Study on the scope of tert-amino effect: New extensions of type 2 reactions to bridged biaryls

Article abstract of DOI:10.1002/poc.3007

Thermal isomerization of aminomethyl- or oxygen-bridged biphenyl systems possessing dicyanovinyl and sec-amino groups in ortho- and ortho0-positions was investigated. Both systems underwent cyclization via tert-amino effect. Thus, 2-(2-{[2-(sec-amino)benz

Full text of DOI:10.1002/poc.3007

Special Issue Article
Received: 15 May 2012,
Revised: 25 June 2012,
Accepted: 26 June 2012,
Published online in Wiley Online Library:
(wileyonlinelibrary.com) DOI: 10.1002/poc.3007
Study on the scope of tert-amino effect: new
extensions of type 2 reactions to bridged
biaryls†
Paola Bottinoa}, Petra Dunkela, Michele Schlicha{, Lorenzo Galavottia},
Ruth Demea, Géza Regdon Jrb, Attila Bényeic, Klára Pintye-Hódib,
Giuseppe Ronsisvalled and Péter Mátyusa*
Thermal isomerization of aminomethyl- or oxygen-bridged biphenyl systems possessing dicyanovinyl and sec-amino
groups in ortho- and ortho0-positions was investigated. Both systems underwent cyclization via tert-amino effect.
Thus, 2-(2-{[2-(sec-amino)benzyl]-N-methylamino}benzylidene)malononitriles gave tetrahydroquinolines, whereas a
2-[2-(sec-amino)phenoxy]benzylidenemalononitrile isomerized to dibenzoxazonine derivative. The ring closure reac-
tion was studied by differential scanning calorimetry measurements. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: tert-amino effect; isomerization; hydrogen migration; tetrahydroquinoline; oxazonine; dibenzoxazonine;
differential scanning calorimetry
degree of enantioselectivity could be achieved with enantiomers
INTRODUCTION
of chiral metal complexes or phosphoric acid.[16,17]
A mechanistically closely related “hydride transfer initiated
cyclization”/“C–H bond functionalization” reaction was employed
for the synthesis of dihydrobenzopyrans from the corresponding
ortho-vinylaryl alkyl ethers with Lewis acid (Sc(OTf)3 or SnCl4)
The term “t-(tert)-amino effect” was introduced by Meth-Cohn
and Suschitzky for isomerization reactions of ortho-substituted
tert-anilines with ring closure to fused aza-ring systems.[1] Several
subtypes of tert-amino effect have been distinguished, depending
on the way of cyclizations and type of the ring formed.[2,3] One
version of type 2 reactions, isomerization of ortho-vinyl-tert-anilines
or their heterocyclic analogs to obtain benzo- or heteroring-fused
tetrahydropyridines, has attracted much attention because of its
predictable substituent effects as well as regio- and stereoisomeric
aspects of the isomerization. In these reactions, a two-step mecha-
nism has been postulated: (i) a rate-limiting hydrogen migration
(with a sigmatropic [1,5] rearrangement or hydride transfer) to form
a dipolar intermediate and (ii) ring closure of the intermediate with
a C–C bond formation (Fig. 1).[3–7]
* Correspondence to: P. Mátyus, Department of Organic Chemistry, Semmelweis
University, Hőgyes Endre utca 7, 1092 Budapest, Hungary.
E-mail: matyus.peter@pharma.semmelweis-univ.hu
†
This article is published in the Journal of Physical Organic Chemistry as a
special issue on the 11th Conference on Physical Organic Chemistry
(CLAFQO-11) Special Issue, edited by Eusebio Juaristi (Centro de Investigacion
y de Estudios Avanzados del Instituto Politecnico Nacional, Quimica, Apartado
Postal 14-740, Mexico, Mexico, 07000).
The first step might often require, particularly for isomerizations
of p-deficient heterocyclic tert-amines, high temperatures and/or
longer reaction times. To overcome the limitation of harsh
conditions led us to apply microwave-assisted chemistry; in fact,
our efforts have not only led to improved yields but also opened
new ways to the syntheses of otherwise hardly accessible
polycyclic ring systems.[8,9]
Further recent examples of type 2 tert-amino effect, including
syntheses of pyrazolinoquinolizines and 1,4-oxazinopyrazolines,[10]
1,2-fused 5H-chromeno[4,3-b]pyridin-5-ones and 6H-benzo[h][1,6]
naphthyridin-5-ones,[11] naphthalenes,[12] a-carbolines,[13] and
spirocyclic 1,2,3,4-tetrahydroquinolines,[14] also demonstrate the
versatility of such reactions.
{
On a leave from Universitá degli Studi di Cagliari
}
On a leave from Universitá degli Studi di Modena
}
On a leave from Universitá degli Studi di Catania
a P. Bottino, P. Dunkel, M. Schlich, L. Galavotti, R. Deme, P. Mátyus
Department of Organic Chemistry, Semmelweis University, Hőgyes Endre utca
7, 1092 Budapest, Hungary
b G. Regdon, K. Pintye-Hódi
Department of Pharmaceutical Technology, University of Szeged, Eötvös utca
6, 6720 Szeged, Hungary
c A. Bényei
Institute of Chemistry, University of Debrecen, Egyetem tér 1, 4010 Debrecen,
Hungary
It has more recently been reported that a Lewis acid (Gd(OTf)3
operated optimal) might efficiently catalyze type 2 cyclization of
alkylidene malonates,[15] although the scope of catalysis seems
to be limited to ester group in the vinyl moiety. As an attractive
feature of this approach, it could be mentioned that some
d G. Ronsisvalle
Department of Drug Sciences, Medicinal Chemistry Section, University of
Catania, Viale A. Doria 6, 95125 Catania, Italy
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

P. BOTTINO ET AL.
Figure 1. tert-Amino effect type 2 cyclizations
catalysis,[18,19] whereas the C-version of cyclizations via “hydride
shift mediated C–H bond functionalization” was applied for the
synthesis of 3-aryltetralines.[20]
In our extensive studies on kinetics, thermodynamics, regio-
and stereochemistry as well as scope and limitations of the
tert-amino effect, while recognizing important features of the
mechanism, new extensions to biaryls and fused bicyclic systems
incorporating the interacting amino and vinyl groups in the two
ortho or ortho and peri positions, respectively, have been devel-
oped to provide easy accesses to medium or macrocyclic rings
(Fig. 2).[21–23]
Interestingly enough, in the biaryl and naphthalene series,
novel zwitterionic phenantridium or benzo[d,e]quinolinium
systems could also be obtained through a Michael type addition
(Fig. 3). Our X-ray data of the vinyl compounds revealed a
nonbonding interaction between the tertiary nitrogen and the
a-vinylic carbon, which might also play a role in the reaction.
As a continuation of these studies, our aim was to investigate
cyclization reactions of nondirectly connected biaryl systems; in
the rate-limiting step of the rearrangement reaction of such
compounds via tert-amino effect, a sigmatropic hydrogen
migration a priori could be excluded (Fig. 1: pathway A); instead,
a direct hydride transfer could only take place (Fig. 1: pathway B).
Although formation of benzazepine derivatives via “homologous
tert-amino effect” was reported,[24] further extensions have not
been explored.
Figure 3. Formation of zwitterionic phenantridium and benzo[d,e]
quinolinium derivatives. [DMB: 1,3-dimethylbarbituric acid, ID: 1H-indene-
1,3(2H)-dione]
between the phenyl rings bearing an amino and vinyl moiety in
ortho- and ortho0-positions.
EXPERIMENTAL
General
All reagents and solvents were purchased from commercial sources and
were utilized without further purification. Melting points were determined
on a Büchi-540 (Büchi Labortechnik AG, Flawil, Switzerland) capillary melting
point apparatus and are uncorrected. The 1H and 13C NMR spectra were
recorded at ambient temperature, in the solvent indicated, with a Varian
Mercury Plus spectrometer (Agilent Technologies, Santa Clara, CA, USA) at a
frequency of 400 or 100 MHz or with a Bruker 500 MHz (Bruker Biospin,
We report herein our preliminary results on the syntheses and
thermal isomerizations of 2-2-{[2-(sec-amino)benzyl](methyl)
amino}- and {2-[2-(sec-amino)phenoxy]benzylidene}malononitriles,
bridged with a methylamino-N-methyl group or an oxygen
Figure 2. Synthesis of medium and macrocyclic ring systems by tert-amino effect
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

CYCLIZATION REACTIONS OF BRIDGED BIARYLS
Rheinstetten, Germany) spectrometer, at a frequency of 500 or 125 MHz, and
are reported in parts per million (ppm). Spectra were recorded at 500 MHz
(1H) or 125 MHz (13C), if not indicated otherwise. Chemical shifts are given
on the d-scale relative to tetramethylsilane or the residual solvent signal
as an internal reference. In reporting spectral data, the following abbrevia-
tions were used: s = singlet, d = doublet, t = triplet, m = multiplet, dd= dou-
blet doublet, dm= doublet multiplet, tm= triplet multiplet, and br = broad.
For structure elucidation, one-dimensional 1H, 13C, DEPT, two-dimensional
1H, 1H-COSY, 1H, 13C-HSQC, 1H, 13C-HMBC measurements were run. Elemen-
tal analyses were performed on a Carlo Erba 1012 apparatus (Thermo Fisher
Scientific, Milan, Italy), analyses indicated by the symbols of the elements
affording satisfactory results. Microwave (MW) irradiation experiments were
carried out in a monomode CEM-Discover MW reactor (CEM Corporation,
Matthews, NC, USA) by using the standard configuration as delivered,
including proprietary software. The experiments were executed in 10 mL
MW process vials with control of the temperature by infrared detection.
After completion of the reaction, the vial was cooled to 50ꢀC by air jet cool-
ing. For flash column chromatography purification, Kieselgel 60 (Merck
0.040–0.063 mm) (Merck KGaA, Darmstadt, Germany) was used; for thin
layer chromatography (TLC) analysis, silica gel 60F254 (Merck) plates were
applied. Solvent mixtures used for chromatography are always given in a
v/v ratio. The structures of all compounds were consistent with their
analytical and spectroscopic data. Compounds 2a, 2b, 3a, 3b, 4a, 4b, and
9 were prepared according to the literature procedures cited[25,26] and
had melting points and/or spectral data identical with the published values.
removed in vacuo, 30mL H2O was added, and the mixture was extracted with
EtOAc (3 ꢂ 30 mL). The organic layer was discarded, and the pH of the
aqueous phase was adjusted to 13 with 2 M NaOH. The aqueous phase was
extracted with EtOAc (5 ꢂ 30 mL), and the combined organic layers were
dried (MgSO4), filtered, and evaporated to dryness.
N,N-Dimethyl-2[(methylamino)methyl]aniline (5a)
The crude product was purified by fractionary distillation under reduced
pressure (102 ꢀC, 5 mmHg). Colorless oil (1.28 g, 40%). 1H NMR (CDCl3)
d (ppm): 2.44 (s, 3H, CH3), 2.70 (s, 6H, N(CH3)2), 3.83 (s, 2H, CH2), 7.02–7.06
(m, 1H, Ar–H), 7.11 (dd, 1H, J = 1.0, 8.0Hz, Ar–H), 7.20–7.25 (m, 1H,
Ar–H), 7.31 (dd, 1H, J = 1.5, 7.5Hz, Ar–H). 13C NMR (CDCl3) d (ppm): 36.8,
45.7, 52.9, 119.9, 124.0, 128.3, 130.3, 134.9, 153.3. For elemental analysis,
HCl salt of the product was formed. Anal. (C10H16N2 ꢂ 2.5 HCl) C, H, N.
N-Methyl-1-(2-piperidin-1-ylphenyl)methanamine (5b)
Colorless oil (2.42 g, 61%). 1H NMR (DMSO-d6) d (ppm): 1.45–1.55 (m, 2H,
CH2), 1.60–1.68 (m, 4H, CH2), 2.30 (s, 3H, CH3), 2.75–2.85 (m, 4H, CH2), 3.66
(s, 2H, CH2), 6.97–7.10 (m, 1H, Ar–H), 7.04 (dm, 1H, J = 1.0, 7.0 Hz, Ar–H),
7.15–7.19 (m, 1H, Ar–H), 7.36 (dm, 1H, J = 7.0 Hz, Ar–H). 13C NMR
(DMSO-d6) d (ppm): 23.9, 26.2, 36.1, 50.6, 53.5, 119.2, 122.8, 127.2, 129.1,
134.5, 152.3. For elemental analysis, HCl salt of the product was formed.
Anal. (C13H20N2 ꢂ 2 HCl) C, H, N.
X-ray diffraction studies
Synthesis of 2-{[2-(sec-amino)benzyl](methyl)amino}benzaldehydes
A good-looking single crystal of the compound was fixed on the top of a
glass fiber using epoxy glue. Data were collected at 293(1) K, Enraf
Nonius MACH3 diffractometer (Bruker Nonius, Delft, Netherlands), Mo
Ka radiation l = 0.71073 nm, o motion. Raw data were evaluated using
the XCAD4 software;[27] the structure was solved using direct methods
by the SIR-92 software[28] and refined on F2 using SHELX-97[29] program.
Refinement was performed anisotropically for nonhydrogen atoms. Hy-
drogen atoms were placed into geometric position. The structure also
contained a disordered hexane molecule. Figures were prepared with
the WINGX-97 suite.[30] The PLATON program[31,32] was used for crystallo-
graphic calculations.
A suspension of the amine compound (4.29 mmol, for 6a: 5a – 705 mg,
for 6b: 5b – 876 mg), 2-fluorobenzaldehyde (4.29 mmol, 0.45 mL), and
K2CO3 (6.54 mmol, 904 mg) in 12 mL dimethylformamide was heated at
110 ꢀC for 7 h (monitored by TLC). The mixture was then cooled down
to room temperature and filtered. The solvent was removed in vacuo, and
the crude product obtained was purified by flash column chromatography
on silica gel.
2-{[2-(Dimethylamino)benzyl](methyl)amino}benzaldehyde (6a)
Column chromatography: n-hexane/EtOAc 9:1, Rf = 0.16. Yellow oil
(1.07 g, 93%). 1H NMR (CDCl3) d (ppm): 2.63 (s, 6H, N(CH3)2), 2.86 (s, 3H,
CH3), 4.46 (s, 2H, CH2), 6.98–7.02 (m, 1H, Ar–H), 7.02–7.06 (m, 1H, Ar–H),
7.11 (dm, 1H, J = 8.0 Hz, Ar–H), 7.12 (dm, 1H, J = 8.0 Hz, Ar–H), 7.21–7.26
(m, 1H, Ar–H), 7.41–7.46 (m, 2H, Ar–H), 7.80 (dm, 1H, J = 7.5 Hz, Ar–H),
10.33 (s, 1H, CHO). 13C NMR (CDCl3) d (ppm): 43.4, 45.6, 58.1, 119.6,
120.0, 121.5, 124.0, 128.1, 128.5, 129.2, 130.7, 132.4, 135.2, 153.5, 156.6,
192.0. For elemental analysis, HCl salt of the product was formed. Anal.
(C17H20N2O ꢂ 2.5 HCl) C, H, N.
Differential scanning calorimetry measurements
The thermoanalytical examinations of the materials were carried out with a
Mettler-Toledo TG/DSC1 instrument (Mettler Toledo AG, Greifensee,
Switzerland). During the measurements, the start temperature was 25 ꢀC, the
end temperature was 500 ꢀC, and the applied heating rate was 10 ꢀC/min.
Nitrogen atmosphere was used. A 2–10 mg sample was measured into
aluminum pans (100 mL). The curves were evaluated with STARe software
(Mettler Toledo AG, Greifensee, Switzerland).
Computational chemistry
2-[(2-Piperidin-1-ylbenzyl)(methyl)amino]benzaldehyde (6b)
Semiempirical PM3 and density functional theory (DFT) calculations were
carried out by using Schrödinger’s Jaguar program package (Jaguar,
version 7.8, Schrödinger, LLC, New York, NY, USA, 2011) on HP (Z800)
workstation. Starting geometries were obtained with ConfGen Advanced
module (with standard settings), followed by PM3 level optimization. For
DFT, gradient-corrected functional BP86 model and hybrid functional
B3P86 model[33–38] with a 6-31G** basis set in vacuum were used.
Column chromatography: n-hexane/EtOAc 4:1, Rf = 0.65. Yellow oil (1.26 g,
95%). 1H NMR (CDCl3) d (ppm): 1.50–1.60 (m, 2H, CH2), 1.60–1.70 (m, 4H,
CH2), 2.75–2.85 (m, 4H, CH2), 2.88 (s, 3H, CH3), 4.44 (s, 2H, CH2), 6.97–7.02
(m, 1H, Ar–H), 7.01–7.06 (m, 1H, Ar–H), 7.10 (dm, 1H, J= 8.0Hz, Ar–H), 7.11
(dm, 1H, Ar–H), 7.20–7.25 (m, 1H, Ar–H), 7.39 (dm, 1H, J = 7.5Hz, Ar–H),
7.40–7.45 (m, 1H, Ar–H), 7.79 (dm, 1H, Ar–H), 10.30 (s, 1H, CHO). 13C NMR
(CDCl3) d (ppm): 24.9, 27.2, 43.7, 55.0, 57.4, 119.6, 120.7, 121.2, 124.1,
128.0, 128.6, 129.2, 130.8, 132.9, 135.2, 153.7, 156.5, 192.0. Anal.
(C20H24N2O) C, H, N.
Synthesis
Synthesis of N,N-dialkyl-2-[(methylamino)methyl]anilines
Synthesis of 2-(2-{[2-(sec-amino)benzyl](methyl)amino}benzylidene)
malononitriles
To 40 wt% aq. methylamine (67 mL, 776.00 mmol) at ꢁ10 ꢀC, a solution of the
2-(chloromethyl)-N,N-dialkylanilines (19.42 mmol, for 5a: 2-(chloromethyl)-N,
N-dimethylaniline hydrochloride – 4.00 g, for 5b: 1-[2-(chloromethyl)phenyl]
piperidine hydrochloride – 4.78 g) in EtOH (70 mL) was added dropwise. The
mixture was stirred at ꢁ10 ꢀC for 2 h (monitored by TLC). The solvent was
A mixture of the benzaldehyde compound (4.86 mmol, for 7a: 6a – 1.30 g,
for 7b: 6b – 1.50g) and malononitrile (4.86mmol, 321 mg) in 24 mL EtOH
was stirred for 3 h at room temperature.
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
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P. BOTTINO ET AL.
34.8, 35.5, 38.8, 46.7, 61.1, 112.1, 114.5, 115.5, 116.2, 118.3, 122.7, 126.0,
127.9, 129.8, 130.2, 131.3, 132.5, 144.6, 154.8. Anal. (C20H20N4) C, H, N.
1-Methyl-2-(2-(piperidin-1-yl)phenyl)-1,2-dihydroquinoline-3,3(4H)-
dicarbonitrile (8b)
Heating: 130 ꢀC, 10 min. White crystals (299 mg, 100%), mp 167–169 ꢀC. 1H
NMR (CDCl3) d (ppm): 1.50–1.80 (m, 6H, CH2), 2.70–3.00 (m, 4H, CH2), 2.95
(s, 3H, CH3), 3.32 (d, 1H, J= 16.0 Hz, CH2), 3.40 (d, 1H, J=16.0Hz, CH2), 5.63
(s, 1H, CH), 6.78 (dm, 1H, J=7.5Hz, Ar–H), 6.78–6.82 (m, 1H, Ar–H), 7.01–7.08
(m, 3H, Ar–H), 7.25–7.30 (m, 2H, Ar–H), 7.33–7.37 (m, 1H, Ar–H). 13C NMR
(CDCl3) d: 24.8, 27.3, 34.8, 35.5, 38.8, 55.0, 61.3, 112.1, 114.6, 115.2, 116.2,
118.3, 123.0, 125.8, 127.8, 129.8, 130.2, 131.2, 132.5, 144.6, 154.6. Anal.
(C23H24N4) C, H, N.
2-(2-{[2-(Dimethylamino)benzyl](methyl)amino}
malononitrile (7a)
benzylidene)
Work-up: the solvent was removed in vacuo, and the crude product
obtained was purified by flash column chromatography on silica gel
(eluent: n-hexane/EtOAc 4:1, Rf = 0.36). Orange oil (1.32 g, 86%). H NMR
1
(CDCl3) d (ppm): 2.61 (s, 6H, CH3), 2.82 (s, 3H, CH3), 4.29 (s, 2H, CH2),
7.03–7.11 (m, 2H, Ar–H), 7.14 (dm, 2H, J = 8.5 Hz, Ar–H), 7.24–7.29
(m, 2H, Ar–H), 7.45–7.49 (m, 1H, Ar–H), 8.01 (dm, 1H, J = 8.0 Hz, Ar–H),
8.12 (s, 1H, CH). 13C NMR (CDCl3) d (ppm): 43.5, 45.7, 58.4, 80.7, 113.7,
115.0, 120.6, 120.6, 122.9, 124.2, 125.0, 129.1, 129.6, 129.9, 132.0, 135.3,
153.5, 155.8, 159.0. For elemental analysis, HCl salt of the product was
formed. Anal. (C20H20N4 ꢂ 2.5 HCl) C, H, N.
2-[2-(Pyrrolidin-1-yl)phenoxy]benzaldehyde (10)
2-(2-{[2-(Piperidin-1-yl)benzyl](methyl)amino}benzylidene)malononitrile
To a solution of 2-(pyrrolidin-1-yl)phenol[12] (15.00 mmol, 2.45 g) in N,N-
dimethylacetamide (15 mL), 2-fluorobenzaldehyde (15.00 mmol, 1.58 mL)
and K2CO3 (30.00mmol, 4.15 g) were added. The mixture was heated at
160 ꢀC (oil temperature) under argon atmosphere for 1.5h. To the cooled
reaction mixture, EtOAc (20 mL) was added. The organic phase was washed
with H2O (1ꢂ 20 mL) and aq. saturated Na2CO3 solution (1ꢂ 20mL). The or-
ganic layer was dried (MgSO4), filtered, and evaporated to dryness. The
crude product obtained was purified by flash column chromatography on
silica gel (toluene). Yellow crystals (1.98g, 51%), mp 82–83 ꢀC. 1H NMR
(400 MHz, CDCl3) d (ppm): 1.82–1.86 (m, 4H, CH2), 3.31–3.36 (m, 4H, CH2),
6.69 (dm, 1H, J= 8.0Hz, Ar–H), 6.74 (tm, 1H, J = 7.6Hz, 1H, Ar–H), 6.82 (dm,
1H, J=8.0Hz, Ar–H), 6.94 (dm, 1H, J= 8.0Hz, Ar–H), 7.04–7.15 (m, 2H, Ar–H),
7.40–7.45 (m, 1H, Ar–H), 7.90 (dm, 1H, J=8.0Hz, Ar–H), 10.64 (d, 1H, J=0.7,
CHO). 13C NMR (100 MHz, CDCl3) d (ppm): 26.0, 50.7, 116.3, 116.7, 118.5,
122.4, 123.5, 126.0, 126.8, 128.9, 136.5, 142.7, 142.9, 162.0, 190.3. Anal.
(C17H17NO2) C, H, N.
(7b)
Work-up: the precipitated crystals were filtered off and washed with
EtOH. Orange crystals (1.56 g, 90%), melting point (mp) 95–96 ꢀC. 1H
NMR (CDCl3) d (ppm): 1.50–1.60 (m, 2H, CH2), 1.65–1.70 (m, 4H, CH2),
2.65–2.75 (m, 4H, CH2), 2.85 (s, 3H, CH3), 4.26 (s, 2H, CH2), 7.03–7.14
(m, 3H, Ar–H), 7.19 (dm, 1H, J = 8.5 Hz, Ar–H), 7.22–7.28 (m, 2H, Ar–H),
7.45–7.50 (m, 1H, Ar–H), 8.00 (dm, 1H, J = 8.0 Hz, Ar–H), 8.03 (s, 1H, CH).
13C NMR (CDCl3) d: 24.8, 27.3, 44.2, 55.0, 57.5, 80.6, 113.7, 115.0, 120.7,
121.0, 122.9, 123.0, 124.4, 125.0, 129.1, 129.4, 129.9, 132.6, 135.3, 153.6,
155.7, 158.9. Anal. (C23H24N4) C, H, N.
Cyclization of 2-(2-{[2-(sec-amino)benzyl](methyl)amino}benzylidene)
malononitriles
The vinyl precursors (0.84 mmol, for 8a: 7a – 266 mg, for 8b: 7b – 299 mg)
in a 10 mL MW process vial were irradiated at the temperature and for
the reaction time indicated (at 250 W maximum power level). The vial
was subsequently cooled to ambient temperature, and 15 mL CH2Cl2
was added. The mixture was washed with H2O (3 ꢂ 15 mL), and the or-
ganic layer was dried (MgSO4), filtered, and evaporated to dryness to af-
ford the pure products.
{2-[2-(Pyrrolidin-1-yl)phenoxy]benzylidene}propanedinitrile (11)
To a solution of the aldehyde (10) (2.00 mmol, 535 mg) in EtOH (2.50 mL),
malononitrile (2.00 mmol, 132 mg,) and a few drops of piperidine were
added. The mixture was stirred at room temperature until the starting
material had been consumed (monitored by TLC, 2 h). The precipitated
crystals were filtered off and washed with 5 ꢂ 1 mL EtOH to afford the
analytically pure product. Orange crystals (410 mg, 65%), mp 92–93 ꢀC.
1H NMR (400 MHz, CDCl3) d (ppm): 1.83–1.92 (m, 4H, CH2), 3.23–3.32
(m, 4H, CH2), 6.70 (dm, 1H, J = 8.0 Hz, Ar–H), 6.71–6.78 (m, 1H, Ar–H),
6.83 (dm, 1H, J = 8.0 Hz, Ar–H), 6.86 (dm, 1H, J = 8.0 Hz, Ar–H), 7.09–7.18
(m, 2H, Ar–H), 7.41–7.48 (m, 1H, Ar–H), 8.29 (dm, 1H, J = 8.0 Hz, Ar–H),
8.46 (s, 1H, CH). 13C NMR (100 MHz, CDCl3) d (ppm): 26.0, 50.7, 82.7,
113.6, 114.9, 116.6, 116.6, 118.8, 121.2, 123.0, 123.4, 127.3, 129.2, 137.0,
142.3, 142.8, 154.8, 159.2. Anal. (C20H17N3O) C, H, N.
2-(2-(Dimethylamino)phenyl)-1-methyl-1,2-dihydroquinoline-3,3
(4H)-dicarbonitrile (8a)
Heating: 135 ꢀC, 10 min. White crystals (266 mg, 100%), mp 170–172 ꢀC.
1H NMR (CDCl3) d (ppm): 2.74 (s, 6H, CH3), 2.97 (s, 3H, CH3), 3.35 (d, 1H,
J = 16.0 Hz, CH2), 3.42 (d, 1H, J = 16.0 Hz, CH2), 5.74 (s, 1H, CH), 6.78 (dm,
1H, J = 8.0 Hz, Ar–H), 6.79–6.82 (m, 1H, Ar–H), 7.04–7.09 (m, 3H, Ar–H),
7.25–7.30 (m, 1H, Ar–H), 7.33–7.39 (m, 2H, Ar–H). 13C NMR (CDCl3) d:
Scheme 1. Synthesis and cyclization of 2-(2-{[2-(sec-amino)benzyl](methyl)amino}benzylidene)malononitriles
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CYCLIZATION REACTIONS OF BRIDGED BIARYLS
Table 1. Enthalpies of reaction determined by differential scanning calorimetry (DSC) (ΔHr) and by calculation (ΔΔHf = ΔHf pr ꢁ ΔHf st
)
Compound
Structure
Optimized structure
Tm (ꢀC)a Tr (ꢀC)b
ΔHr
ΔΔHf
(kcal/mol)c (kcal/mol)d
7b
96.3
NA
NA
NA
8b-R
169.7
161.4
ꢁ11.26
ꢁ15.15
8b-S
169.7
161.4
ꢁ11.26
ꢁ15.13
13
NA
NA
NA
ꢁ14.76
14-R
NA
NA
NA
4.98
(Continues)
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P. BOTTINO ET AL.
Table 1. (Continued)
Compound
Structure
Optimized structure
Tm (ꢀC)a Tr (ꢀC)b
ΔHr
ΔΔHf
(kcal/mol)c (kcal/mol)d
14-S
NA
NA
NA 6.74
11
93.9
NA
NA
NA
12-R
171.99
169.9
ꢁ8.58
ꢁ6.04
12-S
171.99
169.9
ꢁ8.58
ꢁ6.25
aTm corresponds to the melting temperature (DSC endothermic peak).
bTr corresponds to the temperature of cyclization (DSC exothermic peak).
cΔHr is the enthalpy of reaction.
dΔΔHf corresponds to the difference of calculated heats of formation as obtained by DFT method (B3P86).
CDCl3) d (ppm): 1.97–2.09 (m, 1H, CH2), 2.24–2.36 (m, 2H, CH2), 2.56–
2.65 (m, 1H, CH2), 3.03 (d, 1H, J = 14.8 Hz, CH2), 3.41–3.48 (m, 1H, CH2),
3.74 (d, 1H, J = 14.8 Hz, CH2), 3.87–3.95 (m, 1H, CH2), 5.35 (br s, 1H, CH),
6.78–6.83 (m, 1H, Ar–H), 6.89 (dm, 1H, J = 8.0 Hz, Ar–H), 6.92 (dm, 1H,
J = 8.0 Hz, Ar–H), 7.06–7.11 (m, 1H, Ar–H), 7.14–7.18 (m, 2H, Ar–H), 7.29
(dm, 1H, J = 8.0 Hz, Ar–H), 7.37–7.43 (m, 1H, Ar–H). 13C NMR (100 MHz,
CDCl3) d (ppm): 23.2, 32.7, 38.5, 45.6, 51.9, 62.9, 114.6, 116.3, 118.8,
121.3, 122.9, 122.9, 124.1, 125.5, 126.6, 131.4, 135.0, 140.4, 146.1, 156.3.
Anal. (C18H15N3O) C, H, N.
5,6,7,7a-Tetrahydrodibenzo[e,h]pyrrolo[1,2-a]oxazonine-8,8(9 H)-
dicarbonitrile (12)
A solution of the vinyl precursor (11, 2.00 mmol, 631 mg) in 1 mL dry
DMSO was heated at 100 ꢀC for 15 min. The reaction mixture was subse-
quently cooled to ambient temperature and poured into CH2Cl2 (15 mL).
The organic layer was washed with H2O (3 ꢂ 15 mL), dried (MgSO4),
filtered, and evaporated to dryness. The residue obtained was purified
by flash column chromatography on silica gel with n-hexane:EtOAc 4:1
1
eluent. White crystals (133 mg, 21%), mp 172–174 ꢀC. H NMR (400 MHz,
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CYCLIZATION REACTIONS OF BRIDGED BIARYLS
Scheme 2. Synthesis and cyclization of {2-[2-(sec-amino)phenoxy]benzylidene}malononitriles
amino)benzylamines 6a,b, which upon reacting with malononitrile
RESULTS AND DISCUSSION
under mild conditions led to vinyl derivatives 7a,b (Scheme 1).
Compounds 7a,b, may a priori cyclize in three pathways, either
with involvement of methylene-carbon, N-methyl-carbon, or the
a-carbon of the sec-amino group attached to the other phenyl
ring (leading to compounds 8, 13, or 14, respectively, as listed
in Table 1). Not fully unexpectedly, cyclization, following our
solvent-free protocol, exclusively took place via the first route,
affording the product with six-membered ring in excellent yield.
Synthesis and isomerization of 2-(2-{[2-(sec-amino)benzyl]
(methyl)amino}benzylidene)malononitriles
2-(2-{[2-(sec-Amino)benzyl](methyl)amino}benzylidene)malononitriles
were prepared in several steps.[25] Thus, 2-(chloromethyl)-N,
N-dialkylanilines (4a,b) obtained via a known procedure from
2-fluorobenzaldehyde were reacted with methylamine to give
the corresponding N,N-dialkyl-2-[(methylamino)methyl]anilines
(5a,b). Arylation with 2-fluorobenzaldehyde afforded (2-sec-
Synthesis and cyclization of (2-[2-(sec-amino)phenoxy]ben-
zylidene)malononitriles
2-Pyrrolidinophenoxybenzaldehyde (10) was prepared from 2-
fluorobenzaldehyde with 2-pyrrolidinophenol (9)[26] (Scheme 2).
Its subsequent Knoevenagel condensation with malononitrile
afforded 11. In DMSO solution at 100 ꢀC, the expected oxazonine
12, representing a novel ring system, could be isolated, albeit
only in modest yield, presumably because of decomposition.
Structure of 12 was unambiguously confirmed by X-ray crystal-
lography. Upon cyclization – also for compounds 8a,b – formation
of racemic mixtures may be expected. Indeed, for compound 12,
two molecules were observed in the asymmetric unit, with R or S
configuration at the stereogenic carbon, respectively. Although
the inversion of the pyrrolidino nitrogen might result in detectable
isomers, interestingly, it was found to be planar, with location in
plane of the aromatic ring (Fig. 4). The angle of planes of two
aromatic rings is around 74ꢀ and 69ꢀ for the two molecules present
in the asymmetric unit, respectively. Nine-membered heterocycles
are hardly represented in the Cambridge Structural Database[39]
(moreover, a direct structural comparison is difficult, because of
high fluxionality of such systems).
Figure 4. ORTEP view and numbering scheme of 12; only one molecule
from the asymmetric unit is shown. The other enantiomer from the
asymmetric unit was omitted because of clarity. Moreover, as the space
group is centric, the unit cell contains the exact mirror images of both
enantiomers
Figure 5. The thermogravimetry (upper) and differential scanning calorimetry (lower) curves of compounds 7b and 8b
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P. BOTTINO ET AL.
Figure 6. The thermogravimetry (upper) and differential scanning calorimetry (lower) curves of compounds 11 and 12
Thermochemical studies
isomerization, led to tetrahydroquinolines 8a,b with the involve-
ment of benzylic hydrogen. In the case of the oxygen-bridged
vinyl compound 11, the expected novel dibenzoxazonine ring
system 12 was obtained. These finding may indicate on the one
hand an inherent migratory aptitude of hydrogen and a wider
scope of ring closure reactions via tert-amino effect.
Our previous differential scanning calorimetry (DSC) study of
tert-amino effect[40] showed the applicability of this method for
detection of the ring closure. Calculations (PM3, DFT) and exper-
imental data (DSC) suggested that the cyclization is an exother-
mic process that could also be well detected on the DSC curves.
Differential scanning calorimetry measurements complemen-
ted by parallel thermal gravimetry (between room temperature
and 500 ꢀC) were run for 7b–8b and 11–12 (Figs 5 and 6) to
assess whether cyclization could be monitored with this method
for novel scaffolds. In the temperature range of the endothermic
and exothermic peaks, no significant weight loss – that is,
decomposition – was observed. The peaks corresponding to
the melting points could be identified as endothermic peaks at
96.3 and 93.9 ꢀC, respectively. The second exothermic peaks
observed might indicate that cyclization did take place upon
heating; that is, it corresponds to the temperature of ring closure.
TLC monitoring and 1H NMR spectra recorded from the samples
following the DSC experiment confirmed that only thermal ring
closure occurred in the case of 7b, whereas in the case of 11,
considerable decomposition could be detected. Integrals of the
areas under the exothermic peaks (related to cyclization) provide
the enthalpy changes of the reactions. These experimental
enthalpy changes together with the calculated ones are listed
in Table 1. The calculated heat of reaction values were deter-
mined as the differences of heat of formation of fused products
and that of the starting vinyl compounds (full geometrical
optimization was carried out for all compounds). In the case of
7b, the two potential alternative products (with N-methyl: 13,
and with ortho0 tert-amino moiety: 14) were included as well.
We also found that DSC may be a suitable method for identi-
fication and characterization of thermal isomerization reactions.
Acknowledgements
The work was supported by the TÁMOP 4.2.1./B-09/1/KONV-
2010-007 project co-financed by the European Union and the
European Social Fund. The authors also thank the Hungarian
Scientific Research Fund (OTKA, K73389) and the National Devel-
opment Agency (TET_10-1-2011-0050) for financial support, Dr
Tamás Gáti for the measurement and assignment of NMR spectra,
and Dr Balázs Balogh for calculations.
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