Dehydrogenative C(sp3)-H bond functionalization of tetrahydroisoquinolines mediated by organic oxidants under mild conditions

Article abstract of DOI:10.1039/c9ob01090d

The organocatalyzed Mannich reaction of unsubstituted and N-aryl-substituted tetrahydroisoquinolines (THIQs) and the Strecker reaction of several N-aryl-substituted THIQs through dehydrogenative C(sp3)-H bond functionalization (cross-dehydrogenative coupling) promoted by organic single electron oxidants DDQ and IBX are presented. The C-H oxidation/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products in an effective and time preserving manner.

Full text of DOI:10.1039/c9ob01090d

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DOI: 10.1039/C9OB01090D
Dehydrogenative C(sp3)–H Bond Functionalization of Tetrahydroisoquinolines
Mediated by Organic Oxidants under Mild Conditions
Zdravko Džambaski, Bojan P. Bondžić*
Dr. Z. Džambaski, Dr. B. P. Bondžić*
Center for Chemistry, ICTM institute, University of Belgrade,
Njegoševa 12, 11 000 Belgrade, Serbia
E-mail: bbondzic@chem.bg.ac.rs
Abstract
Organocatalyzed
Mannich
reaction
of
unsubstituted
and
N-Aryl-substituted
tetrahydroisoquinolines (THIQs) and Strecker reaction of several N-aryl-substituted THIQs
through dehydrogenative C(sp3)–H bond functionalization (cross-dehydrogenative coupling)
promoted by organic single electron oxidants DDQ and IBX is presented. Oxidative C-H
functionalization/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via
metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products
in effective and time preserving manner.
Tetrahydroisoquinoline (THIQ) ring system is present in numerous natural and synthetic organic
compounds, many of which display useful and interesting biological activities (Figure 1).1
Covering a wide range of structural types, they are very attractive targets for synthesis and have
stimulated the development of new synthetic approaches and methodologies. Recently cross-
dehydrogenative coupling (CDC) reactions emerged as effective tool for functionalization of
THIQs.
Figure 1. Selected examples of bioactive molecules containing THIQ motif
COOH
Me
COOH
Me
N
N
N
O
N
OMe
OH
OMe
O
Quinocarcin
OH
O
N
(-)-Lemonomycin
MeO
HO
MeO
HO
NH
N
O
O
N
OH
Coclaurine
Solifenacin (Vesicare)

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Since the seminal studies on cross-dehydrogenative coupling by Murahashi and Li through the
activation of the α-C(sp3)–H bond of tertiary amines,2 tremendous progress has been made in the
THIQ functionalizations mostly employing high-valent transition-metal catalysts combined with
co-oxidants such as tert-butyl hydroperoxide (TBHP), H2O2, molecular oxygen, etc.3,4 or utilizing
visible light photoredox catalysis with transition metal complexes as catalysts.5
However, the use of organic oxidants possessing a high activity for C–H oxidation would be more
desirable from the viewpoint of green and sustainable chemistry.6 Moreover, metal impurities can
be detrimental in pharmaceutically important intermediates and final products.7 Hence, significant
efforts have been made to accomplish CDC reactions in the absence of metal catalysts. Visible
light photoredox catalysis in the presence of organic photosenzitizers such as Eritrozine B8, eosin
Y,9 or carbon nitride10 has proven to be very effective tool for the functionalization of THIQs.
11
Among organic oxidants, elemental Iodine,
2-iodoxybenzoic acid (IBX)12 and hipervalent
iodine (III)13 reagents are notable examples in the oxidations and functionalizations of THIQs.
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an organic oxidant with high
oxidation potential has been extensively used in benzylic oxidation reactions and subsequent
coupling reactions with various nucleophiles in the presence or in the absence of metal catalysts.14
Stoichiometric DDQ had been used in tertiary amine C-H oxidations and the subsequent synthesis
of vicinal diamines,15 in the THIQ arylations,16 Mukaiama/Manich type reactions of N-aryl
17
pyrrolidines and silyl enol ethers
and in the intramolecular aza-Prins-type cyclizations.18
Catalytic DDQ in the presence of catalytic amounts of AIBN was used in THIQ functionaizations
by Prabhu group, using oxygen as stoichiometric oxidant.19 Single example of oxidative carbon–
carbon bond-forming reaction of THIQ and acetone catalyzed by DDQ in the presence of
organocatalyst proceeding via an isolable iminium ion has been shown previously.20
Our aim was to develop a domino organocatalyzed Mannich reaction coupled with an organic
oxidant promoted C-H oxidation of THIQs. As the single reported example20 is limited to acetone
as a nucleophile, systematic investigation about the reactivity, selectivity and substrate scope in
these reactions are needed. Mannich products such as β-amino ketones and aldehydes are versatile
synthetic intermediates for numerous pharmaceuticals and natural products and can be easily
converted to 1,3-amino alcohols by reduction, or to Michael acceptors by elimination of amine
functionality.21
In order to make the reaction more practical and operationally simple it is essential to activate
ketones to their enolate form since ketones are less reactive pronucleophiles. Adding catalytic
amount of organocatalyst increases reaction rate and ads to operational simplicity since
organocatalysts are neither water nor oxygen sensitive. Herein we report a Mannich-type reaction
of THIQs with ketones by employing organic oxidants and catalytic amount of amine catalyst.
Short studies on Strecker reaction of THIQs employing organic oxidants and metal complex
promoted photoredox oxidation of N-aryl pyrrolidines are also shown.
Table1. Optimization of N-aryl substituted THIQ oxidation/organocatalyzed Mannich reactiona

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O
CH3
O
CH3
N
N
CH3
CH3
*HCl
CH3
CH3
COOH
N
N
N
H
H
Ph
H
Ph
CH3
L-Proline
McMillan I gen.
McMillan II gen.
Catalyst 30 mol%
additive 30 mol%
O
+
N
N
Oxidant 1.05 eq.
Solvent
Ph
Ph
5 eq.
O
1
1a
Entry
Catalyst
/
Time (h) Oxidant Additive Solvent Yield (%)b
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
48
48
2
DDQ
DDQ
DDQ
/
/
CH3CN
CH3CN
CH3CN
Acetone
CH3CN
CH3CN
CH3CN
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
<10
65
78
72
57
61
63
<10
<10
/
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
TFA
2
DDQ
TFA
4
DDQ
PTSA
4
DDQ
AcOH
4
Chloranil
IBX
PIDA
PIFA
NHPI
mCPBA
DDQ
TFA
/
/
/
/
/
/
24
24
24
24
24
4
/
/
McMillan I gen.
McMillan II gen.
pyrrolidine
65
68
48
34
4
12
16
DDQ
DDQ
DDQ
TFA
TFA
TFA
benzylamine
a Reaction conditions unless otherwise noted: Tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Oxidant (0.263 mmol,
1.05 equiv.), L-proline (0.075 mmol, 0.3 equiv.) and acetone (10 equiv.) were added to solvent (2 mL) and stirred
for designated period of time; b Isolated yield after column chromatography.
IBX= 2-Iodoxybenzoic acid; PIDA = phenyliododiacetate; PIFA= (bis(trifluoroacetoxy)iodo)benzene; NHPI = N-
hydroxyphthalimide; mCPBA = meta-chloroperoxybenzoic acid.
Our investigation started by testing various organic oxidants in our envisaged reaction setup.
Firstly, we tested DDQ as an oxidant of N-Phenyl-tetrahydroisoquinoline 1 in the presence of 5
equivalents of acetone as a nucleophile in CH3CN as a solvent. Reaction proceeds sluggishly to
yield 10% of desired target material after 48h (Table 1, Entry 1). Addition of the 30 mol% of L-
proline tremendously improved the reaction yield and 65% of desired product was obtained after
48h (Table 1, Entry 2). It is known that acidic additives can increase the reaction rate of
organocatalyzed reactions by increasing the rate of enamine formation and hydrolysis. Upon
addition of 30 mol% of TFA as an additive, reaction rate is dramatically increased, reaction is
finished in 2 hours, and the yield is improved to 78% (Table 1, Entry 3). If reaction was performed
in acetone as a solvent slightly lower yield of the product is obtained (Table 1, Entry 4). Several

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acidic additives such as AcOH and PTSA were tested but did not perform as good as TFA (Table
1, Entries 5 and 6). Using Chloranil as an oxidant gave slightly lower yield of 63% of final product
(Table 1, Entry 7). Hypervalent iodine reagents did not give any product under optimized
conditions (Table 1, Entries 8-11). NHPI and mCPBA also did not promote oxidation step in this
reaction (Table 1, Entries 12 and 13). In the presence of McMillan type organocatalysts I and II
with DDQ as an oxidant reaction proceeds to give 65% and 68% yield of desired product
respectively (Table 1, Entries 14 and 15). It is worth noting that 5-10% ee in final product was
observed with L-proline and McMillan type catalysts. Achiral secondary and primary amines such
as pyrrolidine and benzylamine in the presence of TFA also give rise to desired product, in 48%
and 34% yield respectively (Table 1, Entries 16 and 17), in absence of TFA reaction doesn’t
proceed.
Scheme 1. Organocatalyzed, DDQ promoted, THIQ oxidation /Mannich reaction
R1
L-proline 30 mol%
O
TFA 30 mol%
+
N
N
R1
R3
DDQ (1.05 equiv.)
CH3CN
O
R2
R2
R1= H, OMe
R2= H, Me, F
R3= Me, Et, Ph, Cy
R3
1-7
a-d
O
O
O
N
N
N
Ph
PG
PG
PG
Compd. PG
Yield(%)
78
73
Compd. PG
Yield(%)
62
Compd. PG
Yield(%)
1a
2a
3a
4a
Ph
1b
2b
3b
Ph
p-F-C6H4
p-Me-C6H4
1c
2c
3c
Ph
p-F-C6H4
p-Me-C6H4
60
61
57
p-F-C6H4
p-Me-C6H4
o-Me-C6H4
54
55
71
52
OMe
OMe
OMe
O
OMe
O
O
N
N
N
PG
PG
PG
Compd. PG
Yield(%)
61
55
Compd. PG
Yield(%)
48
57
Compd. PG
Yield(%)
5b
6b
7b
Ph
p-F-C6H4
p-Me-C6H4 58
1d
2d
Ph
p-F-C6H4
5a
Ph
71
65
70
6a
7a
p-F-C6H4
p-Me-C6H4
OMe
OMe
OMe
OMe
O
O
N
Ph
N
PG
PG
Compd. PG
Yield(%)
55
44
Compd. PG
Yield(%)
60
71
6d
7d
p-F-C6H4
p-Me-C6H4
5c
6c
Ph
p-F-C6H4

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After the optimal conditions were found, scope of the reaction was investigated. N-phenyl, N-p-
tolyl, N-p-C6H4-F- or N-o-tolyl substituted THIQs were tested. N-aryl groups stabilize reactive
intermediates in cross-dehydrogenative couplings,22 and these tertiary substituted substrates
proved to be the best choice in this reaction setup.
As the nucleophilic partners several ketones were tested: acetone, ethyl methyl ketone,
acetophenone and cyclohexanone (Scheme 1). In all cases good yields were obtained, reactions
with acetone proceeded most efficiently giving the best yields among tested ketones. Ethyl methyl
ketone having two enolizable positions reacts exclusively at the less substituted side of the
molecule to give products in very good yields (Scheme 1, products 1-3b and 5-7b). Acetophenone
reacts efficiently as well giving very good yields of products in all cases (Scheme 1, products 1-
3c and 5,6c). Cyclohexanone reacts a bit slower compared to other tested ketones giving desired
products 1,2d and 6,7d in approximately 1:1.3 diastereomeric ratio (see Scheme 1 and Supporting
information). o-Tolyl substituted THIQ reacted only with acetone (product 4a, Scheme 1) and did
not react with any other nucleophile under optimized conditions, most probably due to the
increased sterical hindrance close to the reaction center. All the aryl substituted tertiary THIQs
reacted very efficiently, however, it is often required to remove the protecting group of the amine
to have unsubstituted secondary amine for the synthetic or biomedical purposes.
Unprotected THIQ 8a did not react under optimized conditions using DDQ as an oxidant.
After oxidant screening tests it was found that IBX is effective oxidant of unprotected THIQs in
DMSO as a solvent. It was possible to isolate intermediary imines 9a and 9b under these conditions
in 69% and 78% respectively. Isolated imines from both, tetrahydroisoquinoline 8a and 6,7-
dimethoxy-tetrahydroisoquinoline 8b reacted with ketones under Mannich reaction conditions
(enamine formed from ketone and catalytic amount of L-proline) to give moderate yields of desired
products 10a and 11a,b (Scheme 2). One pot reaction was attempted but did not proceed at all:
upon addition of ketone, catalyst and additive to DMSO solution of imine formed in situ from
THIQ 8a and IBX, Mannich reaction did not take place. Oxidation of 8a with IBX also proceeds
in MeOH at 60 °C, to give iminium ion 9a. Upon addition of acetone, L-proline and additive to
this reaction mixture no reaction occurs. Optimization of this reaction and making it a one pot or
tandem process is the subject of our continued interest, as it is known that tandem reaction could
be far more effective and time saving omitting isolation of intermediates.
Scheme 2. C-H Oxidation/Mannich reaction of unprotected THIQs
L-Proline (0.3 equiv.)
TFA (0.3 equiv)
R1
R1
R1
R1
R1
R1
IBX (1 equiv.)
N
NH
R2
NH
DMSO, r.t. 20 min
O
(solvent)
R2
8a
8b
9a
R1=H, 69%
9b
R1=H
R1=OMe
10
, R1=H
R1=OMe, 78%
11
, R1=OMe
O
with TFA 4h
without TFA 20h
10
, R1=H, R2= Me
49%
11a
11b
, R1=OMe, R2= Me 41%
, R1=OMe, R2= Et 38%

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Plausible mechanism of THIQ C-H oxidation/Mannich reaction is shown in Scheme 3. DDQ
promoted oxidations are thought to begin with single electron oxidation of tertiaty amines. 23 In
the next step upon hydride abstraction iminium ion is formed. Counterion exchange with TFA may
take place giving iminium ion I which undergoes nucleophilic attack from enamine II formed from
ketone and L-proline. Mannich adduct III undergoes hydrolysis with water to give desired product,
recovering L-proline catalyst, which enters the next cycle (Scheme 3).
Scheme 3. Plausible mechanism of DDQ promoted C-H oxidation/L-proline catalyzed Mannich
reaction
N
Ar
O
H2O
R
Ar
O
O
N
N
Cl
Cl
CN
CN
Ar
H
+
CF3COO-
N
R
HOOC
O
III
N
H
OH
Ar
CN
N
NC
O
TFA
H
N
O
Cl
Ar
Cl
CF3COO-
O
I
OH
OH
O
R
Cl
Cl
CN
CN
N
OH
R
II
H2O
DDQ promoted C-H oxidation of THIQs/Strecker reaction
As the extension of the methodology of using organic oxidants for CDC functionalizations of
THIQs we also tested DDQ as an oxidant in C-H oxidation/Strecker reaction using TMSCN as the
source of CN- ion. α-Cyanations of THIQs using 2,2,6,6-tetramethylpiperidine N-oxide
fluoroborate salt as an oxidant are known24 while DDQ has been used as an oxidant in the α-
cyanation of allyl ethers.25
DDQ oxidation of N-aryl substituted THIQs proceeded very efficiently providing imine in situ,
upon imine formation completion as confirmed by TLC, TMSCN is added to reaction mixture to
provide Strecker product in good yields (Scheme 4). Reduction of Strecker adducts might provide
vicinal diamines, potentially pharmaceutically important compounds.

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Scheme 4. DDQ promoted C-H oxidation/Strecker reaction of N-aryl substituted THIQs
R
R
DDQ 1equiv.
CH3CN
TMSCN
+
N
N
R
PG
R
PG
12
CN
R= H, OMe
12a
12b
12c
12d
R= H, PG=Ph, 75%
R= H, PG= p-F-C6H4, 58%
R= OMe, PG= p-F-C6H4, 67%
R= OMe, PG= p-Me-C6H4, 62%
CDC coupling of pyrrolidines
Most of CDC coupling methodologies (vide supra) are still limited to activated amines such as
tetrahydroisoquinolines or benzylamines, and only a few examples have been reported using
pyrrolidine or piperidine derivatives.17,26 Thus, it is very challenging to develop an oxidative
Mannich reaction of nonactivated tertiary amines. N-aryl substituted pyrrolidines or piperidines
did not react under optimized conditions of DDQ or IBX promoted C-H oxidation/Mannich
reaction. No reaction was observed also when other organic oxidants: mCPBA, PIDA, PIFA or
NHPI were tested. Under conditions of metal catalyzed photoredox catalysis, using [Ru(bpy)3]Cl2
in the presence of L-proline and irradiating with 15W CFL lamp reaction with acetone proceeded
to give products in low yields after few days of reaction time (See supporting information)
(Scheme 4). Yields up to 36% were obtained, main issue being loss of activity of catalyst after 12-
24h. [Ru(bpz)3][PF6]2 catalyst was tested as well but did not provide better yields of the product
13a compared to [Ru(bpy)3]Cl2 catalyst. 8W CFL lamp didn’t provide better yields and 13a was
isolated in 15% yield after 4 days of reaction. Mechanism of this type of reaction is very well
known and has been previously described.5b Reaction proceeds via single electron transfer (SET)
2+
from the N-aryl substituted tertiary amine to Ru(bpy)3 * species formed upon irradiation of
Ru(bpy)32+ catalyst. Amine radical cation that is formed looses hydride to give iminium ion that
undergoes nucleophilic attack by enamine species present in the reaction mixture and formed from
ketone and secondary amine catalyst. Ru+ species are reoxidized by molecular oxygen in situ to
reenter catalytic cycle.
A number of substrates possessing different aryl groups have also been tested but in all cases
desired reaction was not observed (See Supporting information, Scheme S1). We are currently
working on the further improvements of this reaction and we will report results in due course.
Scheme 4. Visible-light-promoted asymmetric cross-dehydrogenative coupling of tertiary amines
to ketones

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15W CFL lamp
L-proline 30 mol%
O
O
+
N
Ru(bpy)3Cl2 *6H2O
CH3CN
N
PG
PG
(2)
13
13a
13b
13c
13d
PG = p-MeO-C6H4-
PG = 3,4,5-tri-MeO-C6H2- 18%
PG = 3,4-di-Me-C6H3-
PG = p-Cl-C6H4-
34%
36%
13%
Conclusion
We have shown that organic oxidants, DDQ and IBX can be successfully used in the C(sp3)−H
bond oxidation/organocatalyzed Mannich reaction of tertiary N-Aryl-substituted and N-
unsubstituted THIQs in the effective manner. Use of organocatalyst and acidic additive in the
Mannich reaction of in situ formed iminium ions and ketones tremendously improved the reaction
times and yields of this domino process. Besides Mannich reaction, Strecker type addition of
TMSCN to iminium ion (formed in situ) can also be performed with tertiary aryl substituted THIQs
using DDQ as an oxidant. Less reactive N-aryl pyrrolidines did not undergo oxidation reaction
with organic oxidants. However, under conditions of metal complex catalyzed photoredox
reactions, C-H oxidation and subsequent organocatalyzed Mannich reaction take place. These
procedures represent a powerful method to form new carbon−carbon bonds directly from two
different C−H bonds under oxidative conditions.
Conflicts of interest
There are no conflicts to declare.
Acknowledgement
This work was supported by the Ministry of Education, Science and Technology of the Republic
of Serbia (Grant No. 172020). We gratefully acknowledge COST action CA15106: C-H Activation
in Organic Synthesis (CHAOS) for support.

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