Synthesis of new pentacyclic chromophores through a highly regio- and diastereoselective cascade process

Article abstract of DOI:10.1039/c0ob00390e

A new family of pentacyclic compounds incorporating a central 1,2-dihydropyridine core is obtained through a pseudo three-component reaction. Four new bonds and two stereocenters with trans relationship are produced during the cascade process under palladium catalysis.

Full text of DOI:10.1039/c0ob00390e

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Synthesis of new pentacyclic chromophores through a highly regio- and
diastereoselective cascade process†‡
Zein el abidine Chamas,a Olivier Dietz,a,b Emmanuel Aubert,b Yves Forta and Victor Mamane*a
Received 6th July 2010, Accepted 2nd September 2010
DOI: 10.1039/c0ob00390e
A new family of pentacyclic compounds incorporating a
central 1,2-dihydropyridine core is obtained through a pseudo
three-component reaction. Four new bonds and two stere-
ocenters with trans relationship are produced during the
cascade process under palladium catalysis.
was found to be diastereoselective since two contiguous stereo-
centers with trans configuration between R1 and H were formed.
Structurally, 3 can be seen as two distinct substructures incorporat-
ing the central dihydropyridine core, the indeno-dihydropyridine
system in the right and the pyrido[2,1- a]isoindolone in the left
(Scheme 1).
Aza-polycyclic compounds containing the pyridine core or its
polyhydro derivatives constitute a great family of natural products
with diverse biological activities1 and have found numerous
applications in material science.2 Thus, Haouamine A 1 with
an unusual indeno-tetrahydropyridine ring system was shown to
possess a selective anticancer activity in human colon carcinoma
cells (IC50 = 0.1 mg mL-1)3 and indolizino[3,4,5-ab]isoindoles 2 were
described as highly fluorescent heterocyclic systems4 (Fig. 1).
Scheme 1 “One-pot” synthesis of pentacycles 3.
During our work on the synthesis of benzo-(iso)quinoline
derivatives,6a we were interested in the reaction of pyridine 4a
with 2-formylphenylboronic acid 5a (R3 = H) (1.2 equiv). Under
classical Suzuki conditions9 (5% Pd(PPh3)4, 2 equiv Na2CO3 1M in
H2O, toluene, methanol, 100 ◦C, 12 h), the desired cross-coupling
product was accompanied with a small amount of a fluorescent
by-product.10 Increasing amounts of 5a (2.5 equiv), base (5 equiv)
and catalyst loading (10 mol%) led to the formation in 50%
yield of 3a, structure of which was assigned on the basis of its
NMR spectra and X-ray crystal structure11 (Scheme 2 and Fig. 2).
Interestingly, only the trans product was formed and C4-addition
was not observed.
Fig. 1 Aza-polycycles with interesting properties.
Our interest in the synthesis of polyheterocyclic compounds
with potential use in material science5 or in biological chemistry6
led us to develop new cascade reactions. Indeed the development of
new chemical processes designed to produce elaborate heterocyclic
structures in rapid, environmentally friendly way has become
an important area of research in organic chemistry.7 We have
recently described a palladium-catalyzed reaction that allowed the
one-pot formation of pyrido[2,1-a]isoindolones starting from 2-
halopyridines and 2-formylphenylboronic acid.8 We report herein
a new cascade process that led after four bonds formation to a
new p-conjugated pentacyclic structure 3. In addition to the excep-
tional increase in molecular complexity, this reaction between 2,5-
dihalopyridines 4 and two-fold of 2-formylphenylboronic acids 5
Scheme 2 Regioselective and diastereoselective cascade reaction.
aLaboratoire SRSMC-SOR, UMR CNRS-UHP 7565, Nancy Universite´,
BP 70239, Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France.
E-mail: victor.mamane@srsmc.uhp-nancy.fr; Fax: (+33) 383684785;
Tel: (+33) 383684320
bLaboratoire CRM2, UMR CNRS-UHP 7036, Nancy Universite´, BP 70239,
Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France
† Electronic supplementary information (ESI) available: General and
experimental procedures, spectral data, copy of 1H and 13C NMR spectra,
CIF files for 3a, 3c and 3f, theoretical calculations data. CCDC reference
numbers 734891–734893. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00390e
Fig. 2 ORTEP plot of 3a (hydrogen atoms, except those in trans relation-
ship and involved in the hydrogen bond, are omitted for clarity); thermal
ellipsoids set at 50% probability. Intramolecular hydrogen bond (shown as
◦
˚
‡ Dedicated to Prof. Henri Kagan on the occasion of his 80th birthday.
a broken line) distances and angles: H ◊ ◊ ◊ O = 2.00 A, O ◊ ◊ ◊ H ◊ ◊ ◊ O = 149 .
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Table 1 Scope of the reactiona
Entry Boronic acid 5 Pyridine 4
Next, the substrate scope was studied by changing both the
pyridine and the boronic acid (Scheme 1 and Table 1). It appeared
that the C6 regioselectivity was not dependant on the pyridine
substitution since pyridine 4b with no methyl group in C4 reacted
only at C6 with formation of compound 3b in 57% yield (entry
1).12 Similarly, pyridine 4c with a methyl group in C6 reacted again
at the same position to give 3c bearing a quaternary center in a
good yield of 59% (entry 2).
Pentacycle 3 (Yield)
1
2
3
5a
5a
5a
4,6-Dimethylsubstituted pyridine 4d afforded the expected
pentacycle 3d in a lower yield of 36% (entry 3) whereas the 4-
phenylsubsituted pyridine 4e generated compound 3e with a good
yield of 60% (entry 4). The reaction of the p-MeO-substituted
boronic acid 5b with pyridine 4b resulted in the formation of 3f in
a low yield of 17% (entry 5). However, the yield of 3f was increased
to 55% by employing the more reactive 2-bromo-5-iodopyridine 4f
(entry 6). Analogously, compound 3g was produced in a moderate
yield of 31% (entry 7) by using boronic acid 5c. Boronic acid 5d
did not react well yielding the dimethylamino-substituted product
3h in a poor yield of 12% (entry 8). The low yields of 3g and 3h
can be explained by the fact that donating groups such as MeO
(in para to CHO) and NMe2 rendered the second cyclization more
difficult (vide supra). Finally fluorinated pentacycle 3i was formed
starting from boronic acid 5e13 in a good yield of 51% (entry 9).
For all compounds, the same trans stereochemistry was obtained
4
5
5a
1
as evidenced by X-ray diffraction analysis (3c and 3f) or by H
NMR by comparison with compound 3a.
In order to have some insight about the mechanism, different
experiments have been conducted. It appeared that the C5 then
C2 order of reactivity toward palladium was crucial since 2,5-
dibromopyridine 4g having the reverse order of reactivity14 failed
to give the desired product 3b. Therefore, C5 functionalised
compounds 6a, b were prepared by coupling pyridines 4b and
4f with one equivalent of 5a. These compounds were then used in
the cascade reaction with boronic acid 5a to give 3b in 32% and
56% yields respectively (Scheme 3). In both cases, compound 3b
was obtained with the same regio- and stereoselectivity.
4b
6
5b
3fc (55%)
7b
4f
8b
4f
4f
Scheme 3 Prior C5-functionalisation of dihalopyridines.
Considering that aldehyde 6a is the first intermediate in the
cascade process, we assume that a second coupling in 2-position
would deliver bis-aldehyde A (Scheme 4). Until now, our efforts to
isolate this intermediate failed. Intermediate A seems to be very
reactive, suffering an intramolecular attack of the carboxaldehyde
by the pyridine nitrogen to give intermediate B. The involvement
of a similar intermediate B¢ was already proposed in the synthesis
of pyrido[2,1-a]isoindolones 7.8,15 Indeed, the 1,4-dihydropyridine
system was obtained after isomerisation to give C¢ following by
proton trapping from the reaction mixture. In the present case,
after isomerisation of B to C, the second carboxadehyde serves
as the electrophilic trapping group resulting in the formation of
9b
a Reaction conditions: 4 (0.5 mmol), 5 (0.5 M in MeOH, 2.5 equiv,
1.25 mmol), Pd(PPh3)4 (10 mol%, 0.05 mmol), Na2CO3 (1M in H2O,
5 equiv, 2.5 mmol), toluene (5 mL), 100 ◦C, 12 h. b 3 equiv of 5 and
6 equiv of Na2CO3 were used. c Crystal structure given in the ESI.†
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Fig. 3 Structures of compounds considered in the DFT calculations.
intramolecular proton transfer when the cyclization is attempted
at C4 (i.e. no reaction pathway found between C-C4cis(trans) and
C4cis(trans)), together with the fact that C4cis and C4trans are 5.56
and 4.82 kcal mol-1 respectively less stable than the experimentally
observed structure 3b also account the obtained regioselectivity
(Fig. 4).
Scheme 4 Proposed mechanism for the cascade process.
Scheme 5 Involvement of an imine in the cascade process.
pentacycle 3b.16 Interestingly, changing the electrophile to an imine
resulted in the regio- and diastereoselective formation of the new
pentacyclic amine 817 in 36% overall yield starting from aldehyde
6b (Scheme 5).
The observed C6-regioselectivity for compounds 3 and 8 is
probably the result of an internal chelation between the two
oxygen atoms of intermediate C. Indeed, several components of
the reaction mixture can be drawn to assist the internal chelation
including hydrogen, sodium, boron and palladium. In order to
have some insight about the regioselectivity and diastereoselectiv-
ity of the reaction, we performed density functional theory (DFT)
calculations (at the B3LYP 6-311+G(d,p) level of theory) about the
last cyclization step taking the hydrogen as the simplest chelating
group leading directly, by hydrogen transfer, to compound 3b
which displays in the crystalline state an intramolecular hydrogen
bond between the keto and hydroxyl functions. All the possible
conformations of C have been considered (C-3b, C-C6cis, C-
C4trans and C-C4cis) leading respectively to 3b, the hypothetical
product cyclized at C6 with cis configuration (C6cis) and hypo-
thetical products cyclized at C4 with both configurations (C4trans
and C4cis) (Fig. 3). As shown by DFT calculations, the cyclization
at C6 proceeds in the gas phase through an intra-molecular proton
transfer from the hydroxyl group to the carboxaldehyde in C (C-3b
and C-C6cis), passing through transition states characterized by
a strong hydrogen bond between the alcohol and aldehyde oxygen
atoms. Both the larger stability of the final trans product 3b over
the cis form C6cis (DG373 K = 3.48 kcal mol-1) and the smaller
activation energy in the case of trans configuration compared to
the cis configuration (DD‡ G373 K = 8.20 kcal mol-1) tend to favor the
observed diastereoselectivity. Moreover, the impossibility of the
Fig. 4 Energetic profile for the last cyclization step displaying the
products of cyclization at C6 and C4, together with the corresponding
C- intermediates and the associated transitions states structures (TS). Free
energies (at 373 K) are given in kcal mol-1. Hydrogen atoms, except those
involved in trans relationship (in green) and in the intramolecular hydrogen
bond are omitted for clarity. All the calculations were performed at the
B3LYP 6-311+G(d,p) level of theory.
In summary, we have developed a new cascade reaction that
allowed the one-pot synthesis of diversely substituted pentacyclic
compounds. The cascade process was initiated by a palladium-
catalyzed cross-coupling reaction and was followed by two suc-
cessive nucleophilic cyclizations; the first cyclization performed
on the pyridine nitrogen and the second occurred regioselectively
on the adjacent carbon atom. The overall process led to the
creation of four chemical bonds with complete regioselective
and diastereoselective control interpreted by Density Functional
Theory calculations which evidenced the occurrence of an internal
chelation in the transition state. In regard to their original
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pentacyclic structure and to the strong fluorescence emission
observed for 3a, these new compounds would found important
applications in material science and biology.
7 (a) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63, 5341; (b) V. Mamane,
in Targets in Heterocyclic Systems. Chemistry and Properties (Ed. O. A.
Attanasi, D. Spinelli), Societa` Chimica Italiana, Rome, 2006, vol. 10,
pp. 197–231.
8 V. Mamane and Y. Fort, Tetrahedron Lett., 2006, 47, 2337.
9 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
10 Compound 3a fluoresces between 481 and 506 nm with a high quantum
yield (91% in CH2Cl2). Fluorescein (U = 95% in 0.1 M NaOH) was used
as a reference for the measurement.
Acknowledgements
This work was supported by the CNRS and Nancy Universite´.
The IJB and GENCI-CINES (Grant 2009-X2009085106) are
thanked for providing access to computing facilities. We thank
A. Doudouh, E. Wenger and S. Parant for technical assistance,
11 3a: C20H15NO2, Mr = 301.33, crystal dimensions: 0.31*0.28*0.10 mm,
˚
orthorhombic, space group P212121, a = 4.03310(7) A, b = 15.7754(2)
3
˚
˚
˚
A, c = 22.1253(3) A, V = 1407.69(4) A , T = 110(2) K, Z = 4, rc =
1.422 g cm-3, m = 0.09 mm-1, 23052 reflections collected, 3499 unique
reflections, Rint = 0.022, 2qmax = 69.28◦, 210 parameters, R1 = 0.050,
´
and M. Beley and J. Angya´n for helpful discussions.
-3
-3
˚
˚
wR2 = 0.125, Drmin = -0.308e.A , Drmax = 0.512e.A . CCDC734892 3a
contain the detailed crystallographic data. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.ik/data_request/cif.
Notes and references
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5 V. Mamane and Y. Fort, J. Org. Chem., 2005, 70, 8220.
6 (a) V. Mamane, F. Loue¨rat, J. Iehl, M. Abboud and Y. Fort, Tetrahedron,
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12 The 1H NMR spectrum of the crude mixture indicated the presence of
only one regioisomer. See spectrum in Supporting Information.
13 S. Lozano Yeste, M. E. Powell, S. D. Bull and T. D. James, J. Org.
Chem., 2009, 74, 427.
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16 For the electrophilic substitution of the pyrido[2,1-a]isoindole system,
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1603.
17 The stereochemistry of 8 was determined by analogy to compound 3a
(JHa - Hb around 5–6 Hz for 3a and 8).
4818 | Org. Biomol. Chem., 2010, 8, 4815–4818
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