Self-catalyzed Mannich-type reaction of enolizable cyclic 1,3-dicarbonyls to acyclic nitrones: An entry to functionalized β-enamino diones

Article abstract of DOI:10.1021/jo400331b

A new method for the preparation of highly functionalized β-enamino diones has been developed. The protocol involves an initial self-catalyzed Mannich-type reaction of enolizable cyclic 1,3-dicarbonyls to nitrones, followed by a spontaneous intramolecular reorganization of the resulting nonisolated hydroxylamine to enamino derivatives. These compounds retain the features of unnatural α-amino acids. The ease of preparation makes them attractive intermediates for the synthesis of peptidomimetics, polyheterocycles, and other multifunctional compounds. All experimental results have been efficiently rationalized by in silico studies at the M06-2X level of theory, and a valid mechanistic pathway has been proposed.

Full text of DOI:10.1021/jo400331b

Article
pubs.acs.org/joc
Self-Catalyzed Mannich-Type Reaction of Enolizable Cyclic 1,3-
Dicarbonyls to Acyclic Nitrones: An Entry to Functionalized
β‑Enamino Diones
Massimiliano Cordaro,† Francesco Risitano,† Angela Scala,† Antonio Rescifina,‡ Ugo Chiacchio,‡
and Giovanni Grassi*,†
†Dipartimento di Scienze Chimiche, Universita
̀
di Messina, V. le F. Stagno d’Alcontres 31, Messina 98166, Italy
di Catania, Viale Andrea Doria, Catania 95125, Italy
‡Dipartimento di Scienze del Farmaco, Universita
̀
W
S
* Web-Enhanced Feature * Supporting Information
ABSTRACT: A new method for the preparation of highly functionalized β-
enamino diones has been developed. The protocol involves an initial self-
catalyzed Mannich-type reaction of enolizable cyclic 1,3-dicarbonyls to nitrones,
followed by a spontaneous intramolecular reorganization of the resulting
nonisolated hydroxylamine to enamino derivatives. These compounds retain the
features of unnatural α-amino acids. The ease of preparation makes them
attractive intermediates for the synthesis of peptidomimetics, polyheterocycles,
and other multifunctional compounds. All experimental results have been
efficiently rationalized by in silico studies at the M06-2X level of theory, and a
valid mechanistic pathway has been proposed.
Interestingly, the nucleophilic addition of the carbonyls to
INTRODUCTION
■
nitrones is the pathway effectively pursued, and we have
observed the formation, under mild conditions, of highly
substituted and functionalized β-enaminodione derivatives,
retaining the features of unnatural aminoacids.
The synthesis of unnatural amino acids has attracted special
attention in recent years.26 Because of their structural diversity
and functional versatility, they are widely used as chiral building
blocks in the design and synthesis of combinatorial libraries of
pharmacologically relevant molecules, peptidomimetics, and
enzyme inhibitors.27−29
Nitrones are powerful tools in organic synthesis. They easily
undergo 1,3-dipolar cycloaddition reactions with a large variety
of olefinic dipolarophiles. The resulting isoxazolidines are key
intermediates for the synthesis of more complex molecular
architectures, such as isoxazolidinyl nucleoside analogues.1−4 In
addition to their classical reactivity as 1,3-dipoles, nitrones are
able to reacting as electrophiles in nucleophilic addition
reactions.5−7 Representative examples are the organometallic8,9
and Mannich-type10 additions.
Over the past years, the reactions between enolizable
carbonyl derivatives and a variety of CN systems, such as
imines, iminium ions, hydrazones, and nitrones, have been used
for preparing enantiomerically pure amino acids, nucleoside
analogues, carbohydrates, and alkaloids.11
In particular, the reaction employing preformed imines has
received considerable attention as a powerful method for
constructing a variety of β-amino carbonyl derivatives.12−14
Less attention has been paid to other CN-functionalized
substrates, such as nitrones, oximes, and hydrazones, which can
also act as electrophiles in this process to generate products
containing nitrogen functionality in an intermediate oxidation
state, such as hydroxylamino and hydrazine derivatives.10
In the framework of our studies dealing with the design of
new polifunctionalized N,O-heterocycles,15−25 we have found a
new route for the construction of unnatural amino acids, in very
good yield, starting from a variety of nitrones and selected
enolizable cyclic 1,3-dicarbonyls.
RESULTS AND DISCUSSION
■
Chemistry. Initially, we performed preliminary experiments
using C-ethoxycarbonyl-N-methyl-nitrone. Our strategy is
outlined in Scheme 1. Enolizable cyclic 1,3-dicarbonyls 1a−h
reacted with nitrone 2 in 1,4-dioxane under reflux conditions,
affording the β-ethoxycarbonyl-β-enaminodiones 3a−h. After
work up, the final compounds, having the structure of
dehydroamino acids, were isolated in good to excellent yields
(Scheme 1).
All products 3a−h were characterized by spectroscopic
methods and were exclusively observed as the β-enamino dione
tautomer (Scheme 2, form A) under the studied conditions,
according to the literature.30,31
Received: February 13, 2013
Published: March 18, 2013
© 2013 American Chemical Society
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a
Scheme 1. Synthesis of Compounds 3a−h and Yields
Scheme 3. Synthesis of Compounds 9a−c and 10a−c and
Yields
DC) between a nitrone and some 1,3-dicarbonyl compounds.32
In Scheme 4, we report the reaction of C,N-diphenyl nitrone 12
a
Key: (i) 1,4-dioxane, reflux, 1 h; yields referred to pure isolated
compounds.
Scheme 4. Reaction of C,N-Diphenyl Nitrone 12 with
Scheme 2. Tautomers of Compounds 3a−h: Enaminone
Form A and Ketoenol Form B
Dicarbonyls 1132
Moreover, for asymmetric compounds 3b, 3f, and 3g, both
E/Z diastereomers were observed (E/Z ratio 2.5−2.8:1); the
assignment of stereochemistry was made on the basis of the
chemical shift observed for the NH proton of symmetric
compounds 3a,c,d,e, and for compounds 3b, further confirmed
by selective heteronuclear 1D NOE (s-1DHOESY) experi-
ments and DFT calculations. In particular, for compounds
3a,d,e the NH proton, hydrogen bonded with the carbonyl
moiety, resonates at 12.1−12.3 ppm, whereas in compound 3c,
in which the hydrogen bond is established with a carbamoyl
moiety, it resonates highfield, at 11.3 ppm. So, in the 1H NMR
spectra of E/Z mixtures of compounds 3b,f,g the observed
resonances at 12.9−13.4 ppm are reasonably due to (E)-isomer,
whereas the ones at 10.8−12.0 ppm belong to the (Z)-isomer.
Moreover, for compounds 3b the s-1DHOESY on proton at
12.9 ppm gives rise to an enhancement of the carbonyl
resonance at 185.0 ppm whereas the same experiment
conducted on the signal at 10.8 ppm shows an enhancement
with dicarbonyls 11a,b that resemble the cyclic ones, 1a,b, used
by us. In both cases, only the two anomeric hemiacetals 13 and
14 have been isolated, with an overall yield of 85−90%.
Compounds containing a 5-hydroxyisoxazolidinyl core have
been isolated as stable products both from 1,3-DC of nitrones
to enolic substrates33−38 and Mannich-type reaction (MR) of
N-alkylhydroxylamines to α,β-insaturated carbonyl com-
pounds;39−42 in two of these cases, it was demonstrated that
there exists a hemiketal equilibrium of 5-hydroxyisoxazolidines
that involves a ring-opening and subsequent recyclization of the
corresponding hydroxylamine acyclic isomers33,37 and in one of
these cases the hydroxylamine intermediate was isolated as
stable compound.33 Moreover, the dehydration of 5-hydrox-
yisoxazolidine core to the corresponding Δ4-isoxazoline one
was never observed if not intentionally induced by a
quantitative Lewis acid treatment at reflux temperature in
toluene.43
On the basis of aforementioned experimental results, the
formation of compounds 3 can occur, theoretically, by an initial
five-membered concerted [3 + 2] 1,3-DC or by an initial seven-
membered concerted Mannich-type reaction (MR) of the
enolic compounds 1 to the electron-poor nitrone 2, followed by
a dehydration of the enolic form III of the hydroxylamine
intermediate II (Scheme 5). The reaction via 1,3-DC leads to
the nonisolated 5-hydroxyisoxazolidine derivative I that
1
of the resonance at 164.6 ppm, according with the H NMR
observations.
Thus, we turned our attention to testing the reactivity of
nitrones 4−8 toward seleted enolizable cyclic 1,3-dicarbonyls
1a−c (Scheme 3). Under similar reaction conditions, the
expected β-enaminodione derivatives 9a−c and 10a−c were
isolated only with nitrones 4 and 5, bearing a carbonyl group
on the carbon atom. Conversely, the proposed reaction carried
out using nitrones 6−8, without a carbonyl group, did not
proceed and upon further 2, 4, 8, 16 h of reflux we isolated only
reduced quantities of the initial 1,3-dicarbonyl and an ever
more complex mixture of decomposition compounds.
Considerations on Reaction Mechanism. To date, only
one paper reports the formal 1,3-dipolar cycloaddition (1,3-
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enolizes to III (due to the formation of two intramolecular
cyclic six-membered hydrogen bonds), which dehydrates to the
corresponding imine B that tautomerizes to the more stable
compound 3.
Scheme 5. Proposed Mechanisms for the Obtainment of
Compounds 3a−h
Computational Studies. To solve which of the two
proposed pathways, 1,3-DC or MR, is effectively pursued, to
get more insight into the reaction mechanisms, and to
understand the failure of the reaction with C-aryl and C-alkyl
nitrones 6−8, we have conducted a DFT computational study
at the M06-2X level of theory44,45 and the Dunning’s
correlation-consistent polarized valence triple-ζ (cc-pVTZ)46
basis set in dioxane with the polarizable continuum model
(PCM) developed by Tomasi and co-workers,47 choosing the
asymmetric enol 1b and nitrones 2 and 7 as representative
model compounds.
For all carbonyls at hand, it is already documented that they
exist in equilibrium between enolic and dicarbonyl tautomers,
whose distribution depends by solvent and temperature;
however, we computationally verified that, in dioxane at 25
°C, the enolic form of compound 1b is more stable than the
ketonic one by 2.09 kcal/mol, so we utilize only it for
computation purposes.
Considering that nitrone 2 exists as a mixture of E/Z-isomers
(3.5:1) with the E-one being more reactive,48 and in the cisoid
conformation,49 and nitrone 7 exists only as Z-isomer,50 and
that both undergo 1,3-DC to enols with the exclusive formation
of 5-regioisomers,48 we have studied, at first approach and only
for comparative energy evaluation respect to MR pathway, the
transition states originating from a 5-E-endo and 5-Z-endo
approach to nitrones 2 and 7, respectively (Scheme 6).48 In
both cases, the endo approach was referred to the enolic
hydroxyl.
equilibrates with II, whereas in the MR the hydroxylamine
intermediate II is directly generated; finally, the intermediate II
The MR pathway was studied considering the approach of
both Re and Si faces of enol 1b to the Re face of nitrones 2 and
Scheme 6. Nomenclature Used for Defining Transition States and Stationary Points of 1,3-DC and MR Pathways
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7 in E- and Z-configuration, respectively. The nomenclature
used for defining stationary and transition-state points for the
1,3-DC and MR is given in Scheme 6, whereas Table 1 reports
all enthalpies and free energies for transition states,
intermediates, and products involved in the two proposed
pathways.
the reaction precludes the obtainment of the hydroxylamine
and the prolonged reaction times give rise only to a moderate
recovery of the starting dicarbonyl, whereas the nitrone is
degraded.
Presumably, nitrones 4 and 5 operate as nitrone 2; in these
cases, the more electron-withdrawing carbonyl group improves
both the hydrogen bond of the hydroxylamine intermediate and
the acidity of Ha, making the dehydration easier.
Table 1. M06-2X Relative Enthalpies (ΔH) (kcal/mol) and
Relative Free Energies (ΔG) (kcal/mol) for the Reactions of
Enol 1b with Nitrones 2 and 7
For the asymmetric products 3b, 3f, and 3g, dealing with a
tautomerization process, the E/Z configuration ratio respects
the thermodynamic stabilities.
a
b
b
entry
transition states and stationary points
ΔH
ΔG
Interestingly, the concerted MR at hand, engaging eight
electrons in a pericyclic process, should be forbidden according
to Woodward−Hoffmann (WH) rules. A more detailed study
inside the IRC path showed that the process takes a
roundabout route to avoid the direct approach of the two
molecules and the violation of the WH rules. In Table 2 are
resumed the opportunely selected bond lengths, Wiberg bond
indexes52 (WIs) (utilized to obtain a more deepen analysis of
the extent of bond formation or bond breaking along a reaction
pathway), and NPA charges for the key stages involved in the
MR of ketoenol 1b to nitrone 2, computed by using the NBO
population analysis as implemented in Gaussian 09. From the
comparison of the WIs between the reactants and the 2-pre-TS-
Si/Re intermediate it is evident the formation of the hydrogen
bond, already highlighted by the high negative enthalpy of
reaction (−10.09 kcal/mol, Table 1), accomplished by a change
in the charges of the two carbon atoms directly involved in the
MR; the Cenol becomes slightly more negative (−0.47 to −0.49
au), whereas the Cnitrone becomes almost neutral and the entire
nitrone fragment takes a slight positive charge (0.06 au). This
picture can be interpreted as an internal H-bonding additive
that acts like Lewis acid catalysts;53,54 i.e., the reaction is
triggered by acid self-catalysis.
1
2-TS-EN
2-TS-Re/Re
2-TS-Si/Re
2-P-Re/Re
2-P-Si/Re
2-P-EX
18.73
3.01
31.97
17.14
17.86
−2.68
−1.94
−0.04
−1.81
−11.57
−51.24
−54.74
−54.12
−0.95
0.22
2
3
4.05
4
−16.59
−16.66
−14.55
−16.59
−25.33
−52.85
−56.37
−55.71
−9.88
−10.09
18.99
5
6
7
2-P-EN
8
2-P-enol
9
3b-enol
10
11
12
13
14
15
16
17
18
19
20
(E)-3b
(Z)-3b
2-pre-TS-Re/Re
2-pre-TS-Si/Re
7-TS-ZN
7-TS-Re/Re
7-TS-Si/Re
7-P-Re/Re
7-P-Si/Re
7-P-ZN
34.07
17.52
20.36
3.84
3.41
7.05
−8.92
−10.10
−10.20
−10.97
3.49
5.26
7-P-ZX
4.34
a
b
For nomenclature, see Scheme 6. Relative to reagents, 1b + 2 or 1b
+ 7; for TS read as activation enthalpy and activation free energy.
Successively, at the TS (2-TS-Si/Re) the enolic hydrogen
results almost completely transferred to the nitronic oxygen
and the WI of 0.59 is very close to that of 0.73 calculated for
both reactant 1b and product 2-P-Si/Re, whereas the incoming
bond between Cenol−Cnitrone atoms has a WI of only 0.31 with
respect to the 0.94 value observed in the product. Moreover,
considering that the enolic hydrogen now belongs to the
nitrone moiety, the NPA charge on nitrone fragment is 0.71 au
and the same charge with opposite sign is on the quasi enolate
1b, which is the reaction pass to charge control. Then the MR
is characterized by a concerted but very asynchronous self-
catalyzed process that permits bypassing the violation of WH
rules.
Finally, from the results of the second-order perturbation
theory (SOPT) analysis of the Fock matrix in NBO basis,
according to the definition of delocalization energy given by
Weinhold,55,56 it emerges that the TS is stabilized by a series of
delocalizations of which the main are the n→π* (136.08 kcal/
mol) of the Cenol p-orbital (the quasi-anion sp2 hybridized
carbon atom, i.e., the nucleophilic center) with the antibonding
orbital of the CnitroneNnitrone double bond and the n→σ *
(42.05 kcal/mol), due to the Oenol long pair with the
antibonding orbital of the Onitrone−Henol single bond (Figure
2); a series of minor secondary orbitals interactions between
the lactone and ester moieties further contributing to the
stabilization. This is in accord with an almost complete transfer,
at the TS, of the enolic proton to the nitrone oxygen atom, and
now, the quasi-enolate anion acts as nucleophile on the quasi-
protonate nitrone (see the animated IRC.gif).
From inspection of Table 1, it is evident that the 1,3-DC of
dicarbonyl 1b with both nitrones 2 and 7 possess a higher
activation energy with respect to the MR (up to 14−16 kcal/
mol, entries 1 and 14 vs 2 and 15, respectively), so only this last
pathway effectively operates. In the case of MR of 1b with 2,
both Si and Re channels are populated (entries 2 and 3) leading
to intermediate products 2-P-Re/Re and 2-P-Si/Re (entries 4
and 5) that rapidly tautomerize to give, in both cases, the more
stable 2-P-enol (entry 8). In the most stable conformation of 2-
P-enol the relatively acid proton Ha and the hydroxylaminic
hydroxyl are reciprocally diaxial and antiperiplanar so that the
dehydration, by an E2 elimination, is deeply favored (Figure 1)
and the afforded 3b-enol rearranges in the E/Z mixture of the
final most stable compound 3b, with the E-isomer that
predominates according to its higher stability (entries 10 vs
11). Moreover, the intrinsic reaction path (IRC) from 2-TS-Si/
Re and 2-TS-Re/Re to reactants gives a molecular complex, pre-
2-TS-Si/Re and pre-2-TS-Re/Re, respectively, in which the
enolic hydrogen atom of 1b establishe a hydrogen bond with
the oxygen atom of nitrones 2 and 7. Finally, the two
intermediate compounds 2-P-Si/Re and 2-P-Re/Re are in
equilibrium with their closed isoxazolidine isomers 2-P-EN
and 2-P-EX, formally corresponding to the products of the
direct 1,3-DC channel, but the dehydration step shifts the
equilibrium to compound 3b.
In the case of the MR of 1b with 7 the two intermediates 7-
P-Re/Re and 7-P-Si/Re are both higher in energy with respect
to the reactants (entries 17 and 18) so the endoergonicity of
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Figure 1. Transition states, intermediates, and product for the MR reaction of 1b with 2 according to Si/Re channel. Carried out with CYLview.51
Table 2. Bond Lengths (Å), Bond Orders (Wiberg Indexes), and NPA Charges (au) for the Key Stages of the MR of Enol 1b to
Nitrone 2
Bond lengths/Wiberg indexes
NPA charges
Cnitrone
a
transition states and stationary points
O−H enol
O−H nitrone
Cenol−Cnitrone
Cenol
nitrone fragment
1b
0.96/0.73
−0.47
2
−0.15
−0.09
0.06
2-pre-TS-Si/Re
2-TS-Si/Re
2-P-Si/Re
0.99/0.63
1.54/0.13
1.67/0.08
1.02/0.59
0.96/0.73
3.43/0.00
2.22/0.31
1.56/0.94
−0.49
−0.53
−0.46
0.06
b
0.71
−0.11
a
b
For nomenclature, see Scheme 6. With enolic hydrogen.
terms of an initial self-catalyzed MR of the enolic form of
dicarbonyls to nitrones leading to an hydroxylamine
intermediate; the latter, upon dehydration, furnishes the desired
product.
The procedure offers several advantages, including mild
conditions, high product yield, and simple workup, and
provides straightforward access to important synthetic inter-
mediates.
The observed results and the reaction mechanism have been
rationalized on the basis of an in silico study at the quantum
mechanical DFT level of calculation in dioxane that has
evidenced the importance of the C-substituent in the nitrone. A
fine-tuning of this substituent could expand the possibilities of
this reaction and future developments of the discussed
approach are expected to contribute to the synthesis of more
complex molecular architectures and novel biologically
interesting compounds.
Figure 2. Principal orbital interactions for 2-TS-Si/Re as derived by
the SOPT analysis.
CONCLUSION
EXPERIMENTAL SECTION
General Remarks. Melting points were determined on a melting
point apparatus and are uncorrected. IR spectra were recorded in
Nujol. 1H and 13C NMR spectra were obtained on a 500 MHz
■
■
In conclusion, an efficient approach for the synthesis of highly
substituted and functionalized β-enamino diones has been
achieved. Their formation was computationally rationalized in
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spectrometer at 300 K. The chemical shifts (δ) and coupling constants
(J) are expressed in ppm and hertz, respectively. Microanalyses are
reported. Mass spectrometry analyses were carried out on a mass
spectrometer. All solvents and reagents were obtained from
commercial sources and purified before use if necessary. TLC
separations were performed on silica gel GF254 plates; silica gel 60
(0.063−0.100 mm) was used for column chromatography. Nitrones
were prepared according to literature procedures.57,58
Typical Experimental Procedure for the Preparation of
Compounds 3a−h, 9a−c, and 10a−c. 1,3-Dicarbonyl 1a−h (500
mg; 1 equiv) and nitrone 2, 4, 5 (1 equiv) were dissolved in 1,4-
dioxane. The reaction mixture was stirred and heated at reflux for 1 h.
The solvent was removed by vacuum evaporation, and the residue was
purified by flash column chromatography on silica gel (eluent CH2Cl2/
EtOAc 95:5) or recrystallization from CH2Cl2/Et2O to afford 3a−h,
9a−c, and 10a−c. Compounds 3b, 3f, 3g, 9b, and 10b were isolated
by column chromatography as an inseparable mixture of E/Z isomers;
the E/Z ratio was determined on the crude reaction mixture in
perdeuterated 1,4-dioxane, and the reported percent yields are referred
to these measurements.
Ethyl 2-(2,6-dioxocyclohexylidene)-2-(methylamino)acetate
(3a): yellowish solid; yield 900 mg; 88%; mp 108−110 °C; IR (Nujol,
ν, cm−1) 1742, 1653, 1582; 1H NMR (500 MHz, CDCl3) δ = 12.3 (bs,
1H), 4.47 (q, J = 7.1 Hz, 2H), 3.07 (d, J = 5.3 Hz, 3H), 2.52 (t, J = 6.0
Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.97 (quin, J = 6.0 Hz, 2H), 1.42 (t,
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 200.7, 195.0,
162.7, 162.4, 106.0, 62.6, 37.9, 37.2, 31.2, 19.4, 13.8; MS (ESI) m/z
226 [M + H]+. Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N, 6.22.
Found: C, 58.76; H, 6.73; N, 6.19.
Ethyl (E,Z)-2-(2,4-dioxo-1,2-dihydroquinolin-3(4H)-ylidene)-
2-(methylamino)acetate (3f): inseparable 2.8:1 mixture of E/Z
isomers; mp 209−210 °C; yellowish solid; yield 720 mg; 85%; IR
(Nujol, ν, cm−1) 3248, 1748, 1662, 1578; (E)-isomer (62.6%) 1H
NMR (500 MHz, CDCl3) δ = 13.4 (bs, 1H), 10.3 (s, 1H), 8.09−7.00
(m, 4H), 4.65−4.58 (m, 2H), 3.21 (d, J = 5.3 Hz, 3H), 1.44 (t, J = 7.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 183.1, 164.5, 164.1, 140.1,
133.7 133.6, 125.9, 122.5, 120.4, 115.8, 98.9, 62.9, 31.8, 14.1; (Z)-
1
isomer (22.4%) H NMR (500 MHz, CDCl3) δ = 12.0 (bs, 1H), 9.4
(s, 1H), 8.09−7.00 (m, 4H), 4.56−4.45 (m, 2H), 3.23 (d, J = 5.3 Hz,
3H), 1.46 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ =
183.0, 164.6, 162.0, 140.1, 133.4, 133.3, 126.2, 122.1, 120.4, 115.8,
98.9, 62.7, 31.8, 14.1; MS (ESI) m/z 275 [M + H]+. Anal. Calcd for
C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.42; H, 5.15;
N, 10.18.
(E,Z)- Ethyl 2-(2,4-dioxochroman-3-ylidene)-2-(methyl-
amino)acetate (3g): inseparable 2.7:1 mixture of E/Z isomers; mp
133−135 °C; white solid; yield 750 mg; 86%; IR (Nujol, ν, cm−1):
1
1737, 1709, 1641, 1596; (E)-isomer (62.7%) H NMR (500 MHz,
CDCl3) δ = 13.1 (bs, 1H), 8.03−7.20 (m, 4H), 4.53 (q, J = 6.9 Hz,
2H), 3.22 (d, J = 5.3 Hz, 3H), 1.43 (t, J = 6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ = 182.1, 165.6, 161.9, 161.0, 154.3, 134.5, 126.4,
125.7, 123.9, 120.0, 117.0, 94.4, 63.3, 32.4, 13.8; (Z)-isomer (23.3%)
1H NMR (500 MHz, CDCl3) δ = 11.1 (bs, 1H), 8.03−7.20 (m, 4H),
4.59 (q, J = 6.9 Hz, 2H), 3.23 (d, J = 5.3 Hz, 3H), 1.45 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ = 177.1, 164.3, 161.9, 161.0,
154.3, 134.5, 126.2, 125.6, 124.3, 120.4, 116.9, 94.8, 63.2, 32.0, 13.8;
MS (ESI) m/z 276 [M + H]+. Anal. Calcd for C14H13NO5: C, 61.09;
H, 4.76; N, 5.09. Found: C, 61.22; H, 4.78; N, 5.07.
(E,Z)-Ethyl 2-(6-methyl-2,4-dioxo-2H-pyran-3(4H)-ylidene)-
2-(methylamino)acetate (3b): inseparable 2.5:1 mixture of E/Z
isomers; mp 182−183 °C; white solid; yield 950 mg; 99%; IR (Nujol,
Ethyl 2-(1,3-dioxo-1H-inden-2(3H)-ylidene)-2-(methyl-
amino)acetate (3h): light orange solid; yield 450 mg; 55%; mp
1
201−203 °C; IR (Nujol, ν, cm−1) 1742, 1651, 1585; H NMR (500
1
ν, cm−1) 1746, 1713, 1652, 1592; (E)-isomer (70.7%) H NMR (500
MHz, CDCl3) δ = 12.3 (bs, 1H), 7.74−7.71 (m, 2H), 7.63−7.60 (m,
2H), 4.57 (q, J = 7.1 Hz, 2H), 3.12 (d, J = 5.5 Hz, 3H), 1.47 (t, J = 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 195.1, 189.5, 164.4, 162.0,
147.8, 145.0, 123.6, 123.5, 118.4, 118.0, 105.2, 62.7, 31.8, 13.8; MS
(ESI) m/z 260 [M + H]+. Anal. Calcd for C14H13NO4: C, 64.86; H,
5.05; N, 5.40. Found: C, 64.92; H, 5.06; N, 5.39.
MHz, CDCl3) δ = 12.9 (bs, 1H), 5.69 (s, 1H), 4.51 (q, J = 7.2 Hz,
2H), 3.14 (d, J = 5.4 Hz, 3H), 2.12 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ = 185.0, 165.2, 164.6, 161.0, 107.3,
93.9, 63.3, 32.2, 20.1, 13.79; (Z)-isomer (28.3%) 1H NMR (500 MHz,
CDCl3) δ = 10.8 (bs, 1H; NH), 5.68 (s, 1H, CH), 4.51 (q, J = 7.2 Hz,
2H, CH2), 3.17 (d, J = 5.4 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 1.42 (t, J
= 7.1 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ = 185.0, 165.2,
164.6, 161.0, 108.2, 93.9, 63.2, 31.9, 19.9, 13.84; MS (ESI) m/z 240
[M + H]+. Anal. Calcd for C11H13NO5: C, 55.23; H, 5.48; N, 5.86.
Found: C, 55.12; H, 5.46; N, 5.88.
2-(1-(Methylamino)-2-oxo-2-phenylethylidene)cyclo-
hexane-1,3-dione (9a): yellowish solid; yield 1.05 g; 90%; mp 190−
1
191 °C; IR (Nujol, ν, cm−1) 1679, 1642, 1599, 1571; H NMR (500
MHz, CDCl3) δ = 12.4 (bs, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.59 (t, J =
7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 2.93 (d, J = 5.8 Hz, 3H), 2.57 (t,
J = 6.6 Hz, 2H), 2.40−2.30 (m, 2H), 1.99−1.95 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ = 200.1, 195.6, 189.3, 169.6, 134.7, 133.8, 129.1,
127.6, 108.2, 37.9, 37.0, 31.3, 19.7; MS (ESI) m/z 258 [M + H]+. Anal.
Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.10; H,
5.88; N, 5.45.
(E,Z)-6-Methyl-3-(1-(methylamino)-2-oxo-2-phenylethyli-
dene)-2H-pyran-2,4(3H)-dione (9b): inseparable 2.6:1 mixture of
E/Z isomers; mp 168−170 °C; white solid; yield 1.05 g; 85%; IR
(Nujol, ν, cm−1) 1692, 1651, 1581; (E)-isomer (61.4%) 1H NMR (500
MHz, CDCl3) δ = 13.1 (bs, 1H), 7.90−7.49 (m, 5H), 5.75 (q, J = 1.1
Hz, 1H), 2.98 (d, J = 5.4 Hz, 3H), 2.09 (d, J = 1.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ = 188.5, 184.9, 171.3, 164.7, 134.7, 129.3, 128.3,
127.7, 107.5, 95.6, 32.0, 20.1; (Z)-isomer (23.6%) 1H NMR (500
MHz, CDCl3) δ = 10.9 (bs, 1H), 7.90−7.49 (m, 5H), 5.58 (q, J = 1.1
Hz, 1H), 3.00 (d, J = 5.4 Hz, 3H), 2.12 (d, J = 1.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ = 188.7, 186.5, 170.9, 162.9, 134.3, 129.3, 128.3,
127.7, 108.1, 96.4, 31.9, 19.9; MS (ESI) m/z 272 [M + H]+. Anal.
Calcd for C15H13NO4: C, 66.41; H, 4.83; N, 5.16. Found: C, 66.50; H,
4.84; N, 5.14.
Ethyl 2-(1,3-dimethyl-2,4,6-trioxotetrahydropyrimidin-
5(6H)-ylidene)-2-(methylamino)acetate (3c): purple solid; yield
700 mg; 80%; mp 113−115 °C; IR (Nujol, ν, cm−1) 1738, 1713, 1645,
1592; 1H NMR (500 MHz, CDCl3) δ = 11.3 (bs, 1H), 4.60−4.44 (m,
2H), 3.32 (s, 3H), 3.29 (s, 3H), 3.13 (d, J = 5.3 Hz, 3H), 1.43 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 165.5, 163.3, 161.9,
161.6, 151.5, 88.6, 63.0, 31.7, 27.8, 27.4, 13.9; MS (ESI) m/z 270 [M +
H]+. Anal. Calcd for C11H15N3O5: C, 49.07; H, 5.62; N, 15.61. Found:
C, 49.18; H, 5.63; N, 15.57.
Ethyl 2-(3,5-dioxo-2H-thiopyran-4(3H,5H,6H)-ylidene)-2-
(methylamino)acetate (3d): yellow solid; yield: 600 mg; 65%; mp
1
135−136 °C; IR (Nujol, ν, cm−1) 1747, 1670, 1576; H NMR (500
MHz, CDCl3) δ = 12.1 (bs, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.36 (s,
2H), 3.31 (s, 2H), 3.09 (d, J = 4.5 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ = 195.1, 189.5, 164.4, 162.0, 105.2,
62.7, 36.3, 35.9, 31.6, 13.8; MS (ESI) m/z 244 [M + H]+. Anal. Calcd
for C10H13NO4S: C, 49.37; H, 5.39; N, 5.76, S 13.18. Found: C: 49.26;
H, 5.38; N, 5.77, S 13.22.
Ethyl 2-(4,4-dimethyl-2,6-dioxocyclohexylidene)-2-(methyl-
amino)acetate (3e): yellowish solid; yield: 700 mg; 76%; mp 95−96
°C; IR (Nujol, ν, cm−1) 1747, 1670, 1576; 1H NMR (500 MHz,
CDCl3) δ = 12.1 (bs, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.00 (d, J = 5.5
Hz, 3H), 2.32 (s, 2H), 2.26 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.99 (s,
6H); 13C NMR (125 MHz, CDCl3) δ = 200.0, 194.6, 162.5, 162.2,
104.8, 67.0, 62.5, 51.6, 50.9, 31.3, 30.9, 28.1, 13.8; MS (ESI) m/z 254
[M + H]+. Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53.
Found: C, 61.72; H, 7.58; N, 5.51.
1,3-Dimethyl-5-(1-(methylamino)-2-oxo-2-phenylethyl-
idene)pyrimidine-2,4,6(1H,3H,5H)trione (9c): brownish solid;
yield 1.23 g; 90%; mp 168−171 °C; IR (Nujol, ν, cm−1) 1711,
1
1685, 1646, 1582; H NMR (500 MHz, CDCl3) δ = 11.5 (bs, 1H),
7.93 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz,
2H), 3.34 (s, 3H), 3.15 (s, 3H), 2.96 (d, J = 5.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ = 189.2, 169.4, 165.4, 161.9, 151.6, 134.5, 134.3,
129.4, 128.0, 90.3, 31.6, 27.8, 27.5; MS (ESI) m/z 302 [M + H]+. Anal.
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Article
Calcd for C15H15N3O4: C, 59.79; H, 5.02; N, 13.95. Found: C, 59.86;
H, 5.00; N, 13.99.
(7) Merino, P. C. R. Chim. 2005, 8, 775.
(8) Milcent, T.; Hinks, N.; Bonnet-Delpon, D.; Crousse, B. Org.
2-(1-(Methylamino)-2-oxopropylidene)cyclohexane-1,3-
dione (10a): yellowish solid; yield 840 mg; 95%; mp 164−166 °C; IR
(Nujol, ν, cm−1) 1708, 1641, 1572; 1H NMR (500 MHz, CDCl3) δ =
12.2 (bs, 1H), 3.03 (d, J = 5.4 Hz, 3H), 2.52 (t, J = 6.4 Hz, 2H), 2.45
(t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 1.96 (quin, J = 6.4 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ = 200.8, 195.9, 195.8, 170.3, 106.5, 37.8,
37.0, 30.9, 29.4, 19.7; MS (ESI) m/z 196 [M + H]+. Anal. Calcd for
C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C, 61.60; H, 6.70; N,
7.16.
Biomol. Chem. 2010, 8, 3025.
(9) Fu, Y.; Liu, Y. H.; Chen, Y. J.; Hugel, H. M.; Wang, M. Z.; Huang,
D. F.; Hu, Y. L. Org. Biomol. Chem. 2012, 10, 7669.
(10) Merino, P.; Tejero, T. Synlett 2011, 1965.
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Asymmetry 2010, 21, 2934.
(12) Enders, D., Schaumann, E., Eds. Compounds with One
Saturated Carbon-heteroatom Bond Amines and Ammonium Salts.
Sci Synth. 2009, 40a.
(E,Z)-6-Methyl-3-(1-(methylamino)-2-oxopropylidene)-2H-
pyran-2,4(3H)-dione (10b): inseparable 2.6:1 mixture of E/Z
isomers; mp 123−125 °C; white solid; yield 850 mg; 90%; IR
(13) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044.
1
(14) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis:
Selectivity, Strategy, And Efficiency in Modern Organic Chemistry, 1st ed.;
Pergamon Press: Oxford, 1991.
(15) Rescifina, A.; Chiacchio, M. A.; Corsaro, A.; De Clercq, E.;
Iannazzo, D.; Mastino, A.; Piperno, A.; Romeo, G.; Romeo, R.; Valveri,
V. J. Med. Chem. 2006, 49, 709.
(16) Cordaro, M.; Grassi, G.; Risitano, F.; Scala, A. Synlett 2009, 103.
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Tetrahedron 2010, 66, 9493.
(Nujol, ν, cm−1) 1700, 1650, 1586; (E)-isomer (65%) H NMR (500
MHz, CDCl3) δ = 12.8 (bs, 1H), 5.69 (q, J = 0.9 Hz, 1H), 3.08 (d, J =
5.8 Hz, 3H), 2.48 (d, J = 0.9 Hz, 3H), 2.12 (s, 3H); 13C NMR (125
MHz, CDCl3) δ = 195.7, 180.3, 171.8, 164.6, 164.2, 107.5, 93.8, 31.6,
1
29.3, 19.9; (Z)-isomer (25%) H NMR (500 MHz, CDCl3) δ = 10.7
(bs, 1H), 5.66 (q, J = 0.9 Hz, 1H), 3.11 (d, J = 5.8 Hz, 3H), 2.46 (d, J
= 0.9 Hz, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 195.8,
185.1, 174.4, 166.4, 164.6, 107.9, 95.3, 31.4, 29.4, 19.6; MS (ESI) m/z
210 [M + H]+. Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70.
Found: C 57.34; H, 5.29; N, 6.72.
(18) Altieri, E.; Cordaro, M.; Grassi, G.; Risitano, F.; Scala, A. Synlett
1,3-Dimethyl-5-(1-(methylamino)-2-oxopropylidene)-
pyrimidine-2,4,6(1H,3H,5H)-trione (10c): brownish solid; yield
1.02 g; 95%; mp 146−147 °C; IR (Nujol, ν, cm−1): 1725, 1709, 1652,
2010, 2106.
(19) Piperno, A.; Giofre, S. V.; Iannazzo, D.; Romeo, R.; Romeo, G.;
Chiacchio, U.; Rescifina, A.; Piotrowska, D. G. J. Org. Chem. 2010, 75,
2798.
(20) Cordaro, M.; Grassi, G.; Risitano, F.; Scala, A. Tetrahedron 2010,
66, 2713.
1
1579; H NMR (500 MHz, CDCl3) δ = 11.2 (bs, 1H), 3.29 (s, 3H),
3.25 (s, 3H), 3.06 (d, J = 5.3 Hz, 3H), 2.49 (s, 3H); 13C NMR (125
MHz, CDCl3) δ = 196.2, 170.2, 165.4, 162.3, 151.5, 88.5, 31.2, 29.7,
27.7, 27.4; MS (ESI) m/z 240 [M + H]+. Anal. Calcd for C10H13N3O4:
C, 50.21; H, 5.48; N, 17.56. Found: C, 50.32; H, 5.52; N, 17.60.
(21) Cordaro, M.; Grassi, G.; Rescifina, A.; Chiacchio, U.; Risitano,
F.; Scala, A. Tetrahedron 2011, 67, 608.
(22) Rescifina, A.; Chiacchio, U.; Corsaro, A.; Piperno, A.; Romeo, R.
Eur. J. Med. Chem. 2011, 46, 129.
ASSOCIATED CONTENT
■
(23) Scala, A.; Cordaro, M.; Mazzaglia, A.; Risitano, F.; Venuti, A.;
Sciortino, M. T.; Grassi, G. Med. Chem. Comm. 2011, 2, 172.
(24) Rescifina, A.; Varrica, M. G.; Carnovale, C.; Romeo, G.;
Chiacchio, U. Eur. J. Med. Chem. 2012, 51, 163.
(25) Scala, A.; Cordaro, M.; Risitano, F.; Colao, I.; Venuti, A.;
Sciortino, M. T.; Primerano, P.; Grassi, G. Mol. Divers. 2012, 16, 325.
(26) Najera, C. Synlett 2002, 1388.
(27) Giannis, A. Angew. Chem., Int. Ed. 1993, 32, 1244.
(28) Goody, R. S.; Alexandrov, K.; Engelhard, M. ChemBioChem
2002, 3, 399.
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. Additional
details on computations, including Cartesian coordinates and
energies for computed structures. The animated IRC
calculation for the MR of 1b to 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
W
* Web-Enhanced Feature
An animated molecule is available in the HTML version of the
paper.
(29) Wang, L.; Schultz, P. G. Chem. Commun. 2002, 1.
(30) Dobosz, R.; Kolehmainen, E.; Valkonen, A.; Osmiaowski, B.;
Gawinecki, R. Tetrahedron 2007, 63, 9172.
(31) Dobosz, R.; Osmialowski, B.; Gawinecki, R. Struct. Chem. 2010,
21, 1037.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ggrassi@unime.it.
■
Notes
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K. Synlett 2012, 23, 107.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledges helpful discussions with Professor Pierluigi
Caramella (University of Pavia) and CINECA (Italy) for CPU
time support and availability of the Gaussian09 package
implemented on the IBM/SP6 cluster.
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