Evidence map›Paper›PMID 41526488›Full record

ArticleNature chemistry2026

Thermal [2+2] cycloaddition as a route to gem-difluoro heterobicyclo[n.1.1]alkanes.

Yongquan Ning, Rongkai Wu, Yongyue Ning, Qingmin Song, Jiahua Deng, Qingchi Jiao, Paramasivam Sivaguru, Jacek Mlynarski, Graham de Ruiter, Xin Hong and 1 more

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Article in Nature chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Yongquan Ning *Department of Chemistry, Northeast Normal University, Changchun, China.ORCID http://orcid.org/0000-0001-8791-6254
Rongkai Wu *Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, China.ORCID http://orcid.org/0000-0003-3184-7573
Yongyue Ning *Department of Chemistry, Northeast Normal University, Changchun, China.
Qingmin SongDepartment of Chemistry, Northeast Normal University, Changchun, China.ORCID http://orcid.org/0000-0003-3546-2961
Jiahua DengDepartment of Chemistry, Northeast Normal University, Changchun, China.
Qingchi JiaoDepartment of Chemistry, Northeast Normal University, Changchun, China.ORCID http://orcid.org/0009-0002-4394-8064
Paramasivam SivaguruDepartment of Chemistry, Northeast Normal University, Changchun, China.ORCID http://orcid.org/0000-0003-2225-0054
Jacek MlynarskiInstitute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.ORCID http://orcid.org/0000-0002-1794-306X
Graham de RuiterSchulich Faculty of Chemistry, Technion - Israel Institute of Technology, Technion City, Haifa, Israel.ORCID http://orcid.org/0000-0001-6008-286X
Xin HongCenter of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, China. hxchem@zju.edu.cn.ORCID http://orcid.org/0000-0003-4717-2814
Xihe BiDepartment of Chemistry, Northeast Normal University, Changchun, China. bixh507@nenu.edu.cn.ORCID http://orcid.org/0000-0002-6694-6742

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The [2+2] cycloaddition reaction has been pivotal in advancing synthetic organic chemistry. However, thermal [2 + 2] cycloaddition reactions are symmetry-forbidden due to ground-state orbital symmetry constraints, making them challenging to achieve under non-photochemical conditions. Here we report a stepwise radical intramolecular thermal crossed [2 + 2] cycloaddition, enabled by the fluorine effect of in-situ-generated N-(homo)allyl gem-difluoroenamines and homoallyl gem-difluorovinyl ethers. Silver-catalysed gem-difluoroalkenylation of N-(homo)allylamines and homoallyl alcohols with trifluoromethyl triftosylhydrazones, respectively, followed by an intramolecular crossed [2 + 2] cycloaddition of the in-situ-generated gem-difluoroalkenes enables the synthesis of a range of medically relevant gem-difluoro heterobicyclo[n.1.1]alkanes, including azabicyclo[2.1.1]hexanes, azabicyclo[3.1.1]heptanes and oxabicyclo[3.1.1]heptanes. This methodology features readily available starting materials, high chemo-, regio- and stereoselectivity, excellent functional group compatibility and high yields. Notably, further conversion of the formed azabicyclo[2.1.1]hexanes into azabicyclic endoperoxides via oxygen incorporation highlights the properties of these gem-difluorinated bridged azabicyclic compounds. Combined experimental and computational studies support a stepwise radical mechanism for the thermal crossed [2+2] cycloaddition.

Identifiers

PMID41526488

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.