Reduction of N,N-Dimethylcarboxamides to Aldehydes by Sodium Hydride–Iodide Composite

Article abstract of DOI:10.1002/hlca.201800049

A new and concise protocol for selective reduction of N,N-dimethylamides into aldehydes was established using sodium hydride (NaH) in the presence of sodium iodide (NaI) under mild reaction conditions. The present protocol with the NaH-NaI composite allows for reduction of not only aromatic and heteroaromatic but also aliphatic N,N-dimethylamides with wide substituent compatibility. Retention of α-chirality in the reduction of α-enantioriched amides was accomplished. Use of sodium deuteride (NaD) offers a new step-economical alternative to prepare deuterated aldehydes with high deuterium incorporation rate. The NaH-NaI composite exhibits unique chemoselectivity for reduction of N,N-dimethylamides over ketones.

Full text of DOI:10.1002/hlca.201800049

(1 of 8) e1800049
Reduction of N,N-Dimethylcarboxamides to Aldehydes by Sodium
Hydride–Iodide Composite
Guo Hao Chan, Derek Yiren Ong, Zhihao Yen, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, e-mail: shunsuke@ntu.edu.sg
A new and concise protocol for selective reduction of N,N-dimethylamides into aldehydes was established using
sodium hydride (NaH) in the presence of sodium iodide (NaI) under mild reaction conditions. The present protocol
with the NaH-NaI composite allows for reduction of not only aromatic and heteroaromatic but also aliphatic N,N-
dimethylamides with wide substituent compatibility. Retention of a-chirality in the reduction of a-enantioriched
amides was accomplished. Use of sodium deuteride (NaD) offers a new step-economical alternative to prepare
deuterated aldehydes with high deuterium incorporation rate. The NaH-NaI composite exhibits unique
chemoselectivity for reduction of N,N-dimethylamides over ketones.
Keywords: amides, aldehydes, reduction, sodium hydride, iodide.
diisobutylpiperidinohydroaluminate.[19] It should be
noted that the Schwartz’s reagent [Cp2Zr(H)Cl] is cap-
Introduction
Hydride reduction of carbonyl compounds is one of able of reducing a variety of amides (primary, sec-
the most fundamental and important processes in ondary, and tertiary) to the corresponding aldehydes
organic synthesis.[1][2] Among various carbonyl com- under very mild reaction conditions with wide func-
pounds, bench-stable amides are used as a versatile tional group compatibility (Scheme 3,a).[20 – 22] There
precursor to be reduced into amines and alcohols as have been reported several methods for reduction of
well as aldehydes (Scheme 1).[3 – 6] Especially, to per- amides to aldehydes using hydrosilanes with the aid
form the efficient and selective reduction of amides of transition metals. Buchwald developed reduction of
into aldehydes, specific setups in the amide sub- aliphatic amides into aldehydes by combined use
stituents, the reductants, and/or the reaction condi- of Ph2SiH2 and Ti(OiPr)4, that proceeds via formation
tions are required to prevent fragmentation of of an enamine intermediate (Scheme 3,b).[23] There-
transient tetrahedral metalated aminal intermediates, fore, racemization is observed in the reduction of a-
that results in over-reduction to amines or alcohols.
enantioriched amides. Adolfsson disclosed versatile
For this purpose, N-methoxy-N-methylamides (the reduction of piperidine amides into aldehydes with
Weinreb amides), that form stabilized tetrahedral five- 1,1,3,3-tetramethyldisiloxane catalyzed by Mo(CO)6
membered-chelate intermediates,[7 – 9] have typically (Scheme 3,c).[24] Temperature control is the key to
been utilized with reactive hydride donors such as enable selective formation of aldehydes over that of
lithium
aluminum
hydride,
diisobutylaluminium amines (À5 to 60 °C), in which unique chemoselectiv-
hydride, and Red-Al under cryogenic reaction condi- ity for the reduction of amides over other susceptible
tions (commonly at < 0 °C) (Scheme 2,a).[10] There has p-polar functional groups such as keto, formyl, and
also been reported use of tertiary amides having spe- imine moieties was observed. On the other hand,
cial substituents which reduce the electron-donating transition-metal free reduction of secondary amides
nature of the amide nitrogen onto the carbonyl group, into aldehydes was reported by Charette (Scheme 3,
including N-acylsultam,[11] N-acylsaccharin,[12] N-acyl d).[25] The process requires prior activation of amides
carbazoles[13] and N-acylaziridines (Scheme 2,b).[14][15]
On the other hand, the reduction of simple N,N-
with Tf2O followed by reduction with Et3SiH.
Despite the recent progress, there is still ample
dialkylamides to aldehydes needs use of modified room to develop methods for reducing simple amides
hydride reagents such as LiAlHn(OEt)4–n (n = 1 or into aldehydes, that can be conducted in operationally
2),[16][17]
disiamylborane,[18]
and
lithium simple and cost-effective manners under milder
DOI: 10.1002/hlca.201800049
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Helv. Chim. Acta 2018, 101, e1800049
Scheme 1. Reduction of amides.
Scheme 2. Special setups onto amides for reduction to
aldehydes.
reaction conditions. We recently disclosed that sodium
hydride (NaH) could act as a hydride donor in the
presence of NaI or LiI in THF, capable of performing a
series of unprecedented hydride reduction such as
hydrodecyanation of carbonitriles (Scheme 4,a),[26][27]
hydrodehalogenation of haloarenes (Scheme 4,b),[28]
and dearylation of arylphosphine oxides[29] (Scheme 4,
c).[30][31] In this context, we envisioned that use of the
sodium hydride–iodide composite for the reduction of
amides results in unique outcomes.1 This article
describes a full account on hydride reduction of
amides to aldehydes by the sodium hydride–iodide
composite with broad evaluation in scope and limita-
tions (Scheme 4,d).
Scheme 3. Reduction of simple N,N-dialkylamides into
aldehydes.
equiv.) and NaI (1 equiv.) in THF at 85 °C (under
sealed reaction conditions) completed within 1 h to
give 2-naphthaldehyde (2a) in 90% yield as a sole
product (Table 1, entry 1). Surprisingly, the transient
tetrahedral hemiaminal intermediate could be kept
stable even at high reaction temperature (85 °C),
enabling selective formation of aldehyde 2a. This
unprecedented discovery stimulated us further to
optimize the reaction conditions to render the
reduction process more selective and versatile.
Slower reaction rate was observed when the iodide
Results and Discussion
Our preliminary investigation revealed that the reac-
tion of N,N-dimethyl-2-naphthamide (1a) with NaH (3
1
For our preliminary communications on reduction of
simple amides onto aldehydes, see: ref. [26] and ref. [31]. additive was changed to LiI (entry 2). We found that
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Helv. Chim. Acta 2018, 101, e1800049
Scheme 4. Reduction by the NaH–I composite.
Table 1. Optimization of reaction conditions
infra). Further lowering of the reaction temperature
to 25 °C or the amount of NaI to 0.1 equivalent
made the process incomplete even after 24 h (entries
4 and 5). It should be noted that use of NaH in the
absence of iodide additives is not sufficient to drive
the hydride reduction (entry 6).
Having optimized the reaction conditions, we next
investigated the substituent effect of the amide nitro-
gen (Scheme 5). We found that as the steric demand
increases, the reaction becomes more sluggish. The
reduction of diisopropylamide 1bc was not completed
even after 24 h, providing only 7% yield of aldehyde
2b with 70% recovery of 1bc. Piperidine and morpho-
line amides 1bd and 1be showed similar reactivity as
that of diethylamide 1bb.
Entry
Iodide
Temperature [°C]
Time [h]
Yield of
(equiv.)
2a [%][b]
1
2
3
4
5
6
NaI (1)
LiI (1)
NaI (1)
NaI (1)
NaI (0.1)
–
85
85
40
25
40
40
3
6
10
24
24
10
90
89
93
(63)[c]
(23)[d]
[e]
–
[a] The reactions were conducted using 0.5 mmol of amide 1a
in THF (0.2 M). [b] Yields of isolated products. [c] 1H-NMR yield
based on the internal standard. 1a was recovered in 36% yield.
[d] 1H-NMR yield based on the internal standard. 1a was recov-
ered in 74% yield. [e] 1a was recovered in >95% yield based on
the internal standard.
Reduction of various aromatic N,N-dimethylamides
was next examined (Scheme 6). As electron-donating
substituents, methoxy, methoxymethoxy (MOMO-),
benzyloxy, and methylenedioxy as well as dimethy-
lamino moieties could be tolerated, and the corre-
sponding aldehydes were obtained in 78 – 94%
with the NaH-NaI system, lowering of the reaction yields (for 2b – 2h). Sterically hindered benzamides
temperature to 40 °C could also complete the pro- having ortho-methyl (for 2i) and ortho-benzyl (for 2j)
cess and the yield of 2a was improved to 93% (en- groups as well as 1-naphthamide (1k) could be
try 3). Implementation of the reduction at 40 °C, reduced smoothly, while reduction of 2,6-dimethyl-
despite longer reaction time required, is advanta- benzamide (1l) became sluggish. Synthesis of fer-
geous to make the process more selective (vide rocenecarboxaldehyde (2m) was achieved in 94%
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Scheme 5. Investigation of the substituent effect on the amide
nitrogen. [a] The reactions were conducted using 0.5 mmol of
amides 1 with 3 equiv. of NaH and 1 equiv. of NaI in THF (0.2 M)
at 40 °C and isolated yields of anisaldehyde (2b) and the reac-
tion time were noted above. [b] 1 H-NMR yield based on the inter-
nal standard. 1bc was recovered in 70% yield.
yield. It should be worthy of note that the present
reaction conditions allowed for chemoselective
reduction of amides into benzaldehydes keeping C-
halogen bonds intact (for 2o – 2r). Reduction of
electron-deficient amides 1s and 1t also worked
well, while that of a,b-unsaturated amide 1u per-
formed in moderate efficiency.
We then shifted our attention to the reduction of
heteroaromatic amides (Scheme 7). Various electron-
rich 5-membered heteroaromatic substrates were first
screened (Scheme 7,a). Reduction of N-methyl-2-indo-
lecarboxamide (3a) and N-benzyl-2-pyrrolecarbox-
amide (3b) gave the corresponding aldehydes in
excellent yields. N-Unprotected 2-pyrrolecarboxamide
(3c) could be reduced in good yield, while use of
five equivalents of NaH was required to complete
the process. Other electron-rich heteroaromatic
amides based on furan, thiophene, and benzothio-
phene could be converted into the corresponding
aldehydes in good to moderate yields (for 4d – 4f).
On the other hand, electron-deficient 6-membered-
ring aromatic heterocycles are susceptible to the
conventional hydride reductants. In this regard, use
of the NaH–NaI composite is advantageous as quino-
line and pyridine scaffolds were tolerated during the
amide reduction. Various quinoline and pyridinecar-
boxamides were reduced to the corresponding
aldehydes in good to moderate yields. Nevertheless,
Scheme 6. Reduction of aromatic amides. [a] Unless otherwise
stated, the reactions were conducted using 0.5 mmol of amides
1 with 3 equiv. of NaH and 1 equiv. of NaI in THF (0.2 M) at 40 °C
and isolated yields of aldehydes 2 were noted above. [b] 1 H-NMR
yield with the aid of internal standard. [c] 1l was recovered in
81% yield based on the internal standard. [d] The reaction was
conducted using N1,N1,N4,N4-tetramethylterephthalamide (1t)
with 5 equiv. of NaH and 2 equiv. of NaI at 85 °C.
We next turned our attention to the reduction
this protocol is capable of reducing 7-chloro-2-phe- of aliphatic amides (Scheme 8). Amides having an a-
nylquinoline-4-carboxamide (3i) to 7-chloro-2-phenyl- quaternary carbon are suitable substrates for the
quinoline-4-carboxaldehyde (4i), which is a key inter- reduction (Scheme 8,a), including the ones derived
mediate for supplying a quinolone-based anti-cancer from drug molecule, gemfibrozil (for 6d) and natural
agent.[32]
product, abietic acid (for 6e). We also found that
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[a]
Scheme 7. Reduction of heteroaromatic amides.
Unless
otherwise stated, the reactions were conducted using
0.3 – 0.5 mmol of amides 3 with 3 equiv. of NaH and 1
[a]
Scheme 8. Reduction of aliphatic amides.
Unless otherwise
stated, the reactions were conducted using 0.5 mmol of amides
equiv. of NaI at 40 °C in THF (0.2 M) and isolated yields of
5 with 3 equiv. of NaH and 1 equiv. of NaI at 40 °C in THF (0.2 M)
[b]
[b]
aldehydes 4 were noted above.
The reaction was con-
and isolated yields of aldehydes 6 were noted above.
The
ducted using 5 equiv. of NaH and 2 equiv. of NaI in THF
reaction was conducted using 1 g (4.1 mmol) of 5j at 60 °C.
[c]
[c] The reaction was conducted using 5 equiv. of NaH and 2 equiv.
(0.1 M).
The reactions were quenched by pouring the mix-
[d]
ture into pH7 phosphate buffer solution (see the Supporting
The reaction was quenched by pouring the reaction mixture
[d]
Information for details).
The reaction was conducted using
into pH 7 phosphate buffer solution (see the Supporting Informa-
tion for details).
1 g (3.2 mmol) of 3i. [e] 1H-NMR yield based on the internal
[f]
standard.
The reaction was conducted using 3 equiv. of
NaH and 2 equiv. of NaI.
production of donepezil hydrochloride, an anti-Alz-
heimer drug,[33] and pyrrolidine 6k. We also note
that our reaction conditions were optimal for the
reduction of a-secondary amide 5l.
It is particularly worthy to note that the current
protocol is amenable to reduce a-enantioriched
amides 5f and 5k in good yields and selectivity to
afford the corresponding aldehydes in high ee (6k
the reduction of a-tertiary amides having one enoliz-
able proton gave the corresponding aldehydes in
good yields, emphasizing the mild reaction condi-
tions and functional group tolerance of the NaH–NaI
system (Scheme 8,b). The method is compatible with
aldehydes based on aliphatic heterocycles such as
tetrahydropyran 6i, piperidine 6j which is used for
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[a]
Scheme 9. Reduction of a-enantioriched amides.
The reac-
tions were quenched by pouring the mixture into pH 7 phos-
phate buffer solution to prevent undesired epimerization (see
the Supporting Information for details).
Scheme 11. Chemoselective reduction of amides.
protocol provides a direct and concise method to supply
deuterated aldehydes with high deuterium incorpora-
tion rate, given the fact that existing methods involve
use of expensive reagents and/or require multistep
routes for their preparation (Scheme 10).[34 – 39]
We found that the NaH–NaI composite shows
unprecedented chemoselectivity for reduction of amide
over ketone.3 The reaction of benzamide 8 having a
tethered keto group with the NaH–NaI composite pro-
ceeded smoothly to give benzaldehyde 9 in 88% yield
keeping the keto moiety intact (Scheme 11,a). The
reduction of keto amide 10 exclusively afforded keto
aldehyde 11, which spontaneously cyclized to 2-hydro-
xycyclohexyl phenyl ketone 12.
Scheme 10. Deuterium labeling experiments.
was further converted into alcohol 7k for the pur-
pose to measure the ee by the Mosher method;
Scheme 9).
Conclusions
The reduction of aromatic amides 1a and 1b by
NaD2 resulted in formation of the corresponding deuter-
ated aromatic aldehydes 2a-[D] and 2b-[D] with high
deuterium incorporation rate of 93% and 95%, respec-
tively (Scheme 10). Similarly the reduction of aliphatic
amide 5a afforded 90% deuterium incorporation in 6a-
[D]. These results unambiguously support that sodium
hydride is acting as a hydride donor. Moreover, this
We have developed a new and concise protocol for
selective reduction of N,N-dimethyl amides into alde-
hydes using the NaH–NaI composite under mild reac-
tion conditions. The protocol is capable of reducing
variety of amides ranging from aromatic and
heteroaromatic amides to a-enantioriched aliphatic
amides with retention of enantiomeric excess. Use of
2
Sodium deuteride (NaD) was prepared by following the
3
reported procedure (treatment of Na dispersion in min-
The chemoselective reduction of amides over esters
t
eral oil with D2 gas (1 atm) at 270 °C). The prepared was enabled only when Bu ester was used as the ester
NaD contained metallic Na (ca. 3%), which was charac- moiety. Methyl and isopropyl esters were partially con-
terized by solid state NMR (23Na and H) spectroscopy as verted into carboxylates probably due to the presence of
2
well as powder X-ray diffraction. For details, see the Sup- NaOH in NaH, that somehow hampered reduction of
porting Information.
amides. For details, see the Supporting Information.
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Helv. Chim. Acta 2018, 101, e1800049
[9] M. P. Sibi, ‘Chemistry of N-Methoxy-N-methylamides. Appli-
sodium deuteride (NaD) offers a new step-economical
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other carbonyl functions such as ketones. Further
investigation of the reactivity of NaH–iodide compos-
ites to develop other types of hydride reduction pro-
cesses is ongoing in our laboratory.
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This work was financially supported by Nanyang
Technological University (NTU), Singapore Economic
Development Board (EDB), Pfizer Asia Pacific Pte. Ltd.,
and the Singapore Ministry of Education (Academic
Research Fund Tier 1: RG10/17). G. H. C. thanks to
EDB-Industrial Post-graduate Program (IPP) for the
scholarship support. We thank Prof. Han Sen Soo
and Mr. Zhonghan Hong (Division of Chemistry and
Biological Chemistry, NTU) for the assistance in pow-
der XRD experiments.
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Author Contribution Statement
G. H. C., D. Y. O., and S. C. designed the studies. G. H.
C., D. Y. O., and Z. Y. performed the experiments. G. H.
C. and S. C. wrote the manuscript.
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