Superbase promoted synthesis of dienamides as useful intermediates for the synthesis of α-ketoamides, γ-lactams and cyclic imino ethers

Article abstract of DOI:10.1039/c0ob00867b

Alkoxydienamides 2 have been synthesized exploiting the reactivity of α,β-unsaturated acetals 1 with isocyanates in the presence of Schlosser's superbase LIC-KOR. In a mild acidic medium, 2 can then be promptly converted both into α-ketoamides 3 and into

Full text of DOI:10.1039/c0ob00867b

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PAPER
Superbase promoted synthesis of dienamides as useful intermediates for the
synthesis of a-ketoamides, c-lactams and cyclic imino ethers†
Marco Blangetti,a Annamaria Deagostino,a Giuliana Gervasio,b Domenica Marabello,b Cristina Prandi*a and
Paolo Venturelloa
Received 12th October 2010, Accepted 20th January 2011
DOI: 10.1039/c0ob00867b
Alkoxydienamides 2 have been synthesized exploiting the reactivity of a,b-unsaturated acetals 1 with
isocyanates in the presence of Schlosser’s superbase LIC–KOR. In a mild acidic medium, 2 can then be
promptly converted both into a-ketoamides 3 and into substituted 2-pyrrolidinones 4 or imino ethers 5
by choosing the appropriate experimental conditions.
functionality both for enhanced reactivity in Michael type ad-
Introduction
ditions and for the occurrence in several natural products.24–26
Dienamides are widely occurring structural features in a number of
Nevertheless, general and efficient approaches to this class of
compound are still scarce.27 Furthermore, (E)-alkoxydienamides
pharmacologically relevant natural products, as well as taste active
substances.1–5 Moreover, these compounds can be undoubtedly
considered as key intermediates with high and versatile synthetic
can be exploited in the synthesis of functionalized 1H-pyrrol-
2(5H)-ones (4) or N-(3-ethoxy-furan-2(5H)-ylidene)-1-amines (5)
potential, and their use both as electron rich and electron poor
through an electrophilic cyclization that takes place selectively
dienes in Diels–Alder reactions or in asymmetric cycloaddition
is, as a matter of fact, well documented.6–9 Even though di-
enamides can be in principle used in electrophilic cyclization
to afford unusual and interesting heterocyclic frameworks, very
according to an O- or N- 5-exo-attack pathway, depending on the
substrate.
few references appear in the literature concerning this kind of
application.10 Recently Xi and co-workers published an attrac-
tive approach to cyclic imino ethers starting from conjugate
dienamides.11 Several methods are reported in the literature for
the stereoselective preparation of dienamides, among them Wittig-
type approaches,12–14 transformation of dienic sulfones15,16 pho-
tochemical electrocyclic reaction from cyclobutenes,17 or cross-
coupling reactions have all been used.18–22 Moreover, stereode-
fined multisubstituted dienamides can be concisely prepared in
high yields by reaction of 1-lithiobutadienyl derivatives with
N-alkyl or N-aryl isocyanates.11 Very recently we reported an
original synthesis of alkoxydienylamines obtained starting from
a,b-unsaturated acetals in superbasic medium and their use as
substrates for aminopalladation reactions to obtain pyrroles.23 In
this paper we describe an alternative way to prepare conjugate
(E)-alkoxydienamides 2 and their utilization in the synthesis
of b,g-unsaturated a-ketoamides 3, that represent an attractive
Results and discussion
Metalation of acetals 1 with LIC–KOR (equimolar mixture of
nBuLi and tBuOK) superbase28–33 afforded the corresponding 1-
metalated-1,3-dienes34 whose treatment in situ with isocyanates
produced stereodefined a-alkoxydienamides 2 in good yields after
mild acidic work-up (see Experimental Section). As reported
in Table 1, both N-alkyl (entry 1) and N-aryl (entries 2–
11) isocyanates can be used in this reaction to obtain 2. N-
Cyclohexyl isocyanate smoothly reacted with metalated diene
to afford the corresponding (E)-N-cyclohexyl-2-ethoxypenta-2,4-
dienamide in 79% yield after purification. Aromatic phenyl, tolyl,
m-methoxyphenyl, p-bromophenyl and a-naphthyl isocyanates all
gave good yields of the corresponding dienamides, while slightly
lower yields are obtained in the case of acetal 1b (R1 = Me,
entries 8–10). Acetal 1c (R1 = H, R2 = Me, entry 11) affords the
corresponding dienamide 2k in 65% yield. The E stereochemistry
of the double bond has been assessed by ROESY experiments,
thus confirming that the conjugate elimination reaction takes place
according to a stereoselective process, as previously reported.35
At this point, the choice of a suitable acidic catalyst may direct
further synthetic elaborations of 2, hence allowing the selective
hydrolysis of the vinyl ether moiety to a-ketoamides 3 from one
side or an electrophilic cyclization to heterocyclic frameworks 4
and 5 from the other. Accordingly, when dienamides 2 were treated
with a stoichiometric amount of PTSA monohydrate in CH2Cl2–
MeOH the unmasking process leads to a-ketoamides 3 with good
aDipartimento di Chimica Generale e Chimica Organica, Universita` di
Torino, via P. Giuria, 7 I-10125 Torino, Italy. E-mail: cristina.prandi@
unito.it
bDipartimento di Chimica IFM e Centro Interdipartimentale di Ricerca sullo
Sviluppo della Cristallografia Difrattometrica CrisDi, Universita` di Torino,
via P. Giuria 7, I-10125 Torino, Italy
† Electronic supplementary information (ESI) available. CCDC reference
numbers 776930 and 776929 (5f and 5j, respectively). For ESI and
crystallographic data in CIF or other electronic format, see DOI:
10.1039/c0ob00867b
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Table 1 Superbase promoted synthesis of stereodefined dienamides from
acetals
Table 3 Electrophilic cyclization of 2
Entry
R1
R
Product
Yield (%)a
Entry
R1
R2
R
Product 2
Yield (%)a
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Me
Me
Ph
p-Tol
MMP
p-BrPh
a-Naph
o-ClPh
Ph
4b
4c
4d
4e
5f
91
93
94
96
81
88
95
92
83
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Me
Cy
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
79
74
71
77
64
72
72
52
59
68
65
p-Tol
MMPb
p-BrPh
a-Naph
o-ClPh
Ph
p-Tol
a-Naph
Ph
5g
5h
5i
p-Tol
a-Naph
5j
9
10
11
a Yields refer to isolated purified products
2j
2k
a Yields refer to isolated purified products. b MMP meta-methoxyphenyl.
(Table 3). In this case the structure of the imino ether has been
confirmed by single crystal X-ray analysis (Fig. 1).
Table 2 Synthesis of a-ketoamides 3
Entry
R1
R2
R
Product 3
Yield (%)a
1
2
3
4
5
6
H
H
H
H
Me
Me
H
H
H
H
H
H
Cy
Ph
p-Tol
p-BrPh
Ph
3a
3b
3c
3e
3h
3i
93
88
84
79
81
86
Fig. 1 ORTEP plot (thermal ellipsoids at 30% of probability) of 5j
showing the atom labeling.
p-Tol
The asymmetric unit contains two molecules, A and B, with
different conformations: in molecule A the naphthalene moiety
forms an angle of 87◦ with the penta-atomic ring, in the other
molecule B the angle value is 40◦. This fact demonstrates the
possibility of a free rotation around the N(1)–C(9) bond in the
isolated molecule and therefore its single bond feature. The C(1)–
a Yields refer to isolated purified products.
to excellent yields as reported in Table 2. Several attempts to
convert alkoxydienamides 2 into a-ketoamides 3 in the presence
R
of Amberlyst-15ꢀ, CSA in CH2Cl2 or triflic acid in CH2Cl2 were
N(1) bond values agree with a double bond value (1.263(2) A
˚
unsuccessful.
av.), and the angle around N(1) is that of an sp2 hybridization.
Besides, 2 can be used as substrates for electrophilic cyclization.
Among the experimental conditions reported in the literature that
may promote an intramolecular electrophilic process,36 we found
that the use of neat TFA at 0 ◦C allows to selectively obtain pure
products. Substrates 2b–2e underwent an electrophilic cyclization,
namely the N-5-exo attack leading to 1H-pyrrol-2(5H)-ones 4 (as
depicted in Table 3). Direct cyclization of a-ketoamides 3 into
compounds 4 or 5 have been attempted in the presence of protic
or Lewis acids or under organocatalytic conditions (proline in
CH2Cl2) with discouraging results.
The structures of lactams 4c and 4d have been confirmed by
ROESY experiments (diagnostic is the cross peak between methyl
at 1.40 ppm for 4c, 1.33 ppm for 4d and o-aromatic protons, see
the ESI†). Conversely, when substrates 2h–2j were subjected to
the same reaction conditions the electrophilic cyclization takes
place according to an O-exo attack affording imino ethers 5h–j
The C(1)–O(1) and C(6)–O(2) bond values agree with a Csp2–
˚
O distance (1.349(2) A av.), while the C(5)–C(6) bond length
˚
corresponds to a double bond (1.318(2) A av.). The crystal
packing shows only weak C–H ◊ ◊ ◊ N and C–H ◊ ◊ ◊ O intermolecular
hydrogen bonds.
Our results seem then to confirm the hypothesis that the 4
position is crucial in determining the N- or the O-cyclization
pathway (Scheme 1).10,11,37 According to this assumption, the
attack of the less bulky O atom (leading to imino ethers 5) is
favoured when the 4-position is substituted, on the other hand the
encumbered N atom of the amide group is more likely to attack
an unsubstituted 4 position (leading to lactams 4, Scheme 1).
Intrigued by these results, we decided to investigate if the
increase in bulkiness of the N-substituent would lead to an O-
cyclization pathway even in the case of an unsubstituted C4
position of the starting dienamide. To this purpose we synthesized
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Conclusions
In this work a convenient synthesis of stereodefined alkoxydi-
enamides has been developed, and both their hydrolysis to a-
ketoamides, and electrophilic cyclization to heterocyclic frame-
works have been described. The cyclization occurs according to a
5-exo-attack by either the O or the N depending on the substrate
structure, thus allowing the selective synthesis of pyrrol-2(5H)-
ones or cyclic imino ethers. The worthwhile and synthetically
useful aspects involved in this approach are that the formation
of either 2-pyrrolidinones or imino ethers can be easily tuned by
a suitable choice of the substrate. We have demonstrated that the
cyclization pathway is determined both by steric and electronic
parameters, and that not only the C4 position on the dienyl moiety,
but also the bulkiness of the substituent on the nitrogen atom is
responsible for the product outcome. This approach should prove
quite useful for a rapid access to dienamides and their further
synthetic elaboration to heterocyclic derivatives.
Scheme 1 Electrophilic cyclization of dienamides 2.
compounds 2f and 2g, unsubstituted on C4 and with a naphthyl
group (2f) or o-chlorophenyl (2g) on nitrogen (entries 6 and 7,
Table 1) and subjected them to electrophilic cyclization under the
usual conditions. In this case we obtained imino ethers 5f and 5g
(entries 5 and 6, Table 3) as the only product in excellent yield.
Single crystal X-ray structure of 5f is herein reported (Fig. 2).38
Experimental
General procedure for the syntheses of pentadienamides 2
A solution of freshly sublimated tBuOK (5 mmol, 560 mg, 2.5
equiv.) in THF (7 mL) was cooled to -78 ◦C. 1,1-Diethoxybut-2-
ene (2 mmol, 288 mg) in THF (2 mL) and nBuLi (1.6 M in hexanes,
5 mmol, 3.13 mL) were added in quick succession and the mixture
was stirred for 2 h during which time the temperature was raised
to -40 ◦C. Afterwards the reaction was cooled back to -78 ◦C and
the appropriate isocyanate (2.2 mmol) in THF (2 mL) was added.
◦
After stirring the mixture at -78 C for 2 h, a saturated NH4Cl
solution (10 mL) was added. The resulting mixture was extracted
with Et2O (3 ¥ 10 mL), washed with water (10 mL) and brine (2 ¥
10 mL), and dried with anhydrous K2CO3. After filtration and
evaporation of the solvent, the crude products were purified by
flash column chromatography.
Fig. 2 ORTEP plot (thermal ellipsoids at 30% of probability) of 5f
showing the atom labeling. The two disordered rings are shown: the ring
with open bonds corresponds to the occupancy factor 0.38 (ring B).
(E)-N-Cyclohexyl-2-ethoxypenta-2,4-dienamide 2a. Purified
by flash chromatography (Et2O : petroleum ether 3 : 7, 1% Et3N,
Rf 0.45) to give 2a (356 mg, 79%). 1H NMR (200 MHz, CDCl3). d
ppm 7.69 (dt, J = 17.2, 10.7 Hz, 1H), 6.53 (br, 1H), 5.68 (d, J = 10.7
Hz, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 3.83
(q, J = 6.9 Hz, 2H) superimposed to 3.92–3.78 (m, 1H), 2.00–1.82
(m, 2H), 1.79–1.54 (m, 4H), 1.36 (t, J = 6.9 Hz, 3H) superimposed
to 1.27–1.07 (m, 4H). 13C NMR (50.2 MHz, CDCl3). d 162.0 (s),
145.9 (s), 132.4 (d), 117.6 (t), 111.9 (d), 63.5 (t), 47.4 (d), 32.7 (t),
25.3 (t), 24.6 (t), 14.3 (q). MS m/z 223 (M+, 26), 193 (100), 111
(98), 67 (50), 55 (39). Anal. Calcd for C13H21NO2: C, 69.92; H,
9.48. Found C, 69.84; H, 9.29.
Owing to the disorder of the molecule and to the great thermal
motion the data have been collected at 153 K. The disorder of the
penta-atomic ring (Fig. 2) may be described as a reflection with
respect to the plane defined by the N(1), C(1) and C(6) atoms. The
two penta-atomic rings have an asymmetric carbon atom (C(2A)
and C(2B)) and the two faced rings are enantiomerically related.
The naphthalene moiety and the planes of the penta-atomic ring
form angles of 143◦ and 110◦ respectively (A ring, B ring). Also
in 5f C(1)–N(1) and C(5)–C(6) bonds are formal double bonds
˚
˚
(1.247(4) A and 1.35(1) A av.), while C(1)–O(1) and C(6)–O(2)
2
˚
distances are in keeping with a Csp –O distance (1.413(6) A av. and
˚
1.321(4) A, respectively). As in 5j the crystal structure shows only
General procedure for the syntheses of a-ketoamide derivatives 3
weak C–H ◊ ◊ ◊ N and C–H ◊ ◊ ◊ O intermolecular hydrogen bonds.
As represented in Scheme 1, the cyclization pathways selectively
follow a 5-exo-trig mechanism, as a matter of fact products coming
from an endo attack have never been detected. The choice between
N or O as nucleophilic attacking atom is determined by both
electronic and steric reasons. In the absence of bulky substituents
on C4 of the diene or on the nitrogen the cyclization is prompted
by the more nucleophilic N atom, otherwise, in the presence of
encumbered substituents it is the less sterically demanding oxygen
that acts as attacking nucleophile.
A solution of the appropriate pentadienamide (0.5 mmol) in
CH2Cl2–MeOH (3 mL) was stirred in the presence of PTSA·H2O
(0.5 mmol, 95 mg, 1 equiv.) and the reaction progress monitored
by TLC. After 0.5 h the reaction was complete, the reaction was
quenched with water. After extraction with CH2Cl2 (3 ¥ 10 mL),
the collected organic layers were washed with water (10 mL)
and brine (2 ¥ 10 mL), and dried with anhydrous K2CO3. After
filtration and evaporation of the solvent, the crude products were
purified by column flash chromatography.
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(E)-N-Cyclohexyl-2-oxopent-3-enamide 3a. Purified by flash
chromatography (Et2O : petroleum ether 3 : 7, 1% Et3N, Rf 0.40)
to give 3a (91 mg, 93%). H NMR (200 MHz, CDCl3). d ppm
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314136.
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1
7.41–7.24 (m, 1H), 7.14 (dd, J = 15.7, 1.4 Hz, 1H), 7.03 (br, 1H),
4.19–4.01 (m, 1H), 3.88–3.69 (m, 1H), 2.02 (dd, J = 6.8, 1.4 Hz,
3H), 1.99–1.87 (m, 4H), 1.82–1.60 (m, 6H), 1.45–1.31 (m, 4H),
1.33–1.12 (m, 6H). 13C NMR (50.2 MHz, CDCl3). d 185.3 (s),
160.0 (s), 149.1 (d), 124.4 (d), 48.1 (d), 32.4 (t), 24.5 (t), 18.8 (q).
MS m/z 195 (M+, 8), 180 (12), 126 (15), 83 (72), 69 (100), 55 (58).
Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78. Found C, 67.32; H,
8.75.
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cyclic imino ethers 5
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A 20-mL sealed tube fitted with a rubber septum cap and
connected to a nitrogen filled balloon was charged with the
appropriate pentadienamide (0.5 mmol) and cooled to 0 ◦C. Then
TFA (5 ml) was added dropwise, and the resulting mixture was
stirred for 1 h. Afterwards the reaction was cooled back to 0 ◦C and
a solution of NaOH (10%) was added, and the resulting mixture
was extracted with several portions of Et2O. The combined organic
layers were washed twice with NaHCO3, water and brine, and
dried over anhydrous K2CO3. After filtration and evaporation of
the solvent, the crude products were purified by column flash
chromatography.
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(E)-3-Ethoxy-5-methyl-1-phenyl-1H-pyrrol-2(5H)-one
4b.
Purified by flash chromatography (Et2O : petroleum ether 7 : 3,
1% Et3N, Rf 0.50) to give 4b (98 mg, 91%). 1H NMR (200 MHz,
CDCl3). d ppm 7.36–7.20 (m, 4H), 7.12–7.02 (m, 1H), 5.70 (d,
J = 1.9 Hz, 1H), 5.13 (qd, J = 6.2, 1.9 Hz, 1H), 4.04 (q, J = 7.0
Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H), 1.40 (d, J = 6.2 Hz, 3H). 13C
NMR (50.2 MHz, CDCl3). d 156.1 (s), 148.6 (s), 146.1 (s), 128.2
(d), 123.6 (d), 123.2 (d), 111.5 (d), 78.7 (d), 66.6 (t), 20.9 (q), 14.0
(q). MS m/z 217 (M+, 11), 202 (38), 174 (19), 120 (24), 83 (100),
77 (34). Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96. Found C,
71.46; H, 6.73.
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(E)-N -(3-Ethoxy-5-methylfuran-2(5H)-ylidene)naphthalen-1-
amine 5f. Purified by flash chromatography (EtOAc : petroleum
ether 1 : 1, 1% Et3N, Rf 0.50) to give 5f (108 mg, 81%). 1H NMR
(200 MHz, CDCl3). d ppm 8.13–7.94 (m, 1H), 7.75–7.69 (m, 1H),
7.53–7.45 (m, 1H), 7.42–7.28 (m, 3H), 7.18–7.10 (m, 1H), 5.63 (d,
J = 1.9 Hz, 1H), 4.98 (qd, J = 6.4, 1.9 Hz, 1H), 3.96 (q, J = 7.0,
1H), 1.43 (t, J = 7.0 Hz, 1H), 1.24 (d, J = 6.4 Hz, 1H). 13C NMR
(50.2 MHz, CDCl3). d 155.6 (s), 147.6 (s), 142.4 (s), 133.1 (s),
126.8 (s), 126.7 (d), 124.7 (2C, d), 123.9 (d), 123.3 (d), 122.5 (d),
116.0 (d), 111.2 (d), 77.7 (d), 65.8 (t), 20.1 (q), 13.3 (q). MS m/z
267 (M+, 100), 252 (34), 168 (76), 143 (27), 69 (91). Anal. Calcd
for C17H17NO2: C, 76.38; H, 6.41. Found C, 76.11; H, 6.38. m.p.
102–103 ◦C.
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38 5g has been recovered as an oil. NOESY spectra are reported in the
ESI†.
2538 | Org. Biomol. Chem., 2011, 9, 2535–2538
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