Key words
regioselective synthesis - 1,3-dipolar cycloaddition - isoquinolinium ylide - cyclopentadienones - DFT calculations
Cyclopentadienone (1) represents an unusual system of crossed conjugated double bonds in a five-membered ring.[1] Cyclopentadienones are antiaromatic dienes having low HOMO–LUMO energy gaps.[2] Although 1 and nearly all of the simple cyclopentadienones that have been prepared are dimeric, tetraarylcyclopentadienones 2 and fused-ring cyclopentadienones, such as disubstituted 8H-cyclopent[a]acenaphthylen-8-ones (3 and 4), are monomeric (Figure [1]).[3] The factors that determine whether a monomer or a dimer is formed appear to be steric in nature. All of the monomeric cyclopentadienones are colored and many have been studied for the effect of substituents and fused rings on the ultraviolet and visible absorption.[4] The tetraaryl derivatives 2 are powerful dienes in a Diels–Alder reaction and have been used for the synthesis of highly arylated compounds.[5] With alkenes or alkynes the reaction can lead to the formation of bridged carbonyl compounds, which can lose carbon monoxide upon heating. The catalytic reactivity of iron cyclopentadienone complexes have been reported.[6] The synthesis, reactions, and physical properties of cyclopentadienones have been extensively reviewed.[3]
Figure 1 Cyclopentadienone and its monomeric derivatives
The cyclopentadienone system has been proved to be a privileged and peculiar dipolarophile. Thus, in the cycloaddition of tetrasubstituted cyclopentadienones with nitrile oxides, the 1,3-dipole attacks the ring C=C double bond,[7a] whereas with nitrile imines[7b] and nitrile ylides,[7c] the dipole attacks the carbonyl double bond (Scheme [1]). It was of interest, therefore, to study the cycloaddition of the ring-fused 7,9-bis(alkoxycabonyl)-8H-cyclopent[a]acenaphthylen-8-ones[8] with carbonyl-stabilized isoquinolinium ylides,[9] to examine the position of attack by this dipole and the regioselectivity of the cycloadducts. As shown in Scheme [1], the 1,3-dipole attacks the ethylene double bond of cyclopentadienone derivative to afford a heptacyclic adduct.
Scheme 1 Dipolar cycloaddition of fused cyclopentadienones with: a) diphenylnitrilimine, b) benzonitrile-4-nitrobenzylide, and carbonyl-stabilized isoquinolinium ylide.
Initially, the reaction between 7,9-bis(methoxycabonyl)-8H-cyclopent[a]acenaphthylen-8-one (4a) and 2-(2-oxo-2-phenylethyl)isoquinolin-2-ium bromide (7a), prepared in situ from isoquinoline (5) and phenacyl bromide (6a), was investigated in the presence of Et3N. The reaction proceeded smoothly in MeCN at room temperature (25 °C) and afforded dimethyl 4-benzoyl-5-oxo-4H,12cH-naphtho[1′′,8′′:4′,5′,6′]pentaleno[1′:3,4]pyrrolo[2,1-a]isoquinoline-4a,6(5H)-dicarboxylate (8a) in 80% yield (Table [1]). In order to optimize the reaction conditions for the formation of 8a, the effects of solvent and temperature were studied. As shown in Table [1], H2O, MeOH, DMF, MeCN, and CH2Cl2 were examined. Ultimately, MeCN was found to be the best solvent at 80 °C.
Table 1 Optimization of Reaction Conditions for the Formation of 8aa
|
|
Entry
|
Solvent
|
Temp (°C)
|
Yield (%)b
|
|
1
|
H2O
|
60
|
trace
|
|
2
|
MeOH
|
60
|
15
|
|
3
|
CH2Cl2
|
25
|
50
|
|
4
|
DMF
|
25
|
20
|
|
5
|
MeCN
|
25
|
80
|
|
6
|
MeCN
|
80
|
86
|
a Reaction conditions: 4a (1.0 mmol), 7a (1.0 mmol), Et3N (1.0 mmol), solvent (6 mL), 2 h.
b Yield of isolated product.
To determine the scope of this approach, a number of phenacyl bromides 6 were tested under the reaction conditions. As shown in Table [2], phenacyl bromides bearing electron-donating or electron-withdrawing substituents provided the functionalized pyrrolo[2,1-a]isoquinoline derivatives 8 in good yields (84–92%).[10]
Table 2 Synthesis of Fused Pyrrolo[2,1-a]isoquinolines 8
a
|
|
Entry
|
Z
|
Ar
|
Product 8
|
Yield (%)b
|
|
1
|
CO2Me
|
Ph
|
8a
|
86
|
|
2
|
CO2Et
|
Ph
|
8b
|
88
|
|
3
|
CO2Me
|
4-ClC6H4
|
8c
|
85
|
|
4
|
CO2Et
|
4-ClC6H4
|
8d
|
90
|
|
5
|
CO2Me
|
4-MeC6H4
|
8e
|
87
|
|
6
|
CO2Et
|
4-MeC6H4
|
8f
|
86
|
|
7
|
CO2Me
|
4-MeOC6H4
|
8g
|
92
|
|
8
|
CO2Et
|
4-MeOC6H4
|
8h
|
85
|
|
9
|
CO2Me
|
4-O2NC6H4
|
8i
|
90
|
|
10
|
CO2Et
|
4-O2NC6H4
|
8j
|
84
|
a Reaction conditions: 4 (1 mmol), 7 (1 mmol), Et3N (1 mmol), solvent (6 mL).
b Isolated yield.
The structures of products 8a–j were elucidated by 1H NMR, 13C NMR, IR, and mass spectral data. The 1H NMR spectrum of 8a exhibited four sharp singlets for the methoxy (δ = 3.51 and 3.86 ppm) and methine (δ = 4.82 and 6.13 ppm) protons. The aromatic protons show characteristic multiplets (δ = 6.37–8.27 ppm) in the spectrum. The 13C NMR spectrum of 8a showed 34 signals in agreement with the proposed structure. The mass spectrum of 8a displayed the molecular ion peak at m/z = 567. The NMR spectra of compounds 8b–j were similar to those of 8a, except for the substituents, respectively.
Clear evidence for the structure of 8e was obtained from single-crystal X-ray analysis.[11] The ORTEP diagram of 8e is shown in Figure [2]. There are eight molecules of 8e in the unit cell, which are arranged in a centrosymmetric manner. The structure obtained from the crystallographic data, and those of 8a–d and 8f–j were assumed to be analogous on account of their similar NMR spectra.
Figure 2 X-ray crystal structure of compound 8e
The 13C NMR spectra of compounds 8a–j showed five signals above δ = 160 ppm. Two of these signals which appear between δ = 160–170 ppm are assigned to the ester C=O groups, and two of the remaining peaks appearing above δ = 190 ppm are attributed to the ketone carbonyl groups. In order to assign the last signal appearing above δ = 190 ppm, we turned to DFT calculations at the b3lyp/6-311+g(d,p) level of theory.[12] Thus, the NMR calculations performed to estimate the chemical shifts of the five 13C signals in compound 8e that appear above δ = 160 ppm are shown in Figure [3].
Figure 3 Comparison of the experimental (and theoretical) values of 13C NMR chemical shifts (in ppm) for the five low-field signals (between δ = 160–200 ppm) observed in the 13C NMR spectrum of compound 8e
The frontier molecular orbital diagram for carbonyl-stabilized isoquinolinium ylide 10 and cyclopentadienone 4 is shown in Figure [4]. The HOMO–LUMO energy levels are given in eV. According to this diagram, the dipolar cycloaddition reaction between 4 and 10 is controlled by the orbital energy of isoquinolinium ylides.[13]
Figure 4 Frontier orbital diagram for isoquinolinium ylides 10 (left) and cyclopentadienone 4 (right). The HOMO–LUMO energy levels are given in eV.
DFT has been accepted by chemists as a reliable approach for computation of molecular structures and energies of chemical systems.[14] To estimate the molecular reactivities of 4 and 10, the values of global chemical reactivity descriptors such as electronic chemical potentials (μ),[15] chemical hardness (η),[16] and electrophilicity (ω)[17] for reactants 4 and 10 are calculated by this method. As shown in Table [3], the chemical hardness for the reactants is almost the same, but the electronic chemical potential value of 10 is higher than that of 4. Therefore, charge transfer is expected to take place from isoquinolinium ylide 10 to 4. Also, the comparison of the nucleophilicity and the electrophilicity of the reactants showed that the dipolar species 10 would act as the nucleophile in this cycloaddition reaction.
Table 3 Frontier MO Energies and Reactivity Descriptors for Reactants 4 and 10 Calculated at the b3lyp/6-311+G(d,p) Level of Theorya
|
Comp
|
E
HOMO
|
E
LUMO
|
μ
|
η
|
N
|
ω
|
|
10
|
–5.20
|
–2.42
|
–3.80
|
1.395
|
4.24
|
5.19
|
|
4
|
–6.32
|
–3.54
|
–4.93
|
1.390
|
3.17
|
8.74
|
a All energetics are given in eV.
A DFT diagram for mechanistic rationalization of the regioselective nonconcerted formation of product 8 is given in Figure [5]. It is presumed that initially the reaction of isoquinoline (5) and phenacyl bromide (6a) generates the isoquinolinium salt (7), which is converted into the isoquinolinium ylide (10) by Et3N. A nonconcerted regioselective addition reaction occurs between the electron deficient C2–C3 π bond of cyclopentadienone and the isoquinolinium ylide to afford the zwitterionic intermediate 11. This intermediate is converted into the heptacyclic pyrrolo[2,1-a]isoquinoline 8.
Figure 5 DFT diagram for mechanistic rationalization of the regioselective nonconcerted formation of product 8. Relative energies (ΔE) for cycloaddition reaction are calculated according to reactants whose E = –1932.777495 Hartree at b3lyp/6-311+G(d,p) level of theory.
In summary, we have developed a regio- and diastereoselective synthesis of functionalized 5a,5b-dihydro-5H,13H-naphtho[1′′,8′′:4′,5′,6′]pentaleno[1′:3,4]pyrrolo[2,1-a]-isoquinolin-5-ones via 1,3-dipolar cycloaddition of 7,9-bis(alkoxycabonyl)-8H-cyclopent[a]acenaphthylen-8-ones with carbonyl-stabilized isoquinolinium ylides, derived from isoquinoline and phenacyl bromides in the presence of Et3N in MeCN. Based on DFT calculations at b3lyp/6-311+g(d,p) level of theory, a nonconcerted mechanism is proposed to explain the selectivity of this reaction. The methodology reported here may serve as a convenient strategy to create a wide range of functionalized heptacyclic pyrrolo[2,1-a]isoquinoline derivatives.
