Synthesis and X-ray crystallographic analysis of free base and hexafluorophosphate salts of 3,4-dihydroisoquinolines from the Bischler-Napieralski reaction

Article abstract of DOI:10.1039/d0nj05235c

The Bischler-Napieralski reaction of N-phenylethyl cinnamamides was investigated in acetonitrile and 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF6). Strong effects on the nature of the isolated products were observed depending on the structur

Full text of DOI:10.1039/d0nj05235c

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Synthesis and X-ray crystallographic analysis of free base and
hexafluorophosphate salts of 3,4-dihydroisoquinolines from the
Bischler-Napieralski reaction
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
c
a
c
DOI: 10.1039/x0xx00000x
Carlos E. Puerto Galvis, Cristian C. Granados, Vladimir V. Kouznetsov * and Mario A. Macías* .
The Bischler-Napieralski reaction of N-phenylethyl cinnamamides was investigated in acetonitrile and 1-butyl-3-
methylimidazolium hexafluorophosphate ([bmim]PF
observed depending on the structure of the starting materials and the solvent used. The corresponding 3,4-
dihydroisoquinoline as free base was isolated when acetonitrile was employed, but the respective 3,4-
dihydroisoquinolines, as hexafluorophosphate salts, were obtained when [bmim]PF was used as a reaction media due to
6
). Strong effects on the nature of the isolated products were
a
6
an anion methatesis between the reaction intermediates and the solvent. A full X-ray crystallographic analysis for a 1-
phenethyl-3,4-dihydroisoquinoline derivative is reported for the first time and revealed that in this core, as a free base, the
torsion angle C10-N1-C9-C8 allows the existence of two conformers, crystallizing in a centrosymmetryc P2
However, only one conformer crystallized in the hexafluorophosphate salt, therefore describing an enantiomorphic P6
space group. The absence of type II symmetry operations allowed the formation of 1D-channels that contain the PF
1
/n space group.
1
6
-
anions and cross the entire structure along [001] direction giving interesting potential uses as ionic conductor.
Additionally, CE-B3LYP model energies showed that in both crystal structures, dispersion forces have an important role in
the supramolecular architecture. Nevertheless, in the hexafluorophosphate salt electrostatic forces increase the structural
stability to a total packing energy of -173.6 kJ/mol, compared with the free base with a value of -135.0 kJ/mol.
1
. Introduction
One of the largest family of naturally occurring alkaloids are
the nitrogen-containing heterocycles with the isoquinoline
1
core. Nowadays, these natural and synthetic derivatives are
2
recognized for their broad range of pharmacological activities,
and among them, the C1- substituted 3,4-dihydroisoquinolines
3
3,4
5
7
such as: Nelumstemine
1
, Longifolonine
2
,
Velucryptine
, Dysoxyline
3
5
,
,
6
and the tetrahydroisoquinolines: Noscapine
4
8
and Cryptostiline I
6
that represent an important and
promising group of analogues with diuretic, astringent,
cardiac, antiviral and anticancer activities (Figure 1).
Currently, for the synthesis of 3,4-dihydroisoquinolines a
9
series of interesting protocols, such as Pictet-Spengler and
10
Pomeranz-Fritsch strategies have been well developed, but
the Bischler-Napieralski reaction has been one of the preferred
Fig
1.
Representative
).
bioactive
3,4-dihydro-
and
tetrahydroisoquinolines (1-6
methodologies due to its practicability and reliability for
11
accessing the 3,4-dihydroisoquinoline core. This has been a
well-studied reaction in organic chemistry, where N-arylethyl
amides bearing electron-rich arenes are well tolerated as
substrates, and POCl , PCl or P O can be used as dehydrating
3
5
2 5
reagents, while the reaction can be carry on in CH CN, toluene
3
or CH Cl as a solvent or under free-solvent conditions at
2
2
1
2,13
different temperatures (40-100 °C).
In the special cases in
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which N-phenylethyl cinnamamides are employed as SHELXL2014. Molecular and supramolecular graphics were
substrates
dihydroisoquinolines, Cortes et al. reported previously that better understanding of the crystal packing, the
intermediates with the 1-styryl-3,4-dihydroisoquinoline core crystallographic analysis was complemented with calculations
were unstable and these authors choose to transform these using CE-B3LYP energy model based on B3LYP/6-31G(d,p)
View Article Online
2
0
DOI: 10.1039/D0NJ05235C
1-styryl-3,4- carried out using the software Mercury. In order to obtain a
for
the
synthesis
of
1
4
derivatives instead of study their isolation.
Recently, we established an efficient protocol for the monomers which was applied to the molecular crystals. This
synthesis and isolation of series of 1-styryl-3,4- model is implemented in CrystalExplorer. In these calculations,
dihydroisoquinolines as hexafluorophosphate salts in excellent the total interaction energy was modeled as the sum of the
quantum mechanical charge distribution for unperturbed
a
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yields , in contrast to the previous methodology reported by electrostatic (E ), polarization (E ), dispersion (E ), and
ele
pol
dis
McCluskey et al. who obtained simple 3,4-dihydroisoquinolines exchange–repulsion (E ) terms based on molecular
derivatives as a free bases. The isolation of isoquinolinium wavefunctions calculated applying the crystal symmetry
salts is relevant from the pharmacological point of view, in obtained from X-ray crystallographic results.
order to increase oral biodisponibility (absortion), aqueous surfaces (HFs) mapped over dnorm were calculated using
solubility (blood transport) and stability, or for chemical TONTO, a Fortran-based object-oriented system for quantum
purposes such as facilitate the asymmetric hydrogenation of chemistry and crystallography, by the B3LYP method using the
isoquinolines. Therefore, it is highly desirable to obtain these 6-31G(d,p) basis set implemented in CrystalExplorer.
derivatives in one step instead of the current protocols, which
isolate the respective isoquinolines and then treat them in an
additional step with organic or inorganic acids to obtain the
corresponding salts.
rep
16
2
1,22,23
Hirshfeld
1
7
1
8
24
3
. Results and discussion
3.1 Synthesis
We began our study performing the synthesis of the respective
-styryl-3,4-dihydroisoquinolin hexafluorophosfates 2a-b
through the Bischler-Napieralski reaction starting from the N-
phenethyl cinnamamides 1a-b and employing the ionic liquid
Thus, considering the interest in exploring the chemistry of
3
,4-dihydroisoquinolines, we envisioned that manipulating the
1
structure of the starting materials and the reaction conditions,
specially the solvent and temperature of the Bischler-
Napieralski reaction, we could obtain 3,4-dihydroisoquinolines
[
(
bmim]PF as a solvent accordingly to our previous report
6
of great interest, as free bases or PF -salts, crystalize them,
6
15
Scheme 1).
confirm their structure by single crystal X-ray diffraction
analysis and perform computational calculations at B3LYP level
of theory to explore their supramolecular characteristics in
In this stage, the reaction proceeded smoothly to form the
corresponding 1-styryl-3,4-dihydroisoquinoline 2a’
, which
immediately reacted with the HCl released from the Bischler-
Napieralski reaction to furnish the respective hydrochloride
a’’ (Scheme 1). The excess of POCl used also increases the
3
solid state and stability regarding the PF -anion.
6
2
concentration of HCl (pK = -5.9) in the reaction media, and
a
2
. Experimental
when the reaction was treated with crushed ice during the
work-up, an aqueous solution is formed in which two cations
2.1 Synthesis
+
-
(
[bmim] and dihydroisoquinolinium) and two anions (Cl and
-
6
A general procedure and the characterization data of PF ) are present and interacting. At this point, an anion
compounds are shown in supporting information.
metathesis occurs, in which the chlorine anion affects the
2.2 Refinement and computational methods
The X-ray intensity data were measured at room
temperature [298 (2) K] using MoKα radiation (λ = 0.71073 Å),
and ω scans, in an Agilent SuperNKova, Dual, Cu at Zero, Atlas
four-circle diffractometer equipped with a CCD plate detector.
The collected frames were integrated with the CrysAlis PRO
software package (CrysAlisPro 1.171.39.46e, Rigaku Oxford
Diffraction, 2018). Data were corrected for the absorption
effect using the CrysAlis PRO software package by the
empirical absorption correction using spherical harmonics,
implemented in the SCALE3 ABSPACK scaling algorithm. All the
non-hydrogen atoms were refined anisotropically, while the
hydrogen atoms were generated geometrically, placed in
calculated positions (C−H = 0.93−0.97 Å; N−H = 0.86 Å), and
included as riding contributions with isotropic displacement
parameters set at 1.2−1.5 times the Ueq value of the parent
atom. The crystal structures were refined using the program
Scheme 1. Anion metathesis promoted by the ionic liquid [bmim]PF
6
during the synthesis of dihydroisoquinoline-hexafluorophosfates 2a-b
.
2
| J. Name., 2012, 00, 1-3
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+
-
[
bmim] environment and displaces the PF anion to form the
6
View Article Online
DOI: 10.1039/D0NJ05235C
more stable ionic liquid [bmim]Cl and HPF (pK = -10), since
6
a
+
-
the interactions between [bmim] and the Cl are stronger than
-
25
with the PF6 anion. Finally, in a parallel process, the
dihydroisoquinolinium cation reacted with HPF to form an
insoluble product that precipitated as hexafluorophosfate salts
6
2
a-b, which were then recrystallized from a mixture of ethanol
an ethyl acetate in a 5:2 ratio at room temperature (Scheme
). In particular, compound 2a resulted to be partially soluble
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in CDCl , and for practicity, during its characterization through
3
NMR spectroscopy, small drops of non-deuterated ethanol
were added to improve its solubility and analysis by this
technique (Please see ESI).
Then, we focused our efforts in exploring the synthesis and
isolation of the intermediate 2a’. In first place, we found that
when substrate 1a was subjected to the most common
reaction conditions of the classical Bischler-Napieralski
Scheme 2. Attempts in preparing the 3,4-dihydroisoquinoline core as a
free-base in acetonitrile. A) starting from cinnamamide 1c; B) starting
reaction, using 8 equiv. of POCl , toluene as a solvent and
3
from propanamide 1d
.
warming the reaction at 100°C for 3 hours, the full conversion
of the cinnamamide 1a was achieved. But unfortunately,
during the purification process of the obtained product by
routine physical methods, we noticed that this compound
rapidly decomposed and it could not be well manipulated and
stored under standard laboratory conditions.
With the hypothesis that including more methoxy groups as
substituents on both aromatic rings of the starting
cinnamamide would increase the stability of the desired 3,4-
dihydroisoquinoline, we evaluated the respective N-(3,4-
results were that we could isolate this derivative as a free-base
and as a solid which was crystalized from ethanol. To the best
of our knowledge, this is the first time that a 1-phenethyl-3,4-
dihydroisoquinoline of this nature is isolated as a solid instead
of an oil or a gummy product difficult to handle (Scheme 2B).
3.2 Crystal structure description
Crystal data, data collection and structure refinement
details are summarized in Table 1.
Single crystals of 1-styryl-3,4-dihydroisoquinolin
hexafluorophosfates 2a-b were obtained from a mixture of
ethanol and ethyl acetate in a 5:2 ratio at room temperature,
dimethoxyphenylethyl)-4-methoxycinnamamide 1c as
a
substrate of the Bischler-Napieralski reaction under the
common reaction conditions (Scheme 2A). Although the full
conversion of this substrate was determined by TLC, once
again, any attempt to isolate the desired 1-styryl-3,4-
dihydroisoquinoline 2c’ as a free base failed.
Clearly, the conjugated C=C-C=N system of the
dihydroisoquinoline core in the respective intermediate 2c’
affected the stability of these compounds, inducing their
degradation under aerobic, basic or neutral conditions, as was
evidenced when we tried their purification by column
chromatography using silica gel or alumina as stationary
phase. In this sense, we established that 1-styryl-3,4-
dihydroisoquinolines could be stable only under acidic
while
1-phenethyl-3,4-dihydroisoquinoline
2d
was
recrystallized from ethanol. These molecules were studied in
their solid states and their molecular structures are shown in
Figure 2.
Single crystal X-ray analyses revealed that 2a and 2d
crystallize in the Hexagonal P6 , and Monoclinic P2 /n space
groups, respectively. While 2d forms a centrosymmetric crystal
structure, 2a crystallizes in an enantiomorphic space group.
This last behaviour contrasts with the centrosymmetric
3,4-dihydroisoquinoline-
hexafluorophosphate 2b with a Triclinic P-1 space group (Table
1
1
structure
observed
in
conditions and that they could only be isolated as PF -salts,
where the use of [bmim]PF as a solvent induced the discussed
anion metathesis and stabilized these derivatives as
hexafluorophosfates instead of hydrochlorides.
6
6
1
5
1
). This difference is due to a conformational effect mediated
by changes over the C10-N1-C9-C8 torsion angle (2a/2d
numbering) as shown in Figure 3.
Being aware of the negative effect that the α,β-unsaturation
in compounds 1a-c induced on the stability of the expected
products 2a’-c’, and that recently Chen et al. also reviewed in
specialized literature that during the total synthesis of some
tetrahydroisoquinoline alkaloids the preferred starting
materials were substrates without the conjugated C=C-C=N
In the case of compounds 2b and 2d (Figures 3B and 3C), these
conformations are not superimposable. In the case of
compound 2a, only one conformer crystallizes forming an
enantiomorphic structure (Figure 3A).
According to the search in the CSD database version 5.41
November 2019 with 2 updates, May 2020) through the
26
(
system, we focused our efforts in preparing the stable 1-
phenethyl-3,4-dihydroisoquinoline 2d analogue from N-
phenethylpropanamide 1d (Scheme 2B). Compound 2d was
ConQuest software version 2020.1.1 for molecules with the
same core, only two related crystal structures are reported so
1
5
far: the 3,4-dihydroisoquinoline-hexafluorophosphate 2b and
readily synthetized using 8 equiv. of POCl , acetonitrile as a
solvent at 70 °C for 6 h in 78 % yield, but the very delightful
3
the methanol-solvate 6,7-dimethoxy-2-[(4-
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Crystal data and structure refinement parameters for 2a-b and 2d
View Article Online
DOI: 10.1039/D0NJ05235C
2
a
2b
2d
Crystal data
Chemical formula
C
18
H
18NO·F
409.30
6
P
C
22
H
26NO
529.41
5
·F
6
P
20 3
C H23NO
325.39
M
r
Crystal system,
space group
Temperature (K)
Hexagonal, P6
1
Triclinic, P-1
298(2)
.3124 (9),
11.6899 (11),
2.2686 (8)
8.204 (7), 88.640
7), 84.652 (8)
1
Monoclinic, P2 /n
298(2)
298(2)
8
11.8343 (16),
12.4529 (11),
14.8774 (18)
9
.8217 (9), 9.8217
9), 32.600 (5)
0
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a, b, c (Å)
(
1
7
α, β, γ (°)
90, 90, 90
90, 106.205 (13), 90
(
3
V (Å )
2723.4 (7)
6
Mo Kα
1161.88 (19)
2105.4 (4)
4
Mo Kα
Z
2
Radiation type
Mo Kα
0.20
−
1
µ (mm
)
0.22
0.07
Data collection
Diffractometer
Absorption
SuperNova, Dual, Cu at zero, Atlas
Multi-scan (CrysAlis PRO; Agilent, 2014)
correction
Tmin, Tmax
0.369, 1.000
0.709, 1.000
0.882, 1.000
No. of measured,
independent and
observed [I >
3
2276, 4016, 3153 25972, 5125, 3963
24600, 4619, 3110
2σ(I)] reflections
R
int
0.087
0.641
0.048
0.641
0.050
0.641
−
1
(sin θ/λ)max (Å
)
Refinement
2
2
R[F > 2σ(F )],
2
0.064, 0.187, 1.07
0.058, 0.174, 1.07
0.085, 0.264, 1.76
wR(F ), S
No. of reflections
No. of parameters
4016
300
5125
388
4619
221
H-atoms treated
by a mixture of
independent and
constrained
refinement
0.44, −0.43
H-atom parameters
constrained
H-atom parameters
constrained
H-atom treatment
−
3
Δρmax, Δρmin (e Å )
0.32, −0.26
Flack x determined
using 1212
0.50, −0.40
Absolute structure
---
---
---
2
7
quotients
Absolute structure
parameter
0.05 (7)
---
methylphenyl)sulfonyl]-1-[2-(4-nitrophenyl)ethenyl]-1,2,3,4-
tetrahydroisoquinoline, in the
which 28crystallizes
enantiomorphic P2 2 2 space group.
1
1 1
i
For 2a, a combination of strong N1‒H1D‧‧‧F5 , C12‒H12‧‧‧
i
ii
F3 and C1‒H1B‧‧‧F4 (symmetry codes: (i) y,1-x+y,-1/6+z; (ii)
+x,1+y,z) hydrogen bonds join molecules forming a molecular
1
helix wrapped around c axis (Table 2 and Figure 4), which is a
consequence of the 6-fold screw axis with direction [001] and
screw component [0 0 1/6]. These short interactions have H‧‧ 2b, the crystal structure was reported in Puerto, et al.
Fig. 2. Molecular structures of (A) 2a, (B) 2b, and (C) 2d, showing
displacement ellipsoids drawn at the 50% probability level. In case of
1
5
‧
F distances of 2.14 Å, 2.48 Å, and 2.18 Å, respectively.
Between neighbouring spirals, the fluorophosphate ions act as
linkers with weak interactions C6‒H6‧‧‧F6, C15‒H15‧‧‧F1, (Figure 5B), and the PF anions are occupying the 9.7% of the
hexafluorophosphate 2b, such channels are not present
-
6
3
and N1‒H1D‧‧‧F2 with H‧‧‧F distances of ~2.65 Å (Figure 4).
The fluorophosphate groups are contained in [001]
channels occupying the 20.6 % of the crystalline space which dimensions, this behaviour constitutes an important feature
corresponds to a volume of 560.4 Å in the unit cell. This value considering that changes in the C10-N1-C9-C8 torsion angle
was calculated assuming a molecular contact surface, that is,
the walls of the channels directly in contact with the 1-dimensional ion conductivity. The supramolecular assembly
surrounding molecules (Figure 5A). The formation of these in compound 2a is built mainly by the intermediation of the
channels is a consequence of the absence of inversion centers fluorophosphates groups which act as molecular linkers. These
due to the presence of only one conformer which allows the interactions were confirmed by the B3LYP-calculated Hirshfeld
crystalline space with 112.6 Å in the unit cell.
Considering the structural similarities and molecular
3
(2a/2d numbering) could modify potential properties, such as
building of the spiral-like crystal structure (Figure 5A).
When the space occupied by the fluorophosphate groups is constitute the 32.6 % of the total Hs showing a high
calculated in the related 3,4-dihydroisoquinoline-
surface (Hs) mapped over dnorm. The H‧‧‧F/F‧‧‧H interactions
4
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v
participation in the formation of the crystal (for details see see ESI). Between chains, C8‒H8A‧‧‧Cg1 (symmetry code: (v)
ESI).
View Article Online
DOI: 10.1039/D0NJ05235C
-
1/2+x,1/2-y,-1/2+z; Cg1 is the centroid of the C13/C18 ring)
interactions help to build the supramolecular assembly along
001] direction (Figure 6B and Table 2). This C8‒H8A‧‧‧
[
π
contact is interestingly strong (2.75 Å) compared with usual
values (>2.8 Å). Along [-101] direction, π‧‧‧π stacking
interactions help to define the 3-dimensional structure (Figure
6
B).
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Table 2. Selected hydrogen-bond geometry (Å, °) for 2a and 2d.
2
a
D-H···A
N1‒H1D‧‧‧F5
C12‒H12‧‧‧F3
C1‒H1B‧‧‧F4
2d
C9‒H9A‧‧‧O2
C1‒H1A‧‧‧O3
C8‒H8A‧‧‧Cg1
D-H H···A
0.86 2.14
D···A
2.98(2)
0.93 2.48 3.375(19)
D-H···A
166
161
i
i
ii
0.96 2.18
3.10(2)
159
iii
0.97 2.63
0.96 2.72
0.97 2.75
3.465(4)
3.505(5)
3.640
145
140
123
iv
v
Symmetry codes: (i) y,1-x+y,-1/6+z; (ii) 1+x,1+y,z; (iii) -x,1-y,-z; (v) 1-x,1-y,-z. Cg1 is
the centroid of the C13/C18 ring in 2d
Fig. 3. (A) Compound 2a crystallizing in an enantiomorphic P6
1
space
group.
(B)
3,4-dihydroisoquinoline-hexafluorophosphate
2b
crystallizing in a centrosymmetric P-1 space group. (C) Compound 2d
crystallizing in a centrosymmetric P2 /n space group.
Fig. 4. (N,C)‒H‧‧‧F hydrogen interactions (2.14-2.50 Å) forming
molecular spirals wrapped along c axis for compound 2a. Between
spirals, fluorophosphate ions act as molecular linkers through weaker
1
As it was mentioned above, compound 2d crystallizes in a
centrosymmetric P2 /n space group. This means that both
possible conformers are present. In fact, inversion-related
(
N,C)‒H‧‧‧F interactions (2.65 Å).
1
For this crystal (2d), some diffuse electronic densities were
molecules are connected by pairs of equivalent C9‒H9A‧‧‧
observed in the intermolecular voids which were related to
disordered ethanol molecules. After several refinements
involving disordered models, it was not possible to obtain a
iii
O2 (symmetry code: (iii) -x,1-y,-z) hydrogen interactions to
iv
form dimers which are further connected by C1‒H1A‧‧‧O3
(
[
symmetry code: (iv) 1-x,1-y,-z) contacts to grow chains along
100] direction (Figure 6A and Table 2). These connections
29
reasonable refined structure. Therefore, the SQUEEZE utility
29,30
in PLATON
was used to model its contribution to the
constitute the 11.5% of the total Hirshfeld surface (for details
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overall intensity data. In this case, the void spaces are present
in localized positions with center at (1/2, 1/2, 1/2) of the unit
cell, representing the 14.9 % of the structure and 314.6 Å of
the unit cell volume, as was observed for the 3,4-
dihydroisoquinoline-hexafluorophosphate 2b (Figure 6C). This
behaviour confirms that the presence of both conformers
induces a centrosymmetric structure. However, when only one
conformer crystallizes, the solid grows in an enantiomorphic
structure with the formation 1D-channels.
View Article Online
DOI: 10.1039/D0NJ05235C
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Fig. 6. The crystal structure of 2d, showing (A) the C‒H‧‧‧O (Å), (B)
C8‒H8A‧‧‧π and π‧‧‧π interactions (Å). (C) Voids available for solvent
molecules in 2d
.
Fig. 5. (A) Fluorophosphate ions inside the channels directed along 4. Conclusions
001] in the enantiomorphic 2a structure. (B) Fluorophosphate ions
[
In summary, we have demonstrated that controlling the
reaction conditions of the Bischler-Napieralski reaction 3,4-
dihydroisoquinolines from N-phenylethyl cinnamamides can
inside located voids in 3,4-dihydroisoquinoline-hexafluorophosphate
2b crystallizing in a centrosymmetric P-1 space group.
CE-B3LYP model energies showed that a great contribution be obtained as a free base or as hexafluorophosphate salts in
of electrostatic forces is involved in the formation of the good to excellent yields. In this study, a 1-phenethyl-3,4-
molecular spirals in 2a, connecting the fluorophosphate ions dihydroisoquinoline derivative was crystalized and fully
with the 6-methoxy-1-styryl-3,4-dihydroisoquinolin core characterized for the first time by X-ray crystallographic
(Figure 7A). However, as observed for the 3,4- techniques, being an important intermediate in the total
dihydroisoquinoline-hexafluorophosphate 2b these contacts synthesis of natural isoquinoline metabolites. In general, X-ray
are not enough to build a supramolecular assembly with analysis of 3,4-dihydroisoquinolines showed that the torsion
defined 1D-channels that cross the structure. Apparently, the angle
C10-N1-C9-C8
(2a
/2d
numbering)
in
the
presence of one or two conformers induces a change in the dihydroisoquinoline fragment allows the formation of two
symmetry of the crystal which determines the formation of the inversion-related conformers. The presence of both
channels. In crystals 2a and 2d, dispersion forces have an conformers induces a centrosymmetric crystal structure.
important role in the formation of the solids (Figure 7), which However, when only one conformer crystallizes, an
1
4
was also observed in 2b
.
Pairwise interactions energies enantiomorphic crystal structure, with P6 space group in the
1
allowed the interpretation of the crystal packing in terms of case of 2a, is formed. The 6-fold screw axis parallel to [001]
energy, obtaining total packing energies of -173.6 and -135.0 direction describes a spiral-like molecular behaviour with 1-D
kJ/mol for 2a and 2d, respectively, which was consistent with channels containing the fluorophosphate ions. This feature
the presence of electrostatic forces of greater magnitude in 2a allows us to imagine a potential structural modulation based
(Figure 7).
on the crystallization of one or both possible conformers.
6
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3
a) H. Yongkang, X. Wenjing, L. Yongqiang,VieFw.ArtQicileqOi,nlinZe.
Xingliang, L. Shiling and S. Xiaoxin, First Total Syntheses of 1-
DOI: 10.1039/D0NJ05235C
Benzoyl-3,4-dihydroisoquinoline Alkaloids Nelumstemine
and Longifolonine Based on the Photo-oxidation, Chinese J.
Org. Chem., 2020, 40, 1281; b) X. H. Duan and J. Q. Jiang, A
new benzylisoquinoline alkaloid from stems of Nelumbo
nucifera, Chinese Chem. Lett., 2008, 19, 308.
4
5
6
7
8
9
I. C. Bick, T. Sevenet, W. Sinchai, B. Skelton and A. White,
Alkaloids of Cryptocarya longifolia: X-Ray Crystal Structure of
Thalifoline and Longifolonine, Aus. J. Chem., 1981, 34, 195.
M. Leboeuf, A. Ranaivo, A. Cavé and H. Moskowitz, La
Velucryptine, Nouvel Alcaloïde Isoquinoléique Isolé de
Cryptocarya velutinosa, J. Nat. Prod., 1981, 52, 516.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
R. Tomar, A. Sahni, I. Chandra, V. Tomar and R. Chandra,
Review of Noscapine and its Analogues as Potential Anti-
Cancer Drugs, Mini-Rev. Org. Chem., 2018, 15, 345.
C. E. Puerto Galvis and V. V. Kouznetsov, Biomimetic Total
Synthesis of Dysoxylum Alkaloids, J. Org. Chem., 2019, 84
,
1
5294.
S. Ruchirawa, V. Bhavakul and M. Chaisupakitsin, A One-Pot
Synthesis of (±) Cryptostylines I, II, III, Synth. Commun., 2003,
33, 621.
A. Nash, X. Qi, P. Maity, K. Owens and U. K. Tambar,
Development of the Vinylogous Pictet-Spengler Cyclization
and Total Synthesis of (±)-Lundurine, A. Angew. Chem., 2018,
57, 6888.
1
0 A. B. J. Bracca, T. S. Kaufman, Synthesis of the Carbon
Framework of the Stephaoxocanes Employing a Sequential
RCM/Pomeranz-Fritsch Approach, Eur. J. Org. Chem., 2007,
Fig. 7. Energy framework diagrams for electrostatic (red) and
dispersion (green) contributions to the total interaction energies (blue)
in (A) 2a viewed along [100], and (B) 2d viewed along [010].
31, 5284.
1
1
1 L. Min, W. Yang, Y. Weng, W. Zheng, X. Wang and Y. Hu, A
Method for Bischler−Napieralski-Type Synthesis of 3,4-
Dihydroisoquinolines, Org. Lett., 2019, 21, 2574.
2 M. M. Heravi and N. Nazari, Bischler-Napieralski Reaction in
Total Synthesis of Isoquinoline-based Natural Products, An
Conflicts of interest
There are no conflicts to declare.
Old Reaction, a New Application. Curr. Org. Chem., 2015, 19
358.
,
2
Acknowledgements
The authors thank the Facultad de Ciencias and Departamento
de Química at Universidad de los Andes, Colombia, for their
support and X-ray diffraction facilities. M.A.M. thanks the
1
3 Y. Han, Z. Hu, M. Liu, M. Li, T. Wang and Y. Chen, Synthesis,
Characterization, and Properties of Diazapyrenes via
Bischler–Napieralski Reaction. J. Org. Chem., 2019, 84, 3953.
14 J. Párraga, A. Galán, M. J. Sanz, N. Cabedo, and D. Cortes,
Synthesis of hexahydrocyclopenta[ij]isoquinolines as a new
‘
Fondo de Apoyo para Profesores Asistentes’ of the Facultad
class of dopaminergic agents, Eur. J. Med. Chem., 2015, 90
01.
,
1
de Ciencias, Universidad de los Andes, Bogotá, FAPA-
P18.160422.043. CEPG acknowledges the fellowship given by
the doctoral program COLCIENCIAS-Conv. 617. VVK thanks to
the Colombian Institute for Science and Research,
COLCIENCIAS under project no. 007-2017, cod. 110274558597
for financial support.
1
5 C. E. Puerto Galvis, M. A. Macías and V. V. Kouznetsov,
Unexpected PF6 Anion Metathesis during the Bischler–
Napieralski Reaction: Synthesis of 3,4-Dihydroisoquinoline
Hexafluorophosphates and Their Tetrahydroisoquinoline
Related Alkaloids, Synthesis, 2019, 51, 1949.
6 Z. M. A. Judeh, C. B. Ching, J. Bu and A. McCluskey, The first
Bischler–Napieralski cyclization in a room temperature ionic
liquid, Tetrahedron Lett., 2002, 43, 5089.
17 D. Gupta, D. Bhatia, V. Dave, V. Sutariya and S. V. Gupta,
Salts of Therapeutic Agents: Chemical, Physicochemical, and
Biological Considerations, Molecules, 2018, 23, 1719.
8 A. N. ꢀim, A. Ngamnithiporn, ꢁ. ꢂ. ꢃelin, M. T. Daiger, C. ꢄ.
ꢅrꢆnanger, M. D. Bartberger, ꢇ. C. ꢈirgil and B. M. ꢇtoltꢉ,
Iridium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of 1,3-Disubstituted Isoquinolines, ACS Catal.,
1
Notes and references
1
a) R. D. Taylor, M. MacCoss and A. D. G. Lawson, G. Rings in
Drugs, J. Med. Chem., 2014, 57, 5845; b) E. Vitaku, D. T.
Smith and J. T. Njardarson, Analysis of the Structural
Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals, J.
Med. Chem., 2014, 57, 10257; c) S. D. Roughley and A. M.
Jordan, The Medicinal Chemist’s Toolbox: An Analysis of
Reactions Used in the Pursuit of Drug Candidates, J. Med.
Chem., 2011, 54, 3451.
a) I. P. Singh and P. Shah, Tetrahydroisoquinolines in
therapeutics: a patent review (2010-2015), Expert Opin.
Ther. Pat., 2017, 27, 17; b) J. D. Scott and R. M. Williams,
Chemistry and Biology of the Tetrahydroisoquinoline
Antitumor Antibiotics, Chem. Rev., 2002, 102, 1669.
1
2
020, 10, 3241.
1
2
9 G. M. Sheldrick, Crystal structure refinement with SHELXL,
Acta Crystallogr. Sect. C: Struct. Chem., 2015, 71, 3.
0 C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P.
McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de
Streek and P. A. Wood, Mercury CSD 2.0 - new features for
the visualization and investigation of crystal structures, J.
Appl. Crystallogr, 2008, 41, 466.
2
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ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1 M. J. Turner, S. Grabowsky, D. Jayatilaka and M. A.
View Article Online
DOI: 10.1039/D0NJ05235C
Spackman, Accurate and efficient model energies for
exploring intermolecular interactions in molecular crystals, J.
Phys. Chem. Lett, 2014, 5, 4249.
22 C. F. Mackenzie, P. R. Spackman, D. Jayatilaka and M. A.
Spackman, CrystalExplorer model energies and energy
frameworks: extension to metal coordination compounds,
organic salts, solvates and open-shell systems, IUCrJ, 2017,
75.
3 M. J. Turner, J. J. McKinnon, S. K. Wolff, D. J. Grimwood, P. R.
Spackman, D. Jayatilaka, M. A. Spackman. (2017).
CrystalExplorer17. University of Western Australia.
http://hirshfeldsurface.net/
4,
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
4 D. Jayatilaka, D. J. Grimwood, A. Lee, A. Lemay, A. J. Russel,
C. Taylor, S. K. Wolff, P. Cassam-Chenai and A. Whitton.
(
2005), TONTO – a system for computational chemistry.
Available at: http://hirshfeldsurface.net
2
2
2
5 R. S. Payal and S. Balasubramanian, Homogenous mixing of
ionic liquids: molecular dynamics simulations, Phys. Chem.
Chem. Phys., 2013, 15, 21077.
6 P. Tang, H. Wang, W. Zhang and F-E. Chen, Asymmetric
catalytic hydrogenation of imines and enamines in natural
product synthesis, Green Synth. Catal., 2020, 1, 26.
7 S. Parsons, H. D. Flack and T. Wagner, Use of intensity
quotients and differences in absolute structure refinement,
Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater.,
2
013, B69, 249.
2
2
8 J. E. Jakobsson, E. Gourni, S. Khanapur, B. Brito, P. J. Riss. CSD
Communication(Private Communication). CCDC-1857094
9 Spek, A. L. Spek, PLATON SQUEEZE: a tool for the calculation
of the disordered solvent contribution to the calculated
structure factors, Acta Crystallogr., Sect. C: Struct. Chem.,
2
015, C71, 9.
3
0 A. L. Spek, Structure validation in chemical crystallography,
Acta Crystallogr., Sect. D: Struct. Biol., 2009, D65, 148.
8
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Free base and hexafluorophosphate salts of 3,4-dihydroisoquinolines from the Bischler-
Napieralski reaction: potential supramolecular modulation.
Centrosymmetric/enantiomorphic crystals