α-Angelica Lactone in a New Role: Facile Access to N-Aryl Tetrahydroisoquinolinones and Isoindolinones via Organocatalytic α-CH2 Oxygenation

Article abstract of DOI:10.1021/acs.orglett.9b00224

A method for the direct oxidation of various N-aryl tetrahydroisoquinolines and isoindolines to the corresponding lactams using α-angelica lactone as a catalyst was developed. The utility of the method was further demonstrated by synthesis of indoprofen and indobufen.

Full text of DOI:10.1021/acs.orglett.9b00224

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
α‑Angelica Lactone in a New Role: Facile Access to N‑Aryl
Tetrahydroisoquinolinones and Isoindolinones via Organocatalytic
α‑CH2 Oxygenation
Thanusha Thatikonda,† Siddharth K. Deepake,†,‡ and Utpal Das*,†,‡
†Division of Organic Chemistry, CSIR − National Chemical Laboratory, Pune 411008, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
S
* Supporting Information
ABSTRACT: A method for the direct oxidation of various N-
aryl tetrahydroisoquinolines and isoindolines to the corre-
sponding lactams using α-angelica lactone as a catalyst was
developed. The utility of the method was further demonstrated
by synthesis of indoprofen and indobufen.
catalysts, high reaction temperature, and longer reaction periods.
Formations of dihydroisoquinolinone via cross-dehydrogenative
coupling reactions are well-known but only as a byproduct.5 Very
recently, oxidation of N-alkyl tetrahydroisoquinolines to the
correspondinglactamsusinggoldnanoparticles(Scheme1a)and
he lactam moiety has attracted particular interest in the
Tchemical community because it is present in a myriad of
natural products and clinically approved medicinal agents.1 A
numberofnaturalproductswithbiologicalactivitiesandsynthetic
pharmaceutical compounds containing an isoquinolinone/
isoindolinone scaffold are known (Figure 1).
Scheme 1. Lactam Formation via C−H Oxidation of Cyclic
Amines
Figure 1. Bioactive natural products and pharmaceuticals containing an
isoquinolinone and isoindolinone scaffold.
a copper−salicylate complex (Scheme 1b) as catalyst in the
presence of either t-BuOOH or oxygen as oxidant was reported.6
This process looks attractive, but in many cases, the reaction
requires higher temperature and longer reaction periods. 9H-
Fluoren-9-imine offers an alternative to metal catalysts; however,
the substrate scope is limited by the requirement of a
stoichiometric amount of fluorenimine along with reflux
temperature.7a During the preparation of this paper, Das group
reported α-oxygenation of tertiary and secondary amines by
visible light using Rose Bengal as catalyst.7b Consequently, the
ACSGCIpharmaceuticalroundtableidentified“amideformation
avoidingpoor atomeconomy reagents”as themost desiredgreen
chemistry research area and organocatalysis as one of the “more
Consequently, development of an efficient catalytic method to
synthesize compounds containing a isoquinolinone or isoindo-
linone core in a direct and cost-effective manner is of huge
importance. A straightforward method for the synthesis of the
isoquinolinone/isoindolinone core would be direct oxygenation
oftheα-methylenegroupofisoquinoline/isoindolinederivatives.
However,selectiveoxidationsoftheα-methylenegroupofamines
to amides are notoriously challenging because of the higher
reactivity of the amines in comparison to that of the α-methylene
carbon.2 In general, α-oxygenation of amines requires a
stoichiometric amount of organic or metal peroxides as oxidant
and use of transition-metal-based catalysts.3 Recently, gold
nanoparticlessupportedonalumina(Au/Al2O3)weredeveloped
for the catalytic oxidation of cyclic and acyclic amines to the
corresponding lactams and amides.4 However, the reaction
requires use of an air-sensitive catalyst, multistep synthesis of
Received: January 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00224
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Letter
aspirational reactions”.8 In the past decade, unsaturated γ-
lactones have emerged as a very useful and versatile class of
vinylogous nucleophiles.9 We herein report commercially
available α-angelica lactone as an efficient organocatalyst for
C−H amidations of N-aryl tetrahydroisoquinolines and isoindo-
lines in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO)
asthebaseunderoxygenatmosphere(Scheme1c),thusimitating
nature’s oxidant combination of O2/NAD(P)H. In many known
examples,4,6 molecular oxygen has been used as the greenest
possible oxidant, though it is a kinetically poor one10 and acts so
mainly in the presence of metal reagents/catalysts.4,6,11 This
protocol also shows high selectivity toward benzylic C−H
oxidation, and no undesired oxidative Mannich-type reaction of
N-aryl tetrahydroisoquinoline with lactone is detected, as
reported by Doyle and others.12 We commenced our
optimization reactions by using N-phenyl-1,2,3,4-tetrahydroiso-
quinoline 1a as a model substrate. The initial reaction was
performed with 1a in the presence of α-angelica lactone (25 mol
%) (A) and DABCO as base in THF under oxygen atmosphere.
The oxidation product, benzolactam 2a, was obtained in 41%
yield (Table 1, entry 1). The yield was improved to 58 and 81%
a b
,
Table 2. Substrate Scope
a
Table 1. Optimization Studies
b
entry
base
catalyst
yield (%)
c
1
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
A
A
A
A
A
B
C
D
E
F
41
58
81
49
85
72
67
63
54
ND
d
2
3
e
4
f
5
6
7
8
9
a
Reaction conditions: 1 (0.1 mmol), DABCO (0.3 mmol), A (25 mol
%), THF (0.5 mL), rt for 36 h under O2 atmosphere (balloon).
10
b
Isolated yields.
a
Reaction condition: 1a (0.1 mmol), DABCO (0.3 mmol), catalyst A
(25 mol %), in THF (0.5 mL) at rt for 36 h under O2 (balloon)
b
c
d
atmosphere. Isolated yield. 0.1 mmol of DABCO was used. 0.2
mmol of DABCO was used. 10 mol % of A was used. 50 mol % of A
e
f
N-Aryl/heteroaryl-substitutedtetrahydroisoquinolines1a−1x
gave the corresponding oxidized products 2a−2x in a good to
excellent yields. The optimized reaction conditions successfully
included substrates containing strong electron-withdrawing
group substitutions at the para- and meta-positions on the N-
phenyl ring. Corresponding products 2b−2e were obtained in
good to excellent yields (71−85%). The presence of a keto
functional group is beneficial for further transformations as in 2c.
However, reaction withelectron-withdrawinggroups substituted
attheortho-positionontheN-phenylringgavethecorresponding
products2f−2ginmoderateyields(52%each),probablybecause
of the steric hindrance on the α-position of the tetrahydroisoqui-
noline.Similarly,halogengroupssubstitutedontheN-phenylring
also gave the corresponding products 2h−2l in good yields (52−
84%). The carbon−bromine bond in 2i creates a good reaction
siteforfurthertransformations,andasaresult,substrate2imaybe
considered as a precursor of a known BCATm inhibitor.13 The
presence of electron-donating groups like tert-butyl, methyl, and
was used. ND = not determined.
when DABCO was used in 2 and 3 equiv, respectively (entries 2
and3).Theyieldof2adecreasedto49%when10mol%ofcatalyst
Awasused(entry4). Marginalimprovementofisolatedyieldwas
observed upon using 50 mol % of A (entry 5). Other lactone
catalysts B−E were also investigated, but they were found to be
less effective than α-angelica lactone A (entries 6−9) in terms of
chemical yields. Notably, with itaconic anhydride F, no oxidation
product was observed (entry 10). Further, the effect of various
solventandbasesontheoxidationreactionwerealsostudied(see
the Supporting Information (SI) for details).
Using the optimized reaction conditions (entry 3), the scope
for α-angelica lactone (A)-catalyzed benzylic CH2 oxidation of
different tetrahydroisoquinoline derivatives was investigated
(Table 2).
B
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Letter
methoxysubstitutedatthepara-,meta-,andortho-positionsofthe
N-phenyl ring furnished the desired products 2m−2p with 59−
84% yields. Heteroaryl group (pyridyl and thiophenyl)-
substituted 1,2,3,4-tetrahydroisoquinolines gave the desired
products 2q and 2r in 76 and 74% yields, respectively. Next, we
examined the substitution effect on the attached aryl ring of the
tetrahydroisoquinolinemoiety, 6,7-dimethoxylN-4-chlorophen-
yl 1,2,3,4-tetrahydroisoquinoline, and 6,7-dimethoxyl N-4-
methylphenyl 1,2,3,4-tetrahydroisoquinoline was chosen as a
substrate. The corresponding lactams 2s and 2t were obtained in
52 and 59% yields, respectively. Similarly, 7-chloro N-4-
chlorophenyl 1,2,3,4-tetrahydroisoquinoline, 7-bromo N-4-
chlorophenyl 1,2,3,4-tetrahydroisoquinoline, and 5-nitro N-4-
chlorophenyl 1,2,3,4-tetrahydroisoquinolines gave the desired
lactams2u,2v,and2winyieldsof63,56,and47%,respectively.N-
4-Chlorophenyl-substituted (S)-1,2,3,4-tetrahydro-3-isoquino-
linemethanol was also proven to be a good substrate in our
protocol to give the corresponding lactam 2x in 49% yield. The
methylenehydroxygroupin1xremaineduntouchedandretained
itsopticalactivity.However,noreactionwasobservedwithN-allyl
and N-phenylsulfonyl-protected substrates 1y and 1y′. We also
observed that N-phenyl tetrahydroquinoline was not compatible
with the present protocol and failed to afford any product like 2z.
We have examined the feasibility of our methodology on a larger
scale. Benzolactam 2h was obtained in 81% yield on a 1.5 g scale
reaction (Scheme 2).
Scheme 3. Application in the Synthesis of Indoprofen and
Indobufen
Table 4. Mechanistic Investigations
entry
condition
result
1
2
3
4
5
no base
no catalyst A
no reaction
no reaction
no reaction
no reaction
N2 or argon atmosphere
H2O as solvent
THF/H2O18
>98% unlabeled, no O18-labeled
(4 equiv, 492 μL/8 μL)
2a
6
7
TEMPO or BHT (1 equiv)
CuCl2 (1 equiv)
<10% 2a
trace 2a
notoperationalintheabsenceofeitherbaseorcatalystA(entries1
and 2), indicating the key role of both components in the overall
transformation. Again, no oxidation product was detected when
thereactionwasperformedunderN2 orargonatmosphere,which
indicates that the oxygen atom in the lactam moiety might be
coming from air or moisture (entry 3). Next, the reaction was
performed in water, and again, no oxidation product was
observed. Starting material was recovered back at the end of the
reaction (entry 4). This is due to very poor solubility of the N-
phenyl tetrahydroisoquinolines in water. The reaction was also
performed in the presence of 4 equiv of H2O18 in THF. However,
noO-18-labeledproduct wasdetected(m/z forC15H13N(18O)=
225, entry 5; details in SI) in the mass spectrum. Theses
observations indicate that the source of lactam oxygen in the
productmightbemolecularO2.Whenthereactionwasperformed
in the presence of stoichiometric amounts of a radical scavenger
such as TEMPO or BHT, yield decreased to <10%. This
observation pointed out possible participation of radical
intermediates (entry 6). Additionally, on addition of CuCl2, a
traceamountofproductwasnoticed,whichpossiblyindicatesthe
involvement of single-electron processes and the presence of
peroxide species in the system (entry 7).
Scheme 2. Scale-up Synthesis of 2h
The present catalytic system was also applicable for the α-
oxygenationofisoindolines3tothecorrespondingisoindolinone
4 in moderate yields (Table 3). In all cases, no N-phenyl-
phthalimide was detected as a byproduct by GC-MS and NMR
studies.
a b
,
Table 3. α-Oxygenation of Isoindolines
Based on the above results and previous reports,7b,17 a possible
mechanism of this transformation is proposed (Scheme 4).
Deprotonation of lactone A by DABCO gives dienolate species I,
which is proposed to react with triplet oxygen18 to form radical II
and peroxy radical III. Next, single-electron transfer from
tetrahydroisoquinoline 1a to radical species II or III gives radical
cation V7b,19 and I (or IV) to close the catalytic cycle.
Deprotonation of radical cation V by base gives more stable
radical VI, which was confirmed by HRMS (details in SI). The
generated radical VI reacts with peroxy radical III to give the
intermediate VII. Finally, this intermediate VII transformed to
the desired oxidation product 2a.
a
b
Reaction conditions: same as in Table 2. Isolated yields.
Theisoindolinonecoreispresentinalargenumberofbioactive
productssuchasindoprofen14 andindobufen,15 whichareknown
as anti-inflammatory drug and platelet aggregation inhibitors.
Currently, indobufen is in phase 4 clinical trials.16 The synthetic
utility of our present α-CH2 oxidation of cyclic amines as the key
step was further elaborated for the synthesis of indoprofen and
indobufen(Scheme3).Lactams4eand4fwereobtainedin44and
38% yields, respectively, under the standard reaction conditions.
Hydrolysis of 4e and 4f led to indoprofen 5e and indobufen 5f.
We have performed some control experiments to understand
thereactionmechanism(Table4).Wefoundthatthereactionwas
In conclusion, we have demonstrated for the first time that α-
angelica lactone is an efficient catalyst for the direct oxidation of
various N-aryl tetrahydroisoquinolines and isoindolines to
C
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ASSOCIATED CONTENT
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Experimentalprocedures,characterizationdata,NMR,and
mass spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: u.das@ncl.res.in.
ORCID
Utpal Das: 0000-0002-4580-8957
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Science and Engineering Research
Board (SERB), New Delhi (YSS/2014/000713, EEQ/2016/
000203),isgratefullyacknowledged.T.T.andS.K.D.arethankful
to SERB (PDF/2016/002733) and UGC, New Delhi, for their
fellowships.
DEDICATION
■
Dedicated to Professor Deevi Basavaiah on the occasion of his
68th birthday.
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