1-Phenyl-1,2-benziodoxol-3-(1H)-one as Synthon for Phthalide Synthesis through Pd-Free, Base-Free, Sonogashira-Type Coupling Cyclization Reaction

Article abstract of DOI:10.1002/ejoc.201700940

Hypervalent iodine(III) five-membered heterocycles have found broad application as atom-transfer reagents for organic synthesis. Among them, 1-phenyl-1,2-benziodoxol-3-(1H)-one is known as a traditional benzyne precursor, but no further synthetic applicat

Full text of DOI:10.1002/ejoc.201700940

A Journal of
Accepted Article
Title: 1-Phenyl-1,2-benziodoxol-3-(1H)-one as Synthon for Phthalide
Synthesis via Pd-Free, Base-Free, Sonogashira-Type Coupling
Cyclization
Authors: Esteban Mejía and Ahmad Al Barakat Almasalma
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700940
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
1-Phenyl-1,2-benziodoxol-3-(1H)-one as Synthon for Phthalide
Synthesis via Pd-Free, Base-Free, Sonogashira-Type Coupling
Cyclization
Ahmad A. Almasalma,[a] and Esteban Mejía*[a]
Abstract: Hypervalent iodine (III) five-membered heterocycles have
+
130-160
+
°C
PhI
PhI
CO2
found broad application as atom-transfer reagents for organic
synthesis. Among them, 1-Phenyl-1,2-benziodoxol-3-(1H)-one is
known as a traditional benzyne precursor, but no further synthetic
applications have been reported. Herein, we report the first synthetic
application of 1-phenylbenzidoxole to the synthesis of Phthalides
using only CuI as catalyst. High selectivity and yield were achieved
under mild reaction conditions with good functional group tolerance.
During our investigations, the efficiency of different CuI and CuII
catalysts under various reaction conditions were studied. The nature
of the leaving group, the substituents on the substrate and
temperature, play an important role on both yield and selectivity.
Moreover, a plausible mechanistic pathway for this transformation
was proposed based on our observations and previous literature
reports.
I
O
O
Nu-
Nu
CuII
,
COOH
-
+
20 100 °C
1
Scheme 1. Reactivity of 1-phenyl-1,2-benziodoxol-3-(1H)-one.
Phthalides are frequently found in naturally occurring products,
exhibiting a broad spectrum of biological activity,[17] and are also
used as a versatile building blocks in organic synthesis.[18] Some
examples of bio-active phtalides (Figure 1) are n-butylphthalide
(2), which is currently in the market as an antiplatelet drug for
ischemia-cerebralapoplexy,[19] Mycophenolic acid (3), which is in
clinical trials for the prevention and reversal of transplant
rejection and anti-cancer treatments,[20] and the benzalphtalide
derivative 4 which has anti-HIV activity.[21] Most of the recent
studies deal with 3-substituted phthalides due to their wide
range of pharmacological applications. The isolation of these
compounds from natural sources is not cost effective, hence,
their laboratory synthesis by either chemical or biochemical
means has been an active research area.[22]
Introduction
Thanks to their cyclic nature, hypervalent iodine (III) five-
membered heterocycles (benziodoxoles and benziodoxolones)
have considerably higher thermal stability than their acyclic
counterparts, thanks to the bridging of the equatorial and the
apical positions at the hypervalent iodine center.[1] This
enhanced stability made possible the preparation of otherwise
elusive hypervalent iodine derivatives with, fluoride,[2] chloride,[3]
Bromide,[4] peroxide,[5] azido,[6] cyano,[7] methoxy,[8] alkynyl[9] and
trifluoromethyl[10] substituents, which in some cases, notably
ethynyl (EBX)[11] and trifluoromethy (Togni’s reagent),l[12] made
their way into the organic chemist’s tool-box as powerfull atom-
transfer reagents.[13] 1-Phenylbenziodoxole (1)[14] is known
mostly as a benzyne precursor under heating (scheme 1).[15]
Reactions of 1-arylbenziodoxoles with nucleophiles proceed
solely by substitution at the ipso-carbon of the aromatic
benziodoxolone ring, giving aryl iodides and the corresponding
ortho-substituted benzoic acids as major products (scheme 1). [14,
16] Beyond that, the chemistry of these compounds has not been
further developed, and their utilization as synthons in organic
synthesis has not been exploited.
OH
O
HO
2C
O
O
1
2
O
O
3 O 2
3
O
2
O
O
4
Figure 1. Some bio-active phthalide derivatives.
Traditionally, phthalides can be prepared by the reaction of
phthalic anhydride with acetic anhydride or acetic acid at high
temperatures,[23] and by condensation of phthalide phosphate
with aldehydes.[24] An attractive method for the synthesis of
phthalides and isocoumarins is the metal-catalyzed 5-exo-dig or
[a]
A. A. Almasalma, E. Mejía
Leibniz-Institut für Katalyse e. V. an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: Esteban.Mejia@catalysis.de
https://www.catalysis.de/forschung/uni-in-leibniz/polymerchemie-
und-katalyse/
6-endo-dig cyclization of 2-alkynylbenzoic acid/esters which are
[25]
available
or synthesized in situ.[26] One of these approaches,
the Sonogashira-type coupling cyclization reaction, although
having high substrate scopes, requires the use of
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
superstoichiometric amounts of bases.[27] The latter feature,[25b]
limits the substrate scope, especially in total synthesis, since it
requires additional protecting/de-protecting steps.[28]
10, table 1). Interestingly, this selectivity is complementary to the
reported by Lee and co-workers, who selectively obtained the
corresponding 6-membered regioisomers (isocoumarin 7a) at
similar reaction temperatures.[27] Further lowering the amount of
catalysts to 5 mol-% only results in 28 % yield (table 1, entry 11).
By reacting 1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) with
phenylacetylene (5a) using only CuI as catalyst, we have
serendipitously discovered the direct, regioselective synthesis of
phtalides 6, in a Pd-free Sonogashira-like coupling reaction. The
reaction proceeds under mild conditions and does not require
the addition of a base. Coupling reactions of this type are scarce
in the literature,[29] and to the best of our knowledge, this is the
first report of a Sonogashira-type coupling cyclization reaction
which requires neither Pd nor base.[30] Herein, we also report the
first synthetic application of 1-arylbenziodoxoles, namely for the
preparation of phthalides (Scheme 2) under mild conditions with
an excellent functional-group tolerance and high yield.
Table 1. Screening of reaction conditions for the synthesis of phthalides via
coupling cyclization of 1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) with
phenylacetylene (5)
O
I
Ph
O
CuCl
+
O
O
Ph
5a
Solvent, 16h
-PhI
Ph
1
6a
Entry
CuCl
(mol-%)
Ratio 1:5a
Temp.
(°C)
Solvent
Yield (%)[a]
works:
Previous
COOH
I
1[b]
2[e]
3[e]
4
20
1.5 : 1
1.5 : 1
2 : 1
80
80
80
40
40
25
25
25
100
100
40
CH3CN
CH3CN
CH3CN
DCM
>99 (95)[c]
[Cu], [Pd]
Base
+
R
10
78
72
70
63
3
O
10
O
work:
This
O
10
1.5 : 1
1 : 1
I
Ph
R
6
[Cu]
R
5
10
DCM
O
+
6
10
1 : 1
DCM
1
5
7
10
1 : 1
DMSO
CH3CN
DMSO
DMSO
DCM
5
Scheme 2. Phthalide syntheses by Sonogashira-type coupling cyclizations.
8
10
1 : 1
n.d.[d]
63
64
28
9
10
1 : 1
Results and Discussion
10
11
20
1 : 1
The starting material, 1-Phenyl-1,2-benziodoxol-3-(1H)-one (1)
5
1 : 1
was
synthesized
following
published
procedures.[14]
Phenylacetylene 5a was chosen as the model substrate. The
reaction between 1 and 5a in the presence of CuCl (20 mol-%)
in CH3CN at 80 oC produced only phthalide 6a (yield >99 %)
within 2 hours (table 1 entry 1). Using a lower amount of catalyst
(10 mol-%) the desired compound was obtained overnight (16 h)
with a lower yield (78 %) together with 1,4-diphenylbutadiyne,
product of the homocoupling of 5a. (table 1 entry 2). The yield
was not improved after 24 hours under these conditions. An
even lower yield (72 %) resulted when the equivalent amount of
1a was increased (table 1, entry 3). The observed oxidative
dimerization reaction of phenylacetylene (5a), presumably
promoted by the hypervalent iodine (vide infra), was also
observed at 40 oC with 10 mol-% of the catalyst (table 1, entry 4).
Further increase of the equivalents of 1 decreased the yield
even further (table 1, entry 5). Reactions at room temperature
yield only to traces of the product in either DCM, DMSO or
[a] Determined by GC (see supporting information for details) [b] Reaction time
2 hours. [c] Isolated yield in parentheses. [d] Not detected, [e] Reaction time 5
hours.
After screening the catalyst load, solvent, and temperature, we
chose the reaction conditions in entry 4 (table 1) as starting point
for the screening of the influence of the copper source (table 2).
Changing the chloride counter-ion for bromine or iodine resulted
in a decrease of the yield of 6a (table 2, entry 2 and 3). A similar
drop in the yield was observed when nitrate was employed
(table 2, entry 4). Conversely, the use of Cu(NCMe)4PF6 led to
the highest yield (72 %, table 2, entry 5), so it was selected for
the subsequent studies. Interestingly, we did not observe any
conversion using CuII as catalyst (table 2, entry 6).
acetonitrile (table 1, entry 6,
7 and 8). Interestingly, by
increasing the reaction temperature to 100 °C, the
corresponding isocoumarin 7a was produced in small amount
(6 %) together with phthalide 6a, still as the major product (63 %
table 1, entry 9). Almost no changes in the reaction selectivity
were observed with 20 mol-% of catalyst (6a 64 %, 7a 4 %, entry
Table 2. Screening of copper sources and solvents[a]
Entry
Copper source
Solvent
Yield (%)[b]
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
ethynyltrimethylsilane under optimal reaction conditions yield
selectively to the corresponding phthalide 6h, alas, with
moderate yield (table 3, entry 8). Contrariwise, under the same
conditions, no reaction was observed with substrates devoid of
an acetylenic proton, like 1-(Trimethylsilyl)propyne and 1-
(phenyl)propyne. In the former case, increasing of both the load
of the catalyst and the amount of 1 resulted in a desilylation-
annulation reaction, yielding to the isocoumarin 7i (table 3, entry
9).[31] Two more 1-phenylbeziodoxole derivatives bearing iodo
(17) and bromo (18) substituents were synthesized and its
reactivity was tested under the previously described reaction
conditions (Table 3, entries 10 and 11). Unfortunately, these
halogenated substrates did not undergo coupling cyclization with
5.
1[c]
2
CuCl
DCM
DCM
DCM
DCM
DCM
DCM
DMSO
CH3CN
DMF
70
CuBr
50
3
Cul
60
4
CuNO3(PPh3)2
Cu(NCMe)4PF6
Cu(OTf)2
53
5
72
6
n.d.[d]
35
7
Cu(NCMe)4PF6
Cu(NCMe)4PF6
Cu(NCMe)4PF6
Cu(NCMe)4PF6
Cu(NCMe)4PF6
8
20
9
28[e]
n.d. [d]
5[f]
10
11
THF
Table 3. Substrate scope investigation
DCM
O
O
I
Ph
X
O
PF6
Cu(NCMe)4
(10
-
mol
%)
[a] Reaction conditions:1 0.66 mmol, 5a 0.44 mmol, catalyst 0.04 mmol, dry
solvent, argon atmosphere, 16 hours [b] Determined by GC (see supporting
information for details. [c] Table 1, entry 4. [d] Not detected. [e] Isocumarine
(7a, 5 %) was also detected. [f] addition of 1,10-phenantroline (10 mol-%)
O
+
+
O
O
DCM, 40 °C, 16h
-PhI
R
R
X
R
1
5
6
7
Entry
1[c]
Major product
Yield (%)[a]
Ratio
6:7
O
O
From the tested solvents, 1-Phenyl-1,2-benziodoxol-3-(1H)-one
(1) was only soluble in DCM at room temperature, being this
also the solvent in which better yields were obtained. When the
reaction was performed in DMF, isocoumarin 7 was produced
(5 %) along with the desired phthalide 6 (28 %, table 2, entry 9).
No product was detected using THF (table 2, entry 10), perhaps
due to catalysts poisoning by the highly coordinating solvent.
Similarly, addition of 1,10-phenanthroline (10 mol-%) as ligand
resulted in a dramatic yield drop, perhaps due to a blocking of
the catalytic centers (table 2, entry 11). In the absence of the
copper catalyst no product was observed, even after 24 hours at
90 °C. This rules out the possible cross-coupling and cyclization
triggered by the mere thermal decomposition of the hypervalent
iodine reagent.
With the optimal conditions in hand, we investigated the scope
and limitations of the reaction (table 3). Different Arylalkynes,
having electron-donating groups at the para position yield
phthalides as the major product, accompanied by the
corresponding isocoumarins as a minor product (6b-d). Reaction
with 4-(dimethylamino)phenylacetylene (table 3, entry 4). yield
preferably to the corresponding isocumarine 7e, as confirmed by
single-crystal X-ray analysis (see Figure S36 in the supporting
66
93:7
Bu
6b
O
2
63
92:8
O
6c
O
3
4
63
82
92:8
O
OCH3
6d
O
35:65
O
N
7e
O
5
6
55
66
100:0
50:50
information).
Conversely,
the
electron-poor
4’-
O
fluorophenylacetylene produced the corresponding phthalide 6f
as a sole product (Table 3, entry 5). In addition to aryl alkynes,
aliphatic alkynes showed to be reactive under these reaction
conditions, delivering the desired phthalide (6g) only in
moderate yield accompanied by the corresponding isocoumarin
(7g). By increasing the catalyst load (20 mol-%) and the reaction
temperature (up to 80 oC), 7g was obtained as the major product
(table 3, entry 7,). It is noteworthy that only Z isomers were
observed in all cases (as confirmed by comparison with
literature reports). Reaction with the common C2 synthon
F
6f
O
O
6g
H9
C4
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
O
7[b]
90
35:65
phthalide precursor 14 (path D). It has been proposed that under
basic conditions[29a] the O-alkynyl carboxylate intermediate (13)
in the presence of CuI yields to 14 through a 5-exo-dig
cyclization (path D’’). To prove this hypothesis, we synthesized
13 (Ar = Ph) following reported procedures[34] and subjected it to
our reaction conditions. Interestingly, the cyclization of 13 lead
exclusively to isocoumarin 7 in a quantitative yield, which
indicates the crucial role of the five-member ring intermediate 11
in determining the regioselectivity of the resulting product.
O
H9
C4
7g
6h
O
8
26
17
100:0
100:0
O
TMS
O
9[b]
O
O
I
Ph
O
O
O
7i
+
CuI
6
Ar
O
O
O
10
11
n.dC
-
-
I
1
E
A
OH
O
Ph
Ar
14
O
O
n.dC
B’
O
Ar
CuI
Br
+ CuI
OH
I
O
8
I+
Ph
Ph
CuI
D
Ph
B
O
H
9
[a] Isolated yields of the regioisomer mixture; the isomeric ratios 6:7 were
determined by GC and GC-MS (see supporting information for details) [b] 20
mol-% of catalyst; 5 hours, CH3CN as solvent at 80 °C. [C] not detected.
O
OH
5
CuI
O
CuIII
Ar
12
D’
Ar
I+
Ph-I
10
O
Ph
C
Considering our observations and previous literature reports, a
plausible reaction mechanism was proposed (scheme 3). It has
been established that the benziodoxolone ring (i.e. in the Togni’s
reagent) can be activated by the presence of Lewis acids
through coordination of the metal with the carboxyl group.[12b, 32]
Hence, the catalytic cycle shall start with the coordination
between the CuI and 1 (scheme 3, step A), to produce an
activated copper(I) dialkylodonium salt (8). The substrate
activation can be followed either by deprotonation of 5 by the
carboxylate group acting as an internal base (step B’). It guards
close resemblance to the Pd-free Sonogashira reaction reported
by Rothenberg et al., where a single equivalent of a carboxylate
was added as external base.[29b] This leads to the formation of
the corresponding CuI-cuprate and carboxylic acid (9).
Alternatively, intermediate 8 can undergo oxidative addition to
form a CuIII-aryl intermediate (10, step B), analogously to the
reaction of 1-Hydroxy-1,2-benziodoxol-3(1H)-one with a Pd
catalyst in the Suzuki-Miyaura cross-coupling reported by Xia
and Chen.[33] A highly electrophilic d8-species (11) results from
OH
CuIII
11
C'
Ar
O
O
7
+
OH
CuI
O
Ar
Ar
13
Scheme 3. Proposed reaction mechanism.
To assess the influence of the iodoaryl leaving group on the
reaction outcome, two new derivatives of 1,2-benziodoxol-3(1H)-
one were synthesized: 15, substituted with 1,3,5-trifluoro-2-
iodobenzene and 16, with 1-iodo-4-methoxybenzene groups,
respectively. For both compounds, single crystals of X-ray
diffraction quality were obtained (figure 2). Selected bond
distances are presented in table 4.
Both substrates were subjected to optimized cyclization
conditions taking aliquots periodically. The same procedure was
applied to 1. The resulting plot of phthalide (6a) production
versus time (Figure 3) shows how it is clearly (although slightly)
accelerated compared to 1 when the electron-enriched p-
methoxy derivative 16 is used. Conversely, a dramatic decrease
in the reaction rate is observed for the electron-poor 15.
either oxidative addition of the reactive couple
9 or by
deprotonation/ligand exchange from 10 and 5. From 11, two
intermediates can be formed (12 and 13), depending on the
ligands involved in the subsequent reductive elimination (RE)
step. On the one hand, if the RE involves the alkynyl ligand
together with the aryl moiety, 13 will be obtained (path C’). On
the other hand, if the RE takes place between the alkynyl and
the alkoxy ligands (path C), an aryl cuprate ester intermediate
would be formed (12) which, upon intramolecular migratory
insertion of the alkyne into the Ar-Cu bond, yields to the
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
Figure 3. Plot of phthalide (6a) production versus time for the different 1-alkyl-
benziodoxolone derivatives.
Conclusions
In summary, we have developed new method to synthesize
different types of phthalide compounds directly from 1-Phenyl-
1,2-benziodoxol-3-(1H)-one under mild reaction conditions with
good selectivity and yield. Importantly, this investigation explores
and exploits for the first time the latent reactivity of 1-alkyl-
beziodoxolones. The regioselectivity of this transformation was
affected by temperature and the nature of acetylene coupling
partner. The advantages of this method over the reported
alternatives are that neither palladium, nor super-stoichiometric
amounts of base are required, increasing the scope of the
reaction. Moreover, we studied the effect of the iodoalkyl leaving
group on the reaction rate and proposed a plausible reaction
mechanism. Kinetic experiments as well as deeper mechanistic
studies are currently ongoing in our laboratories. We hope that
the present contribution serves as a starting point for the usage
of 1-alkyl-benziodoxolones as building blocks in organic
transformations.
Figure 2. X-ray molecular structure of compounds 15 and 16. Hydrogen
atoms are omitted for clarity. Compound 16 presents two molecules in the
asymmetric cell together with two water molecules (omitted for clarity). The
thermal ellipsoids correspond to 50 % probability. For selected bond distances
see table 4. CCDC deposition numbers: 1558837 (15); 1558836 (16)
Table 4. selected bond distances in Å for compounds 1, 15 and 16
Bond
I-O
1[a]
15
16
2.4787 (52)
2.1063 (53)
2.1187 (35)
2.371 (22)
2.1199 (32)
2.1248 (28)
2.5188 (17)
2.098 (2)
2.131 (2)
I-C1
I-C2
[a] Taken from reference [35]
Experimental Section
General Remarks
This marked difference in reactivity between the three
benziodoxole analogues 1,[35] 15 and 16, follows the same trend
as the lengths of their reactive I-O bond. Compound 15 has the
shortest (hence strongest) bond in the series probably making
the Cu-O bond formation difficult, while 16, possessing the
longest I-O bond, is more prone to dissociate, resulting in an
enhanced reactivity compared to 15. To explain this issue,
further kinetic and mechanistic insights are necessary.
Chemicals, reagents, and solvents were purchased from commercial
suppliers
chromatography (TLC) was performed on silica HSGF254 plates. Melting
points were determined with a digital melting-point apparatus. 1H and 13
and
used
without
further
purification.
Thin-layer
C
NMR spectra were obtained from a solution in CDCl3 using a 400/101
MHz (1H/13C) or 300/75 MHz (1H/13C) spectrometer. Chemical shifts (δ)
are given in ppm and coupling constants (J) in Hz. High-resolution mass-
spectrometry (HRMS) analyses were carried out on an electrospray
ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry
General Procedure for Synthesis of Phthalides (6)
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
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To a dried two-neck round-bottom flask flushed with Argon and equipped
with a reflux condenser, 0.66 mmol of 1-Phenyl-1,2-benziodoxol-3-(1H)-
one (1) were added, followed by addition of the corresponding acetylene
derivative (5) (0.4 mmol), Cu(NCMe)4PF6 (0.04 mmol) and 2 ml of dried
DCM were added. The suspension was stirred for 16h at 40oC. After
cooling, the mixture was poured into DCM (50 mL) and filtrated over
Celite. Evaporation of the solvent under reduced pressure provided the
crude product, which was purified by column chromatography
(EtOAc/hexane 15 %) or recrystallized from hexane to afford the final
product.
3-(4-(dimethylamino)phenyl)-1H-isochromen-1-one (7e)[27]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (301 mg, 0,930 mmol), and 4-
ethynyl-N,N´-dimethylaniline (5e) (90 mg, 0.62 mmol) afforded the
mixture of phthalide 6e and isocoumarin 7e in a ratio of 65:35 as a pale
yellow solid; yield 135 mg (0.5 mmol, 82 %); mp 121–124 oC; 1H NMR
(300 MHz, Chloroform-d) δ 7.89 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 2.1 Hz,
2H), 7.65 (s, 1H), 7.40 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 2.3 Hz, 2H), 6.35
(s, 1H), 3.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 167.70, 150.37,
141.66, 141.16, 134.77, 131.73, 128.62, 125.47, 122.75, 121.21, 119.29,
112.14, 111.86, 108.20, 40.26; HR-MS (ESI-TOF): m/z=266.1175, calcd.
for C17H15NO2 [M+H]+ 266.1173.
(Z)-3-Benzylideneisobenzofuran-1(3H)-one (6a)[36]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (214 mg, 0.66 mmol), and
phenylacetylene (5a) (45 mg, 0.44 mmol) afforded the desired product as
a pale yellow solid; yield 68 mg (0.3 mmol, 70%) mp 82–85oC; 1H NMR
(300 MHz, Chloroform-d) δ 7.95 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 7.2 Hz,
2H), 7.79 (d, J = 7.8 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.59 – 7.51 (m, 1H),
7.42 (t, J = 7.4 Hz, 2H), 7.32 (m, 1H), 6.44 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 167.23, 144.73, 140.77, 134.63, 133.23, 130.28, 129.94,
128.93, 128.58, 125.75, 123.57, 119.97, 107.22, HR-MS (ESI-
TOF):m/z=223.0754, calcd. for C15H10O2[M+H]+ 223.0755.
(Z)-3-(4-Fluorobenzylidene)isobenzofuran-1(3H)-one (6f)[36]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (364 mg, 1.1 mmol), and 1-
ethynyl-4-flurobenzene (5f) (90 mg, 0.75 mmol) afforded 6f as a white
solid; yield 100 mg (0.41 mmol, 55 %); mp 148- 151 oC; 1H NMR (300
MHz, Chloroform-d) δ 7.94 (d, J = 7.7 Hz, 1H), 7.84 (dd, J = 8.9, 5.5 Hz,
2H), 7.79 – 7.69 (m, 2H), 7.59 – 7.51 (m, 1H), 7.10 (t, J = 8.7 Hz, 2H),
6.39 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 167.11, 164.33, 161.02,
144.38, 144.34, 140.64, 134.69, 132.11, 132.00, 129.98, 129.51, 129.46,
125.79, 123.46, 119.89, 116.15, 115.86, 105.99.HR-MS (ESI-TOF): m/z
241.0659, calcd. for C15H9FO2 [M+H]+ 241.0662
(Z)-3-(4-Butylbenzylidene)isobenzofuran-1(3H)-one (6b)[27]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (276 mg, 0.85 mmol), and 1-
butyl-4-ethynylbenzene (5b) (98 mg, 0.57 mmol) afforded a mixture of
the phthalide 6b and isocoumarin 7b in the ratio of 93:7 as white solid;
yield 105 mg( 0.37 mmol, 66%); mp 152- 154 oC; 1H NMR (300 MHz,
Chloroform-d) δ 7.92 (d, J = 7.7 Hz, 1H), 7.74 (dd, J = 15.1, 7.7 Hz, 4H),
7.52 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 6.40 (s, 1H), 2.70 – 2.57
(m, 2H), 1.62 (p, J = 7.8, 7.4 Hz, 2H), 1.38 (h, J = 7.3 Hz, 2H), 0.94 (d, J
= 14.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.28, 144.05, 143.78,
140.80, 134.50, 130.60, 130.22, 129.61, 128.98, 125.60, 123.36, 119.79,
107.34, 77.58, 77.16, 76.74, 35.64, 33.54, 22.47, 14.06. HR-MS (ESI-
TOF): m/z=279.1379, calcd. for C19H18O2 [M+H]+ 279.1378.
(Z)-3-pentylideneisobenzofuran-1(3H)-one (6g)[38]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (324 mg, 1.0 mmol), and 1-
hexyne (5g) (75 mg, 0.67 mmol) afforded a mixture of phthalide 6g and
isocoumarin 7g in a ratio of 50:50 as a colorless oil; yield 89 mg (0.44
mmol, 66%) mp 40-40.5oC; 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d,
J = 8.0 Hz, 1H), 7.64 – 7.62 (m, 1H), 7.45 – 7.39 (m, 1H), 7.33 (d, J = 7.9
Hz, 1H), 6.23 (s, 1H), 2.53 – 2.48 (m, 2H), 1.67 (dt, J = 15.3, 7.5 Hz, 2H),
1.38 (dt, J = 14.7, 7.5 Hz, 4H), 0.95 – 0.93 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 163.18, 158.38, 134.78, 134.30, 129.54, 127.59, 125.28,
119.71, 102.95, 33.29, 29.05, 22.19, 13.85; HR-MS (ESI-TOF):
m/z=203.1066, calcd. for C13H14O2 [M+H]+ 203.1067.
3-(4-(tert-butyl)benzylidene)isobenzofuran-1(3H)-one (6c)[29a]
(Z)-3-((trimethylsilyl)methylene)isobenzofuran-1(3H)-one (6h)[25a]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (230 mg, 0.71 mmol), and 1-
(tert-butyl)-4-ethynylbenzene (5c) (75 mg, 0.47 mmol) afforded a mixture
of the phthalide 6c and isocoumarin 7c in the ratio of 92:8 as white solid;
yield 83 mg( 0.3 mmol, 63%); mp 96- 98 oC; 1H NMR (400 MHz,
Chloroform-d) δ 7.91 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 16.1, 8.2 Hz, 3H),
7.69 (t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H),
6.41 (s, 1H), 1.35 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.21, 151.82,
144.18, 140.75, 134.47, 130.39, 130.02, 129.67, 129.61, 125.86, 125.81,
125.55, 123.37, 119.81, 107.12, 34.83, 31.28. ; HR-MS (ESI-TOF):
m/z=279.1379, calcd. for C19H18O2 [M+H]+ 279.1382.
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (371 mg, 1.15 mmol), and
acetylene ethynyltrimethylsilane (5h) (75 mg, 0.76 mmol) afforded the
phthalide 6h as a yellow oil; yield 30 mg (0.2 mmol, 26 %); 1H NMR (300
MHz, Chloroform-d) δ 7.89 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 3.6 Hz, 2H),
7.56 (dd, J = 7.7, 3.9 Hz, 1H), 5.65 (s, 1H), 0.29 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 167.54, 156.02, 139.44, 134.43, 130.40, 125.22, 125.10,
120.84, 105.50, -0.27.
3-methyl-1H-isochromen-1-one (7i)[39]
(Z)-3-(4-Methoxybenzylidene)isobenzofuran-1(3H)-one (6d)[37]
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (520 mg, 1.6 mmol), and
trimethyl(prop-1-yn-1-yl)silane (5i) (90 mg, 0.8 mmol), Cu (NCCH3)4PF6
(0.16 mmol) afforded the title compound 7i as a white solid; mp 75-77 °C;
yield 25 mg ( 0.15 mmol, 17%); 1H NMR (300 MHz, Chloroform-d) δ 8.25
(d, J = 8.0 Hz, 1H), 7.75 - 7.62 (m, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.34 (d, J
= 7.9 Hz, 1H), 6.26 (s, 1H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
163.14, 154.70, 137.78, 134.88, 129.66, 127.69, 124.99, 120.07,
103.67,19.81.
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1) (331 mg, 1.0 mmol), and 1-
ethynyl -4- methoxybenzene (5d) (90 mg, 0.68) afforded the desired
phthalide 6d and the corresponding isocoumarin 7d in a ratio of 92:8 as a
white solid; yield 108 mg (0.42 mmol, 63%); mp 108–110 °C; 1H NMR
(300 MHz, Chloroform-d) δ 7.92 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.9 Hz,
2H), 7.71 (d, J = 7.8 Hz, 2H), 7.55 – 7.47 (m, 1H), 6.94 (d, J = 8.9 Hz,
2H), 6.38 (s, 1H), 3.85 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.41,
159.92, 143.20, 140.92, 134.49, 131.83, 129.42, 126.01, 125.65, 123.22,
119.64, 114.41, 107.09, 55.47. HR-MS (ESI-TOF): m/z=253.0859 calcd.
for C16H12O3 [M+H]+ 253.0860.
2-(phenylethynyl)benzoic acid (11, Ar = Ph)
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
This intermediate was synthesized following the method reported by
The reaction of 2-iodobenzoic acid (1.00 g, 4.03 mmol), Oxone© (1.6g,
2.6 mmol), conc. H2SO4 (total 3.2 mL), and 1,3,5-trifluorobenzene (0.6
mL) according to the general procedure, afforded 1.1 g (71 %) of 15,
isolated as a white crystalline solid, mp 240 - 242 °C; 1H NMR (300 MHz,
Chloroform-d) δ 8.40 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.53 (t,
J = 7.7 Hz, 1H), 7.06 - 6.85 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 167.18,
136.73, 134.58, 133.49, 133.19, 132.81, 131.95, 131.62, 131.31, 127.05,
125.32, 115.59; 19F NMR (282 MHz, Chloroform-d) δ -90.75 - -91.03 (m),
-97.02 (p, J = 9.1 Hz).
1
Gabriele et al.[34], H NMR (300 MHz, Chloroform-d) δ 8.15 (dd, J = 7.9,
1.1 Hz, 1H), 7.70 (dd, J = 7.7, 1.0 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.44 (td, J
= 7.7, 1.4 Hz, 1H), 7.31 (dd, J = 5.1, 2.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.45, 134.33, 132.75, 131.90, 131.54, 130.64, 128.78,
128.53, 128.13, 124.50, 123.24, 95.54, 88.14, NMR data matched with
the reported values.
3-phenyl-1H-isochromen-1-one (7a)
1-(4-methoxyphenyl)-1,2-benziodoxol-3-(1H)-one (16).
In a dry two-neck round-bottom flask charged with a magnetic stirrer and
flushed with argon, 100 mg (0.45 mmol) of 2-(phenylethynyl) benzoic
acid, 17 mg (0.04 mmol) of Cu(NCMe)4PF6, and 2 ml of dry DCM were
added. The mixture was heated at 40 °C for 5 hours. After cooling, the
mixture to room temperature, it was poured into DCM (50 mL) and
filtrated over Celite. Evaporation of the solvent under reduced pressure
provided the crude product, which was purified by column
chromatography (EtOAc/hexane 15 %), affording the title compound (7a)
as a white solid mp 88-90 °C, yield 90 mg (90 %, 0.4 mmol); 1H NMR
(400 MHz, Chloroform-d) δ 8.33 - 8.24 (m, 1H), 7.86 (dd, J = 8.1, 1.6 Hz,
2H), 7.70 (td, J = 7.7, 1.3 Hz, 1H), 7.50 - 7.40 (m, 5H), 6.92 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 162.28, 153.55, 137.49, 134.88, 131.92,
129.97, 129.58, 128.83, 128.14, 126.02, 125.22, 120.50, 101.82.
The reaction of 2-iodobenzoic acid (1.00 g, 4.03 mmol), Oxone© (1.6 g,
2.6 mmol), H2SO4 (total 3.2 mL), and anisole (0.75 mL) according to the
general procedure afforded 0.8 g (62 %) of 16, isolated as brown
crystalline solid, mp 212-214 °C; 1H NMR (300 MHz, Chloroform-d) δ
8.37 (dd, J = 7.5, 1.7 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.52 (t, J = 7.8 Hz,
1H), 7.37 (t, J = 6.9 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 7.8 Hz,
1H), 5.28 (s, 0H), 3.91 (s, 3H);13C NMR (75 MHz, CDCl3) δ 166.63,
163.09, 139.14, 133.51, 132.71, 130.69, 125.90, 117.79, 116.09, 104.21,
55.78.
5-iodo-1-Phenyl-1,2-benziodoxol-3-(1H)-one (17)
General Procedure for Preparation of 1-Arylbenziodoxones (1, 15,
16)
The reaction of 2,5 diiodobenzoic acid (0.5 g, 1.33 mmol), Oxone©
(0.53g, 0.86 mmol), conc. H2SO4 (total 1.6 mL), and benzene (0.4 mL)
according to the general procedure, afforded 420 mg (97 %) of 17,
isolated as white solid, mp 224 - 226oC, 1H NMR (300 MHz, Chloroform-
d) δ 8.73 (s, 1H), 7.99 (dd, J = 8.1, 1.2 Hz, 2H), 7.78 (t, J = 7.5 Hz, 1H),
7.67 (dd, J = 8.6, 2.1 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 6.42 (d, J = 8.6 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 142.53, 141.84, 137.26, 133.01,
132.16, 127.84, 115.70, 114.99, 97.60.
The finely crushed, solid 2-iodobenzoic acid (4.03 mmol) was mixed with
powdered Oxone© (potassium peroxymonosulfate) (2.6 mmol) in a 100
mL round-bottom flask and stirred without solvent for 5 min using a
magnetic stirrer until a homogeneous mass was formed. Then the
reaction mixture was cooled with ice to 5 °C and, under magnetic stirring,
concentrated H2SO4 (total 3.2 mL) was added via syringe in 0.2 mL
portions to the reaction mixture. After addition of each portion of H2SO4,
the reaction mass was mechanically shaken to achieve better mixing; the
color of the resulting mass can vary from pale yellow to brown depending
on the intensity of mixing. After all H2SO4 was added, the magnetic
stirring was continued for 30min at room temperature, the mixture was
cooled to 5 °C, and CH2Cl2 (4 mL) and the corresponding ArH (10 mmol)
was added. The magnetic stirring of the resulting mixture was continued
at 5 °C for 1 h and then at room temperature for 2 h. The reaction mixture
was cooled again to 5 °C and CH2Cl2 (10 mL), followed by a saturated
aqueous solution of NaHCO3 were added in small portions until pH 8.0.
The organic layer was separated, and the aqueous layer was additionally
extracted with CH2Cl2 (10 mL). The organic extracts were combined and
dried with Na2SO4, the solvent was evaporated, and the crystalline
product was dried in vacuum. Additional purification of products can be
performed by crystallization from water.
5-bromo-1-Phenyl-1,2-benziodoxol-3-(1H)-one (18)
The reaction of 5-bromo-2-iodobenzoic acid (1 g, 3.05 mmol), Oxone©
(1.12 g, 6.4 mmol), conc. H2SO4 (total 3.2 mL), and benzene (0.8 mL)
according to the general procedure, afforded 785 mg (64%) of 18,
isolated as off white solid, mp 234 - 236oC, 1H NMR (300 MHz,
Chloroform-d) δ 8.43 (s, 1H), 8.02 (d, J = 9.2 Hz, 2H), 7.76 (t, J = 8.0 Hz,
1H), 7.59 (t, J = 7.6 Hz, 2H), 7.42 (dd, J = 8.7, 2.3 Hz, 1H), 6.52 (d, J =
8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 137.35, 136.45, 135.69, 132.88,
132.11, 128.11, 125.90, 115.03, 114.46.
Acknowledgements
Thanks to Dr. A. Spannenberg for the crystallographic
measurements and assistance. Financial support by the German
Academic Exchange Service, DAAD (Leadership for Syria
Program) is gratefully acknowledged.
1-Phenyl-1,2-benziodoxol-3-(1H)-one (1)
The reaction of 2-iodobenzoic acid 1 (1.00 g, 4.03 mmol), Oxone (1.6g,
2.6 mmol), H2SO4 (total 3.2 mL), and benzene (0.8 mL) according to the
general procedure afforded 1g (77%) of 1, isolated as an off-white
crystalline solid, mp 221−222 °C; 1H NMR (300 MHz, Chloroform-d) δ
8.24 (dd, J = 7.5, 1.7 Hz, 1H), 7.97 (dd, J = 8.1, 1.2 Hz, 2H), 7.65 (t, J =
7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 6.9 Hz, 1H), 7.26 (t, J =
6.9 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
166.74, 137.21, 133.50, 133.41, 132.48, 132.42, 131.72, 130.45, 126.36,
115.67, 115.37.
Keywords: C-C coupling • Carbocycles • Hypervalent
Compounds • Iodine •Copper•
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10.1002/ejoc.201700940
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Hypervalent Iodine
Ahmad A. Almasalma, Esteban Mejía*
Page No. – Page No.
1-Phenyl-1,2-benziodoxol-3-(1H)-one
as Synthon for Phthalide synthesis
via Pd-Free, Base-Free Sonogashira-
Type Coupling Cyclization
Text for Table of Contents
Herein, we report the first synthetic application of 1-Phenyl-1,2-benziodoxol-3-(1H)-one to the synthesis of phthalides using CuI as
catalyst. This unprecedented transformation exploits for the first time the latent reactivity of this somehow neglected kind of
hypervalent iodine derivatives. The advantages of this method over the reported alternatives are that neither palladium, nor super-
stoichiometric amounts of base are required.
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