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
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
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
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.
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
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