Hydride Reduction by a Sodium Hydride-Iodide Composite

Article abstract of DOI:10.1002/anie.201600305

Sodium hydride (NaH) is widely used as a Br?nsted base in chemical synthesis and reacts with various Br?nsted acids, whereas it rarely behaves as a reducing reagent through delivery of the hydride to polar π electrophiles. This study presents a series of reduction reactions of nitriles, amides, and imines as enabled by NaH in the presence of LiI or NaI. This remarkably simple protocol endows NaH with unprecedented and unique hydride-donor chemical reactivity.

Full text of DOI:10.1002/anie.201600305

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International Edition: DOI: 10.1002/anie.201600305
German Edition: DOI: 10.1002/ange.201600305
Synthetic Methods
Hydride Reduction by a Sodium Hydride–Iodide Composite
Pei Chui Too, Guo Hao Chan, Ya Lin Tnay, Hajime Hirao,* and Shunsuke Chiba*
Abstract: Sodium hydride (NaH) is widely used as a Brønsted
base in chemical synthesis and reacts with various Brønsted
acids, whereas it rarely behaves as a reducing reagent through
delivery of the hydride to polar p electrophiles. This study
presents a series of reduction reactions of nitriles, amides, and
imines as enabled by NaH in the presence of LiI or NaI. This
Scheme 1. Serendipitous reductive decyanation during the methylation
of 1.
remarkably simple protocol endows NaH with unprecedented
and unique hydride-donor chemical reactivity.
H
ydride reduction of polar p electrophiles, such as carbonyl
Table 1: Optimization of reaction conditions for the decyanation of 2a.[a]
compounds, carbonitriles, and imines, is one of the most
fundamental and important molecular transformations in
chemical synthesis.[1] In this context, a variety of covalent
hydrides, such as borane, alane, metal borohydrides, metal
aluminum hydrides, and silanes, have often been employed as
the reagents of choice for stereo-, regio-, and chemoselective
hydride-transfer processes. By contrast, alkali-metal hydrides
have rarely been employed as hydride sources; instead, they
are used almost exclusively as strong Brønsted bases for
deprotonation reactions in chemical synthesis.[2,3] Herein, we
report that NaH can act as a hydride donor in reactions with
nitriles, amides, and imines when it has been subjected to
simple solvothermal treatment with LiI or NaI in THF. Of
particular interest is the outcome of hydride reduction
reactions of nitriles and amides, which deliver the corre-
sponding alkanes (through decyanation) and aldehydes,
respectively.
Entry
NaH (equiv)
Additive (equiv)
t [h]
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
–
24
14
40
3.5
20
24
24
6
trace[c]
96
NaI (2)
KI (2)
9[c]
LiI (1)
MgI2 (1)
LiBr (2)
LiCl (2)
LiI (1)
LiI (0.2)
LiI (1)
LiI (1)
98
96
8[c]
3[c]
98
98
98
3
2
1.5
48
7
24
10
11
79 (17)[d]
[a] The reactions were conducted with 0.3–0.5 mmol of nitrile 2a in THF
(2.5 mL). [b] Yield of the isolated product. [c] Recovery of 2a in >90%
yield was confirmed by 1H NMR spectroscopy of the crude material.
[d] Recovery yield of 2a.
During the course of our experiments on the a-methyl-
ation of diphenylacetonitrile (1) to prepare tertiary carbo-
nitrile 2a, we investigated its reaction with NaH (3 equiv) and
MeI (1.2 equiv) in THF (858C in a sealed tube; Scheme 1).
Although the desired tertiary nitrile 2a was isolated in 74%
yield, we were surprised to observe the formation of 1,1-
diphenylethane (3a) in 25% yield as a side product. Assum-
ing that 3a was formed by the decyanation of nitrile 2a, we
expected that this decyanation reaction could be generalized
to a more versatile synthetic strategy. Therefore, we opti-
mized the reaction conditions for the decyanation of nitrile 2a
by NaH (Table 1). We found that NaH alone was not
sufficient to drive the decyanation (Table 1, entry 1). Upon
the methylation of 1 with NaH and MeI (Scheme 1),
a stoichiometric amount of sodium iodide (NaI) is necessarily
generated, and thus we speculated that the cooperation of
NaH and NaI could be the key to the decyanation. Indeed, the
treatment of 2a with NaH (3 equiv) and NaI (2 equiv) in THF
delivered 3a in 96% yield (Table 1, entry 2). Although KI was
not optimally effective as an additive (Table 1, entry 3), LiI
rendered the process very rapid to afford 3a in 98% yield
within 3.5 h (entry 4). Similarly, a reaction with MgI2 pro-
duced 3a in 96% yield, albeit at a slower reaction rate
(Table 1, entry 5). Interestingly, LiBr or LiCl did not promote
the decyanation effectively (Table 1, entries 6 and 7), thus
indicating the important role of dissolved iodide ions in
enabling this unprecedented decyanation by NaH. When the
amount of LiI was decreased (Table 1, entries 8 and 9), we
found that the use of even a catalytic amount of LiI
(20 mol%) enabled full conversion of 2a with a longer
reaction time (48 h; entry 9). When 1 equivalent of LiI was
used as the promoter, the amount of NaH could be decreased
[*] Dr. P. C. Too, G. H. Chan, Dr. Y. L. Tnay, 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 for this article can be found under http://dx.
doi.org/10.1002/anie.201600305.
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KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited and is not used for commercial purposes.
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to 1.5–2 equivalents (Table 1, entries 10 and 11). However,
the reduction of 2a with LiH in the presence of LiI did not
proceed at all, thus indicating the specific reactivity of NaH
for the present decyanation.
thus indicating unprecedented and unique reactivity of the
NaH–Li(Na)I composites in the present decyanation.
The reactions of certain substrates provided critical clues
about the reaction mechanism. When the reaction of nitrile
2k was quenched after 2.5 h, before full conversion, aldehyde
4k was isolated in 42% yield along with the decyanated
alkane 3k in 37% yield (Scheme 3a). The formation of
aldehyde 4k indicated that the decyanation might involve an
iminyl anion intermediate, which could be formed by hydride
attack on the CN triple bond. Moreover, the reaction of nitrile
2x, which contains a 2-chlorophenyl moiety (Scheme 3b),
afforded not only decyanated 3x (61% yield) but also
dihydroindole 5x (17% yield); the latter product should be
formed by cyclization of the iminyl anion species through
either ipso aromatic substitution or nucleophilic addition to
the benzyne, followed by further hydride addition to the
resulting cyclic imine (see also Scheme 5c). The assumption
of hydride transfer is further supported by the reduction of
adamantane-1-carbonitrile (2y; Scheme 3c), which gave the
corresponding aldehyde 4y and primary amine 6y in 29 and
7% yield, respectively.
The stereochemical outcomes of the present decyanation
were also investigated. Decyanation of exo-2-(4-methoxy-
phenyl)-endo-2-norbornylcarbonitrile (2z) afforded only
decyanated 3z with retention of the original stereoconfigura-
tion (Scheme 4a). Significantly, decyanation of optically
active (+)- and (À)-2b (Scheme 4b) gave the corresponding
product containing a tertiary carbon center with the original
enantiomeric purity.
We conducted DFT calculations to investigate the origin
of the hydride-donor reactivity of these NaH inorganic
composites and the reaction mechanisms of the decyanation
by using 2-phenylisobutyronitrile as a model substrate. NaH
has ionic character with the cubic halite crystal structure
composed of sodium cations and hydride anions, which make
The present protocol with NaH–LiI (Table 1, entry 10) is
complementary to existing methods for the reductive decya-
nation of carbonitriles[4–7] and could be useful as a new
protocol with a distinct reaction mechanism. Therefore, we
next examined the scope of the decyanation of carbonitriles
under these reaction conditions (Scheme 2). The present
protocol is suitable for the facile construction of tertiary
carbon centers of monoaryl (products 3b–p), diaryl (products
3q–u), and even triaryl methanes (products 3v and 3w) from
the corresponding carbonitriles, thus offering a new retro-
synthetic strategy to access this class of compounds.[8] Notably,
this method allows the preparation of cycloalkyl arenes
(products 3j–p) possessing strained cyclobutyl (products 3m
and 3n) and tetrahydropyranyl moieties (product 3o) as well
as 2-cyclohexylpyridine (3p) with high efficiency. It was
observed that an electron-rich 4-methoxyphenyl group ren-
dered the reaction rate of the decyanation slower (3j vs. 3k
and 3m vs. 3n). We initially speculated that the decyanation
might be mediated by single-electron reduction of the
carbonitrile by NaH,[9] followed by C CN bond homolysis
À
to give the corresponding C radical and a cyanide anion.
However, all of the results of experiments with radical-clock
substrates (for 3i, 3t, and 3u),[10] as well as deuterium-labeling
experiments with [D8]THF and D2O (see Scheme S1 in the
Supporting Information), exclude this possibility. The decya-
nation of carbonitriles 2 with the NaH–NaI system (Table 1,
entry 2) gave comparable yields of products 3, although much
longer reaction times were generally required (see
Scheme S2). In contrast, the reduction of carbonitriles with
LiAlH4 and iBu2AlH (DIBAL) generally provides the
corresponding primary amines and aldehydes, respectively,
Scheme 2. Scope of the decyanation. [a] The reaction was conducted with 3 equivalents of NaH and 1 equivalent of LiI.
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Figure 1. Free-energy profiles for decyanation by NaH (in kcalmolÀ1
determined at the B3LYP/def2-TZVP//B3LYP/6-31G level of theory).
,
Scheme 3. Implications of hydride transfer from NaH.
The values obtained at the B3LYP/def2-TZVP level of theory are also
shown in parentheses for comparison. a) Reaction of 2-phenyliso-
butyronitrile with NaH. b) Decyanation.
located the transition state TS-II (Figure 1b) for concerted
À
C C bond cleavage and H-atom transfer with elimination of
NaCN[14] from putative E iminyl anion intermediate C, in
which a sodium cation–p interaction occurs.[15] Intermediate
C is formed by facile isomerization of the initially formed
À
Z isomer B. The energy barrier for the C C bond cleavage
was very low (4.6 kcalmolÀ1) when Na+ acted as the counter-
ion. In the transition state TS-II, the hydrogen atom
originating from NaH bears partial positive charge (d +)
and thus has some protic character. This hydrogen atom is
likely to be rearranged to the adjacent carbon atom (dÀ)
through proton transfer with retention of the stereoconfigu-
ration. This result demonstrates the unique umpolung
nature[16] of the decyanation, in which the nucleophilic
hydride derived from NaH acquires electrophilic protic
properties in the later stages. Li+ as the counterion also
Scheme 4. Stereochemical outcomes of the reductive decyanation.
these compounds insoluble in inert organic solvents.[2] To
evaluate the intrinsic hydride-donor ability of NaH, we
performed DFT calculations by using a single molecule of
NaH (Figure 1a).[11,12] Interestingly, the barrier for hydride
transfer to the nitrile moiety to form iminyl anion intermedi-
ate B is very low (TS-I, 13.3 kcalmolÀ1). This result indicates
that NaH is intrinsically reactive as a hydride donor to polar
p electrophiles, and a reactive state of NaH close to its single
molecule state might be generated in the composite with LiI
or NaI.[13] Next, we investigated the mechanism of the
decyanation process in which the original stereoconfiguration
was retained (Scheme 4). DFT calculations successfully
provided a low C C cleavage barrier (5.0 kcalmolÀ1; see
À
Figure S2 in the Supporting Information). However, the
+
transition state with AlMe2 as the counterion (for the
model of DIBAL reduction) could not be determined (see
Figure S2). This result is consistent with the actual outcome of
the DIBAL reduction of carbonitriles, that is, formation of the
corresponding aldehydes.
Having identified the unprecedented hydride-donor reac-
tivity of the NaH–Li(Na)I composites, we next turned our
attention to the use of this protocol to reduce other polar
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Tier 2: MOE2012-T2-1-014). H.H. gratefully acknowledges
a Nanyang Assistant Professorship and the computer resour-
ces at the High-Performance Computing Centre of NTU.
Keywords: amides · decyanation ·
density functional calculations · reduction · sodium hydride
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3719–3723
Angew. Chem. 2016, 128, 3783–3787
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Scheme 5. Reduction of N,N’-dimethylamides, an N-methyl lactam,
and an N-aryl aldimine.
p electrophiles (Scheme 5). It was found that the reduction of
N,N’-dimethylamides 7a–c and N-methyl lactam 7d pro-
ceeded smoothly to give the corresponding aldehydes 8a–c
(Scheme 5a) and hemiaminal 8d (Scheme 5b), respectively,
in good yields. Because of its instability, the resulting hemi-
aminal 8d was further converted into acyclic carbamate 9d.
N-Methoxy-N-methylamides (Weinreb amides)[17] are com-
monly utilized for synthesis of the corresponding aldehydes
by their hydride reduction with LiAlH4 or DIBAL, which
proceeds via tetrahedral five-membered-chelate intermedi-
ates. The present protocol uniquely produces aldehydes from
simple N,N-dimethylamides. Moreover, the reduction of N-
aryl aldimine 10 proceeded smoothly to give the correspond-
ing amine 11 in good yields (Scheme 5c). However, the
reduction of esters and aldehydes was found to give complex
results because of the inherent basicity of NaH (see
Scheme S3).
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À
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Further materials characterization to gain an in-depth
understanding of the origin of the hydride-donor reactivity of
NaH in the present inorganic composites is currently under
way. We are also continuously working to explore further
applications of the present protocol for the development of
other types of hydride-reduction processes.
Acknowledgements
[10] M. Newcomb in Encyclopedia of Radicals in Chemistry, Biology
and Materials, Vol. 1 (Eds.: C. Chatgilialoglu, A. Studer), Wiley,
Chichester, 2012, p. 107.
Funding of S.C. for this research was provided by the
Singapore Ministry of Education (Academic Research Fund
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[11] For a DFT study on the bonding nature of several alkal-metal
[14] After decyanation by the NaH–NaI system, the ATR-FTIR
hydrides, see: F. M. Bickelhaupt, M. Solµ, C. F. Guerra, Faraday
Discuss. 2007, 135, 451.
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(2086 cmÀ1; see the Supporting Information).
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or LiH with carbonyl compounds, see: a) Y.-D. Wu, J. A. Tucker,
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[17] S. Balasubramaniam, I. S. Aidhen, Synthesis 2008, 3707.
[13] The kinetic profiles of the decyanation suggested that the
reaction of NaH with LiI (or NaI) resulted in the formation of
new inorganic composite materials that probably display hy-
dride-donor reactivity. See the Supporting Information for more
details.
Received: January 11, 2016
Published online: February 17, 2016
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