NEW FRONTIERS OF DIFLUOROCYCLOPROPANATION OF ALKENES USING RUPPERT–PRAKASH REAGENT

Prof. Sergey V. Ryabukhin Prof. Dmitriy M. Volochnyuk

257th ACS National Meeting April 2019 Orlando

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Enamine profile • Scientifically driven chemical company • Privately owned, founded in 1991 • Research & Production facility in Kiev, Ukraine • Over 500 synthetic chemists • 2.7M Screening Compounds, the world’s largest! • 180k Building Blocks, 50% of the world’s stock! • Biology services: ADME/T tests, animal studies and molecular screening • No own drug research, 100% service orientated • Representative and distribution offices in EU, USA, Japan, and China

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Goldberg F. W. et al Drug Discov Today 2015, 20, 11-17. Itoh, T. 2009, in Fluorine in Medicinal Chemistry & Chemical Biology

Why are difluorocyclopropanes?

Chapter 9: gem-Difluorocyclopropanes as Key

Building Blocks for Novel Biologically Active Molecules

All Hallmarks of the Building Blocks for MedChem:

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Why is Difluorocyclopropanation?

J. Am. Chem. Soc., 1996, 118, 8860 – 8870 .

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Starting materials

! Tolerant to majority of protected common functional group

Prakash Protocol: 2,5 eq TMSCF3, 0,2 eq NaI, 650C, 2 h.

Prakash G. K. S. et al Angew. Chem. Int. Ed. 2011, 50, 7153. Bychek R., Levterov V. et al Eur. J. Org. Chem, 2018, 24, 12291.

Products Dr. P. Mykhailiuk

Tolerance of FG to Prakash protocol

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TMSCF3/NaI Prakash protocol: limitation Failed but not critical Failed but CRITICAL!!!

not applicable for wide using

+ in some cases Dolbier (FSO2CF2SiMe3) or Haszeldine

(ClF2CO2Na or BrF2CO2Na) reagents are applicable

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TMSCF3/NaI competition experiment

Solvent Conversion of 9a, (%)

after 2 h after 4 h

THF >99 >99

1,4-Dioxane 0 N/A

t-BuOMe 0 N/A

MeCN 0 N/A

1,2-DME 33 77

Adv. Synth. Catal., 2017, 359, 3126.

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TMSCF3/NaI blank experiment

Batch Prakash protocol to Flow Charette protocol (10 min residence time) leads to increasing of the yield.

Angew. Chemie Int. Ed. 2011, 50, 7153–7157 Org. Lett., 2016, 18, pp 1988–1991

Modified batch protocol (“slow addition”): Slow (up to 24h) addition of the excess Me3SiCF3 (up to 10 eq) to the reaction mixture according to the difluorocyclopropanation kinetics.

Adv. Synth. Catal., 2017, 359, 3126.

Pavel Nosik

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TMSCF3/NaI “slow addition”

Prakash protocol: Slow addition protocol:

Adv. Synth. Catal., 2017, 359, 3126.

trace amounts of desired product

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TMSCF3/NaI “slow addition” impact Chemical space of BB covered by TMSCF3

difluorocyclopropanation as a key step (Enamine LTD data)

New fluorinated BBs with diverse 3D architecture

Procedure # of BBs synthesi

sed

# of BBs included

into validated virtual set

Prakash 76 1043

Prakash + “slow addition” 121 1812

Another reagents 112 2486

Adv. Synth. Catal., 2017, 359, 3126.

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TMSCF3/NaI “slow addition” impact

M. Goswami et al Chem. Commun., 2017, 53, 4382-4385

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TMSCF3/NaI “slow addition” impact

Adv. Synth. Catal. 2018, 360, 4104–4114

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TMSCF3/NaI “slow addition”

Adv. Synth. Catal. 2018, 360, 4104–4114

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TMSCF3/NaI “slow addition”

First functionalized alkenes:

2017 2018

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TMSCF3/NaI “slow addition” impact

Nosik, P. S. et al, Gram‐Scale Synthesis of Amines Bearing a

gem‐Difluorocyclopropane Moiety Adv. Synth. Catal. 2017, 359, 3126

Very Important Publication Nosik, P. S., et al Transition Metal‐free

gem‐difluorocyclopropanation of Alkenes with CF3SiMe3−NaI System: a Recipe for

Electron‐deficient Substrates. Adv. Synth. Catal. 2018, 360, 4104–4114

How to train the dragon?

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Difluorocyclopropanes

https://www.enamine.net/download/posters/Enamine_Difluorocyclopropanes-for-drug-discovery_A4_2018.pdf

Adv. Synth. Catal. 2018, 360, 4104–4114

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1-hetaryl-2,2-difluorocyclopropanes

In a case of two fluorine atoms only cyclopropane derivatives “in a Ro2” e.g. ΔMW of BB fragment <

200 Da

Drug Discov Today 2015, 20, 11-7

Heterocycle: decreased LogP and increased water solubility in comparison with arene derivative

Eur J Med Chem. 2016, 29, 1057-1068.

J. Fluor. Chem. 2019, 217, 80–89.

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Pyrazole: good model heterocycle

• 3- p-acceptor • 4- p-donor • 5- p-amphoteric

Monatsh. Chem. 2016, 147, 1629-1634.

SynOpen 2017, 01, 84-90.

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1-pyrazolyl-2,2-difluorocyclopropanes

General retrosynthetic scheme

Experimental validation: “push-pull like” alkene still does not working but “kapto-dative like” alkenes are active in a “slow

addition” protocol conditions

J. Fluor. Chem. 2019, 217, 80–89.

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Limitations: Expected

K. R. Gassen, et al J. Fluor. Chem. 1990, 49, 127–139 V. Kubyshkin, et al J. Fluor. Chem. 2015, 175, 73–83.

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Limitations: Unexpected

Schneider, T. F. et al Angew. Chem. Int. Ed. 2014, 53, 2–22

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# FG Heterocycle type

BB type BB Type

1 COOH, p-acceptor feasible

feasible but problematic

2 - //- p-amphoteric/neutral feasible with low yield 3 - //- p-donor non- feasible

4 CH2OH, CH2NH2

p-acceptor feasible

feasible but problematic

5 - //- p-amphoteric/neutral feasible with low yield 6 - //- p-donor

7 NH2 p-acceptor non- feasible non- feasible 8 - //- p-amphoteric/neutral

9 - //- p-donor

General guidelines

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Future directions

Tolerate Unstable towards

HNO3 – H2SO4

Br2

DMF – POCl3

LiBH4

KMnO4 or MnO2

2/12 M aq. HCl, 100 C

2 M aq. NaOH, 100 C

Pd(dppf)Cl2, B2Pin2, 80 Ca

Pd(PPh3)4, 85 C

Pd(OAc)2, PPh3, CuI, 85 C

n-BuLi, LiHMDS, LDA or

i-PrMgClLiCl, THF, –78 C

LiTMP, THF, –100C

H2 (1 atm), Pd-C, rt

CH3C(O)Cl, AlCl3

Tolerance of N-(gem-difluorocyclopropyl)pyrazoles to common organic reactions

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Summary

Scope of the substrates Extremely expanded

Understanding of scope No

Mechanistic investigations No

Scale up To 300 g Tolerance to common FG or its

protected forms Investigated

Tolerance to deprotection of final functional F2cPr Investigated

Tolerance to common organic reactions of final functional

F2cPr Partially investigated

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Acknowledgements

Pavel S. Nosik Dr. Oleksandr O. Grygorenko Kostiantyn P. Melnykov Andrii S.Poturai Mykola O. Pashko

THANK YOU FOR YOUR KIND ATTENTION