Tertiary amide-based Knoevenagel-type reactions: A direct, general, and chemoselective approach to enaminones

Article abstract of DOI:10.1039/c4cc03826f

We report one-pot and chemoselective Knoevenagel-type reactions using highly stable amides and lactams as the electrophilic substrates. The method is based on the in situ activation of amide carbonyl with triflic anhydride and a subsequent reaction with carbanions generated in situ from carbonyl compounds. The amide-based method is an alternative to the versatile thioamide-based Eschenmoser sulfide contraction.

Full text of DOI:10.1039/c4cc03826f

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Tertiary amide-based Knoevenagel-type reactions:
a direct, general, and chemoselective approach to
enaminones†‡
Cite this: Chem. Commun., 2014,
50, 8761
Received 19th May 2014,
Accepted 18th June 2014
Pei-Qiang Huang,*ab Wei Ou,a Kai-Jiong Xiaoa and Ai-E Wanga
DOI: 10.1039/c4cc03826f
www.rsc.org/chemcomm
We report one-pot and chemoselective Knoevenagel-type reac- approach to enaminones due to its high chemoselectivity,13–16
tions using highly stable amides and lactams as the electrophilic which has been extensively used in the synthesis of alka-
substrates. The method is based on the in situ activation of amide loids.14,15 The direct transformation of amides to Knoevenagel
carbonyl with triflic anhydride and a subsequent reaction with type condensation products (enaminones) has nevertheless been
carbanions generated in situ from carbonyl compounds. The rarely reported.12,17,18 The latest progress has been a rhodium-
amide-based method is an alternative to the versatile thioamide- catalyzed method, which is limited to synthesizing pyrrolidine
based Eschenmoser sulfide contraction.
substituted silyloxy acrylic esters.18 The known methods either
lack chemoselectivity, or are restricted to some specific sub-
The Knoevenagel reaction is the condensation of an aldehyde strates/nucleophiles/electrophiles, or are in need of an extra step
or an unhindered ketone with an active methylene compound for the conversion of lactams to activated forms.
to yield an a,b-unsaturated system bearing two electron-
In recent years, the development of direct and general C–C
withdrawing groups.1 Since the product is a versatile inter- bond formation methods based on tertiary amide carbonyl has
mediate for a number of transformations, the Knoevenagel attracted considerable attention.12,19–21 In our investigation on
reaction has found widespread applications in the total synthesis the Tf2O-activated one-pot reductive alkylation20 of lactam 1
of natural products,2 tandem/domino reactions3 and organo- with enolate of ethyl acetate, the vinylogous urethane 3 was
catalytic reactions.4 Extension of the Knoevenagel reaction to unexpectedly isolated in 26% yield besides the desired bis-
amides is highly desirable because it would allow a rapid access alkylation product 2 (Scheme 1). Interestingly, when the reac-
to enaminones,5 versatile intermediates for the synthesis of tion was carried out with enolate of acetone, the enaminone 4
bioactive N-containing compounds and alkaloids.6 However, was obtained as the major product in 64% yield with only traces
amides are a class of highly stable carbonyl compounds and of the bisalkylation product 5 observed. These findings
direct use of amides in the Knoevenagel-type reaction has been prompted us to develop the direct and versatile Knoevenagel-
hampered by the poor electrophilicity of amide carbonyl. To type reactions of tertiary amides and lactams based on Tf2O-
tackle this problem, an amide has to be converted to an activated activation for the synthesis of different kinds of enaminones,
intermediate such as amideacetal,7 alkoxyimidate,8 chloroimi- and the results are reported herein.
date (Vilsmeier reagent),9 thioamide (Eschenmoser sulfide con-
The Knoevenagel-type condensation of N,N-dibenzyl-
traction),10 (alkylthio)alkylideniminium salt,11 and iminium benzamide 6a with dimethyl malonate was first examined
triflate.12 Among them, the umpoled stepwise method based (Scheme 2). The desired vinylogous urethane 7a was obtained
on the Eschenmoser sulfide contraction is the most popular
a Department of Chemistry, College of Chemistry and Chemical Engineering, and
Fujian Provincial Key Laboratory of Chemical Biology, Xiamen University, Xiamen,
Fujian 361005, P. R. China. E-mail: pqhuang@xmu.edu.cn; Tel: +86-592-2182240
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
† Dedicated to Professor Dr Bertrand Castro.
‡ Electronic supplementary information (ESI) available: General experimental
procedures, compound characterization data, 1H and 13C NMR spectra of new
Scheme 1 Unexpected products from the reactions of enolates with
compounds, and NOESY spectra of compound 3a, 4b and 9e. See DOI: 10.1039/
activated lactam.
c4cc03826f
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Table 2 Knoevenagel-type condensation reactions of lactams
Entry
Lactam
E1
E2
Product
Yielda (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
8
CO2Me
CO2Bn
CN
CO2Me
CO2Bn
CN
CO2Et
COPh
H
9a
72
75
78
78
69
64
57
60
71
73
70
9b
9c
CN
9db
9ec
4d
Scheme 2 The Knoevenagel-type condensation reaction of N,N-dibenzyl-
benzamide 6a with dimethyl malonate.
CO2Et
COMe
COPh
COnPr
CO2tBu
CO2Et
CO2Me
H
H
4ae
4bc
3ac
3e
in 68% yield when amide 6a was treated at À78 1C successively
with triflic anhydride (Tf2O)12,22,23 (1.0 equiv.), DTBMP (2,6-di-tert-
butyl-4-methylpyridine) (1.2 equiv.), and carbanion generated from
malonate (1.2 equiv.) and tBuOK (3.0 equiv.) (conditions A).12
A survey of the optimal conditions revealed that the use of
DTBMP was unnecessary. When the reaction was run with Tf2O
(1.0 equiv.), malonate (1.2 equiv.) and NHMDS (2.2 equiv.) in
dichloromethane at À78 to 0 1C, vinylogous urethane 7a could
be obtained in 73% yield (conditions B).
With the optimal conditions defined, the scope of the
reaction was then investigated. As can be seen from Table 1,
the N-substituents of amides could vary from benzyl to alkyl,
aryl and cyclic substituents and the desired vinylogous urethanes
7a–7f were obtained in 73–81% yields (entries 1–6). For aryl
substituted benzamide derivatives, benzamides bearing electron-
donating groups (entries 7–9) gave higher yields than those having
electron-withdrawing groups (entries 10–13). Significantly, the
reaction not only tolerates methoxyl, bromo and fluoro groups,
but also shows excellent chemoselectivity. As can be seen from
entries 12 and 13, the reactions took place chemoselectively at the
amide group in the presence of the reactive ester and aldehyde
9
10
11
H
H f
CO2Me
10
a
b
c
Isolated yield. Z/E geometry not determined. Z/E geometry deter-
d
mined by NOESY. Z/E geometry deduced by correlation with com-
pound 4b (dH vinylic = 5.21 and 5.22). Z/E geometry determined by
correlation with the reported data. di-ion generated from malonic acid
mono-ethyl ester and three equiv. of NHMDS was used as a nucleophile.
e
f
groups to give the corresponding functionalized vinylogous
urethanes 7l and 7m in 74% and 60% yield, respectively.
Heteroarylamide (thiophenylamide) also reacted chemoselec-
tively to produce the desired vinylogous urethane 7n in 72%
yield (entry 14). The reaction could also proceed smoothly with
alkylamides (entries 15, 16).
This Knoevenagel-type reaction could be extended to
lactams as well (Table 2). Not only dimethyl malonate (entry 1)
but also dibenzyl malonate (entry 2), malononitrile (entry 3),
cyanoacetic ester (entry 4) and b-ketoester (entry 5) could
serve well as effective active methylene compounds in the
Knoevenagel-type reaction of lactam 1. Moreover, the reaction
could be further extended to less acidic methyl ketones, which
produced the corresponding vinylogous enaminones 4, 4a and
4b in 57–64% yields (entries 6–8). Extension of the reaction to
tert-butyl acetate was also successful, giving the vinylogous
urethane 3a in 71% yield (entry 9). In contrast, only 45% yield
was obtained by Yamaguchi–Hirao’s method.17 Interestingly,
the reaction of lactam 1 with the dianion generated from the
malonic acid monoester and three equiv. of NHMDS produced
3 directly in a much higher yield (73%, entry 10) than with the
enolate of ethyl acetate (cf. Scheme 1). A similar reaction with
amide 6d produced ethyl benzoylacetate, a hydrolytic product
of the metastable condensation product, in 58% yield. It is
worth noting that the reaction of ethyl (S)-N-benzylpyroglutamate 8
also proceeded chemoselectively to give vinylogous urethane 10 in
70% yield (entry 11). In all cases, only one stereoisomer was
obtained. The geometry of compound 9e was determined as E
by the NOESY technique on the basis of the observed NOE
correlation between the phenyl H (dHCOPh = 7.21) and the benzyl
H (dHBn = 4.33).
Table 1 Knoevenagel-type condensation reactions of tertiary amides
Entry
Amide
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Et
Ph
–(CH2)5–
–(CH2)4–
Bn
Et
Me
7a: 73
7b: 80
7c: 76
7d: 78
7e: 81
7f: 75
7g: 76
7h: 79
7i: 76
7j: 70
7k: 69
7l: 74
7m: 60
7n: 72
7o: 73
7p: 75
–(CH2)2O(CH2)2–
4-Me-Ph
4-MeO-Ph
2-MeO-Ph
4-Br-Ph
4-F-Ph
4-CO2Me-Ph
4-CHO-Ph
2-Thienyl
nBu
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
9
10
11
12
13
14
15
16
In summary, we have developed general and chemoselective
one-pot Knoevenagel-type reactions of amides and lactams.
The reactions were run under mild conditions, which allow a
nC11H23
a
Isolated yield.
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The authors are grateful for financial support from the
National Basic Research Program (973 Program) of China
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