatment of overactive
urinary bladder. Besides these, many more examplesknown in
literature,whichexhibits promising bio-activity. Hence the
installation of such structural core warrants the development of
an efficient protocol which could provide easy access to 1-
aryltetrahydroisoquinolines. The increased environmental
awareness and from green chemistry point-of-view, the direct
arylation of C–H bond through cross-dehydrogenative coupling
reaction has been reported by several groups.[5–8]However, to
the best of our knowledge, the synthesis of 1-
phenyltetrahydroisoquinoline derivatives isless exploited using
direct C─H bond activation. In 2008, Li and co-workers reported
Cu-catalyzed sp3 C─H bond arylation of THIQs with a variety of
[a]
Dr.MahendraPatil, Mr.Jagrut Shah, Dr.A. Vijay Kumar
Figure 2:Comparative studies of previous work and current work.
Dr.Anant R. Kapdi
Department of Chemistry
Institute of Chemical Technology
Nathalal Parekh road, Matunga, Mumbai-400019, India
E-mail: v.kumar@ictmumbai.edu.in, ar.kapdi@ictmumbai.edu.in
+Both authors have contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1: sp3 C─H arylation of a tertiary amine.
Table 1: Optimization table of sp3 C─H arylation of a tertiary amine.
(Photo) Catalyst/ Organic
Yielda
(%)
No.
NHPI (mol%)
Solvent
Time
LED
Dyes (mol%)
Green 5W
Green 5W
Green 5W
Green 5W
Green 5W
Green 5W
Green 5W
Green 5W
1
Eosin Y (0.3)
35
35
35
35
35
35
20
10
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
MeCN
MeCN
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
3h
12h
24h
6h
6h
24h
6h
72
2
Fluorescein (0.3)
Rose Bengal (0.3)
Alizarin Red (0.3)
Methylene Blue (0.3)
Rose Bengal (0.1)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Rose Bengal (0.3)
Co(OAc)2.4H2O (5.0)
CuBr (5.0)
69
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3
75
4
67
5
71
6
70
7
60
8
40
Green 14W
Green 30W
Blue 30W
Red 30W
MeCN
MeCN
MeCN
MeCN
9
78
10
11
12
13
14
15
16
17
18
19
20
21
23
24
25
26
27
78
72
71
Sunlight
Tube Light 20W
Dark
MeCN
MeCN
MeCN
MeOH
CHCl3
EtOAc
DCM
70
68
15
Green 14W
Green 14W
Green 14W
Green 14W
Green 14W
Green 14W
Green 14W
-
62
47
45
50
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
70
78
78
60/40b
20/80c
65d
45e
-
Green 14W
Green 14W
Rose Bengal (0.3)
Rose Bengal (0.3)
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Green 14W
MeCN
MeCN
MeCN
MeCN
MeCN
28
29
30
31
32
Rose Bengal (0.3)
35
35
35
-
6h
15f
35
-
-
6h
6h
6h
6h
-
-
60g
Green 14W
Green 14W
Rose Bengal (0.3)
Rose Bengal (0.3)
NR
35
~10%h
Reaction conditions: 0.5 mmol of 1a, 0.65 mmol of 2a, NHPI (35 mol%), Rose Bengal dye (0.3 mol%), 3.0 ml of solvent, reaction kept in a
an
b
c
d
e
closed system with appropriate LED for 6 hours with O2 balloon at rt, isolated yields, Scheme 2; Scheme 3, open system (air), N2
balloon, fAr balloon, g Temperature at 60 oC, h TEMPO (3.0 equiv.) – the reaction is sluggish.
Successively, in 2013 and 2014 the same groupimproved the
catalytic protocol of sp3 C─H bond arylation of THIQs with the
employment of aryl-magnesium halides and using DDQ/
hypervalent iodine combination as oxidant.[10,11] Finally, Peng
and co-workers reported the use of Knochel-type arylzinc
reagents under oxidative conditions providing a comprehensive
substrate study.[12].We herein, report the first visible light-
mediated metal-free and environmentally benign cross-
dehydrogenative coupling(CDC) arylation, cyanation and
nitroalkylation of sp3 C–H bonds adjacent to nitrogen at
roomtemperatureunder mild conditions precluding any harsh or
specialized reagents.
light of 20W power which is used for interior lighting. But, it
furnished product (3a) in lower yields (Table 1, entries 13 and
14). The reaction carried in dark showed extremely poor results,
which was expected (Table 1, entry 15).
In the case of the solvent study, the different solvents such
as MeOH, CHCl3,CH3CN, EtOAc and DCM were also screened
(Table 1, entry 16−19), which revealed CH3CN as the best
choice of the reaction solvent. Even though RB in MeOH has
more absorption maxima compared to RB in MeCN, the product
yield was comparatively less. This might be because of the
solvent molecules which could be competing as nucleophilesand
also the less stability of benzenediazonium tetrafluoroborate salt
in MeOH[14] (ESI-MS in SI). We also examined metal salts like
Co(OAc)2.4H2O and CuBr in combination with NHPI as an
oxidant (Table 1 entries 24 and 25). However, the results
obtained were poor. When examined by ESI-MS we found the
molecular weight corresponding to amideproduct(α-oxidation of
N-Ph THIQ) in presence of Co-salt (Scheme 2), whereas homo-
coupling of aryldiazonium tetrafluroborate salts in presence of
Cu-salt gives biaryl (probable Ullmann type coupling of
aryldiazonium salts in presence of Cu-catalyst) (Scheme 3),
products were analysed by GC-MS.
Initial screening studies involved the optimization of the reaction
conditions by choosing N-phenyl THIQ (1a) as a model substrate in
combination with 4-methoxybenzenediazonium tetrafluoroborate (2a)
for the α-arylation of tertiary amines. The optimized reaction
conditions were obtained by screening of different photosensitizers
(organic dyes), LED light sources and solvents by varying the
reaction conditions and the catalyst concentration (Table 1). To
develop a metal-free protocol, several oxidants that have found
applications in literature could be employed, however, we chose to
employ NHPI (N-hydroxyphthalimide),which is an inexpensive,
stable and efficient oxidant.
Initially, we examined different organic dyes or photosensitizers
like Eosin Y, Fluorescein, Rose Bengal, Alizarin Red and
Methylene blue. with NHPI as an oxidant in acetonitrile. Among
them Rose Bengal (RB) was proven to be a good photocatalyst
and afforded the desired product (3a) in a 75% yield (Table 1,
entries 1−5) The stoichiometry of the organic dye- RB as well
as the oxidant, NHPI was decreased to 0.1 mol% and 20 and 10
mol% (Table 1, entries 5−8) respectively.The study shows
decreasing mol% of them both gave lesser yields. Next, we
changed various light sources, in which we triedwith14W and
30W greenLED, 30W RedLED, and30W blueLED bulbs(Table 1,
entries 9-12). We observed 14W greenLED afforded the best
results of the conditions tested(Table 1, entry 9). This can be
attributed to the fact that green light falls on the appropriate part
of the visible light spectrum which sensitizes the organic dye the
most.[13] We also tried reactions under sunlightandnormal white
Scheme 2:Formation of amide.
Scheme 3: Formation of biaryl, Cu-catalyzed Ullmanncoupling.
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Additionally, the reactions were performed under the Ar, N2
atmosphere and also was tried underopen-air condition(Table 1,
entries 27 and 28). The yield of the product for the reaction
under open-air was 65%. The yield is certainly not low but
requires much higher time (Table 1, entry 26). Moreover, the
reactions in Ar and N2 atmosphere were very sluggish and
afforded the product (3a) in less yield (Table 1, entries 27 and
28). It can be seen that the reaction is more progressive only
under O2 atmosphereand afforded good yields of the product.
This suggests that the reaction is predominantly driven by
oxygen, thus confirming an oxidative CDC pathway.
To invoke the role of RB and co-oxidant NHPI, we
performed experiments without the addition of RB at rt as well as
60 oC. The reactions went through with lesserproduct yields. We
also tried reactions without the addition of NHPI. The reaction
did not proceed in this case at all proving the irreplaceable use
of NHPI as a co-oxidant as well as a radical generator. Finally,
we tried a reaction with an additional reagent, TEMPO (Table 1,
entry 32) and the reaction went through sluggishly and to much
lesser yield. This suggests a quenching of singlet oxygen[15] and
radical generated SET mechanism for the reaction.
Based on these results, we, therefore, suggest a mechanism
where Green LED excites Rose Bengal to higher state which
serves two purposes, 1) generates singlet oxygen radicals from
molecular oxygen. The singlet oxygen oxidizes NHPI to PINO
radical and 2) generates aryl radical from tetrofluoroborate salts.
PINO gets reduced to NHPI thereby converting THIQ into THIQ
radical by abstracting hydrogen radical. There is a single
electron transfer which generates a cation (ESI-MS provided in
SI) and subsequent α-arylation (Figure in SI). With an efficient
protocol established, we studied the scope for substrates using
a variety of N-Aryl THIQs and various benzenediazonium
tetrafluoroborates.
Table 2:
NHPI-RB-Green LED sp3 C-H bond arylation in
acetonitrile
Initially, we used 4-Methoxybenzenediazonium tetrafluoroborate
as the aryl source and used it in combination with various N-Aryl
THIQs,
where
N-PMP
THIQ
(N-para-methoxyphenyl
tetrahydroisoquinoline) gave the highest yield of the group (3b –
Table 2). This can be attributed to the EDG substituent present
on N-Aryl group. The presence of weakly EDG on the meta
position of thearyl group like Me–CH3gave comparatively less
yield.
The reactionprotocol tolerates the presence of halogens like Cl
on the aryl group and gave surprisingly good yields (3d – Table
2). The presence of strong EDG on the benzene of the THIQ, for
example, two OMe groups as in (3e - Table 2)gave less yield.
We attribute this to the lowered oxidation potentials of the
tertiary amine, favouring side reactions.We moved on to use of
other benzenediazonium tetrafluoroborate salts as aryl source.
As mentioned earlier, the presence of EDG on N-aryl group
gave high yields which can be ascribed to its capacity to
stabilize the subsequently forming radical intermediate. N-PMP
THIQ
combined
with
4-Methylbenzenediazonium
tetrafluoroborate gave a product with 78% yield (3f – Table 2).
Benzenediazonium tetrafluoroborate salts with halogens like F
and Br also reacted well with N-Aryl THIQs to give products in
good yields (3g and 3h – Table 2). Lastly, we used a simple
benzenediazonium tetrafluoroborate salt as the Phenyl source
and got the corresponding product in good yields – 78% (3i). In
the case of 3-pyridinediazonium tetrafluoroborate as the source
of heteroaryl group, the reaction was unsuccessful (3j – Table 2).
We also tried Benzenediazonium tetrafluoroborate salt with
EWG like 4-NO2 however we were again unsuccessful in our
endeavour (3k– Table 2). Both the results can be attributed to
the poor stabilityof the diazonium salts under reaction. We finally
tried N-Phenyl piperidine and unfortunately, the reaction did not
proceed thereby proving the need of benzene ring beside the
tertiary amine for stabilization (3i – Table 2).
Reaction conditions: 0.5 mmol of 1, 0.65 mmol of 2, Rose Bengal
0.3 mol%, NHPI35 mol%, Green LED,MeCN as a solvent 3 mL, O2,
at ambient temperature (27 °C)
To show the versatility of the newly found unprecedented α-
arylation
of
N-Aryl
THIQs
using
benzenediazonium
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tetrafluoroborates,RB, NHPI and Green LED, we carried
outtwoshort schemes as well. Wherein we performed α-
nitroalkylation and α-cyanation of N-Ph THIQs, which were
previously reported by our group using Co-metal catalysts.
The CDC reaction ofethyl cyanoformate (4a), a user-friendly
cyanide source withTHIQs under optimized conditions furnished
α-aminonitriles (5a-e, Table 3)in good to excellent yields (72-
82%).The optimized conditions used for α-arylation were used
directly. To our delight, we found favourable results. Although,
this particular coupling is well-known, there are only a few
reports which have metal-free aspects and at room temperature
with such good yields.
Table 4: sp3 C-H nitroalkylation of a tertiary amine.
Table 3: sp3 C-H cyanation of a tertiary amine.
Reaction conditions: 0.5 mmol of 1, 0.65 mmol of 4a, Rose Bengal
(0.3 mol%), NHPI (35 mol%), Green LED,MeCN as a solvent 3 mL,
MeCN O2, at ambient temperature (27 °C).
In conclusion, a metal-free, mild and efficient protocol for
photoredox cross-dehydrogenative coupling of unprecedented
aryl groups derived from tetrafluorborate salts and upgraded in
cyanation and nitroalkylation reactions with THIQs have been
reported. Moreover, the activation of C−H bond α- to the
Nitrogen in N-ph THIQ’s demonstrated by using cheap and
easily available reagents
-
NHPI, Rose Bengal and
benezenediazodium tetrafluoroborate salts. The preliminary
reports using control experiments and support from ESI-MS data
suggest a radical based SET mechanism involved in the
reaction with iminium ion as an intermediate.Furthermore, we
anticipate such approaches to increase the photoredox CDC
reactions viability for large scale utility,thereby paving the way
for the development of green and safeprotocolshaving
mildconditions.
Reaction conditions: 0.5 mmol of 1, 0.65 mmol of 4a, Rose Bengal
0.3 mol%, NHPI35 mol%, Green LED,,MeCN as a solvent 3 mL, O2,
at ambient temperature (27 °C)
Further, to extend the study, we chose to investigate
thenitroalkylation of THIQs. Literature reports of the coupling
ofnitroalkanes with N-phenyl THIQ derivatives via CDC reactions
were successfullydemonstrated in several studies.[16,17]
Thenitroalkyalation of THIQ derivatives through an iminium ion
intermediate is a nitro-Mannich/Aza-Henry type of CDCreaction.
Also, the reduction products of β-nitroamine derivatives
generated by nitroalkylation furnish vicinaldiamines, which are
important structural motifs to synthesize the pharmaceutically
important molecules[18] and are also used as chiral auxiliaries in
asymmetric catalysis.[19]
AcknowledgementsThe authors would like to acknowledge
CSIR for providing JRF and SRF to MP.
Keywords:Photo Redox Catalysis • Cross dehydrogenative
coupling • Rose Bengal • NHPI • Green LED
Hence consideringthe potential benefits of these compounds,
nitromethane (6a)and nitroethane (6b) were tested for reaction
with N-phenylTHIQs, which furnished the products(7a-e) in
excellent yields (82-70%)with shorter reaction times (Table 4).
However, the nitromethylation reactions were more facile than
nitro ethylations,which can be attributed to the steric effects.
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