Light-Promoted Allylation of Iododifluoromethylated Alcohols

Article abstract of DOI:10.1002/ejoc.201800543

A method for the synthesis of β,β-difluorinated alcohols by the formal substitution of iodine in the iododifluoromethyl fragment by the allyl group is described. The reaction involves silylation of the starting alcohols with allyl(chloro)dimethylsilane followed by an light-promoted atom transfer process. The C,C-bond-forming event proceeds through 7-endo-trig radical cyclization.

Full text of DOI:10.1002/ejoc.201800543

A Journal of
Accepted Article
Title: Light-promoted allylation of iododifluoromethylated alcohols
Authors: Alexander Dilman, Liubov Panferova, and Marina Struchkova
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800543
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800543
Supported by

10.1002/ejoc.201800543
European Journal of Organic Chemistry
COMMUNICATION
Light-promoted allylation of iododifluoromethylated alcohols
Liubov I. Panferova,[a] Marina I. Struchkova,[a] Alexander D. Dilman*[a]
Abstract: A method for the synthesis of β,β-difluorinated alcohols by
the formal substitution of iodine in the iododifluoromethyl fragment
by the allyl group is described. The reaction involves silylation of the
starting alcohols with allyl(chloro)dimethylsilane followed by light-
promoted atom transfer process. The C,C-bond forming event
proceeds through 7-endo-trig radical cyclization.
radical attack at the silicon-tethered group can be applied to the
introduction of the allyl group. It should also be pointed out that
light initiated reactions have attracted increasing attention over
last decade.[9]
Results and Discussion
Introduction
Alcohols 1 were first treated with allyl(chloro)dimethylsilane and
triethylamine in acetonitrile for one hour to generate silyl ethers
2 (Table 1). Then, to the same reaction flask, an iridium
photocatalyst, fac- Ir(ppy)3 (0.5 mol%), was added along with 0.2
equiv of triphenylphlosphine,[8] and the mixture was irradiated
with a strip of 400 nm light-emitting diodes. After consumption of
the silyl ether (from 12 to 18 h), tetrabutylammonium fluoride
was added to effect the removal of the silyl fragment, and then
the mixture was worked-up. In some cases, products 3 were
contaminated with 1-3% of starting alcohols 1 which cannot be
separated by flash chromatography. Since, even after prolonged
reaction times we have not been able to drive the reaction to
completion, alcohols 1 were eliminated chemically by heating
the mixture with 0.5 equiv of trimethylamine in ethanol. Finally,
allylated products 3 were obtained in good yields based on
alcohols 1. The reaction worked well with alcohols 1 derived
from aromatic aldehydes bearing electron-withdrawing and
electron-donating groups, and substituents at the ortho-position,
as well as heteroaromatic aldehydes. However, for the alcohol
originating from hydrocinnamaldehyde, product 3o was obtained
in reduced yield of 50%. Unfortunately, in the reaction of an
alcohol derived from cinnamaldehyde, the expected product was
formed in about 15% yield according to 19F NMR.
Organofluorine compounds have found widespread applications
in medicinal chemistry, agrochemistry and materials science.[1]
While the trifluoromethyl group has been in the focus for a long
time,[2] compounds bearing the difluoromethylene fragment have
gained increasing attention only recently. In particular, isosteric
relationship of the CF2-unit to ethereal oxygen makes such
compounds useful for drug design.[3] Several strategies toward
CF2-containing molecules are known involving deoxofluorination
reaction, building block approach, and transformations of
difluorocyclopropanes.[4] At the same time, assembling
difluorinated compounds from two independent non-fluorinated
[5]
and the difluoromethylene fragment would be desirable
(Scheme 1, eq. a).
Recently, we[6] and the group of Hu[7] developed efficient
methods to access iododifluoromethylated alcohols 1 from
carbonyl compounds and equivalents of iododifluoromethyl
carbanion (eq. b). We also demonstrated that in alcohols 1, the
iodine atom can be formally substituted by the vinyl group
through the radical atom transfer protocol[8]. Herein we report
that similar light-promoted processes relying on intramolecular
Concerning the mechanism, it is likely that the reaction
proceeds via radical atom transfer[10] pathway (Scheme 2). First,
the reductive cleavage of the carbon-iodine bond by the light
activate photocatalyst[11] generates radical 4. Subsequent 7-
endo-trig cyclization leads to radical 5, which abstracts the
iodine atom from silyl ether 2 with concomitant regeneration of
radical 4. Finally, intermediate 6 undergoes facile chloride-
mediated fragmentation of the β-iodo-substituted silane.[12,13]
Scheme 1. Transformations of alcohols 1.
[a]
L. I. Panferova, M. I. Struchkova, A. D. Dilman
N. D. Zelinsky Institute of Organic Chemistry
119991 Moscow, Leninsky prosp. 47, Russian Federation
E-mail: adil25@mail.ru
http://www.ioc.ac.ru/dilman/index_engl.html
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Proposed mechanism.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800543
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Allylation of alcohols 1.[a]
[a] Isolated yield.
When
allyltrimethylsilane
was
used
instead
of
allyl(chloro)dimethylsilane in the reaction with alcohol 1a (R = 4-
ClC6H4) under typical conditions, the expected product 3a was
formed in the yield of 40%. However, noticeable amounts of
hydrodeiodinated compound were observed, which is produced
from gem-difluorinated radical by hydrogen atom abstraction.
Apparently, intermolecular radical attack onto allyltrimethylsilane
is less efficient compared to intramolecular pathway.
The selectivity of the cyclization of radical 4 deserves
additional comments. Thus, the cyclization may proceed either
via 6-exo or 7-endo modes. While for radical systems 6-exo
mode can be preferable,[14] we have not observed products
originating from this pathway. To support the observed
selectivity, we performed quantum chemical calculations of
intramolecular radical attack. For comparison, data for the
previously reported process involving radical attack at the vinyl
group,[8] were also obtained. Free energy profiles of these
elementary steps were calculated at the UM06-2X/6-31+G(d)
level (Figure 1). For the allyl system (left), the activation energy
of the 7-endo process is 2.5 kcal/mol lower than that of 6-exo
(black). In this case, the relative energies of transition states
Figure 1. Calculated free energy profiles (in kcal/mol).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800543
European Journal of Organic Chemistry
COMMUNICATION
[1]
[2]
(a) J. Wang, M. Sanchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014,
114, 2432–2506. (b) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330. (c) P. Kirsch,
Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004.
(a) J.-A. Ma, D. Cahard, J. Fluorine Chem. 2007, 128, 975–996. (b) G.
K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757–786. (c) J.
Charpentier, N. Früh, A. Togni, Chem. Rev. 2015, 115, 650–682. (d) A.
Studer, Angew. Chem. Int. Ed. 2012, 51, 8950–8958. (e) L. Chu, F.-L.
Qing, Acc. Chem. Res. 2014, 47, 1513–1522. (f) C. Alonso, E. M. de
Marigorta, G. Rubiales, F. Palacios, Chem. Rev. 2015, 115, 1847–1935.
(g) A. D. Dilman, V. V. Levin, Eur. J. Org. Chem. 2011, 831–841.
(a) G. M. Blackburn, D. A. England, F. Kolkmann, J. Chem. Soc., Chem.
Commun. 1981, 930–932. (b) Y. Xu, J. Aoki, K. Shimizu, M. Umezu-
Goto, K. Hama, Y. Takanezawa, S. Yu, G. B. Mills, H. Arai, L. Qian, G.
D. Prestwich, J. Med. Chem. 2005, 48, 3319–3327.
may come from higher thermodynamic stability of the resulting
secondary vs. primary radicals.[15] On the other hand, for the
vinyl system (right), transition state of 5-exo mode is lower than
that of 6-endo, despite formation of the less stable primary
radical. In the latter case, the entropic contribution likely
overrides thermodynamic driving force.
Conclusions
In summary, a method for the substitution of the iodine atom in
the iododifluoromethyl group by the allyl group is described. The
silyl tether serves to connect the reacting functional groups,
thereby rendering radical attack intramolecular. In the reaction,
7-endo radical cyclization constitutes the key carbon-carbon
bond forming event.
[3]
[4]
[5]
[6]
(a) M. J. Tozer, T. F. Herpin, Tetrahedron 1996, 52, 8619–8683. (b) F.-
L. Qing, F. Zheng, Synlett 2011, 1052–1072. (c) X. Song, C. Xu, M.
Wang, Tetrahedron Lett. 2017, 58, 1806–1816. (d) B. Gao, C. Ni, J. Hu,
Chimia 2014, 68, 414–418.
(a) V. V. Levin, A. A. Zemtsov, M. I. Struchkova, A. D. Dilman, Org. Lett.
2013, 15, 917–919. (b) V. V. Levin, A. A. Zemtsov, M. I. Struchkova, A.
D. Dilman, J. Fluorine Chem. 2015, 171, 97–101. (c) A. D. Dilman, V. V.
Levin, Mendeleev Commun. 2015, 25, 239–244.
Experimental Section
Allyl(chloro)dimethylsilane (91 μL, 0.6 mmol) and triethylamine (84 μL,
0.6 mmol) were added to a solution of alcohol 1 (0.5 mmol) in acetonitrile
(1.5 mL) at room temperature, and the mixture was stirred for 3 h. Then,
triphenylphosphine (26.2 mg, 0.1 mmol), and fac-Ir(ppy)3 (1.6 mg, 0.0025
mmol) were added. The reaction vessel was irradiated with a strip of 400
nm LEDs (for 3a,c-j,o, 12 h; for 3b,k-m, 16 h; for 3n, 18 h); during
irradiation the mixture was cooled with room temperature water. Tetra-n-
butylammonium fluoride trihydrate (315 mg, 1 mmol) was added, and the
mixture was stirred at room temperature (for 3a-g,m,o, 3 h; for 3h-l,n, 5
h). For the workup, the mixture was diluted with water (5 mL) and
extracted with hexane/EtOAc (2/1, 3×10 mL). The combined extracts
were filtered through Na2SO4 and concentrated under reduced pressure,
and the residue was purified by column chromatography.
(a) M. D. Kosobokov, V. V. Levin, M. I. Struchkova, A. D. Dilman, Org.
Lett. 2014, 16, 3784–3787. (b) V. V. Levin, V. O. Smirnov, M. I.
Struchkova, A. D. Dilman, J. Org. Chem. 2015, 80, 9349–9353.
(a) Y. Zhao, B. Gao, J. Hu, J. Am. Chem. Soc. 2012, 134, 5790–5793.
(b) W. Miao, C. Ni, Y. Zhao, J. Hu, Org. Lett. 2016, 18, 2766–2769.
L. I. Panferova, M. I. Struchkova, A. D. Dilman, Synthesis 2017, 49,
4124–4132.
[7]
[8]
[9]
(a) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322–5363. (b) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org.
Chem. 2016, 81, 6898–6926. (c) J. W. Tucker, C. R. J. Stephenson, J.
Org. Chem. 2012, 77, 1617–1622. (d) D. M. Schultz, T. P. Yoon,
Science 2014, 343, 1239176. (e) T. P. Yoon, ACS Catal. 2013, 3, 895–
902.
[10] (a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J. Stephenson, J.
Am. Chem. Soc. 2012, 134, 8875–8884. (b) E. Arceo, E. Montroni, P.
Melchiorre, Angew. Chem. Int. Ed. 2014, 53, 12064–12068. (с) R.
Beniazza, R. Atkinson, C. Absalon, F. Castet, S. A. Denisov, N. D.
McClenaghan, D. Lastécouères, J.-M. Vincent, Adv. Synth. Catal. 2016,
358, 2949–2961.
For compounds 3b,c,e,g,h,j,n, the material obtained after
chromatography was dissolved in ethanol (1 mL) followed by addition of
trimethylamine (2.5 mmol, 340 µL of 50% aqueous solution). The
reaction vessel was tightly closed, and the mixture was heated at 70 °C
for 2 h with stirring. Then, the mixture was cooled to room temperature,
water (3 mL) was added, and the product was extracted with pentane
(3×5 mL). The combined organic layers were filtered through Na2SO4,
and pentane was evaporated at atmospheric pressure.
[11] (a) D. Staveness, I. Bosque, C. R. J. Stephenson, Acc. Chem. Res.
2016, 49, 2295–2306. (b) T. Chatterjee, N. Iqbal, Y. You, E. J. Cho, Acc.
Chem. Res. 2016, 49, 2284–2294.
[12] J. B. Lambert, Y. Zhao, R. W. Emblidge, L. A. Salvador, X. Liu, J.-H. So,
E. C. Chelius, Acc. Chem. Res. 1999, 32, 183–190.
Acknowledgements
[13] Chloride ion comes from triethylammonium chloride formed at the
silylation step.
[14] (a) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925–
3941. (b) W. F. Bailey, S. C. Longstaff, Org. Lett. 2001, 3, 2217–2219.
[15] For an example of preferred 7-endo cyclization, see: (a) J. Justicia, J. L.
Oller-Lopez, A. G. Campana, J. E. Oltra, J. M. Cuerva, E. Bunuel, D. J.
Cardenas, J. Am. Chem. Soc. 2005, 127, 14911–14921. (b) T.
Taniguchi, K. Iwasaki, M. Uchiyama, O. Tamura, H. Ishibashi, Org. Lett.
2005, 7, 4389–4390.
This work was supported by the Russian Science Foundation
(project 17-13-01041).
Keywords: organofluorine compounds• silicon reagents •
radicals • atom transfer • photocatalysis
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800543
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Organofluorine chemistry*
Liubov I. Panferova, Marina I.
Struchkova, Alexander D. Dilman*
Page No. – Page No.
Light-promoted allylation of
A formal substitution of the iodine atom in iododifluoromethylated alcohols by the
allyl group is described. The reaction involves silylation of the hydroxy group with
allyl(chloro)dimethylsilane followed by a light mediated radical process based on 7-
endo-trig cyclization. The method provides straightforward access to β,β-
difluorinated alcohols.
iododifluoromethylated alcohols
This article is protected by copyright. All rights reserved.