Direct condensation of functionalized sp3 carbons with formanilides for enamine synthesis using an in situ generated HMDS amide catalyst

Article abstract of DOI:10.1039/c4cc02228a

The efficient synthesis of functionalized enamines including β-enaminoesters was effectively accomplished by the direct condensation of functionalized sp³ carbanions such as acetates with formamides using in situ generated HMDS base from catalytic cesium fluoride and stoichiometric tristrimethylsilylamine. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02228a

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Direct condensation of functionalized sp3 carbons
with formanilides for enamine synthesis using an
in situ generated HMDS amide catalyst†
Cite this: Chem. Commun., 2014,
50, 6523
Received 26th March 2014,
Accepted 23rd April 2014
Hiroshi Taneda, Kiyofumi Inamoto and Yoshinori Kondo*
DOI: 10.1039/c4cc02228a
www.rsc.org/chemcomm
The efficient synthesis of functionalized enamines including
b-enaminoesters was effectively accomplished by the direct con-
densation of functionalized sp3 carbanions such as acetates with
formamides using in situ generated HMDS base from catalytic
cesium fluoride and stoichiometric tristrimethylsilylamine.
Functionalized enamines have been employed as versatile key
intermediates in organic synthesis and are widely used for many
transformations.1 In particular, b-enaminones are recognized as
important precursors for the synthesis of benzene derivatives2
and heteroaromatics3 such as pyridines,4 pyrroles,5 pyridinones,6
pyrimidines7 and triazoles.8 And these enamine structures are
basic or partial structural moieties of important pharmaceutical
drugs containing anticonvulsant,9 anti-inflammatory,10 anti-
tumor agents11 and quinolone antibacterials.12 In addition,
b-enaminones are very useful intermediates for natural product
Fig. 1 Well-known synthetic methodologies of functionalized enamines.
syntheses.13 Furthermore, these compounds show polyfunction- alkynes.18 In addition to this condensation, our group also has
ality: that is, having the nucleophilicity of enamines and electro- developed a way to obtain b-enaminones by the phosphazene
philicity of enones. Therefore these compounds enable a variety base-catalyzed Peterson type reaction of formanilides with
of reactions, and a number of reviews about the chemistry of a-trimethylsilylalkyl compounds.19
b-enaminones have been published.14 Despite their synthetic
Deprotonation of C(sp3)–H bonds using metal amide bases
potential for wide range applications and importance, prepara- followed by reaction with an electrophile has been recognized
tion methodologies of b-enaminones are rather limited (Fig. 1). as a useful method to form C–C bonds. The utilization of
The most well-known route to these compounds is direct con- strongly basic amide bases such as lithium amides and zinc
densation of amines with b-dicarbonyl compounds15 or addition amides for deprotonative functionalization has been investi-
of amines to alkynes.16 Another important methodology for the gated.20 However, these procedures require stoichiometric
synthesis of functionalized enamines is the transition metal amounts of organometallic reagents and need to be carried
catalyzed amination of alkenyl halides, and this has been out at low temperature. Thus, a chemoselective organocatalytic
employed for recent natural product syntheses.17 On the other process for deprotonative functionalization remains an attrac-
hand, the novel C–C condensation method using Reformatsky tive challenge.
reagents and formamides has reported for the preparation of
Recently, we developed the catalytic deprotonation of aro-
these compounds without using b-dicarbonyl compounds or matic C(sp2)–H bonds using onium amide bases, generated
in situ via the combination of aminosilanes and fluoride salts,
and the subsequent reaction with carbonyl compounds pro-
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki,
ceeded smoothly at room temperature.21 This method was
Aoba-ku, Sendai 980-8578, Japan. E-mail: ykondo@m.tohoku.ac.jp;
suggested to be extendable to the functionalization of activated
Fax: +81-22-795-6804; Tel: +81-22-795-6804
C(sp3)–H bonds a- to a carbonyl group. We expected that the
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral/analytical data. See DOI: 10.1039/c4cc02228a
system would be applicable to the synthesis of b-enaminones
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Table 2 Deprotonative functionalization of tbutyl acetate with N-methyl-
formanilide
Fig. 2 New C–C condensation for enamine synthesis.
Entry Ar
Yielda (%) Entry Ar
Yielda (%)
Table 1 Deprotonative functionalization of tbutyl acetate with N-methyl-
formanilidea
1
2
3
4
( p-OMe)C6H4 (2b) 3b : 81
5
6
7
8
(o-Me)C6H4 (2f) 3f : 0
( p-I)C6H4 (2g) 3g : 44
( p-NMe2)C6H4 (2c) 3c : 74
( p-Me)C6H4 (2d) 3d : 82
(m-Me)C6H4 (2e) 3e : 84
( p-Br)C6H4 (2h) 3h : 47
( p-CN)C6H4 (2i) 3i : 7b
a
b
Isolated yield. Determined using 1H-NMR analysis.
Entry
Fluoride source
Temp.
Yieldb,d (%)
Substrates which have halogen atoms on the p-position of the
benzene ring could also be utilized for this process, and the desired
enaminoesters 3g and 3h were obtained in moderated yields
(entries 6 and 7). These results indicate that the reactivity of the
formanilide is tunable with the substituents on the aromatic ring.
In addition, reactions with N-methylformanilide, which has
1
2
3
4
5
None
TMAF
CsF
CsF
CsF
rt
rt
rt
40 1C
60 1C
0 (0)
0 (25)
74c (6)
76c (10)
56 (14)
a
b
Reaction were carried out on a 0.20 mmol scale. Determined using
1H-NMR analysis. Isolated yield. Yield of the by-product (N-methyl- an electron-withdrawing group such as the cyano group at the
aniline) in parentheses.
c
d
p-position, gave the enamine derivative in a low yield (entry 8).
Subsequently, the reactions with nucleophiles other than tbutyl
acetate were examined. The reaction of methyl phenyl sulfone
using formanilides as an electrophile. To the best of our
knowledge, there has been no report of preparation of
b-enaminones via deprotonative functionalization of acetic acid
derivatives; therefore this simple methodology can be one of
which has a relatively acidic a-proton (pKa = 29.0) compared to
tbutyl acetate (pKa = 30.3) and N-methylformanilide (2a) pro-
ceeded smoothly to give the desired product 4b in 88% yield
(Table 3, entry 1). However, upon using acetonitrile (pKa = 31.3),
methyl phenyl sulfoxide (pKa = 33.0) and N,N-diethylacetamide
the challenging topics in enamine synthesis (Fig. 2).
In our initial investigation for our enamination, we chose
(pKa = 35.0), which contain fewer reactive a-protons, enamination
tbutyl acetate (1a) and N-methylformanilide (2a) as substrates,
reactions did not proceed well. After examining the various
using tris(trimethylsilyl)amine [(TMS)3N] as an aminosilane.
conditions, we found that the reaction using TMAF as a fluoride
First, under the reaction conditions without silyl activators
such as fluorides, the reaction did not proceed at all (Table 1,
entry 1). When tetramethylammonium fluoride (TMAF) was used
as a fluoride source, only the formation of N-methylaniline was
observed as a by-product, which was produced by deformylation of
2a (entry 2). The use of CsF as another fluoride source showed
source and 40-methoxy-N-methylformanilide as an electrophile
(2b) under the solvent-free conditions improved the yields of the
products 4c–4e up to 57–93% (entries 2–4). In this case, the use of
N-methylformanilide as an electrophile did not give successful
results, and the undesired deformylation reaction predominated.
excellent performance for the desired enamination and the
enaminoester 3a was successfully obtained in 74% yield (entry 3).
Table 3 Deprotonative functionalization of C(sp3)–H bonds
By elevating the reaction temperature to 40 1C, the yield of 3a
increased to 76% (entry 4). Under the higher temperature condi-
tions, the yield of the product decreased (entry 5).
To investigate further scope and limitation, we next focused
our interest on the effect of the substituted group on the
benzene ring of N-methylformanilide. Reactions with electro-
philes which have electron-donating group such as methoxy
and dimethylamino group at the p-position proceeded smoothly
to generate 3b and 3c in 81% and 74% yields (Table 2, entries 1, 2).
To examine the influence of the position of substituted groups
on the benzene ring, reactions of N-methylformanilide derivatives
bearing a methyl group in the p-, m- and o-positions were
performed. In the case of substitution at the p- and m-positions,
the corresponding enaminoesters 3d and 3e were obtained in good
yields (entries 3 and 4).
Fluoride
source
Temp. Yielda
Entry FG–CH2–H
2 (R)
Solvent (1C)
(%)
1
2a (H)
CsF
DMF
50
4b : 88
2
3
2b (OMe) TMAF
2b (OMe) TMAF
None
None
50
50
4c : 73
4d : 93
4
5
2b (OMe) TMAF
2b (OMe) CsF
None
DMF
50
4e : 57b
4g : 52
120
However, when a methyl group was substituted at the
o-position, the reaction did not give the desired product (entry 5).
a
b
Isolated yield. Determined using 1H-NMR analysis.
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Notes and references
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1
reaction was monitored using H-NMR and the formation of the
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Grant-in-Aid for Young Scientists (B) (No. 23790002) from Japan
Society for the promotion of Science, a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Advanced Molecular Transforma-
tions by Organocatalysis’’ (No. 23105009) and the project
‘‘Platform for Drug Discovery, Informatics, and Structural Life
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Chem. Commun., 2014, 50, 6523--6525 | 6525