Cerium Chloride Catalyzed, 2-Iodoxybenzoic Acid Mediated Oxidative Dehydrogenation of Multiple Heterocycles at Room Temperature

Article abstract of DOI:10.1002/ejoc.201601419

Catalytic cerium chloride was found to activate 2-iodoxybenzoic acid (IBX) for the oxidative dehydrogenation of tetrahydroisoquinolines, tetrahydro-β-carbolines, and thiazolidines to their dehydrogenated and aromatic forms at room temperature in moderate to excellent yields. The robustness of the protocol was demonstrated by scaling up the reactions to multigram quantities.

Full text of DOI:10.1002/ejoc.201601419

A Journal of
Accepted Article
Title: Anhydrous Cerium chloride catalyzed-IBX mediated oxidative
dehydrogenation of multiple heterocycles at room temperature
Authors: Subhabrata Sen and Santanu Hati
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601419
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601419
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10.1002/ejoc.201601419
European Journal of Organic Chemistry
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cerium
chloride
catalyzed-IBX
mediated
oxidative
dehydrogenation of multiple heterocycles at room temperature
Santanu Hati and Subhabrata Sen*
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar,
Uttar Pradesh 201314, India, Phone (o) 0091 (0) 1203819417; Email: subhabrata.sen@snu.edu.in;
http://www.snu.edu.in/naturalsciences/Subhabrata_Sen_profile.aspx
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
optimization stage all the reactions were conducted at
benzoic acid (IBX) for the oxidative dehydrogenation of 50 mg scale of 2a. The reaction in acetonitrile looked
Abstract.Catalytic cerium chloride activates 2-Iodoxy
tetrahydroisoquinolines,
tetrahydro--carbolines
and
propitious with about 24% conversion (as detected by
LCMS) to the corresponding dihydroquinazoline
analog 3a. In general the reactions at r.t. were
sluggish and were not complete even after 48h. Next,
we tried to improve the yield by elevating the
reaction temperature gradually. Accordingly the
reaction was conducted in acetonitrile with 1 equiv.
of IBX at 40, 50, 60 and 70 °C (Table 1, entry 5-8).
Higher temperature did improve the conversion, with
the best being 69% at 70 °C (Table 1, entry 8).
However we intend to develop a protocol for
oxidative dehydrogenation of heterocycles which
would be amenable to scale up and focused on
thiazolidines to their dehydrogenated and aromatic forms at
room temperature, in moderate to excellent yields. The
robustness of the protocol was further demonstrated by
scaling up the reactions in multigram quantity.
Keywords: Tetrahydroisoquinolines; Tetrahydro--
carbolines; Thiazolidines; Oxidative dehydrogenation
Oxidative dehydrogenation is an attractive strategy to
access variety of nitrogen containing heteroaromatic
compounds from their heterocyclic precursors.1
Diverse oxidants are used in catalytic as well as
stoichiometric quantities to achieve this.2 2-
Iodoxybenzoic acid, also known as IBX, had been
demonstrated to serve similar purpose.3
developing
a
room
temperature
strategy.
Consequently in the following experiments we
screened various Lewis acid catalysts along with IBX
at room temperature to improve or at the minimum
reproduce the yield reported in entry 8. Accordingly,
2a was reacted with 1 equiv. of IBX in acetonitrile
with variety of Lewis acids (0.25 equiv.) such as
aluminium chloride (AlCl3), ferric chloride (FeCl3),
IBX is a versatile reagent to conduct oxidation of
organic compounds.4 It is economical, readily
available and environmental benign. Due to its
fantastic reactivity it is used in different organic
transformations.5 However its major drawback is
incompatibility with major organic solvents (barring
dimethyl sulfoxide) and also that it requires higher
temperature for most of its reactions. Majority of IBX
reactions are conducted at ~45 °C or higher.6 Hence
to widen further the scope of IBX, search for a
catalyst/agent that will enable to harness the
oxidizing ability of IBX at room temperature is
desirable. In our continuous effort towards
cerium
chloride
heptahydrate
(CeCl3.7H2O),
anhydrous cerium chloride (CeCl3), titanium chloride
(TiCl4) and BF3.OEt2 (Table 1, entry 9-14). Only
reactions with CeCl3 and FeCl3 exhibited 81 and 45%
of conversion to 3a respectively, with minor
formation of the over oxidized product 4a (10-15%)
(Table 1, entry 12 and 10). The average reaction time
ranged from 4-6 h. To our utmost gratification the
reduced quantity of CeCl3 catalyst (0.1 equiv.) also
displayed similar conversion as with 0.25 equiv
(Table 1, entry 15). Hence the optimized protocol for
the room temperature oxidative dehydrogenation of
2a, included 1 equiv. of IBX and 0.1 equiv. of CeCl3
in acetonitrile.
discovering
mild
protocols
for
oxidative
dehydrogenation of heterocycles, herein we report
that catalytic cerium chloride (CeCl3) activates IBX
towards oxidative dehydrogenation of various
heterocycles such as tetrahydroisoquinolines,
tetrahydro--carbolines and thiazolidines at room
temperature in moderate to excellent yield.7-9
To begin with, the oxidative hydrogenation of 6, 7-
dimethoxy-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline,
2a, was explored at room temperature with 1 equiv.
of IBX, in a range of solvents that include dimethyl
sulfoxide, acetonitrile, 1, 4-dioxane and dimethyl
formamide (Table 1, entry 1-4). During the
1
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10.1002/ejoc.201601419
European Journal of Organic Chemistry
Table 1. Optimization of oxidative dehydrogenation of 6,
7-dimethoxy-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline, 2a. classes of heterocycles.
synthetic strategy adds immense value to access these
#
Solventc
Catalyst
(0.25
T
Time Conversion
(°C) (h)
(%)a
equiv.)
3a
4a
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
DMSO
ACN
1, 4-Dioxane
-
-
-
-
-
-
-
-
r.t.
̎
̎
̎
40
50
60
70
r.t.
̎
48
̎
̎
̎
6
̎
̎
̎
21
24
16
12
40 02
45 06
52 06
69 10
-
-
-
-
DMF
ACN
̎
̎
̎
̎
̎
Scheme 1. Oxidative dehydrogenation of 1-THIQs.
AlCl3
FeCl3
24
6
02
45 08
-
A tentative mechanism for this transformation is
depicted below with 2a as the model substrate. The
reaction might have been initiated with a facile
coordination of CeCl3 (anh.) with IBX, thereby
increasing its oxidative capability and leading to the
formation of intermediate A. Next, we envision a
sequence based on pertinent iodine oxidation
chemistry where iodine reduction occurs in a
concerted pathway to afford B, which undergoes
elimination to generate 3a.11 Complete aromatization
to 4a with 2 equiv. of IBX could also be an IBX
dependent pathway where a continuous oxidation of
the dehydrogenated product 2a, with the 2nd
equivalent of IBX led to the formation of the desired
aromatic product.
̎
̎
̎
̎
̎
CeCl3.7H2
O
CeCl3
(anh.)
TiCl4
̎
̎
̎
̎
̎
24
4
10
-
81 12
24
24
4
-
-
-
BF3.OEt2
8
CeCl3
75 10
(anh.)b
Conversion monitored by LCMS.b) Reaction with 0.1
a)
equiv. of CeCl3 (anh.).c) DMSO: Dimethyl Sulfoxide;
ACN: Acetonitrile; DMF: Dimethyl Formamide
With the condition optimized, variety of 1-substituted
tetrahydroisoquinolines (1-THIQs), 2a-l underwent
oxidative
dehydrogenation
to
afford
the
corresponding 3, 4-dihydroisoquinoline analogs 3a-k
in good to excellent yields. Interestingly the condition
was amenable to aromatic, heteroaromatic and
aliphatic substitutions. For aromatic moieties both the
electron donating and electron withdrawing
substituents were fluently accessed (Scheme 1,
pathway A). The final products 3a-k were obtained
after column purification of the reaction mixture.
Taking a cue from the formation of over oxidized
aromatic isoquinolines as side products (during the
optimization studies [Table 1, entry 12]), the 1-
THIQs were readily converted to their aromatic
analogs 4a-k with two equivalents of IBX (Scheme 1,
pathway B) and the desired compounds were isolated
after column purification. A variety of substituents
were again tolerated. 1-substituted dihydro and
aromatic isoquinoline products obtained from these
reactions are observed frequently as motifs in natural
products and drug candidates.10 Hence, this mild
Scheme
dehydrogenation of 1-THIQs
2.
Putative mechanism of oxidative
To rule out the possibility for anhydrous cerium
chloride to work as a drying agent, we performed the
reaction of 2a in acetonitrile in presence of activated
4 Å molecular sieves and one equivalent of IBX and
2
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10.1002/ejoc.201601419
European Journal of Organic Chemistry
without anhydrous CeCl3. We obtained compound 3a
in 41% yields after 8 hr of the reaction along with 5%
of 4a. Since, the yield of 3a reduced drastically, in
this reaction in comparison to the one with anhydrous
CeCl3, we believe that it is not acting as a drying
agent.
Similar procedure was harnessed to aromatize 2-
arylbenzothiazolidines 8a-d to their corresponding
benzothiazoles.
benzothiazoles
A
focused library of four
7a-d, containing aromatic,
heteroaromatic and aliphatic substitution at 2-position
were synthesized in excellent yield (Scheme 4).
In a bid to observe the coordination of anhydrous
CeCl3 with IBX or with the amines we monitored the
1
reaction via H-NMR in DMSO-D6 solvent. In the
first case we took IBX in DMSO-D6 and recorded the
NMR. After which we have added CeCl3 in the NMR
tube and recorded the NMR in an interval of half an
hour for four hours. Unfortunately we did not observe
any visible change in the chemical shift values.
In another effort we took compound 2a and CeCl3
and performed similar experiment. Here too we did
not observe any change in the chemical shift of the
peaks in the NMR.
We believe that may be our proposed pathway is
the one opted by this transformation, however we
were unable to prove the same through NMR. To
decipher this further investigation is being conducted
right now.
Scheme 4. Oxidative dehydrogenation of thiazolidines
Finally to demonstrate the robustness of this protocol
the syntheses of compounds 3a, 4g and 5k were
scaled up to ~3 g quantity to afford them in 65-74%
yield (Figure 1). Interestingly during the scale-up
mild exotherm was observed during the addition of
IBX, hence the reaction mixture was cooled to ~4 °C
during the addition and the reagents were added
slowly. This resulted in the increment of reaction
time to about 8 to 15 h for all the heterocycles.
To demonstrate the versatility of this methodology,
dihydro--carbolines 5a-l were synthesized in good
yields from their corresponding tetrahydro--
carboline precursor 6a-l. Unlike the substituted
dihydro and aromatic isoquinolines, herein the
dihydro--carbolines
with
electron
donating
substituted aromatic group at 1-position such as 4-
methyl,2-methyl, 3 and 4-methoxy (5c, d, e and g)
were synthesized in much higher yields compared to
their electron withdrawing analogs viz. 3-
trifluoromethyl and 3-fluoro, 5f and l (Scheme 3). A
variety of -dihydrocarbolines with di and
trisubstituted aromatic moiety such as 5b, h, i, j and k
could also be synthesized (Scheme 3). Average
reaction time ranged from 6 to 8 h. There were nearly
5-10% formation of the over oxidized aromatic -
carbolines. Hence pure 5a-l were obtained after
column purification of the reaction mixture.
Figure 1. Scale-up synthesis of 3a, 4g and 5k in 3g scale
To summarize, we have identified catalytic cerium
chloride (anh.) that activates IBX at room
temperature towards oxidative hydrogenation of
substituted-THIQs,
tetrahydro--carbolines
and
thiazolidines. This methodology augments the
effectiveness of IBX as an oxidant and widens its
application. Since the methodology was tolerated by
diverse substitution on the N-heterocycles (38
analogues over three different heterocycles) it can be
applied in generating library of molecules for
structure activity relationship studies in drug
discovery research. Finally it was demonstrated to be
robust even at higher scale.
Experimental Section
General Procedure
Scheme 3. Oxidative dehydrogenation of tetrahydro--
carbolines
All reactions were carried out in flame-dried round bottom
flasks with magnetic stirring. Unless otherwise noted, all
3
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10.1002/ejoc.201601419
European Journal of Organic Chemistry
experiments were performed under argon atmosphere. All
reagents and most of the saturated building blocks were
purchased from Sigma Aldrich, Acros, Alfa Aesar, Ark
Pharm, AK Scientific, Acros Organics, Aurora Building
Blocks, Aurora Screening Library, Chemlievliva
Pharmaceutical Product List (China) and Chembridge
Screening Library. Solvents were treated with 4 Å
molecular sieves and distilled prior to use. Purifications of
reaction products were carried out by column
chromatography using Chem Lab silica gel (100-200
chromatography (40% ethyl acetate in hexane) (Rf 0.55) to
obtain the desired compound 3a in 2.94 g (yield: 74%).
Scale up synthesis of 4g
To a solution of compound 2g (5 g, 16.70 mmol) in 200
mL of acetonitrile, 2-Iodoxy benzoic acid (10.05 g, 33.40
mmol) was added at 0-4 °C, followed by the addition of
CeCl3 (0.1 equiv.). The reaction mixture was stirred at this
temperature for one hour and slowly warmed to room
temperature. Once TLC confirms complete consumption of
the starting material (12h) the reaction mixture was
quenched with sodium thiosulfate and extracted with ethyl
acetate. The organic layer was evaporated and purified
through column chromatography (40% ethyl acetate in
hexane) (Rf 0.4)to obtain the desired compound 4g in 3.21
g (yield: 65%).
1
mesh). H NMR and 13C NMR spectra were recorded with
tetramethylsilane (TMS) as internal standard at ambient
temperature unless otherwise indicated at Bruker 400 and
1
500 MHz at 400 and 500 MHz for H NMR and 100 and
125 MHz for 13C NMR. Chemical shifts are reported in
parts per million (ppm) and coupling constants are reported
as Hertz (Hz). Splitting patterns are designated as singlet
(s), broad singlet (bs), doublet (d), triplet (t). Splitting
patterns that could not be interpreted or easily visualized
are designated as multiple (m). The Mass Spectrometry
analysis was done on the 6540 UHD Accurate-Mass QTOF
LC/MS system (Agilent Technologies) equipped with
Agilent 1290 LC system obtained by the Dept. of
Chemistry, School of Natural Sciences, Shiv Nadar
University, Uttar Pradesh 201314, India.
Scale up synthesis of 5k
To a solution of compound 6k (4 g, 11.37 mmol) in 200
mL of acetonitrile, 2-Iodoxy benzoic acid (3.42 g, 11.37
mmol) was added at 0-4 °C, followed by CeCl3 (0.1 equiv.).
The reaction mixture was stirred at at this temperature for
one hour and slowly warmed to at room temperature. Once
TLC confirms complete consumption of the starting
material (15h) the reaction mixture was quenched with
sodium thiosulfate and extracted with ethyl acetate. The
organic layer was evaporated and purified through column
chromatography (50% ethyl acetate in hexane) (Rf 0.4) to
obtain the desired compound 5k in 2.72 g (yield: 69%).
Synthesis of 3a-k
To a solution of compound 2 (200 mg, 1 equiv.) in
acetonitrile, 2-Iodoxy benzoic acid (1 equiv.) was added
followed by CeCl3 (0.1 equiv.) and the resulting mixture
was stirred at room temperature. Once TLC confirms
complete consumption of the starting material the reaction
mixture was quenched with sodium thiosulfate and
extracted with ethyl acetate. The organic layer was
evaporated and purified through column chromatography
(40-60% EtOAc in hexane) to obtain the desired
compounds 3a-k with.
Acknowledgements
We thank Shiv Nadar University for support.
Synthesis of 4a-k
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and extracted with ethyl acetate. The organic layer was
evaporated and purified through column chromatography
(30-50% EtOAc in hexane) to obtain the desired
compounds 4a-k.
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European Journal of Organic Chemistry
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5
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10.1002/ejoc.201601419
European Journal of Organic Chemistry
COMMUNICATION
Cerium chloride catalyzed-IBX mediated oxidative
dehydrogenation of multiple heterocycles at room
temperature
European Journal of Organic Chemistry.Year,
Volume, Page – Page
Santanu Hati and Subhabrata Sen*
6
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