Amides as surrogates of aldehydes for C-C bond formation: amide-based direct Knoevenagel-type condensation reaction and related reactions

Article abstract of DOI:10.1007/s11426-019-9586-3

Aldehydes are perhaps the most versatile compounds that enable many C-C bond forming reactions, which are not amenable for other subclasses of carbonyl compounds. We report the first use of amides as surrogates of aldehydes for C-C bond formation, namely,

Full text of DOI:10.1007/s11426-019-9586-3

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Amides as surrogates of aldehydes for C–C bond formation:
amide-based direct Knoevenagel-type condensation reaction and
related reactions
Wei Ou & Pei-Qiang Huang*
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, China
Received July 11, 2019; accepted August 14, 2019; published online October 22, 2019
Aldehydes are perhaps the most versatile compounds that enable many C–C bond forming reactions, which are not amenable for
other subclasses of carbonyl compounds. We report the first use of amides as surrogates of aldehydes for C–C bond formation,
namely, the direct Knoevenagel-type condensation based on amides. The one-pot method consists of controlled reduction of an
amide with LDBIPA [LiAlH(iBu)2(OiPr)], Lewis acid-mediated release of a reactive iminium ion intermediate, nucleophilic
addition, and in situ elimination of amine. The reaction shows good functional group tolerance. We also demonstrated that the
Schwartz reagent could be used as an alternative of LDBIPA. The employment of nitromethane and a silyl enol ether as the
nucleophiles opens an avenue for the unprecedented amide-based nitro-aldol condensation reaction and aldol condensation
reaction, respectively.
amides, Knoevenagel condensation, C–C bond formation, one-pot reaction, amide transformation
Citation:
Ou W, Huang PQ. Amides as surrogates of aldehydes for C–C bond formation: amide-based direct Knoevenagel-type condensation reaction and
related reactions. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9586-3
The carbonyl group is one of the most versatile functional
groups in organic chemistry. However, there exists remark-
able difference on reactivity among different classes of car-
bonyl compounds. In this regard, thanks to the high
electrophilicity of their carbonyl groups, aldehydes and ke-
tones display rich chemistry, whereas amides is a class of the
least reactive carbonyl compounds. Actually, it is well-
known that the aldol reaction, Mukaiyama reaction, Wittig
reaction, and Knoevenagel reaction etc. are feasible only for
aldehydes and ketones. In particular, only aldehydes and
some unhindered ketones are feasible substrates for the
Knoevenagel reaction (Scheme 1(a)) [1]. Although the
Knoevenagel reaction is a classical reaction, this reaction is
still being widely used in organic synthesis due to the ver-
satility of the multi-functional α,β-unsaturated compounds
that formed [2]. Moreover, in an essay appeared in 2010, List
[3] revealed that the Knoevenagel reaction is the roots of
aminocatalysis.
On the other hand, common amides are ubiquitous in
Nature [4]. The inherent high stability of amides rend them
ideal starting materials and versatile intermediates in organic
synthesis and medicinal chemistry [5], and thus the sub-
sequent transformation becomes imperative and challenging.
This can account for the fact that multistep methods have
long been employed for the transformations of amides [5g–
5i]. The direct transformation of amides has attracted con-
siderable attention in recent years [6], and breakthroughs
have been achieved on several aspects [6–8]. However, to the
best of our knowledge, the use of amides as surrogates of
aldehydes for one-pot C–C bond formation is unprecedented.
*Corresponding author (email: pqhuang@xmu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

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Ou et al. Sci China Chem
selected for our purpose.
At the outset of our investigation, the chemoselective re-
duction of 2-naphthamide 1a with LDBIPA was checked.
Indeed, exposure of a THF solution of amide 1a to LDBIPA,
yielded, after acidic work-up with 1 M HCl, 2-naphthalde-
hyde (3) in excellent yield (93%, Scheme 2). Next, a one-pot
tandem partial reduction-Knoevenagel condensation reaction
was attempted. To our disappointment, after successive
treatment of amide 1a with LDBIPA, and with enolate gen-
erated from sodio dimethyl malonate and sodium hydride,
the desired condensation product 2a was not observed, in-
stead 2-naphthaldehyde (3) was obtained again (Scheme 2
and Table 1, entry 1). These results implicated that the pre-
sumed chelating intermediate A [11], generated from the
partial reduction of amide with LDBIPA, was stable enough
which prevented further reduction or addition of another
nucleophile.
Scheme 1 (a) Classical Knoevenagel condensation reaction. (b) Our plan.
(c) Preparation of LDBIPA. LDBIPA=lithium diisobutyl-isopropoxyalu-
minum hydride.
It was envisaged that by employing a Lewis acid, it would
be possible to release a reactive species from A allowing thus
Whereas challenging, if this can be achieved, the scope of
both the aforementioned classical C–C bond-forming reac-
tions such as the Knoevenagel condensation reaction, and the
chemistry of amides would be extended. Herein, we report a
tertiary amide-based Knoevenagel condensation reaction
leading to α,β-unsaturated compounds (Scheme 1(b)).
To realize our plan, we have to face with multiple chal-
lenges. First, we needed a reliable method for the partial
reduction of quite stable tertiary amides. Second, we had to
overcome the problem of chemoselectivity, namely, to gen-
erate an aldehyde (C–N bond cleavage) instead of an imi-
nium intermediate (C–O bond cleavage) from an amide,
although the latter is more popular (vide infra). Third, it was
important to ensure that the subsequent tandem condensation
of the aldehyde intermediate occurs chemoselectively with
the carbanion generated in situ from active methylene
compounds, instead of with the amine generated along with
aldehyde (from amide). A survey of literature showed that
the Schwartz reagent [9] and lithium diisobutyl-iso-
propoxyaluminum hydride [LiAlH(iBu)2(OiPr), LDBIPA)
(Scheme 1(c)) [10] might suit our need. Taking advantages
of the Schwartz reagent, Ganem and Georg have developed
highly chemoselective and reliable methods for the partial
reduction of amides to give imines [11] and aldehydes [12],
respectively. Ganem et al. [13], Zhao et al. [14], and Chida
and Sato et al. [8d,8e] have demonstrated independently that
Schwartz’s reagent can be used for the one-pot, chemose-
lective reductive functionalization of amides via an iminium
intermediates (C–O bond cleavage) [13]. As regarding
LDBIPA, An and co-workers [10] reported that the partial
reduction of tertiary amides to aldehydes could be achieved
in excellent yields (GC). In view of the easy preparation of
LDBIPA from less expensive DIBALH, this reagent was
Scheme 2 Unsuccessful attempt for the tandem reduction–Knoevenagel
condensation reaction.
Table 1 Reaction conditions screeninga)
a) Reaction conditions: amide 1a (1.0 mmol), LDBIPA (1.2 mmol), THF
(0.2 M), 0 °C, 1 h; Lewis acid, 10 min; sodium enolate, freshly prepared
from dimethyl malonate and NaH for 30 min at 0 °C.

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Ou et al. Sci China Chem
an in situ nucleophilic addition. For this purpose, several
Lewis acids including ZnCl2, BF3•OEt2, TMSOTf, Ti(OiPr)4,
AlCl3, SnCl4, and TiCl4 were surveyed. As can be seen from
Table 1, whilst most of them are ineffective in promoting the
tandem reduction–Knoevenagel condensation reaction (Ta-
ble 1, entries 2–6), employment of 1.5 equiv. of SnCl4 or
TiCl4 produced the desired product 2a in 68% (entry 7) and
90% yield (entry 8), respectively. Thus, TiCl4 was Lewis acid
and a brief optimization was next undertaken. Use of a lower
amount of TiCl4 led to a decrease in yield (entries 9 and 10).
To our delight, lowering the equivalents of nucleophile from
3.0 equiv. to 2.0 equiv., the yield was almost unaffected
(entry 11 vs. entry 8). Thus, the optimized reaction condi-
tions were defined as: amide (1.0 equiv.), LDBIPA (1.2
equiv.), TiCl4 (1.5 equiv.), NaH (2.0 equiv.)/Nu (2.0 equiv.).
Under these conditions, 2a was obtained in 88% yield (Table
2, entry 1). It is worth mentioning that, during this in-
vestigation, no alcohol, namely, the over-reduction side
product was observed.
With the optimized reaction conditions in hand, scope of
the one-pot reductive Knoevenagel-type condensation reac-
tion was investigated. We first examined scope of amide
substrate, and the results are displayed in Table 2. N,N-Di-
methyl analogue (1b) of 1a reacted smoothly to give 2a in
90% yield (entry 2), whereas sterically hindered N,N-diiso-
propyl analogue (1c) failed to react (entry 3). The reactions
of benzamide and derivatives bearing electron-donating
groups including methyl at either para- meta-, or ortho-po-
sition, and 3,4,5-trimethoxybenzamide (1d–1h) reacted
smoothly to yield the corresponding products 2b–2f in ex-
cellent yields (85%–89%, entries 4–8). However, the steri-
cally hindered 2,4,6-trimethylbenzamide (1i) failed to react
(entry 9). p-Bromobenzamide (1j) reacted to afford 2h in
80% yield (entry 10), implicating that the reaction also tol-
erated benzamide bearing an electron-withdrawing group.
Indeed, even p-nitrobenzamide (1k) reacted to afford the
desired product 2i in 68% yield (entry 11) reflecting good
functional group tolerance and chemoselectivity of the re-
action. The reactions of electron-rich heteroaromatic amides
N,N-dimethylfuran-2-carboxamide (1l), N,N-dimethylthio-
phene-2-carboxamide (1m), and N,N-dimethylbenzo[b]
thiophene-2-carboxamide (1n) are also viable substrates,
which reacted to give the desired products 2j, 2k, and 2l in
84%–88% yields (entries 12–14).
Table 2 Scope of the reaction with respect to the amide useda)
The functional group tolerance was further surveyed. As
shown in entries 15–19, the reaction tolerated several sen-
sitive functional groups such as t-butyldimethylsilyl (TBS)
(1o, a silyl ether), tetrahydropyranyl (THP) (1p, an acetal),
methoxymethyl (MOM) (1q, an acetal), allyl (1r) and pro-
pargylic ether (1s), and the expected products were obtained
in 81%–89% yields. Besides para-nitrobenzamide (1k) that
bearing a reducible nitro group, the reaction of 1t also pro-
ceeded chemoselectively at the amide group to produce 2b in
an excellent yield of 88% (entry 20). It is worth noting that 1t
contains both a reducible cyano group and an α-amidonitrile
moiety, which is cleavable in the presence of a Lewis acid. It
is remarkable that both sensitive functional groups remained
intact under the reducing and Lewis acid-mediated reaction
conditions. To our disappointment, attempted reaction of
aliphatic amide 1u was unsuccessful, and the corresponding
aldehyde was observed.
We next turned our attention to investigate nucleophile
scope. As can be seen from Table 3. The reactions of di-
benzyl malonate, malononitrile, and ethyl 2-cyanoacetate
gave the corresponding products 4, 5, and 6 in good to ex-
cellent yields (86%, 89% and 81%, Table 3, entries 2–4). 2-
(Phenylsulfonyl)acetonitrile and ethyl 2-nitroacetate reacted
without incident to afford the corresponding products 7 and 8
albeit in moderate yields (66% and 70%, entries 5 and 6).
To further extend the scope of the reaction, the reductive
condensation of N,N-dimethyl-2-naphthamidethe (1b) with
a) Reaction condition: amide (1.0 mmol), LDBIPA (1.2 mmol), THF
(0.2 M), 0 °C, 1 h; TiCl4 (1.5 mmol), 10 min; sodium enolate (2.0 mmol),
freshly prepared from dimethyl malonate and NaH (2.0 mmol) for 30 min
at 0 °C.

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Ou et al. Sci China Chem
Table 3 Scope of the reaction with respect to the nucleophile used
Thus, a plausible mechanism is displayed in Scheme 4. The
reduction of an amide with LDBIPA generates a stable
chelating intermediate A, which collapses to release the
corresponding iminium intermediate B upon treating with a
Lewis acid such as TiCl4. A nucleophilic addition then oc-
curs to yield β-amino diester C, which eliminates the amine
to yield the Knoevenagel condensation product 2.
Encouraged by the success in employing LDBIPA as a
chemoselective reducing agent for the tandem reaction, the
use of the Schwartz reagent was examined. To our delight,
successive treatment of naphthalen-2-yl(piperidin-1-yl) me-
thanone 1a with Schwartz reagent and dimethyl sodio mal-
onate produced 2a in 86% yield (Scheme 5), comparable
with that with LDBIPA (90%). Moreover, the reductive
nitromethane was attempted. Unfortunately, following the
general procedure, the desired product was not observed.
Pleasantly, when potassium tert-butoxide was used to replace
NaH as a base, the reaction proceeded smoothly to afford
(E)-nitroalkene 9 in 78% yield (entry 7). The reason for the
failure in using NaH as a base in this reaction is unclear at
this stage, however, the base-dependence of the nitroalkane-
based reactions have been documented previously [15]. This
reaction can be viewed as an amide-based nitro-aldol con-
densation, which is also unprecedented. Next, the use of silyl
enol ether as a nucleophile was examined. Pleasantly, when
silyl enol ether derived from acetophenone was employed, its
reductive condensation with N,N-dimethyl-2-naphthami-
dethe (1b) produced the expected α,β-unsaturated enone 10
in 75% yield (entry 8). This also constitutes the first example
using an amide as a surrogate of an aldehyde for an amide-
based direct reductive aldol condensation reaction.
Scheme 3 Control experiments (color online).
Scheme 4 Plausible mechanisms of the tandem reduction-Knoevenagel
condensation reactions of tertiary amides (color online).
The reductive allylation of 2-naphthamide derivative 1b
was also attempted. Much to our surprise, instead of the
expected alcohol 12, homoallylic amine 11 was obtained in
86% yield. Moreover, successive treatment of 1a with
LDBIPA and diethyl phosphonate produced α-amino phos-
phonate 13 in 85% yield.
The results showed in Scheme 3 are very interesting,
which not only constitute valuable chemo-divergent trans-
formations of tertiary amides, but are also informative for an
understanding of the mechanism of the amide-based direct
Knoevenagel condensation reaction. Indeed, the observed
reductive functionalization products 11 and 13 allowed
precluding the possibility of intermediacy of an aldehyde.
Scheme 5 Employing the Schwartz reagent for the amide-based Knoe-
venagel-type one-pot condensation reaction.

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Ou et al. Sci China Chem
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Knoevenagel condensation reaction of amido ester 1v oc-
curred chemoselectively at the amide group to give com-
pound 2s in 80% yield.
6
7
In summary, we have realized, for the first time, the use of
amides as surrogates of aldehydes for C–C bond formation.
Although this concept has mainly demonstrated for the
Knoevenagel condensation reaction, and the mechanism is
different from what we have designed, successful examples
also cover the amide-based reductive nitro-aldol condensa-
tion reaction and aldol condensation reaction. Moreover, the
successful replacement of LDBIPA by the Schwartz reagent
implicates that other amide reducing methods, including the
catalytic ones, would find application in this methodology.
This will on one hand, extend the scope of the aldehyde-
based C–C bond forming reactions, and on the other hand,
further validate amides as a class of stable and reliable
building blocks in both natural product synthesis and med-
icinal chemistry. Work on these directions are ongoing in our
laboratory, and the results will be reported in due course.
8
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21931010, 21672176) and the National Key
Research and Development Program of China (2017YFA0207302).
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
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