Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

  1. Artem A. Zemtsov1,
  2. Alexander D. Volodin1,2,
  3. Vitalij V. Levin1,
  4. Marina I. Struchkova1 and
  5. Alexander D. Dilman1

1N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
2Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Miusskaya sq. 9, Russian Federation

  1. Corresponding author email

This article is part of the Thematic Series "Copper catalysis in organic synthesis".

Guest Editor: S. R. Chemler
Beilstein J. Org. Chem. 2015, 11, 2145–2149. https://doi.org/10.3762/bjoc.11.231
Received 20 Aug 2015, Accepted 20 Oct 2015, Published 10 Nov 2015

  • Letter

Abstract

α,α-Difluoro-substituted organozinc reagents generated from conventional organozinc compounds and difluorocarbene couple with 1-bromoalkynes affording gem-difluorinated alkynes. The cross-coupling proceeds in the presence of catalytic amounts of copper iodide in dimethylformamide under ligand-free conditions.

Keywords: 1-bromoalkynes; cross-coupling; organofluorine compounds; organozinc reagents

Introduction

gem-Difluorinated organic compounds have attracted increasing attention nowadays due to their applicability in medicinal chemistry [1,2] and other fields. Indeed, unique stereoelectronic properties of the CF2-unit may be exploited in conformational analysis [3-5], carbohydrate and peptide research [6,7], and reaction engineering [8,9].

Typically, the difluoromethylene fragment is created by deoxyfluorination, which requires harsh or hazardous conditions [10,11]. Alternatively, functional group manipulations starting from available CF2-containing building blocks can be considered, but multistep sequences render this approach laborious [12-14]. Difluoro-substituted cyclopropanes and cyclopropenes constitute a specific class of compounds accessible by difluorocarbene addition to multiple bonds [15].

Recently, we proposed a general method for assembling gem-difluorinated structures from organozinc reagents 1, difluorocarbene, and a terminating electrophile [16-21] (Scheme 1). (Bromodifluoromethyl)trimethylsilane [16-18] or potassium bromodifluoroacetate [19] can be used as precursors of difluorocarbene. In this process, the use of C-electrophiles is particularly important since it allows for the formation of two C–C bonds within one experimental run. Previously, as C-electrophiles in this methodology, only allylic substrates [17] and nitrostryrenes (with the NO2 serving as a leaving group) [20], were employed. Herein, we report that 1-bromoalkynes, which are known to be involved in reactions with various organometallic compounds [22-27], can be used as suitable coupling partners for difluorinated organozinc compounds 2. This reaction provides straightforward access to α,α-difluorinated alkynes [13,14,28-31]. Our method is based on facile zinc/copper exchange allowing for versatile couplings described for non-fluorinated organozinc compounds [32-37].

[1860-5397-11-231-i1]

Scheme 1: Reaction of organozinc compounds.

Results and Discussion

Organozinc compound 2a generated from benzylzinc bromide was first evaluated in a reaction with haloalkynes derived from phenylacetylene (Table 1). First, most reactive iodo-substituted alkyne 3a-I (X = I) was evaluated in the presence of copper iodide (10 mol %). Expected product 4a was formed in 12% yield, but its yield was tripled simply by adding 2 equiv of DMF additive (Table 1, entries 1 and 2). However, in these experiments, the reaction mixtures contained about 40% of (2,2-difluoro-2-iodoethyl)benzene (PhCH2CF2I) arising from zinc/iodine exchange between 2a and the iodoalkyne. Chloroalkyne 3a-Cl was markedly less reactive, likely because of the strong carbon–chlorine bond. Fortunately, bromoalkyne 3a-Br provided the best results, with the optimal conditions involving the use of DMF as a solvent and only 5 mol % of copper iodide at 0 °C to room temperature, which afforded the coupling product in 79% isolated yield (Table 1, entry 5). The addition of various ligands, as well as the use of other copper salts, did not had a beneficial effect.

Table 1: Optimization studies.

[Graphic 1]
Entry X 2a (equiv) Conditions Solvent CuI (equiv) Additive (equiv) Yield of 4a, %a
1 I 2 −50 °C → rt; 4 h at rt MeCN 0.1 – 12
2 I 1.3 −50 °C → rt; 4 h at rt MeCN 0.1 DMF (2) 35
3 Cl 2 0 °C → rt; 16 h at rt MeCN 0.1 DMF (2) 32
4 Br 1.5 0 °C → rt; 16 h at rt MeCN 0.1 DMF (2) 60
5 Br 1.5 0 °C → rt; 16 h at rt DMF 0.05 – 79b

aDetermined by 19F NMR with internal standard. bIsolated yield.

Under the optimized conditions, a series of organozinc compounds 2 were coupled with bromoalkynes 3 (Table 2). Good yields of coupling products 4 were typically achieved. The reaction tolerates ester groups or TBS-protected hydroxy groups. Aromatic iodide also remains unaffected (Table 2, entry 2).

Table 2: Reaction of organozinc compounds 2 with bromoalkynes 3.

[Graphic 2]
Entry 2 3 4 Yield of 4, %a
1 [Graphic 3]
2a 		[Graphic 4]
3b 		[Graphic 5]
4b 		84
2 2a [Graphic 6]
3c 		[Graphic 7]
4c 		82
3 2a [Graphic 8]
3d 		[Graphic 9]
4d 		70
4 2a [Graphic 10]
3e 		[Graphic 11]
4e 		84
5 2a [Graphic 12]
3f 		[Graphic 13]
4f 		67
6b 2a [Graphic 14]
3g 		[Graphic 15]
4g 		80
7b 2a [Graphic 16]
3h 		[Graphic 17]
4h 		75
8 [Graphic 18]
2b 		[Graphic 19]
3a-Br 		[Graphic 20]
4i 		80
9 [Graphic 21]
2e 		[Graphic 22]
3a-Br 		[Graphic 23]
4j 		81
10 [Graphic 24]
2c 		[Graphic 25]
3a-Br 		[Graphic 26]
4k 		72
11b [Graphic 27]
2c 		[Graphic 28]
3g 		[Graphic 29]
4l 		71
12b [Graphic 30]
2d 		[Graphic 31]
3g 		[Graphic 32]
4m 		62

aIsolated yield. bThe crude product was desilylated.

As for the mechanism, we believe that the reaction starts with the zinc/copper exchange resulting in the formation of fluorinated organocopper species 5 (Scheme 2). Compound 5 interacts with bromoalkyne 3 either by oxidative addition generating copper(III) intermediate 6 or by triple bond carbometallation [38] generating copper(I) intermediate 7. Subsequent reductive elimination (from 6) or β-elimination (from 7) leads to the product and regenerates the copper(I) catalyst.

[1860-5397-11-231-i2]

Scheme 2: Proposed mechanism.

Conclusion

In summary, a method for the copper-catalyzed coupling of α,α-difluoro-substituted organozinc compounds with 1-bromoalkynes has been developed. The reaction is performed under mild conditions affording gem-difluoro-substituted alkynes in good yields.

Supporting Information

Supporting Information File 1: Full experimental details, compound characterization, and copies of NMR spectra.
Format: PDF Size: 2.1 MB Download

Acknowledgements

This work was supported by the Ministry of Science (project MD-3256.2015.3) and Russian Foundation for Basic Research (projects 14-03-00293, 14-03-31253, 13-03-12074).

References

  1. Ojima, I., Ed. Fluorine in Medicinal Chemistry and Chemical Biology; John Wiley & Sons: Chichester, 2009.
    Return to citation in text: [1]
  2. Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons: Hoboken, New Jersey, 2008. doi:10.1002/9780470281895
    Return to citation in text: [1]
  3. O'Hagan, D.; Wang, Y.; Skibinski, M.; Slawin, A. M. Z. Pure Appl. Chem. 2012, 84, 1587–1595. doi:10.1351/PAC-CON-11-09-26
    Return to citation in text: [1]
  4. Wang, Y.; Callejo, R.; Slawin, A. M. Z.; O'Hagan, D. Beilstein J. Org. Chem. 2014, 10, 18–25. doi:10.3762/bjoc.10.4
    Return to citation in text: [1]
  5. Urbina-Blanco, C. A.; Skibinski, M.; O'Hagan, D.; Nolan, S. P. Chem. Commun. 2013, 49, 7201–7203. doi:10.1039/c3cc44312d
    Return to citation in text: [1]
  6. Leclerc, E.; Pannecoucke, X.; Ethève-Quelquejeu, M.; Sollogoub, M. Chem. Soc. Rev. 2013, 42, 4270–4283. doi:10.1039/C2CS35403A
    Return to citation in text: [1]
  7. Kubyshkin, V. S.; Mykhailiuk, P. K.; Afonin, S.; Ulrich, A. S.; Komarov, I. V. Org. Lett. 2012, 14, 5254–5257. doi:10.1021/ol302412a
    Return to citation in text: [1]
  8. Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang, P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 16793–16797. doi:10.1073/pnas.0707090104
    Return to citation in text: [1]
  9. Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. J. Am. Chem. Soc. 2008, 130, 11486–11493. doi:10.1021/ja803086r
    Return to citation in text: [1]
  10. Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683. doi:10.1016/0040-4020(96)00311-0
    Return to citation in text: [1]
  11. Al-Maharik, N.; O'Hagan, D. Aldrichimica Acta 2011, 44, 65–75.
    Return to citation in text: [1]
  12. Qing, F.-L.; Zheng, F. Synlett 2011, 1052–1072. doi:10.1055/s-0030-1259947
    Return to citation in text: [1]
  13. Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X. Chem. – Eur. J. 2015, 21, 12836–12865. doi:10.1002/chem.201501475
    Return to citation in text: [1] [2]
  14. Gao, B.; Ni, C.; Hu, J. Chimia 2014, 68, 414–418. doi:10.2533/chimia.2014.414
    Return to citation in text: [1] [2]
  15. Dolbier, W. R., Jr.; Battiste, M. A. Chem. Rev. 2003, 103, 1071–1098. doi:10.1021/cr010023b
    Return to citation in text: [1]
  16. Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2013, 15, 917–919. doi:10.1021/ol400122k
    Return to citation in text: [1] [2]
  17. Zemtsov, A. A.; Kondratyev, N. S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 818–822. doi:10.1021/jo4024705
    Return to citation in text: [1] [2] [3]
  18. Smirnov, V. O.; Struchkova, M. I.; Arkhipov, D. E.; Korlyukov, A. A.; Dilman, A. D. J. Org. Chem. 2014, 79, 11819–11823. doi:10.1021/jo5023537
    Return to citation in text: [1] [2]
  19. Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. J. Fluorine Chem. 2015, 171, 97–101. doi:10.1016/j.jfluchem.2014.08.021
    Return to citation in text: [1] [2]
  20. Kondratyev, N. S.; Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. J. Fluorine Chem. 2015, 176, 89–92. doi:10.1016/j.jfluchem.2015.06.001
    Return to citation in text: [1] [2]
  21. Smirnov, V. O.; Maslov, A. S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Russ. Chem. Bull. 2014, 63, 2564–2566. doi:10.1007/s11172-014-0778-1
    Return to citation in text: [1]
  22. Thaler, T.; Guo, L.-N.; Mayer, P.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 2174–2177. doi:10.1002/anie.201006879
    Return to citation in text: [1]
  23. Corpet, M.; Bai, X.-Z.; Gosmini, C. Adv. Synth. Catal. 2014, 356, 2937–2942. doi:10.1002/adsc.201400369
    Return to citation in text: [1]
  24. Cornelissen, L.; Lefrancq, M.; Riant, O. Org. Lett. 2014, 16, 3024–3027. doi:10.1021/ol501140p
    Return to citation in text: [1]
  25. Wang, S.; Wang, M.; Wang, L.; Wang, B.; Li, P.; Yang, J. Tetrahedron 2011, 67, 4800–4806. doi:10.1016/j.tet.2011.05.031
    Return to citation in text: [1]
  26. Castagnolo, D.; Botta, M. Eur. J. Org. Chem. 2010, 3224–3228. doi:10.1002/ejoc.201000393
    Return to citation in text: [1]
  27. Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012, 41, 4165–4179. doi:10.1039/c2cs35034c
    Return to citation in text: [1]
  28. Besset, T.; Poisson, T.; Pannecoucke, X. Eur. J. Org. Chem. 2014, 7220–7225. doi:10.1002/ejoc.201402937
    Return to citation in text: [1]
  29. Arimitsu, S.; Fernández, B.; del Pozo, C.; Fustero, S.; Hammond, G. B. J. Org. Chem. 2008, 73, 2656–2661. doi:10.1021/jo7025965
    Return to citation in text: [1]
  30. Hammond, G. B. J. Fluorine Chem. 2006, 127, 476–488. doi:10.1016/j.jfluchem.2005.12.024
    Return to citation in text: [1]
  31. Xu, B.; Mae, M.; Hong, J. A.; Li, Y.; Hammond, G. B. Synthesis 2006, 803–806. doi:10.1055/s-2006-926334
    Return to citation in text: [1]
  32. Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004, 126, 10240–10241. doi:10.1021/ja0467768
    Return to citation in text: [1]
  33. Thapa, S.; Kafle, A.; Gurung, S. K.; Montoya, A.; Riedel, P.; Giri, R. Angew. Chem., Int. Ed. 2015, 54, 8236–8240. doi:10.1002/anie.201502379
    Return to citation in text: [1]
  34. Karstens, W. F. J.; Moolenaar, M. J.; Rutjes, F. P. J. T.; Grabowska, U.; Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40, 8629–8632. doi:10.1016/S0040-4039(99)01808-0
    Return to citation in text: [1]
  35. Knochel, P. Organomagnesium and Organozinc Chemistry. In Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2013; pp 223–372. doi:10.1002/9781118484722.ch2
    Return to citation in text: [1]
  36. Knochel, P. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 387–419.
    Return to citation in text: [1]
  37. Geurts, K.; Fletcher, S. P.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Pure Appl. Chem. 2008, 80, 1025–1037. doi:10.1351/pac200880051025
    Return to citation in text: [1]
  38. Cahiez, G.; Gager, O.; Buendia, J. Angew. Chem., Int. Ed. 2010, 49, 1278–1281. doi:10.1002/anie.200905816
    Return to citation in text: [1]

Article is part of the thematic issue

Copper catalysis in organic synthesis

Sherry R. Chemler

Interesting articles

Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs

Fabrice Chemla, Florian Dulong, Franck Ferreira and Alejandro Pérez-Luna

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

Fei Wang, Lingchun Li, Chuanfa Ni and Jinbo Hu

Annulation of 1H-pyrrole-2,3-diones by thioacetamide: an approach to 5-azaisatins

Aleksandr I. Kobelev, Ekaterina E. Stepanova, Maksim V. Dmitriev and Andrey N. Maslivets

News

Register for this Beilstein Symposium - it's free and online!
Logo OA

2.622 is the 2019 Journal Impact Factor.
Logo OA

Beilstein Archives – the preprint server for the Beilstein Journals
Logo OA

© 2015 Zemtsov et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

 
Back to Article List

Other Beilstein-Institut Open Science Activities

Logo
Logo
Logo
Logo

Keep Informed

RSS Feed

Subscribe to our Latest Articles RSS Feed.

Subscribe

Follow the Beilstein-Institut

LinkedIn

Twitter: @BeilsteinInst