Gold-Catalyzed Highly Selective Photoredox C(sp2)-H Difluoroalkylation and Perfluoroalkylation of Hydrazones

Article abstract of DOI:10.1002/anie.201508622

The first gold-catalyzed photoredox C(sp²)-H difluoroalkylation and perfluoroalkylation of hydrazones with readily available R_F-Br reagents is reported. The resulting gem-difluoromethylated and perfluoroalkylated hydrazones are highl

Full text of DOI:10.1002/anie.201508622

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International Edition: DOI: 10.1002/anie.201508622
German Edition: DOI: 10.1002/ange.201508622
Fluoroalkylation
2
À
Gold-Catalyzed Highly Selective Photoredox C(sp ) H
Difluoroalkylation and Perfluoroalkylation of Hydrazones
Jin Xie, Tuo Zhang, Fei Chen, Nina Mehrkens, Frank Rominger, Matthias Rudolph, and
A. Stephen K. Hashmi*
2
À
Abstract: The first gold-catalyzed photoredox C(sp ) H
generate active carbon-centered radicals from organic hal-
À
difluoroalkylation and perfluoroalkylation of hydrazones
with readily available RF Br reagents is reported. The resulting
ides. We have now examined the possibility of a direct C H
À
difluoroalkylation of benzaldehyde (1a) and its synthetic
equivalents (oxime 2a, imines 3a–5a, and hydrazones 6a–9a)
gem-difluoromethylated and perfluoroalkylated hydrazones
are highly functionalized, versatile molecules. A mild reduction
of the coupling products can efficiently produce gem-difluoro-
methylated b-amino phosphonic acids and b-amino acid
derivatives. In mechanistic studies, a difluoroalkyl radical
intermediate was detected by an EPR spin-trapping experi-
ment, indicating that a gold-catalyzed radical pathway is
operating.
O
wing to its unique properties, the difluoromethylene
group (CF2) is a very useful and valuable structural motif in
organic synthesis, drug discovery, and life science.[1] It can
serve as an effective functional group to improve biological
activity[2] and as a bioisostere for an oxygen atom or a carbonyl
group.[3] Therefore, the development of efficient difluorome-
thylation methods has attracted considerable attention,[4] and
many transition-metal-mediated difluoromethylations of aryl
boron[5] and organohalogen[6] compounds as well as other
substrates[7] have been developed. Aromatic aldehydes and
their synthetic equivalents, such as imines, hydrazones, and
oximes, are versatile building blocks and important inter-
mediates for the synthesis of fine chemicals and the pharma-
Scheme 1. Screening for an effective difluoromethylation. Reaction
conditions: [Au2(m-dppm)2](OTf)2 (1 mol%), 1–9 (0.1 mmol), “CF2”
reagent (1.5 equiv), K2HPO4 (2 equiv), MeCN (0.3 mL), sunlight, RT,
8 h.
with diethyl (bromodifluoromethyl)phosphonate and ethyl 2-
bromo-2,2-difluoroacetate by using [Au2(m-dppm)2](OTf)2
(10) as the photocatalyst in sunlight[12] (Scheme 1).[13] The
results demonstrate that hydrazones 8a and 9a can undergo
a difluoroalkylation reaction in moderate yields with excel-
lent stereo- and regioselectivities.[14] Even though the copper-
catalyzed trifluoromethylation of N,N-dialkyl hydrazones
with Togniꢀs reagent is known,[15] a transition-metal-catalyzed
ceutical industry. To the best of our knowledge, the direct
2
À
C(sp ) H difluoroalkylation of benzaldehyde or its synthetic
equivalents is unexplored,[8] but could complement existing
strategies.
The exploitation of solar energy in current organic
synthesis represents a promising approach to mimic photo-
synthesis.[9] Recently, the use of gold(I) complexes in photo-
redox catalysis has gained considerable attention.[10,11] Both
Barriault[10a,b] and co-workers and our group[10c] have shown
that [Au2(m-dppm)2]2+ is an efficient photocatalyst to readily
À
C H difluoro- and perfluoroalkylation of hydrazones by
À
photocatalysis with inexpensive and readily available RF Br
reagents is unprecedented.
Owing to the potential of the gem-difluoroalkylation of
N,N-dialkyl hydrazones, an optimization of the reaction
conditions of the coupling of hydrazone 9a with (bromodi-
fluoromethyl)phosphonate 11a was conducted by variation of
the bases, the photocatalyst loading, the light source, and the
reaction time (see Table 1 and also the Supporting Informa-
tion for details). Whereas sunlight is the preferred light
source, its replacement with a UVA light source substantially
improved the yields. The optimized reaction conditions
entailed the use of 2 mol% of 10 with 3 equivalents of 2,6-
lutidine as a base (to neutralize the HBr formed during the
reaction) and irradiation with UVA light (315–400 nm) for
about 24 hours (76% yield, entry 1). Other available photo-
catalytic systems delivered no, or only traces of, product
(entries 2–5). Irradiation with harder UV light (l = 254 nm)
[*] Dr. J. Xie, M. Sc. T. Zhang, M. Sc. F. Chen, Dr. F. Rominger,
Dr. M. Rudolph
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
M. Sc. N. Mehrkens
Anorganisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University (KAU)
Jeddah 21589 (Saudi Arabia)
E-mail: hashmi@hashmi.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508622.
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Table 1: Representative examples from the optimization of the reaction
Table 2: Substrate scope with regard to phosphonyl-
conditions.[a,13]
difluoromethylation.[a,b]
Entry Catalyst (mol%)
Light source
Yield[b] [%]
1
2
3
4
5
6
7
8
[Au2(m-dppm)2](OTf)2 (10; 2)
[Ru(bpy)3]Cl2 (2)
[Ir(ppy)3] (2)
UVA (315–400 nm) 76
blue LEDs
0
blue LEDs or CFL trace
[Ir{dF(CF3)ppy}2(dtbpy)]PF6 (2) blue LEDs or CFL
0
0
0
0
0
0
0
eosin Y (2)
10 (2)
–
blue LEDs
UV (254 nm)
UVA
in the dark
–
–
10 (2)
9[c] Pd(OAc)2 (10)
10[c] [Ni(glyme)Cl2] (10)
[a] Reaction conditions: 9a (0.2 mmol), 11a (2 equiv), 2,6-lutidine
(3 equiv), MeCN (0.6 mL), room temperature, 24 h. [b] Yields of isolated
products. [c] 808C. CFL=compact fluorescent light bulb.
did not lead to the formation of 12a (entry 6). Control
experiments showed that the phosphonyldifluoromethylation
does not proceed in the absence of either light or the gold
photocatalyst (entries 7 and 8). With Pd(OAc)2 and [NiCl2-
(glyme)] as the catalyst system, only the decomposition of
both 9a and 11a was observed at 808C (entries 9 and 10).
With the optimized conditions in hand, the scope of the
phosphonyldifluoromethylation of N-morpholine hydrazones
was explored (Table 2). The method has a very broad
substrate scope and displayed excellent chemoselectivity.
The desired products 12a–12x were obtained in moderate to
good yields, and the corresponding phosphonyldifluorome-
thylated arenes were not formed. Versatile functional groups,
such as halogens, ethers, esters, boronic esters, alcohols,
amides, and alkynes, were tolerated. The possibility of a late-
stage modification was explored with medically important
[a] Reaction conditions as mentioned in Table 1, 24–30 h. [b] Yields of
isolated products. [c] 1 mmol scale. [d] Yield determined by 19F NMR
spectroscopy. [e] Imidazole (3 equiv) was used instead of 2,6-lutidine.
=
helicide and vitamin E derivatives (12w and 12x). The C N
bond of the products 12 is exclusive formed in E configuration
(confirmed by NMR studies, DFT calculations, and X-ray
crystal-structure analysis[16] of 12r).[13] Propiolaldehyde
hydrazone gave the desired product only in moderate yield
(12v, 60% starting material recovery).
Scheme 2. E/Z selectivities achieved with different photocatalysts. The
isomeric ratios were determined by 1H NMR analysis.
Then, the scope of the reaction was explored by studying
the reactions of various benzaldehyde hydrazones with ethyl
bromodifluoroacetate (11b).[13] Although the difluoroacety-
lation reaction also proceeded smoothly with [Ir(ppy)3] as the
photocatalyst, the E/Z selectivity of the difluoromethylated
product 13a was much lower than when gold complex 10 was
used (2.5:1 vs. 8:1, Scheme 2). [Ir(ppy)3] enables the isomer-
ization of the E-configured product to the less stable
Z product, and its use thus resulted in low E/Z selectivity,[17]
which highlights another advantage of the gold photocatalyst.
During the screening of different N,N-dialkyl hydrazones
(13a–13c), we found that when N,N-dimethyl hydrazone was
used as the starting material in the presence of the gold
ration. A variety of aromatic aldehyde hydrazones were
converted (Table 3). All investigated substrates underwent
the difluoroacetylation reaction, yielding the difluoroacety-
lated products 13a–13t in 42–83% yield, including the
heterocyclic aldehyde hydrazones 13s and 13t.
Given the importance of perfluoroalkyl groups, we
examined the possible incorporation of such groups into
hydrazones. As shown in Table 4, with perfluoroalkyl bro-
mides, perfluoroalkylated hydrazones could be obtained in
moderate to good yields. In sunlight, the trifluoromethylated
hydrazones 14g and 14h could be isolated in satisfactory
yields when trifluoroiodomethane was used as an inexpensive
=
catalyst, the C N bond was exclusively formed in E configu-
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Table 3: Substrate scope of the difluoroacetylation of hydrazones.[a,b]
Table 4: Scope with respect to other fluoroalkyl moieties.[a]
[a] Reaction conditions: hydrazone (0.2 mmol), [Au2(m-dppm)2](OTf)2
À
(10; 2 mol%), RF Br (2 equiv), imidazole (3 equiv), MeCN (0.6 mL),
UVA light (315–400 nm), RT; yields of isolated products. [b] Fluoroalkyl
bromide (3 equiv). [c] CF3I (4 equiv), irradiated with sunlight.
[a] Reaction conditions: hydrazone (0.2 mmol), [Au2(m-dppm)2](OTf)2
(10; 2 mol%), BrCF2EWG (2 equiv), imidazole (3 equiv), MeCN
(0.6 mL), RT, UVA light (315–400 nm). [b] Yields of isolated products.
[c] Reaction irradiated with sunlight. [d] 2-Bromo-1-(4-chlorophenyl)-2,2-
difluoroethanone (1.5 equiv).
shape. A radical chain pathway could be ruled out by light on/
off experiments as well as the reaction quantum yield (F =
1.44%).[13]
trifluoromethylating reagent. Even with strongly electron-
donating groups on the arene, no perfluoroalkylation of the
aromatic ring was observed (14d, 14 f, and 14h).
A possible mechanism is shown in Scheme 4. First, the
irradiation of [Au2(m-dppm)2](OTf)2 (10) generates a high-
energy, long-lived photoexcited state, *[Au2(m-dppm)2]2+ (24),
which is a strong one-electron donor [E0([Au2]3+/*[Au2]2+) =
À1.5–1.7 V].[18] Next, a single electron transfer from the gold
species 24 to 11a delivers difluoromethyl phosphonate radical
25 and gold intermediate 21.[19] The electrophilic radical 25
then attacks hydrazone 9a to produce the three-electron
p-bonding aminyl radical intermediate 26. Owing to the lone
pair on the adjacent nitrogen atom, 26 is much more stable
than other aminyl radicals produced from imines and
oximes.[20] Finally, oxidation of aminyl radical 26[21] by gold
species 21 followed by deprotonation affords the desired
difluoromethylated product 12a. DFT calculations showed
=
As illustrated in Scheme 3, the C N double bonds of the
products could be selectively reduced with BH3–THF under
very mild reaction conditions to yield compounds 15 and 16.
Thus, this method constitutes a powerful route to gem-
difluoromethylated b-amino phosphonic acids and b-amino
acid derivatives. Furthermore, the difluoromethylated hydra-
zones can be hydrolyzed to the corresponding difluoromethyl
ketones 17 and 18 by simple acid treatment. Direct heating of
the difluoromethylated product in methanol at 708C enabled
À
the substitution of two C F bonds by methanol, producing
dimethoxy ketal 19.
The addition of radical trapping reagents (TEMPO, 1,1-
diphenylethylene) or an electron-transfer scavenger (1,4-
dinitrobenzene) significantly inhibited this transformation,[13]
indicating that a single-electron-transfer radical process is
operating. Moreover, the key radical intermediate was
observed in an EPR spin-trapping experiment with 5,5-
dimethyl-1-pyrroline N-oxide (Figure 1). A simulated spec-
trum matched the experimental data in terms of the line
=
that the products with the C N bond in E configuration are
lower in energy than those with Z configuration, and the
isomerization activation energy usually amounts to more than
20 kcalmolÀ1.[13] The gold photocatalyst favors the formation
of the thermodynamic, E-configured product.
In conclusion, we have developed the first gold-catalyzed
2
À
intermolecular photoredox C(sp ) H difluoroalkylation and
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Scheme 4. Proposed mechanism.
kylated hydrazone products are excellent substrates for
further transformations, for example, to gem-difluoromethy-
lated b-amino phosphonic acids and b-amino acids. An EPR
spin-trapping experiment indicated the involvement of
a difluoroalkyl radical intermediate.
Acknowledgements
Scheme 3. Important transformations.
We thank Umicore AG & Co. KG for the generous donation
of gold salts and Prof. Peter Comba for access to his EPR
spectrometer.
À
Keywords: C H functionalization · fluorine · gold catalysis ·
photocatalysis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2934–2938
Angew. Chem. 2016, 128, 2987–2991
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[21] The calculated SOMO energy for 26 is À6.26 eV (DFT/
UM062X/6-311 ++ g(d,p)).
Received: September 15, 2015
Published online: January 21, 2016
2938
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Angew. Chem. Int. Ed. 2016, 55, 2934 –2938