A Direct, Versatile, and Chemoselective Synthesis of Vinylogous Bis- and Monourethanes/amides and β-Keto Esters by Aza-Knoevenagel-Type Reactions of Tertiary Amides with Enolates

Article abstract of DOI:10.1002/ejoc.201601326

Full details of our investigations into aza-Knoevenagel-type reactions with common tertiary amides as the electrophilic partner are reported. The method is based on the addition of stabilized carbanionic nucleophiles to the amides, which are activated in situ with triflic anhydride (Tf₂O). The reaction proceeds under mild conditions and tolerates several sensitive functional groups including enamide and tert-butyldimethylsilyloxy (TBSO) groups. Significantly, with amides bearing more reactive ester, cyano, and aldehyde groups, the reaction occurs chemoselectively at the least reactive amide group. Such “umpolung” of the chemoselectivity in C=C bond formation is challenging, rare, and of synthetic value. Vinylogous bis-urethanes (aza-Knoevenagel-type condensation products), vinylogous urethanes, and vinylogous amides can be synthesized by employing enolates/carbanions generated from methyl ketones, malonic acid monoester, 2-phenylacetate, or (benzylsulfonyl)benzene. Moreover, when higher homologues of acetate were used, β-keto esters were obtained directly from amides. The method has been applied to the one-step syntheses of several known key intermediates in the total syntheses of alkaloids and 4-quinolone antibiotics. An efficient and mild intramolecular Friedel–Crafts-type cyclization of an anilinyl ester has also been achieved with Tf₂O as an effective promoter. This amide-based method is a direct and umpoled alternative to the versatile but stepwise one based on thionation and the Eschenmoser sulfide contraction.

Full text of DOI:10.1002/ejoc.201601326

A Journal of
Accepted Article
Title: A Direct, Versatile, and Chemoselective Synthesis of Vinylogous
Bis- and mono-urethanes/Amides, and β-Keto Esters by Aza-
Knoevenagel-type Reactions of Tertiary Amides with Enolates
Authors: Pei-Qiang Huang and Wei Ou
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601326
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A Direct, Versatile, and Chemoselective Synthesis of Vinylogous
Bis- and mono-urethanes/ Amides, and β-Keto Esters by Aza-
Knoevenagel-type Reactions of Tertiary Amides with Enolates
Pei-Qiang Huang,* [a,b] and Wei Ou[a]
In memory of the late Professor Dr. Qi-Rui Cai
ciprofloxacin (5), pefloxacin (6), and bioactive analogue 7 in Fig.
1], a very important alternative to -lactams, tetracyclines and
aminoglycosides.[2]
Abstract: Full details of investigations into the aza-Knoevenagel-
type reactions using common tertiary amides as the electrophilic
partner are reported. The method is based on the addition of
stabilized carbanionic nucleophiles to the in situ triflic anhydride-
activated amides. Running under mild conditions, the reaction
tolerated several sensitive functional groups including enamide and
TBSO. Significantly, with the amides bearing more reactive ester,
cyano, and aldehyde groups, the reaction took place
chemoselectively at the least reactive amide group. Such
“umpolung” of chemoselectivity in C=C bond formation is challenging,
rare, and of synthetic value. Vinylogous bis-urethanes (aza-
Knoevenagel-type condensation products), vinylogous urethanes,
and vinylogous amides can be synthesized by employing enolates/
carbanions generated from methyl ketones, malonic acid monoester,
2-phenylacetate, or (benzylsulfonyl)benzene. Moreover, when higher
homologous of acetate was used, -keto esters were obtained
directly from amides. The method has been applied to the one-step
synthesis of several known key intermediates in the total synthesis
of alkaloids and quinoline antibiotics. An efficient and mild
intramolecular Friedel-Crafts type cyclization of anilinyl ester has
also been achieved using Tf2O as an effective promotor. This
amides-based method is a direct and umpoled alternative to the
versatile but stepwise one based on the thionation and
Eschenmoser sulfide contraction.
Figure 1. Structures of vinylogous bis-urethanes and analogues, vinylogous
urethanes/ vinylogous amides and analogues; amides; thioamides; two
quinoline antibiotics and an analogue.
From retrosynthetic point of view, amides (3) are ideal starting
material for the synthesis of both 1 and 2. This approach is
particularly attractive because amides are a class of highly
stable compounds been widely used in organic synthesis, and
their subsequent transformation into other classes of
compounds are imperative.[3] Thus the direct transformation of
amides (3)/ lactams (3L) into the vinylogous bis-urethanes and
analogues (1), vinylogous urethanes (2A), vinylogous amides
(2B), and analogues is highly desirable. Such transformation is
reminiscent of the classical Knoevenagel condensation reaction,
which involves the piperidine-mediated condensation of
aldehydes with active methylene compounds[4] (Scheme 1, a).
However, aldehydes are a class of reactive carbonyl compounds
prone to a number of nucleophilic addition reactions, while
amides constitute the least reactive carbonyl compounds.
Because of the poor electrophilicity of amide carbonyl group, the
direct aza-Knoevenagel-type condensation reaction of amides
with active methylene compounds to give vinylogous bis-
urethanes and analogues (1) (Scheme 1, b2) is challenging and
has hitherto been unknown. Even for the direct synthesis of
vinylogous urethanes (2A)/ amides (2B) from amides, only (1)
the Wittig-Horner type reactions of perfluoro-amides, a special
class of amides,[5] (2) the BF3OEt2-mediated direct addition of
lithium tert-butyl acetates with tertiary lactams to give vinylogous
urethanes (2A, E = CO2tBu),[6] and (3) the Bėlanger's triflic
anhydride (Tf2O)/ 2,6-di-tert-butyl-4-methylpyridine (TBDMP)-
promoted Vilsmeier–Haack-type intramolecular reaction of
amides with silyl enol ethers to give vinylogous amides (2B, E =
Introduction
The vinylogous bis-urethanes and analogues (1, Fig. 1),
vinylogous urethanes (2A), vinylogous amides (2B), and
analogues are multi-functionalized compounds whose ambident
electrophilicity and nucleophilicity make them versatile building
blocks for a number of transformations.[1] In addition, the
structural motif 1 also constitutes the key structural feature of the
many bioactive compounds including quinoline antibiotics [cf.
[a]
[b]
Prof. Dr. P.–Q. Huang, W. Ou
Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian Province, iChEM (Collaborative Innovation Center
of Chemistry for Energy Materials), College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005
(P.R. China)
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China
E-mail: pqhuang@xmu.edu.cn
Supporting information for this article is given via a link at the end of
the document. Crystallographic data in CIF of the products 1ab
CCDC 1510802.
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10.1002/ejoc.201601326
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CHO, COPh),[7] have been reported. In addition, the direct
synthesis of vinylogous urethanes 2A is low to moderate yielding
(21-54%) and the reaction failed with acyclic amides.[6]
In this paper, we report the full details of the study of direct aza-
Knoevenagel-type condensation reaction of tertiary amides,[15b]
namely, the direct transformations of amides to 1 and 2A, 2B. In
addition, a direct transformations of amides 3 to -keto esters 8,
as well as application of the newly developed methods to the
efficient construction of the scaffolds of quinoline antibiotics and
to the formal synthesis of several alkaloids are also included.
In fact, stepwise procedures relied on the pre-conversion of
amides to other activated forms are used routinely to achieve
the desired transformation.[1h-j,8-10] Among them, the method
based on the pre-conversion of amides to thioamides followed
by the Eschenmoser coupling reaction (ECR, or the
Eschenmoser sulfide contraction)[8] has found widespread
applications in organic synthesis (Scheme 1, b1).[1h-j,8b-10] It is
worth mentioning that the sulfide contraction has also been
applied to the synthesis of -keto esters 8.[11] Nevertheless, even
with many modifications made by several research groups,[10]
this methodology suffers from disadvantages such as the
necessity to first convert an amide (3) to a thioamide (4), most
often by thionation with the Lawesson reagent, low atom-
economy of both steps, and use of hazardous reagents.
Scheme 2. Observation of a vinylogous urethane side product. Tf2O =
trifluoromethanesulfonic anhydride; DTBMP = 2,6-di-tert-butyl-4-
methylpyridine.
Results and Discussion
The aza-Knoevenagel-type condensation reaction
In the light of our previous work on the amide-based C-C bond
forming reactions,[14] the tactic of amide activation with Tf2O was
adopted to achieve the aza-Knoevenagel-type condensation
reaction. On the basis of the foregoing findings (Scheme 2), our
investigation started with examining the condensation reaction of
N,N-dibenzylbenzamide 3a with diethyl malonate. In the event,
amide 3a was successively treated with Tf2O (1.1 equiv),
DTBMP (1.2 equiv), and enolate generated from diethyl
malonate (1.5 equiv) and a base (3.0 equiv) at 78 C. A survey
of base suitable for the deprotonation of malonate (Table 1)
showed that although piperidine, the base used in the classical
Knoevenagel reaction (Scheme 1, a) failed to mediate the
desired reaction (Table 1, entry 1), several stronger bases
turned out to be effective. Thus employing EtONa, t-BuOK NaH,
LDA (lithium diisopropylamde), and NaHMDS (sodium
hexamethyldisilazane) as base, the desired product 1a was
obtained in 50%, 68%, 73%, 70%, and 75% yield, respectively
(entries 2-6). Selecting NaHMDS as the base, the amount of
base was next examined. Comparing the results listed in entries
6-9 allowed concluding that use of 2.2 equiv of NaHMDS was
optimal. It was further envisaged that with the use of 2.2 equiv of
base NaHMDS, the expensive DTBMP, used as a base additive
in conjunction with Tf2O, could be waived. Indeed, in the
absence of DTBMP, and without increasing the amount of
NaHMDS, the reaction proceeded smoothly to afford the desired
product 1a in 73% yield (entry 10). Thus, the optimized ratio of
reagents for the aza-Knoevenagel-type reaction was defined as:
Scheme 1. The Knoevenagel reaction and two approaches for the
transformation of amides into vinylogous bis-urethanes and analogues (aza-
Knoevenagel-type condensation products)/ vinylogous urethanes, vinylogous
amides, and -keto esters.
In recent years, the C-C bond forming reactions based on the
direct nucleophilic addition to amides have attracted
considerable attention.[12-15] In our own investigation[14,15] on the
Tf2O-activated one-pot reductive alkylation[15a] of lactam 3a with
enolate of ethyl acetate, in addition to the desired bis-
functionalized product 9, vinylogous urethane 2A-a has been
unexpectedly formed in 26% yield (Scheme 2). This observation
stimulated us to explore the possibility to develop a direct and
general aza-Knoevenagel-type condensation reaction of
common tertiary amides[15b] and lactams (Scheme 1, 3 to 1).[15b]
secondary amide: Tf2O: malonate: NaHMDS = 1.0: 1.1: 1.5: 2.2.
Table 1. Base and Molar Ratio Screening.
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10.1002/ejoc.201601326
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substituents (Table 2, 3a – 3f), and aryl substituents (3g – 3k),
as well as a hereroaromatic amide (N,N-dibenzylthiophene-2-
carboxamide, 3l), aliphatic amides (3m and 3n), and lactams
(3L-a, 3L-b) to give the corresponding products in 70-81% yields.
The reaction showed exceptional functional group tolerance. For
amides/ lactams bearing ester, cyano, aldehyde, enamide, and
TBSO groups (3L-b, 3o, 3p, 3q, 3r and 3s), the reaction took
place chemoselectively at the lactam/ amide group. This is
significant because those functional groups are sensitive. In
particular ester and aldehyde groups are more reactive than an
amide group, which remained intact. To verify the observed high
chemoselectivity of the reaction at the amide group instead of
the aldehyde group, a crude sample of 1q was examined by
means of 1H NMR. Integrating of the peak appeared at vinylic
8.55 (corresponding to the condensation product of the aldehyde
group) and that of the desired product (aldehyde 10.05) allowed
concluding that the chemoselectivity was 25: 1.
Entry
DTBMP (equiv)
Base
Equiv. of Base
%Yield[a]
1
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0
Piperidine
EtONa
3
3
-
50
68
73
70
75
74
76
65
73
3
tBuOK
3
4
NaH
3
5
LDA
3
6
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
3
7
2.5
2.2
1.5
2.2
8
9
10
[a] Isolated yield. LDA = lithium diisopropylamide; NaHMDS = sodium
hexamethyldisilazane.
With the optimized conditions for the aza-Knoevenagel-type
reaction in hand, we proceeded to investigate the scope of the
reaction. A survey of a series of tertiary amides showed that the
reaction is applicable to aromatic amides bearing different N-
Table 2. Amide Scope of the aza-Knoevenagel-type condensation reaction.
[a] Only the structures of starting materials displayed; [b] isolated yield of product 1.
The reaction was next extended to other active methylene
compounds. As can be seen from Table 3, the aza-
Knoevenagel-type reactions of N-benzyl-2-pyrrolidinone (3L-a)
with dibenzyl malonate, malononitrile, ethyl 2-cyanoacetate, and
ethyl benzoylacetate proceeded smoothly to give the
corresponding aza-Knoevenagel-type condensation products 1v
– 1y in 69-78% yields.
Table 3. The aza-Knoevenagel-type condensation reactions of different active
methylene compounds.
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[a] Isolated yield. [b] Z/E geometry not determined.
Tf2O (4.0)
0 to RT
0 to RT
0 to RT
0 to RT
16
16
16
16
60
78
87
75
Tf2O (3.0)/ DMAP (5.0)
Tf2O (4.0)/ DMAP (5.0)
Tf2O (4.0)/ DMAP (4.0)
Synthetic Application of the Aza-Knoevenagel-type
condensation reaction.
Next, we turned our attention to investigate the application of our
method to the construction of the 3-carboxy-4-quinolone motif
(Fig. 1), which is the scaffold of many medicinal agents
exhibiting a variety of bioactivities including antitumor, anxiolytic,
and antiviral activities.[16] In this context, ciprofloxacin (5) and
pefloxacin (6)[1] are two representatives currently in clinical use
worldwide for treating genitourinary, gastrointestinal respiratory
and skin infections, as well as sexually transmitted diseases.[17]
In addition, quinolinone 7, a tricyclic analogue of pefloxacin (6)
exhibited a minimal inhibitory concentration (MIC) of 0.78 g mL-
[a] Isolated yield.
The synthesis of 11 (Scheme 4), the scaffold of quinoline
antibiotics currently in clinical use, was also addressed. Under
our newly established conditions, the Tf2O-mediated
Knoevenagel-type reaction of 3c with sodio dimethyl malonate
afforded 1c in 76% yield (Scheme 4). The Tf2O/ DMAP-
promoted Friedel-Crafts-type ring closure produced quinoline 11
in 82% yield.
against Staphylococcus aureus CMX686B, and 1.56 g mL-1
1
against Escherichia coli.[18]
Scheme 3. Aza-Knoevenagel-type condensation reaction of lactam 3L-c with
dimethyl malonate.
Scheme 4. synthesis of quinoline 11.
We opted for the scaffold (10, Table 4) of the tricyclic
quinolinone 7 as our first target. The aza-Knoevenagel-type
reaction of 3L-c with sodio dimethyl malonate under standard
conditions produced 1z in 81% yield (Scheme 3). Subjecting of
1z to the classical intramolecular Friedel-Crafts reaction
conditions (in neat PPA = polyphosphoric acid, 100 C, 2 h)
afforded the desired 10 in 80% yield (Table 4, entry 1). Although
the cyclization reaction was successful as expected, we
envisaged that an alternative protocol under milder reaction
conditions would be desirable. A survey of literature showed that
Wulff and co-workers have reported in 1999 the first use of Tf2O
to effect a Friedel-Crafts-type ring closure on a tert-butyl ester.[19]
Although the reaction ran quickly (30 min) at rt, the yield was
only moderate (58%), and a large excess of Tf2O (33 equiv) has
been used. In our case, a quick survey of reaction conditions
(Table 4, entries 2-5) showed that in the presence of Tf2O (4.0
equiv)/ DMAP[20] (5.0 equiv), the cyclization reaction of 1z took
place smoothly at 0 C to rt to give the cyclization product 10 in
87% yield.
Direct transformation of tertiary amides into vinylogous
urethanes and synthetic applications
After establishing the conditions for the aza-Knoevenagel-type
condensation reaction, we focused our attention to the direct
vinylogous urethanation of amides. Because direct use of
enolate of ethyl acetate led to vinylogous urethane 2A-a in only
26% yield (Scheme 2), the use of ethyl bromoacetate
possessing more acidic -protons to replace ethyl acetate was
taken into consideration. To our delight, that successive
treatment of amide 3L-a with Tf2O (1.1 equiv) and enolate
generated from bromoacetate (1.5 equiv) and NaHMDS (2.2
equiv) at 78 C produced the desired vinylogous urethane 2A-a
in 65% yield (Scheme 5, eq. 1). Encouraged by this result, use
of active methylene compound malonic acid monoester as a
surrogate of acetate was attempted. Pleasantly, treatment of
Tf2O-activated lactam 3L-a with dianion generated from malonic
acid monoester and 3.0 equiv of NaHMDS directly produced
urethane 2A-a in 73% yield (Scheme 5, eq. 2).
In contrast to the results obtained in Scheme 2, the
condensation reaction of phenylacetate with activated amide 3e
produced vinylogous urethane 1aa in 85% yield (Scheme 5, eq.
Table 4. Cyclization of the aza-Knoevenagel-type condensation product 1z.
3).
Similarly,
reaction
of
carbanion
derived
from
(benzylsulfonyl)benzene with activated 3e yielded vinylogous E-
sulfonamide 1ab (Scheme 5, eq. 4), whose structure was
determined by single crystal X-ray analysis (Fig. 2).
Reagent (equiv)
T/ C
Time/ h
2
%Yield[a]
80
PPA (used as solvent)
100
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of acetate (26% yield, Scheme 2, in that case, bis-
functionalization product 9 was the major product) is surprising,
which merits comments. Three facts may account for this
difference. First in the reaction in Scheme 2, 3.0 equiv of enolate
was used, while herein, only 1.5 equiv of enolate was used.
Second, enolate generated from dimethyl succinate is sterically
more hindered as compared with enolate of ethyl acetate, which
disfavored bis-addition of enolate (cf. product 9 in Scheme 1).
Third, the enolate generated from succinate is stabilized by
chelation with another carbonyl group, which also disfavors a
possible addition of second molecule of enolate.
Scheme 5. Direct transformation of tertiary amides into vinylogous urethanes.
Scheme 6. Synthesis of the key intermediates (S)-2A-b and (S)-2A-c en route
to the alkaloids (−)-209B (12) and (+)-laburnine (13).
Figure 2. X-Ray structure of -sulfonyl enamine 1ab.
We next addressed the chemoselective synthesis of
urethane (S)-2A-d, a key intermediate in the total synthesis of
(−)-anatoxin-a (14).[10b] (−)-Anatoxin-a is a potent postsynaptic
depolarizing neuromuscular toxin known as very fast death
factor (VFDF) isolated from strains of Anabaena flos-aquae, a
fresh-water blue-green alga.[22] As one of the most potent
nicotinic acetylcholine receptor (nAChR) agonists known, (−)-
anatoxin-a serves as a valuable chemical probe for elucidating
the mechanism of acetylcholine-mediated neurotransmission
and the disease states associated with abnormalities in this
important signaling pathway. Thus, the chemistry[10b,23] and
pharmacological study[24] of (−)-anatoxin-a have attracted
considerable attention. In Rapoport’s enantioselective synthesis
of (−)-anatoxin-a (14),[10f] urethane (S)-2A-d has been served as
a key intermediate, which was synthesized from tert-butyl N-
benzylpyroglutamate (S)-3L-e by thionation followed by
Eschenmoser sulfide contraction. By our current method, the
vinylogous urethanation of pyroglutamate (S)-3L-e with dianion
generated from malonic acid monoester produced directly and
chemoselectively (S)-2A-d in 56% yield (Scheme 7, eq. 1). In
the light of the transformations of (S)-3L-d to (S)-2A-c (Scheme
6) and (S)-3L-e to (S)-2A-d (Scheme 7, eq. 1), the method
should be applicable to the one-step synthesis of vinylogous
urethanes (R)-2A-e and (S)-2A-f, key intermediates in the total
To further demonstrate the synthetic potential of the method,
the synthesis of vinylogous urethane (S)-2A-b was undertaken.
Serving as a key intermediate in the total synthesis of the
indolizidine alkaloid ()-209B (12),[21] (S)-2A-b has previously
been synthesized from N-(S)-(1-phenylethyl)--lactam (3L-d) by
thionation followed by Eschenmoser sulfide contraction.[9a]
Employing our newly developed method, compound 3L-d was
directly converted into (S)-2A-b in 68% yield (Scheme 6, a).
Similarly, compound (S)-2A-c has been synthesized from lactam
(S)-3L-d by thionation followed by Eschenmoser sulfide
contraction, and used as a key intermediate in the total
synthesis of the pyrrolizidine alkaloid (+)-laburnine (13).[9f] In our
hand, the one-pot synthesis of vinylogous urethane (S)-2A-c
was achieved with monoenolate of dimethyl succinate, which
produced (S)-2A-c as a mixture of geometric isomers (ratio =
2.3: 1) in 64% yield (Scheme 6, b). Since compound (S)-2A-c
(as geometric mixture) has been converted in three steps to (+)-
laburnine (13), our synthesis constitutes a formal total synthesis
of this alkaloid.
The successful vinylogous urethanation of lactam 3L-d with
monoenolate of dimethyl succinate in a significantly improved
yield of 64% as compared with that of lactam 3L-a with enolate
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synthesis of natural (−)-cocaine (16)[10f] and carbapenem
antibiotic 6-epi PS-5 (17),[10d] respectively. It is worth noting that
previous syntheses of (R)-2A-e from (R)-3L-e and 15a (Scheme
7, eq. 2), and (S)-2A-f from (S)-3L-f and 15b (Scheme 7, eq. 3)
required three steps, respectively.
Scheme 8. Direct transformation of lactam 3L-a into vinylogous lactams.
Direct transformation of tertiary amides into -keto esters
To our surprise, the reaction of enolate generated from methyl
butanoate with the activated form of amide 3e produced, after
work-up with 1 M HCl and chromatographic purification, -keto
ester 8a in 78% yield (Table 5, entry 1). Similarly, reactions of
enolates of ethyl pent-4-enoate and dimethyl succinate yielded
-keto esters 8b and 8c in 76% and 73% yield, respectively
(entries 2 and 3). Interestingly, the reaction of dianion generated
from malonic acid monoester with 3e yielded the unsubstituted
-keto ester 8d. We anticipated that the direct formation of -
keto esters is a result of hydrolysis of the vinylogous urethanes
during the work-up and column chromatography purification on
silica gel. It is worth noting that in this reaction, amides serves
as effective acylating agents under mild conditions.
Table 5. Direct transformation of tertiary amides 3e into -keto esters.
Entry
1
Product (% yield)[a]
8a (78)
2
8b (76)
Scheme 7. Synthesis of the key intermediate (S)-2A-d en route to (−)-
anatoxin-a (14), and the previous approaches to vinylogous urethanes (R)-2A-
e
and (S)-2A-f for the asymmetric syntheses of (−)-cocaine (16) and
3
4
carbapenem antibiotic 6-epi PS-5 (17).
8c (73)
8d (60)
Direct transformation of tertiary amides into vinylogous
lactams
Encouraged by the result of the reaction of dimethyl succinate
(Scheme 6, b), the vinylogous amidation of lactams with simple
ketones were examined. The reaction of acetone enolate with
activated form of lactam 3L-a afforded the vinylogous amide 2B-
a in 64% yield (Scheme 8). Interestingly, the reaction of 2-
butanone produced regioselectively 2B-b in 60% yield. Similarly,
reaction of acetophenone afforded 2B-c in 57% yield.
[a] Isolated yield. [b] 3.0 equiv of NaHMDS used.
Mechanistic considerations
Plausible mechanism of the Tf2O-activated reaction of amides
with enolates is depicted in Scheme 9. Upon treatment with Tf2O,
a highly electrophilic imidate C is formed, which reacts with in
situ generated enolate. The resulting N,O-acetate D eliminates
TfO to generate iminium intermediate E. The latter contains
both a highly electrophilic iminium center and an acidic proton.
When both E and E’ are electron-withdrawing groups, the -
proton in intermediate E is highly acidic, and prone to be
deprotonated to form the aza-Knoevenagel-type condensation
product 1. The -proton in the methyl ketone, phenylacetate,
and (benzylsulfonyl)benzene derived intermediates (cf. E) are
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10.1002/ejoc.201601326
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also sufficiently acidic to undergo chemoselective deprotonation
to yield the vinylogous products 2B, 1aa, and 1ab (cf. Scheme
5) instead of undergoing a bis-addition (vide supra).
several key intermediates of alkaloids and demonstrated the
potential of this general method in the total synthesis of alkaloids
and medicinal agents.
That the formation of bis-functionalized product 9 as the major
product from the reaction of enolate of parent ethyl acetate
(Scheme 2) may be attributed to its higher nucleophilicity due to
less steric hindrance and less acidity of the ester -proton. As a
result, bis-addition to the iminium intermediate E dominates over
deprotonation. The enolates generated from higher homologous
of acetate (cf. Table 5) are less nucleophilic due to steric
hindrance, which prevents a bis-addition.
The easy formation of -keto esters 8 may be due to the
presence of a A1,3-interaction, which destabilizes the vinylogous
urethane intermediates F. In contrast, a phenyl group at –
position of the vinylogous urethane 1aa may exhibit certain
stabilizing effect. A similar stabilizing effect can also be found in
-sulfonyl enamine 1ab. On the other hand, the vinylogous
urethane derived from -lactam (S)-2A-c is stable because of the
high stability of the five-membered ring system.[9d]
Experimental Section
General Methods: Melting points were determined on a Büchi M560
Automatic Melting Point apparatus and are uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer using film
KBr pellet techniques. NMR spectra were recorded on a Bruker AV 400
spectrometer at 25 ºC in the solvents indicated. Chemical shifts (δ) are
reported in ppm and respectively referenced to internal standard Me4Si
and solvent signals (Me4Si, 0 ppm for 1H NMR and CDCl3, 77.0 ppm for
13C NMR). Mass spectra were recorded on a Bruker Dalton ESquire 3000
plus LC-MS apparatus (ESI direct injection). HRMS spectra were
recorded on a 7.0T FT-MS apparatus. Silica gel (300-400 mesh) was
used for flash column chromatography, eluting (unless otherwise stated)
with EtOAc/ n-hexane mixture. Trifluoromethanesulfonic anhydride (Tf2O)
was distilled over phosphorous pentoxide and was stored for no more
than
a week before redistilling. All other commercially available
compounds were used as received. Dry dichloromethane was distilled
over calcium hydride under N2.
General procedure A: Synthesis of vinylogous bis-urethanes,
vinylogous urethanes, vinylogous amides from tertiary amides/
lactams and active methylene compounds.
Trifluoromethanesulfonic anhydride (185 L, 1.1 mmol, 1.1 equiv) was
added dropwise to a cooled (78 °C) solution of a tertiary amide (1.0
mmol, 1.0 equiv) in dichloromethane (5 mL). The reaction mixture was
warmed to 0 °C in an ice bath and stirred for 1 h before re-cooled to
78 °C. To the resulting mixture, a solution of sodium enolate (1.5 mmol,
1.5 equiv), freshly prepared by addition of active methylene compounds
(1.5 mmol, 1.5 equiv) to a THF solution (5 mL) of NaHMDS (2.2 mmol,
2.2 equiv; 3.0 mmol, 3.0 equiv when using monoethyl malonate as a pro-
nucleophile), was added. The mixture was warmed to RT and stirred for
3 h. The reaction was quenched with a saturated aqueous NH4Cl solution
and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel to afford the desired vinylogous bis-
urethanes, vinylogous urethanes, vinylogous amides.
For General procedure B (Synthesis of vinylogous lactams from
lactams and methyl ketones), and the data of compounds 2B-a, 2B-b,
2B-c, see ref 15b.
Scheme 9. Plausible mechanism.
General procedure C: Synthesis of -keto esters from tertiary
amides and esters.
Conclusions
General procedure A was adapted for the reaction of enolates generated
from higher homologous of acetate with amide 3e to give -keto ester
except that the reaction was quenched with 1 M HCl aq.
To conclude, we have developed an efficient and versatile one-
pot method for the synthesis of aza-Knoevenagel-type
condensation products (vinylogous bis-urethanes, and
analogue) as well as vinylogous urethanes, vinylogous amides,
and analogues from tertiary amides/ lactams. The reaction
conditions are mild which tolerate several sensitive functional
groups. The reaction displayed remarkable and unusual
chemoselectivity allowing the reaction to take place at the less
electrophilic amide group while more reactive groups such as
ester, cyano, and aldehyde groups remained intact. This feature
will constitute as base for the procedure-economical and
protecting group-free C-C bond forming reaction using enolates
or carbanions. The one-step synthesis from amides/ lactams of
For the data of compounds 1a-1r, 1v-1y, 2A-a, see ref 15b.
Dimethyl
2-((2-cyanophenyl)(dimethylamino)methylene)malonate
(1s): Following the general procedure A, the reaction of amide 3q (174
mg, 1.0 mmol) with sodium dimethyl malonate enolate, freshly prepared
from dimethyl malonate and NaHMDS, gave, after flash column
chromatography on silica gel (eluting with 6-10% EtOAc in hexane), the
vinylogous urethane 1s (245 mg, yield: 85%) as a colorless oil; IR
(film)max: 2946, 2225, 1693, 1553, 1431, 1396, 1293, 1216, 1075, 774
cm-1. 1H NMR (400 MHz, CDCl3): δ 2.93 (s, 6H), 3.54 (s, 6H), 7.44-7.78
(m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ 42.9 (2C), 51.4 (2C), 98.5,
113.2, 117.0, 129.9, 130.1, 132.8, 133.1, 141.1, 163.2 (2C), 167.2 ppm;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601326
European Journal of Organic Chemistry
FULL PAPER
MS (ESI) m/z 311 (M + Na+); HRMS (ESI) m/z calcd for C15H16N2NaO4
(ESI) m/z 266 (M + Na+); HRMS (ESI) m/z calcd for C14H13NNaO3+ [M +
Na+] 266.0788, found 266.0788.
+
[M + Na+] 311.1002, found 311.0999.
Dimethyl
(E)-2-(1-(methyl(3-phenylprop-1-en-1-
Methyl 1-methyl-4-oxo-2-phenyl-1,4-dihydroquinoline-3-carboxylate
(11): To a 0°C solution of 1c (163 mg, 0.5 mmol) and DMAP (2.5 mmol,
5.0 equiv) in CH2Cl2 (5 mL) was added Tf2O (0.36 mL, 2.0 mmol, 4.0
equiv) and the resulting solution was warmed to RT. After stirred 16 h,
the mixture was quenched with sat. aq NaHCO3 (10 mL) and extracted
with CH2Cl2 (3×10 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (eluting with 10-15% EtOAc in hexane) to afford the
compound 11 (120 mg, yield: 82%) as a pale yellow solid. M.p. 208-210
oC; IR (film)max: 2914, 2846, 1690, 1601, 1524, 1146, 1079, 774 cm-1. 1H
NMR (400 MHz, CDCl3): δ 3.49 (s, 3H), 3.52 (s, 3H), 7.37–7.73 (m, 8H),
8.48–8.51 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 37.1, 51.8, 116.0,
118.9, 124.2, 126.7, 127.0, 128.5, 128.7, 129.8, 132.8, 133.4, 141.0,
152.4, 166.8, 173.9 ppm; MS (ESI) m/z 316 (M + Na+); HRMS (ESI) m/z
calcd for C18H15NNaO3+ [M + Na+] 316.0944, found 316.0944.
yl)amino)propylidene)malonate (1t): Following the general procedure
A, the reaction of amide 3r (203 mg, 1.0 mmol) with sodium dimethyl
malonate enolate, freshly prepared from dimethyl malonate and
NaHMDS, gave, after flash column chromatography on silica gel (eluting
with 6-10% EtOAc in hexane), the vinylogous urethane 1t (247 mg, yield:
78%) as a colorless oil; IR (film)max: 2939, 1690, 1649, 1543, 1210,
1075 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J = 7.4 Hz, 3H), 2.74 (q,
J = 7.4 Hz, 2H), 2.93 (s, 3H), 3.72 (s, 6H), 4.05 (d, J = 5.8 Hz, 2H), 6.13
(dt, J = 5.8, 15.8 Hz, 1H), 6.61 (d, J = 15.8 Hz, 1H), 7.26-7.39 (m, 5H)
ppm; 13C NMR (100 MHz, CDCl3): δ 13.2, 25.5, 41.0, 51.4, 55.3 (2C),
123.6, 126.5 (2C), 128.0 (2C), 128.6 (2C), 133.3, 136.1, 168.7 (2C),
171.8 ppm; MS (ESI) m/z 340 (M + Na+); HRMS (ESI) m/z calcd for
C
18H23NNaO4+ [M + Na+] 340.1519, found 340.1516.
Dimethyl 2-((4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-((tert-
butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclope-
nta[a]phenanthren-17-yl)-1-(dibenzylamino)pentylidene)malonate
(1u): Following the general procedure A, the reaction of amide 3s (335
mg, 0.5 mmol) with sodium dimethyl malonate enolate, freshly prepared
from dimethyl malonate and NaHMDS, gave, after flash column
chromatography on silica gel (eluting with 6-10% EtOAc in hexane), the
vinylogous urethane 1u (325 mg, yield: 83%) as a colorless foam; IR
(film)max: 2920, 2846, 1684, 1521, 1428, 1203, 1069 cm-1. 1H NMR (400
MHz, CDCl3): δ 0.06 (s, 6H), 0.62 (s, 3H, CH3), 0.89-0.93 (m, 15H), 1.04-
1.29 (m, 4H), 1.37-1.45 (m, 9H), 1.54-1.63 (m, 3H), 1.73-1.94 (m, 6H),
2.43-2.49 (m, 1H), 2.69-2.75 (m, 1H), 3.52-3.61 (m, 1H), 3.73 (s, 6H),
4.19 (d, J = 15.5 Hz, 2H), 4.23 (d, J = 15.5 Hz, 2H), 7.17-7.36 (m, 10H)
ppm; 13C NMR (100 MHz, CDCl3, some peaks overlapped): δ 4.6, 12.0,
18.2, 18.3, 20.8, 23.4, 24.3, 26.0, 26.4, 27.3, 28.4, 30.5, 31.0, 34.6, 35.0,
35.6, 35.9, 36.6, 36.9, 40.1, 40.2, 42.3, 42.8, 51.6, 54.9, 56.1, 56.4, 72.8,
98.5, 127.8 (2C), 127.9 (4C), 128.7 (4C), 136.4 (2C), 168.6 (2C), 170.8
Methyl 2,3-diphenyl-3-(piperidin-1-yl)acrylate (1aa): Following the
general procedure A, the reaction of amide 3e (189 mg, 1.0 mmol) with
sodium methyl 2-phenylacetate enolate, freshly prepared from methyl 2-
phenylacetate and NaHMDS, gave, after flash column chromatography
on silica gel (eluting with 3-5% EtOAc in hexane), the vinylogous
urethanes 1aa (273 mg, yield: 85%) as an inseparable mixture of
geometric isomers (ratio = 2.5: 1, determined by 1H NMR). Colorless oil;
IR (film)max: 3061, 3028, 2938, 2855, 1689, 1523, 1441, 1362, 1291,
1246, 1154, 1113, 1076, 1009, 764, 698 cm-1. 1H NMR (400 MHz, CDCl3,
data of the two geometric isomers): δ 1.44-1.47 (m, 6H), 1.64-1.69 (m,
2.5H), 2.64 (t, J = 5.3 Hz, 4H), 3.05 (t, J = 5.5 Hz, 1.6H), 3.30 (s, 3H),
3.74 (s, 1.23H), 6.87-7.34 (m, 14H) ppm; 13C NMR (100 MHz, CDCl3,
data of the two geometric isomers, some peaks overlapped): δ 23.8, 24.0,
26.6, 26.8, 50.7, 51.2, 51.8, 52.0, 106.6, 107.9, 124.5, 125.4, 127.1,
127.6, 127.8, 128.1, 128.8, 129.3, 129.4, 130.6, 131.4, 131.7, 139.7,
140.0, 161.7, 162.0, 169.0, 171.4 ppm; MS (ESI) m/z 344 (M + Na+);
ppm; MS (ESI) m/z 806 (M
C49H73NNaO5Si+ [M + Na+] 806.5150, found 806.5149.
+
Na+); HRMS (ESI) m/z calcd for
HRMS (ESI) m/z calcd for C23H19NNaO2 [M + Na+] 344.1621, found
+
344.1620.
Dimethyl 2-(1-phenylpyrrolidin-2-ylidene)malonate (1z): Following the
general procedure A, the reaction of amide 3L-c (161 mg, 1.0 mmol) with
sodium dimethyl malonate enolate, freshly prepared from dimethyl
malonate and NaHMDS, gave, after flash column chromatography on
silica gel (eluting with 6-10% EtOAc in hexane), the vinylogous urethane
(E)-1-(1,2-Diphenyl-2-(phenylsulfonyl)vinyl)piperidine
(1ab):
Following the general procedure A, the reaction of amide 3e (189 mg, 1.0
mmol) with sodium (benzylsulfonyl)benzene enolate, freshly prepared
from (benzylsulfonyl)benzene and NaHMDS, gave, after flash column
chromatography on silica gel (eluting with 1-2% EtOAc in hexane), the
vinylogous urethanes 1ab (286 mg, yield: 71%) as a white solid. M.p.
168-169 oC; IR (film)max: 2927, 2846, 1530, 1444, 1296, 116, 1082, 797,
720, 598 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.32-1.40 (m, 6H), 2.60 (t, J
= 5.3 Hz, 4H), 7.21-7.30 (m, 7H), 7.32-7.38 (m, 5H), 7.43-7.46 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3, some peaks overlapped): δ 23.6, 26.4,
51.7, 113.3, 126.9, 127.1, 127.8, 127.9, 128.2, 129.8, 130.4, 131.2,
133.2, 137.0, 137.1, 144.8, 162.2 ppm; MS (ESI) m/z 426 (M + Na+);
HRMS (ESI) m/z calcd for C25H25NNaO2S+ [M + Na+] 426.1498, found
426.1501.
1z (223 mg, yield: 81%) as a white solid. M.p. 93-95 oC; IR (film)max
:
3030, 2952, 2899, 2862, 1736, 1677, 1597, 1500, 1406, 1305, 1210,
1172, 1118, 764, 695 cm-1. 1H NMR (400 MHz, CDCl3): δ 2.13 (tt, J = 7.4,
7.5 Hz, 2H), 3.07 (s, 3H), 3.39 (t, J = 7.4 Hz, 2H), 3.56 (s, 3H), 3.84 (t, J
= 7.5 Hz, 2H), 7.16–7.37 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): δ
20.9, 35.0, 50.9 (2C), 58.0, 92.5, 124.6, 126.5 (2C), 129.2 (2C), 142.2,
164.6, 167.5 (2C) ppm; MS (ESI) m/z 298 (M + Na+); HRMS (ESI) m/z
calcd for C15H17NNaO4+ [M + Na+] 298.1050, found 298.1049.
Methyl 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate
(10): To a 0°C solution of 1z (275 mg, 0.5 mmol) and DMAP (2.5 mmol,
5.0 equiv) in CH2Cl2 (5 mL) was added Tf2O (0.36 mL, 2.0 mmol, 4.0
equiv) and the resulting solution was warmed to RT. After stirred 16 h,
the mixture was quenched with sat. aq NaHCO3 (10 mL) and extracted
with CH2Cl2 (3×10 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (eluting with 10-15% EtOAc in hexane) to afford the
compound 10 (101 mg, yield: 83%) as a pale yellow solid. M.p. 154-156
oC; IR (film)max: 2920, 2846, 1725, 1594, 1088, 765 cm-1. 1H NMR (400
MHz, CDCl3): δ 2.34 (tt, J = 7.6, 7.8 Hz, 2H), 3.49 (t, J = 7.8 Hz, 2H),
3.90 (s, 3H), 4.25 (t, J = 7.6 Hz, 2H), 7.25–7.63 (m, 3H), 8.38–8.41 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3): δ 20.3, 33.4, 50.8, 51.6, 108.8,
115.7, 124.5, 127.1, 127.4, 132.3, 137.7, 160.3, 167.1, 174.8 ppm; MS
Ethyl (S, E)-2-(1-(1-phenylethyl)pyrrolidin-2-ylidene)acetate (2A-b):
Following the general procedure A, the reaction of lactam (S)-3L-d (189
mg, 1.0 mmol) with dianion freshly prepared from monoethyl hydrogen
malonate and NaHMDS, gave, after flash column chromatography on
silica gel (eluting with 6-10% EtOAc in hexane), the known vinylogous
[9a]
20
urethane (S)-2A-b
(176 mg, yield: 68%) as a colorless oil. []D
278.2 (c = 0.68, CHCl3); IR (film)max: 1735, 1670, 1595, 765, 695 cm-1.
1H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 1.54 (d, J = 7.1 Hz,
3H), 1.81-1.83 (m, 2H), 3.17-3.05 (m, 2H), 3.33-3.25 (m, 2H), 4.12-4.04
(m, 2H), 4.70 (s, 1H), 4.88 (q, J = 7.0 Hz, 1H), 7.35-7.22 (m, 5H) ppm;
13C NMR (100 MHz, CDCl3) δ 14.6, 16.6, 20.8, 32.8, 47.0, 52.7, 58.2,
78.2, 126.6, 127.4 (2C), 128.6 (2C), 140.2, 164.8, 169.6 ppm; MS (ESI)
m/z 282 (M + Na+).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601326
European Journal of Organic Chemistry
FULL PAPER
Dimethyl 2-(1-(1-phenylethyl)pyrrolidin-2-ylidene)succinate (2A-c):
Following the general procedure A, the reaction of lactam (S)-3L-d (189
mg, 1.0 mmol) with sodium dimethyl succinate enolate, freshly prepared
from dimethyl succinate and NaHMDS, gave, after flash column
chromatography on silica gel (eluting with 6-10% EtOAc in hexane), the
known vinylogous urethane (S)-2A-c [9f] (203 mg, 64%) as an inseparable
mixture of geometric isomers (ratio = 2.3: 1, determined by 1H NMR).
Pale yellow oil; IR (film)max: 3061, 3028, 1677, 1598, 1407, 1308, 1230,
1117, 764, 694 cm-1. 1H NMR (400 MHz, CDCl3, data of the two
geometric isomers): δ 1.59 (d, J = 6.9 Hz, 2.1H), 1.65 (d, J = 6.9 Hz, 1H),
1.72-1.87 (m, 2.1H), 2.59-2.63 (m, 0.6H), 2.93-3.04 (m, 1.0H), 3.12 (t, J =
7.9 Hz, 1.4H), 3.25-3.34 (m, 1.6H), 3.38 (d, J = 3.9 Hz, 1.4H), 3.64-3.70
(s, 6H), 5.18 (q, J = 6.9 Hz, 0.7H), 5.56 (q, J = 6.9 Hz, 0.3H), 7.25–7.36
(m, 7.4H) ppm; 13C NMR (100 MHz, CDCl3, data of the two geometric
isomers, some peaks overlapped): δ 15.7, 18.1, 20.1, 21.6, 34.3, 35.2,
35.8, 36.6, 47.2, 48.3, 50.6, 51.7, 55.8, 56.7, 85.4, 87.4, 126.4, 127.0,
127.1, 127.3, 128.2, 128.6, 141.3, 141.4, 165.6, 167.6, 170.1, 174.0
ppm; MS (ESI) m/z 340 (M + Na+).
49.2, 52.0, 52.8, 128.7, 128.8, 133.7, 135.7, 169.1, 171.6, 194.0 ppm;
MS (ESI) m/z 273 (M + Na+).
Ethyl 3-oxo-3-phenylpropanoate (8d): Following the general procedure
C (except the 3.0 equiv NaHMDS was used), the reaction of amide 3e
(189 mg, 1.0 mmol) with sodium malonic acid mono-ethyl ester enolate,
freshly prepared from malonic acid mono-ethyl ester and NaHMDS, gave,
after flash column chromatography on silica gel (eluting with 1-2% EtOAc
in hexane), the known ß-keto ester 8d[28] (115 mg, yield: 60%) as a
colorless oil; IR (film)max: 1730, 1688, 1656, 1598, 1230, 1117, 764, 694
cm-1. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 7.1 Hz, 3H), 3.99 (s, 2H),
4.21 (q, J = 7.1 Hz, 2H), 7.46–7.96 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3): δ 14.0, 45.9, 61.4, 128.4, 128.6, 133.6, 135.9, 167.4, 192.5 ppm;
MS (ESI) m/z 215 (M + Na+).
Acknowledgements
The authors are grateful for financial support from the National
Natural Science Foundation of China (21332007), and the
Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT) of Ministry of Education, China.
tert-Butyl (S, E)-1-benzyl-5-(2-methoxy-2-oxoethylidene)pyrrolidine-
2-carboxyl ate (2A-d): Following the general procedure A, the reaction
of tert-butyl (S)-N-benzylpyroglutamate 3L-e (275 mg, 1.0 mmol) with
sodium monomethyl hydrogen malonate enolate, freshly prepared from
monomethyl hydrogen malonate and NaHMDS, gave, after flash column
chromatography on silica gel (eluting with 6-10% EtOAc in hexane), the
known vinylogous urethane (S)-2A-d[10b] (185 mg, yield: 56%) as a white
solid. M.p. 53-55 °C; []D20 80.7 (c = 1, CHCl3); IR (film)max: 1730, 1670,
1600, 1291, 1262, 1109, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.41 (s,
9H), 2.04-2.11 (m, 1H), 2.16-2.26 (m, 1H), 3.04-3.13 (m, 1H), 3.45-3.37
(m, 1H), 3.61 (s, 3H), 3.95 (dd, J = 2.9, 9.0 Hz, 1H), 4.20 (d, J = 15.6 Hz,
1H), 4.53 (d, J = 15.6 Hz, 1H), 4.75 (s, 1H), 7.34-7.17 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3) δ 26.3, 27.9 (3C), 31.0, 49.4, 50.1, 65.1, 80.2,
82.0, 127.6, 128.1 (2C), 128.8 (2C), 135.6, 165.1, 169.6, 171.2 ppm; MS
(ESI) m/z 354 (M + Na+).
Keywords: Chemoselectivity • Amides • Knoevenagel-type
reaction • Vinylogous Urethanes • One-pot Reaction
[1]
For related reviews, see: a) K.-M. Wang, S.-J. Yan, J. Lin, Eur. J. Org.
Chem. 2014, 1129-1145; b) P. Adler, A. Fadel and N. Rabasso,
Tetrahedron 2014, 70, 4437-4456; c) Y. Han, J. Sun, Y. Sun, H. Gao, C.
Yan, Chin. J. Org. Chem. 2012, 32, 1577-1586; d) H. M. C. Ferraz, E. R.
S. Gonçalo, Quim. Nova 2007, 30, 957-964; e) G. Negri, C. Kascheres,
A. J. Kascheres, J. Heterocycl. Chem. 2004, 41, 461-491; f) A.-Z. A.
Elassar, A. A. El-Khair, Tetrahedron 2003, 59, 8463-8480; g) N. D.
Eddington, D. S. Cox, R. R. Roberts, J. P. Stables, C. B. Powell, K. R.
Scotte, Curr. Med. Chem. 2000, 7, 417-436; For reviews on the
application of Eschenmoser sulfide contraction in the synthesis of
alkaloids, see: h) S. R. Hussaini, R. R. Chamala, Z. Wang, Tetrahedron,
2015, 71, 6017-6086; i) J. P. Michael, C. B. de Koning, D. Gravestock,
G. D. Hosken, A. S. Howard, C. M. Jungmann, R. W. M. Krause, A. S.
Parsons, S. C. Pelly, T. V. Stanbury, Pure Appl. Chem. 1999, 71, 979-
988; j) J. P. Michael, D. Gravestock, Pure Appl. Chem. 1997, 69, 583-
588.
Methyl 2-benzoylbutanoate (8a): Following the general procedure C,
the reaction of amide 3e (189 mg, 1.0 mmol) with sodium methyl butyrate
enolate, freshly prepared from methyl butyrate and NaHMDS, gave, after
flash column chromatography on silica gel (eluting with 1-2% EtOAc in
hexane), the known ß-keto ester 8a[25] (161 mg, yield: 78%) as a
colorless oil; IR (film)max: 1733, 1677, 1598, 764, 694 cm-1. 1H NMR
(400 MHz, CDCl3): δ 0.99 (t, J = 7.4 Hz, 3H), 2.01-2.09 (m, 2H), 3.69 (s,
3H), 4.25 (t, J = 7.2 Hz, 1H), 7.46–8.00 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3): δ 12.1, 22.4, 52.4, 55.6, 128.5, 128.7, 133.4, 136.2, 170.4, 195.2
ppm; MS (ESI) m/z 229 (M + Na+).
[2]
For selected reviews, see: a) A. Ahmed, M. Daneshtalab, J. Pharm.
Pharm. Sci. 2012, 15, 52-72; b) C. Mugnaini, S. Pasquini, F. Corelli,
Curr. Med. Chem. 2009, 16, 1746–1767; For recent examples, see: c) L.
Zhang, K. V. Kumar, R.-X. Geng, C.-H. Zhou, Bioorg. Med. Chem. Lett.
2015, 25, 3699-3705. d) L.-Z. Gao, Y.-S. Xie, T. Li, W.-L. Huang, G.-Q.
Hu, Chin. Chem. Lett. 2015, 26, 149-151; e) J.-P. Lin, Y.-Q. Long,
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Ethyl 2-benzoylpent-4-enoate (8b): Following the general procedure C,
the reaction of amide 3e (189 mg, 1.0 mmol) with sodium ethyl pent-4-
enoate enolate, freshly prepared from ethyl pent-4-enoate and NaHMDS,
gave, after flash column chromatography on silica gel (eluting with 1-2%
EtOAc in hexane), the known ß-keto ester 8b[26] (176 mg, yield: 76%) as
a colorless oil; IR (film)max: 3081, 3028, 1723, 1688, 1677, 1117, 771,
698 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.17 (t, J = 7.1 Hz, 3H), 2.71-
2.78 (m, 2H), 4.11-4.17 (m, 2H), 4.40 (t, J = 7.2 Hz, 1H) 5.03-5.14 (m,
2H), 5.77-5.87 (m, 1H), 7.36–8.01 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3): δ 13.9, 32.9, 53.9, 61.4, 117.3, 128.6, 128.7, 133.5, 134.4, 136.1,
169.3, 194.4 ppm; MS (ESI) m/z 266 (M + Na+).
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Dimethyl 2-benzoylsuccinate (8c): Following the general procedure C,
the reaction of amide 3e (189 mg, 1.0 mmol) with sodium dimethyl
succinate enolate, freshly prepared from dimethyl succinate and
NaHMDS, gave, after flash column chromatography on silica gel (eluting
with 1-2% EtOAc in hexane), the known ß-keto ester 8c[27] (183 mg,
yield: 73%) as a colorless oil; IR (film)max: 1736, 1698, 1678, 1598, 769,
695cm-1. 1H NMR (400 MHz, CDCl3): δ 3.04 (dd, J = 7.6, 17.4 Hz, 1H), δ
3.11 (dd, J = 7.6, 17.4 Hz, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 3.89 (t, J =
7.65, 1H), 7.47–8.05 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): δ 33.0,
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10.1002/ejoc.201601326
European Journal of Organic Chemistry
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
Synthetic Method
Pei-Qiang Huang,* and Wei Ou
Page No. – Page No.
A
Direct,
Versatile,
Synthesis
Bis- and mono-
and
of
Chemoselective
Vinylogous
112 Years Later: the extension of the aldehyde-based Knoevenagel reaction to the
amide-based aza-Knoevenagel-type reaction has been achieved, which allows an
one-pot and versatile synthesis of vinylogous bis- and mono-urethanes/ amides.
The method has been applied to the one-step synthesis of several key
intermediates of alkaloids and quinoline antibiotics.
urethanes/ Amides, and β-Keto Esters
by Aza-Knoevenagel-type Reactions
of Tertiary Amides with Enolates
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