Synthesis, Characterization, and Reactivity of an Ethynyl Benziodoxolone (EBX)-Acetonitrile Complex

Article abstract of DOI:10.1021/acs.orglett.9b00005

The synthesis of a crystalline ethynyl-1,2-benziodoxol-3(1H)-one (EBX)-acetonitrile complex is described. EBX has been widely used as an active species for a variety of reactions; however, its high instability has so far prevented its isolation. The EBX-acetonitrile is self-assembled into a double-layered honeycomb structure through weak hypervalent iodine secondary interactions and hydrogen bonding. The N-ethynylation of a variety of sulfonamides using the EBX-acetonitrile complex as a substrate under mild conditions is also described.

Full text of DOI:10.1021/acs.orglett.9b00005

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis, Characterization, and Reactivity of an Ethynyl
Benziodoxolone (EBX)−Acetonitrile Complex
Masaharu Yudasaka,† Daisuke Shimbo,† Toshifumi Maruyama,‡ Norihiro Tada,*,†
and Akichika Itoh*,†
†Gifu Pharmaceutical University1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
‡Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: The synthesis of a crystalline ethynyl-1,2-benziodoxol-
3(1H)-one (EBX)−acetonitrile complex is described. EBX has been
widely used as an active species for a variety of reactions; however, its
high instability has so far prevented its isolation. The EBX−acetonitrile
is self-assembled into a double-layered honeycomb structure through
weak hypervalent iodine secondary interactions and hydrogen bonding.
The N-ethynylation of a variety of sulfonamides using the EBX−
acetonitrile complex as a substrate under mild conditions is also
described.
In the past decade, the chemistry of benziodoxol(on)e
derivatives has attracted considerable interest because of their
higher stability compared with their acyclic analogs.7,10
Although the first cyclic hypervalent iodine was synthesized
over 100 years ago, the history of alkynyl benziodoxolone (5−
8, Figure 1) is comparatively short, probably because the
internal carboxylate easily reacts with the alkynyl hypervalent
iodine.8c,d In 1991, the first synthesis of alkynyl benziodox-
olone (5) was achieved by Ochiai.11a In 1996, Zhdankin
reported silyl-protected EBX derivatives (TMS-EBX (6) and
TIPS-EBX (7)).11b In 2010, Waser reported the α-
ethynylation of activated carbonyl derivatives using unpro-
tected EBX (8) as crucial active species.12a EBX is generated in
situ from TMS-EBX by using TBAF; however, it decomposes
at around −20 °C in dichloromethane. Recently, EBX has been
used as an active species for various reactions, including
enantioselective ethynylation. Nevertheless, due to its insta-
bility, all attempts at its isolation have been unsuccessful.12
Coordination of additional ligands through hypervalent
bonding and secondary bonding has been used to modify the
stability and reactivity of hypervalent iodine.7 For example, the
physical and chemical properties of pseudocyclic hypervalent
iodine compounds are significantly altered.13 Furthermore, the
intermolecular coordination of small molecules has been
shown to stabilize the hypervalent iodine not only in the
solid state but also in solution.14 In this context, our group has
recently focused on the stabilization of hypervalent iodine
compounds through both internal and external coordination.15
In view of the above-mentioned background, we hypothesized
that deprotection of TMS-EBX with a mild base in a
coordinating solvent would stabilize EBX, thereby enabling
he terminal alkyne is a very important and useful
Tfunctional group not only in the organic synthetic field
but also in other fields such as biochemistry and material
science.1 Thus, the development of ethynylating reagents that
are applicable to the manufacturing of biological compounds
and complex molecules under mild conditions, thereby
expanding the application scope of this rich alkyne chemistry,
is of high interest. In regular nucleophilic alkynylation
reactions of carbonyls or imines2 and cross-coupling reactions,3
the reactivity of terminal alkynes is governed by the high
acidity of the alkyne C(sp)−H bond. In contrast, umpolung,
electrophilic alkynylation reactions involve C(sp)−X (X = Br,
Cl, F, Pb(III), I(III)) bonds.4 Especially, the highly electron-
withdrawing nature5 and hyper-leaving group ability of the λ3-
iodanyl group6 of alkynyl hypervalent iodine compounds (X =
I(III)) have been exploited in the electrophilic alkynylation.7
The first alkynyl iodonium salt (1) was reported in 1965
(Figure 1).8a In 1988, a silyl protected ethynyl iodonium
derivative (2) was synthesized by Stang,8b which was followed
shortly after by the independent reports by Ochiai and Stang
on unprotected ethynyl iodonium salts having different
counteranions (BF4 (3) and OTf (4)).9a,b
Received: January 2, 2019
Figure 1. Alkynyl hypervalent iodine(III) compounds.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
its synthesis and isolation. Herein, we report on the synthesis,
isolation, characterization, and reactivity of the EBX−
acetonitrile complex.
highest yield (entry 15 vs entries 16 and 17). Interestingly,
when increasing the amount of starting 6 to 0.05 mmol, we
1
obtained EBX in 69% yield with no TMS-EBX, and H NMR
To prove our hypothesis, we commenced our study by using
TBAF for the desilylation of TMS−EBX (6) in acetonitrile as a
coordinating solvent (entry 1, Table 1). Unfortunately, EBX
analysis indicated that acetonitrile was contained in a 3:1 ratio
(entry 19). In contrast, sodium bicarbonate gave lower yields
on the 0.05 mmol scale (entries 20 and 21). With the
optimized conditions for the deprotection of TMS-EBX in
hand, we examined the synthesis of EBX from 1-hydroxy-1,2-
benziodoxol-3-one (9). Scheme 1 summarizes the optimized
conditions, which provided the desired EBX−acetonitrile
complex (8a) in 68% yield (1.2 g) in two steps.
a
Table 1. Study of Reaction Conditions for Desilylation
Scheme 1. Gram Scale Synthesis of EBX−Acetonitrile
Complex
yield (%)
entry
solvent
base
TBAF (1 equiv)
TBAF (1 equiv), 18C6 (1 equiv)
NaHCO3 (1 equiv)
8a
6
c
1
MeCN
MeCN
MeCN
MeCN
EtCN
EtOAc
THF
MeOH
TFE
0
0
0
c
2
0
19
31
3
10
20
14
1
38
53
0
9
33
0
0
3
0
0
46
39
3
4
5
6
7
8
9
36
21
31
42
12
34
41
16
0
14
19
20
43
24
23
64
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. NaHCO3 aq. (5 mL)
sat. Na2CO3 aq. (5 mL)
sat. K2CO3 aq. (5 mL)
sat. NaHCO3 aq. (2.5 mL)
sat. NaHCO3 aq. (5 mL)
NaHCO3 (1 equiv)
The synthesized EBX−acetonitrile complex (8a) is stable at
room temperature, and no decomposition was observed when
it was left standing under ambient conditions for 3 days.
Surprisingly, this complex also remained stable for the same
period in a chloroform solution, which contrasts with previous
reports on EBX.12,16 To elucidate the solid-state structure of
the EBX−acetonitrile complex, a suitable single crystal of 8a
grown from acetonitrile was subjected to X-ray crystallographic
analysis (CCDC 1886379; Figure 2).17 The distorted three-
coordinated T-shape geometry around the iodine displayed in
Figure 2a is in good agreement with that of related
compounds.11 The complex adopts a distorted pentagonal
planar geometry around the iodine atom due to the root-mean-
square deviation of 0.094 Å (I1, C1, C2, O4, O3, and O1)
from their least-squares plane and the sum of the iodine-
centered bond angles of Σ°I1 = 360.6°. The nearly linear C1−
I1···O4 angle (163.7°) and the relatively strong I1···O4 contact
(2.819(3) Å) are indicative of the presence of hypervalent
secondary interactions. Through these secondary bondings,
EBX has a trimeric structure as reported previously for c-Hex-
EBX and TBDPS-EBX (Figure 2a).11a,d Interestingly, one
acetonitrile molecule seems to be weekly coordinated to the
iodine center of an EBX from the other layer, with a N1···I2
distance of 3.473 Å, which is slightly shorter than the sum of
the van der Waals radii (3.53 Å) (Figure 2a, Figure S2).18,19
Note that TBDPS−EBX also contains an acetonitrile molecule
in the crystal, albeit not coordinated to the iodine center.11d In
contrast to other related alkynyl hypervalent iodine com-
pounds, the trimer of EBX is linked with the adjacent three
trimers via two hydrogen bondings, each of which involves an
acidic acetylenic hydrogen atom and a carboxyl oxygen,
forming a tetramer of EBX with a parallelogram structure
(Figure 2a). The H1···O5 distance of 2.146 Å is shorter than
their combined contact radii (2.72 Å),19 and the C3−H1···O5
bond shows a nearly linear conformation with an angle of
166.06°. The ratio of isotropic displacement parameters
U(C3)/U(C2) = 1.19) is close to 1, which supports the
H1···O5 hydrogen bonding, since hydrogen bonding reduces
the thermal vibrations of the engaged residues.14a,20 Very
interestingly, EBX is self-assembled into a double-layered
honeycomb structure through hypervalent secondary bonding
and hydrogen bonding (Figure 2b). Although the solid-state
10
11
HFIP
CHCl3
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
d
12
d
13
e
14
f
15
f
16
f
17
18
f
g
b
19
69
4
11
g
20
g
21
NaHCO3 (100 equiv)
a
Reaction conditions: 6 (0.025 mmol), base, solvent (0.5 mL), room
1
temperature, air. Yields are determined by H NMR using 1,1,2,2-
tetrachloroethane as an internal standard. Isolated yield. Reaction
b
c
d
e
carried out at −40 °C. Reaction carried out for 30 min. MeCN
f
g
(0.25 mL). MeCN (2.5 mL). 6 (0.05 mmol), MeCN (5 mL).
TBAF: tetrabutylammonium fluoride. 18C6: 18-Crown-6 ether. TFE:
trifluoroethanol. HFIP: hexafluoro-2-propanol.
decomposed under these conditions affording 2-iodobenzoic
acid as the sole product. Then, we used 18-crown-6 ether as a
stabilizing agent; however, the same result was obtained (entry
2).14a In contrast, when using sodium bicarbonate instead of
TBAF, a peak at 3.24 ppm attributable to C(sp)−H hydrogen
was observed in the 1H NMR spectrum, indicating the
generation of EBX in a 36% NMR yield; however, unreacted
TMS−EBX still remained in 19% yield (entry 3). Using an
aqueous solution of sodium bicarbonate also gave EBX, albeit
in low yield (entry 4). A screening of solvents revealed that the
reaction progressed in polar solvents (entries 5−10), whereas
nonpolar solvents such as chloroform gave no EBX (entry 11).
Increasing the reaction time from 5 to 30 min resulted in
decreased yields (entries 12 and 13), probably due to the
instability of EBX in the presence of a base. Meanwhile,
completion of the reaction was achieved upon decreasing the
concentration to 0.01 M, affording EBX in 43% yield without
any remaining TMS−EBX (entries 14 and 15). Regarding the
base, saturated sodium bicarbonate aqueous solution gave the
B
DOI: 10.1021/acs.orglett.9b00005
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
molecules is essential to preserve the honeycomb structure of
EBX. Then, we tried to replace the acetonitrile molecule with
other solvents by evaporation with various solvents. The
1
corresponding H NMR spectroscopic analysis revealed that
related EBX−ethyl acetate (8b) and EBX−chloroform (8c)
complexes were obtained in an EBX/solvent ratio of 6:1 in
both cases. This result indicates that one ethyl acetate or
chloroform molecule was captured in the honeycomb
structure. Importantly, the stability of these complexes (8b
and 8c) is similar to that of 8a not only in the solid state but
also in chloroform solution, indicating that, in the absence of a
base, coordination of acetonitrile is not required for the
stability of EBX in chloroform.
Next, we examined the reactivity of the synthesized EBX−
acetonitrile complex (8a). Ynamides are unique and syntheti-
cally valuable building blocks for organic synthesis and other
fields.21 N-Ethynylation with highly reactive alkynyliodonium
salts, which was first reported by Stang,9c has been broadly
used for the synthesis of ynamides. In contrast, N-alkynylation
using EBX derivatives is highly limited. Cossy reported the N-
ethynylation of sulfonamide to construct the tetrahydro-
pyrazine framework using a strong base (NaH); however, the
substrate scope was limited to primary sulfonamides.12b
Therefore, we decided to explore the N-ethynylation using
the EBX−acetonitrile complex (8a). Table 2 summarizes the
Figure 2. ORTEP drawing of 8a (thermal ellipsoids set at 50%
probability). (a) Top view of six EBXs. (b) Wider top view. Selected
bond lengths [Å] and angles [deg]: I1−C1, 2.123(4); I1−C2,
2.043(3); I1−O1, 2.354(2); C2−C3, 1.170; I1···O3, 3.309(3); I1−
O4, 2.819(3); C2−C3, 1.170(4); C3−H1, 0.930; H1···O5, 2.146;
C1−I1−O1, 75.2(1); C1−I1−C2, 91.3(1); C2−I1−O1, 166.4(1);
C1−I1···O4, 163.7; C1−I1···O3, 154.0; N1···I2, 3.473; H1···O5,
2.146; C3−H1···O5, 166.06; H2···H3, 10.019; N1···H3, 3.052; N1···
H4, 2.931; C4···H5, 3.101.
Table 2. Study of Reaction Conditions for N-Ethynylation
with EBX−Acetonitrile Complex
a
structure of hypervalent iodine has been intensely studied, to
the best of our knowledge, there is no precedent of such a
honeycomb structure formed by hypervalent iodine com-
pounds.7,14 The linearity of the hydrogen bonding is key for
the construction of the honeycomb structure by connecting the
trimer of EBX, which works as a C3h-symmetric molecular
building block. Two acetonitrile molecules are included with
opposite directions in the nanopores of the structure, which
have diameters of ca. 10 Å (10.019 Å for H2···H3) probably
due to the weak coordination of each acetonitrile to the
iodine(III) center of the other layer (Figure 2b).18 This
structure provides an explanation for the EBX/acetonitrile
a
Reaction conditions: 10 (0.05 mmol), Cs2CO3 (0.065 mmol),
solvent (1 mL), room temperature, 5 min, dark, argon. Then, 8a
(0.065 mmol), room temperature, 30 min, dark, argon. Yields are
determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal
standard. Isolated yield. Cs2CO3 (1.2 equiv). 4 was used instead of
8a. 6 was used instead of 8a. 1 mmol scale reaction.
1
ratio of 3:1 observed by H NMR spectroscopy. Finally, no
interaction between acetonitrile and the hydrogen atoms of the
benzene ring is observed, since the distances N···H and C···H
(N1···H3, 3.052 Å; N1···H4, 2.931 Å; C4···H5, 3.101 Å) are
longer than the sum of the corresponding van der Waals radii
(2.75 Å for N and H; 2.9 Å for C and H).18,19
b
c
d
e
f
To gain more insight into the stability of the EBX−
acetonitrile complex, 8a was subjected to thermogravimetric/
differential thermal analysis (TG−DTA)(Figure S1). The
results showed that the included acetonitrile molecule was not
released from the nanopores at the boiling point of acetonitrile
(82 °C), but 8a was decomposed above 100 °C to give the tar.
After decomposition, the weight of 8a decreased by ca. 50%,
and the corresponding H NMR spectrum showed that the
decomposition product contains 2-iodobenzoic acid. These
observations suggest that the presence of guest acetonitrile
results obtained. Using the optimized reaction conditions
(Method A), ynamide 11a was obtained in 90% yield (entry 7,
Table 2). Note that ethynyl iodonium 4 and TMS-EBX 6 gave
a lower yield of product under the present conditions (entries
8 and 9).
Then, we examined the scope and limitation of various
sulfonamides (Scheme 2). Under the optimized conditions
(Method A), methanesulfonamide and 4-nitrobenzene-
sulfonamide were transformed into the corresponding products
11b and 11c in 84% and 60% yields, respectively. In contrast,
1
C
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Letter
ynamide 11x in a lower yield when using ethynyl iodonium salt
4 and TMS-EBX 6 as substrates under our and previously
reported conditions.9d,12b Furthermore, dipeptides were
selectively ethynylated at the sulfonamide in moderate yields
(11ac, 11ad).12b It is worth noting that these amino acid and
peptide derived ynamides are new products. These results
demonstrate the useful reactivity of 8a, which allowed the
performance of the ethynylation reaction under mild
conditions using a simple procedure.
Scheme 2. Scope of the N-Ethynylation with EBX-
Acetonitrile Complex
a
In conclusion, we have presented the synthesis, character-
ization, and reactivity of a crystalline ethynyl-1,2-benziodoxol-
3(1H)-one (EBX)−acetonitrile complex (8a). EBX−acetoni-
trile 8a is self-assembled through weak interactions into a rigid
double-layered honeycomb structure, containing two acetoni-
trile molecules in the cavity. These results show the potential
of cyclic hypervalent iodine in the crystal engineering field.
Furthermore, using EBX−acetonitrile 8a, the N-ethynylation of
sulfonamides, including amino acid and peptide derivatives, to
produce ynamides could be performed under mild and simple
reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00005.
a
Reaction conditions: Method A: 10 (0.05 mmol), Cs2CO3 (0.06
mmol), 1-propanol (1 mL), room temperature, 5 min, dark, argon.
Then, 8a (0.065 mmol), room temperature, 30 min, dark, argon.
Method B: 10 (0.05 mmol), Cs2CO3 (0.1 mmol), DMF (1 mL),
room temperature, 5 min, dark, argon. Then, 8a (0.065 mmol), room
Experimental procedures and characterization data
(PDF)
b
temperature, 30 min, dark, argon. Isolated yields. Cs2CO3 (0.12
c
mmol) and 8a (0.13 mmol) were used. Yields are determined by 1H
Accession Codes
d
NMR using 1,1,2,2-tetrachloroethane as an internal standard. 11t
was not isolated because it is labile. MeOH was used instead of 1-
e
CCDC 1886379 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
f
propanol. 4 was used instead of 8a. 10x was recovered in 53% yield.
g
h
6 was used instead of 8a. 10x was recovered in 12% yield. 4 (1.3
equiv), Cs2CO3 (1.3 equiv), DMF/DCM, rt, 3 h. 10x was recovered
in 28% yield. 6 (1 equiv), NaH (1equiv), DMF, rt, 2 h. 10x was
recovered in 34% yield. MeCN (1 mL) was used instead of 1-
propanol (1 mL), 90 min.
i
j
AUTHOR INFORMATION
■
amide and carbamate were recovered unchanged, as reported
previously for TMS−EBX (11d, 11e).12b Meanwhile, the
reactions of methyl-, bromo-, and iodo-substituted N-tosylani-
line, benzylamine, diamide, and primary aliphatic amine
derivatives were ethynylated in good yields (11f−11r). In
contrast, the sterically demanding amine derivatives gave the
corresponding products in low yields (11s, 11t). Since the N-
alkynylation of amino acid derivatives with alkynyl hypervalent
iodine to give the corresponding amino acid derived ynamide
has been rarely reported,9d we applied our reaction conditions
to amino acid derived tosylamides. Thus, glycine and β-alanine
derivatives gave the corresponding ynamide products 11u and
11v in good yields, respectively; however, the phenylalanine
derivative 10w afforded the desired product 11w only in 21%
yield. Thus, we optimized further the reaction conditions with
phenylalanine derivative 10w. Using dimethylformamide
(DMF) as a solvent and 2 equiv of Cs2CO3 (Method B),
11w was obtained in an improved 65% yield. This condition
also provided higher yields of the sterically demanding amine-
derived ynamides (11s, 73%; 11t, 38%). Then, Method B was
used to investigate various N-tosylamino acid derivatives.
Valine, leucine, aspartic acid, glutamic acid, and tryptophan
derivatives gave the corresponding products in moderate to
high yields (11x−11ab). Note that the valine derivative gave
Corresponding Authors
*E-mail: ntada@gifu-pu.ac.jp.
*E-mail: itoha@gifu-pu.ac.jp.
ORCID
Norihiro Tada: 0000-0003-2871-5406
Akichika Itoh: 0000-0003-3769-7406
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Kazunori Miyamoto for useful discussions about
X-ray crystallographic analysis. The authors would like to
thank Enago (www.enago.jp) for the English language review.
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̅
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DOI: 10.1021/acs.orglett.9b00005
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