Highly efficient synthesis of trans-β,γ-unsaturated α-keto amides

Article abstract of DOI:10.1055/s-0029-1216869

A highly efficient, metal-free, and selective access to trans-β,γ-unsaturated α-keto amides is described via peptidic coupling, involving easy to prepare trans-β,γ-unsaturated α-keto acids and commercially available amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216869

PAPER
2523
Highly Efficient Synthesis of trans-b,g-Unsaturated a-Keto Amides
S
ynthesis of tran
h
-
b
,
g
-Unsatu
r
rated
a
-
i
eto
A
s
Aix-Marseille Université, Institut des Sciences Moléculaires de Marseille, CNRS UMR 6263 iSm2,
Centre Saint Jérôme - Service 531, 13397 Marseille Cedex 20, France
Fax +33(4)91289187; E-mail: thierry.constantieux@univ-cezanne.fr; E-mail: jean.rodriguez@univ-cezanne.fr
Received 7 April 2009; revised 27 April 2009
amides. In this context, herein we wish to report a simple,
metal-free, highly efficient and selective route to these
valuable compounds (Scheme 1).
Abstract: A highly efficient, metal-free, and selective access to
trans-b,g-unsaturated a-keto amides is described via peptidic cou-
pling, involving easy to prepare trans-b,g-unsaturated a-keto acids
and commercially available amines.
O
O
R1
N
Key words: b,g-unsaturated a-keto amide, a-keto acid, amine, pep-
tidic coupling, Michael acceptor
BOPCl, Et3N
OH
Ar
Ar
R2
CH2Cl2
0 °C to r.t. overnight
O
O
R1R2NH
+
a-Keto amides are compounds of widespread interest in
organic chemistry since the electrophilicity of the ketone
functionality is enhanced by the presence of electron-
withdrawing group on the a-position. Apart from its en-
hanced reactivity, this functionality is also associated with
biological properties,1 and a-keto amides are present in
several bioactive natural products.2 Therefore, develop-
ment of numerous efficient synthetic strategies for their
preparation emerged in the literature, particularly: 1) Ugi
or Passerini like reactions from isonitriles;3 2) oxidation
of amides,4 a-hydroxy amides,5 ynamides,6 or N-glycosyl
indoles;7 3) substitution on oxalyl chlorides;8 4) ring
opening of cyclic dehydrodipeptides9 or N-acetylisatins;10
5) oxidative cleavage of cyanoketo phosphoranes11 or
acyl derivatives of cyanomethylamines;12 6) peptidic cou-
pling reactions;13 7) double carbonylation of aryl halides
with amines;14 and 8) reactions of acyl chlorides with met-
alated carbamoyls.15 However, none of these synthetic
pathways are efficient for the preparation of b,g-unsatur-
ated a-keto amides. Quite surprisingly, although b,g-un-
saturated a-keto esters16 or b,g-unsaturated a-keto
phosphonates17 are well documented,18,19 the chemistry of
their amide analogues has not stimulated much interest so
far. Thus, although the coupling of two different trans-
b,g-unsaturated a-keto acids with a two-fold excess of
aniline using thionyl chloride was described,8a there is still
a lack of a general, efficient and user-friendly approach.
In this field, palladium-catalyzed double carbonylation of
alkenyl halides20nowadays leads the way. However, use
of air-sensitive phosphine ligands and toxic carbon mon-
oxide, under high pressure and temperature conditions,21
are major drawbacks of this reaction.
Scheme 1 General scheme for the coupling reaction
Indeed, we have now developed a peptidic coupling reac-
tion involving stoichiometric amounts of easily available
b,g-unsaturated a-keto acids23 and amines. The reactions
are performed at room temperature in dichloromethane in
the presence of bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BOPCl) and triethylamine, affording the desired
products generally with excellent chemical purity. To ini-
tiate our study with a test reaction, we submitted a 1:1
mixture of (E)-2-oxo-4-phenylbut-3-enoic acid (1a)23 and
aniline (2a) to different peptidic coupling agents
(Figure 1). The results are reported in Table 1.
N
C N
N
C N
N
Me
DCC (4a)
EDC (4b)
Me
N
N
O
P
N
N
N
O
P
N
N
N
Cl
O
O
–
PF6
O
O
BOPCl (4c)
PyBOP (4d)
Figure 1 Various coupling agents
Classical peptidic coupling systems such as DCC with
DMAP24(entry 1) and EDC with HOBt25 (entry 2) gave
complex mixtures without significant traces of product
3a. In contrast, BOPCl (4c) combined with
triethylamine26 (entry 3) and benzotriazol-1-yl-oxytripyr-
rolidinophosphonium hexafluorophosphate (PyBOP, 4d)
combined with diisopropylethylamine27 (entry 4) were ex-
tremely efficient and afforded 3a in quantitative yield and
with excellent chemical purity.28
In accordance with our studies on the development of
Michael addition-initiated domino multicomponent reac-
tions,22 we required a rapid, versatile and efficient meth-
odology to prepare a variety of b,g-unsaturated a-keto
SYNTHESIS 2009, No. 15, pp 2523–2530
x
x.
x
x
.
2
0
0
9
Advanced online publication: 26.06.2009
DOI: 10.1055/s-0029-1216869; Art ID: P05109SS
© Georg Thieme Verlag Stuttgart · New York

2524
C. Allais et al.
PAPER
Table 1 Screening of Coupling Systems for b,g-Unsaturated a-Keto Amides
O
O
H2N
H
N
OH
+
O
O
1a
2a
3a
Entry
Coupling systema
DCC (4a), DMAP
EDC (4b), HOBt
BOPCl (4c), Et3N
PyBOP (4d), DIPEA
Product
mixture
mixture
3a
Yield (%)b
1
2
3
4
–
–
99
99
3a
a For more details, see experimental.
b Yields of crude product which needed no further purification.
Stimulated by these results, we examined the scope of the ciency of the reaction is clearly seen from the results de-
protocol with several b,g-unsaturated a-keto acids and a picted in Table 2. The reaction systematically afforded the
variety of commercially available amines (Figure 2). expected trans-b,g-unsaturated a-keto amides in good to
BOPCl (4c), less expensive than PyBOP (4d), was elected excellent yields, and with few exceptions, without need of
as the coupling agent. The general applicability and effi- further purification.
Table 2 Peptidic Coupling of b,g-Unsaturated a-keto Acids with Amines
O
O
BOPCl (1.2 equiv)
Et3N (3.4 equiv)
NR1R2
OH
R1R2NH
Ar
Ar
CH2Cl2, 0 °C to r.t. overnight
O
O
3
1
2
Entry Acid 1 Amine 2 Product 3
Yield
(%)a
Entry Acid 1 Amine 2 Product 3
Yield
(%)a
O
O
O
O
H
N
H
N
O
1
2
3
4
5
1a
1a
1a
1a
1a
2a
2b
2c
2d
2f
99
11
12
13
14
15
1b
1b
1b
1b
1b
2a
2d
2e
2g
2i
99
O
O
O
O
3a
3b
3c
3k
O
O
O
H
N
H
N
95
98
88
70
73b
75b
99
O
O
O
O
3l
H
N
H
N
O
3m
O
O
H
N
N
N
O
3n
3d
3e
O
O
O
H
N
O
99
O
O
3o
Synthesis 2009, No. 15, 2523–2530 © Thieme Stuttgart · New York

PAPER
Synthesis of trans-b,g-Unsaturated a-Keto Amides
2525
Table 2 Peptidic Coupling of b,g-Unsaturated a-keto Acids with Amines (continued)
O
O
BOPCl (1.2 equiv)
Et3N (3.4 equiv)
NR1R2
OH
R1R2NH
Ar
Ar
CH2Cl2, 0 °C to r.t. overnight
O
O
3
1
2
Entry Acid 1 Amine 2 Product 3
Yield
(%)a
Entry Acid 1 Amine 2 Product 3
Yield
(%)a
O
Me
N
O
O
Me
N
O
6
7
1a
1a
2g
2h
99
16
17
1b
1b
2j
94
77
O
O
O
O
3p
3f
Me
N
O
NH2
O
99
99
2k
O
3q
3g
O
H
O
O
N
N
N
N
8
1a
1a
1a
2i
18
19
20
1c
1c
1c
2a
2g
2l
95
93
99
O
O
O
O
3h
3r
3s
3t
O
O
Me
N
Me
O
9
2j
88
O
3i
O
O
NH2
10
2k
70
O
3j
a Yield of crude product which needed no further purification.
b Isolated yield after purification by flash chromatography over silica gel.
Aromatic amine such as aniline (2a) gave excellent results amides 3j and 3q using the system magnesium nitride/wa-
(entries 1, 11, and 18), but reaction occurred also very ter 2k as a source of ammonia29 (entries 10 and 17). Multi-
well with aliphatic primary amines 2b–f (entries 2–5, 12, step sequences are generally required to prepare these
and 13). Additionally, secondary acyclic 2g, 2h, 2l, and substrates whereas they can be obtained in a single opera-
cyclic amines 2i were excellent substrates (entries 7–9, tion with this protocol.
14, 15, 19, and 20), affording an easy access to tertiary
In conclusion, we have developed a highly efficient route
amides. Interestingly, amine hydrochloride salt can be
used without previous neutralization as shown by the for-
mation of a-keto Weinreb amides 3i and 3p (entries 9 and
16). Excess of triethylamine in the mixture is sufficient to
reload in situ the Weinreb amine from 2j, which can then
perform peptidic coupling. Moreover, chiral amine 2e was
also easily introduced by the developed strategy (entry
13), allowing preparation of potential new Michael accep-
ucts, especially as activated Michael acceptors in domino
tors bearing a chiral inductor. Finally, this methodology
provided a rapid synthetic access to challenging primary
to trans-b,g-unsaturated a-keto amides from readily avail-
able b,g-unsaturated a-keto acids and various primary and
secondary amines. Products are generally obtained in
quantitative yield and with high chemical purity. This
one-step method constitutes a good and general alterna-
tive to other previously published methodologies. We are
currently developing the reactivity of these news prod-
multicomponent processes.
Synthesis 2009, No. 15, 2523–2530 © Thieme Stuttgart · New York

2526
C. Allais et al.
PAPER
mL). The organic layers were combined, washed with H2O (300
mL), brine (300 mL), and dried (Na2SO4). After filtration through a
cotton plug, the solvent was removed under reduced pressure to af-
ford the b,g-unsaturated a-keto acid 1 as a solid.
O
O
OH
OH
O
O
O
1b
1a
(E)-2-Oxo-4-phenylbut-3-enoic Acid (1a)
Yield: 49%; yellow solid; mp 58–59 °C.
O
1H NMR (300.13 MHz, CDCl3): d = 7.40–7.49 (m, 3 H), 7.58 (d,
J = 15.9 Hz, 1 H), 7.67 (d, J = 8.1 Hz, 2 H), 8.11 (d, J = 15.6 Hz, 1
H), 9.39 (br s, 1 H).
OH
O
1c
13C NMR (75.47 MHz, CDCl3): d = 118.1, 129.2 (2 C), 129.4 (2 C),
132.3, 133.7, 151.0, 161.2, 182.7.
MS (ESI): m/z = 199 ([M + Na]+, 100%).
NH2
NH2
NH2
NH2
(E)-4-(Furan-2-yl)-2-oxobut-3-enoic Acid (1b)
Yield: 67%; brown solid; mp 112–113 °C.
2d
2c
2b
2a
1H NMR (300.13 MHz, CDCl3): d = 6.58 (dd, J = 3.4, 1.6 Hz, 1 H),
6.93 (d, J = 3.6 Hz, 1 H), 7.37 (d, J = 15.9 Hz, 1 H), 7.62 (d, J = 1.2
Hz, 1 H), 7.88 (d, J = 15.9 Hz, 1 H), 9.23 (br s, 1 H).
Me
HN
NH2
NH2
N
H
13C NMR (75.47 MHz, CDCl3): d = 113.6, 115.4, 120.2, 136.0,
147.3, 151.0, 160.7, 181.8.
2e
2f
2g
2h
MS (ESI): m/z = 189 ([M + Na]+, 100%).
Me
HN
(E)-4-(Anthracen-10-yl)-2-oxobut-3-enoic Acid (1c)
Yield: 11%; red solid; mp 171–172 °C.
Me⋅HCl
O
NH
N
H
Mg3N2/H2O
O
1H NMR (300.13 MHz, CDCl3): d = 7.51–7.61 (m, 4 H), 7.65 (d,
J = 16.2 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 2 H), 8.29 (d, J = 8.7 Hz, 2
H), 8.54 (s, 1 H), 9.26 (d, J = 16.2 Hz, 1 H).
2k
2l
2i
2j
Figure 2 Substrates used in the study
13C NMR (75.47 MHz, DMSO-d6): d = 124.6 (2 C), 125.6 (2 C),
127.0 (2 C), 128.4, 128.8 (2 C), 128.9 (2 C), 129.0, 130.4, 130.7 (2
C), 143.2, 163.9, 184.9.
Melting points were determined with a Büchi melting point B-450
apparatus and are not corrected. 1H and 13C NMR spectra were re-
corded in solution at 300.13 MHz and 75.47 MHz, respectively, on
a Bruker AC 300 spectrometer. NMR data were collected at r.t., and
chemical shifts are given in ppm referenced to the appropriate sol-
vent peak. Data for 1H NMR are reported as follows: chemical shift,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quadruplet, hept = heptuplet, dd = doublet of doublets,
dt = doublet of triplets, dq = doublet of quadruplets,
dhept = doublet of heptuplets, m = multiplet), integration. Low-res-
olution mass spectra were recorded on a Bruker Esquire 6000 with
ESI source and high-resolution mass spectra were recorded on an
API QStar Elite (Applied Biosystems SCIEX) mass spectrometer.
Analytical TLC was performed using 0.20 mm silica gel 60 plates.
Flash chromatography was performed using 70–230 mesh silica gel
60 (Merck). Petroleum ether (PE) used refers to the fraction with
boiling range 40–50 °C.
MS (ESI): m/z = 299 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C18H13O3 [M+H]+: 277.0859; found:
277.0857.
Peptidic Coupling of b,g-Unsaturated a-Keto Acids 1 with
Amines 2 Using BOPCl; General Procedure
To a 10 mL one-necked round-bottomed flask, equipped with a
magnetic stirring bar and were added b,g-unsaturated a-keto acid 1
(200 mg, 1 equiv), freshly distilled CH2Cl2 (5 mL), and Et3N (3.4
equiv) under argon. The mixture was cooled at 0 °C and BOPCl (4c;
1.2 equiv) was added in one portion. The mixture was stirred at this
temperature for 30 min, and the distilled amine 2 (1 equiv) was add-
ed. The reaction mixture was allowed to warm to r.t. and stirred
overnight. Then, it was diluted with CH2Cl2 (12 mL) and the organ-
ic layer was washed with aq 1 N HCl (2 × 30 mL), H2O (2 × 30 mL)
and brine (50 mL). The organic layer was dried (Na2SO4), filtered
through a cotton plug, and the solvent was evaporated under reduce
pressure to afford the corresponding b,g-unsaturated a-keto amide
3 in excellent yield and very good chemical purity.
b,g-Unsaturated a-Keto Acids 1; General Procedure
To a stirred solution of pyruvic acid (0.266 mol, 1 equiv) and aro-
matic aldehyde (0.266 mol, 1 equiv) in MeOH (15 mL) in an ice
bath was added a solution of KOH (0.398 mol, 1.5 equiv) in MeOH
(75 mL). The first 50 mL of the base solution was added dropwise
and the reaction temperature was kept below 25 °C. The ice bath
was then removed and the rest of the base solution was added quick-
ly. A yellow precipitate was formed at once. The solution was kept
at r.t. for 1 h and then at 0 °C overnight. The yellow crystals were
collected by filtration, washed with cold MeOH (2 × 50 mL) and
Et2O (50 mL), and then dried to afford the potassium salt.4 H2O (300
mL) was added and then aq 35% HCl was added dropwise under
magnetic stirring until pH 1. A precipitate was generally formed
and EtOAc (300 mL) was added to the mixture. The layers were
separated and the aqueous layer was extracted with EtOAc (3 × 150
Particular Cases: Primary amides 3j and 3q were formed by addi-
tion of Mg3N2 (1 equiv) instead of amine. The flask was sealed and
H2O (6 equiv) was added to form ammonia in situ. The mixture was
then stirred at r.t. overnight. For compounds 3i and 3p, hydrochlo-
ride form of Weinreb amine was used.
(E)-2-Oxo-N,4-diphenylbut-3-enamide (3a)
Yield: quant; brown solid; mp 140–141 °C.
1H NMR (300.13 MHz, CDCl3): d = 7.19 (t, J = 7.5 Hz, 1 H), 7.37–
7.46 (m, 5 H), 7.70 (d, J = 7.5 Hz, 4 H), 7.89 (d, J = 16.2 Hz, 1 H),
8.03 (d, J = 15.9 Hz, 1 H), 9.00 (br s, 1 H).
Synthesis 2009, No. 15, 2523–2530 © Thieme Stuttgart · New York

PAPER
Synthesis of trans-b,g-Unsaturated a-Keto Amides
2527
13C NMR (75.47 MHz, CDCl3): d = 117.9, 119.8 (2 C), 125.1, 129.0
(2 C), 129.1 (2 C), 129.2 (2 C), 131.6, 134.2, 136.6, 148.7, 158.8,
185.4.
H), 6.89 (d, J = 16.2 Hz, 1 H), 7.40–7.43 (m, 3 H), 7.55–7.58 (m, 2
H), 7.61 (d, J = 16.2 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 12.7, 14.3, 39.1, 42.2, 123.6,
128.7 (2 C), 129.0 (2 C), 131.3, 134.0, 148.0, 166.6, 191.2.
MS (ESI): m/z = 274 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C16H14NO2 [M + H]+: 252.1019; found:
252.1019.
MS (ESI): m/z = 254 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C14H18NO2 [M + H]+: 239.1332; found:
239.1336.
(E)-N-Isopropyl-2-oxo-4-phenylbut-3-enamide (3b)
Yield: 95%; yellow solid; mp 66–67 °C; Rf = 0.33 (EtOAc–PE,
1:6).
(E)-N-Allyl,N-methyl-2-oxo-4-phenylbut-3-enamide (3g)
Yield: quant; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 1.24 (d, J = 6.5 Hz, 6 H), 4.11
(dhept, J = 8.3, 6.6 Hz, 1 H), 7.03 (br s, 1 H), 7.40–7.43 (m, 3 H),
7.64–7.68 (m, 2 H), 7.77 (d, J = 16.2 Hz, 1 H), 7.93 (d, J = 16.2 Hz,
1 H).
1H NMR (300.13 MHz, CDCl3): d = 2.88 (s, 3 H), 2.93 (s, 3 H), 3.81
(d, J = 5.7 Hz, 2 H), 4.02 (d, J = 6.0 Hz, 2 H), 5.12–5.22 (m, 4 H),
5.64–5.81 (m, 2 H), 6.84 (d, J = 16.2 Hz, 1 H), 7.31–7.33 (m, 6 H),
7.48–7.50 (m, 4 H), 7.56 (d, J = 16.5 Hz, 1 H), 7.57 (d, J = 16.2 Hz,
1 H).
13C NMR (75.47 MHz, CDCl3): d = 22.4 (2 C), 41.6, 118.6, 129.0
(2 C), 129.1 (2 C), 131.3, 134.4, 147.8, 160.4, 185.7.
13C NMR (75.47 MHz, CDCl3): d = 31.6, 34.3, 48.7, 52.0, 118.1,
118.5, 123.0 (2 C), 128.4 (4 C), 128.7 (4 C), 131.1 (2 C), 131.2,
132.0, 133.5 (2 C), 148.0, 148.1, 166.3, 166.8, 190.6, 190.8.
MS (ESI): m/z = 240 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C13H16NO2 [M + H]+: 218.1176; found:
218.1167.
MS (ESI): m/z = 252 [M + Na]+, 100%).
HRMS (ESI): m/z calcd for C14H16NO2 [M + H]+: 230.1176; found:
230.1176.
(E)-N-tert-Butyl-2-oxo-4-phenylbut-3-enamide (3c)
Yield: 98%; yellow solid; mp 90–91 °C.
1H NMR (300.13 MHz, CDCl3): d = 1.42 (s, 9 H), 7.01 (br s, 1 H),
7.36–7.39 (m, 3 H), 7.61–7.64 (m, 2 H), 7.79 (d, J = 16.2 Hz, 1 H),
7.89 (d, J = 15.9 Hz, 1 H).
(E)-1-Morpholino-4-phenylbut-3-ene-1,2-dione (3h)
Yield: quant; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 3.39–3.42 (m, 2 H), 3.59–3.62
(m, 2 H), 3.65–3.70 (m, 4 H), 6.87 (d, J = 16.5 Hz, 1 H), 7.33–7.36
(m, 3 H), 7.50–7.53 (m, 2 H), 7.63 (d, J = 16.2 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 28.1 (3 C), 51.1, 118.1, 128.8
(2 C), 128.9 (2 C), 131.1, 134.3, 147.3, 160.4, 186.1.
MS (ESI): m/z = 254 ([M + Na]+, 100%).
13C NMR (75.47 MHz, CDCl3): d = 41.5, 46.0, 66.3, 66.5, 123.0,
128.5 (2 C), 128.8 (2 C), 131.3, 133.5, 148.3, 165.0, 190.1.
HRMS (ESI): m/z calcd for C14H18NO2 [M + H]+: 232.1332; found:
232.1334.
MS (ESI): m/z = 268 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C14H16NO3 [M + H]+: 246.1125; found:
246.1123.
(E)-N-Benzyl-2-oxo-4-phenylbut-3-enamide (3d)
Yield: 88%; yellow solid; mp 102–103 °C; Rf = 0.28 (EtOAc–PE,
1:6).
(E)-N-Methoxy,N-methyl-2-oxo-4-phenylbut-3-enamide (3i)
Yield: 88%; scale up on 1 g of acid: quant; orange oil.
1H NMR (300.13 MHz, CDCl3): d = 4.55 (d, J = 6.1 Hz, 2 H), 7.30–
7.36 (m, 5 H), 7.42–7.45 (m, 3 H), 7.52 (br s, 1 H), 7.66–7.69 (m, 2
H), 7.80 (d, J = 16.1 Hz, 1 H), 7.96 (d, J = 16.1 Hz, 1 H).
1H NMR (300.13 MHz, CDCl3): d = 3.25 (s, 3 H), 3.63 (s, 3 H), 6.75
(d, J = 16.8 Hz, 1 H), 7.33–7.36 (m, 3 H), 7.49–7.52 (m, 2 H), 7.51
(d, J = 16.5 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 43.5, 118.6, 127.7, 127.8 (2 C),
128.8 (2 C), 129.0 (2 C), 129.1 (2 C), 131.5, 134.3, 137.1, 148.1,
161.1, 185.3.
13C NMR (75.47 MHz, CDCl3): d = 31.2, 61.9, 122.9, 128.4 (2 C),
128.8 (2 C), 131.1, 133.5, 148.1, 166.9, 190.6.
MS (ESI): m/z = 288 ([M + Na]+, 100%).
MS (ESI): m/z = 242 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C17H16NO2 [M + H]+: 266.1176; found:
266.1176.
HRMS (ESI): m/z calcd for C12H14NO3 [M + H]+: 220.0968; found:
220.0969.
(E)-2-Oxo-4-phenyl-N-(prop-2-ynyl)but-3-enamide (3e)
Yield: 70%; orange gum; Rf = 0.32 (EtOAc–PE, 1:4).
(E)-2-Oxo-4-phenylbut-3-enamide (3j)
Yield: 70%; brown solid; mp 104–105 °C.
1H NMR (300.13 MHz, CDCl3): d = 2.29 (t, J = 2.6 Hz, 1 H), 4.15
(dd, J = 5.6 Hz, J = 2.6 Hz, 2 H), 7.38-7.43 (m, 3 H), 7.58 (br s, 1
H), 7.65–7.68 (m, 2 H), 7.74 (d, J = 16.2 Hz, 1 H), 7.96 (d, J = 16.2
Hz, 1 H).
1H NMR (300.13 MHz, CDCl3): d = 6.39 (br s, 1 H), 7.15 (br s, 1
H), 7.39–7.41 (m, 3 H), 7.62–7.65 (m, 2 H), 7.71 (d, J = 16.2 Hz, 1
H), 7.91 (d, J = 16.2 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 118.1, 128.9 (2 C), 129.1 (2 C),
131.5, 134.2, 148.1, 163.5, 185.0.
13C NMR (75.47 MHz, CDCl3): d = 30.0, 73.1, 79.2, 119.2, 129.9
(2 C), 130.0 (2 C), 132.4, 135.1, 149.2, 161.7, 185.5.
MS (ESI): m/z (%) = 198 ([M + Na]+, 100), 176 ([M + H]+, 12).
MS (ESI): m/z = 236 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C10H10NO2 [M + H]+: 176.0706; found:
176.0699.
HRMS (ESI): m/z calcd for C13H12NO2 [M + H]+: 236.0682; found:
236.0689.
(E)-4-(Furan-2-yl)-2-oxo-N-phenylbut-3-enamide (3k)
Yield: quant; brown solid; mp 105–106 °C.
(E)-N,N-Diethyl-2-oxo-4-phenylbut-3-enamide (3f)
Yield: quant; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 6.56 (dd, J = 3.6, 1.7 Hz, 1 H),
6.88 (d, J = 3.8 Hz, 1 H), 7.16–7.20 (m, 1 H), 7.39 (t, J = 7.9 Hz, 2
1H NMR (300.13 MHz, CDCl3): d = 1.20 (t, J = 7.0 Hz, 3 H), 1.24
(t, J = 7.0 Hz, 3 H), 3.31 (q, J = 7.2 Hz, 2 H), 3.51 (q, J = 7.2 Hz, 2
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H), 7.60 (d, J = 0.9 Hz, 1 H), 7.67 (d, J = 1.5 Hz, 2 H), 7.68 (d,
J = 15.6 Hz, 1 H), 7.80 (d, J = 15.9 Hz, 1 H), 8.98 (br s, 1 H).
HRMS (ESI): m/z calcd for C12H14NO4 [M + H]+: 236.0917; found:
236.0920.
13C NMR (75.47 MHz, CDCl3): d = 113.1, 115.7, 118.5, 119.7 (2
C), 125.0, 129.1 (2 C), 133.8, 136.6, 146.4, 151.4, 158.8, 185.1.
(E)-4-(Furan-2-yl)-N-methoxy,N-methyl-2-oxobut-3-enamide
(3p)
Yield: 94%; brown oil.
MS (ESI): m/z = 264 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C14H12NO3 [M + H]+: 242.0812; found:
242.0812.
1H NMR (300.13 MHz, CDCl3): d = 3.21 (s, 3 H), 3.61 (s, 3 H), 6.44
(dd, J = 1.5, 3.3 Hz, 1 H), 6.57 (d, J = 16.5 Hz, 1 H), 6.69 (d, J = 3.3
Hz, 1 H), 7.23 (d, J = 16.5 Hz, 1 H), 7.48 (d, J = 1.5 Hz, 1 H).
(E)-N-Benzyl-4-(furan-2-yl)-2-oxobut-3-enamide (3l)
Yield: 73%; orange solid; mp 123–124 °C; Rf = 0.34 (EtOAc–PE,
1:5).
13C NMR (75.47 MHz, CDCl3): d = 31.2, 61.9, 112.8, 117.5, 120.0,
133.5, 145.9, 150.2, 167.0, 190.0.
MS (ESI): m/z (%) = 210 ([M + H]+, 8), 232 ([M + Na]+, 100).
1H NMR (300.13 MHz, CDCl3): d = 4.53 (d, J = 6.3 Hz, 2 H), 6.53
(dd, J = 1.8, 3.6 Hz, 1 H), 6.82 (d, J = 3.3 Hz, 1 H), 7.28–7.37 (m,
5 H), 7.51 (br s, 1 H), 7.57 (d, J = 1.8 Hz, 1 H), 7.59 (d, J = 15.9 Hz,
1 H), 7.73 (d, J = 15.9 Hz, 1 H).
HRMS (ESI): m/z calcd for C10H12NO4 [M + H]+: 210.0761; found:
210.0763.
(E)-4-(Furan-2-yl)-2-oxobut-3-enamide (3q)
Yield: 77%; brown solid; mp 97–98 °C.
13C NMR (75.47 MHz, CDCl3): d = 43.4, 113.0, 116.5, 118.1,
127.7, 127.8 (2 C), 128.7 (2 C), 133.4, 137.1, 146.2, 151.5, 161.1,
185.1.
1H NMR (300.13 MHz, CDCl3): d = 6.42 (br s, 1 H), 6.51 (dd,
J = 1.6, 3.5 Hz, 1 H), 6.82 (d, J = 3.6 Hz, 1 H), 7.16 (br s, 1 H), 7.51
(d, J = 15.6 Hz, 1 H), 7.55 (d, J = 1.5 Hz, 1 H), 7.69 (d, J = 15.6 Hz,
1 H).
MS (ESI): m/z = 278 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C15H14NO3 [M + H]+: 256.0968; found:
256.0964.
13C NMR (75.47 MHz, CDCl3): d = 113.0, 116.0, 118.3, 133.5,
146.3, 151.3, 163.7, 184.7.
(S,E)-4-(Furan-2-yl)-2-oxo-N-(1-phenylethyl)but-3-enamide
(3m)
MS (ESI): m/z = 188 ([M + Na]+, 100%).
Yield: 75%; orange solid; mp 86–87 °C; Rf = 0.33 (EtOAc–PE,
1:5).
HRMS (ESI): m/z calcd for C8H8NO3 [M + H]+: 166.0499; found:
166.0501.
1H NMR (300.13 MHz, CDCl3): d = 1.57 (d, J = 6.9 Hz, 3 H), 5.13
(dq, J = 8.4, 6.9 Hz, 1 H), 6.51 (dd, J = 1.7, 3.5 Hz, 1 H), 6.81 (d,
J = 3.6 Hz, 1 H), 7.27–7.30 (m, 1 H), 7.34–7.35 (m, 4 H), 7.47 (br
s, 1 H), 7.55 (d, J = 15.9 Hz, 1 H), 7.56 (d, J = 1.5 Hz, 1 H), 7.72 (d,
J = 15.9 Hz, 1 H).
(E)-4-(Anthracen-10-yl)-2-oxo-N-phenylbut-3-enamide (3r)
Yield: 95%; orange solid; mp 214–215 °C.
1H NMR (300.13 MHz, CDCl3): d = 7.21 (t, J = 7.4 Hz, 1 H), 7.42
(t, J = 7.9 Hz, 2 H), 7.46–7.59 (m, 4 H), 7.75 (d, J = 9.6 Hz, 2 H),
7.92 (d, J = 16.2 Hz, 1 H), 8.03 (d, J = 9.3 Hz, 2 H), 8.32 (d, J = 8.7
Hz, 2 H), 8.50 (s, 1 H), 9.10 (br s, 1 H), 9.11 (d, J = 16.2 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 21.6, 49.0, 113.0, 116.5, 118.0,
126.1 (2 C), 127.6, 128.7 (2 C), 133.3, 142.2, 146.2, 151.5, 160.3,
185.2.
13C NMR (75.47 MHz, CDCl3): d = 119.8 (2 C), 124.9 (2 C), 125.2,
125.5 (2 C), 126.8, 127.0 (2 C), 128.8 (2 C), 129.0 (2 C), 129.2 (2
C), 129.8 (2 C), 129.9, 131.2, 136.5, 145.9, 158.8, 185.1.
MS (ESI): m/z = 292 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C16H16NO3 [M + H]+: 270.1125; found:
270.1126.
MS (ESI): m/z = 374 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C24H18NO2 [M + H]+: 352.4052; found:
352.4049.
(E)-N,N-Diethyl-4-(furan-2-yl)-2-oxobut-3-enamide (3n)
Yield: quant; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 1.20 (t, J = 7.2 Hz, 3 H), 1.23
(t, J = 7.2 Hz, 1 H), 3.30 (q, J = 7.1 Hz, 2 H), 3.49 (q, J = 7.2 Hz, 2
H), 6.52 (dd, J = 3.5, 1.9 Hz, 1 H), 6.75 (d, J = 3.6 Hz, 1 H), 6.76
(d, J = 15.9 Hz, 1 H), 7.37 (d, J = 15.9 Hz, 1 H), 7.55 (d, J = 1.8 Hz,
1 H).
(E)-4-(Anthracen-10-yl)-N,N-diethyl-2-oxobut-3-enamide (3s)
Yield: 93%; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 0.31 (t, J = 7.2 Hz, 3 H), 0.79
(t, J = 7.1 Hz, 3 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3
H), 2.38 (q, J = 7.1 Hz, 2 H), 2.66 (q, J = 7.1 Hz, 2 H), 3.48 (q,
J = 7.3 Hz, 2 H), 3.58 (q, J = 7.8 Hz, 2 H), 6.91 (d, J = 16.8 Hz, 1
H), 7.02 (d, J = 12.0 Hz, 1 H), 7.43–7.55 (m, 8 H), 7.87 (d, J = 12.3
Hz, 1 H), 7.95–8.05 (m, 6 H), 8.21 (d, J = 8.7 Hz, 2 H), 8.40 (d,
J = 9.0 Hz, 2 H), 8.64 (d, J = 16.5 Hz, 1 H).
13C NMR (75.47 MHz, CDCl3): d = 12.6, 14.2, 39.0, 42.0, 112.8,
117.4, 120.7, 133.3, 145.9, 150.5, 166.5, 190.7.
MS (ESI): m/z = 244 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C12H16NO3 [M + H]+: 222.1125; found:
222.1127.
13C NMR (75.47 MHz, CDCl3): d = 11.6, 12.8, 13.5, 14.4, 38.5,
38.5, 39.2, 41.3, 42.3, 124.6 (2 C), 125.3 (2 C), 125.4 (2 C), 125.6
(2 C), 125.9 (2 C), 126.8 (2 C), 127.5, 128.2 (2 C), 128.5 (2 C),
128.8 (2 C), 128.9 (2 C), 129.3 (4 C), 129.3, 130.9, 131.0, 131.7,
132.1, 142.0, 145.4, 165.2, 166.5, 189.9, 190.9.
(E)-4-(Furan-2-yl)-1-morpholinobut-3-ene-1,2-dione (3o)
Yield: quant; brown oil.
1H NMR (300.13 MHz, CDCl3): d = 3.48–3.51 (m, 2 H), 3.67–3.70
(m, 2 H), 3.73–3.79 (m, 4 H), 6.53 (dd, J = 3.4, 1.8 Hz, 1 H), 6.79
(d, J = 3.6 Hz, 1 H), 6.80 (d, J = 16.2 Hz, 1 H), 7.43 (d, J = 15.9 Hz,
1 H), 7.57 (d, J = 1.5 Hz, 1 H).
MS (ESI): m/z = 354 ([M + Na]+, 100%).
HRMS (ESI): m/z calcd for C22H22NO2 [M + H]+: 332.1645; found:
332.1645.
13C NMR (75.47 MHz, CDCl3): d = 41.7, 46.2, 66.5, 66.7, 113.0,
117.9, 120.4, 133.7, 146.2, 150.5, 165.1, 189.7.
(E)-4-(Anthracen-9-yl)-N,N-diisopropyl-2-oxobut-3-enamide
(3t)
Yield: quant; brown oil.
MS (ESI): m/z = 258 ([M + Na]+, 100%).
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Synthesis of trans-b,g-Unsaturated a-Keto Amides
2529
1H NMR (300.13 MHz, CDCl3): d = 1.33 (d, J = 6.6 Hz, 6 H), 1.60
(d, J = 6.6 Hz, 6 H), 3.63 (hept, J = 6.7 Hz, 1 H), 4.03 (hept, J = 6.6
Hz, 1 H), 6.81 (d, J = 16.8 Hz, 1 H), 7.46–7.55 (m, 4 H), 8.00 (d,
J = 7.5 Hz, 2 H), 8.20 (d, J = 9.0 Hz, 2 H), 8.44 (s, 1 H), 8.61 (d,
J = 16.5 Hz, 1 H).
(5) (a) Sheha, M. M.; Mahfouz, N. M.; Hassan, H. Y.; Youssef,
A. F.; Mimoto, T.; Kiso, Y. Eur. J. Med. Chem. 2000, 35,
887. (b) Chen, C.-T.; Bettigeri, S.; Weng, S.-S.; Pawar, V.
D.; Lin, Y.-H.; Liu, C.-Y.; Lee, W.-Z. J. Org. Chem. 2007,
72, 8175. (c) Lamberth, C.; Jeanguenat, A.; Cederbaum, F.;
De Mesmaecker, A.; Zeller, M.; Kempf, H.-J.; Zeun, R.
Bioorg. Med. Chem. 2008, 16, 1531. (d) Nam, D. H.; Lee,
K. S.; Kim, S. H.; Kim, S. M.; Jung, S. Y.; Chung, S. H.;
Kim, H. J.; Kim, N. D.; Jin, C.; Lee, Y. S. Bioorg. Med.
Chem. Lett. 2008, 18, 205. (e) See also ref. 1b.
13C NMR (75.47 MHz, CDCl3): d = 20.2, 20.7, 46.0, 50.2, 124.6,
125.3 (2 C), 125.4 (2 C), 126.8 (2 C), 128.9 (3 C), 129.2 (2 C), 131.1
(2 C), 132.4, 145.5, 166.9, 191.2.
MS (ESI): m/z (%) = 360 ([M + H]+, 8), 382 ([M + Na]+, 100).
HRMS (ESI): m/z calcd for C24H26NO2 [M + H]+: 360.1958; found:
360.1961.
(6) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.;
Yao, P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780;
and references cited therein.
(7) Sassatelli, M.; Bouchikhi, F.; Messaoudi, S.; Anizon, F.;
Debiton, E.; Barthomeuf, C.; Prudhomme, M.; Moreau, P.
Eur. J. Med. Chem. 2006, 41, 88.
(8) (a) Ibrahim, Y. A.; Eid, M. M.; Badawy, M. A.; Abdel-Hady,
S. A. L. J. Heterocycl. Chem. 1981, 18, 953. (b) Sanz, R.;
Castroviejo, M. P.; Guilarte, V.; Pérez, A.; Fañanás, F. J.
J. Org. Chem. 2007, 72, 5113. (c) Maresh, J. J.; Giddings,
L.-A.; Friedrich, A.; Loris, E. A.; Panjikar, S.; Trout, B. L.;
Stöckigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem. Soc.
2008, 130, 710. (d) See also refs. 1e, 1f, and 1g.
Acknowledgment
C.A. thanks the French Research Ministry for a fellowship award.
We also thank the French Research Ministry, the Université Paul
Cézanne, and the CNRS (UMR 6263 iSm2) for financial support.
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(21) One example is reported using mild conditions, see ref. 14b.
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MeOH gave only clean methyl a-keto ester in our case.
Synthesis 2009, No. 15, 2523–2530 © Thieme Stuttgart · New York