Cobalt(II)/ N -Hydroxyphthalimide-Catalyzed Cross-Dehydrogenative Coupling Reaction at Room Temperature under Aerobic Condition

Article abstract of DOI:10.1021/acs.joc.8b00203

This work reports a cobalt(II)/N-hydroxyphthalimide (NHPI)-catalyzed cross-dehydrogenative oxidative coupling of N-aryl tetrahydroisoquinolines with various pro-nucleophiles, such as indoles, nitroalkanes, and trialkylphosphites, active methylene compound

Full text of DOI:10.1021/acs.joc.8b00203

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Cobalt(II)/N-hydroxyphthalimide Catalyzed Cross-Dehydrogenative
Coupling Reaction at Room Temperature Under Aerobic Condition
Mahendra Ramesh Patil, Noopur P. Dedhia, Anant R. Kapdi, and A. Vijay Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00203 • Publication Date (Web): 27 Mar 2018
Downloaded from http://pubs.acs.org on March 27, 2018
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Cobalt(II)/Nꢀhydroxyphthalimide Catalyzed CrossꢀDehydrogenative
Coupling Reaction at Room Temperature Under Aerobic Condition
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Mahendra R. Patil, Noopur P. Dedhia, Anant R. Kapdi and A.Vijay Kumar*
Department of Chemistry, Institute of Chemical Technology, Mumbaiꢀ400 019, India
Eꢀmail: vijayakki@gmail.com
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ABSTRACT: This work reports a Cobalt(II)/Nꢀhydroxyphthalimide (NHPI) catalyzed crossꢀ
dehydrogenative oxidative coupling of Nꢀaryl tetrahydroisoquinolines with various proꢀ
nucleophiles such as indoles, nitroalkanes, trialkylphosphites, active methylene compounds
and other nucleophiles such as cyanide (ethyl cyanoformate) at room temperature under
aerobic conditions. The present protocol is operationally simple, can be carried out without
photoirradiation and under peroxide free conditions even on gram scale to afford the products
in good to excellent yields. Based on mass spectrometry and control experiments, a catalytic
reaction pathway has been proposed.
TOC Graphic
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INTRODUCTION:
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In the recent years, C–H bond activation has emerged as a promising ideal synthetic
tool for the C–C bond formations. CrossꢀDehydrogenativeꢀCoupling (CDC) reaction is an
attractive stateꢀofꢀtheꢀart CꢀH bond activation process for CꢀC bond formations, which is
deemed beneficial and atom economic from the green chemistry perspective as it precludes
the requirement of preꢀfunctionalized substrates.1 The CDC activation of CꢀH bonds adjacent
to the Nꢀatoms in tertiary amines especially the 1, 2, 3, 4ꢀTetrahydroisoquinolines (THIQs)
core via oxidation is attractive, as it is commonly found in many natural products including
several alkaloids and medicinally active molecules.2 Many THIQ analogues are of particular
interest as they are used as key intermediates/precursors for the synthesis of various bioactive
molecules.3 On account of their importance and wide spread utility, the synthesis of THIQ
motifs and scaffolds has gained prominence and significant efforts have been dedicated to
synthesize them.
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Murahashi and coꢀworkers4 are the initial pioneers to introduce the CꢀC bond
formation via CꢀH bond activation adjacent to the nitrogen atom in tertiary amines4 and
further break through developments were established by his group,4aꢀc,1f ChaoꢀJun Li’s5 and
others.6,7 Generally, these CDC reactions rely upon the use of transition metal catalysts such
as ruthenium, copper and iron along with oxidants such as H2O2, O2, tertꢀbutylhydroperoxide,
and 2, 3ꢀdichloroꢀ5,6ꢀdicyanobenzoquinone (DDQ). In addition, CDC is also reported with
several other metals such as Ir,8 Pt,9 Au,10 V,6e,11 Mo,11b etc and under metalꢀfree
conditions.12,6a However, most of these catalysts are expensive, suffer from several
disadvantages such as complicated synthesis, use of peroxides and other nonꢀbenign oxidant
systems. Peroxides are corrosive and unstable at room temperature, thus needs to be stored at
low temperatures. They are prone to fire and explosive hazards which makes them less
suitable for large scale industrial reactions. Besides this, the excess use of hazardous (or)
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toxic oxidants such as tertꢀbutyl hydroperoxide (TBHP), diꢀtertꢀbutyl peroxide (DTBP), 2ꢀ
iodoxybenzoic acid (IBX), 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone (DDQ), and
benzoquinone (BQ) in CDC processes is considered nonꢀbenign according to green metrics.
These limitations prevent the scope of CDC for further wide applications. However, CDC is
well reported with CuBr by using O2 as the sole oxidant precluding the other oxidants such as
TBHP, H2O2, DTBP, DDQ, etc.5g Therefore, the development of CDC reactions that make
use of cheap and abundant oxidants such as air/oxygen which generate water as the sole by
product are highly desirable.13,12a In this context, to overcome these limitations, our attention
was drawn towards Nꢀhydroxyphthalimide (NHPI),14 which is cheap, nontoxic and stable
oxidant. In the 1990s, Ishii and coworkers reported the use of NHPI in combination with
redoxꢀactive metal salts, such as Co(OAc)2 in presence of O2 to facilitate efficient aliphatic
and benzylic CꢀH oxygenation.15 Though, this methodology was used in numerous oxidation
reactions and industrial applications,16 majority of the studies have been focused on CꢀH
oxygenation only.17 Therefore, we envisaged that the use of inexpensive and easily available
metal salts in combination with NHPI would be a superior choice and shall meet the
requirements of sustainable chemistry. Moreover, ChaoꢀJun Li and his coꢀworkers reported
an interesting CDC reaction catalysed by a bimetallic system using copper & other metal salts
in combination with NHPI .18
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Over the past few years, cobalt has emerged as a good choice to replace precious
transition metals for the development of C–H bond functionalizations.19 It can promote
several reactions under milder conditions.20 Cobalt catalysis is a credible alternative for
sustainable processes when compared to the costly rareꢀearth transition metal catalysed
reactions. Due to its economy, low toxicity, and unique reaction mode, cobalt as a catalyst
has attracted much attention in the development of applicable transformations in organic
synthesis for crossꢀcoupling reactions,21 hydroformylation,22 Pauson–Khand reactions,23 and
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other cobalt catalyzed C–C bond formations.24 To the best of our knowledge, Co metal is less
exploited for CDC reactions in the past.25 Only few reports are known in the literature
wherein cobalt metal is used for CDC reactions, but needs the aid of either UVꢀvisible light25a
or peroxides.25bꢀd However, an elegant CDC method is reported with antimonite salts and
NHPI,26 but, the antimonite salts are toxic and are used in a relatively high loading.
Henceforth, considering all the aboveꢀaforementioned facts and in the continuation of our
previous work, i.e. αꢀcyanation of tertiary amines27 via oxidative CDC reactions, we report a
facile and operationally convenient protocol for the oxidative coupling of tertiary amines with
various proꢀnucleophiles by Co(II) / NHPI in acetonitrile solvent at room temp under aerobic
conditions (Scheme 1). To the best of our knowledge, this is a first report to show the use of
Co(II)/NHPI system for CDC reaction.
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Scheme 1: A Different Catalytic Approach for the αꢀSubstitution of NꢀArylꢀ1,2,3,4ꢀ
Tetrahydroisoquinoline
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RESULT AND DISCUSSION:
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In the preliminary studies, we optimized the reaction conditions, we choose Nꢀphenyl
THIQ as a model substrate and ethyl cyanoformate as cyanation source for the α–cyanation of
tertiary amines. The optimized reaction conditions were obtained by screening of different
cobalt metal salts, oxidants and solvents by varying atmospheric conditions and
stoichiometric amounts (Table 1). Initially, we examined different cobalt metal salts such as
Co(acac)2, CoCl2.6H2O, Co(NO)3.6H2O and Co(OAc)2.4H2O with NHPI as an oxidant.
Among them Co(OAc)2.4H2O was proven to be a good catalyst and afforded the desired
product (3a) in 91% yield (Table 1, entries 1ꢀ4). The stoichiometry of the oxidant NHPI was
decreased up to as low as 0.1 equivalent (Table 1, entries 5ꢀ6), of which 0.2 equivalent was
effective to complete the transformation. Moreover, anhydrous Co(OAc)2 showed less
catalytic activity (Table 1, entry 7) than hydrated Co(OAc)2. This might be due to the
increase in polarity of the catalyst by the hydrated part which alters the electronic
environment thereby helping in stabilizing the transition state and thus favoring reaction
progress for CDC. Also, literature reports suggest that the presence of water favors CDC
reactions and other oxidative coupling reactions.5g,6e,28 The other oxidants and radical initiator
viz H2O2, TBHP, and BPO in combination with cobalt salt furnished low (70ꢀ40%) yields
(Table 1, entries 8ꢀ10), which showed that among the oxidants, NHPI (Table 1, entry 5) has
the best activity as oxidant and as a radical initiator.
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To find out the necessity of Co and NHPI combination, individual reaction runs were
carried out the in absence of Co(OAc)2.4H2O and NHPI (Table 1, entries 11ꢀ12). The
reaction did not go to for completion and afforded very less yields yield, 30% and 20% yields
yield respectively. These results suggest a possible mechanistic synergy between Co (II) and
NHPI in the oxidative CꢀH activation. Additionally, the reactions performed under the N2
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atmosphere were very sluggish and afforded the product (3a) in very less yield (Table 1,
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entry 13). Whereas, under O2 atmosphere, the reaction was progressive and afforded 91% of
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Table 1: Optimization of Reaction Conditionsa
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oxidant
(equiv.)
air/O2 time yieldb
entry
metal salt
solvent
/N2
Air
Air
Air
Air
(h)
1
1
(%)
88
85
1
2
3
4
Co(acac)2
CoCl2.6H2O
NHPI (0.3) CH3CN
NHPI (0.3) CH3CN
Co(NO3)2.6H2O NHPI (0.3) CH3CN
Co(OAc)2.4H2O NHPI (0.3) CH3CN
NHPI
(0.2)
Co(OAc)2.4H2O NHPI (0.1) CH3CN
Co(OAc)2 NHPI (0.2) CH3CN
1
1
82
91
5
Co(OAc)2.4H2O
CH3CN Air
1
91
6
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Air
Air
Air
1
1
1
80
89c
40
Co(OAc)2.4H2O H2O2 (1.5) CH3CN
aq.TBHP
(1.2)
Co(OAc)2.4H2O BPO (0.3) CH3CN
9
Co(OAc)2.4H2O
CH3CN
Air
1
65
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Air
O2
24
24
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24
0.75d
1
70
30
20
15
91
65
75
87
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NRe
Co(OAc)2.4H2O
ꢀ
ꢀ
CH3CN
NHPI (0.2) CH3CN
Air
N2
Co(OAc)2.4H2O NHPI (0.2) CH3CN
Co(OAc)2.4H2O NHPI (0.2) CH3CN
Co(OAc)2.4H2O NHPI (0.2) CHCl3
Co(OAc)2.4H2O NHPI (0.2) EtOH
Co(OAc)2.4H2O NHPI (0.2) MeOH
Co(OAc)2.4H2O NHPI (0.2) Toluene
Co(OAc)2.4H2O NHPI (0.2) EtOAc
O2
Air
Air
Air
Air
Air
Air
1
1
1
1
24
Co(OAc)2.4H2O NHPI (0.2)
H2O
aReaction conditions: 1a (0.35 mmol), 2 (0.7 mmol), cobalt salt (2 mol %), solvent (1.6 mL) at room
temperature. Isolated yield. anhydrous Co(OAc)2 (obtained by vacuum oven drying at 100oC) and reaction
b
c
under dry air. d45 minutes. eβꢀcyclodextrin as a phase transfer catalyst, NR: no reaction
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the product yield (Table 1, entry 14). This suggests that the reaction is predominantly driven
by oxygen thus confirming an oxidative CDC pathway. In case of solvent study, the different
solvents such as CHCl3, EtOH, MeOH, acetonitrile, toluene, EtOAc, H2O were screened
(Table 1, entry 15ꢀ20), which revealed CH3CN as the best choice of the reaction solvent. In
the case of MeOH as reaction solvent, the product yield was comparatively less than the
reaction in CH3CN, which might be because of the solvent molecules competing as
nucleophiles. We also examined other metal salts in combination with NHPI as oxidant (ref.
supporting information, Table S1), of which desired product (3a) was obtained in excellent
yield in the case of Co(OAc)2.4H2O and it was identified as a most effective redox metal
catalyst of all.
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With the optimized reaction conditions in our hand, we studied the substrate scope by
using various proꢀnucleophiles to check the versatility of the developed protocol. Initially, the
αꢀcyanation of tertiary amines was tried as they provide access to a variety of αꢀamino nitriles
which are key intermediates of natural products and drug molecules.27,29 The CDC reaction
of ethyl cyanoformate (2), a userꢀfriendly cyanide source with THIQs 1aꢀ1k under optimized
conditions furnished αꢀamino nitriles (3aꢀ3k) in good to excellent yields (Scheme 2). Among
all the substrates (1aꢀ1k), the model substrate 1a afforded the highest yield of the product 3a
in 91%. Later, the effect of electronꢀdonating and electronꢀwithdrawing substituents on the
phenyl group attached to nitrogen of the THIQs was studied. Electron donating group (pꢀMe,
pꢀOMe) substituted THIQs, 1b and 1c furnished the product 3b and 3c in 82% and 80% yield
respectively, which was comparatively less than the electron withdrawing group (pꢀCN)
substituted THIQ, 1d which gave the product 3d in 88% yield. Whereas, pꢀCl substrate 1e
afforded the product 3e in comparatively good yield. This might be because of the influence
of substituents on the intermediate formed during the progress of the reaction and product
stability. Moreover, the effect of the substituent, on the aromatic part of THIQ was studied.
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The reaction in the case of 1f and 1g furnished good yields, but were comparatively lower
than the simple Nꢀphenyl THIQ analogs. The product (3f) was obtained from corresponding
6, 7ꢀdimethoxyꢀNꢀphenyl THIQ (1f) in 80% yield which was better than the product (3g)
obtained from 1g, which can be due to substituent effect.
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With the optimised reaction conditions, we also tried αꢀcyanation of N,Nꢀdimethyl
aniline (1h), Nꢀphenyl piperidine (1i) and Nꢀphenyl morpholine (1j). The products 3h, 3i and
3j were obtained in good to excellent yields. Unfortunately, the NꢀBOC THIQ (1k) substrate
did not furnish the expected cyanation coupled product even under prolonged heating
conditions, rather it formed CꢀH oxygenation amide product 3k in 82% yield.
Scheme 2: Reaction Scope for αꢀCyanationa
aReaction conditions: 1 (0.5 mmol), 2 (1 mmol), CH3CN (2.3 mL), Co(OAc)2.4H2O (2 mol%), NHPI (20 mol%)
at room temperature and open to air. b50oC and O2 atmosphere, isolated yields in parenthesis.
Further the study was extended to the synthesis of indolyl tetrahydroisoquinoline
derivatives owing to the importance of various bioactive indoles substituted THIQs.30
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Scheme 3: Reaction Scope for Indolationa
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9
Co(OAc)2.4H2O (2 mol%)
N
R2
NHPI (20 mol%)
N
+
N
R3
CH3CN (0.2 M), air/O2, rt
R1
R1
N
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R2
R3
1
4
5
1a: R1 = H
4a: R2 = H; R3 = H
1b: R1 = CH3
1c: R1 = OCH3
1h: N,N-dimethyl aniline 4d: R2 = H; R3 = CH3
4e: R2 = 5-Br; R3 = CH3
4b: R2 = 5-Br; R3 = H
4c: R2 = 5-CN; R3 = H
4f: R2 = 5-CN; R3 = CH3
N
N
N
Br
NC
NH
NH
NH
5aa (82%)b, 1h; (67%)c, 24h
5ab (78%)b, 1h
5ac (69%)b, 3h
N
N
N
OCH3
CH3
Br
N
N
NH
5bb (74%)b, 1h
5ad (84%)c, 15 min
5cd (78%)c, 1h
N
N
N
Br
NC
N
H
N
N
5ae (83%)c, 30 min
5af (73%)c, 3h
5ha (NR)b,d, 24h
aReaction conditions: 1 (0.45 mmol), 4 (0.5 mmol), CH3CN (2 mL), Co(OAc)2.4H2O (2 mol %), NHPI (20
mol%) at room temperature , bO2 atmosphere. open air, d50 oC, isolated yields in parenthesis.
c
The indolation of Nꢀaryl THIQs through dehydrogenative pathway is azaꢀFriedelꢀCrafts/CDC
reaction. To the best of our knowledge, coupling between Nꢀaryl THIQs and NHꢀunprotected
indole derivatives are either reported in photoꢀirradiation or in peroxide condition.1dꢀe,1h, 25a
But in this report, we have successfully overcome these challenges and as well extended the
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substrate scope of the indolation CDC methodology. The Nꢀaryl THIQs 1a, 1b, 1c and 1h
reaction with various indole derivatives 4a, 4b, 4c, 4d, 4e and 4f under the optimized reaction
conditions afforded the coupled products 5aa, 5bc, 5ad, 5ab, 5cb, 5db, 5ae and 5af in good
to excellent yields (Scheme 3). Both the electronꢀdonating and electronꢀwithdrawing
substituents on indole ring and Nꢀaryl THIQs worked well under optimized conditions. In the
case of THIQs with an electronꢀdonating group, the yield of the product decreased slightly
due to the decreased electrophillicity. Similarly, the electronꢀwithdrawing substituent on
indole ring (4c, 4f) furnished coupled products in lesser yields than those with a strongly or a
weakly electronꢀdonating group substituted indoles (4b, 4e). This can be explained by the
fact that the electronꢀwithdrawing substituents could profoundly decrease the nucleophilicity
of the indoles. Moreover, the coupling of Nꢀaryl THIQs 1a and 1b with free (NH) indoles 4a,
4b and 4c in open to air atmosphere, afforded the desired products in comparatively less yield
and also required longer reaction times. When the same reactions were carried out in O2
atmosphere, a significant increase in the yields of the desired products (5aa, 5ab 5ac and
5bb) (82ꢀ72%) along with decreased reaction times was observed. However, it was observed
that Nꢀmethyl indole derivatives 4d, 4e and 4f worked well in open to air atmosphere and
afforded coupled product in good yields with a shorter reaction times. This might be due to
the increased nucleophilicity of Nꢀmethyl indole than free indoles (ꢀNH). Unfortunately, the
reaction of N,Nꢀdimethyl aniline 1h with indole 4a did not furnish the coupled product 5ha
even after prolonged heating for 24h.
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Further, to extend the study we chose to investigate nitroalkylation of THIQs.
Literature reports of the coupling of nitroalkanes with Nꢀphenyl THIQ derivatives were
successfully demonstrated via CDC reactions in several studies.1d,1h The nitroalkyalation of
THIQ derivatives through iminium ion intermediate is nitroꢀmannich /AzaꢀHenry type of
CDC reaction. Also, the reduction products of β–nitroamine derivatives generated by
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nitroalkylation furnish vicinal diamines, which are important structural motifs to synthesize
the pharmaceutically important molecules3a and are also used as chiral auxiliaries in
asymmetric catalysis.31 Hence considering the potential benefits of these compounds, nitro
methane (6a) and nitro ethane (6b) were tested for their reaction with NꢀPhenyl THIQs 1a,
1b, 1c and 1d, which furnished the products 7aa, 7ba, 7ca, 7da, 7ab and 7bb in excellent
yields (90ꢀ75%) with shorter reaction timings (Scheme 4). However, the nitro methylation
reactions were more facile than nitro ethylations, which can be attributed to the steric effects.
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Scheme 4: Reaction Scope for Nitroalkylationa
aReaction conditions: 1 (0.5 mmol), 6 (0.5 mL), CH3CN (2.3 mL), Co(OAc)2.4H2O (2 mol%), NHPI (20 mol%)
at room temperature open to air, isolated yields in parenthesis.
After successful establishment of CDC reaction for cyanation, indolation and nitro
alkylation, our attention was focused on to investigate the CꢀP bond formation reactions. The
phosphonation of tertiary amines is a promising route to synthesize αꢀaminoꢀphosphonates.
These compounds have been known to show a broad range of biological activities such as
antifungal, antibacterial, and enzyme inhibitor activity.32 Therefore we attempted the
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synthesis of various αꢀaminoꢀphosphonates under the developed conditions. The reaction of
1a, 1b and 1c was tried with various dialkyl phosphites such as dimethyl phosphite (8a),
diethyl phosphite (8b) and diisopropyl phosphite (8c). The coupled products 9aa, 9ab, 9ac,
9ca, 9bb and 9cb were obtained in 80ꢀ68% yield (isolated yield). In the phosphonation study,
the coupling reactions of diethyl phosphite (8b) were more efficient when compared to other
dialkyl phosphite reactions wherein the corresponding products 9ab, 9bb, and 9cb were
obtained in good to moderate yields (80ꢀ72%). Surprisingly, it is also noteworthy to mention
that the stoichiometric amount of dialkyl phosphonates was sufficient for phosphonation of
tertiary amines (Scheme 5).
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Scheme 5: Reaction Scope for Phosphonationa
Co(OAc)2.4H2O (2 mol%)
O
R2
N
O
NHPI (20 mol%)
N
P
+
O
O
H
O
R2
CH3CN (0.2 M), O2,
rt
P
O
R1
R1
R2 R2
1a 1c
8a 8c
9
N
N
N
O
O
O
O
O
O
O
P
P
P
O
O
9aa (68%), 3h
9ab (80%), 1h
9ac (75%), 3h
N
N
P
N
P
O
P
O
O
O
O
O
O
O
OCH3
O
OCH3
9ca (66%), 6h
9bb (78%), 6h
9cb (72%), 6h
aReaction conditions: 1 (0.45 mmol), 8 (0.5 mmol), CH3CN (2 mL), Co(OAc)2.4H2O (2 mol%), NHPI (20
mol%) at room temperature in O2 atmosphere, isolated yields in parenthesis.
After successful establishment of CDC reaction with various proꢀnucleophiles, we
decided to explore the developed protocol with active methylene compounds and other
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nucleophiles. The oxidative coupling of active methylene compounds with tertiary amines is
also called as the oxidativeꢀMannich type CDC reaction. The Co(II)/ NHPI mediated reaction
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Scheme 6: Reaction Scope for Oxidative Coupling of Tetrahydroisoquinolines with
Active Methylene Compound and other Nucleophilesa
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Co(OAc)2.4H2O (2 mol%)
NHPI (20 mol%)
N
N
+
Nu
10
CH3CN (0.2 M), air/O2
rt
Nu
R1
R1
1
11
1a: R1 = H
10a: Diethylmalonate
1b: R1 = CH3
1c: R1 = OCH3
10b: Ethylcyanoacetate
10c: Dimethylmalonate
10d: Malanonitrile
10e: Acetone
10f: Phenol
10g: 4-Hydroxycoumarin
10h: Phthalimide
N
O
N
O
N
Ph
Ph
MeO
OMe
EtO
O
11aa (76%)b, 24h
OEt
EtO
O
CN
O
11ab (83%)b,12h
11ac (80%)b,12h
N
N
N
N
CN
3a (27%)
CH3
NC
CN
O
O
11ad (52%)
11ad Mixture (71%)b, 24h
11ae (81%)b,c,18h
11be (79%)b,c,18h
N
N
O
N
N
Ph
Ph
HO
O
N
O
HO
O
O
O
O
OH
11af (60%)d, 6h
aReaction conditions: 1 (0.5 mmol), [10aꢀ10c (0.85 mmol), 10d (0.6 mL), 10eꢀ10g (0.58 mmol)], CH3CN (2.3
11ag (90%)d,1h
11cg (68%)d, 3h
11ah (55%)d, 6h
b
c
mL), Co(OAc)2.4H2O (0.02 mmol), NHPI (0.2 mmol%) at room temperature, O2 atmosphere, Lꢀproline (35
mol%), dopen air, isolated yields in parenthesis.
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was also found to be amenable to several active methylene compounds such as
diethylmalonate (10a), ethyl cyanoacetate (10b), dimethylmalonate (10c) with Nꢀphenyl
THIQ (1a). All these substrates underwent smooth reactions to afford desired products 11aa,
11ab and 11ac in good yields (Scheme 6).
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However, the reaction of malononitrile 10d with 1a under the established conditions
afforded a mixture of 11ad (malononitrile adduct) as the major product along with an αꢀ
cyanated Nꢀphenyl THIQ (3a) in minor quantity. It is noteworthy to mention that, under the
optimized conditions we obtained 11ad as the major product, as opposed to previous
literature reports wherein 3a was the major product in CDC reaction of malononitrile with 1a.
However oxidative coupling between Nꢀaryl THIQs (1a and 1b) and unactivated ketone
(acetone, 10e) did not proceed under optimized conditions, but after the addition of Lꢀproline
as additive (via enamine), underwent reaction smoothly to afford the corresponding products
(11ae, 11be) in good yields. Next, the other nucleophiles such as phenol (10f), 4ꢀhydroxy
coumarin (10g) and phthalimide (10h) were also tested as coupling partners for CDC reaction
with tertiary amine 1a and 1c (Scheme 6). In case of 10f and 10h as coupling partners the
coupled products 11af and 11ah were obtained in moderate to good yields. To our delight,
the oxidative coupling of 1a and 1c with 4ꢀhydroxy coumarin (10g) has successfully
furnished the desired products 11ag and 11cg in good to excellent yield.
Having studied the substrate scope, with the intention to gain insight into the
mechanism of the developed CDC protocol, some control experiments were performed
(Scheme 7). To find out whether the reaction proceeds through a radical pathway, the stable
free radical TEMPO was deliberately added to the reaction at the beginning, as the nitroxide
radicals are widely used as radical scavenging agents due to their radical inhibition activity.
In scheme 7a, the employment of 1 equivalent of TEMPO decreased the product yield to 41%
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and when 3 equivalents was added, only a slight amount of product (3a) was formed. These
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results suggest that the reaction might go through a radical pathway.
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Scheme 7: Control experiments
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aIsolated yield, bGCꢀMS analysis of reaction mixture, cGC yield and confirmed by mass spectrometry
Another control experiment was performed wherein the reaction was carried out in the
absence of nucleophile to check for the formation of the iminium ion, which is reported to be
the intermediate of many CDC reactions (Scheme 7b). To our delight, the ESI mass
spectrometry analysis of this reaction mixture after 12 h showed the presence of the
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corresponding iminium ion along with an amide side product. To quantify the ratio of imine
and amide, the imine was trapped by adding ethyl cyanoformate (cyanide source) to convert
it into an αꢀcyanated product. The product 3a was isolated in 57% yield along with the amide
in 35% yield. These results strongly support that the reaction goes through an iminium ion
intermediate, which in the absence of nucleophile forms the amide side product. The
generation of iminium ion as intermediate was also confirmed by performing the reaction in
methanol, which furnished the methoxy substituted Nꢀphenyl THIQ 13 in 68% yield (Scheme
7c). To our fortune, serendipitously we were able to observe the amide formation from
tertiary amine in absence of nucleophile at room temperature using Co/NHPI catalytic
protocol after 48 h. To understand the origin of oxygenation process for formation of amide
12, we performed another control experiment wherein 1a was stirred in acetonitrile with
Co(acac)2/NHPI under oxygen atmosphere (in which oxygen was bubbled through a dreschel
bottle filled with concentrated sulphuric acid). The amide 12 was isolated in 85% yield. This
result shows that the oxygen atom originated from molecular dioxygen, but not the traces of
water present in the reaction.
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Further in continuation to understand the mechanism of the reaction, we examined the
conversion of oxidative coupling reaction of 1a with ethyl cyanoformate under the standard
reaction conditions by terminating the reaction with a radical quencher after a specific time
interval (Figure 1). As seen in radical trapping experiments, the reaction was completely
terminated upon the addition of 3 equivalents of TEMPO. Hence, to observe how quickly the
imine formation takes place from the substrate, we added the 3 equivalents of TEMPO at a
specific time interval (0 min, 5min, 10min, 20min, 30 min) in separate experiments under
same conditions followed by isolation of 1a and the product by flash chromatography. A plot
of the substrate/product concentration versus time of TEMPO addition as shown in Figure 1
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suggests that both product formation and reactant consumption traverse an exponential trace,
where the reactant consumption path was more exponential than the product formation.
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Figure 1: Conversion study of the oxidative coupling reactiona
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aReaction conditions: 1a (1mmol), 2 (2.5 mmol), Co(OAc)2.4H2O (0.02 mmol), NHPI (0.2 mmol), CH3CN (3
mL), rt, 1h and 3 mmol of TEMPO added at specific time interval. bconversions on basis of yield obtained by
flash chromatography of crude reaction mixture.
It is clearly evident from the profile, that much of the substrate conversion to imine (or)
iminium ion takes place within 10ꢀ15 minutes of the reaction initiation. This suggests that the
generation of intermediate iminium ion may be the rate determining step. However, within
first 5 minutes, the reaction shows more than 50% conversion indicating that the rate of the
reaction is initially faster and then further steadily progresses to form the product.
Further next, to demonstrate the synthetic utility of the developed protocol, a gram
scale synthesis of 3c was carried out wherein Nꢀ(4ꢀmethoxyphenyl)ꢀtetrahydroisoquinoline
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(1c) (4.3 mmol, 1.03 g) was reacted with 850 µL (8.6 mmol) of ethyl cyanoformate 2 under
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the standard reaction conditions (Scheme 8).
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Scheme 8: Gram Scale Synthesis of 3c
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The reaction proceeded smoothly to afford 0.82 g (72%) of the product 3c. To illustrate the
utility of the developed methodology, we purposefully used 1c, a pꢀmethoxyphenyl (PMP)
protected amine instead of a simple Nꢀphenyl derivative 1a, as the deprotection of PMP
provides ready access to the secondary amines, which are important key intermediates of
bioactive molecules.2g,33 Additionally, this feature assists the reaction by stabilizing the
oxidized form of the tertiary amine.34
On the basis of the above results and previous reports,16a,19b,6b the mechanism of this
transformation is proposed (Scheme 9). According to Ishii and coꢀworkers, Co(II) salt in
combination with oxygen produces a Co(III) peroxy radical complex, which thereby
generates PINO radical from NHPI at room temperature.15 The PINO radical abstracts a
hydrogen radical from the cationic radical 14 to furnish the iminium ion 15. The formation of
the cationic radical 14 may be by a single electron oxidation of 1a by the high valent Co(III)
complex which causes the regeneration of Co(II) complex. Next, the attack of the nucleophile
on the iminium ion forms the αꢀsubstituted CDC product.6b Interestingly, in absence of the
nucleophile at ambient temperature under O2 atmosphere, the hydrogen radical abstraction
from 1a can form radical 16, which upon reaction with oxygen forms a peroxy radical
complex 17. After which, an NHPI mediated formation of a hydroperoxide moiety 18,
followed by a subsequent dehydration affords the amide compound 12.
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Scheme 9: Proposed Reaction Mechanism.
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CONCLUSION:
In conclusion, we developed an efficient protocol for cross dehydrogenative coupling
reaction by using Co(II)/NHPI system at room temperature under peroxideꢀfree aerobic
conditions and without photo irradiation. In which, a very cheap and less toxic transition
metal catalyst such as Co(OAc)2.4H2O is required in a low sub stoichiometric amounts along
with a sub stoichiometric amount of stable and cheap oxidant NHPI. The undertaken
mechanistic study suggested that the reaction proceeds through a radical pathway with
iminium ion as intermediate. A diverse substrate scope for the developed protocol using
different proꢀnucleophiles was demonstrated along with a gram scale synthesis. Furthermore,
we anticipate such approaches to increase the CDC reactions viability for large scale utility,
thereby paving way for the development of green and safe protocols at ambient conditions.
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EXPERIMENTAL SECTION:
General Methods.
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All starting materials and reagents and metal salts were purchased from commercial
sources and used without further purification. All reactions were performed in ovenꢀdried
glassware. Solvents were purchased with high purity and used without purification. The Nꢀ
arylꢀ1,2,3,4ꢀtetrahydroisoquinoline derivatives were synthesized by reported procedures from
their respective precursors and purified by flash chromatography on neutral silica gel (mesh
60–120) . All the reactions were monitored by using thin layer chromatography (TLC) which
was silica (Silica Gel 60 F254) preꢀcoated aluminum plates and the products were visualized
by UV lamp (PHILIPS TUV 8W lamp) and I2 stain. Most of the reactions were performed at
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room temperature which could be varied between 25ꢀ29 C. Products were purified by flash
column chromatography on neutral silica gel (100ꢀ200 mesh and 60–120 mesh). The
characterization of products were done by 1H and 13CꢀNMR spectroscopy recorded in CDCl3
and TMS as reference slandered on an Avance III and Bruker NMR spectrophotometer at 400
MHz and 101 MHz respectively. Chemical shifts are reported in parts per million (δ) relative
to tetramethylsilane as internal standard. The J (coupling constant) values are expressed in
Hz. Splitting patterns of the proton are represented as s (singlet), d (doublet), t (triplet), and m
(multiplet).
Neutral silica gel preparation: Triethylamine (3ꢀ4 mL) was added to 150 g 100ꢀ200 silica gel
and made into slurry by addition of petroleum ether for the even distribution of the amine.
The solvent was removed under reduced pressure on a rotary evaporator and dried under
vacuum overnight.
Typical procedure for αꢀcyanation of tertiary amines
In a typical experiment, a 15 mL round bottom flask was equipped with a teflon coated
magnetic stirring bar. A weighed quantity of THIQ derivative (0.5 mmol, 1 equiv) and ethyl
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cyanoformate (1 mmol, 2 equiv) was added followed by addition of 2.3 mL of acetonitrile.
To the stirring reaction mixture Co(OAc)2.4H2O (0.01 mmol, 0.02 equiv) and NHPI (0.1
mmol, 0.2 equiv) was added successively. The reaction mixture was stirred at room
temperature in open to air atmosphere and the reaction progress was monitored by thin layer
chromatography (TLC) visualized in UV or I2 chamber. After the reaction completion, the
mixture was passed through the celite bed and the organic layer evaporated under reduced
pressure. The product was isolated by flash column chromatography on neutral silica gel
(mesh 100–200).
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Typical procedure for αꢀindolation of Nꢀaryl THIQ derivatives
In a typical experiment, a 15 mL round bottom flask was equipped with a teflon coated
magnetic stirring bar. A weighed quantity of THIQ derivative (0.45 mmol) and indole
derivative (0.5 mmol, 1.1 equiv) were added followed by addition of 2 mL of acetonitrile. To
the stirring reaction mixture Co(OAc)2.4H2O (0.009 mmol, 0.02 equiv) and NHPI (0.09
mmol, 0.2 equiv) were added successively. The reaction mixture was stirred at room
temperature in open atmosphere and the reaction progress was monitored by TLC visualized
in UV or I2 chamber. After the reaction completion, the mixture was passed through the celite
bed and the organic layer evaporated under reduced pressure. The product was isolated by
flash column chromatography on neutral silica gel (mesh 100–200). (Note: in case of NH free
indole, reaction kept in the O2 atmosphere.)
Procedure for αꢀnitroalkylation of Nꢀaryl THIQ derivatives
In a typical experiment, a 15 mL round bottom flask was equipped with a teflon coated
magnetic stirring bar. A weighed quantity of THIQ derivative (0.5 mmol) and nitroalkane
(0.5 mL) were added followed by addition of 2.3 mL of acetonitrile. To the stirring reaction
mixture Co(OAc)2.4H2O (0.01 mmol, 0.02 equiv) and NHPI (0.1 mmol, 0.2 equiv) was added
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successively. The reaction mixture was stirred at room temperature in open air atmosphere
and the reaction progress was monitored by TLC visualized in UV or I2 chamber. After the
reaction completion, the mixture was passed through the celite bed and the organic layer
evaporated under reduced pressure. The product was isolated by flash column
chromatography on neutral silica gel
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Procedure for phosphonation of Nꢀaryl THIQ derivatives
In a typical experiment, a 15 mL round bottom flask was equipped with a teflon coated
magnetic stirring bar. A weighed quantity of THIQ derivative (0.45 mmol) and dialkyl
phosphite (0.5 mmol, 1.1 equiv) were added followed by addition of 2 mL of acetonitrile. To
the stirring reaction mixture Co(OAc)2.4H2O (0.009 mmol, 0.02 equiv) and NHPI (0.09
mmol, 0.2 equiv) was added successively. The reaction mixture was stirred at room
temperature in the O2 atmosphere and the reaction progress was monitored by TLC visualized
in UV or I2 chamber. After the reaction completion, the mixture was passed through the celite
bed and the organic layer evaporated under reduced pressure. The product was isolated by
flash column chromatography on silica gel (mesh 100–200).
Procedure for oxidative coupling of Nꢀaryl THIQ derivatives with active methylene
compound and other nucleophiles
In a typical experiment, a 15 mL round bottom flask was equipped with a teflon coated
magnetic stirring bar. A weighed quantity of THIQ derivative (0.5 mmol) and pronucleophile
[diethyl malonate or dimethyl malonate or ethyl cyanoacetate or malononitrile (0.85 mmol,
1.7 equiv) and phenol or 4ꢀhydroxycoumarin or phthalimide (0.58 mmol, 1.16 equiv)] was
added followed by addition of 2.3 mL of acetonitrile. To the stirring reaction mixture
Co(OAc)2.4H2O (0.01 mmol, 0.02 equiv) and NHPI (0.1 mmol, 0.2 equiv) was added
successively. The reaction mixture was stirred at room temperature in the O2 atmosphere or
open to air and the reaction progress was monitored by TLC visualized in UV or I2 chamber.
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After that reaction mixture pass through the celite bed and the organic layer evaporated under
reduced pressure. The product was isolated by flash column chromatography on neutral silica
gel (mesh 100–200).
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Procedure for the synthesis of 3c on gram scale
In 50 mL round bottom flask equipped with a teflon coated magnetic stirring bar, a 1.03 g of
Nꢀ(4ꢀmethoxy phenyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline (4.3 mmol) and 850 µL of ethyl
cyanoformate (8.6 mmol) were added followed by addition of 25 mL of acetonitrile. To the
stirred uniform reaction mixture, 21.5 mg of Co(OAc)2.4H2O (0.086 mmol) and 140 mg of
NHPI (0.86 mmol) were added successively. The reaction mixture was stirred at room
temperature in the O2 atmosphere (oxygen balloon used) and the reaction progress was
monitored by TLC (mobile phase: petroleum ether/ ethyl acetate = 8:2). After that, the
reaction mass was passed through the celite bed and the organic layer evaporated under
reduced pressure. The product 3c was eluted in 4% ethyl acetate in petroleum ether from
column chromatography on neutral silica gel (mesh 60–120) and afforded 0.82 g in 72%
yield.
General procedure for the preparation of Nꢀarylꢀ1,2,3,4ꢀtetrahydroisoquinoline
derivatives
Copper (I) Iodide (1.2 mmol, 10 mol%) and potassium phosphate (24 mmol, 2 equiv) were
taken into the 100 mL two neck round bottomed flask with a condenser and filled with
nitrogen gas. 2ꢀpropanol (25 mL) and ethylene glycol (24 mmol, 2 equiv) were added by
syringe and allowed to stir for 5ꢀ10 min at room temperature. Aryl iodides (12 mmol, 1 equiv
) and secondary amine (14.4 mmol, 1.2 equiv) were added successively at room temperature.
The reaction mixture was heated up to reflux temperature for 30 hrs and then allowed to cool
to room temperature. The solvent was removed under vacuo, water ca 10mL was added and
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extracted with dichloromethane/diethyl ether. The organic layer was dried over anhydrous
sodium sulfate. The solvent was concentrated under reduced pressure and purified by column
chromatography on neutral silica gel (hexane/ethyl acetate = 95:5) to give the desired
product.
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General procedure for Nꢀmethylation of indole derivatives
In 100 mL round bottom flask equipped with a teflon coated magnetic stirring bar, a solution
of indole derivative (10 mmol) in THF (30 mL) was prepared. To the stirring reaction
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mixture NaH (600 mg, 60 % dispersed in mineral oil, 15 mmol) was added at 0 C. The
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reaction mixture was stirred at 0 C for 20 minutes and 1.5h at room temperature. After the
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stirring at room temperature, it was cooled to 0 C and iodomethane (834 µL, 13.5 mmol)
was added slowly within 5ꢀ10 min. After the complete addition of iodomethane, the reaction
mixture was allowed to cool room temperature and further stirred till reaction completion as
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monitored by TLC. The reaction mixture was cooled to 0 C and quenched with saturated
NH4Cl (50 mL), and extracted with diethyl ether (3 x 15 mL). The organic layers were
combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude mass was purified by flash chromatography (eluent: petroleum ether/EtOAc
10:1). The products were charactarized by NMR spectroscopy.
2ꢀPhenylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3a)37
o
White solid; mp: 95–96 C, 107 mg, 91% yield, Rf = 0.5 (mobile phase: petroleum ether/
ethyl acetate = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.32 (m, 2H), 7.32 – 7.20 (m, 4H),
7.11 – 7.05 (m, 2H), 7.04 – 6.98 (m, 1H), 5.50 (s, 1H), 3.75 (m, 1H), 3.46 (m, 1H), 3.14 (m,
1H), 2.94 (dt, J = 16.3, 3.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 148.4, 134.6, 129.6,
129.6, 129.4, 128.8, 127.1, 126.7, 121.9, 117.8, 117.6, 53.2, 44.2, 28.5
2ꢀ(pꢀTolyl)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3b)38
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White solid; mp: 94–96 C, 102 mg, 82% yield, Rf = 0.5 (mobile phase: petroleum ether/
ethyl acetate = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.09 (m, 6H), 7.00 (d, J = 8.3 Hz,
2H), 5.45 (s, 1H), 3.69 (dd, J = 11.5, 5.4 Hz, 1H), 3.51 – 3.36 (m, 1H), 3.23 – 3.06 (m, 1H),
2.93 (d, J = 16.3 Hz, 1H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 146.25, 134.5, 131.8,
130.1, 129.6, 129.4, 128.7, 127.1, 126.75, 118.3, 117.7, 54.1, 44.4, 28.6, 20.6
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2ꢀ(4ꢀMethoxyphenyl)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3c)37
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Pale yellow solid; mp: 107–108 C, 106 mg, 80% yield, Rf = 0.45 (mobile phase: petroleum
ether/ ethyl acetate = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.17 (m, 4H), 7.09 – 7.03
(m, 2H), 6.92 – 6.86 (m, 2H), 5.34 (s, 1H), 3.76 (s, 3H), 3.55 (dd, J = 12.1, 6.0 Hz, 1H), 3.40
(td, J = 11.7, 3.9 Hz, 1H), 3.13 (m, 1H), 2.89 (d, J = 16.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 155.7, 142.6, 134.4, 129.7, 129.5, 128.7, 127.1, 126.7, 121.0, 117.65, 114.8, 55.6,
44.9, 28.7
2ꢀ(4ꢀCyanophenyl)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3d)39
Yellow solid; mp: 151–152 oC, 112 mg, 86% yield, Rf =0.45 (mobile phase: petroleum ether/
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ethyl acetate = 9:1). H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.29 (dd, J =
25.5, 9.4 Hz, 4H), 7.00 (d, J = 8.2 Hz, 2H), 5.58 (s, 1H), 3.99 – 3.70 (m, 1H), 3.57 (s, 1H),
3.08 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 150.5, 134.6, 133.8, 129.3, 129.1, 128.7, 127.4,
127.0, 119.4, 117.4, 114.7, 102.5, 50.05, 43.7, 28.2
2ꢀ(4ꢀChlorophenyl)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3e)10a
o
White solid; mp: 152–153 C, 113 mg, 84% yield, Rf = 0.45 (mobile phase: petroleum ether/
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ethyl acetate = 9:1). H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 15.3, 6.4 Hz, 5H), 7.24 –
7.20 (m, 1H), 7.02 – 6.95 (m, 2H), 5.43 (s, 1H), 3.74 – 3.64 (m, 1H), 3.44 (m, 1H), 3.13 (m,
1H), 2.95 (dt, J = 16.3, 3.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 147.34, 134.73, 129.87,
129.71, 129.57, 129.25, 127.39, 127.32, 119.23, 117.79, 53.49, 44.66, 28.78
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6,7ꢀDimethoxyꢀ2ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3f)11b
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Yellow solid; mp: 137–138 oC, 118 mg, 80% yield, Rf = 0.35 (mobile phase: petroleum ether/
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ethyl acetate = 8:2). H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.0
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Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 26.9 Hz, 2H), 5.41 (s, 1H), 3.85 (s, 6H), 3.73
(dd, J = 12.0, 4.6 Hz, 1H), 3.40 (td, J = 11.9, 3.6 Hz, 1H), 3.11 – 2.98 (m, 1H), 2.81 (d, J =
16.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 149.37, 148.43, 148.06, 129.53, 126.87,
121.90, 121.08, 117.88, 117.71, 111.52, 109.32, 56.07, 55.94, 53.05, 44.18, 28.09
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2ꢀ(4ꢀChlorophenyl)ꢀ6,7ꢀdimethoxyꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (3g)27
White crystalline solid; mp 153–155 °C; 125 mg, 76% yield, Rf = 0.4 (mobile phase:
petroleum ether/ ethyl acetate = 7:3). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.9 Hz, 2H),
6.97 (d, J = 8.9 Hz, 2H), 6.69 (d, J = 23.2 Hz, 2H), 5.37 (s, 1H), 3.85 (d, J = 2.1 Hz, 6H),
3.68 (dd, J = 12.3, 4.2 Hz, 1H), 3.44 – 3.33 (m, 1H), 3.04 (m, 1H), 2.82 (dt, J = 16.1, 3.1 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 149.37, 148.03, 146.94, 129.35, 126.86, 126.55, 120.59,
118.85, 117.51, 111.41, 109.18, 55.97, 55.85, 52.82, 44.19, 27.86
2ꢀ(Methyl(phenyl)amino)acetonitrile (3h)37
Colorless oil; 58 mg, 80% yield, Rf = 0.6 (mobile phase: petroleum ether/ ethyl acetate = 9:1).
1H NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H), 6.88 (tt, J = 7.5, 1.0 Hz, 1H), 6.83 – 6.78
(m, 2H), 4.04 (s, 2H), 2.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.74, 129.40, 119.97,
115.62, 114.70, 42.03, 39.08
1ꢀPhenylpiperidineꢀ2ꢀcarbonitrile (3i)37
Light brown oil; 73 mg, 78% yield, Rf = 0.55 (mobile phase: petroleum ether/ ethyl acetate =
9:1). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 2H), 7.05 – 6.97 (m, 3H), 4.64 (t, J = 3.5
Hz, 1H), 3.51 – 3.42 (m, 1H), 3.05 (td, J = 12.0, 2.6 Hz, 1H), 2.10 – 1.96 (m, 2H), 1.92 –
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1.81 (m, 2H), 1.78 – 1.65 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 149.7, 129.3, 122.1,
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118.3, 117.1, 52.0, 46.5, 29.2, 25.1, 20.15
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4ꢀPhenylmorpholineꢀ3ꢀcarbonitrile (3j)40
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Colourless viscous Oil; 78 mg, 83% yield, Rf = 0.4 (mobile phase: petroleum ether/ ethyl
acetate = 9:1). 1H NMR (500 MHz, CDCl3) δ 7.42 – 7.32 (m, 2H), 7.09 – 7.03 (m, 1H), 7.03
– 6.97 (m, 2H), 4.47 – 4.41 (m, 1H), 4.20 – 4.15 (m, 1H), 4.14 – 4.08 (m, 1H), 3.93 (dd, J =
11.5, 2.8 Hz, 1H), 3.81 – 3.72 (m, 1H), 3.30 (dd, J = 8.1, 2.7 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 148.3, 129.7, 122.7, 117.3, 116.0, 68.1, 67.0, 51.1, 45.5
tertꢀButyl 1ꢀoxoꢀ3,4ꢀdihydroisoquinolineꢀ2(1H)ꢀcarboxylate (3k)41
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White solid; mp: 70–73 C, 101 mg, 82% yield, Rf = 0.45 (mobile phase: petroleum ether/
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ethyl acetate = 8:2). H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.4
Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 3.99 (dd, J = 8.8, 3.3 Hz, 2H),
3.00 (t, J = 6.0 Hz, 2H), 1.59 (d, J = 1.0 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ 163.9,
153.1, 139.5, 132.8, 129.6, 129.3, 127.2, 127.1, 83.2, 44.4, 28.3, 28.1
1ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ2ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline (5aa)42
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White solid; mp: 167–169 C, 120 mg, 82% yield, Rf = 0.25 (mobile phase: petroleum ether/
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ethyl acetate = 9:1). H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H),
7.23 (m, 8H), 7.02 (d, J = 8.0 Hz, 3H), 6.77 (t, J = 7.2 Hz, 1H), 6.63 (s, 1H), 6.17 (s, 1H),
3.62 (dd, J = 7.4, 4.6 Hz, 2H), 3.07 (dt, J = 15.6, 7.7 Hz, 1H), 2.80 (dt, J = 16.1, 4.2 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 149.8, 137.4, 136.6, 135.6, 129.2, 128.8, 128.0, 126.7, 126.5,
125.7, 124.15, 122.1, 120.1, 119.6, 119.3, 118.1, 115.9, 111.0, 56.7, 42.3, 26.65
1ꢀ(5ꢀBromoꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline (5ab)25a
o
Yellow solid; mp: 186–188 C, 142 mg, 78% yield, Rf = 0.4 (mobile phase: petroleum ether/
ethyl acetate = 8:2). 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 7.55 (s, 1H), 7.29 (dd, J =
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11.4, 7.1 Hz, 2H), 7.20 – 7.07 (m, 6H), 6.99 (d, J = 8.1 Hz, 2H), 6.79 (s, 1H), 6.65 (t, J = 7.2
Hz, 1H), 6.21 (s, 1H), 3.59 – 3.43 (m, 2H), 3.02 – 2.91 (m, 1H), 2.82 (dd, J = 11.7, 4.7 Hz,
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1H). C NMR (101 MHz, DMSO) δ 149.6, 137.9, 135.6, 135.3, 129.5, 128.9, 128.2, 128.2,
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127.0, 126.5, 126.1, 123.9, 121.9, 117.9, 117.75, 115.3, 114.0, 111.65, 55.7, 42.0, 26.7
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3ꢀ(2ꢀPhenylꢀ1,2,3,4ꢀtetrahydroisoquinolinꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ5ꢀcarbonitrile (5ac)
Light brown solid; mp: 215–217 oC, 109 mg, 69% yield, Rf = 0.32 (mobile phase: petroleum
ether/ ethyl acetate = 7:3). 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.47 – 7.30 (m, 3H),
7.27 – 7.14 (m, 6H), 7.00 (d, J = 8.3 Hz, 2H), 6.84 (t, J = 7.3 Hz, 1H), 6.76 (s, 1H), 6.10 (s,
1H), 3.67 – 3.43 (m, 2H), 3.14 – 2.97 (m, 1H), 2.80 (dt, J = 16.3, 4.1 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 149.8, 138.3, 136.6, 135.4, 129.3, 127.9, 125.9, 119.3, 116.9, 116.8, 112.1,
112.0, 56.8, 42.8, 26.7 FTIRꢀATR (neat, cmꢀ1): 3401, 3309, 2921, 2218, 1593, 1498, 1468,
1425, 1349, 1282, 1213, 1129, 1095, 1031, 937, 882, 806, 750, 684, 642, 610, 521, 495
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HRESIꢀMS (m/z): calculated for C24H20N3 (M + H): 350.1652, Found (M + H): 350.1646
1ꢀ(5ꢀBromoꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀ(pꢀtolyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline (5bb)
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Off white solid; mp: 143–145 C, 139 mg, 74% yield, Rf = 0.37 (mobile phase: petroleum
ether/ ethyl acetate = 8:2). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.51 (s, 1H), 7.16 (td,
J = 20.6, 11.2 Hz, 6H), 7.04 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.50 (s, 1H), 5.98
(s, 1H), 3.50 (d, J = 4.5 Hz, 2H), 3.03 (dt, J = 15.7, 7.9 Hz, 1H), 2.75 (d, J = 16.5 Hz, 1H),
2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.8, 137.05, 135.3, 135.05, 129.7, 128.9,
128.65, 128.3, 128.0, 126.7, 125.7, 125.6, 124.9, 122.7, 118.9, 117.55, 112.9, 112.4, 57.1,
42.8, 26.5, 20.5. FTIRꢀATR (neat, cmꢀ1) 3144, 3023, 2919, 1512, 1451, 1423, 1338, 1210,
1118, 1041, 1012, 918, 870, 840, 813, 792, 764, 732, 671, 613, 561, 529, 513, 488. HRESIꢀ
+
MS (m/z): calculated for C24H22BrN2 (M + H): 417.0961, Found (M + H): 417.0956
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1ꢀ(1ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline (5ad)42
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o
White solid; mp: 126–128 C, 128 mg, 84% yield, Rf = 0.25 (mobile phase: petroleum ether/
ethyl acetate = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 1H), 7.41 – 6.89 (m,
11H), 6.75 (t, J = 7.3 Hz, 1H), 6.48 (s, 1H), 6.17 (s, 1H), 3.59 (s, 5H), 3.04 (m, 1H), 2.78 (dt,
J = 16.2, 4.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 149.8, 137.65, 137.4, 135.6, 129.3,
128.8, 128.8, 128.1, 126.9, 126.7, 125.75, 121.7, 120.2, 119.2, 118.0, 117.7, 115.65, 109.2,
56.6, 42.2, 32.7, 26.7
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2ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline (5cd)43
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White solid; mp: 142–143 C, 129 mg, 78% yield, Rf = 0.2 (mobile phase: petroleum ether/
ethyl acetate = 9:1) 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 1H), 7.27 – 7.06 (m,
6H), 7.04 – 6.87 (m, 3H), 6.84 – 6.68 (m, 2H), 6.40 (s, 1H), 5.97 (s, 1H), 3.72 (s, 3H), 3.60
(s, 3H), 3.57 – 3.39 (m, 2H), 3.01 (m, Hz, 1H), 2.76 (dt, J = 16.4, 3.8 Hz, 1H).13C NMR (101
MHz, CDCl3) δ 153.2, 144.7, 137.7, 137.2, 135.4, 129.0, 128.9, 128.2, 127.25, 126.4, 125.7,
121.5, 120.3, 119.3, 119.0, 117.6, 114.45, 109.1, 57.7, 55.6, 43.5, 32.7, 26.7
1ꢀ(5ꢀBromoꢀ1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylꢀ1,2,3,4ꢀtetrahydroisoquinoline (5ae)
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Pale yellow solid; mp: 127–129 C, 156 mg, 83% yield, Rf = 0.5 (mobile phase: petroleum
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ether/ ethyl acetate = 6:1) H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 1.5 Hz, 1H), 7.17 (m,
7H), 7.05 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H),
6.04 (s, 1H), 3.56 (s, 5H), 3.01 (dt, J = 15.7, 7.7 Hz, 1H), 2.76 (dt, J = 16.3, 4.3 Hz, 1H).13C
NMR (101 MHz, CDCl3) δ 149.8, 137.2, 136.0, 135.4, 130.0, 129.2, 128.9, 128.4, 127.9,
126.8, 125.8, 124.5, 122.7, 118.6, 117.3, 116.3, 112.6, 110.7, 56.6, 42.4, 32.9, 26.6. FTIRꢀ
ATR (neat, cmꢀ1) 3017, 2942, 2899, 1594, 1500, 1472, 1387, 1285, 1217, 1139, 1108, 1030,
993, 938, 864, 779, 794, 761, 745, 692, 648, 626, 587 HRESIꢀMS (m/z): calculated for
+
C24H21BrKN2 (M + K): 455.0520, Found (M + K): 455.0523
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