Hydrodehalogenation of Haloarenes by a Sodium Hydride–Iodide Composite

Article abstract of DOI:10.1002/anie.201611495

A simple protocol for hydrodebromination and -deiodination of halo(hetero)arenes was enabled by sodium hydride (NaH) in the presence of lithium iodide (LiI). Mechanistic studies showed that an unusual concerted nucleophilic aromatic substitution operates in the present process.

Full text of DOI:10.1002/anie.201611495

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Communications
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International Edition: DOI: 10.1002/anie.201611495
German Edition: DOI: 10.1002/ange.201611495
Aromatic Substitution
Hydrodehalogenation of Haloarenes by a Sodium Hydride–Iodide
Composite
Derek Yiren Ong, Ciputra Tejo, Kai Xu, Hajime Hirao,* and Shunsuke Chiba*
Abstract: A simple protocol for hydrodebromination and
-deiodination of halo(hetero)arenes was enabled by sodium
hydride (NaH) in the presence of lithium iodide (LiI).
Mechanistic studies showed that an unusual concerted nucle-
ophilic aromatic substitution operates in the present process.
A
mong various reductive molecular transformations,[1]
hydrodehalogehation of organic halides has attracted much
attention not only as a synthetic strategy[2] but also from their
potential use for detoxification of environmentally hazardous
organic halides.[3] Thus, various methodologies for the hydro-
dehalogenation have been developed,[4] commonly employing
halogen–metal exchange with highly reactive organolithium
or -magnesium reagents under cryogenic reaction condi-
tions,[5] transition metal catalysis with hydride sources,[6] and
radical-mediated processes mainly with toxic tin hydrides.[7]
However, the typical reaction conditions for the established
procedures cause some disadvantageous concerns in process
efficiency, safety, operation, and cost. Recent developments in
the use of organic super electron donors,[8] photo-redox
catalysis,[9] sodium alcoholates as the organic chain reduc-
tant,[10] and catechols as the hydrogen radical source[11] for
hydrodehalogenation under mild reaction conditions could
compensate for such drawbacks.
Scheme 1. Reductive molecular transformations by the sodium hy-
dride–iodide composite.
While studying the substrate scope of the hydrodecyana-
tion by the NaH–iodide composite, we found that the reaction
of bromoaryl substrate 1 provided not only 2-bromocumene
(2) in 14% yield but also cumene (3) in 44% yield
(Scheme 2). It was tempting to assume that cumene (3) was
formed through hydrodebromination by the NaH composite,
and therefore, we explored the scope and limitation as well as
the reaction mechanism of the process.[16]
We recently disclosed that sodium hydride (NaH) could
act as a hydride donor in the hydrodecyanation of nitriles
(Scheme 1a) and hydride reduction of amides into aldehydes
(Scheme 1b) in the presence of LiI or NaI.[12,13] This
unprecedented and unique hydride donor reactivity of
sodium hydride–iodide composite stimulated us to further
explore development of new reductive transformation with
the composite. Herein, we report use of sodium hydride–
iodide composite to perform hydrodehalogenation of a wide
range of bromo- and iodoarenes under mild reaction con-
ditions (Scheme 1c). The detailed mechanistic studies sug-
gested that the present hydrodehalogenation proceeds via
neither a radical nor a metal–halogen exchange pathway, but
through a rather unusual concerted nucleophilic aromatic
substitution mechanism.[14,15]
Scheme 2. Serendipitous observation of hydrodebromination during
hydrodecyanation of 1.
We commenced optimization of the reaction conditions
for the hydrodebromination using 2-bromo-6-methoxynaph-
thalene (4a) (Table 1). The reaction of 4a with NaH (5 equiv)
in THF was completed within 12 h even at 608C when NaI
(2 equiv) was used as an additive, to afford 2-methoxynaph-
thalene (5a) in good yield (entry 1). Use of LiI instead of NaI
rendered the process smoother, completing the process within
6 h (entry 2), while lowering the amounts of NaH and LiI
slowed down the reaction rate (entry 3). Furthermore, the
reaction temperature could be lowered to 40–508C without
[*] D. Y. Ong, Dr. C. Tejo, K. Xu, Prof. H. Hirao, Prof. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: hirao@ntu.edu.sg
shunsuke@ntu.edu.sg
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201611495.
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Table 1: Optimization of reaction conditions for hydrodehalogenation of
4a and 4a’.[a]
Entry
X
NaH
(equiv)
Additive
(equiv)
T
[8C]
t
[h]
Yield of
5a [%][b]
1
2
3
4
5
6
7
8
9
10
Br
Br
Br
Br
Br
Br
Br
I
5
5
3
5
5
5
5
5
5
5
NaI (2)
LiI (2)
LiI (1)
LiI (2)
LiI (2)
LiI (2)
–
NaI (2)
LiI (2)
–
60
60
60
50
40
24
50
30
30
30
12
6
10
7
10
16
10
10
10
10
91
89
90
89 (81)[c]
89
33[d]
4[e]
85 (75)[c]
61
I
I
0[e]
[a] The reactions were conducted using 0.5 mmol of 4a or 4a’ in THF
(2.5 mL). [b] 1H NMR yields. [c] Isolated yield of 5a. [d] Recovery of 4a in
63% yield. [e] Recovery of 4a or 4a’ in more than 90% yield.
diminishment of the yields of 5a (entries 4 and 5), although
the reaction at room temperature (248C) became sluggish
(entry 6). It should be noted that NaH alone is not sufficient
to drive the hydrodebromination (entry 7), indicating that this
unique hydride donor reactivity is conferred on the NaH–
iodide composite. Employment of more reactive iodide 4a’
allowed the reaction to reach full conversion even at 308C
(entries 8 and 9). Similarly, almost no reaction of 4a’ occurred
without iodide additive (entry 10).
Scheme 3. Substrate scope for the hydrodebromination of bromoar-
enes 4. [a] The reactions were conducted using 0.5 mmol of 4 in THF
(2.5 mL) and isolated yields of 5 were noted above unless otherwise
stated. [b] GC yield. [c] H NMR yield. Bn=benzyl; TIPS=triisopropyl-
silyl; Cy=cyclohexyl.
1
Under the optimized reaction conditions (Table 1,
entry 4), we next investigated the substrate scope of hydro-
debromination using various bromoarenes 4 (Scheme 3). As
electron-donating substituents, benzyloxy (for 5b and 5c) and
silyloxy (for 5d) as well as dialkyl amino (for 5e and 5 f) and
benzylthioxy (for 5g) moieties could be tolerated, and the
corresponding reduced arenes were obtained in 61–86%
yields. Sterically hindered bromoarenes having ortho-methyl
(for 5h) and ortho-aryl (for 5i) groups could be reduced
smoothly. It should be worthy of note that hydrodebromina-
tion of 2-bromomesitylene (4j) worked very nicely to give
mesitylene (5j) in quantitative yield, suggesting that benzyne
is unlikely involved as an intermediate in the present hydro-
debromination. The acetal moiety could be kept intact during
the reduction process (for 5k). Bromoarenes 4l and 4m
having ortho-butenyl and ortho-O-allyl tethers, respectively,
gave 5l and 5m while keeping the alkenyl moieties intact.[17]
These results suggest that an aryl radical intermediate may
not be involved in the reaction pathway. Hydrodebromination
of 5-bromoindole 4n and 3-bromobenzothiophene (4o)
proceeded smoothly to give the corresponding heteroarenes
5n and 5o in high yields, whereas the reduction of 3-
bromoquinoline (4p) afforded a moderate yield of 5p (53%
yield). Although the NaH–iodide composite could reduce
tertiary amides to the corresponding aldehydes,[12a] interest-
ingly, secondary amides could be kept intact because the
amide anion generated through deprotonation by NaH is
inert toward hydride reduction by the NaH–iodide composite.
Taking advantage of this unique reactivity pattern, selective
reduction of bromo-N-cyclohexylbenzamides para-4q and
ortho-4q could be achieved, which afforded debrominated 5q
in excellent yields.
To investigate the reaction mechanism, especially how the
hydrogen is installed during the hydrodehalogenation pro-
cess, several deuterium labelling experiments were con-
ducted. Incorporation of deuterium was not observed at all
in the reactions of 4a in THF-D8 or with D2O quench (see the
Supporting Information (SI)), implying that single-electron
reduction of aryl bromides by NaH[18] should not be involved
in the present process. Rather, NaH in the composite state
functions as a hydrogen atom donor in the reduction process,
most probably via nucleophilic aromatic substitution. To
prove this hypothesis, we prepared sodium deuteride (NaD)
from metallic Na and D2 gas following the reported procedure
(Scheme 4a).[19] Treatment of Na dispersion in mineral oil
with D2 gas (1 atm) at 2708C afforded NaD containing
metallic Na (ca. 9%), which was characterized by solid-state
2
NMR (23Na and H) spectroscopy as well as powder X-ray
diffraction. The hydrodebromination of 4e by this NaD
sample resulted in deuterium incorporation of 50% in the
reduced product 5e (Scheme 4b), which unambiguously
exemplified the role of NaH as the hydrogen donor.[20]
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interaction between the hydride and the p* orbital of the
aromatic ring. An analogous concerted substitution reaction
at the vinylic carbon through the hydride attack onto the p*
orbital (SNVp) should result in retention of the stereo-
configuration of the haloalkenes (Scheme 5a).[24] We thus
Scheme 4. Preparation of NaD and a deuterium labelling experiment.
Our recent work on materials characterization of the
NaH–iodide composite indicated that a smaller nanometric
unit of NaH dispersed on NaI might be produced by
solvothermal treatment of NaH with NaI or LiI in THF,
giving rise to unique hydride donor reactivity.[12b] On this
basis, to better understand the reaction mechanism of the
present hydrodehalogenation, DFT calculations were per-
formed for a model reaction of bromobenzene with a single
molecule of NaH,[21] using Gaussian09 software.[22] The bulk
solvent effect of THF was described with an implicit model,
and two molecules of THF were included explicitly. A highly
exothermic pathway having a single transition state (TS-I) for
concerted nucleophilic aromatic substitution was obtained
(Figure 1). The barrier for the reaction was not very high
Scheme 5. Hydrodebromination of bromoalkenes 4r.
investigated the hydrodebromination of bromoalkenes syn-4r
and anti-4r (Scheme 5b).[25] The reduction of syn-4r at 858C
afforded syn-5r in 37% yield. Similarly, the reduction of anti-
4r delivered anti-5r in 31% yield along with a small amount
À
of syn-5r. As expected, in both cases, reduction of the C Br
bond proceeded mostly with retention of the configuration. It
is noted that both of the reactions also produced allene 6 via
an elimination reaction.
DFT calculations of a model reaction of 2-bromo-3-
methyl-2-butene with NaH provided TS-II for concerted
vinylic substitution that involves attack of the hydride on the
p* orbital (SNVp) (Figure 2); the barrier for this reaction was
again not very high. An alternative pathway, in which the
À
hydride attacks the s* orbital of the C Br bond (SNVs), could
Figure 1. Free energy profile for hydrodebromination of bromobenzene
by a single molecule of NaH in THF (in kcalmolÀ1), determined at the
B3LYP(SCRF)-D3(BJ)/def2-TZVP//B3LYP/def2-TZVP level. Key bond
distances are indicated in ꢀ.
(20.9 kcalmolÀ1), indicating that NaH, especially in a fragment
state, is reactive toward an aromatic bromide. Moreover, the
Hammett plot of log(kX/kH) versus s showed a linear
correlation with a positive 1 value of 0.47 (see the SI). This
trend supports the concerted nucleophilic aromatic substitu-
tion mechanism via a rate-determining transition state having
a partial negative charge (dÀ) (TS-I in Figure 1) without
formation of a charged Meisenheimer complex, which is
involved as an intermediate in typical aromatic substitution
reactions proceeding via an addition–elimination mecha-
nism.[23]
Figure 2. Free energy profiles for hydrodebromination of 2-bromo-3-
methyl-2-butene by a single molecule of NaH in THF (in kcalmolÀ1),
determined at the B3LYP(SCRF)-D3(BJ)/def2-TZVP//B3LYP/def2-TZVP
level.
The predicted concerted nucleophilic aromatic substitu-
tion reaction in the hydrodehalogenation is initiated by the
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hydrodebromination of syn- and anti-4r (Scheme 5).
This work demonstrated a new reactivity of sodium
hydride in hydrodehalogenation of haloarenes that proceeds
via a concerted nucleophilic aromatic substitution pathway.
We are currently working to explore other types of reductive
molecular transformations with the NaH–iodide composite.
[13] It should be noted that solvothermal treatment of NaH and LiI
induces counter-ion metathesis to form the NaH–NaI composite,
which is responsible for the present hydride transfer reactions.
See Ref. [12b].
Acknowledgements
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This work was financially supported by Nanyang Technolog-
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a Nanyang Assistant Professorship and the computer resour-
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thank Prof. Han Sen Soo and Zhonghan Hong (Division of
Chemistry and Biological Chemistry, NTU) for the assistance
in powder XRD experiments.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: DFT calculations · haloarenes ·
hydrodehalogenation · reduction · sodium hydride
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bearing the C H bond on the same side of the phenethyl group
and vice versa for the anti-isomer.
[25] For the stereochemistry of bromoalkenes 4r, the syn-isomer is
À
defined as the substrate bearing the C Br bond on the same side
of the phenethyl group and vice versa for the anti-isomer. For the
reduced alkenes 5r, the syn-isomer is defined as the substrate
Manuscript received: November 24, 2016
Final Article published: && &&, &&&&
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Communications
Aromatic Substitution
D. Y. Ong, C. Tejo, K. Xu, H. Hirao,*
S. Chiba*
&&& — &&&
A simple protocol for hydrodebromina-
tion and -deiodination of halo(hetero)-
arenes was enabled by sodium hydride
(NaH) in the presence of lithium iodide
(LiI). Mechanistic studies show that an
unusual concerted nucleophilic aromatic
substitution operates in the present pro-
cess.
Hydrodehalogenation of Haloarenes by
a Sodium Hydride–Iodide Composite
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!