α-Angelica lactone catalyzed oxidation of benzylic sp3C-H bonds of isochromans and phthalans

Article abstract of DOI:10.1039/d0ob00729c

A metal-free organocatalytic system has been developed for highly efficient benzylic C-H oxygenations of cyclic ethers using oxygen as an oxidant. This oxidation reaction utilizes α-angelica lactone as a low cost/low molecular weight catalyst. The optimized reaction conditions allow the synthesis of valued isocoumarins and phthalides from readily available precursors in good yields. Mechanistic studies indicate that the reaction pathway likely involves a radical processviaa peroxide intermediate.

Full text of DOI:10.1039/d0ob00729c

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DOI: 10.1039/D0OB00729C
ARTICLE
3
α-Angelica lactone catalyzed oxidation of benzylic sp C−H bonds
of isochromans and phthalans
Thanusha Thatikonda, a †Siddharth K. Deepake, a, b † Pawan Kumar a, b and Utpal Das a, b
Received 00th January 20xx,
Accepted 00th January 20xx
*
DOI: 10.1039/x0xx00000x
A metal-free organocatalytic system has been developed for highly efficient benzylic C–H oxygenations of cyclic ethers
using oxygen as an oxidant. This oxidation reaction utilizes α-angelica lactone as low cost/low molecular weight catalyst.
The optimized reaction conditions allow the synthesis of valued isocoumarins and phthalides from readily available
precursors in good yields. Mechanistic studies indicate that the reaction pathway likely involve a radical process via a
peroxide intermediates.
2
by using metal oxides of chromium. Since chromium is toxic in
Introduction
The isocoumarin and phthalide derived scaffolds are
frequently encountered in many natural products and drug
nature, transition-metal catalysts using oxygen or peroxides as
the oxidant were developed.The metal catalysts for oxidation
3
3
4
5
of benzylic sp C−H bond include copper, cobalt, rhodium,
6
7
manganese and iron. Among them, iron catalyst containing a
chiral pyridine bissulfonylimidazole ligand is mention worthy
molecules that possess a broad range of biological activities
1
(
Figure 1). Given the immense applications and significance of
7
c
although it experiences low conversion. Use of photoredox
these compounds,
a challenging study of interest is
8
methods and strong base in the presence of oxygen are also
development of concise and efficient method to these oxygen-
containing heterocyclic compounds. Direct oxidation of
9
known for benzylic oxidation which avoid metals. Recently,
application of TEMPO derived sulfonic salt catalyst and mineral
3
benzylic sp C−H bonds of isochromans and phthalansis one of
3
acids for aerobic oxidation of benzylic sp C−H bonds of ethers
the most effective means to enable expeditious synthesis due
to the high step economy and synthetic efficiency.
Traditionally, oxidation of benzylic sp C−H bonds is performed
1
0
and alkylarenes (Scheme 1a) has been reported. DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) as catalyst in the
presence of other co-catalytic system (50 mol% of tert-butyl
nitrite) are also known in literature for such reactions (Scheme
3
1
1
O
OH
O
OH
O
1b).
O
O
O
OH
O
Previous work
O
N
N
SO3Na
Oospolactone
anti-fungal activity)
O
O
Aldosterone synthase
inhibitor
Phyllodulcin
N
O
(
(Natural Sweetener)
(catalyst)
O
O
O
(
a)
O
O
HCl, NaNO2, O2 (1 atm)
CN
O
O
O
NC
O
O
O
O
HO
OH
Cl
(catalyst)
Cl
O
Cl
(b)
Gymnopalynes B
3
-Butylphthalide
commercial antiplatelet drug) (anti-amnesia activity)
Fuscinarin
t-BuCONO, air, MeCN
visible light
(
HO
O
O
Fig
.
1Selected examples of natural products and drugs containing isocoumarin
HO
HO
O
O
and phthalide core structure.
OH
O
(catalyst)
O
O
OH
(
c)
CuCl2. 2H2O, O2, visible light
dimethyl carbonate
This work
a. Division of Organic Chemistry, CSIR – National Chemical Laboratory, Pune-
O
O
(catalyst)
4
11008, India; e-mail: u.das@ncl.res.in
O
b.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
(d)
†
These authors contributed equally.
DMAP, 2Me-THF, O2
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1C−H Oxidation of Isochromans.
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Journal Name
Table 1. Optimization Studiesa
However, DDQ is toxic and liberates HCN upon contact with
water. Therefore, a visible light mediated oxidation method
View Article Online
DOI: 10.1039/D0OB00729C
O
catalyst A-F
using less toxic arbutin (source of 1,4-hydroquinone, BQH
2
)as
O
O
DMAP, solvent,
O2 (balloon), 25°C
36h
pre-oxidant in the presence of copper salt (electron transfer
1a
1
2
2a
mediator) and oxygen gas has been developed (Scheme 1c).
Very recently, we reported α-angelica lactone as an
organocatalyst for benzylic C−H oxidations of N-aryl
tetrahydroisoquinolines and isoindolines in the presence of a
Ph
Ph
O
5
O
O
O
O
O
1
3
O
O
O
O
O
O
base under oxygen atmosphere. Herein, in continuation of
A
B
C
D
E
F
our work on organocatalyzed oxidation with O
2
as a green
3
oxidant, we describe a benzylic sp C−H bond oxidation of
isochromans and phthalans by using α-angelica lactone as an
organocatalyst in the presence of a base for the synthesis of
isocoumarin and phthalide derivatives (Scheme 1d). We have
also found that the oxidation method is highly chemoselective
in nature. α-Angelica lactone (a multicentered nucleophile) has
entry
catalyst
solvent
THF
yield (%) [b]
1
2
3
4
5
A
A
A
A
A
A
A
B
C
D
E
34
27
30
41
47
68
81
46
26
34
71
24
54
83
2
Et O
MTBE
toluene
CH CN
3
CH CN
2-Me THF
2-Me THF
2-Me THF
2-Me THF
2-Me THF
2-Me THF
2-Me THF
2-Me THF
1
4
[c]
been successfully employed as a nucleophile but in the
present case no oxidative cross-coupling product of cyclic
benzylic ethers with α-angelica lactone is detected as reported
6
3
[
[
[
c]
c]
c]
7
8
9
1
5
earlier with aldehydes. Recently, ACS Green Chemistry
[
[
[
c]
th
10
Institute® Pharmaceutical Roundtable (GCIPR) in its 10
c]
c]
1
1
1
1
1
2
3[
anniversary report pointed that “Aliphatic and aromatic C–H
F
A
A
activation, using green oxidants and giving predictable site
c,d]
1
6
selectivities ” as one of the top 10 research areas which
4[c,e]
compliments the elegance of our present research findings.
a
Reaction condition: 1a (0.1 mmol), DMAP (0.3 mmol), catalyst A (25 mol %), in
b
c
solvent (0.5 mL) at rt for 36 h under O
2
(balloon) atmosphere. Isolated yields. at
d
e
8
0 °C for 24h. With 10 mol% catalyst A. With 30 mol% catalyst A.
Results and discussion
As we realized the efficient catalytic activity of amines for the catalyst loading was 10 mol% (54%, entry 13). And only
benzylic C-H oxidation in our previous research, we anticipated marginal improvement in yield was noticed when 30 mol%
that the same might execute α-oxidation reaction of benzo- catalyst was used (83%, entry 14). Further optimization, in
fused cyclic ethers. We selected isochroman1a as the model terms of different bases and solvent concentrations were also
substrate for the desired transformation (Table 1). Most performed and are detailed in the Supporting Information.
accessible oxygen gas is preferred as a source of oxidant which We have then explored the substrate scope of this angelica
also enables high atom economy. We have carried out the lactone (A) catalyzed oxidation reactions of different
oxidation reaction of isochroman1a in the presence oxygen isochromans and pthalans and the results are summarized in
gas, α-angelica lactone A (25 mol %) as an organocatalyst and Table 2. No over oxidation product was formed as confirmed
4
-dimethylaminopyridine (DMAP, 3 equiv.) as a base were by GC-MS and NMR studies. The reason could be instant
used in THF. The reaction proceeded at 25 °C to afford deactivation of the ring by the inserted carbonyl group which
isocoumarin 2a in 34% isolated yield in 36 h (entry 1). With the prohibits further oxidation. Substituted isochromans 1a-1q
encouraging preliminary result, we first tried to figure out the gave the corresponding oxidized products 2a-2q in a moderate
role of different solvents in the reaction conditions. Acyclic to excellent yields (33-81%). The optimized reaction condition
ethers (diethyl ether and MTBE) were not found to be better successfully included substrates containing electron donating
than THF as they delivered low chemical yields (27 and 30% groups on aromatic ring of isochroman. The corresponding
respectively, entries 2 and 3). Toluene and acetonitrile products 2b-2f were obtained in 37-77% yields. Halogen
provided comparatively improved yields (41% and 47% substitutions (˗Br, ˗F) on the phenyl ring of isochroman
respectively, entries 4 and 5). A significant improvement was afforded the corresponding products 2g and 2h in 44 and 33%
observed when the reaction was performed at an elevated of yields. Isochromans with alkyl substitutions (methyl,
temperature (80 °C). The product was obtained in 68% isolated dimethyl and ethyl groups) on the saturated ring were also
yield in acetonitrile (entry 6). A superior result was obtained well toleratedand the corresponding oxidized products (2i−2k)
when 2-methyltetrahydrofuran (2-Me THF) was employed at were obtained in 70%, 76% and 65% yields respectively. Musk
8
0 °C (81% yield, entry 7). We have alsoscreened the chemical hexamethylisochromane 1l (Galoxolide) was also
catalyticefficacy of various lactones (B-F) and found them not found to be a suitable substrate. The corresponding product 2l
so promising except lactone E which afforded the desired was obtained in 71% yield. Benzo-isochroman derivatives were
product in 71% yield (entries 8-12). Use of 25 mol% catalyst A responded well to our protocol and gave the corresponding
was found to be optimum. A diminished yield was obtained lactones 2m-o in 43-53% yields. Notably, in case of compound
when
2o, which have two benzylic positions for oxidation,
2
| J. Name., 2012, 00, 1-3
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regioisomeric mixtures of isocoumarins were obtained in 60:40 Benzoxazine derivative 1w also remained irresponsive
View Article Online
DOI: 10.1039/D0OB00729C
ratios. We believe the less hindered product was obtained as probably due to the presence of another heteroatom (N).
the major isomer due to steric issues. Heteroaromatic The potential application of this benzylic oxidation was
isochromanes 1p-q were also found to be suitable substrates illustrated for the synthesis of racemic 3-butylphthalide (4a)
and the corresponding products 2p-q were obtained in 49 and using the standard reaction condition starting from 1-butyl
5
6% yields. The application of present catalytic system was phthalan3a in 35% yield (Scheme 2a). The reproducibility of
also extended for the α-oxygenation of pthalans to the the reaction was examined in gram-scale using optimized
corresponding phthalides in good yields. Phthalide 2r was reaction conditions, the products 2r (1.2 g, 69%) and 2a (1.38
obtained in 71% yield. Notably, in case of compound 2s, g, 78%) were isolated without any loss of chemical yield
regioisomeric mixtures of phthalides were obtained in 77:23 (Scheme 2b).
ratios in favor of para oxidation product possibly governed by
electronic effect. Oxidation reaction of alkylarenes is of
O
9
significant challenge. We are delighted to include them in our
catalytic system with slight modification of the reaction
conditions (in toluene at 100 °C). Diphenylmethane and 9H-
fluorene provided the corresponding ketones (2t and 2u) in
low isolated yields (17 and 16% respectively). However, 2,3-
dihydrobenzofuran was not compatible with the present
protocol and failed to afford the product 2v.
Standard reaction
O
(
a)
O
condition
35%, 48 h
4a
-butyl pthalide ()
commercial antiplatelet drug
3a
3
O
Standard reaction
condition
(
b)
O
n
O
n
24 h
n = 1, 2
r or 1a
n = 1, 2r (69%, 1.2 g)
n = 2, 2a (78%, 1.38 g)
1
Table 2 Substrate Scope: Isochromansa,b
Scheme 2. Synthetic manipulation and gram-scale synthesis.
O
O
O
R
R
Control experiments were performed to understand the
reaction mechanism (Table 3). We found that the reaction was
not operational in absence of either base or catalyst A (with
complete recovery of starting material 1a, entries 1-2). Again
no oxidation product was detected when the reaction was
1
2
O
O
O
O
O
O
2
a: 81%, 24 h
2b: 77%; 18 h
2c: 70%,12 h
O
O
O
performed under inert (N
2
or argon) atmosphere which
O
O
O
indicates that the source of oxygen atom in the lactone moiety
is from air or moisture (entry 3). The reaction was also
O
O
2
d: 68%,12 h
2e: 58%, 36 h
2f: 37%, 36 h
O
O
O
1
8
performed in the presence of H
O-18 labelled product was detected in mass spectrum (entry
4). This observation indicates molecular O as the source of
2
O in 2-Me-THF. However, no
Br
F
O
O
O
2
g: 44%, 36 h
2h: 33%, 36 h
2
2
i: 70%,12 h
O
O
O
lactone oxygen in the product. Again yield of product 2a was
dropped to <10% in the presence of stoichiometric amounts of
radical scavenger like TEMPO or BHT which indicates that the
reaction proceeds through radical intermediates (entry 5).
Only trace amount of product was observed on addition of
O
O
O
2
k: 65%, 24 h
2
j: 76%, 12 h
2
l: 71%, 24 h
O
O
O
O
O
O
O
O
2
CuCl in the reaction medium which indicates the operating
2n: 51%, 48 h
Cl
Cl
single electron transfer during the course of the reaction
2
m: 53%, 36 h
2
o: 43%, 48 h
17
(entry 6). Additionally, only traces of 2a were observed (13%
O
O
yield) when the reaction was performed in the presence of
O
O
S
O
S
catalase enzyme (H
peroxide species (entry 7).
2
O
2
scavenger), which indicates presence of
O
2
q: 56%, 24 h
2r: 71%, 24 h
17, 18
2p: 49%, 24 h
Next, oxygen isotope labelling
O
O
O
experiment was performed to ascertain the source of oxygen
and to support the reaction mechanism.The GC-mass
spectrum of the product 2a (m/z = 148) was shifted two mass
O
O
+
O
2u:16%, 48 h
2
t: 17%, 48 h
O
2
s: 52%, 24 h
1
8
units higher to m/z = 150 (2a′) (82% O labeled oxygen atom)
O
O
1
8
O
N
H
2
when the reaction was carried out with O . This experiment
2v: 0%
2w: 0%
clearly indicates that the incorporation of oxygen is from
molecular oxygen (entry 8).
a
Reaction condition: 1a (0.1 mmol), DMAP (0.3 mmol), catalyst A (25 mol %), in
-Me THF (0.5 mL) at 80 °C for indicated time under O (balloon) atmosphere.
2
b
2
Isolated yields.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
Table 3 Mechanistic Investigations
asoxygen atom source in lactones. The reaction cVoienwdAitrtiioclne sOnalirnee
compatible with a range of cyclic ethers.
D
A
OI
r
:
e
1
a
0
c
.1
t
0
i
3
o
9
n
/D
m
0
e
O
c
B
h
0
a
0
n
7
i
29C
s
m
O
O
reaction condition
O
involving a radical pathway via a peroxide species as
intermediates has been further supported by control
experiments. This protocol is successfully applied for the direct
synthesis of bioactive molecule 3-butylphthalide.
1a
2a
Entry
Condition
Result
No reaction
1
No base
No Cat. A
or Argon atm.
2Me-THF:H
80µL:20µL)
TEMPO or BHT (1 equiv.)
CuCl ((1 equiv.)
Catalase (70 mg)
18O
atm.
Conflicts of interest
There are no conflicts to declare.
2
3
4
No reaction
No reaction
N
2
O18 (10 equiv.; >98% unlabeled, no 18
O
2
9
Acknowledgements
5
<10%
6
7
8
2
No reaction
13%
82% 18O incorporation
Financial support from the Science and Engineering Research
Board (SERB), New Delhi (EEQ/2016/000203) is gratefully
acknowledged. T.T.(PDF/2016/002733), S.K.D., and P.K. are
thankful to SERB and UGC, New Delhi, for their fellowships.
2
On the basis of these experimental data and literature
precedents1
2,13,17
a plausible mechanism of this transformation
is proposed (Scheme 3). Deprotonation of acidic proton of A by
DMAP leads to a dienolate species I which captures triplet
Notes and references
1
(a) E. Napolitano, Org Prep Proced Int. 1997, 29, 631; (b) R.
Karmakar, P. Pahari and D. Mal, Chem. Rev. 2014, 114, 6213;
(c) A. León, M. Del-Ángel, J. L. Ávila and G. Delgado in
Progress in the Chemistry of Organic Natural Products 104,
Springer, Berlin, 2017, pp. 127-246; (d) P. Saikia and S. Gogoi.
Adv. Synth. Catal. 2018, 360, 2063.
1
9
oxygen to form peroxide species and then its homolytic
cleavage leads to radical species II and III. Next, H-atom
abstraction of 1a by either the peroxy radical III or alkoxy
radical II leads to radical species V [Formation of intermediate
V was confirmed by the HRMS analysis, detection of V-TEMPO
adduct] which reacts with oxygen to give hydroperoxide
intermediate VI that can collapse to product 2a by further H-
removal by base. Alternatively, single electron transfer from
the substrate 1a may give a radical cation that can undergo H-
atom transfer to give an oxocarbenium ion which on
recombination with peroxy radical III provides intermediate VI
2
3
J. Muzart, Tetrahedron Lett.,1987, 28, 2131; b) S. Yamazaki,
Org. Lett.,1999, 1, 2129.
(a) N. Komiya, T. Naota and S. I. Murahashi,
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Zhang, W. H. Wu and J. Xu, Chem. Commun., 2003, 1172; (c)
H. Tanaka, K.Oisaki and M. Kanai, Synlett, 2017, 28, 1576.
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Ronchetti, A. Scala and L. Toma, Eur. J. Org. Chem., 2003,
2964; (b) Y. Yang and H. Ma, Tetrahedron Lett., 2016, 57,
4
(see SI).
5
278.
5
6
(a) A. J. Catino, J. M. Nichols, H. Choi, S. Gottipamula and M.
P.Doyle, Org. Lett., 2005, 7, 5167; (b) Y. Wang, Y. Kuang and
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Jin, X. Hu, W. Mo, B. Hu, N. Sun and Z.Shen, Tetrahedron,
2017, 73, 3002.
O
O
II
1a
O
OOH
III
O2
or H2O2
IV
H
O
H
O
O
7
O
O
O
I
O
O
O2
O
O
I
DMAP
V
VI
Observed as TEMPO-adduct
in HRMS]
2a
[
D M A P
O
O
8
9
N. V. Tzouras, I. K. Stamatopoulos, A. T. Papastavrou, A. Liori
and G. C. Vougioukalakis, Coord. Chem. Rev., 2017, 343, 25.
(a) H. Sterckx, J. De Houwer, C. Mensch,; W. Herrebout, K. A.
Tehrani and B. U. W. Maes, Beilstein J. Org. Chem., 2016, 12,
A
Scheme 3 Plausible Mechanism.
1
44; (b) H. Wang, Z. Wang, H. Huang, J. Tan and K. Xu, Org.
Lett., 2016, 18, 5680; (c) J.-S. Li, F. Yang, Q. Yang, Z.-W. Li, G.-
Q. Chen, Y.-D. Da, P.-M. Huang, C. Chen, Y. Zhang and L.-Z.
Huang, Synlett, 2017, 28, 994; for a catalyst free aerobic
oxidation under 0.5 MPa oxygen, see (d) X. Tian, X. Cheng, X.
Yang, Y.-L. Ren, K. Yao, H. Wang and J. Wang, Org. Chem.
Front., 2019, 6, 952.
0 (a) Z. Zhang, Y. Gao, Y. Liu, J. Li, H. Xie, H. Li and W. Wang,
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Conclusions
In summary, we have developed an efficient and versatile
synthetic strategy for direct oxidation of various isochromans
and pthalans to corresponding lactones by employing
inexpensive α-angelica lactone as catalyst. Moreover, this
methodology utilizes oxygenas the green oxidant as well
1
4
| J. Name., 2012, 00, 1-3
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7 W. Huang, B.-C. Ma, H. Lu, R. Li, L. Wang, K. Landfester and K.
A. I. Zhang, ACS Catal. 2017, 7, 5438.
8 The same experiment at 40 °C by using the reaction
condition mentioned in entry 5 (table-1) with catalase
enzyme also provided trace amount of product (~8%).
9 For capture of molecular oxygen by dienolate species (a) P.
A. Peixoto, A. Jean, J. Maddaluno and M. De Paolis, Angew.
Chem.,Int. Ed. 2013, 52, 6971; (b) P. A. Peixoto, M. Cormier,
J. E. Epane, A. Jean, J. Maddaluno and M. De Paolis, Org.
Chem. Front. 2014, 1, 748; For conversion of β-angelica
lactone (I') to dienolate (I) in presence of base, (c) X.-J. Wang
and M. Hong, Angew. Chem.,Int. Ed. 2020, 59, 2664.
1
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00729C
Table of contents entry
Oxidation of benzylic sp3 C−H bonds of isochromans and phthalans to
isocoumarins and phthalides has been achieved by employing α-angelica
lactone as organocatalyst.
O
H
H
O
O
C-H Oxidation of cyclic ethers using lactone as organocatalyst
O2 as green oxidant and source of lactone oxygen
Metal free condition
(
catalyst)
O
O
R1
R1
O2, DMAP, 2-Me THF
nR2
nR2
n = 0, 1