Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins

Article abstract of DOI:10.1039/c8sc01537f

The cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates. A new organometallic species in the heterocyclization provides an opportunity to synthesize heterocycles that are difficult to obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position. This new type of metalated isocoumarin provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decomposition of terminal alkynes, respectively. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallographic analysis. The theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the atomic characters of indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied to organic synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.

Full text of DOI:10.1039/c8sc01537f

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DOI: 10.1039/C8SC01537F
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Selective Oxymetalation of Terminal Alkynes via 6-Endo
Cyclization: Mechanistic Investigation and Application to the
Efficient Synthesis of 4-Substituted Isocoumarins
Received 00th January 20xx,
Accepted 00th January 20xx
Yuji Kita,a Tetsuji Yata,a Yoshihiro Nishimoto,*b Kouji Chibac and Makoto Yasuda*a
DOI: 10.1039/x0xx00000x
Cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles
because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates.
A new organometallic species in heterocyclization provides an opportunity to synthesize heterocycles that are difficult to
obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds
with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position. This new type of
metalated isocoumarins provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important
pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of
terminal alkynes while boron or the other metals such as Al, Au, Ag caused 5-exo cyclization or decomposition of terminal
alkynes, respectively. Metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray
crystallographic analysis. Theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-
endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under
kinetic control. Investigation of electrostatic potential maps suggested that the differences in the atomic characters of
indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied
to organic synthetic reactions. Halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins
bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides
gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was
accomplished.
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spontaneously forms a carbon-metal bond and a heterocyclic
framework and produces organometallic intermediates leading
to target heterocycles via appropriate synthetic reactions such
as cross coupling. These features allowed us to directly access
various substituted heterocycles from simple organic substrates.
Introduction
Heterocyclic compounds have attracted much attention in
pharmaceutical chemistry as well as in photochemistry, and also
play a pivotal role as building blocks in organic synthetic
transformation.1 Therefore, a novel efficient synthetic method
for heterocyclic frameworks is highly desired in various fields of
chemistry. Many well-established methods are available in the
literature.2 Heterocyclization of ω-heteroatom-substituted
alkynes using π acidic metal salts is undoubtedly a powerful
strategy for the preparation of heterocycles (Scheme 1).3 This
addition reaction uses readily available alkynes as a starting
material. Furthermore, metal salt-mediated cyclization
Scheme 1 Metal Salt-Mediated Heterocyclization of ω-Heteroatom-substituted
Alkynes.
Various heteroatom-containing alkynes have been
investigated for use in the synthesis of heterocyclic compounds
using π acidic metal salts. Alkyne
and is a feasible and beneficial substrate to obtain 5- or 6-
membered oxacyclic alkenylmetals (Scheme 2A). When is
treated with a metal salt (MX), oxymetalation proceeds to
afford heterocyclic compounds through either 5-exo or 6-endo
cyclization (Type exo or endo). Considering that the structure of
A includes a carbonyl moiety
a.Department of Applied Chemistry, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail:
yasuda@chem.eng.osaka-u.ac.jp
A
b.Frontier Research Base for Global Young Researchers Center for Open Innovation
Research and Education (COiRE), Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail:
nishimoto@chem.eng.osaka-u.ac.jp
A
bears either an internal (R = alkyl, aryl etc.) or a terminal
c. Material Science Division, MOLSIS Inc., 1-28-38 Shinkawa, Chuo-ku, Tokyo 104-
0033, Japan.
† Electronic Supplementary Information (ESI) available: Additional experimental
data, characterization, calculation data and experimental details. See
DOI: 10.1039/x0xx00000x
alkyne (R = H), oxymetalation can be distinguished by four types
of reaction courses: Type exo-i, Type exo-t, Type endo-i, and
Type endo-t. In Type exo-i and exo-t, the furan frameworks
B
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and
isomerization of zwitterion intermediates.4,5 On the other hand, the cyclization showed low selectivity.7,9 FDoOr It:h1e0.1a0b3o9v/Ce8rSeCa0s1o53n7sF,
Type endo-i and endo-t lead to 1H-isochromen derivatives and there is no report of a preparation method for species via Type
via elimination of R’X from zwitterion intermediates.6,7 Among endo-t in contrast to the cases of Types exo-i, exo-t, and endo-i,
these four types, only Type endo-t is kinetically unfavorable due for which target organometallic compounds ( ) are well
to an unstable cationic transition state via an anti-Markovnikov established.4b,5a,6c,6e If the reaction course of oxymetalation is
addition manner (Scheme 2B). Furthermore, recent theoretical realized from to
in Type endo-t,10 various 6-membered
researches about the regioselectivity of cyclization revealed heterocycles based on , which have been difficult to obtain and
C have a metal carbenoid moiety and are obtained via the penalty, but the exo cyclization was not disturbed, and, thus,
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D
E
E
B, C, D
A
E
E
that nucleophilic cyclization of alkynes displays exo selectivity remain unknown, should be synthesized. Therefore, the
intrinsically.8 On the other hand, Lewis acidic metals can establishment of a strategy for Type endo-t is an important
promote endo cyclization by decrease of the stereoelectronic challenge in heterocyclic chemistry.
Scheme 2 (A) Four Types of Metalated Heterocycles from Oxymetalation of Alkyne
Type Endo-t.
A Including Carbonyl Moiety. (B) Comparison of Transition States of Type Exo-t with
Isocoumarins are an important class of oxygen-containing
heterocycles that exhibit a wide range of pharmacological
properties.11 Thus, the development of their general synthetic
method has attracted much attention. The reaction of Type
endo would be a powerful tool for the synthesis of isocoumarins
(Scheme 3A). In fact, reports have described the oxymetalation
of 2-alkynylbenzoate
1 (R = alkyl, alkenyl, aryl) for Type endo-i
and application to the synthesis of isocoumarins.6a,6b,6e Recently,
Blum reported an excellent method for the construction of 4-
borylated isocoumarins by oxyboration of the internal alkynes
1
in the Type endo-i reaction course (Scheme 3B).6e However,
terminal alkyne
1 (R = H) gave only a 5-exo cyclization product
according to the Markovnikov rule (blue path in Scheme 3C).6e
This result prompted us to explore oxymetalation of the
terminal alkynes 1 for Type endo-t. Oxymetalation of Type endo-
t provides 3-unsubstituted and 4-substituted isocoumarins that
are seldom investigated due to the lack of synthetic methods,12
and limited substituents have been introduced at the 4-position Scheme 3 (A) Oxymetalation of 2-Alkynylbenzoate
1 Followed by Transformation
for the Construction of Isocoumarins. (B) Previously Reported Oxyboration of
despite well-known beneficial significant bioactivity Internal Alkynes to Generate 4-Borylated Isocoumarins. (C) Oxymetalation of
Terminal Alkynes, Reported Oxyboration for 5-Membered Compounds (Blue Path),
characteristics such as antitumor,13 antiangiogenic,14 and Our Developed Oxymetalation for 6-Membered Compounds (Red Path).
antifungal,15 and antibiotic.16
Our group developed the indium or gallium salt-mediated
carbometalation of simple terminal alkynes with silyl ketene
acetals by utilizing their high π electron affinity and moderate
Lewis acidity.17 In this context, we investigated the Type endo-t
reaction of 2-ethynylbenzoate using indium or gallium trihalides
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for the synthesis of corresponding metalated isocoumarins. In effect was examined on oxyindation using InI3. Dichloroethane
View Article Online
DOI: 10.1039/C8SC01537F
this report, we successfully achieved a 6-endo selective as a solvent provided a good yield while chlorobenzene and
oxymetalation of terminal alkynes and fully characterized the hexane afforded only moderate yields (entries 18-20). The
target organometallic species E1 via NMR study and X-ray yields were appreciably decreased in CH3CN and THF (entries 21
crystallographic analysis. Furthermore, the intermediate F1 was and 22) probably because the coordination of these solvents to
isolated, which revealed that oxymetalation proceeds via the InI3 decreased the Lewis acidity. Finally, InI3 was the most
zwitterion intermediate F1, and elimination of the alkyl halide effective Lewis acid, and, therefore, we chose entry 3 to
gives the target product E1 (Scheme 4). While benzopyrylium represent the optimal conditions.
species such as
the proposed catalytic oxymetalation cycle,10a,18 the isolation of
species
is a challenge issue.10e,10f,19 To the best of our
knowledge, F1 is the first example of a fully characterized
benzopyrylium intermediate . In addition, we performed full
F are known as highly reactive intermediates in
Table 1 Effect of Lewis Acids on the Oxymetalation of 2-Ethynylbenzoate 1aa
F
F
disclosure of the mechanism by combining experimental data
and theoretical calculation. These mechanistic investigations
were consistent with the achievement of isolation of the
zwitterion intermediate and demonstrated that its stability is a
crucial point in this remarkable cyclization regioselectivity.
Entry
1
MXn
InCl3
InBr3
InI3
GaBr3
GaI3
AlCl3
AlI3
BBr3
TiCl4
PdCl2
CuBr2
FeBr3
AuCl3
AuCl
AgOTf
AuCl/AgOTf
InI3
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ClCH2CH2Cl
ClC6H5
Yield of 2 (%)b
13
2c
82 (77% D)
79 (91% D)
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18
19
20
21
22
30
77
0
0
0
0
0
0
0
Scheme 4 Oxyindation of Alkynes for Synthesis of Isocoumarin Framework via a
Zwitterion Intermediate.
Results and discussion
Optimization of reaction conditions
First, we examined the effect of Lewis acids on oxymetalation
using methyl 2-ethynylbenzoate 1a (Table 1). The reaction of 1a
with metal halides was carried out in toluene at 50 °C, and the
reaction mixture was quenched with acetic acid. The reaction
7
5
31
18
61
78
57
57
17
0
using InCl3 afforded the target isocoumarin
2 via 6-endo
cyclization, albeit in a low yield (entry 1). Gratifyingly, InBr3 and
InI3 mediated oxymetalation smoothly proceeded in 6-endo
InI3
InI3
InI3
InI3
cyclization fashion to give
these cases, the reaction mixture was quenched by deuterated
acetic acid to afford bearing deuterium at the 4-position. We
2 in high yields (entries 2 and 3). In
hexane
CH3CN
THF
2
InI3
did not observe an isocoumarin bearing deuterium at the 3-
position which could be produced through the generation of
indium acetylide20 followed by Lewis acid mediated
cycloaddition. The reaction using InI3 showed a higher ratio of
D/H than the case of InBr3. This result suggested the more
a
Reaction conditions: 1a (0.5 mmol), Lewis acid MXn (0.5 mmol), solvent (1 mL),
50 °C, 24 h. b The yield of 2 was determined by 1H NMR. c The reaction mixture was
quenched by CH3CO2D (30 equiv, 5 min) and a subsequent addition of H2O (10 mL).
d35 °C
efficient generation of the alkenylmetal intermediate
X in the
Mechanistic Investigation
case of InI3. Gallium salts were also suitable for the 6-endo
cyclization of 1a, and GaI3 gave a high yield (entries 4 and 5). On
the other hand, typical Lewis acids such as AlCl3, AlI3, BBr3 and
TiCl4 were ineffective (entries 6-9). Transition metal salts such
as PdCl2, CuBr2 and FeBr3 provided no target product and
resulted in a decomposition of 1a (entries 10-12). Alkynophilic
π-acids such as gold and silver salts were subjected into the
present cyclization. It was found that AuCl3, AlCl, AgOTf and
AuCl/AgOTf resulted in low yields (entries 13-16). A decrease in
yield was observed at lower temperature (entry 17). The solvent
1
To gain insight into the reaction mechanism, we used H NMR
spectroscopy to monitor the oxyindation. When 2-
alkynylbenzoate 1a was mixed with InI3 in CDCl3 at -30 °C, no
reaction occurred. At -5 °C, some amount of a new product was
observed (See Fig. S1 and S2 in ESI†). At room temperature, a
large amount of white precipitation was formed. This white
solid was also obtained in the reaction of 1a with InI3 in toluene
at room temperature (Eq. 1). X-ray crystallographic analysis
revealed that the white solid was a 6-membered oxacycle
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probability (CCDC 1576342). Selected bond lengths (Å) and angles (deg): C1-O1 =
zwitterion
3 bearing a carbon-indium bond (Fig. 1). The bond
1.211(4), C1-O2 = 1.367(5). C2-In = 2.162(3), In-I1 = 2.7148(4), In-I2 = 2.7005(4),
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In-O5 = 2.318(3), In-O6 = 2.371(3), O5-In-O6 = 175.44(10), I1-In-C2 = 116.70(11),
DOI: 10.1039/C8SC01537F
lengths of two carbon-oxygen bonds (C1-O1 = 1.267 Å, C1-O2 =
1.298 Å) in the zwitterion existed between a C-O double bond
C2-In-I2 = 125.51(11), I2-In-I1 = 117.621(12).
3
(1.203 Å) and the single bond (1.377 Å) of a typical isocoumarin
derivative,21 and, thus, the positive charge was delocalized in an
ester moiety. The indium atom was coordinated with three
iodines and showed a distorted tetrahedral structure with a
formal negative charge. The formed zwitterionic alkenyl indium
Theoretical Calculation for Oxyindation
A mechanism for the formation of the target isocoumarin 4a
using InI3 is proposed in Scheme 5 wherein InI3 is coordinated
by the alkyne moiety in
cyclization to give the zwitterion intermediate
the elimination of MeI affords 4a
5
, oxyindation proceeds via 6-endo
3
, and, finally,
3
was heated at 50 °C in toluene to give a neutral alkenylindium
.
product 4a, quantitatively by elimination of MeI (Eq. 2).
Although a suitable single crystal of 4a for X-ray analysis was not
obtained, we successfully conducted X-ray diffraction analysis
of nitro-substituted alkenylindium 4b produced from the 2-
ethynyl-5-nitrobenzoate 1b (Eq. 3 and Fig. 2). The bond lengths
of C1-O1 (1.211 Å) and C1-O2 (1.367 Å) were similar to those of
reported isocoumarin framework.21 The indium complex 4b
displayed trigonal bipyramidal coordination with two THF
ligands in axial positions. These results indicated a two-step
pathway including a fast cyclization and a slow elimination of
Scheme 5 A Proposed Mechanism for Formation of the Isocoumarin 4a
.
MeI during the 6-endo oxyindation processing from 1 to 4.
Density functional theory (DFT) calculations were
performed to more thoroughly consider the reaction
mechanism. Calculation of the potential energy profile for 6-
endo cyclization (red) shows in Fig. 3. We selected 1a and In2I6
as starting materials because InI3 exists in a dimer fashion.22 The
coordination of two 1a to In2I6 dissociates the aggregation of
InI3 to give the complex
moiety and carbonyl group of 1a (Fig. S3 in ESI† shows detail
mechanism of generating the complex from 1a and In2I6).
Dissociation of the carbonyl oxygen atom generates complex
7, in which InI3 is chelated by the alkyne
7
5
,
in which InI3 directly activates the alkyne moiety. In this
pathway, the anti-addition of InI3 and the ester moiety into the
alkyne moiety proceeds in a concerted mechanism to provide a
stable 6-membered zwitterion intermediate 3. Elimination of
MeI proceeds in an intermolecular fashion, because the
intramolecular elimination of MeI requires a very unstable
intermediate (Fig. S4 in ESI† shows the potential energy profile
for the intramolecular elimination of MeI). Two zwitterions
aggregate in a head-to-tail fashion to give complex 8, and then
the elimination step starts from 8. Intermolecular nucleophilic
substitution of the methyl group by I- proceeds in an SN2-
mechanism to give complex 10 and MeI, and then a subsequent
elimination of MeI affords the target product 4a 23
. A carbonyl
group of 4a coordinates to the indium atom of another 4a to
give the stable dimeric product 13. The activation energy of the
Fig. 1 The X-ray crystallographic structure of zwitterion intermediate
3 with the
thermal ellipsoids shown at 50% probability (CCDC 1579824). Selected bond
lengths (Å): C1-O1 = 1.267(9), C1-O2 = 1.298(11), C2-In = 2.171(7), In-I1 = 2.7392(8),
In-I2 = 2.7219(8), In-I3 = 2.6915(7).
elimination step (
8
to TS2-6-endo, 28.7 kcal/mol) is much higher
to TS1-6-endo, 19.7
than that of the cyclization step (
7
kcal/mol).24 Therefore, the elimination of MeI is a rate-
determining step. We also calculated the 5-exo cyclization
pathway (blue) to investigate the regioselectivity. This process
proceeds via concerted cyclization wherein the 5-membered
zwitterion
version . Intermolecular elimination of MeI takes place in an
SN2-manner ( to 11). The energy level of the transition state
6 is much more unstable than the 6-membered
3
9
(TS2-5-exo) shows the highest energy level, and it is higher even
than the energy profile of the 6-endo cyclization process (red)
due to the instability of the 5-membered zwitterion 6.
Fig. 2 The X-ray crystallographic structure of isocoumarin including a carbon-
indium bond at the 4-position, 4b·(THF)2, with the thermal ellipsoids shown at 50%
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40
30
20
10
0
-10
-20
-30
Reaction Process
Fig. 3 The energy profiles of 6-endo and 5-exo oxyindations and 3D molecular structures of transition states. DFT calculation was performed using wB97XD/6-31+G (d,p)
for C, H, and O and using DGDZVP for In and I. Solvation effect was introduced using the IEFPCM model, an d toluene was used as a solvent.
In order to clarify the unique 6-endo cyclization selectivity mediated oxyindation and found the same pathway with the
of oxyindation, the energy profiles of the two cyclization case of InI3 (See Fig. S5 in ESI†). The activation energy of
manners were compared. The activation energy of 5-exo elimination step in the cases of InCl3 is higher than that of InI3
cyclization is lower (
6-endo cyclization (
exo cyclization is reversible because the activation energy for
the elimination of MeI ( to TS2-5-exo, 21.9 kcal/mol) is much the differences in stability between the 6-membered zwitterion
higher than that of retro-cyclization (
kcal/mol) due to the instability of the zwitterion
7
to TS1-5-exo, 15.5 kcal/mol) than that of because of low nucleophilicity of Cl-, and it caused much less
to TS1-6-endo, 19.7 kcal/mol). However, 5- reactivity of InCl3 (entry 1, Table 1).
The remarkable regioselectivity of oxyindation is ascribed to
7
9
6
to TS1-5-exo, 9.3
. On the other
3
6
and the 5-membered
, and this difference in stability originates from the aromaticity
6. Zwitterion 3 is much more stable than
6
hand, during 6-endo cyclization, both activation energies of of these compounds, although ring strain is also a consideration.
elimination ( to TS2-6-endo, 28.7 kcal/mol) and retro- To verify this possibility, the aromaticity of zwitterions was
cyclization (
to TS1-6-endo, 23.0 kcal/mol) are high because the evaluated via NICS(1)25 (Fig. 4), and the 6-membered compound
6-membered zwitterion intermediate is thermodynamically showed a higher level of aromaticity than that of
stable. This result indicates that 6-endo cyclization is irreversible
and the most thermodynamically stable form of intermediate
8
3
3
3
6.
8
is exclusively generated to provide the target product 4a, which
is consistent with the successful isolation of the zwitterion
intermediate
3 (Fig. 1). Therefore, oxyindation proceeds under
thermodynamic control to afford the stable 6-membered
product 4a. We also calculated an energy profile of InCl3-
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result of comparison between these three pathways showed
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-
DOI: 10.1039/C8SC01537F
that the most probable path was the use of [Cl2Bcat] (Details of
the comparison are shown in ESI†).
Fig. 4 NICS(1) values of 6-membered zwitterion
3 and 5-membered zwitterion 6.
The aromaticity was calculated using B3LYP/6-31G (d,p) for C, H, and O and using
DGDZVP for In and I for their optimized structures.
Theoretical Calculation for Oxyboration
Blum and co-workers reported that oxyboration of 1a using B-
chlorocatecholborane (ClBcat) gave a 5-membered product6e
rather than the 6-membered version (Scheme 6). ClBcat is
coordinated by the carbonyl moiety of 1a. Then, oxyboration
proceeds via 5-exo cyclization to give the zwitterion
intermediate 16, and the elimination of MeCl gives the target
product 18. We also performed DFT calculation of oxyboration
to investigate the striking change in the regioselectivity
between oxyboration and oxyindation. First, the calculation of
Scheme 6 A Proposed Mechanism for Oxyboration.
The total reaction profile of oxyboration is described in Fig.
5 and 6. In that profile, 5-exo cyclization from 1a and 2ClBcat to
16 has an activation energy (27.9 kcal/mol) that is lower than
that of 6-endo cyclization (1a and 2ClBcat to 15, 34.4 kcal/mol).
The chloride moiety of zwitterion 16 coordinates to another
ClBcat to provide complex 19. The chloride transfer process (19
to 20) has a low energy barrier (5.8 kcal/mol), and [Cl2Bcat]- is
generated rapidly. Cl in [Cl2Bcat]- approaches the methyl group
oxyboration was performed for
a similar oxyindation
mechanism via concerted cyclization and SN2-type elimination
of MeCl from aggregated zwitterion intermediates (see Fig. S6
in ESI†). We considered another possibility for the elimination
step, because recent theoretical investigation of ClBcat-
mediated heterocyclization has shown other mechanisms,26
whereby the Me group is attacked either by dissociated
chloride26a or by [Cl2Bcat]-26b. Thus, we considered these
additional two plausible elimination steps assisted either by
free Cl- or [Cl2Bcat]- (See Fig. S7 in ESI† and Fig. 5 and 6). The
in the ester moiety (20
→21→22), and an elimination of MeCl
(22 to 23) in the SN2-mechanism occurs to give 5-membered
product 18. The activation energy of the elimination of MeCl (22
to TS3-5-exo) is 20.7 kcal/mol, which allows the elimination of
MeCl to proceed smoothly to give the final product 18. The fast
elimination step allows oxyboration to proceed under kinetic
control to accomplish the 5-exo selective cyclization.
40
30
20
10
0
-10
-20
-30
Reaction Process
Fig. 5 The energy profiles of 5-exo and 6-endo oxyborations. DFT calculation was performed by wB97XD/6-31+G (d,p) for C, H, O, B, and Cl. Solvation effect was
introduced using the IEFPCM model, and toluene was used as a solvent.
6 | J. Name., 2012, 00, 1-3
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View Article Online
DOI: 10.1039/C8SC01537F
Fig. 6 3D molecular structures of transition states in oxyborations.
Comparing the Transition State of the Cyclization Step in
Oxyindation with That in Oxyboration Based on an Electrostatic
Potential Map
between indium and boron atoms imparts a significant amount
of influence to the regioselectivity of oxymetalation.
The significant difference between oxyindation and oxyboration
was investigated because each showed a characteristic energy
profile, particularly for the cyclization step. The energy barrier
of cyclization in oxyindation (6-endo: 19.7 kcal/mol, 5-exo: 15.5
kcal/mol) is much lower than that of oxyboration (6-endo: 34.4
kcal/mol, 5-exo: 27.9 kcal/mol). Therefore, the electrostatic
potential maps for the transition states of cyclization (TS1-6-
endo and TS1-5-exo) were calculated (Fig. 7). The value of Vmin
,
which represents the most negative surface electrostatic
Fig. 7 Electrostatic potential maps were calculated on the 0.001 au isosurface of
potential, was investigated to evaluate the degree of electron density for optimized structures of the transition states of oxyindation
(left) and oxyboration (right). The potential is depicted by a color gradient from
localization for
a
negative charge.27 The Vmin of the the most negative (red) to the most positive (blue) value (kcal/mol). Vmin
represents the most negative surface electrostatic potential.
organoindium species (left, in Fig. 7) was less negative than that
of boron (right, in Fig. 7), which showed that the negative
charge was delocalized in the transition state of oxyindation
compared with oxyboration. The value of Vmax, which is the
most positive surface electrostatic potential, was also
calculated and was less affected by the differences in the metals
(see Table S2 in ESI†). The polarizability of the indium, boron
and heteroatoms binding to a metal explained these results.
Indium and iodine atoms have large polarizability (αIn = 69 a.u.,
αI = 35.1 a.u.),28 and the increasing negative charge in the TS1
of oxyindation was efficiently delocalized to stabilize the
zwitterionic TS1-6-endo.29 On the other hand, boron, chlorine
and oxygen atoms have smaller polarizability (αB = 20.5 a.u., αCl
= 14.7 a.u., αO = 6.04 a.u.)28 than indium and iodine atoms, so
that TS1-5-exo becomes unstable due to the localization of a
negative charge. The difference in the fundamental features
Summary of DFT Calculation
In oxyindation (Fig. 8A), the activation energy of 5-exo
cyclization is much lower than that required for the elimination
of MeI to lead reversible 5-exo cyclization. Therefore, the
thermodynamically stable 6-membered zwitterion
selectively produced to accomplish the remarkable 6-endo
selectivity. The elimination step from is a rate-determining
step that provides the target metalated isocoumarin 4a. On the
other hand, the energy barrier for cyclization in oxyboration (Fig.
8B) is higher than that for the elimination of MeCl and the
cyclization step is a rate-determining step, which leads to
irreversible 5-exo cyclization to afford the 5-membered product
18 under kinetic control. Therefore, activation energies of
cyclization as well as elimination are important factors to
determine the regioselectivity in cyclization.
3 was
3
Fig. 8 The summarized results of DFT calculation.
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Application to the Synthesis of Isocoumarin Derivatives
were obtained from an isocoumarin that included a carbon-
indium bond by utilizing palladium-catalyzed cross coupling.
View Article Online
DOI: 10.1039/C8SC01537F
Our developed oxyindation was applied to the synthesis of
isocoumarin derivatives. First, the gram-scale synthesis of an
organoindium species was carried out. Methyl ester 1a (10
mmol) reacted with InI3 to give organoindium 4a, and 1.14 g of
isocoumarin was isolated by the addition of H2O (Scheme 7).
Table 2 Sequential Oxymetalation/Halogenation of Various Types of 2-Alkynylbenzoate
1a
Entry
1
1
MX3
InI3
Target
Yield
(%)b
Scheme 7 Gram-Scale Synthesis of Isocoumarin Including a Carbon-Indium Bond.
64
Next, the oxidation of produced alkenylindium compounds
was performed (Table 2). An oxyindation of 1a using InI3 was
carried out, and the organoindium 4a was oxidized by PhI(OAc)2
in a one-pot procedure to give 4-iodoisocoumarin 24a (entry 1).
Subjecting InBr3 to the oxidation reaction provided 4-
bromoisocumarin 25a in a high yield (entry 2). Therefore,
various types of 2-alkynylbenzoates were surveyed in the
sequential oxyindation/halogenation process to give 4-
halogenated isocoumarins. Substrates with electron
withdrawing groups such as nitro and carbonyl groups gave the
target products 24b and 24c in high yields (entries 3 and 4). The
structure of 24b was characterized by X-ray crystallographic
analysis (See Fig. S11 in ESI†). Substrates with methyl or aryl
groups efficiently afforded the target isocoumarins 24d and 24e
(entries 5 and 6). Also, 2-alkynylbenzoates, including halogen
moieties (Br, Cl and F), were suitable for this reaction system to
2
3
4
InBr3
InI3
73
61
70
InI3
5
6
InI3
InI3
54
54
give the isocoumarins 25f-24h in moderate yields (entries 7-9).
The synthesis of isocoumarins from internal alkynes was also
investigated. Optimization of the reaction conditions showed
that gallium salts were more suitable than indium salts for the
oxymetalation of an internal alkyne (See Table S3 in ESI†).
Therefore, gallium salts were employed in the reactions of
7
8
InBr3
InI3
47
67
61
60
internal alkynes 1i
, 1j and 1k to provide the 3,4-disubstituted
isocoumarins 24i 24j and 25k (entries 10-12).
,
One-pot syntheses of 4-substituted isocoumarins were
performed via oxyindation followed by a palladium-catalyzed
cross-coupling reaction (Table 3).30 After the oxymetalation of
1a using InBr3, the addition of a palladium catalyst, lithium
chloride, organic halides 27, and an additional solvent to the
9
InI3
10
GaI3
resultant toluene solution afforded the coupling product 28
.
Iodobenzene 27a and the aryl iodides bearing electron donating
group 27b or electron withdrawing group 27c were applicable
to give the 4-arylisocoumarins 28aa-28ac in high yields (entry 1).
Palladium-catalyzed cross coupling with acid chlorides also
proceeded efficiently. Reactions using the benzoyl chloride
11
12
GaI3
56
60
derivatives 27d and 27e, as well as the alkanoyl chloride 27f
,
GaBr3
afforded the isocoumarins 28ad 28af with ketone moieties in
-
good yields (entries 2 and 3). The structure of 28ae was
characterized by X-ray crystallographic analysis (See Fig. S12 in
ESI†). In this reaction system, alkyl halides such as the benzyl
bromide 27g and the allyl bromide 27h were also suitable to
give the 4-alkylisocoumarins 28ag and 28ah, respectively
(entries 4 and 5). Various types of 4-substituted isocoumarins
a First step: 1 (0.5 mmol), MX3 (0.5 mmol), toluene (1 mL), 50 °C, 24 h. Second step:
PhI(OAc)2 (1.0 mmol), Et2O (1 mL), rt, 12 h. b Isolated yields.
8 | J. Name., 2012, 00, 1-3
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Table 3 One-Pot Formation of 4-Substituted Isocoumarins by Palladium-Catalyzed Cross
Coupling of Organoindium Species 26 with Organic Halides 27a
View Article Online
DOI: 10.1039/C8SC01537F
Entry
1
27
Target
Yield (%)b
28aa: 81
28ab: 71
28ac: 72
28ad: 82
28ae: 64
2
Scheme 8 Formal Total Synthesis of Oosponol. Reagents and reaction conditions:
a) BBr3 (1 M in CH2Cl2, 2.0 equiv), CH2Cl2, RT, 20 h, 100%. b) H2SO4 (20 mol %),
MeOH, Reflux, 20 h, 87%. c) AcCl (1.04 equiv), Pyridine (1.04 equiv), Acetone, RT,
14 h, 97%. d) Ethynyltrimethylsilane (1.1 equiv), PdCl2(PPh3)2 (2.0 mol %), CuI (20
mol %), NEt3, RT, 17 h, 100%. e) 1M KF aq. (1.65 equiv), DMF, RT, 0.5 h, 76%. f)
InBr3 (1.0 equiv), Toluene, 50 °C, 24 h. g) Pd2dba3 (5.0 mol %), LiCl (2.0 equiv), 2-
(acetyloxy)acetyl chloride 27i (2.0 equiv), HMPA, RT, 9 h, 44%.
3c
61
4d
5d
51
Conclusions
45e
We achieved the synthesis of isocoumarins bearing a metal-
carbon bond at the 4-position via 6-endo selective
oxymetalation of 2-alkynylbenzoate 1 (Type endo-t). Indium and
gallium salts showed high activity for the oxymetalation of 2-
ethynylbenzoate 1a. Both the metalated isocoumarin 4b and
a Basic reaction conditions of the first step: 1a (0.5 mmol), InBr3 (0.5 mmol), toluene
(1 mL), 50 °C, 24 h. Second step: Pd2dba3 (0.025 mmol), LiCl (1.0 mmol), 27 (1.0
the zwitterion intermediate
crystallographic analysis. This is the first example of the
isolation of the product and the benzopyrylium intermediate
proposed in the mechanism of oxymetalation (Scheme 2A).
The elimination of MeI from zwitterion occurred under
3 were identified by X-ray
d
mmol), NMP (2.5 mL), 50 °C, 24 h. b Isolated yields. c HMPA (2.5 mL), rt, 24 h.
HMPA (2.5 mL), 50 °C, 24 h. e E/Z = 90:10.
E
Formal Total Synthesis of Oosponol
F
3
Finally, a formal total synthesis of oosponol, which exhibits
strong antifungal activity,15 was conducted (Scheme 8). Firstly,
iodination of commercially available compound 29 proceeded
via a method found in the literature.31 During the initial
investigation, 30 was transformed into methyl 2-ethynyl-6-
methoxybenzoate, and then we attempted the synthesis of the
precursor of oosponol via oxyindation and cross-coupling, but
the reaction returned a complicated mixture (See Scheme S1 in
ESI†). Therefore, in another synthetic route, the OMe group of
29 was converted to an OAc group with less ability to donate
electrons. The OMe moiety of 30 was completely deprotected
by BBr3. Acid-catalyzed esterification and acetylation of the
phenol moiety gave methyl 6-iodoacetylsalicylate 33 in a high
yield. Sonogashira coupling followed by the removal of a silyl
heating conditions to give the target product 4a, which means
the rate-determining step was the elimination step. DFT
calculation suggested that thermodynamic control led to 6-
endo selective oxyindation, while kinetic control led to 5-exo
selective oxyboration. The 6-membered product proved much
more stable than the 5-membered product due to a difference
in the degree of aromatic stability. The investigation of
electrostatic potential of the transition state in the cyclization
pathway suggested that a delocalization of negative charge by
large atomic radii of In and I atoms stabilizes the zwitterionic
transition state. In contrast, small atomic radii of B, Cl, and O
atoms causes a localization of negative charge to destabilize the
corresponding transition state. The difference in stability
between the 6- and 5-membered zwitterions and the elemental
character of InI3 both played important roles in the unique
regioselectivity of oxymetalation and in the facile preparation
moiety afforded the desired 2-alkynylbenzoate derivative 35
.
Oxymetalation of 35 using InBr3 and sequential palladium-
catalyzed cross coupling with acid chloride 27i produced the key
of the E species.
intermediate 36
, and the hydrolyzation of 36 yielded
These isocoumarins bearing a carbon-metal bond at the 4-
position were applied to organic synthesis. Oxymetalation
provided isocoumarins on a gram scale. The oxidation of
organoindium or gallium species yielded various types of 4-
halogenated isocoumarins. Palladium-catalyzed cross coupling
oosponol.16b Our method used a readily available starting
material and gave a higher yield than previous works.16b,32
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Tummatorn and S. Ruchirawat, Tetrahedron Lett., 2018. 59
(a) Y. Kato, K. Miki, F. Nishino, K. Ohe anDdOSI.:U10e.1m0u39r/aC,8OSrCg0.1L5e3t7tF.,
2003, 5, 2619-2621; (b) C. P. Casey, N. A. Strotman and I. A.
,
with aryl iodide, acid chloride, and alkyl bromide gave a wide
range of 4-substituted isocoumarins in a one-pot reaction.
Therefore, the unprecedented regioselectivity of the present
oxymetalation contributed to the synthesis of new types of
isocoumarins. We accomplished a formal total synthesis of
oosponol to demonstrate the utility of our reaction system.
View Article Online
675-680.
4
Guzei, Organometallics, 2004, 23, 4121-4130; (c) R. Vicente, J.
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S. Qu, Q. Xiao, Z.-X. Wang, P. Qu, L. Chen, Z. Liu, L. Tian, Z.
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Conflicts of interest
There are no conflicts to declare.
13502-13511; (f) J.-M. Yang, Z.-Q. Li, M.-L. Li, Q. He, S.-F. Zhu
and Q.-L. Zhou, J. Am. Chem. Soc., 2017, 139, 3784-3789.
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Organomet. Chem., 2002, 645, 228-234; (b) K. Miki, T. Yokoi,
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Chem., 2004, 69, 1557-1564; (c) K. Okamoto, M. Watanabe, A.
Mashida, K. Miki and K. Ohe, Synlett, 2013, 24, 1541-1544.
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106, 4218-4227; (b) A. Nagarajan and T. R. Balasubramanian,
Indiun J. Chem. B, 1987, 26B, 917-919; (c) Y. Zhu and B. Yu,
Angew. Chem. Int. Ed., 2011, 50, 8329-8332; (d) Y. Tang, J. Li,
Y. Zhu, Y. Li and B. Yu, J. Am. Chem. Soc., 2013, 135, 18396-
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Am. Chem. Soc., 2016, 138, 2126-2129; (f) B. Akkachairin, J.
Tummatorn, N. Supantanapong, P. Nimnual, C.
5
6
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP15H05848 in Middle Molecular Strategy and JP16K05719. Y.N.
acknowledges support from the Frontier Research Base for
Global Young Researchers, Osaka University, of the MEXT
program and from Mitsui Chemicals Award in Synthetic Organic
Chemistry. We thank Prof. Dr. S. Blum (Department of
Chemistry, University of California, Irvine) for helpful
suggestions. We would like to thank Prof. Dr. S. Akai (Graduate
School pf Pharmaceutical Science, Osaka University, Japan) for
suggestions about total synthesis of oosponol. Thanks are due
to the Analytical Instrumentation Facility, Graduate School of
Engineering, Osaka University, for assistance in obtaining the
MS spectra.
Thongsornkleeb and S. Ruchirawat, J. Org. Chem., 2017, 82
,
3727-3740.
7
The metal species E was proposed as intermediate for
oxymetalation/protonation sequential reactions, and these
cyclic reactions showed low regioselectivity to afford mixture
of 5- and 6-membered rings. (a) E. Marchal, P. Uriac, B.
Legouin, L. Toupet and P. v. d. Weghe, Tetrahedron, 2007, 63
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9979-9990; (b) B. Y.-W. Man, A. Knuhtsen, M. J. Page and B. A.
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9
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Soc., 2011, 133, 12608-12623. (b) K. Gilmore, R. K. Mohamed
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