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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
1
The ISHC Bulletin Recent Publications of ISHC Members
Issue 37; November 2019 Anion-Capture-Induced Fluorescence
Enhancement of Bis(cyanostyryl)pyrrole Based on Restricted Access
to a Conical Intersection Soichi Yokoyama,* Akitaka Ito, Haruyasu
Asahara, and Nagatoshi Nishiwaki* ([email protected]
or [email protected]) Bull. Chem. Soc. Jpn.
2019, 92, 1807–1815. DOI: 10.1246/bcsj.20190196
Abstract: Understanding the mechanism of fluorescence
enhancement of a fluorophore via anion addition is of critical
importance for designing anion sensors. The distyrylpyrrole
framework with cyano groups on olefin has a low rotation barrier in
the excited state, which results in easy access to the conical
intersection and, thus, fast non-radiative decay. In this study, it
was proposed that the anion capture of a molecule with protons on
the pyrrole and olefin moieties with a high anion affinity should
induce fluorescence enhancement via restricted access to the
conical intersection. It was revealed that the pyrrole derivative
possessing cyano groups in the a-position of the pyrrole showed a
strong enhancement in the fluorescence quantum yield up to 60% with
an increasing concentration of anions in solution. NMR and X-ray
single crystal diffraction revealed that the molecule formed a 1:1
complex with a chloride anion in solution and in the single crystal
state. The fluorescence lifetime of the compound was prolonged via
the addition of the chloride anion, indicating that fast
non-radiative decay was suppressed by anion capture. The results
support that the anion capture of the molecule can restrict access
to the conical intersection to produce a fluorescence enhancement.
1,4-Diazacubane Crystal Structure Rectified as Piperazinium Kasun
S. Athukorala Arachchige, Tyler Fahrenhorst-Jones, Jed M. Burns,
Hydar A. AL-Fayaad, Jogendra N. Behera, C. N. R. Rao,* Jack K.
Clegg,* and Craig M. Williams* ([email protected]) Chem.
Commun. 2019, 55, 11751–11753. DOI: 10.1039/c9cc06272f
Abstract: All 21 [n]-azacubanes are proposed by theoreticians to
be stable, however, to-date only the synthesis of 1,4-diazacubane
has been reported – as a Ni2+ templated Kagome metal organic
framework (MOF). Described herein is the structural reassignment of
this Kagome MOF on the basis of deducing the precise experimental
procedure, and demonstrating that rather than the formation of
1,4-diazacubane, charge is balanced by disordered piperazinium
cations across a twelve-fold symmetry site. Furthermore, quantum
chemical calculations reveal that 1,4-diazacubane is unlikely to
form under the reported conditions due to unfavorable enthalpies
for select hypothetical reactions leading to such a product. This
significant structure correction upholds the unconquered synthesis
status quo of azacubane.
N
N NH
HN
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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
2
Metal-Free Nitrogen-Containing Polyheterocyclic Near-Infrared
(NIR) Absorption Dyes: Synthesis, Absorption Properties, and
Theoretical Calculation of Substituted
5-Methylisoindolo[2,1-a]quinolines Yuki Fujii, Yukinori Suwa, Yuki
Wada, Tsunayoshi Takehara, Takeyuki Suzuki, Yusuke Kawashima,
Norihito Kawashita, Tatsuya Takagi, Hiromichi Fujioka, and
Mitsuhiro Arisawa* ([email protected]) ACS Omega 2019, 4,
5064–5075. DOI: 10.1021/acsomega.9b00315
Abstract: We have synthesized and theoretically calculated
5-methylisoindolo[2,1-a]quinoline derivatives as novel
near-infrared absorption dyes via a ruthenium-catalyzed one-pot
metathesis/oxidation/1,3-dipolar cycloaddition protocol. The
reactivity in 1,3-dipolar cycloaddition was governed by the
electronic effect of aromatic ring substituents. Substrates with an
electron-withdrawing group on the aromatic ring afforded higher
yields. The maximal absorption wavelength of
3,5-dimethyl-11-phenylisoindolo[2,1-a]quinoline-7,10-dione and
11-(4-methoxyphenyl)-5-methyl-isoindolo[2,1-a]quinoline-7,10-dione
in MeOH increased to 736 and 737 nm, although that of 3a was 727
nm. Total Synthesis of (+)-CC-1065 Utilizing Ring Expansion
Reaction of Benzocyclobutenone Oxime Sulfonate Taku Imaizumi, Yumi
Yamashita, Yuki Nakazawa, Kentaro Okano, Juri Sakata, and Hidetoshi
Tokuyama* ([email protected]) Org. Lett. 2019, 21,
6185–6189. DOI: 10.1021/acs.orglett.9b01690
Abstract: Total synthesis of (+)-CC-1065 was accomplished. The
middle and the right segments possessing the highly substituted
1,2-dihydro-3H-pyrrolo[3,2-e]indole skeleton were constructed via
double [2+2] cycloaddition of 1,3-benzdiyne and two directional
step-wise double ring expansion reaction of bis-benzocyclobutenone
oxime sulfonate using NaBH4 and KCN, as key steps. After
condensation of three segments, the total synthesis was
accomplished by the late-stage trans-annular cyclopropane
formation.
NH
O
NO
HN
N
OMe
O
N
OH
N O
H2N
OH
OMe
Me
H
(+)-CC-1065 IC50 = 20 pM
MeOMeO
N
N
RO
OR
NaBH4THF/t-BuOH
50 °C63%
NH
MeOMeO
NRO
KCN DMSO CH2Cl2
0 °C, 75%
MeOMeO
HN
NH
NC
BnO
HNMe
NH
OTBS
left segment
HOMeO
HN
NR
HOOC
middle segment (R = Fmoc)right segment (R = CONH2 )
condensation&
cyclopropanation
NaNH2
THFreflux
89%
MeOMeO
BrBr
OMeMeO
MeOMeO
MeO
MeO
OMeOMe
double [2+2] cycloaddition (R = p-ClC6H4SO2)
Two Directional Double Ring Expansion
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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
3
Synthesis and Antimicrobial Activity of New Derivatives of
Pyrano[4'', 3'':4',5']pyrido[3',2':4,5]theno[3,2-d]pyrimidine and
New Heterocyclic Systems Samvel N. Sirakanyan,* Domenico Spinelli,*
Athina Geronikaki, Viktor G. Kartsev, Elmira K. Hakobyan, and Anush
A. Hovakimyan ([email protected] or [email protected]) Synth.
Commun. 2019, 49, 1262–1276. DOI: 10.1080/00397911.2019.1595659
Abstract: Taking into account previously obtained biological
results on some polyheterocyclic compounds (containing different
heteroatoms) and in particular on several
8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
I we have carried out the synthesis of twenty one
8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2-d]pyrimidines
6. We have slightly modified the structure of the previously
studied I introducing at C-5 an isobutyl group instead of the
previously examined isopropyl ones in order to see if this
variation (changing a little the lipophilicity) will affect the
biological activity. Furthermore, thieno[3,2-d]pyrimidine-8-thione
7 and their S-alkylated 8 were synthesized. Finally by alkylation
of
5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one
3 with alkyl dichlorides (bifunctional reagents) we realized the
cyclization of a thiazole or thiazine ring on the [b] side of the
pyrimidine ring with formation of the new condensed
pentaheterocyclic systems:
pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one
11 and
pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one
12. It was found that some of the synthesized compounds showed
interesting antimicrobial activity (by agar diffusion method)
against some gram-positive and gram-negative bacilli strains.
Heterocyclic Chemistry – A Mature Area in Its Infancy! Oliver
Reiser* ([email protected]) Eur. J. Org. Chem.
2019, 4973–4975. DOI: 10.1002/ejoc.201901162
Abstract: For a long time, the construction of heterocycles
reliably forged a carbon heteroatom bond by the interaction between
a nucleophilic heteroatom and an electrophilic C=X or C-X-moiety.
This concept has been greatly expanded with the development of many
synthetic methods that seemingly defy standard reactivities in
molecules. The collection of almost 100 articles in the special
issues of Eur. J. Org. Chem. and Asian Org. Chem. impressively
attest to the creativity and efforts that are going on in this
field: mature, but still young at heart.
NN
N N
NH
OOP
OO
O
O
NN
N
O
HN
N
OOP
O O
O
OPO
O
HHH
OO P
OO
O
O
OO P
OO
O
O PO
O
N
NO
NHH
N
NO
OH
G
A
T
C
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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
4
A General Acid-Mediated Hydroaminomethylation of Unactivated
Alkenes and Alkynes Daniel Kaiser, Veronica Tona, Carlos R.
Gonçalves, Saad Shaaban, Alberto Oppedisano, and Nuno Maulide*
([email protected]) Angew. Chem. Int. Ed. 2019, 58,
14639–14643. DOI: 10.1002/anie.201906910
Abstract: In comparison to the extensively studied
metal‐catalyzed hydroamination reaction, hydroaminomethylation has
received significantly less attention despite its considerable
potential to streamline amine synthesis. Here we report a broadly
applicable, acid‐mediated approach to the hydroaminomethylation of
unactivated alkenes and alkynes. This methodology employs cheap,
readily available, and bench‐stable reactants and affords the
desired amines with excellent functional group tolerance and
impeccable regioselectivity. The broad scope of this
transformation, as well as mechanistic investigations and in situ
domino functionalization reactions are reported. Decahydroquinoline
Ring 13C NMR Spectroscopic Patterns for the Stereochemical
Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of
(–)-Serralongamine A and Structural Reassignment and Synthesis of
(–)-Huperzine K and (–)-Huperzine M (Lycoposerramine Y) Caroline
Bosch, Ben Bradshaw,* and Josep Bonjoch* ([email protected] or
[email protected]) J. Nat. Prod. 2019, 82, 1576–1586. DOI:
10.1021/acs.jnatprod.9b00071
Abstract: Analysis of 13C NMR spectroscopic data of the
phlegmarine subset of Lycopodium alkaloids revealed spectral
patterns that allowed the stereochemical arrangement of the four
stereogenic carbons in the decahydroquinoline core to be
established. A relatively simple predictive set of chemical shift
combinations is reported, providing a tool for the challenging
stereochemical assignment of phlegmarine-type alkaloids. Based on
the chemical shifts in their NMR spectroscopic profiles, the
alkaloids huperzine K and huperzine M, formally reported as cis
derivatives, were structurally reassigned as
trans-decahydroquinolines. The NMR spectroscopic data for huperzine
M were identical to those reported for lycoposerramine Y and,
hence, also implied the configurational reassignment of the latter.
The revised structures of the above alkaloids were confirmed by
enantioselective total synthesis. Additionally, the synthesis of
(−)-serralongamine A via a common intermediate precursor is
reported.
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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
5
Organoselenium Accelerated Bromolactonization Reaction Jørn E.
Tungen,* Renate Kristianslund, Anders Vik, and Trond V. Hansen
([email protected]) J. Org. Chem. 2019, 84, 11373–11381.
DOI: 10.1021/acs.joc.9b01294
Abstract: A highly efficient and regioselective
bromolactonization protocol is reported. The quantitative formation
of synthetically versatile d-bromolactones occurs in the presence
of only 0.1 mol% of an organoselenium-compound within 90 minutes.
The organoselenium catalyst is conveniently prepared on multi-gram
scale from cheap racemic camphor. The presented protocol was easy
to scale up and performed equally well on gram scale.
Investigations of the mechanism using additives and
NMR-spectroscopy revealed that the catalysts forms a selenonium
ylen in situ. This operationally simple protocol should be
attractive for making a plethora of heterocyclic compounds.
Stereoselective Synthesis of Cyclopropylidene Iminolactones and
Functionalized Cyclopropanecarboxamides Mediated by Triflic Acid
Adrielle P. Maximiano and Marcus M. Sá* ([email protected]) Eur. J.
Org. Chem. 2019, 6515–6524. DOI: 10.1002/ejoc.201900931
Abstract: A straightforward synthesis of cyclopropylidene
iminolactones mediated by triflic acid under mild conditions is
described. Different types of hydroxy-substituted
cyclopropanecarboxamides containing a variety of functional groups
participated in this smooth cyclization through an intramolecular
SN2 attack of the amidic oxygen on the protonated carbinol group
with the release of water. Ten cyclopropylidene iminolactones were
readily obtained in high purity after a basic work-up with no
additional chromatographic separation (62-98% yield). Besides the
simplicity, the method is highly diastereoselective and tolerates
several functional groups, demonstrating the broad scope of this
process. Selected iminolactones were applied in further synthetic
transformations to give functionalized cyclopropanecarboxamides
through hydrogenolysis or nucleophilic ring opening reactions.
O N
CO2MeH
Ph
NHO R
HOH CO2Me
Ph CH2Cl2rt
TfOH
O NPh
CO2Me
R
HH
NHO R
NuH CO2Me
PhAl2O3
R10 examples62-98% yield
6 examples30-99% yield
(±)
NHO R
H CO2Me
Ph
H2
NuHor Nu-
Pd(OH)2/C
2 examples50-72% yield
Nu = R'O, N3, NO2
rt
- Diastereoselective- High yields- Mild conditions- Structural
diversity
Iminolactonization
TfO
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Issue 37; November 2019
International Society of Heterocyclic
Chemistry
ISHC
6
Pd-Catalyzed Migratory Cycloisomerization of
N-Allyl-o-allenylaniline Derivatives Yasuhiro Ii, Satoru
Hirabayashi, Shohei Yoshioka, Hiroshi Aoyama, Kenichi Murai,
Hiromichi Fujioka, and Mitsuhiro Arisawa*
([email protected]) Org. Lett. 2019, 21, 3501–3504. DOI:
10.1021/acs.orglett.9b00676
Abstract: The Pd-catalyzed migratory cycloisomerization of
N-allyl-o-allenyl aniline derivatives is first reported to give
indoles having a substituent at the 2-position. Rh(II)-Catalyzed
Monocyclopropanation of Pyrroles and Its Application to the
Synthesis Pharmaceutically Relevant Compounds Jiantao Fu, Nikolai
Wurzer, Verena Lehner, Oliver Reiser,* and Huw M. L. Davies*
([email protected] or [email protected]) Org.
Lett. 2019, 21, 6102–6106. DOI: 10.1021/acs.orglett.9b02250
Abstract: Here we report Rh(II)-catalyzed monocyclopropanation
reactions on pyrroles in the presence of aryldiazoacetates,
providing the corresponding dearomatized products with high levels
of enantioselectivity (up to >99% ee). Under the catalysis of
Rh2(R-p-PhTPCP)4, a broad range of pyrrole substrates and
aryldiazoacetates are shown to be compatible. Utilizing these
valuable chiral building blocks, we further demonstrate the
application of this transformation by synthesizing a homo-b-proline
analog and a b-aminocarboxylic acid (b-ACC) derivative from the
monocyclopropanated product.
Ph
Ph
PhO
O
Rh
Rh
4
Rh2(R-p-PhTPCP)4
TsNR1
N2
CO2R2Ar
Rh2(R-p-PhTPCP)4(0.5 mol %)
TsNR1
H
H
CO2R2
Ar
23 examples(up to 87% yield, >99% ee)
• diastereoselective• gram scale• medicinal applications
