Catalytic Undirected Intermolecular C-H Functionalization of Arenes with 3-Diazofuran-2,4-dione: Synthesis of 3-Aryl Tetronic Acids, Vulpinic Acid, Pinastric Acid, and Methyl Isoxerocomate

Article abstract of DOI:10.1021/acs.orglett.6b03087

A variety of 3-aryl tetronic acids have been synthesized by an undirected, intermolecular C-H functionalization of arenes with 3-diazofuran-2,4-dione. This methodology featured as a key step in the synthesis of a series of naturally occurring 3-aryl-5-arylidene tetronic acids (pulvinates) from commercially available tetronic acid. Salient features of the pulvinic acid synthesis include a one-step, stereoselective synthesis of the C5 arylidene group and a single step introduction of the C3 aryl substituent.

Full text of DOI:10.1021/acs.orglett.6b03087

Letter
pubs.acs.org/OrgLett
Catalytic Undirected Intermolecular C−H Functionalization of Arenes
with 3‑Diazofuran-2,4-dione: Synthesis of 3‑Aryl Tetronic Acids,
Vulpinic Acid, Pinastric Acid, and Methyl Isoxerocomate
Amarender Manchoju and Sunil V. Pansare*
Department of Chemistry, Memorial University, St. John’s, Newfoundland, Canada, A1B 3X7
S
* Supporting Information
ABSTRACT: A variety of 3-aryl tetronic acids have been synthesized by
an undirected, intermolecular C−H functionalization of arenes with 3-
diazofuran-2,4-dione. This methodology featured as a key step in the
synthesis of a series of naturally occurring 3-aryl-5-arylidene tetronic acids
(pulvinates) from commercially available tetronic acid. Salient features of
the pulvinic acid synthesis include a one-step, stereoselective synthesis of
the C5 arylidene group and a single step introduction of the C3 aryl substituent.
etronic acid (4-hydroxy-2-5[H]-furanone) functionality
has attracted considerable attention in recent years as a
foods and beverages.9d The synthesis of tetronic acids has
therefore been extensively investigated in recent years.10
Practically all of the reported syntheses of 3-aryl tetronates
require a starting material which contains the aryl group that is
required in the target. The majority of these methods use aryl
acetic acids,11 esters,12 or α-hydroxy alkyl aryl ketones13 as the
starting materials (Scheme 1). An alternative, but synthetically
T
distinctive feature of many natural products.1 Many tetronic
acid derivatives display a wealth of biological activities which
include insecticidal and acaricidal,2 HIV−I protease inhibitory,3
antineoplastic,4 antiinflammatory,5 and cyclooxygenase inhib-
itory activity.6 In addition, these tetronic acids are also of
interest for their role as pigments in mushrooms and lichens.1
Among a large group of structurally related tetronates that are
substituted at C3 with an aryl group are pulvinic acid (1, Figure
1), vulpinic acid (2), 4-hydroxypulvinic acid (3), pinastric acid
Scheme 1. Strategies for the Synthesis of 3-Aryl Tetronic
Acids
intensive, approach14 involves the cross-coupling of aryl
boronic acid derivatives with C3-functionalized tetronic acid
derivatives. All of these procedures are primarily limited by the
availability of suitably functionalized starting materials, and
methodology that overcomes this limitation would be useful.
With this objective in mind, a review of the literature
indicated a scarcity of reports on the synthetic applications of 3-
diazofuran-2,4-dione (11, Scheme 1)15 and only a sole report
describing an undesired, low yield, C−H insertion reaction.15c
We were therefore intrigued by the prospect of developing
intermolecular aryl C−H insertion reactions of 11, easily
prepared from commercially available tetronic acid in one
step,15a,c as a direct route to 3-aryl tetronates (Scheme 1).
Herein, we describe preliminary results on this approach and an
Figure 1. Naturally occurring 3-aryl tetronic acid derivatives.
(4), and their oxygenated analogues7 such as xerocomic acid
(5), methyl isoxerocomate (6), and variegatic acid (7). More
elaborate congeners include xerocomorubin (8),8a norbadione
A (9),8b and badione A (10).8b
Synthetic analogs of pulvinic acid have also shown
antioxidant,9a antiulcer,9b and radioprotective9c properties
whereas the natural pulvinate, variegatic acid (7, Figure 1), is
of interest as a precursor of stable, natural blue-colorant for
Received: October 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03087
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
application of the methodology in the synthesis of vulpinic acid
(2), pinastric acid (4), and methyl isoxerocomate (6, Figure 1).
Intramolecular and substrate-directed C−H functionalization
of arenes with diazo compounds is well-known.16 Undirected,
intermolecular, arene C−H functionalization reactions17a have
also been investigated. The majority of these studies have
examined α-aryl-α-diazoacetates17b−i or 3-diazooxindoles,17j−l
and only a few arene C−H functionalization studies are
reported with 2-diazo-1,3-dicarbonyl compounds.17m−q Given
the relative shortage of information available on the key step of
our proposed synthetic plan, a survey of catalysts and reaction
conditions was necessary. Accordingly, we first attempted the
These studies, with biphenyl as the representative arene, are
summarized in Table 1.
Conventional chlorinated solvents, ionic liquids, and α,α,α-
trifluoromethylbenzene were selected as the reaction medium,
and a set of rhodium(II) catalysts differing in the ligand were
screened. The choice of rhodium catalysts that are more
electrophilic than Rh2(OAc)4 was based on previous studies on
competitive intramolecular reactions of diazo carbonyl
compounds19 in which electron-deficient rhodium catalysts
favored aromatic substitution (net C−H insertion) reactions
over competing cyclopropanation. As seen from Table 1,
almost all of the reactions provided 13, but α,α,α-
trifluoromethylbenzene was clearly a superior solvent (Table
1, entries 7 and 12), and Rh2(CF3CO2)4 was the catalyst of
choice (compare entries 7, 12, and 18 in Table 1). The best
results were obtained with an excess of biphenyl (4 equiv, entry
12), and reducing this amount was not beneficial (46% yield
with 2 equiv of biphenyl; Table 1, entry 13). This procedure
(PhCF3 as the solvent, Rh2(CF3CO2)4 as the catalyst, and 4
equiv of the arene; Method B) or Method A, described above,
were applicable to the C−H insertion reactions of 11 with a
variety of arenes to provide 12−31 (Figure 2).
reaction of 11 with anisole in the presence of Cu(OTf)2,17p
17c
Co(OAc)2,18 and (Ph3P)3AuCl/AgSbF6
as catalysts. With
Cu(OTf)2, 12 was obtained in low yield (11%, Table 1, entry
1). Although the Co and Au derived catalysts are known to
promote diazo decomposition, only unreacted 11 was observed
in these reactions.
Table 1. Optimization of the Intermolecular Aryl C−H
Insertion Reaction of 11
entry
catalyst
Cu(OTf)2
solvent
t (h) prod yield (%)
a
1
−
−
−
−
12
−
11 (36)
−
2
Co(OAc)2
3
AuCl/AgSbF6
Rh2(OAc)4
Rh2(OAc)4
−
−
4
12
96
b
5
(CH2)2Cl2
12
79
168
65
96
24
96
5
13
36
b
a
a
6
CH2Cl2
21 (34)
47 (55)
13
c
7
PhCF3
b
b
8
[bmim]PF6
a
9
[bmim]BF4
(CH2)2Cl2
CH2Cl2
16 (22)
27
10
11
12
13
14
15
16
17
18
19
20
Rh2(CF3CO2)4
−
d
e
PhCF3
51 (67)
d
ef
,
PhCF3
21
92
72
5
35(46)
a
[bmim]PF6
[bmim]BF4
(CH2)2Cl2
CH2Cl2
19 (22)
42
Rh2(NHCOC3F7)4
19
7
−
g
PhCF3
2.5
22
55
23
[bmim]PF6
[bmim]BF4
21
23
a
b
c
Based on recovered 11. At reflux or at 100 °C for ionic liquids. At
d
e
f
70 °C. At 100 °C. Including regioisomer. Reaction with 2 equiv of
biphenyl. Reaction at 80 °C.
g
Figure 2. Intermolecular aryl C−H insertion reactions of 11.
We therefore turned to the more conventional rhodium-
based catalysts. Interestingly, heating a solution of 11 in anisole
in the presence of Rh2(OAc)4 provided 12 in excellent yield
(96%) as a single regioisomer (Table 1, entry 4). This
procedure (Method A) was suitable for simple arenes which
could be used as the solvent and then easily separated from the
tetronic acid product and recovered.
In order to expand the scope of the methodology to other
arenes, an optimization of the insertion reaction was conducted
by varying the solvent, catalyst, and stoichiometry of the arene.
The C−H insertion reactions of 11 with alkyl benzenes and
with electronically activated arenes proceeded readily and in
moderate to good yield (method A, 12 examples, 72% average
yield; method B, 7 examples, 60% average yield). Interestingly,
11 also reacted with methyl benzoate to provide 31 (52%), but
reactions with more electron-deficient arenes such as nitro-
benzene, acetophenone, and benzonitrile were unsuccessful.
The regiochemistry of C−H functionalization is what would be
B
DOI: 10.1021/acs.orglett.6b03087
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
expected for electrophilic aromatic substitution of the arene,20
and in a few cases, regioisomeric products were obtained (13,
p/o = 3.1:1; 25/26 = 3.1:1; 29, p/o = 3.5:1) which were easily
separated. The results suggest that the carbenoid derived from
11 reacts with the arenes as an electrophile. This reactivity is
consistent with the superior performance of Rh2(OCOCF3)4
which presumably increases the electrophilicity of the bound
carbene.19
Scheme 2. Synthesis of Naturally Occurring Tetronic Acid
Derivatives
Having established a general procedure for preparing 3-aryl
tetronic acid derivatives, we next examined the application of
our method in the synthesis of selected, naturally occurring
pulvinic acids (Figure 1). While the conversion of 3-aryl
tetronic acids to pulvinates is well-known,14a,21 our objective
was to develop a modular functionalization of 11 by first
introducing the arylidene functionality at C5 (Figure 3) and
Figure 3. Strategy for the synthesis of naturally occurring pulvinates
from 11.
then adding the C3 aryl group employing the C−H insertion
procedure. Compared to current methods for pulvinic acid
synthesis, our procedure would use 11 as the common starting
material for all of the structurally related tetronate natural
products (Figure 3).
The formation of 2, 4, and 6 also confirms the stereochemical
assignments for 32 and 33.
In conclusion, a one-step synthesis of 3-aryl tetronic acids has
been developed from 3-diazofuran-2,4-dione. The synthesis of
vulpinic acid (2), pinastric acid (4), and methyl isoxercomate
(6), as well as a formal synthesis of pulvinic acid (1) and 4-
hydroxypulvinic acid (3), was achieved in three steps from
commercially available tetronic acid. To the best of our
knowledge, the two-step functionalization of 11 offers the
shortest route to these natural products. The methodology
provides direct access to a wide range of 3-aryl tetronates and
has the advantage of furnishing stereoisomerically pure 5-
arylidene tetronates. We anticipate that our modular strategy
will be useful for preparing natural product-like libraries of
tetronic acid derivatives by systematic variation of the C3 aryl
group and the aryl group in the α-keto ester used in the aldol
condensation. Current efforts focus on these and other
applications of 11.
Previous syntheses of C5-arylidene tetronic acid derivatives
from 3-aryl tetronic acids have relied on protocols that involve
multistep assembly of the tetronate ring14a,21a,b or Wittig
reaction of a preformed C3-substituted tetronate derivative.11a
More recent strategies also involve several steps, specifically:
(a) an aldol reaction of a C3 substituted tetronic acid derivative
with a α-keto ester; (b) dehydration of the aldol product by
mesylation and elimination,21b or by conversion to the
trifluoroacetate and elimination; and (c) photoisomerization
of the mixture of isomeric alkenes so obtained to the naturally
occurring E-isomer.21a,b Stereoisomers of the required alkene
products are also obtained in the earlier procedures.11a,14a,21a
Clearly, an alternative to these multistep procedures, and
especially to the stereorandom synthesis of the arylidene
portion, would be useful.
Our search for alternative procedures focused on the
possibility of using a mild aldolization protocol that would
not affect the diazo group in 11. Initial attempts with 11 and
methyl benzoylformate in the presence of MgBr2 and
triethylamine22a provided a very low yield of the required
aldol product. However, the use of a stronger Lewis acid
(TiCl4, Et3N, −78 °C)22b provided a mixture of the aldol
product and the dehydration product 32 (Scheme 2). A brief
optimization revealed that warming the reaction mixture (0 °C)
provided only 32 (64%, Scheme 2) with excellent diaster-
eoselectivity (E/Z = ∼40:1).23 Similarly, 33 was also obtained
as a single isomer (60%) using this procedure. With 32 and 33
in hand, their C−H insertion reactions were examined.
Gratifyingly, Rh(II) catalyzed reactions of 32 with benzene
and anisole (4 equiv in PhCF3) provided vulpinic acid (2, 91%)
and pinastric acid (4, 70%) respectively. A similar reaction of
33 with anisole provided 34 (72%) which was treated with BBr3
to furnish methyl isoxerocomate (6, 72%, Scheme 2). The
conversion of vulpinic acid and pinastric acid to pulvinic acid
(1) and 4-hydroxypulvinic acid (3) respectively24a,b is known.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03087.
■
S
Experimental methods and spectroscopic data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: spansare@mun.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada and the Canada
Foundation for Innovation.
C
DOI: 10.1021/acs.orglett.6b03087
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Organic Letters
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D
DOI: 10.1021/acs.orglett.6b03087
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