Cyclization reactions of 3,4-diazaheptatrienyl metal compounds. Pyridines from an anionic analogue of the Fischer indole synthesis: Experiment and theory

Article abstract of DOI:10.1021/jo200487v

Unsymmetrical N,N′-bisalkylidene hydrazines 7a,b, 10a-c and 13, which are accessible in good to excellent yields from hydrazones 6, 9, and 12 and commercially available α,β-unsaturated carbonyl compounds, are converted into 3,4-diazaheptatrienyl anions 14

Full text of DOI:10.1021/jo200487v

ARTICLE
pubs.acs.org/joc
Cyclization Reactions of 3,4-Diazaheptatrienyl Metal Compounds.
Pyridines from an Anionic Analogue of the Fischer Indole Synthesis:
Experiment and Theory
Tillmann Kleine, Roland Fr€ohlich, Birgit Wibbeling, and Ernst-Ulrich W€urthwein*
Organisch-Chemisches Institut, Westf€alische Wilhelms-Universit€at, Corrensstrasse 40, D-48149 M€unster, Germany
S Supporting Information
b
ABSTRACT: Unsymmetrical N,N0-bisalkylidene hydrazines
7a,b, 10aꢀc and 13, which are accessible in good to excellent
yields from hydrazones 6, 9, and 12 and commercially available
R,β-unsaturated carbonyl compounds, are converted into 3,4-
diazaheptatrienyl anions 14a,b, 16aꢀc, and 18 by treatment
with KO-t-Bu as base. These anionic species form pyridines 15a,
b, 5,6-dihydrobenzo[h]quinolones 17aꢀc, and bipyridine 19 in
moderate yields. We interpret thermodynamics and kinetics of these reactions by quantum chemical calculations and discuss this
multistep anionic rearrangement, based on an electrocyclic ring formation with a M€obius aromatic transition structure 22, the NꢀN
bond fission (25), and the 6-exo-trig cyclization (27) as key steps, considering the results of NICS and NBO-charge calculations.
This novel anionic reaction sequence bears an interesting analogy to the mechanism of the (cationic) Fischer indole synthesis.
Precursor 10c and product 16c could be characterized by X-ray diffraction.
Scheme 1. 3,4-Diazaheptatrienyl Potassium Compound 1
’ INTRODUCTION
Pyridines are among the most important and versatile organic
substances that are known to organic chemistry. They are widely
used as pharmaceuticals and agrochemicals, as ligands, and in
organocatalysis.1,2 Thus, the development of new synthetic
routes for pyridines has always been in the focus of organic
chemists.1ꢀ3 Hydrazones, on the other hand, are reactive starting
compounds for organic synthesis with the Fischer indole re-
arrangement as the best known example.4 In our group, we have
learned that cationic and anionic intermediates derived from
unsaturated hydrazones are interesting precursors for unprece-
dented ring-closure reactions preceding under mild condi-
tions.5,6 NꢀN bond fission, sometimes observed in such com-
pounds, is an additional synthetically useful property.7 Recently,
we reported on ring-forming reactions of hydrazone-derived 1,2-
diaza-4,5-benzoheptatrienyl anions, specifically their alkali metal
compounds, for the synthesis of 3H-benzodiazepines and 1,2-
dihydrophthalzines.6 Now, we present 3,4-diazaheptatrienyl an-
ions 1, specifically potassium compounds (Scheme 1), employed
as substrates in a new versatile pyridine synthesis formed by a
complex multistep reaction cascade, not requiringexternaloxidants
or transition metals.
electronegativity such heteroatoms greatly disturb the electronic
structure of polyenyl anions.12 Thus, if an electronegative hetero-
atom such as nitrogen is located in an odd position of the
unsaturated chain, ring-forming reactions are unlikely; otherwise,
with the electronegative heteroatom in an even position, ring-
forming reactions are frequently observed.13 These observations
were sufficiently explained by coincided positions of the heteroa-
tomsin the unsaturated chain with positions with a largecoefficient
of the HOMO (stabilizing effect), otherwise, with nodal positions
of the HOMO (destabilizing influence).13 The ambiguous char-
acter of N3 in odd and N4 in even positions turns anion 1 into an
interesting model compound. Initially, we expected possible ring-
forming reactions of 1 leading to interesting heterocycles such as
pyrazoles, pyridazines or diazepines (Scheme2). The scope of such
ring-closure reactions is well-known and often applied in synthetic
chemistry.11,14
The species 1 may be understood as 2-fold vinylogues of 1,2-
diazaallyl anions,8 interesting heteroallyl anions like enolates and
azaenolates.9 Electrocyclization reactions are among the most
useful tools for the preparation of carbocycles.10,11 However, in
the field of heterocompounds, apart from the conservation of the
orbital symmetry, kinetics and thermodynamics of such reactions
highly depend on the electronegativity and position of the
heteroatoms within the unsaturated chain. Due to their respective
However, as this study will show below, this particular work
combines the ring-forming aptitude of azapolyenyl anions 1 with
a novel, unexpected organometallic rearrangement reminiscent
of the mechanism of the Fischer indole synthesis.4 It outlines a
Received: March 5, 2011
Published: May 02, 2011
r
2011 American Chemical Society
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Scheme 2. Expected Possible Cyclization Reactions of Anion 1
bipyridine 1919 (Scheme 4) were isolated after aqueous workup.
We were able to grow single crystals of 17c and to characterize
them by X-ray diffraction (Figure 2).
For the investigation of scope and limitation of this novel
multistep reaction we used a variety of precursors with differing
substitution patterns. Modifications at C6 of the 3,4-diazahepta-
trienyl chain are tolerated and allow access to meta-substituted
pyridine 15b, while methylation at C5 inhibits the formation of
any specific product. Furthermore C1 may be part of a cyclic
structure to give access to meta-substituted examples 10aꢀc f
17aꢀc. These R-tetralone-derived hydrazones (10aꢀc) widen
the application of the concept to polycyclic, ring-fused, and more
rigid analogues. Examples 10aꢀc were also studied for investiga-
tions on the influence of p-substituents at C7 with electron-
withdrawing or -donating properties, as the electron density of
the delocalized anions is expected to be a sensitive precondition
for their reactivity. Thus, the phenyl moiety at C7 with its minor
yet stabilizing effect (17b) may be changed to electron-poor
(17a) and electron-rich (17c) aromatics with little influence on
procedure that allows the synthesis of pyridines or more complex
analogues from commercially or easy available substrates.
’ RESULTS AND DISCUSSION
Hydrazones 6,15 9,16 and 1217 are prepared by condensation
of ketones 5, 8, and 11 with an excess of hydrazine hydrate in high
dilution to suppress the formation symmetrical bishydrazones
(azines) as a result of double condensation. In a second step,
hydrazones 6, 9, and 12 are reacted under solvent free conditions
with R,β-unsaturated carbonyl compounds to give unsymme-
trical N,N0-bisalkylidene hydrazines 7aꢀc, 10aꢀc, and 13
(Scheme 3) without formation of byproducts. We were able to
grow single crystals of 10c and to characterize them by X-ray
diffraction (Figure 1).
Treatment of N,N0-bisalkylidene hydrazines 7a-c, 10a-c and
13 with KO-t-Bu in THF at room temperature generates the
reactive anions, specifically potassium salts 14a,b, 16aꢀc, and
18, by abstraction of a proton in R-position to the hydrazone
subunit. Via a complex sequence of rearrangement reactions
pyridines 15a, b,18 5,6-dihydrobenzo[h]quinolones 17aꢀc, and
Figure 1. Molecular structure of 10c as obtained by X-ray diffraction
(Schakal plot).
Scheme 3. Synthesis of Hydrazones 6, 9, and 12 and N,N0-Bisalkylidene Hydrazines 7aꢀc, 10aꢀc, and 13
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the yield. In means of scope the most interesting variation is the
2-acetylpyridine-derived hydrazone 13 from which bipyridine 19
is obtained.
MS(ESI)) proved the formation of a number of unspecific
byproducts. This may be a result of the complex multistep
rearrangement reaction (see below).
The scope of this procedure is quite general. While the yields
are merely moderate, this deficiency is more than offset by the
facility with which a high degree of complexity can straightfor-
wardly be obtained from easily accessible and in many examples
commercially available starting materials. In particular, the
method provides access to a pyridine core unit with up to four
different substituents with full regiochemical control in one ope-
ration. Careful analysis of the crude reaction mixture (HPLC-
In one example we performed the whole reaction sequence as
a one-pot procedure, indicating the preparative simplicity of this
new method. Starting from the hydrazone 10c the condensation
and the subsequent deprotonation step, inducing the rearrange-
ment, the N-heterocycle 17c was formed within 1 h at ambient
temperature in 17% yield. In this case a repeated acidic/basic
pendulum extraction workup process without further purifica-
tion proved to be advantageous (Scheme 5).
For this unprecedented formation of N-heterocyles of type 15,
17, and 19, we suggest an anionic mechanism that is somewhat
related to the rearrangement of the Fischer indole synthesis.4 We
discuss it on the basis of quantum chemical calculations starting
with hydrazone 10c via model anion 20 to give pyridine 17c
(without counterion or solvent effects) carried out at the
B2PLYPD/6-311þG(d,p)//B3LYP/6-31þG(d,p)20 level of
theory (corrected for zero point energies).21 The use of the
double-hybrid functional B2PLYPD for the energy determina-
tions including dispersion interaction is known to give improved
total and relative energies (Scheme 6). All stationary points were
fully optimized and subjected to frequency analyses.
Figure 2. Molecular structure of 17c as obtained by X-ray diffraction
(Schakal plot).
Scheme 4. Synthesis of Pyridines 15aꢀc, 5,6-Dihydrobenzo[h]quinolones 17aꢀc, and Bipyridine 19
Scheme 5. One-Pot Formation of 17ca
a Overall yield is in parentheses. Reagents and conditions: (a) 50 °C, 30 min, no solvent; (b) addition of 1.1 equiv of KOtBu in THF (20 mL/mmol), 1 h;
(c) HCl (2 M), NaOH (2 M) repeated extraction process
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Scheme 6. Suggested Mechanism for the Formation of 5,6-Dihydrobenzo[h]quinolone 17c (R = 4-OMe-Ph)a
a Calculated energies relative to 20-cis-cis at two levels of theory: (a) B3LYP/6-31þG(d,p)//B3LYP/6-31þG(d,p) and (b) (B2PLYPD/6-311þ
G(d,p)//B3LYP/6-31þG(d,p) (both corrected for zero-point energies) [kcal/mol]; see Supporting Information for optimized structures.
Once the open chain anion 20 adopts a suitable helical
conformation (20-trans-trans f 20-cis-cis) with a maximal effort
of 15.5 kcal/mol (B2PLYPD; 21.8 kcal/mol at B3LYP), a new
CꢀC bond is formed among the terminal carbon atoms (C1,
C7) to give diazepinyl anion 22 in a 7-endo-trig cyclization
reaction via transition state 21. The barriers of internal rotations
of the conformers of anion 20 were not considered in the
calculations due to the involvement of counterion and solvent
effects. We assume that these barriers are surmounted easily
under the reaction conditions employed.22 Then, we assume that
cyclic anion 22 tautomerizes to give 24, which then allows the
cleavage of the NꢀN bond via transition state 25. The resulting
1,7-diazaheptatrienyl anion 26 will finally form pyridine 17c in a
6-exo-trig ring-forming reaction (transition state 27) by attack of
the amine at the iminic carbon, tautomerism (28, 29), and after
protonation, elimination of ammonia. Additional calculations
show that the alternative formation of a tertiary amine anion in
the bridgehead position requires more energy. The key steps
(ring-formation 20-cis-cis f 22; NꢀN bond cleavage 24 f 26;
aromatization 29 f 17c) are exothermic and shift the equilib-
rium to the product side. All ring-forming and -breaking transi-
tion states are surprisingly low in energy and are well in
accordance with the reaction conditions applied (room tempera-
ture reaction). Comparison of the neutral structures 10c and 17c
indicate a distinct exothermic reaction (B2PLYPD,: ꢀ53.2 kcal/mol;
B3LYP, ꢀ37.7 kcal/mol) due to aromatization and cleavage of
the high-energy NꢀN bond. Many details of this suggested
mechanism (the pericyclic mode, the NꢀN fission, the necessary
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Figure 3. Calculated NICS values for transition structure 21. Measuring points along an axis perpendicular to the center of the cyclic moiety of the
transition structure are shown in purple (B3LYP/6-311þG(d,p)) (hydrogen atoms omitted for clarity).
The next transition state 25, which is related to the rather
exothermic NꢀN bond fission, appears to have some minor
electrocyclic character, which is indicated by a calculated NICS
value of ꢀ5.7 ppm (Figure 5) and a small charge separation of
0.02 e (N3, ꢀ0.57 e; N4, ꢀ0.55 e). The helical shape of this
transition structure 25 (deviation from plane N3ꢀC2ꢀC1ꢀ
C7 ꢀ6.6°, C2ꢀC1ꢀC7ꢀC6 ꢀ17.5°, C1ꢀC7ꢀC6ꢀC5 ꢀ6.9°,
C7ꢀC6ꢀC5ꢀN4 0.9°, Σ 31.9°) with a NꢀN distance of 1.67 Å
Figure 4. Molecular orbitals HOMO-1 (left) and HOMO-2 (right) of
(NꢀN distance of structure 24 = 1.47 Å) reflects the structural
22 (side view, isocontour value 0.05/0.05; B3LYP/6-311þG(d,p)).
closeness to intermediate 24 (early transition state).
Finally, by inspection of transition structure 27 of the endo-
thermic 6-exo-trig reaction 26 f 28 we found strong evidence for
a charge-controlled electrophileꢀnucleophile mechanism with
huge charge separation of 0.86e (N, ꢀ0.73 e; C, þ0.13 e) and no
markedly magnetic phenomena (NICS, ꢀ2.4 ppm). The CꢀN-
distance (1.94 Å) classifies this transition state to be a late one.
tautomerisms, the NH3 cleavage) bear close mechanistic resem-
blance to the acid-promoted Fischer indole synthesis,4,23
although in our case an anionic (organometallic) route to form
a six-membered heterocycle is realized. Alternative mechanistic
pathways involving three-membered cyclic intermediates (derived
from 22 or 23) require much higher activation barriers according to
calculations.
’ CONCLUSION
On the basis of geometries, charges (determined by NBO24),
and by NICS25,26 values (B3LYP/6-311þG(d,p)) we studied the
transition structures for the 7-endo-trig cyclization reaction
(transition structure 21), the NꢀN bond fission (25), and the
6-exo-trig cyclization (27).
In summary, we have presented a new, widely applicable
preparation of substituted pyridines 15a,b, 5,6-dihydrobenzo-
[h]quinolines 17aꢀc, and bipyridine 19 from 3,4-diazahepta-
trienyl metal compounds 1 as easily accessible starting materials.
This novel transition metal free pyridine synthesis does not
require external oxidants and allows the introduction of at least
four different substituents into the pyridine core unit in one step
under full regiochemical control. For the formation of products
15a,b, 17aꢀc, and 19 we suggest an anionic multistep reaction
mechanism resembling the acid-promoted Fischer indole rearran-
gement and discuss it on the basis of comprehensive quantum
chemical calculations referring to model reaction 10c f 17c. The
transition structure 21 of the 7-endo-trig ring-forming reaction was
found to have the characteristics of a M€obius aromatic electro-
cyclization reaction involving 8π electrons. Then follow an electro-
cyclic NꢀN bond fission step (transition structure 25) and a final
charge-controlled 6-exo-trig cyclization that involves an amine
nucleophile attacking an iminic bond (transition structure 27)
leading to the pyridine derivatives. This work demonstrates the
For the helical, conrotatory, 8π electron transition structure
21 the calculated NICS values of ꢀ7.3 ppm (Figure 3) along an
axis perpendicular to the center of the ring being formed and the
small charge separation of only 0.03 e (C1, ꢀ0.23 e; C7, ꢀ0.26e)
are indicators of a bond-forming step with a predominantly
electrocyclic character. The distinct negative enthalpy of the cycliza-
tion is reflected in the comparatively long distance between the
bond forming atoms C1 and C7 of 2.21 Å. The helically shaped
geometry (deviation from plane C1ꢀC2ꢀN3ꢀN4 7.0°, C2ꢀ
N3ꢀC4ꢀC5 23.2°, N3ꢀN4ꢀC5ꢀC6 13.6°, N4ꢀC5ꢀC6ꢀC7
2.5°, Σ 46.3°) of 21 indicates M€obius aromaticity.26,27
The M€obius aromatic character of the transition structure is
also represented by strong binding interactions in the HOMO-1
and HOMO-2 (Figure 4).
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Figure 5. Calculated NICS values for transition structure 21. Measuring points along an axis perpendicular to the center of the cyclic moiety of the
transition structure are shown in purple (B3LYP/6-311þG(d,p)) (hydrogen atoms omitted for clarity).
versatility ofanionic polyunsaturated hydrazone derivatives for the
development of novel synthetic pathways.
(m, 1H, CHar), 7.05ꢀ7.15 (m, 2H, CHar), 7.81ꢀ7.89 (m, 1H, CHar);
13C NMR (75 MHz, CDCl3) δ 21.5 (γ-CH2), 23.9 (δ-CH2), 29.7 (β-
CH2), 123.9 (CHar), 126.4 (CHar), 127.9 (CHar), 128.2 (CHar), 133.4
(i-CCH2), 138.5 (i-CCN), 147.4(CN); HRMS (ESI) calcd for
C10H13N2þ 161.1073, found 161.1072.
’ EXPERIMENTAL SECTION
Melting points are uncorrected. 1H, 13C NMR spectroscopy:
TMS (1H) (0.00 ppm), CDCl3 (1H) (7.26 ppm), C6D6 (1H) (7.16
ppm), CDCl3 (13C) (77.0 ppm), and C6D6 (13C) (128.1 ppm) were
used as internal reference. All signals in the 1H NMR and 13C
spectra were assigned on the basis of relative intensities, coupling
constants, and GCOSY, GHSQC, and GHMBC experiments. When
necessary, the experiments were carried out with complete exclu-
sion of moisture.
2-Acetylpyridine Hydrazone 12. A three necked flask with a
DeanꢀStark head was charged with 60 mL (1.2 mol) of hydrazine
hydrate and heated to 120 °C. A solution of 2-acetylpyridine (5.13 g,
42.4 mmol) in 30 mL of CHCl3 was added over a period of 5 h. After
cooling to room temperature, the aqueous layer was washed with DCM.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. Compound 12 was obtained as light
yellow solid in 4.87 g (36.0 mmol, 85%) yield. Mp 61 °C (lit. 77 °C17);
1H NMR (300 MHz, C6D6) δ 2.09 (s, 3H, CH3), 4.96 (br, 2H, NH2),
6.62 (ddd, 3JHH = 7.2 Hz, 4JHH = 4.9 Hz, 5JHH = 0.8 Hz, 1H, 5-CHpy),
Acetophenone Hydrazone 6. A three-necked flask with a
DeanꢀStark head was charged with 60 mL (1.2 mol) of hydrazine
hydrate and heated to 120 °C. A solution of acetophenone (4.81 g,
40.0 mmol) in 30 mL of CHCl3 was added over a period of 4 h. After
cooling to room temperature the aqueous layer was washed with DCM.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. Compound 6 was obtained as a
light yellow solid in 5.23 g (39.0 mmol, 95%) yield. Mp 67 °C (lit.
24ꢀ25 °C15); 1H NMR (300 MHz, C6D6) δ 1.52 (s, 3H, CH3), 4.69
(br, 2H, NH2), 7.06ꢀ7.10 (m, 1H, p-CHar), 7.12ꢀ7.17 (m, 2H, m-
CHar), 7.70ꢀ7.75 (m, 2H, o-CHar); 13C NMR (75 MHz, C6D6) δ 10.6
(CH3), 125.7 (m-CHar), 127.9 (o-CHar), 128.4 (p-CHar), 140.1 (i-Car),
3
7.11 (m, 1H, 4-CHpy), 8.21 (d, JHH = 8.1 Hz, 1H, 3-CHpy), 8.45 (d,
3JHH = 4.7 Hz, 1H, 6-CHpy); 13C NMR (75 MHz, C6D6) δ 8.92 (CH3),
119.60 (5-CHpy), 122.15 (3-CHpy), 135.57 (4-CHpy), 146.44 (CN),
þ
148.51 (6-CHpy), 157.29 (2-Cpy); HRMS (ESI) calcd for C7H10N3
136.0869, found 136.0859.
General Procedure A for the Formation of N,N0-Bisalkyli-
dene Hydrazine Derivatives. Hydrazone 6, 9, or 12 (1 equiv) and 1
equiv of the corresponding cinnamaldehyde derivative were each
dissolved in 2 mL of TBME and mixed in a round-bottom flask. The
mixture was heated to 50 °C, and the solvent was removed under
reduced pressure. The mixture was stirred at 50 °C, 5 mbar for 2 h. The
products were obtained without noteworthy byproducts.
þ
145.1 (CN); HRMS (ESI) calcd for C8H11N2 135.0917, found
135.0935.
r-Tetralone Hydrazone 9. A three necked flask with a Deanꢀ
Stark head was charged with 60 mL (1.2 mol) of hydrazine hydrate and
heated to 120 °C. A solution of R-tetralone (11.7 g, 80.0 mmol) in
40 mL of CHCl3 was added over a period of 5 h. After cooling to room
temperature, the aqueous layer was washed with DCM. The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated. Compound 9 was obtained as a light yellow solid in 12.67
g (78.8 mmol, 99%) yield. Mp 41 °C (lit. 38ꢀ40 °C16); 1H NMR (300
MHz, CDCl3) δ 1.79ꢀ1.90 (m, 2H, γ-CH2), 2.34ꢀ2.44 (m, 2H,
δ-CH2), 2.58ꢀ2.69 (m, 2H, β-CH2), 5.21 (s, 2H, NH2), 6.96ꢀ7.05
N-Cinnamylideneacetophenone Hydrazone 7a. According to gen-
eral procedure A 7a was obtained from hydrazone 6 (1.32 g, 10.0 mmol)
and trans-3-phenyl-2-propenal (1.32 g, 10.0 mmol) after purification by
column chromatography (cyclohexane 98%, TBME 2%) as a yellow
solid in 2.38 g (9.59 mmol, 96%) yield. Mp = 92 °C; IR (neat) ν~ = 3053
(w), 3038 (w), 3021 (w), 1626 (m), 1597 (m), 1578 (m), 1487 (w),
1447 (m), 1364 (m), 1285 (m), 1159 (w), 1074 (w), 976 (s), 947 (m),
760 (m), 746 (s), 687 (s), 662 (m), 625 (w), 567 (s), 517 (s), 513 (s),
501 (s); 1H NMR (300 MHz, C6D6) δ 2.50(s, 3H, CH3), 6.75 (d, 3JHH
16.1 Hz, 1H, i-CCHolef), 7.09ꢀ7.18 (m, 3H, CHar) 7.20ꢀ7.30 (m, 5H,
=
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3
CHar), 7.34 (dd, JHH = 16.1, 9.6 Hz, 1H, NdCHCHolef), 8.04ꢀ8.15
N-Cinnamylidene-R-tetralone Hydrazone 10b. According to gene-
ral procedure A 10b was obtained from hydrazone 9 (3.20 g, 20.0 mmol)
and trans-3-phenyl-2-propenal (2.64 g, 20.0 mmol) after purification by
column chromatography (cyclohexane 80%, TBME 15%, TEA 5%) as
a yellow solid in 5.12 g (18.7 mmol, 93%) yield. Mp = 74 °C; IR (neat)
ν~ = 3034 (w), 2932 (w), 2866 (w), 2835 (w), 1624 (m), 1589 (m), 1449
(m), 1321 (m), 1292 (m), 1161 (w), 1123 (w), 976 (m), 768 (m), 752
(s), 733 (s), 691 (s); 1H NMR (300 MHz, C6D6) δ 1.47ꢀ1.65 (m, 2H,
γ-CH2), 2.32ꢀ2.51 (m, 2H, δ-CH2), 2.92ꢀ3.14 (m, 2H, β-CH2), 6.69
(m, 2H, CHar), 8.49 (dd, 3JHH = 9.6 Hz, 1H, NdCH); 13C NMR (75
MHz, C6D6) δ 14.5 (CH3), 126.5 (i-CCHolef), 127.1 (CHar), 127.3
(CHar), 128.2 (CHar), 128.6 (CHar), 128.9 (p-CHar), 129.9
(NdCHCHolef), 136.2 (i-C), 138.7 (i-C),141.4 (p-CHar), 160.þ5
(NdCH), 163.9 (i-CCdN); HRMS (ESI) calcd for C17H17N2
249.1386, found 249.1383. Anal. Calcd for C17H16N2 (248.32): C
82.22, H 6.49, N 11.28. Found: C 82.20, H 6.38, N 11.25.
N-(R-Methylcinnamylidene)acetophenone Hydrazone 7b. Accord-
ing to general procedure A 7b was obtained from hydrazone 6 (670 mg,
5.0 mmol) and R-methyl-trans-3-phenyl-2-propenal (730 mg, 5.0 mmol)
after purification by column chromatography (cyclohexane 87%, TBME
13%) as a yellow solid in 1.14 g (4.3 mmol, 87%) yield. Mp = 90 °C; IR
(neat) ν~ = 3057 (w), 3030 (w), 2959 (w), 1599 (m), 1576 (m), 1491
(w), 1445 (m), 1362 (m), 1287 (m), 1200 (w), 1180 (w), 1078 (w),
1024 (m), 962 (m), 922 (m), 876 (w), 756 (s), 689 (s), 654 (s);1H
NMR (500 MHz, C6D6) δ 1.40 (s, 3H, ColefCH3), 2.34 (d, 3JHH = 1.2
Hz, 3H, CH3CdN), 6.66 (s, 1H, i-CCHolef), 7.01ꢀ7.23 (m, 10H, CHar,
CHolef), 8.52 (s, 1H, CHar); 13C NMR (125 MHz, C6D6) δ 13.2
(ColefCH3), 26.9 (CH3CdN), 126.7 (CHar), 127.6 (CHar), 127.6
(CHar), 128.0 (CHar), 128.1 (i-Car), 128.2 (CHar), 129.3 (i-Car), 129.5
(CHar), 135.5 (ColefCH3), 136.7 (CH3CdN), 1þ39.9 (i-CarCHolef),
166.2 (CHN); HRMS (ESI) calcd for C18H19N2 263.1543, found
263.1540. Anal. Calcd for C18H18N2 (262.35): C 82.41, H 6.92, N 10.68.
Found: C 82.16, H 6.93, N 10.60.
N-(4-Phenyl-3-buten-2-ylidene)acetophenone Hydrazone 7c. Ac-
cording to general procedure A 7c was obtained from hydrazone 6 (0.67
g, 5.0 mmol) and trans-4-phenyl-3-buten-2-one (0.73 g, 5.0 mmol) after
purification by column chromatography (cyclohexane 98%, TBME 2%)
as a yellow solid in 1.1 g (4.2 mmol, 84%) yield. Mp = 87 °C; IR (neat)
ν~ = 3383 (br), 3217 (br), 3063 (w), 1605 (m), 1568 (w), 1493 (w), 1445
(m), 1362 (m), 1310 (w), 1285 (m), 1179 (w), 1076 (w), 1024 (m), 758
(s), 689 (s), 652 (m), 563 (m); 1H NMR (300 MHz, C6D6) δ 2.08 (s,
3H, CHolefCCH3), 2.25 (s, 3H, i-CarCCH3), 6.88 (d, 3JHH = 16.6 Hz,
1H, i-CCHolef), 7.00ꢀ7.14 (m, 3H, CHar), 7.17ꢀ7.24 (m, 3H, CHar),
7.24ꢀ7.31 (m, 2H, CHar), 7.35 (d, 3JHH = 16.6 Hz, 1H, CHolefCdN),
7.90ꢀ8.00 (m, 2H, CHar); 13C NMR (75 MHz, CDCl3) δ 13.2
(CHolefCCH3), 14.6 (i-CarCCH3), 127.2 (CHar), 127.4 (CHar), 128.5
(CHar),128.6 (i-CarCHolef), 129.0 (CHar), 129.8 (p-CHar), 130.8
(CHolefCdN), 134.8 (p-CHar), 137.0 (i-Car), 139.2 (i-Car), 158.4
(CdN), 160.6 (CdN); HRMS (ESI) calcd for C18H19N2þ 263.1543,
found 263.1536.
3
(d, JHH = 16.0 Hz, 1H, i-CCHolef), 6.89ꢀ6.96 (m, 1H, CHar),
6.99ꢀ7.08 (m, 3H, CHar), 7.09ꢀ7.21 (m, 4H, CHar), 7.28 (dd, 3JHH
=
16.0, 9.6 Hz, 1H, NdCHCHolef), 8.43 (d, 3JHH = 9.6 Hz, 1H, NCH),
8.83 (d, 3JHH = 7.7 Hz, 1H, CHar); 13C NMR (75 MHz, C6D6) δ 22.4
(γ-CH2), 27.7 (δ-CH2), 30.2 (β-CH2), 126.4, 126.6, 127.0, 127.5, 128.9,
128.9, 129.1, 130.2, 133.4, 136.5, 141.4, 141.5 (CHar), 160.3 (NCH),
þ
164.2 (R-CN); HRMS (ESI) calcd for C19H19N2 275.1543, found
275.1537. Anal. Calcd for C19H18N2 (274.36): C 83.18, H 6.61, N 10.21.
Found: C 82.89, H 6.80, N 10.11.
N-(40-Methoxy)cinnamylidene-R-tetralone Hydrazone 10c. Accor-
ding to general procedure A 10c was obtained from hydrazone 9 (320
mg, 2.0 mmol) and trans-3-(4-methoxyphenyl)-2-propenal (324 mg,
2.0 mmol) after purification by column chromatography (cyclohexane
80%, TBME 15%, TEA 5%) as a yellow solid in 520 mg (1.7 mmol, 86%)
yield. Mp = 91 °C; IR (neat) ν~ = 3055 (w), 2938 (m), 2837 (w), 1599
(m), 1589 (m), 1508 (m), 1452 (m), 1296 (m), 1252 (s), 1173 (m),
1152 (m), 1026 (s), 989 (s), 820 (vs), 770 (vs), 733 (s), 652 (w), 530
(m), 505 (m), 494 (s); 1H NMR (500 MHz, C6D6) δ 1.53ꢀ1.61 (m,
2H, γ-CH2), 2.40ꢀ2.49 (m, 2H, δ-CH2), 3.02ꢀ3.13 (m, 2H,
β-CH2), 3.24 (s, 3H, OCH3), 6.67ꢀ6.62 (m, 2H, m-CH4-OMe-ph),
6.73 (d, 3JHH = 16.0 Hz, 1H, i-CCHolef), 6.94 (dd, 3JHH = 7.8, 7.2 Hz,
1H, CHar), 7.15ꢀ7.09 (m, 1H, CHar, 2H, o-CH4-OMe-ph), 7.20ꢀ7.16 (m,
1H, CHar), 7.23 (dd, 3JHH = 16.0, 9.6 Hz, 1H, NdCHCHolef), 8.52 (d,
3JHH = 9.6 Hz, 1H, NCH), 8.85 (dd, 3JHH = 7.9 Hz, 4JHH = 1.5 Hz, 1H,
CHar); 13C NMR (126 MHz, C6D6) δ 22.4 (γ-CH2), 27.7 (δ-CH2), 30.2
(β-CH2), 54.8 (OCH3), 114.5 (m-CH4-OMe-ph), 124.8 (NdCHCHolef),
126.3, 126.5, 128.8, 128.9, 129.0 (CHar), 129.3 (i-CCHolef), 129.6 (p-C4-
OMe-ph), 130.1 (i-C), 133.5 (i-C), 141.2 (i-CCHolef), 160.8 (NCH), 163.9
(i-CN); HRMS (ESI) calcd for C20H21N2Oþ 305.1648, found
305.1653. Anal. Calcd for C20H20N2O (304.39): C 78.92, H 6.62, N
9.20. Found: C 78.81, H 6.63, N 9.19. X-ray crystal structure analysis of
10c can be found in the Supporting Information.
N-(40-Methoxy)cinnamylidene-2-acetylpyridine Hydrazone 13. Ac-
cording to general procedure A 13 was obtained from hydrazone 12
(1.35 g, 10 mmol) and trans-3-(4-methoxyphenyl)-2-propenal (1.65 g,
10 mmol) after purification by recrystallization from cyclohexane as a
yellow solid in 1.94 g (7.0 mmol, 70%) yield. Mp = 82 °C; IR (neat) ν~ =
3013 (w), 2965 (w), 2932 (w), 2839 (w), 1630 (m), 1601 (s), 1585 (m),
1564 (m), 1510 (s), 1468 (m), 1437 (m), 1362 (w), 1306 (m), 1298
(m), 1258 (s), 1248 (s), 1173 (s), 1155 (s), 1109 (m), 1030 (s), 991 (s),
976 (m), 959 (w), 833 (s), 814 (s), 785 (s), 762 (m), 741 (m), 671 (m);
1H NMR (400 MHz, C6D6) δ 2.92 (s, 3H, CCH3), 3.23 (s, 3H, OCH3),
6.48ꢀ6.74 (m, 2H, m-CH4-OMe-ph, 1H, CHolef, 1H, CHpy), 7.02ꢀ7.25
(m, 2H, o-CH4-OMe-ph, 1H, CHolef, 1H, CHpy), 8.38 (d, 3JHH = 9.6 Hz,
1H, CHpy), 8.46ꢀ8.51 (m, 1H, CHolef, 1H, CHpy); 13C NMR (101
MHz, C6D6) δ 14.0 (CCH3), 54.8 (OCH3), 114.5 (m-CH4-OMe-ph),
121.3 (5-CHpy), 124.1 (i-CCHolef), 124.6 (3-CHpy), 129.1 (o-CH4-OMe-ph),
129.2 (i-C4-OMe-ph), 135.7 (4-CHpy), 141.9 (NdCHCHolef), 149.0
(NCHolef), 156.7 (2-Cpy), 161.0 (2-CpyCN), 161.1 (6-CHpy), 165.6
(p-C4-OMe-ph); HRMS (ESI) calcd for C17H18N3Oþ 280.1444, found
280.1449.
N-(40-Fluoro)cinnamylidene-R-tetralone Hydrazone 10a. Accord-
ing to general procedure A 10a was obtained from hydrazone 9 (802 mg,
5.0 mmol) and trans-3-(4-fluorophenyl)-2-propenal (750 mg, 5.0 mmol)
after purification by column chromatography (cyclohexane 87%, TBME
13%) as a yellow solid in 1.49 g (4.9 mmol, 98%) yield. Mp = 92 °C; IR
(neat) ν~ = 3034 (vw), 2930 (w), 2866 (vw), 1624 (m), 1593 (m), 1584
(m), 1506 (s), 1290 (w), 1223 (s), 1159 (s), 980 (s), 949 (m), 858 (m),
1
814 (vs), 756 (s), 729 (vs), 658 (m), 640 (m); H NMR (400 MHz,
C6D6) δ 1.42ꢀ1.71 (m, 2H, γ-CH2), 2.36ꢀ2.47 (m, 2H, δ-CH2),
2.99ꢀ3.08 (m, 2H, β-CH2), 6.53 (d, 3JHH = 16.1 Hz, 1H, i-CarCHolef),
3
6.66 (dd, JHH,HF = 8.6, 8.8 Hz, 2H, m-CH4-F-ph), 6.95ꢀ6.84 (m, 3H,
o-CH4-F-ph, CHar), 7.09 (dd, 3JHH = 16.2, 9.5 Hz, 1H, NdCHCHolef),
7.10ꢀ7.15 (m, 1H, CHar), 7.22ꢀ7.16 (m, 1H, CHar), 8.41 (d, 3JHH = 9.6
Hz, 1H, NdCH), 8.83 (d, 3JHH = 7.8 Hz, 1H, CHar); 13C NMR (101
MHz, C6D6) δ 22.4 (γ-CH2), 27.7 (δ-CH2), 30.2 (β-CH2), 115.9
(d, 2JCF = 21.8 Hz, m-CH4-F-ph), 126.4 (CHar), 126.6 (CHar), 126.7 (d,
5JCF = 2.5 Hz, i-CCHolef), 129.0 (CHar), 129.2 (CHar), 130.3 (Nd
CHCHolef), 132.7 (d, 3JCF = 3.4 Hz, o-CH4-F-ph), 133.4 (i-Car), 139.9 (d,
4JCF = 1.2 Hz, i-C4-F-ph), 141.6 (i-Car), 160.1 (NCH), 163.3 (d, 1JCF
249.1 Hz, þp-C4-F-ph), 164.3 (R-CN); HRMS (ESI) calcd for
C19H18FN2 293.1449, found 293.1448. Anal. Calcd for C19H17FN2
(292.35): C 78.06, H 5.86, N 9.59. Found: C 77.72, H 5.97, N 9.33.
=
General Procedure B for the Synthesis of 2,4-Diarylpyr-
idine Derivatives. N,N0-Bisalkylidene hydrazines 7a,b, 10aꢀc, and
12 were dissolved in 20 mL of dry THF and treated with 1.5 equiv of
KOtBu solution (1 M, THF) at room temperature. After the reaction
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The Journal of Organic Chemistry
ARTICLE
was completed according to TLC reaction control (0.5ꢀ2 h), the
mixture was washed with brine, dried over MgSO4, filtered, and
concentrated.
2,4-Diphenylpyridine 15a. According to general procedure B 15a
was obtained from N,N0-bisalkylidene hydrazine 7a (400 mg, 1.6 mmol)
after purification by column chromatography (cyclohexane 70%, TBME
30%) as colorless solid in 78 mg (0.34 mmol, 21%) yield. Mp = 80 °C.
For spectroscopic data see ref 18.
2,4-Diphenyl-5-methylpyridine 15b. According to general procedure
B 15b was obtained from N,N0-bisalkylidene hydrazine 7b (524 mg,
2 mmol) after purification by column chromatography (cyclohexane
85%, TBME 15%) as colorless solid in 110 mg (0.44 mmol, 22%) yield.
Mp = 101 °C. For spectroscopic data see ref 18.
3JHH = 8.6, 5.9 Hz, 2H, CH2), 3.33 (s, 2H, OCH3), 6.76ꢀ6.82 (m, 2H,
m-CH4-OMe-ph), 6.87 (d, 3JHH = 4.9 Hz, 1H, 3-CHquin), 6.89ꢀ7.07 (m,
2H, o-CH4-OMe-ph, CHquin), 7.13ꢀ7.20 (m, 1H, CHquin), 7.31 (m, 1H,
CHquin), 8.61 (d, 3JHH = 4.9 Hz, 1H, 2-CHquin), 8.98 (dd, 3JHH = 7.8 Hz,
4JHH = 1.1 Hz, 1H, 10-CHquin); 13C NMR (75 MHz, C6D6) δ 25.7
(CH2), 28.3 (CH2), 54.8 (CH3), 114.1 (m-CH4-OMe-ph), 123.5 (3-CHquin),
126.4, 127.5, 127.6 (CHquin), 129.2 (4-Cquin), 129.4 (4a-Cquin), 130.3
(o-CH4-OMe-ph), 131.7 (i-C4-OMe-ph), 136 (10-CHquin), 138.2 (6a-Cquin),
147.8 (2-Cquin), 148.1 (10a-Cquin), 153.6 (10b-Cquin), 159.9 (p-C4-OMe-ph);
HRMS (ESI) calcd for C20H18NOþ 288.1383, found 288.1372. X-ray
crystal structure analysis of 17c can be found in the Supporting Information.
4-(4-Methoxyphenyl)-2,20-bipyridine 19. According to general pro-
cedure B 19 was obtained from N,N0-bisalkylidene hydrazine 13
(425 mg, 1.5 mmol) after purification by column chromatography
(cyclohexane 40%, TBME 40%, TEA 20%) as orange solid in 101 mg
(0.33 mmol, 22%) yield. Mp = 133 °C (lit 131ꢀ132.5 °C19); IR (neat)
ν~ = 3059 (w), 2934 (w), 2839 (w), 1672 (w), 1599 (s), 1580 (m), 1512
(s), 1456 (s), 1443 (m), 1391 (w), 1290 (m), 1250 (s), 1182 (s), 1040
(m), 1024 (s), 989 (m), 824 (s), 793 (s), 748 (s), 739 (m), 662 (m), 617
4-(4-Fluorophenyl)-5,6-dihydrobenzo[h]quinoline 17a. According
to general procedure B 17a was obtained from N,N0-bisalkylidene hydra-
zine 10a (585 mg, 2.0 mmol) after purification by column chromatog-
raphy (cyclohexane 85%, TBME 15%) as colorless solid in 131 mg (0.51
mmol, 25%) yield. Mp = 103 °C; IR (neat) ν~ = 3044 (vw), 2924 (w),
2853 (w), 1603 (m), 1545 (w), 1508 (s), 1450 (m), 1439 (m), 1387
(m), 1225 (s), 1157 (m), 1097 (w), 843 (w), 831 (vs), 818 (s), 795 (m),
(m); 1H NMR (300 MHz, C6D6) δ 3.28 (s, 3H, CH3), 6.72 (ddd, 3JHH
=
4
7.5, 4.7 Hz, JHH = 1.3 Hz, 1H, 50-CHbipy), 6.79ꢀ6.73 (m, 2H,
1
746 (vs), 733 (s), 650 (w), 621 (m); H NMR (300 MHz, C6D6) δ
3
4
3
m-CH4-OMe-ph), 7.12 (dd, JHH = 5.1, JHH = 1.9 Hz, 1H, 5-CHbipy),
7.26 (ddd, 3JHH = 8.0, 7.5, 4JHH = 1.8 Hz, 1H, 40-CHbipy), 7.49ꢀ7.39 (m,
2H, o-CH4-OMe-ph), 8.58 (ddd, 3JHH = 4.7, 4JHH = 1.8, 5JHH = 0.9 Hz, 1H,
2.41ꢀ2.55 (m, 4H, 5-CH2, 6-CH2), 6.68 (d, JHH = 4.9 Hz, 1H,
3
3-CHquin), 6.76ꢀ6.83 (m, 3H, m-CH4-F-ph, CHquin), 7.00 (d, JHH
=
=
7.5 Hz, 1H, CHquin), 7.12ꢀ7.20 (m, 2H, o-CH4-F-ph), 7.30 (dd, 3JHH
3
5
60-CHbipy), 8.65 (dd, JHH = 5.1, JHH = 0.8 Hz, 1H, 6-CHbipy),
3
3
7.7 Hz, JHH = 1.2 Hz, 1H, CHquin), 8.56 (d, JHH = 4.9 Hz, 1H,
3
4
8.84ꢀ8.88 (m, 1H, 30-CHbipy), 9.20 (dd, JHH =1.9, JHH = 0.8 Hz,
1H, 3-CHbipy); 13C NMR (75 MHz, C6D6) δ 54.8 (OCH3), 114.7
(m-CH4-OMe-ph), 118.7 (3-CHbipy), 121.2 (5-CHbipy), 121.4 (30-CHbipy),
123.7 50-CHbipy), 128.5 (o-CH4-OMe-ph), 131.1 (i-C4-OMe-ph), 136.6 (40-
CHbipy), 148.8 (4-Cbipy), 149.3 (6-CHbipy), 150.0 (60-CHbipy), 156.9 (2-
Cbipy), 157.2 (20-Cbipy), 160.9 (p-C4-OMe-ph); HRMS (ESI) calcd for
C17H15N2Oþ 263.1179, found 263.1172.
2-CHquin), 8.95 (dd, JHH = 7.8, JHH = 1.2 Hz, 1H, 10-CHquin); 13C
3
4
NMR (75 MHz, C6D6) δ 25.5 (6-CH2), 28.1 (5-CH2), 115.4 (d, 2JCF
=
21.4 Hz, m-CH4-F-ph), 123.3 (3-CHquin), 126.4, 127.5, 127.7 (CHquin),
3
129.2 (4-Cquin), 129.4 (CHquin), 130.8 (d, JCF = 8.0 Hz, o-CH4-F-ph),
4
135.3 (d, JCF = 3.4 Hz, i-C4-F-ph), 135.7 (4a-Cquin), 138.1 (6a-Cquin),
147.2 (10a-Cquin), 147.8 (2-CHquin), 153.7 (10b-Cquin), 162.8 (d, 1JCF
=
247.0 Hz, p-C4-F-ph); HRMS (ESI) calcd for C19H15FNþ 276.1183,
found 276.1171. Anal. Calcd for C19H14FN (275.32): C 82.89, H 5.13,
N 5.09. Found: C 82.64, H 5.53, N 4.78.
’ ASSOCIATED CONTENT
4-Phenyl-5,6-dihydrobenzo[h]quinoline 17b. According to general
procedure B 17b was obtained from N,N0-bisalkylidene hydrazine 10b
(548 mg, 2.0 mmol) after purification by column chromatography
(cyclohexane 88%, TBME 12%) as colorless solid in 165 mg (0.64 mmol,
32%) yield. Mp = 77 °C; IR (neat) ~ν = 3042 (w), 2947 (w), 2882 (w),
1605 (w), 1589 (w), 1568 (m), 1545 (m), 1497 (w), 1450 (w), 1439
(w), 1391 (m), 1275 (w), 1209 (w), 1074 (w), 1030 (w), 895 (w), 845
(m), 793 (m), 773 (m), 764 (m), 746 (s), 733 (m), 704 (s), 642 (m),
625 (s); 1H NMR (500 MHz, C6D6) δ 2.44 (dd, 3JHH = 8.5, 6.1 Hz, 2H,
6-CH2), 2.61 (dd, 3JHH = 8.5, 6.1 Hz, 2H, 5-CH2), 6.81 (d, 3JHH = 4.9
Hz, 1H, 3-CHquin), 6.98 (d, 3JHH = 7.5 Hz, 1H, CHquin), 7.10ꢀ7.05 (m,
2H, CHp3h), 7.12ꢀ7.18 (m, 4H, CHquin, CHph), 7.30 (m, 1H, CHquin),
Supporting Information. 1H and 13C spectra for the new
S
b
compounds; optimized Cartesian coordinates (B3LYP/6-
31þG(d,p) and B2PLYPD/6-311þG(d,p)//B3LYP/6-31þG-
(d,p)þZPE energies for the calculated structures; graphics of
crystal structures with thermal ellipsoids with 50% probability.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: wurthwe@uni-muenster.de.
3
8.58 (d, JHH = 4.9 Hz, 1H, 2-CHquin), 8.96 (d, JHH = 6.9 Hz, 1H,
10-CHquin); 13C NMR (126 MHz, C6D6) δ 25.6 (6-CH2), 28.2
(5-CH2), 123.3 (3-CHquin), 126.4 (CHar), 127.4 (CHar), 127.6
(CHar), 127.9 (CHar), 128.5 (CHar), 129.0 (CHar), 129.2 (4-Cquin),
129.3 (4a-Cquin), 135.8 (o-CHph), 138.2 (10-CHquin), 139.5 (6a-Cquin),
147.7 (2-Cquin), 148.3 (10a-Cquin), 153.6 (10b-Cquin); HRMS (ESI)
calcd for C19H16Nþ 258.1277, found 258.1268. Anal. Calcd for
C19H15N (257.33): C 88.68, H 5.88, N 5.44. Found: C 88.35, H 5.97,
N 5.30.
’ ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsge-
meinschaft (DFG, Bad Godesberg) and the Fonds der Che-
mischen Industrie (Frankfurt). We also thank Paul Bunse for
preparative support.
4-(4-Methoxyphenyl)-5,6-dihydrobenzo[h]quinoline 17c. Accord-
ing to general procedure B 17c was obtained from N,N0-bisalkylidene
hydrazine 10c (330 mg, 1.1 mmol) after purification by column chroma-
tography (cyclohexane 70%, TBME 30%) as orange solid in 120 mg
(0.42 mmol, 38%) yield. Mp = 112 °C; IR (neat) ν~ = 3036 (vw), 2951
(w), 2930 (w), 2835 (w), 1607 (m), 1574 (w), 1512 (s), 1450 (m), 1439
(m), 1387 (m), 1292 (m), 1246 (vs), 1179 (s), 1113 (m), 1034 (s), 829
(vs), 814 (s), 795 (m), 750 (vs), 737 (m), 650 (m), 621 (s); 1H NMR
(300 MHz, C6D6) δ 2.49 (dd, 3JHH = 8.6, 5.9 Hz, 2H, CH2), 2.69 (dd,
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