A general photoinduced electron transfer-directed chemoselective perfluoroalkylation of N,N-dialkylhydrazones

Jin Xie a, Jian Li a, Thomas Wurm a, Vanessa Weingand a, Hui-Ling Sung ab, Frank Rominger a, Matthias Rudolph a and A. Stephen K. Hashmi *ac
aOrganisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany. E-mail: hashmi@hashmi.de
bDivision of Preparatory Programs for Overseas Chinese Students, National Taiwan Normal University, Taiwan
cChemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia

Received 14th April 2016 , Accepted 9th May 2016

First published on 10th May 2016


A selective, practical and general incorporation of fluoroalkyl groups into organic frameworks is of great interest for synthesis. Herein we report the first metal-free, initiator-free, and general photochemical perfluoroalkylation of a variety of N,N-dialkylhydrazones at room temperature in the absence of any external photocatalyst. It constitutes an important advance in perfluoroalkyl radical addition to C[double bond, length as m-dash]N π bonds for the synthesis of hydrazones instead of amines. Affordable and easily available perfluoroalkyl iodides serve as effective precursors. The excellent regio-, stereo- and chemoselectivity as well as the broad substrate scope make this a very promising synthetic tool.

Fluorine-containing organic compounds possess significant biological activities and intrinsic physical properties in pharmaceuticals,1 agrochemicals,2 material science3 and PET (positron emission tomography) imaging technology.4 Thus synthetic and medicinal chemists developed efficient methods for the selective introduction of perfluoroalkyl groups at important organic backbones by using nucleophilic or electrophilic fluoroalkyl reagents.5 Besides transition-metal-mediated cross-coupling methods,6 radical perfluoroalkylations have recently emerged as a new attractive technology to accomplish this target.7 Despite intense efforts to efficiently generate an electron-deficient perfluoroalkyl radical (image file: c6qo00158k-t1.tif), such conversions usually depend on the use of transition-metal catalysts,7c–h oxidants,7i–l stoichiometric radical initiators8 and/or the requirement of high reaction temperatures.9 Therefore, the development of a mild and general method to connect a perfluoroalkyl group to versatile frameworks with cheap and widely available perfluoroalkyl halides would be very appealing. Hydrazones are not only the synthetic equivalent of aldehydes, but also important organic intermediates for a series of transformations.10 Undoubtedly, the successful incorporation of a perfluoroalkyl group into hydrazones could provide excellent fluorine-containing building blocks. Very recently, the others’ group and our group developed Cu-, Ir-, Pd- and Au-catalyzed trifluoromethylation and difluoroalkylation of aromatic aldehyde hydrazones with Togni reagent and difluoromethyl bromides, respectively (Scheme 1).11,12 As our follow-up work, we herein report the first metal-free, initiator-free and general methodology for radical perfluoroalkylation of aromatic as well as non-aromatic aldehyde hydrazones with readily available and affordable perfluoroalkyl iodides in the absence of any external photocatalyst, an important progress in radical additions to C[double bond, length as m-dash]N–π-bonds for the synthesis of hydrazones instead of amines.13
image file: c6qo00158k-s1.tif
Scheme 1 The strategies for perfluoroalkylation of hydrazones.

Photoredox catalysis is a powerful protocol to accomplish chemical transformations via a single electron transfer (SET) process.14 Recently, the photochemical activation of electron donor–acceptor (EDA) complexes became a new catalytic mode for clean intermolecular C–C coupling.15 In continuation of our efforts in fluoroalkylations of hydrazones,12 we hypothesized that an electron-rich hydrazone moiety could donate an electron to electron-deficient perfluoroalkyl iodides via a transiently generated EDA complex, ultimately yielding perfluoroalkylated hydrazones.

We first investigated the reaction of hydrazone 1a and nonafluoro-4-iodobutane 2a under irradiation with sunlight. The desired product 3aa was produced in 75% yield after 8 hours (Table 1, entry 1), which opens up a new route for radical addition to C[double bond, length as m-dash]N bonds not depending on metal reagents, radical initiators or toxic organotin reagents.13 The screening of different light sources showed that at 315–400 nm 3aa was formed in 94% yield (entries 1–6). Screening of different bases and solvents did not improve the reaction yield (entries 7–12, see ESI for details). The control experiment demonstrated that light was essential for the reaction, and no 3aa was formed even upon heating at 60 °C for 24 hours (entry 13). Decreasing the amount of nonafluoro-4-iodobutane 2a from 2 equiv. to 1.3 equiv. reduces the yield to 70% (entry 14). Only an (E)-configuration is observed for the C[double bond, length as m-dash]N bond of 3aa (see ESI for details).

Table 1 Optimization of the reaction conditionsa

image file: c6qo00158k-u1.tif

Entry Light source Base Time/h Yieldb
a Reaction conditions: 1a (0.2 mmol), 2a (2 equiv.), base (3 equiv.), MeCN (0.6 mL). b 19F NMR yield with 1,3,5-trifluorobenzene as an internal standard; the yield in brackets is the isolated yield. c MeOH was used. d CH2Cl2 was used. e The reaction was heated to 60 °C without light. f 1.3 equiv. 2a was employed. TMG = 1,1,3,3-tetramethylguanidine. CFL = compact fluorescent light bulbs.
1 Sunlight (A) Imidazole 8 75%
2 CFL (B) Imidazole 24 16%
3 λ = 400–500 nm (C) Imidazole 24 14%
4 Blue leds (D) Imidazole 24 5%
5 λ = 315–400 nm (E) Imidazole 12 94% (83%)
6 λ = 254 nm (F) Imidazole 12 Trace
7 E K2HPO4 12 87%
8 E Cs2CO3 12 70%
9 E 2,6-Lutidine 12 88%
10 E TMG 12 54%
11c E Imidazole 12 86%
12d E Imidazole 12 90%
13e Imidazole 24 0%
14f E Imidazole 12 70%
15 E with a bandpass filter (375 nm) Imidazole 24 38%

With the optimized reaction conditions (Table 1, entry 5), we first examined different electron donors (Scheme 2). N,N-Dialkyl hydrazones 1a–c were effective coupling partners, while other electron donors in 1d–f failed to show the metal-free perfluoroalkylation reaction, most probably due to their relatively weak electron donating ability. The investigation of the substrate scope of aromatic aldehyde hydrazones showed that both electron-poor and electron-rich substituents at the o-, m-, or p-position of the aromatic ring were compatible with excellent regio- and chemo-selectivity (Table 2). They can uniformly furnish the desired products 3ad–av in 50–97% yield in (E)-configuration (see Fig. 1 and ESI for details). A variety of important functional-groups, such as halogens, amides, tertiary amines, ethers, esters, alcohols and alkynes were tolerated well under the mild reaction conditions. The possibility of a late-stage modification of biologically active compounds was proven by the medically important helicide derivative 3av.

image file: c6qo00158k-s2.tif
Scheme 2 The results of various electron donors. Reaction conditions: 1 (0.2 mmol), 2a (2 equiv.), imidazole (3 equiv.), MeCN (0.6 mL), irradiation 12 hours with 315–400 nm light. Isolated yields.

image file: c6qo00158k-f1.tif
Fig. 1 The solid-state molecular structure of 3ak.16
Table 2 The substrate scope with regard to aromatic aldehyde hydrazonesa
a Reaction conditions: 1 (0.2 mmol), 2a (2 equiv.), imidazole (3 equiv.), MeCN (0.6 mL), irradiation under 315–400 nm light for the indicated time; the yields of isolated products. b 3 equiv. 2a was used.
image file: c6qo00158k-u2.tif

Then, we attempted to expand the substrate scope to non-aromatic aldehyde hydrazones which turned out to be unreactive in our previous work.12 As shown in Table 3, ynal and enal hydrazones indeed provided the desired products 4a–f in moderate yields. However, aliphatic aldehyde hydrazones only show a sluggish reaction.

Table 3 Representative examples of non-aromatic aldehyde hydrazonesa
a Reaction conditions: 1 (0.2 mmol), 2a (3 equiv.), imidazole (3 equiv.), MeCN (0.6 mL), under 315–400 nm light for 36 hours.
image file: c6qo00158k-u3.tif

Next we investigated a variety of cheap perfluoroalkyl iodides (Table 4). With long-chain perfluoroalkyl iodides, good yields were isolated (3aa–3ca), whereas with smaller, volatile reagents only moderate yields of the perfluoroalkylated products 3da–ga were obtained. Secondary perfluoroalkyl iodides and β-ether as well as α-ester fluoroalkyl iodides readily delivered the desired products 3ea, 3ha and 3ia in 74–82% yields. Notably, normal alkyliodides such as iodomethane and iodocyclohexane as well as a perfluoroalkyl bromide (1-bromononafluorobutane) do not undergo this transformation under the optimized reaction conditions. The gram-scale application in Scheme 3 underlines the practicability. The desired coupling product 3aa was obtained in 75% yield from 20 mmol benzaldehyde. The resulting perfluoroalkylated hydrazones can smoothly be reduced or hydrolysed or undergo other organic transformations.11,12

image file: c6qo00158k-s3.tif
Scheme 3 The gram-scale application. Reaction conditions: (1) benzaldehyde (20 mmol), 1,1-dimethylhydrazine (1.3 equiv.). (2) C4F9I (40 mmol), imidazole (60 mmol), MeCN (50 mL), irradiation with 315–400 nm light.
Table 4 The substrate scope of perfluoroalkyl iodidesa
a Reaction conditions: 1 (0.2 mmol), perfluoroalkyl iodide (2 equiv.), imidazole (3 equiv.), MeCN (0.6 mL), irradiation under 315–400 nm light. b 5 equiv. CF3I was used. c 3 equiv. perfluoroalkyl iodide.
image file: c6qo00158k-u4.tif

Scheme 4 shows mechanistic experiments. When TEMPO was added to the model reaction, only trace amounts of 3aa were formed along with 45% of TEMPO-C4F95. It suggests that a radical pathway should be involved. Radical initiators (AIBN, tBuOOBut and Et3B/air) failed to produce the desired product 3aa upon heating to 80 °C, indicating that a radical chain propagation is less likely. The light on/off experiment (Scheme 4b) and the quantum yield (Φ = 2.3%) of the model reaction further verify this statement. The addition of another electron donor, N,N-diisopropylmethylamine (DIPMA) into the model reaction resulted in a lower yield (46% vs. 94%), and by-products 6 and 7, which were not detected in our model reaction, might arise from the H-atom abstraction of a generated aminyl radical and a perfluoroalkyl radical, respectively (see ESI for discussion).17 While it is possible that hydrazone 1a and C4F9I 2a form a transient EDA complex, only slight changes were observed in UV-vis absorption spectra when mixing 1a with 2a in acetonitrile (see ESI for details). The control experiments with a bandpass filter ruled out the feasibility of homolytic cleavage pathway of C4F9I.18 In the light of Melchiorre's recent work,15e direct photoexcitaion of hydrazone 1a was proposed as one possible pathway. The theory calculation of the HOMO–LUMO gap of hydrazone 1a and C4F9I 2a are 4.37 eV and 5.40 eV respectively, which indicates hydrazone 1a is more easily excited than 2a.19 As shown in Scheme 4c, one plausible mechanism starts with a SET of the excited state of 1a to 2a to form radical cation 9 and perfluoroalkyl radical 10. Meanwhile, irradiation of EDA-complex is an alternative pathway to produce 9 and 10. As these species are formed at the same time and radical addition of perfluoroalkyl radical 10 to hydrazone radical cation 9 generates intermediate 11. Then, the bulky perfluoroalkyl group forces the N,N-dimethyl group to the opposite side to give 3aa in E configuration via deprotonation by base.20

image file: c6qo00158k-s4.tif
Scheme 4 Mechanistic studies of model reaction and proposed mechanism. The yields were determined by 19F NMR analysis of the reaction mixture using 1,3,5-trifluorobenzene as a reference standard. a[thin space (1/6-em)]The yields were obtained by 1H NMR analysis of the reaction mixture.

In summary, we have developed the first metal-free and general method for the perfluoroalkylation of aromatic and non-aromatic aldehyde hydrazones with simple and affordable perfluoroalkyl iodides by photochemistry. This opens up new options for photochemical radical C–C coupling in the absence of an external photocatalyst, a radical initiators or organotin reagents. The broad substrate scope, mild reaction conditions, excellent functional group compatibility, scale-up potential as well as the high chemoselectivity makes this protocol very practical in organic synthesis and drug discovery.

Notes and references

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  16. CCDC 1053855 (3ak) contains the supplementary crystallographic data for this paper.
  17. It was rather difficult to isolate byproduct 6 because it was easily volatile. Its structure was determined by 1H NMR, 19F NMR, GC-MS and HRMS.
  18. The homolysis of C4F9I under our reaction conditions is less likely as irradiation of the model reaction with a bandpass filter (375 nm) can furnish the desired product in 38% yield (see entry 15 in Table 1).
  19. The HOMO and LUMO energy of hydrazone 1a and C4F9I 2a was obtained at B3LYP-D3/LanL2DZ level. For hydraznone 1a: HOMO energy, −5.21 eV and LUMO energy −0.84 eV; for C4F9I 2a: HOMO energy, −8.62 eV and LUMO energy, −3.21 eV.
  20. The DFT calculations suggests product 3aa in E configuration has lower energy than that in Z configuration, see ESI for details.


Dedicate to Professor Barry Trost on the occasion of his 75th birthday.
Electronic supplementary information (ESI) available. CCDC 1053855. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00158k

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