Cyclopenta[a]quinolizine: A novel pseudoazulene with a bridgehead nitrogen atom

Article abstract of DOI:10.1002/ejoc.201000753

Cyclopenta[a]quinolizine, a novel tricyclic pseudoazulene, was prepared by reaction of cyclopentadienyllithium with oxazolo[3,2-a]pyridimum or substituted pyridinium salts. Structural analysis (X-ray analysis, NMR and UV spectroscopy) and DFT calculations confirm its highly dipolar nature (due to derealization of the negative charge around the five-membered ring) combined with partial localization of bonds in both six-membered rings.

Full text of DOI:10.1002/ejoc.201000753

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000753
Cyclopenta[a]quinolizine: A Novel Pseudoazulene with a Bridgehead Nitrogen
Atom
Pavel V. Gormay,[a] Victor B. Rybakov,[a] and Eugene V. Babaev*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Lithium / Aromaticity / Ring transformations
Cyclopenta[a]quinolizine, a novel tricyclic pseudoazulene,
was prepared by reaction of cyclopentadienyllithium with
oxazolo[3,2-a]pyridinium or substituted pyridinium salts.
Structural analysis (X-ray analysis, NMR and UV spec-
troscopy) and DFT calculations confirm its highly dipolar na-
ture (due to delocalization of the negative charge around the
five-membered ring) combined with partial localization of
bonds in both six-membered rings.
optical properties.[4] Because scaffolds 1a,b are isostructural
to purines, their appearance among the structures of drug
candidates[5] is not surprising.
Introduction
Pseudoazulenes 1 represent an interesting class of dipolar
aromatic molecules that are π-isoelectronic to azulene,
where the lone pair of electrons of a heteroatom in the six-
membered ring is formally derived from one of double
bonds at the seven-membered ring of the parent azulene
scaffold (Scheme 1).
The synthesis of pseudoazulenes 1a,b frequently involves
attachment of a new azine ring to five-membered carbo-
cycles (e.g., condensations by using cyclopentanone or vari-
ous cycloadditions to fulvenes and cyclopentadiene[1]). One
elegant approach to build scaffolds 1a,b is the reaction of
the cyclopentadienyl anion (CPA) with open-chain reagents
or their cyclic equivalents – heterocyclic salts (Scheme 2).
In this strategy, the novel azine ring is built by stepwise
condensations (Scheme 2, i[6] and ii[7]) or one-pot ring trans-
formations of (usually sulfur-containing) azolium salts
(Scheme 2, iv,[8] v,[9] and vi[10]).
Scheme 1.
This structural analogy leads to similar properties: the
aromaticity of 1, their π-excessive character, and even the
reactivity of pseudoazulenes strongly resemble those of azu-
lenes; they all easily undergo C-protonation and electro-
philic substitution at the five-membered ring. (Indolizines
1c also following these rules, but they are usually considered
separately from families 1a,b.) Several old reviews[1] summa-
rize the synthesis and the chemistry of pseudoazulenes, al-
though the data on parent bicycles 1a,b are less representa-
tive than for their benzo and aza derivatives (like stable
anhydrobases of azafluorenes or azaindoles). Only few fully
aromatic structures of the type 1b exist in nature, for exam-
ple, iridoids of plants (X = O[2]) or tautomers of 2H-pyrind-
ine (X = NH, discovered in oils[3]), whereas partially satu-
rated pseudoazulenes occur more frequently among many
natural products. In modern material science, attention to
pseudoazulenes is quickly growing due to their interesting
Scheme 2.
In Scheme 2, reactions iv–vi, the CPA molecule serves as
a 1,2-binuleophilic counterpart to the 1,4-bielectrophilic
azolium salts, resembling Hafner azulene synthesis
(Scheme 2, iii) from CPA and 1,5-bielectrophilic azinium
salts (X = O, NR) or their open-chain equivalents.[11] Al-
though this method could be expanded to a broader set of
heterocyclic salts, we were unable to find more such exam-
ples in the literature.
[a] Chemistry Department, Moscow State University,
Leninskie gory, Moscow 119991, Russian Federation
E-mail: babaev@org.chem.msu.ru
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A Novel Pseudoazulene with a Bridgehead Nitrogen Atom
During the past decade we have extensively studied the troscopy. (Assignment of signals for 4a was performed by
reactivity of oxazolo[3,2-a]pyridinium salts 2 and their mo- COSY, HMBC, and HSQC experiments.) Finally, the crys-
nocyclic precursors: 2-halopyridinium salts 3.[12] It was tal structure of 4a was determined by X-ray diffraction.
shown that in reactions with many binucleophiles (for ex-
Table 1. Reaction of oxazolo[3,2-a]pyridinium 2 and 2-chloro-N-
ample, Scheme 3, vii and viii), salts 2 and 3 behave as syn-
thetic equivalents, acting as 1,4-bielectrophiles and forming
novel fused five- or six-membered rings.
phenacylpyridinium 3 salts with lithium cyclopentadienylide.
Entry
Substrate
R
Product
Yield [%]
1
2
3
4
2a
2b
2c
3a
4-ClC6H5
4-MeC6H5
Me
4a
4b
4c
4a
35
44
13
11
4-ClC6H5
Reactions ix and x (Scheme 4) represent novel examples
of combining 1,2-binucleophilic CPA and 1,4-bielectro-
philic salts 2 and 3 and look similar to the other reactions
outlined in Schemes 2 and 3. On the other hand, conversion
of 2 into 4 (oxazole into pyridine) has a parallel to the Kon-
dratЈeva reaction (where oxazoles react as azadienes with
alkenes[15]). Meanwhile, from the viewpoint of the pyridine
ring synthesis,[16] the observed polar disconnection of the
central pyridine nucleus of 4 in Scheme 4 belongs to a quite
rare combination of synthons (C–C–)+(C+NCC+). Al-
though some hydrogenated derivatives of 4 have been re-
ported,[17] fully unsaturated skeleton 4 was not known. Up
to now, the only reported example of tricyclic pseudoazu-
lene isomeric to 4 is cyclopenta[c]quinolizine 5,[18] which
has another type of junction between the carbocycle and
quinolizine moieties.
Neutral structure A of tricycle 4 can be represented by
two nonequivalent dipolar resonance forms B and C
(Scheme 5). The resonance A–B in 4 is similar to that in
pyrindine 1b (X = NR), whereas the resonance A–C is anal-
ogous to that in pyridofulvene 6. As is evident, partial local-
ization of the double bonds in the quinolizine fragment of
4 is expected for all three structures.
Scheme 3.
However, with some other nucleophiles (e.g. pyridines or
KSCN) the salts 2 and 3 either react in different ways[13] or
even undergo the concurrent process of pyridine ring open-
ing (as with secondary amines).[14] It was therefore interest-
ing to study the direction and selectivity of reaction of the
salts 2 and 3 with CPA. Due to potential 1,2-binucleophilic
nature of CPA one would expect (by analogy to Scheme 3)
the formation of two C–C bonds [like it is in reaction (vii)
with CH3NO2] leading to novel six-membered ring [similar
to ring expansion (viii) with N2H4], thus opening the way to
novel pseudoazulene scaffolds by the strategy of Scheme 2.
Results and Discussion
We found that oxazolo[1,2-a]pyridinium salts 2 react
with lithium cyclopentadienylide in THF at room tempera-
ture, leading to previously unknown cyclopenta[a]quinoli-
zines 4 (Scheme 4, ix).
Scheme 4.
Scheme 5.
Conversion of 2 into 4 proceeds in moderate yields (35–
44% for R = Ar and 13% for R = Me, see Table 1). The
Experimentally observed bond lengths from our X-ray
same result was observed when salts 2 were changed into study (Figure 1) may help to clarify the actual contribution
monocyclic 2-chloropyridiniums salt 3 (Scheme 4, x), al- of structures A, B, and C. No bond alternation is observed
though the yield was lower. Obtained crystalline com- in the fulvene fragment of 4 and, consequently, the negative
pounds 4 have deep red color and intense fluorescence; they charge is delocalized around the five-membered ring. How-
are stable in air, although they slowly decompose on TLC ever, the presence of significant double bond character of
plates. The constitution of compounds 4 followed from C6–C7 and a butadiene-like pattern for C1–C2–C3–C4 may
their elementary analysis data and mass spectra, and their indicate that the actual contribution of resonance structures
structures were confirmed by 1H and 13C NMR spec- B and C is equal. Therefore, flat tricycle 4 with a 14 π-
Eur. J. Org. Chem. 2010, 5364–5368
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5365

P. V. Gormay, V. B. Rybakov, E. V. Babaev
SHORT COMMUNICATION
electron system is undoubtedly an aromatic system with sig- correspond to the most electron rich carbon atoms C8 and
nificant delocalization of the nitrogen lone pair of electrons C10 in full agreement with structures D and E. (Interest-
toward the fulvene moiety and partial bond localization in ingly, this value is close to δ = 102 ppm in CPA.) The
the quinolizine part.
matching “underlined” atoms in 2H-pyrindine 1b have the
same shifts (δ = 103 and 105 ppm[19]), whereas in azulene it
is 118 ppm for electron-rich atoms C1 and C3.[20a] Hence,
pseudoazulenes 1b and 4 appear to be more π-excessive
than the parent azulene. Remarkably, “noncharged” atom
C9 in 4 resonates at much lower field (δ = 127 ppm), indi-
cating no contribution of structure F; the same trend was
observed for atom C2 of azulene (δ = 137 ppm). The most
downfield signals in 4 are observed for the C4 and C13
atoms (δ = 133 and 136 ppm). Again, according to ab initio
calculations just these atoms (two α-positions to the nitro-
gen in the terminal pyridine ring) have the highest positive
natural charges (see Scheme 6).
Figure 1. Left: ORTEP drawing for 4a (with atom numbering
scheme). Right: C–C bond lengths [Å] in 4a according to X-ray
data (aryl group is not shown).
The above statement can be confirmed by quantum
chemical analysis of structure 4a (ab initio and PM3),
where the calculated lengths of the bonds are in reasonable
agreement with the experimental values (Scheme 6).
Furthermore, in PM3 the overall π-electron population of
the cyclopentadienyl fragment is 5.35, thus confirming its
π-excessive nature. The negative charge is mainly located at
positions 8 and 10, but not at the C9 atom. This can be
rationalized by simple observation that in structures D and
E (Scheme 6) the positive charge can be effectively delocal-
ized around both pyridine rings, whereas in structure F such
delocalization involves only one (terminal) six-membered
cycle with a quinonoid central ring. This charge separation
leads to a high dipole moment (the calculated µ value is
5.25 D for 4a).
1
Scheme 7. Observed chemical shifts in the 13C (top) and H (bot-
tom) NMR spectra of 4a (δ, ppm). Minimal values are underlined;
maximal shifts are shown in square brackets.
1H NMR spectra of 4 display a similar trend. Thus, the
positions of most upfield signals H8 and H10 (δ = 6.82 and
7.31 ppm) and strongly downfield signal H4 (δ = 7.89 ppm)
are parallel to their 13C chemical shifts as well as to the
highest and lowest charges. [In the analogs of 4 the shifts
of the corresponding (“underlined”) protons in the five-
membered fragment are at δ = 6.6–6.9 ppm[19] for pyrind-
ines 1b and at δ = 7.35 ppm for azulene.[20b]] However, the
highest δ value in tricycle 4 is observed for the H1 proton
at δ = 8.16 ppm. This effect, being caused by the short dis-
tance H1–H10, is not surprising: in many angular tricycles,
where a pair of protons from two nonadjacent rings has
close proximity, such signals are frequently shifted down-
field (like in angular isomer 5[18] or phenanthrenes[20c]).
Inspection of proton coupling constants is another useful
tool to study the conjugation in aromatic systems. Accord-
Scheme 6. Calculated bond lengths [Å] in 4a with highest and low-
est natural charges and various possibilities of charge (de)localiza-
tion.
Because the charges in polar aromatic structures are fre- ing to Hess and Schaad[21] the value Jratio = Jab/Jbc (for a
quently linked to experimentally observed signals in their triad of protons along a flat aromatic ring) is a good mea-
NMR spectra, it seems didactical to compare the chemical sure of conjugation of adjacent single/double bonds: the
shifts of novel structures 4 with the data for other (pseudo)- higher the value of Jratio, the better the delocalization. The
azulenes. The most upfield chemical shifts in the 13C NMR Jratio value for the five-membered ring is 0.75 for structure
spectra of 4 (both at δ = 104 ppm, underlined in Scheme 7) 4c, which is close to that of 2H-pyrindine (0.80) and which
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Eur. J. Org. Chem. 2010, 5364–5368

A Novel Pseudoazulene with a Bridgehead Nitrogen Atom
exceeds the Jratio value of fulvene 6 (0.51). For the pyridine
fragment, Jratio = 0.74 for 4c (taken for triad H1–H2–H3),
which is slightly higher than that for pyridofulvene 6 and
indolizine 1c (0.71 for both). These data open another
(complementary to X-ray results) viewpoint to understand
the nature of bond conjugation in pseudoazulenes 4.
Absorbance of light in the visible region is typical for
blue azulene (λmax ≈ 700 nm), and pseudoazulenes 1b have
a yellow to orange color (λmax = 426 nm for X = O[22] and
λmax = 432 for X = NMe[19]). The electronic spectra of tricy-
cles 4 display a broad shoulder at 460–570 nm responsible
for their red color. The spectra of 4 (Figure 2), which are
different from those of 1b by an additional broad maxima
at 350–420 nm, strongly resemble the spectra of pyridoful-
vene 6 (with red-orange color and two broad maxima at λ
= 360–400 and 450–560).[23] Therefore, the color of 4, simi-
larly to 6, is probably linked to charge transfer from the
five- to six-membered terminal ring (cf. dipolar structure C
in Scheme 5).
Conclusions
We have expanded the strategy in Scheme 2 and suc-
ceeded to prepare novel and more complex pseudoazulene
scaffold 4 from salts 2 and 3. The key step in the conversion
of salts 2 to 4 is a previously unknown ring expansion of
the oxazolium ring under the action of CPA. This reaction
seems to have more general character: according to our pre-
liminary data,[19] other oxazolium salts, fused and mono-
cyclic, may be also involved in such a transformation. The
discovered route to tricycles 4 is quite economical, as parent
salts 2 and 3 can be prepared easily[12] from cheap materials
like α-bromoketones and α-substituted pyridines or pyr-
idones.
As we have proved (X-ray, various spectral methods and
calculations), the structure of tricycle 4, which can be alter-
natively named pyrido[1,2-f]2H-pyrindine, is not just a for-
mal junction of pyridine to 2H-pyrindine. Rather, the at-
tached pyridine ring resembles that in pyridofulvene 6 and
contains the most π-deficient centers of entire molecule 4.
From the structural viewpoint, tricycle 4 appeared to be a
sort of union of three parts, namely, a butadiene fragment
of the terminal six-membered ring, significant double bond
character of the central ring, and a strongly dipolar amino-
fulvene residue.
It is important that parent pyrindines 1b (X = NR) are
usually unstable compounds, whereas their pyridoannelated
derivatives 4 are quite stable. Therefore, the newly discov-
ered tricycle (isomeric and isostructural to naphthopyrroles
or benzoindoles) may serve as an attractively simple scaf-
fold for applications in medicinal chemistry and materials
science.
Figure 2. Electronic spectra of 4a–c in ethanol. Vertical lines corre-
spond to calculated values for 4a.
Experimental Section
Because the five-membered ring has a major contri-
bution to the HOMO of 4 and the terminal pyridine ring
has a major contribution to its LUMO (Figure 3), it seems
reasonable to assign the shoulder appearing at long wave-
length in the spectra of 4 to the transition from the HOMO
to the LUMO. However, the quantitative picture is not so
straightforward, and the calculated HOMO–LUMO gap, as
in the case of azulene,[23] does not correspond numerically
to the observed band that is responsible for the color of 4.
The best theoretical simulation of the experimentally ob-
served UV/Vis spectra of 4 was achieved (see vertical lines
in Figure 2) by DFT calculation involving at least six ex-
cited states.
General Methods: Commercial reagents were used as received, un-
less otherwise stated. For the synthesis of salts 2 and 3, see ref.[12]
1H and 13C NMR spectra were recorded with either a Bruker AC-
400 or Bruker DRX-500 spectrometer. Chemical shifts were mea-
sured by using the δ scale with SiMe4 as the internal standard.
LCMS analyses (ES) were performed with a Perkin–Elmer API 150
MCA mass spectrometer. Elemental analyses were obtained with a
Karlo Erba 1106 apparatus. UV/Vis spectra were recorded with a
Hitachi U-2900 spectrometer. Analytical thin-layer chromatog-
raphy (TLC) was carried out on “Silufol” silica gel plates (sup-
ported on aluminum) by using UV light (254 and 365 nm) for visu-
alization. Experimental intensities of diffraction reflections of sin-
gle crystal of compound 4a were measured with a CAD4 auto-
mated diffractometer at room temperature;[24] all subsequent calcu-
lations were carried out with the SHELX97 program package.
Quantum chemical calculations were carried out by using the Spar-
tan 08 package (Wavefunction Inc.); DFT method (B3LYP with
6-31+G* basis set) was used for geometry optimization, calculation
of Natural charges, HOMO/LUMO visualization and UV/Vis spec-
tra simulation, whereas π-charges were calculated by PM3 method.
General Procedure for the Preparation of Pyrido[1,2-f]2H-pyrindines
4 from Salts 2: Cyclopentadienyllithium (554 mg, 7.7 mmol) was
added to a suspension of correspondent oxazolo[3,2-a]pyridinium
salt 2 (6.0 mmol) in absolute THF (60 mL) under an inert atmo-
sphere, and the mixture was stirred for a 48 h at room temperature.
Figure 3. Frontier orbitals of 4a. Left: HOMO; right: LUMO.
Eur. J. Org. Chem. 2010, 5364–5368
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5367

P. V. Gormay, V. B. Rybakov, E. V. Babaev
SHORT COMMUNICATION
The resulting mixture was evaporated in vacuo and purified by col-
umn chromatography on silica (CH2Cl2).
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m.p. 141 °C, red solid. Rf = 0.48 (CHCl3/MeOH, 10:1). H NMR
(500 MHz, CDCl3): δ = 6.77 (m, 1 H, H3), 6.82 (d, J = 2.0 Hz, 1
H, H8), 7.31 (d, J = 3.5 Hz, 1 H, H10), 7.34 (s + m, 2 H, H2 +
H6), 7.46 (m, 1 H, H9), 7.52 (m, 2 H, ArH, AAЈ), 7.76 (m, 2 H,
ArH, BBЈ), 7.89 (d, J = 7.0 Hz, 1 H, H4), 8.16 (d, J = 9.0 Hz, 1
H, H1) ppm. 13C NMR (125 MHz, CDCl3): δ = 103.6 (C10), 103.8
(C8), 113.3 (C3), 115.9 (C6), 119.0 (C11), 122.1 (C1), 123.8 (C12),
127.2 (C9), 128.4 (C2), 128.7 (Ar), 128.8 (Ar + C7), 132.9 (C4),
133.93 (Ar), 135.9 (C13), 136.3 (Ar) ppm. MS (ES): m/z = 278 [M
+ H]+. UV (C2H5OH): λ (logε) = 213 (4.49), 271 (4.43), 329 (4.49)
nm. C18H12ClN (277.76): calcd. C 77.84, H 4.35, N 5.04; found C
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7-(4-Methylphenyl)cyclopenta[a]quinolizine (4b): From salt 2b: 56%,
m.p. 66 °C, red solid. Rf = 0.33 (CHCl3/MeOH, 10:1). 1H NMR
(400 MHz, CDCl3): δ = 2.53 (s, 3 H, CH3), 6.75 (m, 1 H), 6.88 (dd,
J = 1.3, 3.3 Hz, 1 H), 7.32 (m, 2 H), 7.39 (m, 2 H, ArH, AAЈ), 7.42
(s, 1 H), 7.45 (m, 1 H), 7.78 (m, 2 H, ArH, BBЈ), 7.90 (d, J =
7.0 Hz, 1 H), 8.16 (d, J = 9.1 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.5, 103.4, 104.1, 113.4, 116.1, 119.1, 122.2, 124.5,
127.1, 128.4, 128.7, 129.5, 131.3, 133.1, 135.1, 136.0, 138.1 ppm.
MS (ES): m/z = 258 [M + H]+. UV (C2H5OH): λ (logε) 217 (4.51),
276 (4.46), 321 (4.30) nm. C19H15N (257.34): calcd. C 88.68, H
5.88, N 5.44; found C 88.63, H 5.92, N 5.45.
7-Methylcyclopenta[a]quinolizine (4c): From salt 2c: 18%, m.p.
93 °C, red solid. Rf = 0.29 (CHCl3/MeOH, 10:1). 1H NMR
(400 MHz, [D6]acetone): δ = 2.50 (s, 3 H, CH3), 6.52 (dd, J = 1.5,
3.0 Hz, 1 H), 6.88 (m, 1 H), 7.06 (dd, J = 1.5, 4.0 Hz, 1 H), 7.09
(m, 1 H), 7.41 (ddd, J = 1.3, 6.7, 9.0 Hz, 1 H), 7.59 (s, 1 H), 8.13
(d, J = 8.3 Hz, 1 H), 8.34 (d, J = 6.1 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.8, 102.3, 103.0, 113.1, 116.4, 118.1,
122.2, 126.1, 126.4, 126.9, 128.1, 132.7, 136.1 ppm. MS (ES): m/z
= 182 [M + H]+. UV (C2H5OH): λ (logε) 217 (4.51), 276 (4.46),
321 (4.30) nm. C13H11N (181.24): calcd. C 86.15, H 6.12, N 7.73;
found C 86.48, H 6.16, N 7.35.
Reaction of Cyclopentadienyllithium with Pyridinium Salt 3a: Cyclo-
pentadienyllithium (1.1 g, 12.0 mmol) was added to a suspension
of 2-chloro-1-[2-(4-chlorophenyl)-2-oxoethyl]pyridinium bromide
(2.09 g, 6.0 mmol) in absolute THF (60 mL) under an inert atmo-
sphere, and the mixture was stirred for 48 h at room temperature.
The resulting mixture was evaporated in vacuo and purified by col-
umn chromatography on silica (CH2Cl2). 7-(4-Chlorophenyl)cyclo-
pentaquinolizine (4a) was obtained in 11% yield.
[19] Unpublished data from the author’s group (O. Morozov, Di-
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Acknowledgments
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Received: May 25, 2010
We thank Dr. A. S. Shashkov for 2D NMR experiments.
Published Online: August 26, 2010
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Eur. J. Org. Chem. 2010, 5364–5368