Radical Hydrodeiodination of Aryl, Alkenyl, Alkynyl, and Alkyl Iodides with an Alcoholate as Organic Chain Reductant through Electron Catalysis

Article abstract of DOI:10.1002/anie.201601930

A simple and efficient method for radical hydrodeiodination is reported. The novel approach uses electron catalysis. In situ generated Na-alcoholates are introduced as radical chain reducing reagents and reactions work with O₂as cheap initiator. Hydrodeiodination works on aryl, alkenyl, alkynyl iodides and a tert-alkyl iodide also gets reduced applying the method. Albeit less general, the method is also applicable to the reduction of aryl bromides. The novel reagent is successfully used to conduct typical reductive radical cyclization reactions and mechanistic studies are reported.

Full text of DOI:10.1002/anie.201601930

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International Edition: DOI: 10.1002/anie.201601930
German Edition: DOI: 10.1002/ange.201601930
Radical Reduction
Radical Hydrodeiodination of Aryl, Alkenyl, Alkynyl, and Alkyl
Iodides with an Alcoholate as Organic Chain Reductant through
Electron Catalysis
Abhishek Dewanji, Christian Mück-Lichtenfeld, and Armido Studer*
Abstract: A simple and efficient method for radical hydro-
deiodination is reported. The novel approach uses electron
catalysis. In situ generated Na-alcoholates are introduced as
radical chain reducing reagents and reactions work with O2 as
cheap initiator. Hydrodeiodination works on aryl, alkenyl,
alkynyl iodides and a tert-alkyl iodide also gets reduced
applying the method. Albeit less general, the method is also
applicable to the reduction of aryl bromides. The novel reagent
is successfully used to conduct typical reductive radical
cyclization reactions and mechanistic studies are reported.
H
ydrodehalogenation is an essential transformation in
organic synthesis and chemical industry.[1] As halides are
hazardous to the environment this process has also been used
for industrial detoxification.[2] Various methods for dehaloge-
nation of organic halides have been developed for example,
via metal–halogen exchange,[3] reduction with hydride
reagents,[4] metal-mediated reductions[5] and reductive radical
dehalogenations. The first three methods suffer from low
functional-group tolerance and formation of hazardous metal
waste. Radical chain dehalogenation is a valuable option.
However, some initiators and stoichiometric reductants used
in established radical dehalogenation are explosive (AIBN),[6]
toxic (Bu3SnH),[7] and air sensitive (SmI2 and trialkylbor-
anes).[8,9] These shortcomings paved the way to the develop-
ment of “greener” methods for radical dehalogenation.
Various Si-[10] and B-based[11] reagents have been intro-
duced. Murphy[12] successfully used organic super electron
donors, and organometallic complexes[13] in combination with
hydride donors were also developed. Important contributions
by Stephenson[14] and Kçnig[15] show that fac-Ir(ppy)3 and
a perylene diimide are efficient catalysts for radical dehalo-
genation of alkyl and aryl halides using photoredox catalysis.
Herein we show that readily generated Na-alcoholates
efficiently dehalogenate various iodides under electron
catalysis.[16–18]
Scheme 1. Working model.
alcohols.[20b] H-abstraction from an alcoholate leads to
a radical anion that should be an efficient single-electron
transfer (SET) reagent for reduction of aryl halides, as shown
for the NaOCH2 radical anion.[20]
Considering these facts, we decided to develop a mild
method for hydrodehalogenation of aryl halides via electron
catalysis using alcoholates as chain-reducing reagents. SET
À
reduction of the starting Ar X leads to an aryl radical anion,
which reacts via halide fragmentation to an aryl radical.
Reduction of the aryl radical by the alcoholate should then
H-bonding of alcohols with a phosphate anion leads to
À
À
activation of the a-C H bond thereby facilitating H-abstrac-
tion by radicals, as elegantly used by MacMillan
provide the targeted reduction product Ar H along with the
radical anion that formally liberates an electron closing the
catalytic cycle.[16,21] An aldehyde is formed as a byproduct.
The hydrodeiodination of iodobiphenyl 1a to give 2a was
chosen as a test reaction (Table 1). Initial experiments were
conducted with the hypodinitrite 3 as an initiator[22] in 1,4-
dioxane. Alcoholates were generated in situ from the corre-
sponding alcohols upon deprotonation. Pleasingly, reaction of
1a with 3 (50 mol%) and LiOiPr (10 equiv) as a reductant at
458C gave 2a in 60% along with 40% of unreacted 1a
(entry 1). Lowering the reaction temperature did not improve
the conversion (entry 2). Reduction did not work with LiOBn
(Scheme 1).[19] a-C H-activation should be even stronger in
fully deprotonated alcohols. Indeed, it was reported that
alcoholates are far better H-donors than the corresponding
À
[*] A. Dewanji, Dr. C. Mück-Lichtenfeld, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601930.
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Table 1: Reaction optimization.[a]
Further optimization was performed on 8 due to the high
solubility of its sodium salt in ethers. Reducing the amount of
Na-8 from 10 to 5 equivalents resulted in a lower conversion
(entry 20). Interestingly, a control experiment without any
initiator at room temperature showed a 37% conversion,
indicating that the reaction can be initiated with a trace
amount of dioxygen (entry 21). Indeed, under O2 atmosphere
the yield increased to 59% using 5 equivalents of Na-8
(entry 22) and quantitative conversion was achieved with
7 equivalents of the alcoholate at room temperature
(entry 23).
Under optimized condition (Table 1, entry 23) the scope
and limitations of the radical dehalogenation were explored
(Figure 1). Di- and trimethoxy-substituted iodobenzenes
were efficiently reduced and the corresponding arenes 2b–d
were isolated in very good yields (81–95%). Ortho-methyl-
Entry
ROH
Base
Initiator
(mol %)
Conc.
[m]
Yield
[%][b]
1
i-PrOH
i-PrOH
BnOH
MeOH
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
3 (50)
3 (50)
3 (50)
3 (30)
3 (50)
3 (40)
3 (30)
3 (30)
DTBP (30)
3 (30)
3 (30)
3 (30)
3 (20)
3 (20)
3 (10)
3 (10)
3 (5)
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.1
0.06
0.06
0.06
0.06
0.06
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
60 (40)
55 (45)
–
–
>99
81 (19)
37 (63)
28 (72)
–
55 (45)
–
>99
70 (30)
>99
48 (52)
76 (24)
>99
>99
>99
72 (28)
37 (63)
59 (41)
>99
2[c]
3
4
5
6
7
4
4
4
4
4
4
4
4
4
4
4
5
6
7
8
8
8
8
8
8
9[d]
10[e]
11[f]
12
13
14
15
16
17
18
19
20[g]
21[g]
22[g,h]
23[h,i]
3 (5)
3 (5)
3 (5)
–
O2
O2
NaH
NaH
NaH
0.2
[a] The reactions were carried out under argon with 0.4 mmol of 1a,
4.0 mmol (10 equiv) of ROH, 4.0 mmol (10 equiv) of base at 458C for
24 h. [b] Yield determined by GC analysis and % unreacted starting
material in parenthesis. [c] Reaction performed at 308C. [d] Reaction
performed at 808C. [e] Reaction performed in THF. [f] Reaction per-
formed in PhCF3. [g] 5 Equivalents of 8 and 5 equivalents of NaH were
used. [h] Reaction performed under oxygen atmosphere at room
temperature. [i] 7 Equivalents of 8 and 7 equivalents of NaH were used.
Figure 1. Substrate scope of the hydrodeiodination.[a,b] [a] The reactions
were carried out under oxygen atmosphere with 0.4 mmol of 1,
2.8 mmol (7 equiv) of 8, 2.8 mmol (7 equiv) of NaH in 2.0 mL of 1,4-
dioxane as solvent at room temperature for 24 h. [b] Yield of isolated
product. [c] 8 Equivalents of 8 and 8 equivalents of NaH were used.
[d] Reaction was performed done at 458C. [e] 10 Equivalents of 8 and
10 equivalents of NaH were used. [f] 4,4’-Diiodobiphenyl was used as
substrate and reaction run for 65 h. [g] 3 (20 mol%) was used as an
initiator instead of O2.
or LiOMe as reductants (entries 3 and 4). Full conversion was
achieved with the Li-alcoholate derived from 2-phenyletha-
nol (4) to give 2a in a quantitative yield (entry 5). Lowering
the loading of initiator 3 led to significantly lower conversions
indicating short chains (entries 5–7) and conversion did not
increase upon increasing concentration (entry 8). Di-tert-
butylperoxide (DTBP) as an initiator at 808 C did not lead to
any conversion (entry 9). Reaction in THF gave a similar
result as in dioxane but hydrodeiodination did not work in
trifluorotoluene (entries 10 and 11).
We then switched to NaH as a base and to our delight at
higher concentration full conversion was achieved with
20 mol% of initiator 3, showing that the counter cation
influences the reaction (entries 12–15). A further lowering of
the initiator loading to 5 mol% was possible using the Na-
alcoholates derived from alcohols 6, 7 and 8 (entries 16–19).
thiyl-iodobenzene was transformed to 2e (83%). Naphtha-
lene (2 f) and phenanthrene (2g) were obtained in high yields
from the corresponding iodides (88–90%). Benzyl ethers and
silyl ethers are compatible with the applied conditions and 2h
and 2i were isolated in good yields (72–90%). The acetal
functionality is stable under the reducing conditions (see 2j
and 2k). Iodinated heteroarenes such as iodinated indoles,
pyrroles and pyrazoles are efficiently hydrodeiodinated (see
2l–n, 76–85%). The electron-rich N,N-diethyl-para-iodoani-
line and also the electron-poorer iodobenzamide are good
substrates providing 2o and 2p (85% each). Double reduc-
tion was achieved on 4,4’-diiodobiphenyl to give biphenyl 2a
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(84%). Pleasingly, reaction is not restricted to the dehaloge-
nation of iodoarenes. Reduction also worked for iodoacety-
lenes as shown by the successful preparation of 2q and 2r. An
iodinated styrene derivative was successfully dehalogenated
(see 2s) and iodoadamantane was also reduced (see 2t). In
the latter transformation, the O2-initiation process delivered
2t in 42% yield. 1-Adamantol derived from trapping of the
adamantyl radical by dioxygen was formed as a side product.
Therefore, we switched to 3 as an initiator and found the yield
to improve to 90%.[23]
We next tested whether aryl bromides are also suitable
substrates. As expected, reactivity was lower as compared to
the iodides (Scheme 2). 2-Methyl-1-bromonaphthalene was
reduced to 10a in 27% yield.[24] Slightly better results were
achieved for hydrodebromination of 9b and 9c to give the
corresponding arenes 10b and 10c (37–52%).[24] A high yield
Scheme 3. Cyclization and reduction with deuterated 8.
1p. Deuterium incorporation occurred only to 40% showing
that the intermediately generated aryl radical is reduced to
a large extent by the solvent. Considering that the reaction is
initiated with little O2, reduction by 1,4-dioxane is likely not
a chain-terminating step and the generated dioxanyl radical
gets reduced by Na-8 thereby sustaining the chain. If reaction
is conducted with tetrahydropyran, a solvent known to be
a poor H-atom donor,[25] the hydrodeiodination of 1p
occurred in 86% yield, revealing that 1,4-dioxane is not
mandatory for efficient reduction. This is further supported
by running reduction of 1p with perdeuterated 1,4-dioxane-
D8 and Na-8 delivering 2p (90%) with very little deuterium
incorporation (D:H < 5:95).
Finally, DFT calculations on the reaction of the phenyl
radical with 8, the free alkoxide (8À) and Na-8 were
performed to study the effect of deprotonation on the bond
À
dissociation energy (BDE) of the a-C H bond. For compar-
À
ison, we also calculated the relative BDE of the C H bond in
1,4-dioxane. Figure 2 presents the calculated free energies of
Scheme 2. Hydrodebromination and chemoselective dehalogenation.
was obtained for reduction of 5-bromoquinoline (9d) to
quinoline (10d, 81% isolated yield). Knowing reactivity
differences between bromides and iodides we attempted
chemoselective reduction of the bromo-iodo-arene 11. Pleas-
ingly, selective hydrodeiodination occurred in excellent yield
(12, 97%) and octylbenzene derived from a double reduction
was not identified by GC analysis. Along these lines, the aryl–
Cl bond is inert under the standard condition and iodide 13
reacted chemoselectively in good yield to dichlorobenzene 14.
We found that 8 can also be applied to typical reductive
radical cyclization reactions (Scheme 3): iodide 15 was
successfully converted to 16a (56%). As a side product, 16b
derived from direct reduction was formed in 8%. A similar
result was observed for the transformation of 17 to give the
targeted 18a along with 18b. From these results, it is obvious
that Na-8 is likely a highly efficient H-donor. However, since
1,4-dioxane is used as a solvent it might also act as H-donor in
these chain reactions. To address this point we prepared a,a-
dideuterated alcohol 8 and used it for the reduction of iodide
Figure 2. DFT-calculated DG298 [kcalmolÀ1] for hydrogen transfer to PhC
(solvent: 1,4-dioxane).
hydrogen transfer to the phenyl radical (PW6B95-D3//
BHLYP-D3/def2-TZVP).[26] As expected, the C H BDEs in
À
1,4-dioxane and the a-H in 8 are similar. It is obvious that 1,4-
dioxane considering its high concentration as a solvent is
a good H-donor for a phenyl radical, as experimentally
À
À
observed. Upon deprotonation of 8, the a-C H bond in 8 is
strongly weakened by around 18 kcalmolÀ1. If we include the
À
Na-countercation by switching to 8-Na the a-C H bond
relative to alcohol 8 is weakened by around 14 kcalmolÀ1.
Hence, in agreement with the experiments, 8-Na is a very
good H-donor for the reduction of the phenyl and also of the
dioxanyl radical.
In summary, we have introduced alcohol 8 as a commer-
cially available cheap reagent to conduct radical chain
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dehalogenation reactions. Hydrodeiodination works well for
aryl, alkenyl and alkynyl iodides and reactive aryl bromides
are also reduced. Importantly, in contrast to most radical
reducing reagents, alcohol 8 is not sensitive towards air. The
active reagent is the corresponding Na-alcoholate, which is
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of alcohol is removed by simple aqueous extraction.
Acknowledgements
We thank the WWU Münster for financial support.
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Keywords: chemoselectivity · green chemistry ·
hydrodeiodination · radicals · transition-metal free synthesis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6749–6752
Angew. Chem. 2016, 128, 6861–6864
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Received: February 24, 2016
Revised: March 31, 2016
Published online: April 21, 2016
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