A simple synthesis of the pentacyclic lamellarin skeleton from 3-nitro-2-(trifluoromethyl)-2H-chromenes and 1-methyl(benzyl)-3,4- dihydroisoquinolines

Article abstract of DOI:10.1016/j.tet.2011.09.049

The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]isoquinoline derivatives, has been obtained in good yields via Grob synthesis between 3-nitro-2-(trifluoromethyl)-2H-chromenes and 1-methyl-3,4-dihydro

Full text of DOI:10.1016/j.tet.2011.09.049

Tetrahedron 67 (2011) 8685e8698
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A simple synthesis of the pentacyclic lamellarin skeleton from 3-nitro-2-
(trifluoromethyl)-2H-chromenes and 1-methyl(benzyl)-3,4-dihydroisoquinolines
,
a
b
Vladislav Yu. Korotaev a, Vyacheslav Ya. Sosnovskikh a , Alexey Yu. Barkov , Pavel A. Slepukhin ,
*
Marina A. Ezhikova b, Mikhail I. Kodess b, Yurii V. Shklyaev c
a Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russia
b Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620990 Ekaterinburg, Russia
c Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences, 614600 Perm, Russia
a r t i c l e i n f o
a b s t r a c t
The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]
isoquinoline derivatives, has been obtained in good yields via Grob synthesis between 3-nitro-2-(tri-
fluoromethyl)-2H-chromenes and 1-methyl-3,4-dihydroisoquinolines in refluxing isobutanol. In the case
of 1-benzyl-3,4-dihydroisoquinolines, a dynamic NMR effect was observed in the 1H and 19F NMR spectra
of the products as a result of restricted rotation about the single bond linking the benzene ring and the
heterocyclic system. When the reaction was carried out with 3-nitro-2-(trichloromethyl)-2H-chromenes
in toluene at room temperature, only Michael adducts, as a mixture of two diastereomers, were isolated.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 25 May 2011
Received in revised form 25 August 2011
Accepted 12 September 2011
Available online 16 September 2011
Keywords:
Lamellarin skeleton
Grob reaction
3-Nitro-2-(trifluoromethyl)-2H-chromenes
3,4-Dihydroisoquinolines
1. Introduction
and antitumour activities6 and are capable of reacting with elec-
trophilic substrates as C-nucleophiles or 1,3-C,N-dinucleophiles via
Recently, considerable interest has been devoted to the syn-
thesis of partially fluorinated heterocycles, many of which have
found use as agrochemicals and drugs.1 However, reports on the
use of 2-(trifluoromethyl)-2H-chromenes as substrates for organic
synthesis are very scarce, although 2H-chromene (2H-1-
benzopyran) and its derivatives belong to an important class of
oxygen-containing heterocyclic compounds that are common in
plants and exhibit a wide spectrum of useful properties. Structures
containing a benzopyran framework have antitumour, antibacterial
and antiinflammatory activity and inhibit HIV-1 reverse tran-
scriptase, interleukin-1 production and protein kinases and can
cleave DNA.2 In addition, they are also useful intermediates in the
synthesis of complex natural products, such as pterocarpans.3 In
continuation of our studies on the chemical properties of 3-nitro-2-
(trihalomethyl)-2H-chromenes (1, X¼F, Cl),4 which turned out to be
highly reactive substrates in reactions with N-, S-, and C-nucleo-
philes,5 we decided to investigate their reaction with 1-
methyl(benzyl)-3,4-dihydroisoquinolines 2. The latter are another
group of biologically interesting compounds, which exhibit diverse
biological properties including anticonvulsant, antimicrobiological
the enamine tautomeric form.7 Although much attention has been
paid to the chemistry of 3,4-dihydroisoquinolines 2, mainly due to
their use as excellent building blocks for the preparation of a variety
of complex heterocyclic compounds,7 their reactions with 3-nitro-
2H-chromenes have not been described in the literature. There is
only one report on the reaction of ethyl (6,7-dimethoxy-3,4-
dihydroisoquinolin-1(2H)-ylidene)acetate with 2-nitro-1-pheny
lpropene and 1-nitro-1,2-diphenylethene leading to the corre-
sponding 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives.8
A reaction involving the addition of secondary enaminoesters to
nitroolefins followed by intramolecular displacement of the nitro
group by the amino group to yield pyrroles was disclosed by Grob
et al.9 This method makes use of easily prepared reagents and is
particularly suitable for a combinatorial approach to the synthesis
of substituted pyrroles.10 Since imines, which exist in equilibrium
with their enamines, have been shown to react with b-nitrostyrene
to give the corresponding pyrroles,11 it was expected that Michael
addition of enamines derived from 1-methyl- and 1-benzyl-3,4-
dihydroisoquinolines 2 to a powerful Michael acceptor, such as
chromenes 1, followed by ring closure and aromatization (Grob
synthesis) could provide a direct route to 8,9-dihydro-6H-chro-
meno[40,30:4,5]pyrrolo[2,1-a]isoquinolines 3 (Fig. 1).
This heterocyclic system constitutes the basic structural
framework of the well-known lamellarin alkaloids 4 (for example,
* Corresponding author. E-mail addresses: sosn1951@mail.ru, vyacheslav.
sosnovskikh@usu.ru (V.Y. Sosnovskikh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.049

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V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
accessible. Indeed, we have shown quite recently17 that the re-
action of 3-nitro-2-(trifluoromethyl)-2H-chromenes 1 (X¼F) with
1,3,3-trimethyl-3,4-dihydroisoquinolines gave 6-(tri-
2
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]
isoquinolines 3, while the reaction of 3-nitro-2-(trichloromethyl)-
2H-chromenes 1 (X¼Cl) stopped at the initial Michael addition
stage. Herein, we report full details of this study. In addition to our
preliminary communication,17 some novel 8,9-dihydro-6H-chro-
meno[40,30:4,5]pyrrolo[2,1-a]isoquinolines as well as 2,3,4-
trisubstituted chroman derivatives have been prepared and stud-
ied by X-ray diffraction analysis. In the case of 1-benzyl-3,4-
dihydroisoquinolines, dynamic NMR effects are observed in the
1H and 19F NMR spectra.
2. Results and discussion
We found that 3-nitro-2-(trifluoromethyl)-2H-chromenes 1, as
the nitroolefin components, reacted with 1,3,3-trimethyl-3,4-
dihydroisoquinolines 2, as the enamine components, in toluene at
room temperature for 1 h to give Michael adducts 5aef as a mixture
of transecis (tc) and cisetrans (ct) isomers (ca. 1:1) in good to high
combined yields (Scheme 1 and Table 1; in tc-5 the ‘t’ refers to the
relative configurations at C-20 and C-30, and the ‘c’ to the relation-
ship between C-30 and C-40). The double bond of 1 is so reactive that
no catalyst was necessary. Notably, the chroman products 5 contain
three contiguous stereogenic centres, but in all cases, only two
diastereomers could be observed by 1H NMR spectroscopy of the
crude reaction mixtures. The structures of 5 were characterized by
1H, 19F, 13C NMR and elemental analyses.
Fig. 1. Starting materials and target products.
lamellarins L and U), a family of marine natural products, which
exhibit a wide range of biological activities.12 The lamellarins and
related naturally occurring pyrrole-derived alkaloids have shown
promising cytotoxicity and antitumour activity, reversal of multi-
drug resistance (MDR), HIV-1 integrase inhibition, immunomodu-
lation and antibiotic activity.13 In addition, the lamellarins
represent a new series of topoisomerase I inhibitors.14 Therefore,
Scheme 1. Synthesis of compounds 3 and 5.
the development of efficient new methods leading to this hetero-
cyclic framework is highly desirable.15
The most diagnostic parameter for structural assignment was
the coupling constants between protons H-20 and H-30 and H-30 and
H-40. In the cisetrans-isomer (ct-isomer) 5 the coupling constants
Recently, it was reported that the reaction of 3-nitrocoumarins
with 1-benzyl-3,4-dihydroisoquinolines gave the desired lamel-
larins in only 5e6% yields.16 In this context, we anticipated that, if
the reaction occurred with chromenes 1, the pentacyclic lamellarin
ring system would be constructed successfully in one chemical
operation and a series of novel lamellarin derivatives would be
0
0
0
0
J2 ,3 ¼J3 ,4 ¼1.5 Hz are significantly smaller and typical of a gauche
conformation. The cisetrans configuration has been verified by
comparison of spectral data obtained for ct-5 with those appeared
in literature. Earlier, J2,3¼J3,4¼1.2e1.8 Hz values were reported for
cisetrans adducts formed in reactions of thiols and indoles with

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8687
Table 1
We next investigated the reaction of 3-nitro-2-(tri-
chloromethyl)-2H-chromenes 1 (R2¼CCl3), with 1,3,3-trimethyl-
3,4-dihydroisoquinolines 2 in order to prepare CCl3-containing
pentacycles of type 3. When 2-CCl3-chromenes 1 were reacted in
toluene at room temperature for 1 h, the reaction proceeded
smoothly to give, both prior to and after recrystallization, an un-
equal mixture of transecis and cisetrans chromans 6aef sub-
stantially favouring the transecis-isomer (85:15 in CDCl3). This
result shows that the isomer ratio depends on the steric effects of
the trihalomethyl group (Scheme 2, Table 2).
Synthesis of compounds 3aef and 5aef
R1
R2
Adduct 5
Yield
(%)
Product 3
Yielda (%)
Method A
Yieldb (%)
Method B
H
H
H
MeO
Br
Br
H
Me
MeO
MeO
Me
5a
5b
5c
5d
5e
5f
68
73
81
84
39
86
3a
3b
3c
3d
3e
3f
58
67
56
77
63
75
48
60
25
42
26
61
MeO
a
From 5.
From 1 and 2.
b
Table 2
Synthesis of compounds 6aeh
Adduct 6
R1
R2
R3
Yield (%)
chromenes 15aec and J2,3¼J3,4¼2.2 Hz for cisetrans-2-(4-
chlorophenyl)-4-(indol-3-yl)-3-nitrochroman, whose structure
was confirmed by X-ray diffraction analysis.18 Additional evidence
for the cisetrans configuration was obtained from the chemical
6a
6b
6c
6d
6e
6f
H
H
H
MeO
Br
Br
H
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
Ph
H
Me
60
78
71
62
52
58
64
91
MeO
MeO
Me
MeO
H
shift in the narrow range
d 86.5e86.6 ppm (C6F6) and the coupling
constant of the doublet for the CF3 group (3JF,H¼5.7e5.9 Hz), which
agrees well with the literature data for cisetrans adducts of chro-
menes 1 with thiols5a,b and azoles.5c The transecis configuration
(tc-isomer) was also evident from the experimental coupling con-
6g
6h
H
Ph
MeO
0
0
0
0
stants J2 ,3 zJ3 ,4 z4.5 Hz, which correlate with the literature data
for transecis adducts of thiols with chromenes 1.5a,b A character-
istic difference between the two stereoisomers is based on the
chemical shift of the H-20 proton, which was shifted downfield by
0.7e0.8 ppm in tc-isomer compared to ct-isomer. This is due to the
deshielding effect of the NO2 group, which is cis to H-20 in the tc-
isomer. Note that in some cases, the 1H NMR spectra of the Michael
adducts recorded at 298 K displayed broad signals for the aliphatic
and aromatic protons. This phenomenon may be attributed to the
restricted rotation of the dihydroisoquinoline moiety about the
CeC single bond leading to rotamer formation.
When chromans 5aef as a mixture of tc- and ct-diastereomers
were heated at reflux in isobutanol for 1 h, pentacycles 3aef were
obtained in good yields (method A). The progress of the reaction
was monitored by TLC, and the results are summarized in Table 1.
Among different solvents (alcohols, acetonitrile), isobutanol
appeared to give the best results. It was also found that 1 and 2
could be employed directly under these conditions to give 3aef in
25e61% yields (method B), however, better yields and easier pu-
rification of compounds 3 were achieved if the transformation was
performed in a two-step approach (method A). Thus, compounds 3
and 5 could be synthesized from the same starting material simply
by the choice of the reaction conditions (Scheme 1). In accordance
with the proposed mechanism,9b the Michael adduct 5 undergoes
intramolecular displacement of the nitro group by the NH group,
thus affording lamellarin system 3 via elimination of water and
hyponitrous acid.
Scheme 2. Synthesis of compounds 6.
The structures of compounds 6 compare well with the results of
elemental analysis, 1H, 13C NMR and IR spectroscopy. The di-
astereomeric ratio was determined by 1H NMR spectroscopic
analysis. In this case, the coupling constants for the transecis-iso-
To the best of our knowledge, pentacycles 3 represent the first
lamellarin derivatives reported to date bearing a CF3 substituent
instead of a carbonyl group. The structures of 3aef were confirmed
with the help of spectral and analytical data. For example, the 1O
NMR spectrum of compounds 3b in CDCl3 showed two AX doublets
0
0
0
0
mers are J2 ,3 zJ3 ,4 z5.0 Hz and those for the cisetrans-isomers are
0
0
0
0
J2 ,3 ¼J3 ,4 ¼1.5 Hz. The stereochemistry of the tc-isomer 6b and ct-
isomer 6g were independently confirmed by X-ray crystal structure
analysis (Figs. 2 and 3). It should be noted that on dissolution in
DMSO-d6, the ratio of the isomers changed to tc-6/ct-6¼35:65 (for
compounds 5 in DMSO-d6 it was tc-5/ct-5¼15:85). Isomerization to
this extent is evident immediately on dissolution (after 1e2 min),
and at constant temperature there was no subsequent change in
the percentage isomerization. This is associated with epimerization
at the C-3 atom and indicates the higher thermodynamic stability
of the cisetrans-isomer of 2-CX3-chromans 5 and 6, especially for 5
(X¼F). Of the four possible diastereomers (transetrans, cisecis,
transecis, and cisetrans), the dehydroisoquinoline fragment and
trihalomethyl substituent are trans to each other only in the last
two isomers, which probably control the stereochemistry of the
Michael addition (Scheme 3).
(JAX¼15.4 Hz) at
d 2.70 and 3.13 ppm for the CH2 group and
a quartet at
d
6.14 ppm (3JH,F¼6.1 Hz) due to the H-6 proton. The
pyrrole ring proton resonated at
d
6.77 ppm. In the 19F NMR spec-
trum the CF3 group of 3b appeared as a doublet with 3JF,H¼6.1 Hz at
86.43 ppm (C6F6). The 13C NMR spectrum of 3b exhibited a quartet
(1JC,F¼288.0 Hz) at 123.6 ppm for the carbon of the CF3 group and
a quartet (2JC,F¼32.6 Hz) at 71.2 ppm for the CeCF3 atom. This
confirmed that the CF3 group is bonded to the sp3 hybridized car-
bon atom. In addition, another feature of interest was the appear-
ance of a quartet (6JC,F¼2.4 Hz) at 26.4 ppm due to one of the C(8)e
Me groups, indicating that the Me and CF3 groups were spatially
close to each other.

8688
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
from these compounds the corresponding lamellarin derivatives
failed.
It was also found that the hydrochlorides of 1-methyl- and 1-
benzyl-3,4-dihydroisoquinolines 7 bearing one or two methyl
groups at the 3-position reacted with 2-CF3-chromenes 1 at reflux
in isobutanol for 3 h in the presence of triethylamine (1.2 equiv) to
give pentacycles 8aeh as the only isolated products in variable
yields 23e78% (Scheme 4, Table 3). This result clearly shows that
the present reaction could be applicable to various types of 3,4-
dihydroisoquinolines, providing a simple and rapid route to the
synthesis of a great variety of CF3-containing benzopyrano[3,4-b]
pyrroles with potential biological activity. In the case of 1-benzyl-
3,4-dihydroisoquinolines 7, we were also intrigued by the fact that
benzopyrano[3,4-b]pyrroles were structurally reminiscent of axi-
ally chiral biaryl compounds and might display restricted rotation
about the C(14)eC(10) single bond and, depending on the energetic
barrier to rotation, be resolved into two diastereomeric atropiso-
meric forms.
Fig. 2. Molecular structure of tc-6b (thermal ellipsoids at 50% probability).
Fig. 3. Molecular structure of ct-6g (thermal ellipsoids at 50% probability).
Scheme 4. Synthesis of compounds 8.
Table 3
Synthesis of compounds 8aeh
Product 8
R1
R2
R3
R4
Yield (%)
8a
8b
8c
8d
8e
8f
H
H
H
H
H
Me
Me
Me
Me
MeO
MeO
MeO
MeO
H
Me
Me
BuO
H
H
H
78
44
48
51
39
39
38
23
MeO
Br
Br
H
H
Br
Br
3,4-(MeO)2C6H3
Scheme 3. Epimerization at the C-3 atom of compounds 5 and 6.
Ph
Ph
Ph
Ph
Unfortunately, attempts to cyclise trichloromethylated Michael
adducts 6 in the usual manner (methods A and B) gave only mul-
ticomponent reaction mixtures from which no fused pyrroles of
type 3 could be isolated. Thus, the reaction turned out to be very
sensitive to the nature of the CX3 substituent and afforded pyrroles
3 only when the 2-CF3-chromenes 1 were used. This is probably
a result of the equilibrium between the nitro and aci forms of the
Michael adduct. It seems that the CF3 group, due to its powerful
electron-withdrawing character, favours a preponderance of the
latter form A (Scheme 1), from which the pyrroles 3 are derived.
Another reason may be a weak C(40)eCH2 linkage in 6, since partial
decomposition in DMSO-d6 took place and starting materials 1 and
2 were observed in the 1H NMR spectra. It should be noted that the
reaction of 3-nitro-2-phenyl-2H-chromene19 1 (R1¼H, R2¼Ph) with
2 (R3¼H, MeO) also stops at the Michael addition stage to give
chromans 6g,h as a mixture of cisetrans and transecis di-
astereomers (w9:1 in DMSO-d6) and all our attempts to synthesize
8g
8h
Compounds 8aec (R2¼R4¼H) were obtained as a mixture of
trans- (53e86%) and cis-isomers (14e47%), the relative stereo-
chemistry of which was determined by 13C NMR spectroscopy. Al-
though, we were unable to isolate them in pure form, the NMR data
for each isomer can be extracted from the spectrum of the mixture
(see Experimental section). The 13C NMR spectra of 8a,c in CDCl3
revealed a quartet at 19.5 ppm with 6JC,F¼2.6e2.9 Hz and a singlet
at 20.3e20.4 ppm due to the C(8)eMe group of the cis- and trans-
isomers, respectively. Assignment of all signals in the 1H and 13C
NMR spectra of 8c was performed based on results of 2D 1He13C
HSQC and HMBC experiments. In the case of compounds 8eeh
(R2¼Me, R4¼Ph), the steric interactions between the benzene ring

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8689
Table 4
and the peri-hydrogens disfavour co-planarity of the system, which
Synthesis of compounds 10aef
adopts a twisted conformation. In fact, 8eeh possess a conforma-
tional stereogenic axis and, in addition, a configurational stereo-
genic centre. Due to restricted rotation of the phenyl ring at C-14,
these compounds exist in solution as a mixture of two di-
astereomeric rotamers (see below), while benzopyrano[3,4-b]pyr-
role 8d (one chiral axis and two chiral centres) exists as a mixture of
rotamers of trans- (87%) and cis-isomers (13%). It should be noted
that in the case of 3,4-dihydroisoquinolines 7, the intermediates 80
could not be isolated and underwent spontaneous cyclization to
form the fused pyrrole ring (Scheme 4). Attempts to synthesize
compounds 80 in toluene at room temperature failed.
As an extension of this cyclization for the synthesis of bi-
ologically interesting non-natural lamellarin analogues we studied
the reaction of 2-CF3-chromenes 1 with 1-(3,4-dimethoxybenzyl)-
6,7-dimethoxy-3,4-dihydroisoquinoline (dihydropapaverine 9,
R¼Me) and 1-(3,4-diethoxy-benzyl)-6,7-diethoxy-3,4-dihydroiso-
quinoline (drotaverine 9, R¼Et).20 The hydrochloride of the latter is
a well-known spasmolytic agent widely used in medicine and
known as No-Spa. We anticipated that these new analogues pre-
pared from 1 and 9 and differing from lamellarins 4 only by re-
placement of the oxo group with CF3 one can serve as a basis for the
search of new physiologically active compounds.
We found that dihydropapaverine and drotaverine bases or
hydrochlorides reacted with 2-CF3-chromenes 1 in a desired
manner under reflux in isobutanol for 45 min to produce com-
pounds 10aef in 64e92% yields (Scheme 5, Table 4). Since 1-
benzyl-3,4-dihydroisoquinolines 9 are prone to air oxidation to
give 3,4-dihydropapaveraldine and drotaveraldine,21 all operations
should be preformed in an inert atmosphere. Reactions of 3-nitro-
2-(trichloromethyl)- and 3-nitro-2-phenyl-2H-chromenes with
dihydroisoquinolines 7 and 9 did not give the corresponding
lamellarin derivatives even under more drastic conditions.
Product 10
R
R1
Yield (%)
10a
10b
10c
10d
10e
10f
Me
Me
Me
Et
Et
Et
H
MeO
Br
H
MeO
Br
78
66
92
81
71
64
100e120 ꢀC (DMSO-d6). All signals in the 1H and 13C NMR spectra of
compound 10a were assigned on the basis of 2D 1He1H COSY,
1He13C HSQC and HMBC experiments at 100 ꢀC. The structures of
compounds 10bef were firmly established by comparison of their
spectra with the spectra of 10a. A characteristic feature of the 1H
NMR spectra is the presence of quartet at
d
5.69e5.75 ppm with
6.49e6.64 ppm,
3JH,F¼6.0e6.4 Hz in CDCl3 for H-6 proton (
d
3JH,F¼6.8e6.9 Hz in DMSO-d6). It is well-known that the aromatic
group on the pyrrole ring is almost orthogonal to the rest of the
relatively planar pentacyclic system of lamellarins 1 to avoid severe
steric interactions.12 Keeping this fact in mind and in making the 1H
NMR assignments, we have assumed that the ring current of the
phenyl ring attached at C-14 causes shielding of the protons at C-1,
C-13, C-12 and C-2.12 In all cases, the 1H NMR spectra of 8deh and
10aef recorded in CDCl3 and DMSO-d6 at room temperature dis-
played broadened signals in both the aromatic (mainly AreC(14))
and aliphatic region due to the restricted rotation of the aryl moiety
about the C(14)eC(10) bond leading to atropisomers (inter-
converting rotational isomers) (Fig. 4). This process was studied by
variable temperature (VT) 1H and 19F NMR measurements for
compound 10a as
temperature-dependent behaviour.
a typical case, which showed distinct
Fig. 4. Interconverting rotational isomers 10a.
The observed spectra of 10a are shown in Figs. 5 and 6. The 1H
NMR spectrum (500 MHz) recorded at 297 K in DMSO-d6 solution
showed pronounced line broadening of all the resonances sug-
gesting slow intramolecular motions in the system. A single set of
well resolved signals was observed above 373 K (Fig. 5). At low
temperature (below 253 K, CD2Cl2), the protons of the benzene
rings appear as a complex multiplet in the aromatic region,
whereas the H-13, MeO and CF3 signals split into two sets, in-
dicating a 46:54 mixture of rotamers A and B, the ratio of which
was measured by integration of the well resolved H-13 protons (
d
6.45 and 6.53 ppm) and CF3 groups ( 83.7 and 83.9 ppm) (Fig. 6).
d
Note that the spectra of 10a showed one singlet (6H) for two
MeOeC11 and MeOeC30 groups by chance.
Scheme 5. Synthesis of compounds 10.
Although complete line shape analysis was not undertaken in
the present work, the variable temperature 1H and 19F NMR spectra
from 183 to 293 K allowed calculating the rotation energy barrier
for the dynamic NMR process in 10a.22 The signals attributed to the
aromatic H-13 proton (Dn¼43.0 Hz) and the CF3 group (Dn¼75.0 Hz)
coalesced at 285 K, and the barrier to rotation was estimated to be
In the course of our studies of 10aef and related substances
8deh we have consistently noticed exchange broadening of 1H, 19
F
and 13C NMR signals for spectra ran in CDCl3 and DMSO-d6 solu-
D
Gz¼13.0 kcal/mol. The
D
Gz value for 10a, obtained from VT NMR
tions at room temperature, which can be overcome by heating to

8690
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
Fig. 5. VT 1H NMR spectra of 10a in DMSO-d6 in the range 297e413 K (signals at
d 3.2e2.7 ppm due to H2O in solvent).
Fig. 6. VT 1H and 19F NMR spectra of 10a in CD2Cl2 in the range 183e293 K.
measurements, shows that rotamers A and B can be interconverted
by overcoming energy barrier of 13.0 kcal/mol. For the isolation of
the rotamers at room temperature, it should be noted that a free
energy of activation higher than ca. 23 kcal/mol is required.23 Thus,
compounds 10 belong to the class possessing a rather low energy
barrier to rotation about the C(14)eC(10) bond and could not be
isolated as diastereomerically pure atropisomers.
We were also interested in examining the utility of this method
with different benzofused chromenes 11a,b, prepared from (E)-
3,3,3-trifluoro-1-nitropropene and 2-hydroxy-1-naphthaldehyde
and 1-hydroxy-2-naphthaldehyde.4 As expected, the nucleophilic
attack depends on the steric effects and no reaction occurred when
11a was used. The failure of the cyclocondensation with 11a results
possibly from the bulky benzene ring, which hinders the approach
to the nitroolefin fragment and unfavourable steric interactions
become the deciding factor. On the other hand, unlike chromene
11a, isomeric chromene 11b was successfully employed for the
reaction with dihydropapaverine 9 (R¼Me). When 11b and 9 were
heated in isobutanol for 45 min, heterocyclization proceeded
smoothly to give compound 12 in 94% yield, the structure of which
was established by comparison of its 1H NMR spectrum with the
spectrum of compound 10a (Fig. 7).
In conclusion, the current reaction represents a facile method
for the preparation of a diverse range of new pentacyclic lamellarin

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8691
(q, 1H, H-6, J¼6.0 Hz), 6.83 (s, 1H, H-14), 6.99e7.31 (m, 6H, arom.),
7.46 (dd, 1H, H-1/13, J¼7.4, 1.1 Hz), 7.60 (d, 1H, H-13/1, J¼7.7 Hz); 19
F
NMR (376 MHz, CDCl3)
d
86.5 (d, CF3, J¼6.0 Hz); 13C NMR (126 MHz,
CDCl3)
d
26.5 (q, Me0-8, 6JC,F¼2.3 Hz), 27.9 (Me00-8), 45.3 (C-9), 58.3
2
(C-8), 71.2 (q, C-6, JC,F¼32.6 Hz), 99.3 (C-14), 115.7, 116.3, 119.1,
120.6, 122.3, 122.6, 122.7, 123.6 (q, CF3, 1JC,F¼289.0 Hz), 126.7, 126.9,
127.3, 128.0, 128.5, 130.0, 134.3, 149.4. Anal. Calcd for C22H18F3NO:
S, 71.54; O, 4.91; N, 3.79. Found: S, 71.51; O, 4.87; N, 3.73.
3.2.2. 8,8,11,12-Tetramethyl-6-(trifluoromethyl)-8,9-dihydro-6H-
chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (3b). Yield 0.27 g (67%,
A), 0.24 (60%, B), mp 178e179 ꢀC; IR (KBr) 1635, 1616, 1592, 1560,
1532,1498cmꢁ1; 1H NMR(400 MHz, CDCl3)
d1.34,1.78, 2.27, 2.30(all
s, 3H, Me), 2.70 (d,1H, H-90, J¼15.4 Hz), 3.13 (d,1H, H-900, J¼15.4 Hz),
6.14 (q, 1H, H-6, J¼6.1 Hz), 6.77 (s, 1H, H-14), 6.93 (s, 1H, H-10), 7.00
(dd,1H, H-4, J¼7.5,1.3 Hz), 7.02 (td,1H, H-2, J¼7.5,1.3 Hz), 7.10 (td,1H,
H-3, J¼7.5,1.7 Hz), 7.38 (s,1H, H-13), 7.45 (dd,1H, H-1, J¼7.5,1.7 Hz);
19F NMR (376 MHz, CDCl3)
d
86.4 (d, CF3, J¼6.1 Hz); 13C NMR
(100 MHz, CDCl3)
d
19.6 (2C), 26.4 (q, Me0-8, 6JC,F¼2.4 Hz), 28.0 (Me00-
2
8), 44.9 (C-9), 58.3 (C-8), 71.2 (q, C-6, JC,F¼32.6 Hz), 98.6 (C-14),
115.7, 115.9, 118.9, 120.8, 122.3, 122.5, 123.6 (q, CF3, 1JC,F¼288.0 Hz),
123.9, 126.1, 126.8, 127.5, 129.2, 134.5, 135.3, 135.4, 149.4; MS (EI,
70 eV) m/z 397 [M]þ (16), 328 [MeCF3]þ (100), 285 (24),157 (20),149
(12), 142 (11). Anal. Calcd for C24H22F3NO: S, 72.53; O, 5.58; N, 3.52.
Found: S, 72.62; O, 5.67; N, 3.50.
Fig. 7. Benzofused chromenes 11a and 11b and the product 12 from the latter.
derivatives via simple annulation of a pyrrole ring to chromenes, an
important structural moiety found in many bioactive natural
products. The substrate scope was broadly studied, and the in-
corporation of a trifluoromethyl group made these compounds
potentially interesting substrates for drug discovery.
3.2.3. 11,12-Dimethoxy-8,8-dimethyl-6-(trifluoromethyl)-8,9-
dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (3c). Yield
0.24 g (56%, A), 0.11 g (25%, B), mp 171e172 ꢀC; IR (KBr) 1638, 1615,
1563,1536,1494 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.36 (s, 3H, Me),
1.79 (s, 3H, Me), 2.69 (d, 1H, H-90, J¼15.2 Hz), 3.14 (d, 1H, H-900,
J¼15.2 Hz), 3.91 (s, 3H, MeO), 3.96 (s, 3H, MeO), 6.14 (q, 1H, H-6,
J¼6.1 Hz), 6.68 (s, 1H, H-10), 6.71 (s, 1H, H-14), 7.00 (dd, 1H, H-4,
J¼7.4, 1.2 Hz), 7.02 (td, 1H, H-2, J¼7.4, 1.2 Hz), 7.10 (s, 1H, H-13), 7.10
(td, 1H, H-3, J¼7.4, 1.5 Hz), 7.45 (dd, 1H, H-1, J¼7.4, 1.5 Hz); 19F NMR
3. Experimental
3.1. General
NMR spectra were recorded on
a
Bruker DRX-400
(376 MHz, CDCl3)
d
86.4 (d, CF3, J¼6.1 Hz); 13C NMR (126 MHz,
(1Hd400 MHz, 13Cd100 MHz and 19Fd376 MHz) and AVANCE-
500 (1Hd500 MHz, 13Cd126 MHz and 19Fd471 MHz) spectrom-
eters in DMSO-d6 and CDCl3 with TMS and C6F6 as internal stan-
dards, respectively. IR spectra were recorded on a PerkineElmer
Spectrum BX-II instrument as KBr discs. Mass spectra were ob-
tained with the TurboMass (PerkineElmer) mass spectrometer.
Elemental analyses were performed at the Microanalysis Services
of the Institute of Organic Synthesis, Ural Branch, Russian Academy
of Sciences. All solvents used were dried and distilled per standard
procedures. The starting 3-nitro-2H-chromenes 1 were prepared
according to described procedures.4,19
CDCl3)
d
26.3 (q, Me0-8, 6JC,F¼2.4 Hz), 27.9 (Me00-8), 44.9 (C-9), 56.0
2
(Me-11), 56.1 (Me-12), 58.4 (C-8), 71.2 (q, C-6, JC,F¼32.5 Hz), 98.1
(C-14), 106.3 (C-13), 111.2 (C-10), 115.7 (C-4), 115.8 (C-6a), 119.0 (C-
14a), 120.7 (C-14b), 121.3 (C-13a), 122.3 (C-1), 122.5 (C-2), 122.7 (C-
9a), 123.6 (q, CF3, 1JC,F¼288.7 Hz), 126.8 (C-3), 134.4 (C-13b), 148.3
(C-11), 148.4 (C-12), 149.4 (C-4a). Anal. Calcd for C24H22F3NO3: S,
67.13; O, 5.16; N, 3.26. Found: S, 67.05; O, 5.15; N, 3.22.
3.2.4. 2,11,12-Trimethoxy-8,8-dimethyl-6-(trifluoromethyl)-8,9-
dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline
(3d). Yield 0.34 (77%, A), 0.19 (42%, B), mp 177e178 ꢀC; IR (KBr)
1627, 1610, 1565, 1534, 1507, 1494 cmꢁ1; 1H NMR (400 MHz, CDCl3)
3.2. General procedures for the synthesis of compounds 3
d
1.35 (s, 3H, Me), 1.79 (s, 3H, Me), 2.69 (d, 1H, H-90, J¼15.3 Hz), 3.15
(d, 1H, H-900, J¼15.3 Hz), 3.83, 3.91, 3.97 (all s, 3H, MeO), 6.09 (q, 1H,
H-6, J¼6.1 Hz), 6.64 (dd, 1H, H-3, J¼8.7, 2.9 Hz), 6.68 (s, 2H, H-10, H-
14), 6.92 (d, 1H, H-4, J¼8.7 Hz), 6.99 (d, 1H, H-1, J¼2.9 Hz), 7.10 (s,
Method A. A mixture of the corresponding tc- and ct-chromanes
5 (1.0 mmol) was refluxed in isobutanol (2 mL) for 1 h. After that,
the mixture was concentrated under reduced pressure and the
solid formed was recrystallized from dichloromethane/hexane
(1:2) to give compound 3 as a colourless powder.
1H, H-13); 19F NMR (376 MHz, CDCl3)
d
86.7 (d, CF3, J¼6.1 Hz). Anal.
Calcd for C25H24F3NO4: S, 65.35; O, 5.27; N, 3.05. Found: S, 65.19;
O, 5.26; N, 2.96.
Method B.
A mixture of the corresponding chromene 1
(1.0 mmol) and dihydroisoquinoline 2 (1.0 mmol) was refluxed in
isobutanol (2 mL) for 1 h. After that, the mixture was concentrated
under reduced pressure and the solid formed was recrystallized
from dichloromethane/hexane (1:2) to give compound 3.
3.2.5. 2-Bromo-8,8,11,12-tetramethyl-6-(trifluoromethyl)-8,9-
dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline
(3e). Yield 0.30 g (63%, A), 0.12 g (26%, B), mp 197e198 ꢀC; IR (KBr)
1608, 1558, 1530, 1498 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.33 (s,
3H, Me), 1.78 (s, 3H, Me), 2.27 (s, 3H, Me), 2.30 (s, 3H, Me), 2.70 (d,
1H, H-90, J¼15.4 Hz), 3.13 (d, 1H, H-900, J¼15.4 Hz), 6.13 (q, 1H, H-6,
J¼6.0 Hz), 6.74 (s, 1H, H-14), 6.87 (d, 1H, H-4, J¼8.5 Hz), 6.94 (s, 1H,
H-10), 7.17 (dd, 1H, H-3, J¼8.5, 2.4 Hz), 7.37 (s, 1H, H-13), 7.55 (d, 1H,
3.2.1. 8,8-Dimethyl-6-(trifluoromethyl)-8,9-dihydro-6H-chromeno
[40,30:4,5]pyrrolo[2,1-a]isoquinoline (3a). Yield 0.21 g (58%, A), 0.18 g
(48%, B), mp 141e142 ꢀC; IR (KBr) 1635, 1616, 1592, 1560, 1532,
1498 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
1.35 (s, 3H, Me), 1.80 (s, 3H,
H-1, J¼2.4 Hz); 19F NMR (376 MHz, CDCl3)
86.4 (d, CF3, J¼6.0 Hz);
d
Me), 2.78 (d, 1H, H-90, J¼15.4 Hz), 3.20 (d, 1H, H-900, J¼15.4 Hz), 6.15
13C NMR (100 MHz, CDCl3)
d
19.6 (2C), 26.4 (q, Me0-8, 6JC,F¼2.4 Hz),

8692
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
28.0 (Me00-8), 44.8 (C-9), 58.5 (C-8), 71.3 (q, C-6, 2JC,F¼32.6 Hz), 98.6
(C-14), 115.0, 116.1, 117.4, 117.9, 122.9, 123.4 (q, CF3, 1JC,F¼288.8 Hz),
124.0, 125.0, 125.9, 127.5, 129.2 (2C), 134.8, 135.5, 135.6, 148.4; MS
(EI, 70 eV) m/z 477 [Mþ1]þ (12), 475 [Me1]þ (12), 408 [Mþ1eCF3]þ
(92), 406 [Me1eCF3]þ (92), 365 (18), 363 (18), 197 (18), 188 (18).
Anal. Calcd for C24H21BrF3NO: S, 60.52; O, 4.44; N, 2.94. Found: S,
60.45; O, 4.37; N, 3.00.
(376 MHz, CDCl3) (tc, 50%)
d
85.1 (d, CF3, J¼6.6 Hz), (ct, 50%)
d
86.5
(d, CF3, J¼5.9 Hz); 1H NMR (400 MHz, DMSO-d6) (ct, 84%)
d 1.11, 1.14,
2.22, 2.23 (all s, 3H, Me), 2.63 (s, 2H, H-4), 3.22 (dd, 1H, CHH, J¼17.7,
3.8 Hz), 3.33 (dd,1H, CHH, J¼17.7,11.0 Hz), 4.00 (dd,1H, H-40, J¼11.0,
3.8 Hz), 5.53 (qd, 1H, H-20, J¼6.3, 1.9 Hz), 5.57 (d, 1H, H-30, J¼1.9 Hz),
7.02 (s, 1H, H-5), 7.03 (dd, 1H, H-80, J¼8.3, 1.2 Hz), 7.08 (td, 1H, H-60,
J¼7.5, 1.2 Hz), 7.25 (ddd, 1H, H-70, J¼8.3, 7.3, 1.2 Hz), 7.35 (s, 1H, H-8),
7.46 (dd, 1H, H-50, J¼7.8, 1.2 Hz); 19F NMR (376 MHz, DMSO-d6) (ct,
3.2.6. 2-Bromo-11,12-dimethoxy-8,8-dimethyl-6-(trifluoromethyl)-
8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline
(3f). Yield 0.38 g (75%, A), 0.31 g (61%, B), mp 195e196 ꢀC; IR (KBr)
84%)
d
88.1 (d, CF3, J¼6.3 Hz), (tc, 16%)
d
87.8 (d, CF3, J¼7.0 Hz); 13
C
NMR (100 MHz, CDCl3) (tcþct)
d 19.6 (2C), 19.8 (2C), 27.6, 27.7, 28.1,
28.2, 32.0, 33.6, 35.7, 38.2, 38.3, 41.5, 53.9, 54.2, 70.6 (q, C-20,
1633, 1614, 1557, 1532, 1494 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.36
2JC,F¼34.1 Hz), 73.5 (q, C-20, JC,F¼32.5 Hz), 78.5, 80.9, 117.0, 117.2,
2
(s, 3H, Me), 1.79 (s, 3H, Me), 2.69 (d, 1H, H-90, J¼15.4 Hz), 3.15 (d, 1H,
H-900, J¼15.4 Hz), 3.91 (s, 3H, MeO), 3.96 (s, 3H, MeO), 6.14 (q, 1H, H-
6, J¼6.0 Hz), 6.68 (s, 2H, H-10, H-14), 6.88 (d, 1H, H-4, J¼8.5 Hz),
7.08 (s, 1H, H-13), 7.18 (dd, 1H, H-3, J¼8.5, 2.4 Hz), 7.56 (d, 1H, H-1,
122.1 (q, CF3, 1JC,F¼280.9 Hz), 122.3, 122.9, 123.0, 123.0, 123.0 (q, CF3,
1JC,F¼283.0 Hz), 125.1 (2C), 125.3, 125.8, 126.5, 128.3, 128.8, 128.9,
129.8, 130.1, 134.0, 134.3, 134.8, 135.0, 139.7, 140.3, 152.0, 152.1,
158.8, 159.0. Anal. Calcd for C24H25F3N2O3: S, 64.57; O, 5.64; N,
6.27. Found: S, 64.53; O, 5.70; N, 6.24.
J¼2.4 Hz); 19F NMR (376 MHz, CDCl3)
86.4 (d, CF3, J¼6.0 Hz). Anal.
d
Calcd for C24H21BrF3NO3: S, 56.71; O, 4.16; N, 2.76. Found: S, 56.60;
O, 3.86; N, 2.87.
3.3.3. 6,7-Dimethoxy-3,3-dimethyl-1-[3-nitro-2-(trifluoromethyl)
chroman-4-yl]methyl-3,4-dihydroisoquinoline (5c). Yield 0.39
(81%, 3 h), mp 150e151 ꢀC (decomp.); IR (KBr) 1627, 1605, 1574,
1555, 1513, 1493, 1379, 1360 cmꢁ1 1H NMR (400 MHz, CDCl3) (tc,
53%) 1.13 (s, 3H, Me), 1.17 (s, 3H, Me), 2.59 (AB-system, 2H, H-4,
g
3.3. General procedures for the synthesis of compounds 5 and 6
;
A solution of the corresponding chromene 1 (1.0 mmol) and
dihydroisoquinoline 2 (1.0 mmol) in toluene (2 mL) was kept at
room temperature. After that, the mixture was concentrated under
reduced pressure and the solid formed was washed with hexane
and recrystallized from dichloromethaneehexane to give com-
pound 5 or 6 as a colourless powder, except 6b and 6g, which were
obtained as colourless crystals.
d
J¼16.2 Hz), 3.02 (dd, 1H, CHH, J¼16.3, 8.1 Hz), 3.21 (dd, 1H, CHH,
J¼16.3, 6.2 Hz), 3.90 (s, 3H, MeO), 3.92 (s, 3H, MeO), 4.24e4.33 (m,
1H, H-40), 5.32 (qd, 1H, H-20, J¼6.4, 4.8 Hz), 5.76 (t, 1H, H-30,
J¼4.8 Hz), 6.65 (s, 1H, H-5), 6.88 (s, 1H, H-8), 7.00e7.30 (m, 4H,
arom.), (ct, 47%) d 1.20 (s, 3H, Me), 1.22 (s, 3H, Me), 2.66 (s, 2H, H-4),
2.78 (dd, 1H, CHH, J¼17.0, 11.8 Hz), 3.31 (dd, 1H, CHH, J¼17.0,
3.0 Hz), 3.88 (s, 3H, MeO), 3.93 (s, 3H, MeO), 4.08 (dd, 1H, H-40,
J¼11.8, 3.0 Hz), 4.54e4.63 (m, 1H, H-20), 5.54e5.60 (m, 1H, H-30),
6.69 (s, 1H, H-5), 6.89 (s, 1H, H-8), 7.00e7.30 (m, 4H, arom.); 19F
3.3.1. 3,3-Dimethyl-1-[3-nitro-2-(trifluoromethyl)chroman-4-yl]
methyl-3,4-dihydroisoquinoline (5a). Yield 0.29 g (68%,ꢁ41days), mp
111e112 ꢀC; IR (KBr) 1617, 1583, 1562, 1490, 1372 cm
;
1H NMR
NMR (376 MHz, CDCl3) (tc, 53%)
d
d
85.0 (d, CF3, J¼6.4 Hz), (ct, 47%)
(400 MHz, CDCl3) (tc, 54%)
d
1.15 (s, 3H, Me), 1.19 (s, 3H, Me), 2.67
86.5 (d, CF3, J¼5.8 Hz); 1H NMR (400 MHz, DMSO-d6) (ct, 86%)
(AB-system, 2H, H-4, J¼16.3 Hz), 3.08 (dd, 1H, CHH, J¼16.8, 8.5 Hz),
3.31 (dd, 1H, CHH, J¼16.8, 6.0 Hz), 4.31 (ddd, 1H, H-40, J¼8.5, 6.0,
4.6 Hz), 5.29 (qd, 1H, H-20, J¼6.0, 4.6 Hz), 5.84 (t, 1H, H-30, J¼4.6 Hz),
d
1.12 (s, 3H, Me), 1.15 (s, 3H, Me), 2.64 (s, 2H, H-4), 3.24 (dd, 1H,
CHH, J¼17.7, 3.9 Hz), 3.34 (dd, 1H, CHH, J¼17.7, 11.0 Hz), 3.76 (s, 3H,
MeO), 3.81 (s, 3H, MeO), 4.03 (dd, 1H, H-40, J¼11.0, 3.9 Hz), 5.52 (qd,
1H, H-20, J¼6.4, 1.8 Hz), 5.56 (br d, 1H, H-30, J¼1.8 Hz), 6.87 (s, 1H, H-
5), 7.04 (dd, 1H, H-80, J¼8.2, 1.2 Hz), 7.09 (td, 1H, H-60, J¼7.6, 1.2 Hz),
7.10 (s, 1H, H-8), 7.25 (td, 1H, H-70, J¼7.9, 1.5 Hz), 7.45 (dd, 1H, H-50,
7.00e7.45 (m, 8H, arom.), (ct, 46%)
d 1.21 (s, 3H, Me), 1.23 (s, 3H,
Me), 2.74 (s, 2H, H-4), 2.79 (dd, 1H, CHH, J¼16.7, 11.8 Hz), 3.39 (dd,
1H, CHH, J¼16.7, 3.0 Hz), 4.05 (dd, 1H, H-40, J¼11.8, 3.0 Hz), 4.58 (q,
1H, H-20, J¼5.7 Hz), 5.57 (s, 1H, H-30), 7.00e7.45 (m, 8H, arom.); 19F
J¼7.9, 1.5 Hz); 19F NMR (376 MHz, DMSO-d6) (ct, 85%)
d 88.2 (d, CF3,
87.8 (br d, CF3, J¼6.0 Hz). Anal. Calcd for
NMR (376 MHz, CDCl3) (tc, 52%)
d
d
85.1 (br d, CF3, J¼6.0 Hz), (ct, 48%)
J¼6.4 Hz), (tc, 15%)
d
86.5 (br d, CF3, J¼5.7 Hz); 1H NMR (400 MHz, DMSO-d6) (ct, 86%)
C24H25F3N2O5: S, 60.25; O, 5.27; N, 5.85. Found: S, 60.26; O, 5.30;
d
1.14 (s, 3H, Me), 1.15 (s, 3H, Me), 2.73 (s, 2H, H-4), 3.28 (dd, 1H,
N, 5.62.
CHH, J¼17.7, 4.2 Hz), 3.34 (dd, 1H, CHH, J¼17.7, 10.5 Hz), 4.02 (dd,
1H, H-40, J¼10.5, 4.2 Hz), 5.52 (qd, 1H, H-20, J¼6.3, 1.5 Hz), 5.60 (d,
1H, H-30, J¼1.5 Hz), 7.03 (d, 1H, H-80, J¼8.1 Hz), 7.08 (t, 1H, H-60,
J¼7.6 Hz), 7.23e7.27 (m, 2H, arom.), 7.33 (t, 1H, J¼7.6 Hz, arom.),
7.40e7.48 (m, 2H, arom.), 7.57 (d, 1H, H-50, J¼7.6 Hz); 19F NMR
3.3.4. 6,7-Dimethoxy-1-[6-methoxy-3-nitro-2-(trifluoromethyl)chro-
man-4-yl]methyl-3,3-dimethyl-3,4-dihydroisoquinoline (5d). Yield
0.43 (84%, 0.5 h), mp 164e165 ꢀC (decomp.); IR (KBr) 1626, 1607,
1576, 1558, 1515, 1500, 1356 cmꢁ1
;
1H NMR (400 MHz, CDCl3) (tc,
(376 MHz, DMSO-d6) (ct, 84%)
d
88.2 (d, CF3, J¼6.3 Hz), (tc, 16%)
55%) d 1.14 (s, 3H, Me), 1.18 (s, 3H, Me), 2.60 (AB-system, 2H, H-4,
d
87.8 (d, CF3, J¼7.2 Hz). Anal. Calcd for C22H21F3N2O3: S, 63.15; O,
J¼16.1 Hz), 3.00 (dd, 1H, CHH, J¼16.0, 7.7 Hz), 3.18 (dd, 1H, CHH,
J¼16.0, 6.4 Hz), 3.74, 3.91, 3.92 (all s, 3H, MeO), 4.26 (br q, 1H, H-40,
J¼6.1 Hz), 5.28 (qd, 1H, H-20, J¼6.5, 4.5 Hz), 5.70 (br t, 1H, H-30,
J¼4.5 Hz), 6.65 (s, 1H, H-5), 6.71 (d, 1H, H-50, J¼2.7 Hz), 6.77 (dd, 1H,
H-70, J¼8.8, 2.7 Hz), 6.87 (s, 1H, H-8), 6.98 (d, 1H, H-80, J¼8.8 Hz), (ct,
5.06; N, 6.70. Found: S, 62.87; O, 4.89; N, 6.50.
3.3.2. 3,3,6,7-Tetramethyl-1-[3-nitro-2-(trifluoromethyl)chroman-4-
yl]methyl-3,4-dihydroisoquinoline (5b). Yield 0.33 g (73%, 3 h), mp
116e117 ꢀC; IR (KBr) 1618, 1583, 1565, 1491, 1371 cmꢁ1
;
1H NMR
45%) d 1.21 (s, 3H, Me), 1.22 (s, 3H, Me), 2.66 (s, 2H, H-4), 2.79 (dd,
(400 MHz, CDCl3) (tc, 50%)
d
1.13, 1.17, 2.26, 2.27 (all s, 3H, Me), 2.59
1H, CHH, J¼16.8, 12.3 Hz), 3.31 (dd, 1H, CHH, J¼16.8, 3.2 Hz), 3.79,
3.89, 3.93 (all s, 3H, MeO), 4.08 (m, 1H, H-40), 4.52 (br q, 1H, H-20,
J¼5.5 Hz), 5.52 (m, 1H, H-30), 6.69 (s, 1H, H-5), 6.79 (d, 1H, H-50,
J¼2.7 Hz), 6.83 (dd, 1H, H-70, J¼8.8, 2.7 Hz), 6.88 (s, 1H, H-8), 7.00 (d,
(AB-system, 2H, H-4, J¼16.4 Hz), 3.05 (dd, 1H, CHH, J¼16.7, 8.4 Hz),
3.27 (dd, 1H, CHH, J¼16.7, 5.6 Hz), 4.30 (dt, 1H, H-40, J¼8.4, 5.6 Hz),
5.23e5.32 (m, 1H, H-20), 5.85 (t, 1H, H-30, J¼4.4 Hz), 6.92 (s, 1H, H-
5), 7.00e7.13 (m, 2H, arom.), 7.17 (s, 1H, H-8), 7.21e7.30 (m, 2H,
1H, H-80, J¼8.8 Hz); 19F NMR (376 MHz, CDCl3) (tc, 55%)
d 84.9 (d,
arom.), (ct, 50%)
d
1.18, 1.21, 2.27, 2.28 (all s, 3H, Me), 2.65 (br s, 2H,
CF3, J¼6.5 Hz), (ct, 45%)
d
86.5 (d, CF3, J¼5.8 Hz); 1H NMR (400 MHz,
H-4), 2.78 (dd, 1H, CHH, J¼16.7, 12.0 Hz), 3.35 (dd, 1H, CHH, J¼16.7,
3.0 Hz), 4.05 (dd, 1H, H-40, J¼12.0, 3.0 Hz), 4.58 (q, 1H, H-20,
J¼5.9 Hz), 5.56 (br s, 1H, H-30), 6.96 (s, 1H, H-5), 7.00e7.13 (m, 2H,
arom.), 7.17 (s, 1H, H-8), 7.21e7.30 (m, 2H, arom.); 19F NMR
DMSO-d6) (ct, 90%) d 1.11 (s, 3H, Me), 1.16 (s, 3H, Me), 2.64 (s, 2H, H-
4), 3.31 (d, 2H, CH2, J¼7.3 Hz), 3.74, 3.77, 3.81 (all s, 3H, MeO), 4.01
(t, 1H, H-40, J¼7.3 Hz), 5.44 (qd, 1H, H-20, J¼6.3, 1.5 Hz), 5.50 (br d,
1H, H-30, J¼1.5), 6.82 (dd, 1H, H-70, J¼8.9, 3.0 Hz), 6.87 (s, 1H, H-5),

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8693
6.96 (d, 1H, H-80, J¼8.9 Hz), 7.02 (d, 1H, H-50, J¼3.0 Hz), 7.10 (s, 1H,
1H NMR (400 MHz, CDCl3) (tc, 83%)
d
1.14 (s, 3H, Me), 1.19 (s, 3H,
H-8); 19F NMR (376 MHz, DMSO-d6) (ct, 89%)
d
88.2 (d, CF3,
Me), 2.65 (AB-system, 2H, H-4, J¼15.8 Hz), 2.99 (dd, 1H, CHH,
J¼16.5, 8.3 Hz), 3.27 (dd, 1H, CHH, J¼16.5, 6.3 Hz), 4.36 (dt, 1H, H-40,
J¼7.7, 6.0 Hz), 5.38 (d, 1H, H-20, J¼4.9 Hz), 5.99 (t, 1H, H-30,
J¼5.2 Hz), 7.04 (td, 1H, H-60, J¼7.5, 1.1 Hz), 7.1e7.4 (m, 7H, arom.),
J¼6.3 Hz), (tc, 11%)
d
87.6 (br d, CF3, J¼6.3 Hz). Anal. Calcd for
C24H27F3N2O6: S, 59.05; O, 5.35; N, 5.51. Found: 58.69; O, 5.10; N,
5.21.
(ct,17%) d 1.20 (s, 3H, Me),1.27 (s, 3H, Me), 2.74 (AB-system, 2H, H-4,
3.3.5. 1-[6-Bromo-3-nitro-2-(trifluoromethyl)chroman-4-yl]methyl-
3,3,6,7-tetramethyl-3,4-dihydroisoquinoline (5e). Yield 0.21 g (39%,
1 h), mp 128e129 ꢀC (decomp.); IR (KBr) 1629, 1557, 1481, 1386,
J¼15.5 Hz), 2.82 (dd, 1H, CHH, J¼16.6, 12.0 Hz), 3.40 (dd, 1H, CHH,
J¼16.6, 3.2 Hz), 3.98 (br dd, 1H, H-40, J¼12.0, 3.0 Hz), 4.61 (d, 1H, H-
20, J¼1.6 Hz), 6.08 (br t, 1H, H-30, J¼1.3 Hz), 7.1e7.5 (m, 8H, arom.);
1369 cmꢁ1
;
1H NMR (400 MHz, CDCl3) (tc, 54%)
d
1.16, 1.18, 2.28,
1H NMR (400 MHz, DMSO-d6) (ct, 64%)
d 1.12, 1.20 (both s, 3H, Me),
2.29 (all s, 3H, Me), 2.62 (br s, 2H, H-4), 3.05 (m, 1H, CHH), 3.25 (m,
1H, CHH), 4.27 (br q, 1H, H-40, J¼6.5 Hz), 5.27 (br s, 1H, H-20), 5.85
(br s, 1H, H-30), 6.9e7.0 (m, 2H, H-5, H-80), 7.15e7.40 (m, 3H, H-8, H-
2.72 (s, 2H, H-4), 3.25 (dd, 1H, CHH, J¼17.9, 3.2 Hz), 3.52 (dd, 1H,
CHH, J¼17.9, 11.5 Hz), 3.95 (dd, 1H, H-40, J¼11.5, 3.2 Hz), 5.44 (d, 1H,
H-20, J¼1.6 Hz), 6.03 (br s, 1H, H-30), 7.0e7.6 (m, 8H, arom.), (tc, 36%)
50, H-70), (ct, 46%)
d
1.18,1.20, 2.28, 2.29 (all s, 3H, Me), 2.66 (br s, 2H,
d 1.10 (s, 3H, Me), 1.20 (s, 3H, Me), 2.70 (s, 2H, H-4), 2.81 (dd, 1H,
H-4), 2.7e2.9 (m, 1H, CHH), 3.3e3.4 (m, 1H, CHH), 4.08 (br s, 1H, H-
40), 4.56 (br s,1H, H-20), 5.50 (s,1H, H-30), 6.9e7.0 (m, 2H, H-5, H-80),
7.15e7.40 (m, 3H, H-8, H-50, H-70); 19F NMR (376 MHz, CDCl3) (tc,
CHH, J¼17.7, 9.9 Hz), 3.60 (dd, 1H, CHH, J¼17.7, 4.8 Hz), 4.22 (dt, 1H,
H-40, J¼10.0, 4.8 Hz), 5.54 (d, 1H, H-20, J¼3.5 Hz), 6.37 (dd, 1H, H-30,
J¼5.3, 3.5 Hz), 7.1e7.7 (m, 8H, arom.); 13C NMR (100 MHz, CDCl3)
54%)
d
85.2 (d, CF3, J¼6.6 Hz), (ct, 46%)
d
86.5 (d, CF3, J¼5.8 Hz); 1H
(tc) d 27.7, 28.1, 31.9, 35.9, 38.7, 54.0, 85.6, 86.1, 98.6, 117.7, 123.5,
NMR (400 MHz, DMSO-d6) (ct, 84%)
d
1.12 (br s, 6H, 2Me), 2.22 (s,
124.1, 125.2, 126.5, 126.9, 127.9, 128.4, 128.8, 130.7, 136.6, 153.3,
158.9. Anal. Calcd for C22H21Cl3N2O3: S, 56.49; O, 4.53; N, 5.99.
Found: S, 56.53; O, 4.31; N, 5.92.
3H, Me), 2.23 (s, 3H, Me), 2.63 (AB-system, 2H, H-4, J¼16.7 Hz), 3.26
(dd, 1H, CHH, J¼17.5, 5.0 Hz), 3.33 (dd, 1H, CHH, J¼17.5, 9.5 Hz), 4.07
(dd,1H, H-40, J¼9.5, 5.0 Hz), 5.57 (br q,1H, H-20, J¼6.2 Hz), 5.63 (br s,
1H, H-30), 7.02 (s,1H, H-5), 7.02 (d,1H, H-80, J¼8.7 Hz), 7.36 (s,1H, H-
8), 7.40 (dd, 1H, H-70, J¼8.7, 2.2 Hz), 7.71 (d, 1H, H-50, J¼2.2 Hz); 19F
3.4.2. 3,3,6,7-Tetramethyl-1-[3-nitro-2-(trichloromethyl)chroman-4-
yl]methyl-3,4-dihydroisoquinoline (6b). Yield 0.39 g (78%, 10 h), mp
NMR (376 MHz, DMSO-d6) (ct, 84%)
d
88.2 (d, CF3, J¼6.2 Hz), (tc,
136e137 ꢀC; IR (KBr) 1625, 1613, 1588, 1544, 1484, 1458, 1357 cmꢁ1
;
16%)
d
87.8 (d, CF3, J¼6.9 Hz); 13C NMR (100 MHz, CDCl3) (tcþct)
1H NMR (400 MHz, CDCl3) (tc, 84%)
d 1.1e1.3 (br s, 6H, 2 Me), 2.28 (s,
d
19.6 (2C), 19.8 (2C), 27.6, 27.7, 27.9, 28.0, 31.8, 33.3, 35.4, 38.2, 41.2,
6H, 2 Me), 2.6 (m, 2H, H-4), 3.0 (m, 1H, CHH), 3.2 (m, 1H, CHH), 4.4
54.0, 54.2, 70.6 (q, C-20, 2JC,F¼34.0 Hz), 73.4 (q, C-20, 2JC,F¼32.9 Hz),
(m, 1H, H-40), 5.4 (m, 1H, H-20), 6.0 (m, 1H, H-30), 6.9e7.3 (m, 6H,
78.3, 80.3, 115.2, 118.8, 118.9, 121.9 (q, CF3, 1JC,F¼280.5 Hz), 122.8 (q,
arom.), (ct, 16%)
d 1.1e1.3 (br s, 6H, 2 Me), 2.28 (br s, 6H, 2 Me), 2.7
1
CF3, JC,F¼283.1 Hz), 124.5, 125.0 (2C), 125.2, 125.6, 129.6, 129.8,
(br s, 2H, H-4), 2.8 (m, 1H, CHH), 3.4 (m, 1H, CHH), 3.97 (d, 1H, H-40,
J¼11.5 Hz), 4.6 (m, 1H, H-20), 6.1 (m, 1H, H-30), 6.9e7.3 (m, 6H,
130.1, 130.6, 131.3, 131.6, 131.7, 133.9, 134.2, 134.9, 135.1, 139.9, 140.4,
151.0, 151.2, 158.4, 158.7. Anal. Calcd for C24H24BrF3N2O3: S, 54.87;
O, 4.60; N, 5.33. Found: S, 54.78; O, 4.56; N, 5.23.
arom.); 1H NMR (400 MHz, DMSO-d6) (ct, 65%)
d 1.09, 1.19, 2.22,
2.23 (all s, 3H, Me), 2.63 (s, 2H, H-4), 3.19 (dd, 1H, CHH, J¼17.9,
3.2 Hz), 3.51 (dd,1H, CHH, J¼17.9,11.6 Hz), 3.94 (dd,1H, H-40, J¼11.6,
3.3 Hz), 5.42 (d, 1H, H-20, J¼1.6 Hz), 6.01 (br s, 1H, H-30), 7.02 (s, 1H,
3.3.6. 1-[6-Bromo-3-nitro-2-(trifluoromethyl)chroman-4-yl]methyl-
6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinoline
(5f). Yield
H-5), 7.38 (s, 1H, H-8), 7.1e7.5 (m, 4H, arom.), (tc, 35%) d 1.08, 1.18,
0.48 g (86%, 1 h), 0.51 g (91%, solvent-free, 60 ꢀC, 15 min), mp
2.23, 2.25 (all s, 3H, Me), 2.61 (s, 2H, H-4), 2.79 (dd, 1H, CHH, J¼17.5,
9.9 Hz), 3.54 (dd, 1H, CHH, J¼17.5, 4.7 Hz), 4.20 (dt, 1H, H-40, J¼9.9,
4.7 Hz), 5.52 (d, 1H, H-20, J¼2.5 Hz), 6.38 (s, 1H, H-30), 7.0e7.5 (m,
6H, arom.). Anal. Calcd for C24H25Cl3N2O3: S, 58.14; O, 5.08; N, 5.65.
Found: S, 58.14; O, 5.13; N, 5.67.
140e141 ꢀC (decomp.); IR (KBr) 1629, 1605, 1575, 1558, 1514, 1482,
1364, 1353 cmꢁ1; 1H NMR (400 MHz, CDCl3) (tc, 56%)
d 1.15 (s, 3H,
Me), 1.18 (s, 3H, Me), 2.61 (AB-system, 2H, H-4, J¼15.9 Hz), 3.00 (dd,
1H, CHH, J¼16.3, 8.0 Hz), 3.15 (dd, 1H, CHH, J¼16.3, 6.3 Hz), 3.93 (s,
6H, MeO), 4.27 (br q, 1H, H-40, J¼6.0 Hz), 5.30 (qd, 1H, H-20, J¼6.4,
4.4 Hz), 5.75 (t, 1H, H-30, J¼4.4 Hz), 6.67 (s, 1H, H-5), 6.89 (s, 1H, H-
8), 6.93 (d, 1H, H-80, J¼8.5 Hz), 7.30e7.42 (m, 2H, H-50, H-70), (ct,
3.4.3. 6,7-Dimethoxy-3,3-dimethyl-1-[3-nitro-2-(trichloromethyl)
chroman-4-yl]methyl-3,4-dihydroisoquinoline (6c). Yield 0.38
g
44%)
d
1.19 (s, 3H, Me), 1.21 (s, 3H, Me), 2.65 (s, 2H, H-4), 2.80 (dd,
(71%, 5 h), mp 123e124 ꢀC (decomp.); IR (KBr) 1621, 1606, 1572,
1H, CHH, J¼17.2, 11.5 Hz), 3.25 (dd, 1H, CHH, J¼17.2, 3.2 Hz), 3.90 (s,
3H, MeO), 3.93 (s, 3H, MeO), 4.12 (br d, 1H, H-40, J¼11.5 Hz), 4.56 (br
q, 1H, H-20, J¼5.5 Hz), 5.52 (br s, 1H, H-30), 6.69 (s, 1H, H-5), 6.87 (s,
1H, H-8), 6.95 (d, 1H, H-80, J¼8.5 Hz), 7.30e7.42 (m, 2H, H-50, H-70);
1554, 1512, 1492, 1455, 1359, 1340 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(tc, 84%)
d 1.14 (br s, 3H, Me), 1.20 (br s, 3H, Me), 2.58 (m, 2H, H-4),
2.95 (br s, 1H, CHH), 3.20 (br s, 1H, CHH), 3.91 (s, 3H, MeO), 3.92 (s,
3H, MeO), 4.36 (br s, 1H, H-40), 5.47 (br s, 1H, H-20), 5.87 (br s, 1H, H-
30), 6.64 (s, 1H, H-5), 6.86 (s, 1H, H-8), 7.0e7.3 (m, 4H, arom.), (ct,
19F NMR (376 MHz, CDCl3) (tc, 55%)
d
85.1 (d, CF3, J¼6.5 Hz), (ct,
45%)
82%)
d
86.6 (d, CF3, J¼5.7 Hz); 1H NMR (400 MHz, DMSO-d6) (ct,
16%) d 1.21 (br s, 3H, Me), 1.26 (br s, 3H, Me), 2.67 (br s, 2H, H-4), 2.9
d
1.13 (s, 3H, Me), 1.14 (s, 3H, Me), 2.64 (AB-system, 2H, H-4,
(br s, 1H, CHH), 3.3 (br s, 1H, CHH), 3.90 (s, 3H, MeO), 3.94 (s, 3H,
MeO), 4.0 (m, 1H, H-40), 4.61 (br s, 1H, H-20), 6.08 (br s, 1H, H-30),
6.70 (s, 1H, H-5), 6.93 (s, 1H, H-8), 7.0e7.3 (m, 4H, arom.). Anal.
Calcd for C24H25Cl3N2O5: S, 54.61; O, 4.77; N, 5.31. Found: S, 54.68;
O, 4.64; N, 5.42.
J¼16.0 Hz), 3.2e3.3 (m, 2H, CH2), 3.77 (s, 3H, MeO), 3.81 (s, 3H,
MeO), 4.08 (br dd, 1H, H-40, J¼9.5, 4.8 Hz), 5.57 (br q, 1H, H-20,
J¼6.3 Hz), 5.61 (br s, 1H, H-30), 6.87 (s, 1H, H-5), 7.02 (d, 1H, H-80,
J¼8.8 Hz), 7.11 (s, 1H, H-8), 7.41 (dd, 1H, H-70, J¼8.8, 2.3 Hz), 7.68 (d,
1H, H-50, J¼2.3 Hz); 19F NMR (376 MHz, DMSO-d6) (ct, 83%)
d 88.2
(d, CF3, J¼6.2 Hz), (tc, 17%)
d
87.7 (br d, CF3, J¼6.2 Hz). Anal. Calcd for
3.4.4. 6,7-Dimethoxy-1-[6-methoxy-3-nitro-2-(trichloromethyl)
chroman-4-yl]methyl-3,3-dimethyl-3,4-dihydroisoquinoline
(6d). Yield 0.35 g (62%, 3 h), mp 122e124 ꢀC (decomp.); IR (KBr)
C24H24BrF3N2O5: S, 51.72; O, 4.34; N, 5.03. Found: S, 51.64; O, 4.32;
N, 4.91.
1632, 1617, 1604, 1558, 1515, 1500, 1464, 1357 cmꢁ1 1H NMR
;
3.4. Compounds 6aeh
(400 MHz, CDCl3) (tc, 86%) d 1.14 (s, 3H, Me), 1.20 (s, 3H, Me), 2.58
(AB-system, 2H, H-4, J¼15.7 Hz), 2.91 (br dd, 1H, CHH, J¼16.0,
8.2 Hz), 3.17 (br dd, 1H, CHH, J¼16.0, 6.5 Hz), 3.75 (s, 3H, MeO), 3.91
(s, 6H, 2MeO), 4.32 (m, 1H, H-40), 5.37 (d, 1H, H-20, J¼4.7 Hz), 5.87
(br t, 1H, H-30, J¼5.0 Hz), 6.64 (s, 1H, H-5), 6.70 (d, 1H, H-50,
3.4.1. 3,3-Dimethyl-1-[3-nitro-2-(trichloromethyl)chroman-4-yl]
methyl-3,4-dihydroisoquinoline (6a). Yield 0.28 g (60%, 12 h), mp
122e123 ꢀC (decomp.); IR (KBr) 1629, 1552, 1484, 1457, 1363 cmꢁ1
;

8694
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
J¼2.9 Hz), 6.77 (dd, 1H, H-70, J¼8.8, 2.8 Hz), 6.86 (s, 1H, H-8), 7.04 (d,
2.72 (AB-system, 2H, H-4, J¼16.0 Hz), 3.38 (ABX-system, 2H, CH2,
J¼17.3,10.1, 4.6 Hz), 4.02 (dd,1H, H-40, J¼10.1, 4.6 Hz), 5.39 (d,1H, H-
20, J¼2.2 Hz), 5.70 (d, 1H, H-30, J¼2.2 Hz), 7.0e7.7 (m, 13H, arom.),
1H, H-80, J¼8.8 Hz), (ct, 14%)
d 1.20 (s, 3H, Me), 1.25 (s, 3H, Me), 2.66
(AB-system, 2H, H-4, J¼15.5 Hz), 2.77e2.84 (m, 1H, CHH),
3.30e3.35 (m, 1H, CHH), 3.80 (s, 3H, MeO), 3.90 (s, 3H, MeO), 3.93
(s, 3H, MeO), 4.01 (br dd, 1H, H-40, J¼11.0, 3.0 Hz), 4.55 (br s, 1H, H-
20), 6.03 (br s,1H, H-30), 6.70 (s,1H, H-5), 6.80 (d,1H, H-50, J¼2.8 Hz),
6.86 (dd, 1H, H-70, J¼8.8, 2.8 Hz), 6.91 (s, 1H, H-8), 7.08 (d, 1H, H-80,
(tc, 12%) d 0.99,1.06 (both s, 3H, Me), 2.63 (s, 2H, H-4), 3.03e3.16 (m,
2H, CH2), 4.02 (m, 1H, H-40), 5.92 (t, 1H, H-30, J¼4.8 Hz), 5.99 (d, 1H,
H-20, J¼4.6 Hz), 6.9e7.6 (m,13H, arom.). Anal. Calcd for C27H26N2O3:
S, 76.03; O, 6.14; N, 6.57. Found: S, 76.11; O, 6.22; N, 6.47.
J¼8.8 Hz); 1H NMR (400 MHz, DMSO-d6) (ct, 70%)
d 1.10 (s, 3H, Me),
1.20 (s, 3H, Me), 2.64 (br s, 2H, H-4), 3.27 (dd, 1H, CHH, J¼18.0,
3.2 Hz), 3.50 (br dd, 1H, CHH, J¼18.0, 11.0 Hz), 3.75, 3.78, 3.81 (all s,
3H, MeO), 3.94 (br dd, 1H, H-40, J¼11.0, 3.0 Hz), 5.31 (d, 1H, H-20,
J¼1.5 Hz), 5.95 (br s, 1H, H-30), 6.84 (dd, 1H, H-70, J¼8.9, 2.8 Hz), 6.87
(s, 1H, H-5), 6.99 (d, 1H, H-80, J¼8.9 Hz), 7.03 (d, 1H, H-50, J¼2.8 Hz),
3.4.8. 6,7-Dimethoxy-3,3-dimethyl-1-(3-nitro-2-phenylchroman-4-
yl)methyl-3,4-dihydroisoquinoline (6h). Yield 0.44 g (91%, 3 h), mp
183e185 ꢀC (decomp.); IR (KBr) 1624, 1606, 1583, 1574, 1553, 1516,
1490, 1453, 1355 cmꢁ1 1H NMR (400 MHz, DMSO-d6) (ct, 90%)
;
d
1.08, 1.13 (both s, 3H, Me), 2.63 (AB-system, 2H, H-4, J¼16.4 Hz),
7.15 (s, 1H, H-8), (ts, 30%)
d
1.08 (s, 3H, Me), 1.19 (s, 3H, Me), 2.61 (br
3.27e3.44 (m, 2H, CH2), 3.80 (s, 3H, MeO), 3.81 (s, 3H, MeO), 4.02
(dd, 1H, H-40, J¼10.5, 4.5 Hz), 5.36 (d, 1H, H-20, J¼2.3 Hz), 5.71 (t, 1H,
H-30, J¼2.3 Hz), 6.9e7.5 (m,11H, arom.). Anal. Calcd for C29H30N2O5:
S, 71.59; O, 6.21; N, 5.76. Found: S, 71.54; O, 6.19; N, 5.72.
s, 2H, H-4), 2.80 (dd, 1H, CHH, J¼17.9, 9.3 Hz), 3.50 (m, 1H, CHH),
3.74, 3.81, 3.82 (all s, 3H, MeO), 4.14 (dt,1H, H-40, J¼9.3, 4.8 Hz), 5.39
(m, 1H, H-20), 6.30 (m, 1H, H-30), 6.8e7.2 (m, 5H, arom.). Anal. Calcd
for C24H27Cl3N2O6: S, 53.83; O, 4.88; N, 5.02. Found: S, 53.75; O,
4.70; N, 5.00.
3.5. Compounds 8aeh
3.4.5. 1-[6-Bromo-3-nitro-2-(trichloromethyl)chroman-4-yl]methyl-
3,3,6,7-tetramethyl-3,4-dihydroisoquinoline (6e). Yield 0.30 g (52%,
3 h), 62% [benzene, reflux, Et3N (5 mol %), 15 min], mp 159e160 ꢀC
A mixture of the corresponding chromene 1 (1.0 mmol), hydro-
chloride 7 (1.0 mmol) and triethylamine (0.12 g, 1.2 mmol) was
refluxed in isobutanol (2 mL) for 3 h. After that, the mixture was
concentrated under reduced pressure and the solid formed was
washed with water, filtered, dried, and recrystallized from dichloro-
methane/hexane to give compound 8 as a colourless powder.
(decomp.); IR (KBr) 1624, 1544, 1479, 1365, 1356 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) (tc, 84%) d 1.15, 1.18, 2.27, 2.29 (all s, 3H, Me), 2.59
(AB-system, 2H, H-4, J¼15.9 Hz), 2.94 (br dd, 1H, CHH, J¼16.5,
7.6 Hz), 3.18 (br dd, 1H, CHH, J¼16.5, 6.8 Hz), 4.34 (br q, 1H, H-40,
J¼6.5 Hz), 5.38 (d, 1H, H-20, J¼4.2 Hz), 5.96 (br t, 1H, H-30, J¼5.0 Hz),
6.92 (s, 1H, H-5), 7.00 (d, 1H, H-80, J¼8.5 Hz), 7.15 (s, 1H, H-8), 7.34
(d, 1H, H-50, J¼2.3 Hz), 7.36 (dd, 1H, H-70, J¼8.5, 2.3 Hz), (ct, 16%)
3.5.1. 11,12-Dimethoxy-8-methyl-6-(trifluoromethyl)-8,9-dihydro-
6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (8a). Yield 0.32 g
(78%), mp 175e176 ꢀC; IR (KBr) 1612, 1561, 1536, 1492 cmꢁ1 1H
;
d
1.20,1.22, 2.27, 2.29 (all s, 3H, Me), 2.66 (br s, 2H, H-4), 2.94 (m,1H,
NMR (400 MHz, CDCl3) (trans, 53%)
d
1.26 (d, 3H, Me, J¼6.7 Hz),
CHH), 3.18 (m,1H, CHH), 4.03 (m,1H, H-40), 4.59 (br s,1H, H-20), 6.01
(br s, 1H, H-30), 6.97 (s, 1H, H-5), 7.02 (d, 1H, H-80, J¼8.5 Hz), 7.18 (s,
1H, H-8), 7.32e7.42 (m, 2H, H-50, H-70); 1H NMR (400 MHz, DMSO-
2.75 (d,1H, H-90, J¼15.5 Hz), 3.40 (dd,1H, H-900, J¼15.3, 6.0 Hz), 3.91,
3.96 (all s, 3H, MeO), 4.50 (qdd, 1H, H-8, J¼6.7, 6.0, 1.7 Hz), 5.80 (q,
3
1H, H-6, JH,F¼6.1 Hz), 6.66 (s, 1H, H-10/14), 6.71 (s, 1H, H-14/10),
d6) (ct, 65%)
d
1.12, 1.17, 2.23, 2.24 (all s, 3H, Me), 2.62 (m, 2H, H-4),
6.99e7.04 (m, 2H, H-2, H-4), 7.08 (s, 1H, H-13), 7.09 (td, 1H, H-3,
3.25 (dd, 1H, CHH, J¼17.7, 3.7 Hz), 3.52 (br dd, 1H, CHH, J¼17.5,
5.5 Hz), 4.00 (br dd, 1H, H-40, J¼10.5, 3.5 Hz), 5.47 (d, 1H, H-20,
J¼1.5 Hz), 6.04 (br s, 1H, H-30), 7.03 (s, 1H, H-5), 7.04 (d, 1H, H-80,
J¼8.8 Hz), 7.42 (dd, 1H, H-70, J¼8.8, 2.3 Hz), 7.50 (s, 1H, H-8), 7.71 (br
J¼7.6, 2.1 Hz), 7.41 (dd, 1H, H-1, J¼7.7, 1.6 Hz), (cis, 47%)
d 1.21 (d, 3H,
Me, J¼6.4 Hz), 2.71 (dd, 1H, H-90, J¼15.5, 1.3 Hz), 3.29 (dd, 1H, H-900,
J¼15.5, 5.5 Hz), 3.92, 3.97 (all s, 3H, MeO), 4.41 (qdd, 1H, H-8, J¼6.4,
5.5,1.3 Hz), 5.65 (q,1H, H-6, 3JH,F¼6.5 Hz), 6.65 (s,1H, H-10/14), 6.75
(s, 1H, H-14/10), 6.99e7.04 (m, 2H, H-2, H-4), 7.10 (s, 1H, H-13), 7.10
(ddd, 1H, H-3, J¼8.3, 7.0, 1.6 Hz), 7.43 (dd, 1H, H-1, J¼7.7, 1.6 Hz); 19F
s, 1H, H-50), (ts, 35%)
d 1.10, 1.17, 2.24, 2.25 (all s, 3H, Me), 2.64 (br s,
2H, H-4), 2.80 (m, 1H, CHH), 3.52 (m, 1H, CHH), 4.20 (br dt, 1H, H-40,
J¼9.0, 5.0 Hz), 5.60e5.65 (br s, 1H, H-20), 6.36 (br s, 1H, H-30),
7.0e7.7 (m, 5H, arom.). Anal. Calcd for C24H24BrCl3N2O3: S, 50.16;
O, 4.21; N, 4.87. Found: S, 50.18; O, 4.11; N, 4.76.
NMR (376 MHz, CDCl3) (trans, 53%)
d
83.0 (d, CF3, 3JF,H¼6.1 Hz), (cis,
3
47%)
(cisþtrans)
d
84.4 (d, CF3, JF,H¼6.5 Hz); 13C NMR (100 MHz, CDCl3)
6
d
19.5 (q, Me, JC,F¼2.6 Hz), 20.3, 34.6, 35.9, 47.5, 48.6
2
(unres. q), 56.0, 56.1 (2C), 69.9 (q, C-6, JC,F¼34.4 Hz), 70.6 (q, C-6,
2JC,F¼33.9 Hz), 96.5, 97.7, 106.0, 106.2, 112.1, 112.2, 114.8, 115.2, 115.9,
116.0, 117.7, 117.9, 120.1, 120.6, 120.7, 120.8, 121.2, 122.2 (2C), 122.3,
3.4.6. 1-[6-Bromo-3-nitro-2-(trichloromethyl)chroman-4-yl]methyl-
6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinoline
(6f). Yield
1
0.35 g (58%, 5 h), mp 120e121 ꢀC (decomp.); IR (KBr) 1630, 1617,
122.6 (2C), 122.9 (q, CF3, JC,F¼286.7 Hz), 123.3 (q, CF3,
1606, 1576, 1555, 1514, 1482, 1465, 1354 cmꢁ1; 1H NMR (400 MHz,
1JC,F¼288.0 Hz), 126.7, 126.8, 132.2, 132.5, 148.2 (2C), 148.3 (2C),
149.7, 149.8; SMS (EI, 70 eV) m/z 415 [M]þ (27), 346 [MeCF3]þ
(100), 330 [MeCF3eCH4]þ (30), 173 (38), 129 (17), 123 (18). Anal.
Calcd for C23H20F3NO3: S, 66.50; O, 4.85; N, 3.37. Found: S, 66.56;
O, 4.78; N, 3.32.
CDCl3) (tc, 85%) d 1.15 (s, 3H, Me), 1.18 (s, 3H, Me), 2.59 (AB-system,
2H, H-4, J¼15.9 Hz), 2.91 (m, 1H, CHH), 3.11 (m, 1H, CHH), 3.93 (s,
3H, MeO), 3.94 (s, 3H, MeO), 4.34 (m, 1H, H-40), 5.46 (m, 1H, H-20),
5.83 (m, 1H, H-30), 6.66 (s, 1H, H-5), 6.86 (s, 1H, H-8), 6.99 (d, 1H, H-
80, J¼8.5 Hz), 7.27 (m, 1H, H-50), 7.36 (dd, 1H, H-70, J¼8.5, 2.3 Hz), (ct,
15%)
d
1.21 (s, 3H, Me), 1.23 (s, 3H, Me), 2.66 (br s, 2H, H-4), 2.80 (m,
3.5.2. 2,11,12-Trimethoxy-8-methyl-6-(trifluoromethyl)-8,9-dihydro-
6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (8b). Yield 0.20 g
(44%), mp 185e186 ꢀC; IR (KBr) 1622, 1614, 1564, 1534, 1510,
1H, CHH), 3.26 (m, 1H, CHH), 3.92 (s, 3H, MeO), 3.94 (s, 3H, MeO),
4.05 (dd, 1H, H-40, J¼10.7, 2.6 Hz), 4.58 (m, 1H, H-20), 6.03 (m, 1H, H-
30), 6.70 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.03 (d, 1H, H-80, J¼8.6 Hz),
7.27 (m, 1H, H-50), 7.40 (br d, 1H, H-70, J¼8.6 Hz). Anal. Calcd for
C24H24BrCl3N2O5: S, 47.51; O, 3.99; N, 4.62. Found: S, 47.32; O,
3.99; N, 4.50.
1490 cmꢁ1; 1H NMR (400 MHz, CDCl3) (trans, 86%)
d 1.25 (d, 3H, Me,
J¼6.6 Hz), 2.71 (dd, 1H, H-90, J¼15.4, 1.4 Hz), 3.39 (dd, 1H, H-900,
J¼15.4, 5.9 Hz), 3.82, 3.91, 3.96 (all s, 3H, MeO), 4.50 (dqd, 1H, H-8,
J¼6.6, 5.9, 1.4 Hz), 5.74 (q, 1H, H-6, 3JH,F¼6.1 Hz), 6.62 (dd, 1H, H-3,
J¼8.8, 2.9 Hz), 6.64 (s, 1H, H-10/14), 6.71 (s, 1H, H-14/10), 6.92 (d,
1H, H-4, J¼8.8 Hz), 6.95 (d, 1H, H-1, J¼2.9 Hz), 7.08 (s, 1H, H-13);
3.4.7. 3,3-Dimethyl-1-(3-nitro-2-phenylchroman-4-yl)methyl-3,4-
dihydroisoquinoline (6g). Yield 0.27 g (64%, 8 h), mp 143e144 ꢀC
(cis, 14%)
d
1.21 (d, 3H, Me, J¼6.4 Hz), 2.75 (d, 1H, H-90, J¼15.5 Hz),
(decomp.); IR (KBr) 1628, 1585, 1554, 1488, 1454, 1371, 1360 cmꢁ1
;
3.29 (dd, 1H, H-900, J¼15.5, 5.7 Hz), 3.83, 3.92, 3.97 (all s, 3H, MeO),
1H NMR (400 MHz, DMSO-d6) (ct, 88%)
d 1.10, 1.12 (both s, 3H, Me),
4.40 (m, 1H, H-8), 5.59 (q, 1H, H-6, 3JH,F¼6.5 Hz), 6.63 (s, 1H, H-10/

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8695
14), 6.64 (dd, 1H, H-3, J¼8.8, 2.9 Hz), 6.75 (s, 1H, H-14/10), 6.92 (d,
1H, H-4, J¼8.8 Hz), 6.98 (d, 1H, H-1, J¼2.9 Hz), 7.10 (s, 1H, H-13); 19F
0.19 g (39%), mp 223e224 ꢀC; IR (KBr) 1630, 1605, 1587, 1530,
1496 cmꢁ1 1H NMR (400 MHz, CDCl3)
1.37, 1.85, 1.88, 2.16 (all s,
;
d
NMR (376 MHz, CDCl3) (trans, 86%)
d
83.3 (d, CF3, 3JF,H¼6.1 Hz), (cis,
3H, Me), 2.69 (d, 1H, H-90, J¼15.3 Hz), 3.19 (d, 1H, H-900, J¼15.3 Hz),
6.24 (q, 1H, H-6, 3JH,F¼6.2 Hz), 6.53 (s, 1H, H-13), 6.66 (ddd, 1H, H-2,
J¼7.8, 6.6, 2.2 Hz), 6.86 (dd,1H, H-1, J¼7.8, 0.9 Hz), 6.87 (s,1H, H-10),
6.95 (dd, 1H, H-4, J¼8.2, 1.8 Hz), 6.98 (td, 1H, H-3, J¼7.8, 1.2 Hz),
3
14%)
d
84.6 (d, CF3, JF,H¼6.5 Hz). Anal. Calcd for C24H22F3NO4: S,
64.71; O, 4.98; N, 3.14. Found: S, 64.93; O, 4.85; N, 3.00.
3.5.3. 2-Bromo-11,12-dimethoxy-8-methyl-6-(trifluoromethyl)-8,9-
dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (8c). Yield
0.24 g (48%), mp 185e186 ꢀC; IR (KBr) 1605,1556,1534,1495 cmꢁ1; 1H
7.0e7.9 (m, 5H, Ph); 19F NMR (376 MHz, CDCl3)
d 86.8 (d, CF3,
3JF,H¼6.2 Hz). Anal. Calcd for C30H26F3NO: S, 76.09; O, 5.53; N, 2.96.
Found: S, 75.94; O, 5.36; N, 2.82.
NMR (400 MHz, CDCl3) (trans, 78%)
d
1.26 (d, 3H, Me, J¼6.7 Hz), 2.71
(dd, 1H, H-90, J¼15.5, 1.6 Hz), 3.39 (dd, 1H, H-900, J¼15.5, 6.0 Hz), 3.91,
3.95 (all s, 3H, MeO), 4.49 (qdd,1H, H-8, J¼6.7, 6.0,1.6 Hz), 5.79 (q,1H,
H-6, 3JH,F¼6.2 Hz), 6.64 (s,1H, H-10/14), 6.71 (s,1H, H-14/10), 6.87 (d,
1H, H-4, J¼8.5 Hz), 7.06 (s, 1H, H-13), 7.16 (dd,1H, H-3, J¼8.5, 2.3 Hz),
3.5.7. 2-Bromo-8,8,11,12-tetramethyl-14-phenyl-6-(trifluoromethyl)-
8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline
(8g). Yield 0.21 g (38%), mp 212e213 ꢀC; IR (KBr) 1601, 1581, 1528,
1492 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.36, 1.84, 1.89, 2.16 (all s,
7.52 (d, 1H, H-1, J¼2.3 Hz); (cis, 22%)
d
1.21 (d, 3H, Me, J¼6.6 Hz), 2.75
3H, Me), 2.68 (d, 1H, H-90, J¼15.2 Hz), 3.19 (d, 1H, H-900, J¼15.2 Hz),
6.23 (q, 1H, H-6, 3JH,F¼6.1 Hz), 6.59 (s, 1H, H-13/10), 6.82 (d, 1H, H-4,
J¼8.4 Hz), 6.88 (s, 1H, H-10/13), 6.91 (d, 1H, H-1, J¼2.4 Hz), 7.05 (dd,
1H, H-3, J¼8.4, 2.4 Hz), 6.9e7.9 (m, 5H, Ph); 1H NMR (400 MHz,
(dd,1H, H-90, J¼15.2 Hz), 3.28 (dd,1H, H-900, J¼15.3, 5.3 Hz), 3.92, 3.96
(all s, 3H, MeO), 4.40 (qdd,1H, H-8, J¼6.6, 5.3,1.7 Hz), 5.65 (q,1H, H-6,
3JH,F¼6.4Hz), 6.62(s,1H, H-10/14), 6.74 (s,1H, H-14/10), 6.89(d,1H, H-
4, J¼8.5 Hz), 7.08 (s,1H, H-13), 7.17 (dd,1H, H-3, J¼8.5, 2.4 Hz), 7.54 (d,
DMSO-d6)
d
1.31, 1.76, 1.81, 2.12 (all s, 3H, Me), 2.84 (d, 1H, H-90,
1H, H-1, J¼2.4 Hz); 19F NMR (376 MHz, CDCl3) (trans, 78%)
d
83.1 (d,
J¼15.7 Hz), 3.11 (d, 1H, H-900, J¼15.7 Hz), 6.50 (s, 1H, H-13), 6.76 (d,
1H, H-1, J¼2.4 Hz), 6.77 (q, 1H, H-6, 3JH,F¼6.4 Hz), 6.96 (d, 1H, H-4,
J¼8.5 Hz), 6.97 (s, 1H, H-10), 7.15 (dd,1H, H-3, J¼8.5, 2.4 Hz), 7.0e7.9
3
3
CF3, JF,H¼6.2 Hz), (cis, 22%)
d
84.4 (d, CF3, JF,H¼6.5 Hz); 13C NMR
(126 MHz, CDCl3) (trans)
d 20.4 (Me), 34.6 (C-9), 48.8 (q, C-8,
5JC,F¼1.8 Hz), 56.1 (2MeO), 70.7 (q, C-6, JC,F¼34.2 Hz), 96.6 (C-14),
106.2 (C-13), 112.3 (C-10), 115.0 (C-14b), 115.1 (C-6a), 116.8 (C-14a),
117.7 (C-4), 120.6 (C-13a), 120.8 (C-9a), 122.2 (C-2), 123.0 (q, CF3,
1JC,F¼287.9 Hz), 125.0 (C-1), 129.2 (C-3), 132.5 (C-13b), 148.5 (C-11),
(m, 5H, Ph); 19F NMR (376 MHz, DMSO-d6)
d 88.9 (d, CF3,
2
3JF,H¼6.4 Hz). Anal. Calcd for C30H25BrF3NO: S, 65.23; O, 4.65; N,
2.54. Found: S, 65.13; O, 4.56; N, 2.48.
148.5 (C-12), 148.8 (C-4a), (cis)
d
19.5 (q, Me, 6JC,F¼2.9 Hz), 35.9 (C-9),
3.5.8. 2-Bromo-11,12-dibutoxy-8,8-dimethyl-14-phenyl-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (8h). Yield 0.15 g (23%), mp 129e130 ꢀC;IR (KBr) 1601,1573,
47.7 (C-8), 56.0 (MeO), 56.1 (MeO), 70.0 (q, C-6, 2JC,F¼34.6 Hz), 97.8 (C-
14),106.4 (C-13),112.4 (C-10),115.1 (C-14b),115.5 (C-6a),117.0 (C-14a),
117.7 (C-4), 121.0 (C-13a), 122.2 (C-9a), 122.8 (C-2), 122.8 (q, CF3,
1JC,F¼286.7 Hz), 125.1 (C-1), 129.2 (C-3), 132.8 (C-13b), 148.4 (C-11),
148.5 (C-12),148.7 (C-4a). Anal. Calcd for C23H19BrF3NO3: S, 55.89; O,
3.87; N, 2.83. Found: S, 56.01; O, 4.08; N, 2.82.
1548, 1513, 1491, 1466 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 0.91, 0.96
(both t, 3H, Me, J¼7.4 Hz),1.3e1.6 (m, 6H, 3 CH2), 1.38 (s, 3H, Me), 1.76
(m, 2H, CH2), 1.83 (s, 3H, Me), 2.65 (d, 1H, H-90, J¼15.1 Hz), 3.18 (d, 1H,
H-900, J¼15.1 Hz), 3.21 (m,1H, OCHH), 3.37 (m,1H, OCHH), 3.95 (m, 2H,
OCH2), 6.22 (q,1H, H-6, 3JH,F¼6.0 Hz), 6.45 (s,1H, H-13/10), 6.62 (s,1H,
H-10/13), 6.82 (d, 1H, H-4, J¼8.5 Hz), 6.89 (d, 1H, H-1, J¼2.2 Hz), 7.06
(dd, 1H, H-3, J¼8.5, 2.2 Hz), 7.0e7.8 (m, 5H, Ph); 19F NMR (376 MHz,
3.5.4. 2-Bromo-14-(3,4-dimethoxyphenyl)-11,12-dimethoxy-8-
methyl-6-(trifluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyr-
rolo[2,1-a]isoquinoline (8d). Yield 0.32 g (51%), mp 216e217 ꢀC; IR
CDCl3)
d
86.8 (d, CF3, 3JF,H¼6.0 Hz). Anal. Calcd for C35H35BrF3NO3: S,
(KBr) 1602, 1576, 1544, 1515, 1482, 1465 cmꢁ1
;
1H NMR (400 MHz,
64.67; O, 5.58; N, 2.09. Found: S, 64.79; H, 5.54; N, 1.98.
CDCl3) (trans, 87%)
d
1.28 (br s, 3H, Me), 2.70 (d, 1H, H-90, J¼15.6 Hz),
3.35 (s, 3H, MeO), 3.44 (dd, 1H, H-900, J¼15.6, 5.5 Hz), 3.87 (s, 6H, 2
3.6. General procedure for the synthesis of compounds 10aef
MeO), 3.96 (s, 3H, MeO), 4.54 (br quint, 1H, H-8, J¼6.0 Hz), 5.80 (br q,
3
1H, H-6, JH,F¼5.7 Hz), 6.55 (s, 1H, H-13/10), 6.67 (s, 1H, H-10/13),
A mixture of the corresponding chromene 1 (1.0 mmol) and
dihydropapaverine 9 (R¼Me) (0.34 g, 1.0 mmol) or drotaverine 9
(R¼Et) (0.40 g, 1.0 mmol) was refluxed in isobutanol (2 mL) for
45 min. After that, the mixture was concentrated under reduced
pressure and the solid formed was recrystallized from isobutanol/
hexane (2:1) to give compound 10 as a colourless powder.
6.8e7.1 (m, 6H, arom.), (cis,13%) d
1.11 (br s, 3H, Me), 2.7 (m,1H, H-90),
3.3 (m,1H, H-900), 3.4e4.0 (all s,12H, 4 MeO), 4.44 (br s,1H, H-8), 5.67
(q, 1H, H-6, 3JH,F¼5.4 Hz), 6.6e7.2 (m, 8H, arom.); 19F NMR (376 MHz,
CDCl3)(trans,rotamers1:1, 87%)
d
83.7, 83.8(bothd,CF3, 3JF,H¼5.7Hz),
(cis, 13%)
(trans, rotamers 1:1, 83%)
d
84.7 (d, CF3, 3JF,H¼5.4 Hz); 19F NMR (376 MHz, DMSO-d6)
d
85.7 (t, CF3, 3JF,H¼5.7 Hz), (cis, 17%)
d 86.6
(d, CF3, 3JF,H¼7.0 Hz). Anal. Calcd for C31H27BrF3NO5: S, 59.06; O, 4.32;
N, 2.22. Found: S, 58.91; H, 3.98; N, 2.25.
3.6.1. 14-(30,40-Dimethoxyphenyl)-11,12-dimethoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (10a). Yield 0.42 g (78%), mp 183e184 ꢀC; IR (KBr) 1610,
3.5.5. 8,8-Dimethyl-14-phenyl-6-(trifluoromethyl)-8,9-dihydro-6H-
1578, 1542, 1515, 1505, 1485 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 3.05
chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (8e). Yieꢁld1 0.14
g
(t, 2H, H-9, J¼5.9 Hz), 3.36, 3.86, 3.95 (all s, 3H, MeO), 3.7e4.0 (m,
4H, MeO, H-80), 4.07 (dt, 1H, H-800, J¼12.2, 5.9 Hz), 5.75 (q, 1H, H-6,
3JH,F¼6.2 Hz), 6.57 (s, 1H, H-13), 6.69 (s, 1H, H-10), 6.72 (ddd, 1H, H-
2, J¼8.0, 7.0, 2.0 Hz), 6.92 (d, 1H, H-1, J¼7.7 Hz), 6.98 (dd, 1H, H-4,
J¼8.0, 1.5 Hz), 7.00 (td, 1H, H-3, J¼7.5, 1.5 Hz), 6.8e7.2 (m, 3H, Ar);
(39%), mp 180e181 ꢀC; IR (KBr) 1605, 1531, 1494 cm
;
1H NMR
(400 MHz, CDCl3)
d
1.38, 1.87 (all s, 3H, Me), 2.76 (d, 1H, H-90,
J¼15.1 Hz), 3.27 (d, 1H, H-900, J¼15.1 Hz), 6.25 (q, 1H, H-6,
3JH,F¼6.2 Hz), 6.66 (ddd, 1H, H-2, J¼7.9, 6.5, 2.2 Hz), 6.80 (d, 1H, H-
13/1, J¼7.4 Hz), 6.82 (d, 1H, H-1/13, J¼7.5 Hz), 6.89 (t, 1H, H-12/4,
J¼7.4 Hz), 6.96 (dd, 1H, H-4/12, J¼8.2. 1.8 Hz), 6.98 (td, 1H, H-3/11,
J¼7.9, 1.4 Hz), 7.04 (td, 1H, H-11/3, J¼7.3, 1.2 Hz), 7.12 (d, 1H, H-10,
19F NMR (376 MHz, CDCl3)
d
83.4 (br d, CF3, J¼6.2 Hz); 13C NMR
(100 MHz, CDCl3)
d 29.0, 42.0, 55.2, 55.9, 56.0 (2C), 70.0 (q, C-6,
2JC,F¼34.1 Hz), 107.4, 111.0, 111.7 (br s), 114.0 (br s), 115.1, 115.2, 116.1,
116.3, 120.3, 121.6, 122.3, 122.8, 123.3 (q, CF3, 1JC,F¼287.5 Hz), 123.33
(br s), 123.9, 126.4, 128.9, 129.0, 147.3, 147.6, 148.5, 149.4, 150.0; 1H
J¼7.3 Hz), 7.0e7.9 (m, 5H, Ph); 19F NMR (376 MHz, CDCl3)
d 86.9 (d,
CF3, 3JF,H¼6.2 Hz). Anal. Calcd for C28H22F3NO: S, 75.49; O, 4.98; N,
3.14. Found: S, 75.40; O, 4.81; N, 3.12.
NMR (400 MHz, DMSO-d6)
d
3.00 (t, 2H, H-9, J¼5.5 Hz), 3.21, 3.73,
3.82 (all s, 3H, MeO), 3.6e3.9 (m, 4H, MeO, H-80), 4.37 (dt, 1H, H-800,
3
3.5.6. 8,8,11,12-Tetramethyl-14-phenyl-6-(trifluoromethyl)-8,9-
dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline (8f). Yield
J¼12.5, 5.5 Hz), 6.43 (s, 1H, H-13), 6.56 (q, 1H, H-6, JH,F¼6.9 Hz),
6.6e6.8 (br s, 1H, Ar), 6.74 (ddd, 1H, H-2, J¼8.2, 7.5, 2.0 Hz), 6.87 (d,

8696
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
1H, H-1, J¼7.5 Hz), 6.89 (s, 1H, H-10), 6.9e7.0 (m, 2H, H-3, H-4),
(10d). Yield 0.48 g (81%), mp 154e155 ꢀC; IR (KBr) 1608, 1581, 1553,
1542, 1504, 1515, 1475 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1.17, 1.42,
7.0e7.3 (br s, 2H, Ar); 19F NMR (376 MHz, DMSO-d6)
d
85.4 (br d,
3.00 (m,
d
CF3, 3JF,H¼6.9 Hz); 1H NMR (500 MHz, DMSO-d6, 100 ꢀC)
d
1.52 (all t, 3H, Me, J¼7.0 Hz), 1.3e1.5 (br s, 3H, Me), 2.98e3.07 (m,
2H, H-9), 3.58 (ABX3-system, 2H, CH2OeC12, J¼10.0, 7.0 Hz),
3.92e4.01 (m, 2H, H-8), 4.06 (q, 2H, OCH2, J¼7.0 Hz), 4.0e4.2 (m,
4H, 2 CH2O), 5.74 (q, 1H, H-6, 3JH,F¼6.2 Hz), 6.60 (s, 1H, H-13), 6.69
(s, 1H, H-10), 6.70 (ddd, 1H, H-2, J¼8.2, 7.5, 2.0 Hz), 6.90 (d, 1H, H-1,
J¼7.6 Hz), 6.96e7.01 (m, 2H, H-3, H-4), 6.7e7.2 (m, 3H, Ar); 19F NMR
2H, H-9), 3.28 (s, 3H, MeOeC12), 3.74 (s, 6H, MeOeC30, MeOeC11),
3.82 (m, 1H, H-80), 3.84 (s, 3H, MeOeC40), 4.30 (dt, 1H, H-800, J¼12.3,
5.8 Hz), 6.41 (q, 1H, H-6, 3JH,F¼6.7 Hz), 6.51 (s, 1H, H-13), 6.72 (ddd,
1H, H-2, J¼7.5, 7.2,1.4 Hz), 6.86 (s,1H, H-10), 6.88 (dd,1H, H-1, J¼7.7,
1.4 Hz), 6.94 (dd, 1H, H-4, J¼8.0, 1.3 Hz), 6.95 (br d, 1H, H-60,
J¼9.0 Hz), 6.98 (ddd, 1H, H-3, J¼8.1, 7.1, 1.2 Hz), 7.01 (br s, 1H, H-20),
(376 MHz, CDCl3)
1.05, 1.29, 1.38 (all t, 3H, Me, J¼7.0 Hz), 1.15e1.35 (br s, 3H, Me),
d
83.3 (br s, CF3); 1H NMR (400 MHz, DMSO-d6)
13
7.11 (d, 1H, H-50, J¼8.2 Hz); C NMR (126 MHz, DMSO-d6, 100 ꢀC)
d
d
26.6 (C-9), 39.9 (C-8), 53.5 (MeO), 54.5 (MeO), 54.7 (2MeO), 67.4
2.94e3.01 (m, 2H, H-9), 3.40e3.54 (m, 2H, CH2OeC12), 3.76 (m, 1H,
H-80), 3.98 (q, 2H, OCH2, J¼7.0 Hz), 3.8e4.2 (m, 4H, 2 OCH2), 4.36
(dt, 1H, H-800, J¼12.5, 5.0 Hz), 6.45 (br s, 1H, H-13), 6.55 (q, 1H, H-6,
3JH,F¼6.8 Hz), 6.6e6.8 (br s, 1H, Ar), 6.73 (ddd, 1H, H-2, J¼8.2, 7.2,
1.7 Hz), 6.85 (d, 1H, H-1, J¼7.5 Hz), 6.86 (s, 1H, H-10), 6.96 (dd, 1H,
H-4, J¼8.2, 1.2 Hz), 6.99 (td, 1H, H-3, J¼8.0, 1.3 Hz), 7.0e7.2 (br s, 2H,
2
(q, C-6, JC,F¼33.2 Hz), 106.9 (C-13), 111.5 (C-10), 112.2 (C-50), 112.6
(C-14a), 113.9 (C-6a), 114.1 (C-4), 114.2 (C-20), 114.3 (C14), 118.8 (C-
14b), 119.7 (C-13a), 120.4 (C-2/1), 120.5 (C-1/2), 121.9 (C-60), 122.0
(q, CF3, 1JC,F¼285.5), 123.5 (C-9a), 124.6 (C-3), 127.1 (C-13b/10), 127.3
(C-10/13b), 146.2 (C-12/11), 147.5 (C-40), 148.2 (C-4a/30), 148.4 (C-30/
4a). Anal. Calcd for C30H26F3NO5: S, 67.03; O, 4.88; N, 2.61. Found:
S, 66.75; O, 4.87; N, 2.89.
Ar); 19F NMR (376 MHz, DMSO-d6)
d
85.3 (d, CF3, 3JF,H¼6.8 Hz); 13
C
NMR (100 MHz, CDCl3)
d 14.5, 14.7, 14.8, 14.9, 28.9, 42.0, 63.6, 64.2
(br s), 64.4 (br s), 64.6, 70.0 (q, C-6, 2JC,F¼34.0 Hz), 109.0, 113.1 (2C),
113.9 (br s), 115.0, 115.2, 115.6 (br s), 116.0, 116.4, 120.4, 121.7, 122.3,
122.8, 123.3 (q, CF3, 1JC,F¼287.0 Hz), 123.7, 126.3, 129.0 (2C), 146.9,
147.2, 148.0, 149.2, 149.9. Anal. Calcd for C34H34F3NO5: S, 68.79; O,
5.77; N, 2.36. Found: S, 68.58; O, 6.01; N, 2.30.
3.6.2. 14-(30,40-Dimethoxyphenyl)-2,11,12-trimethoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (10b). Yield 0.38 g (66%), mp 174e175 ꢀC; IR (KBr) 1613,
1581, 1558, 1544, 1516 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 3.02e3.08
(m, 2H, H-9), 3.36 (s, 3H, MeOeC12), 3.47 (s, 3H, MeOeC2), 3.86 (s,
6H, 2 MeO), 3.92e4.01 (m, 1H, H-80), 4.01 (s, 3H, MeO), 4.07 (dt, 1H,
H-800, J¼12.2, 5.8 Hz), 5.70 (q, 1H, H-6, 3JH,F¼6.2 Hz), 6.52 (d, 1H, H-1,
J¼3.0 Hz), 6.54 (dd, 1H, H-3, J¼8.7, 3.0 Hz), 6.59 (br s, 1H, H-13), 6.69
(s,1H, H-10), 6.8e7.2 (m, 3H, Ar), 6.90 (d,1H, H-4, J¼8.7 Hz); 19F NMR
3.6.5. 14-(30,40-Diethoxyphenyl)-11,12-diethoxy-2-methoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (10e). Yield 0.44 g (71%), mp 146e147 ꢀC; IR (KBr) 1613,
1578, 1562, 1544, 1515 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.17, 1.43,
(376 MHz, CDCl3)
DMSO-d6)
d
83.5 (br d, CF3, 3JF,H¼5.8 Hz); 1H NMR (400 MHz,
1.49 (all t, 3H, Me, J¼7.0 Hz),1.3e1.5 (br s, 3H, Me), 3.00e3.05 (m, 2H,
H-9), 3.45 (s, 3H, MeOeC2), 3.58 (ABX3-system, 2H, CH2OeC12,
J¼10.0, 7.0 Hz), 3.92e4.02 (m, 2H, H-8), 4.06 (q, 2H, OCH2, J¼7.0 Hz),
4.02e4.22 (m, 4H, 2 CH2O), 5.69 (q,1H, H-6, 3JH,F¼6.4 Hz), 6.50 (d,1H,
H-1, J¼3.0 Hz), 6.52 (dd, 1H, H-3, J¼8.6, 3.0 Hz), 6.61 (s, 1H, H-13),
d
2.97e3.03 (m, 2H, H-9), 3.22 (s, 3H, MeOeC12), 3.44 (s,
3H, MeOeC2), 3.71e3.85 (m, 1H, H-80), 3.73 (s, 6H, 2 MeO), 3.81 (s,
3H, MeO), 4.37 (dt, 1H, H-800, J¼12.6, 5.3 Hz), 6.42 (d, 1H, H-1,
J¼3.0 Hz), 6.48 (s, 1H, H-13), 6.48 (q, 1H, H-6, 3JH,F¼6.8 Hz), 6.55 (dd,
1H, H-3, J¼8.8, 3.0 Hz), 6.66e6.85 (br s, 1H, Ar), 6.88 (d, 1H, H-4,
6.69 (s,1H, H-10), 6.8e7.2 (m, 3H, Ar), 6.88 (d,1H, H-4, J¼8.6 Hz); 19F
J¼8.8 Hz), 6.89 (s, 1H, H-10), 7.0e7.3 (m, 2H, Ar); 19F NMR (376 MHz,
NMR (376 MHz, CDCl3)
d
83.5 (br d, CF3, JF,H¼6.0 Hz); 13C NMR
3
3
DMSO-d6)
d
d
85.6 (d, CF3, JF,H¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3) d 14.5,14.7,14.8 (2C), 28.9, 42.0, 55.1, 63.6, 64.5 (br
2
2
29.0, 42.0, 55.1, 55.2, 55.9, 56.1, 69.9 (q, C-6, JC,F¼33.9 Hz), 107.4,
s), 64.6, 64.8, 69.9 (q, C-6, JC,F¼33.8 Hz), 107.6, 108.9, 111.8, 113.1,
114.2 (br s),115.3,115.5,115.9 (br s),116.3,116.4,120.9,121.7,123.2 (br
s),123.3 (q, CF3,1JC,F¼287.7 Hz),123.7,128.9,129.0 (br s),143.8,146.9,
147.1, 148.0, 149.4, 154.5. Anal. Calcd for C35H36F3NO6: S, 67.41; O,
5.82; N, 2.25. Found: S, 67.14; O, 5.66; N, 2.22.
107.7, 111.0, 111.8, 114.0 (br s), 115.3, 115.7, 116.3, 116.5, 120.9, 121.6,
123.5 (br s), 123.3 (q, CF3, 1JC,F¼287.6 Hz), 123.9, 128.8, 128.9, 143.9,
147.4, 147.6, 148.5, 149.5, 154.6. Anal. Calcd for C31H28F3NO6: S,
65.60; O, 4.97; N, 2.47. Found: S, 65.45; O, 4.62; N, 2.52.
3.6.3. 2-Bromo-14-(30,40-dimethoxyphenyl)-11,12-dimethoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (10c). Yield 0.57 g (92%), mp 204e205 ꢀC; IR (KBr) 1602,
3.6.6. 2-Bromo-14-(30,40-diethoxyphenyl)-11,12-diethoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]iso-
quinoline (10f). Yield 0.43 g (64%), mp 166e167 ꢀC; IR (KBr) 1606,
1576, 1545, 1516, 1502, 1486 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
1577, 1541, 1513, 1501, 1475 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.17
d
3.02e3.08 (m, 2H, H-9), 3.36, 3.86, 3.88, 3.96 (all s, 3H, MeO),
(t, 3H, Me, J¼7.0 Hz), 1.43 (t, 6H, 2 Me, J¼7.0 Hz), 1.50 (t, 3H, Me,
J¼7.0 Hz), 3.00e3.05 (m, 2H, H-9), 3.57 (ABX3-system, 2H,
CH2OeC12, J¼10.0, 7.0 Hz), 3.92e3.98 (m, 2H, H-8), 4.06 (q, 2H,
OCH2, J¼7.0 Hz), 4.02e4.22 (m, 4H, 2 CH2O), 5.73 (q, 1H, H-6,
3JH,F¼6.0 Hz), 6.58 (s, 1H, H-13), 6.68 (s, 1H, H-10), 6.75e6.92 (m,
1H, Ar), 6.84 (d, 1H, H-4, J¼8.5 Hz), 6.94e7.17 (m, 2H, Ar), 7.03 (d,
3.93e4.00 (m, 1H, H-80), 4.07 (dt, 1H, H-800, J¼12.0, 6.0 Hz), 5.74 (q,
1H, H-6, 3JH,F¼6.1 Hz), 6.55 (s, 1H, H-13), 6.69 (s, 1H, H-10), 6.8e7.2
(m, 3H, Ar), 6.85 (d, 1H, H-4, J¼8.3 Hz), 7.07 (d, 1H, H-1, J¼2.4 Hz),
7.09 (dd, 1H, H-3, J¼8.3, 2.4 Hz); 19F NMR (376 MHz, CDCl3)
d 83.4
d 2.97e3.03 (m,
(d, CF3, 3JF,H¼6.1 Hz); 1H NMR (400 MHz, DMSO-d6)
2H, H-9), 3.22, 3.74, 3.78, 3.83 (all s, 3H, MeO), 3.66 (m, 1H, H-80),
4.38 (m, 1H, H-800), 6.45 (s, 1H, H-13), 6.64 (q, 1H, H-6, 3JH,F¼6.7 Hz),
6.7e6.9 (br s, 1H, Ar), 6.90 (s, 1H, H-10), 6.96 (d, 1H, H-4, J¼8.6 Hz),
6.98 (d, 1H, H-1, J¼2.0 Hz), 7.0e7.3 (m, 2H, Ar), 7.15 (dd, 1H, H-3,
1H, H-1, J¼2.4 Hz), 7.07 (dd, 1H, H-3, J¼8.5, 2.4 Hz); 19F NMR
3
(376 MHz, CDCl3)
CDCl3)
d
83.4 (d, CF3, JF,H¼6.0 Hz); 13C NMR (100 MHz,
d
14.5, 14.8, 14.9 (2C), 28.9 (C-9), 42.1 (C-8), 63.7, 64.6, 64.7
(br s), 64.9, 70.1 (q, C-6, 2JC,F¼34.3 Hz),109.1,113.1,114.2,114.5 (br s),
114.8, 115.3, 116.1 (br s), 116.4, 117.6, 121.4, 122.4, 123.1 (q, CF3,
1JC,F¼287.5 Hz), 123.4 (br s), 123.8, 125.4, 128.3, 128.8, 129.3, 147.1,
147.2, 148.4, 149.0, 149.5. Anal. Calcd for C34H33BrF3NO5: S, 60.75;
O, 4.95; N, 2.08. Found: S, 60.75; O, 5.05; N, 2.16.
J¼8.6, 2.4 Hz); 19F NMR (376 MHz, DMSO-d6)
d 85.3 (d, CF3,
d 28.9, 42.1, 55.2, 55.9,
3JF,H¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
56.2 (2C), 70.1 (q, C-6, 2JC,F¼34.3 Hz), 107.5, 111.0, 111.9 (br s), 114.0
(br s), 114.1, 114.8, 115.4, 116.3, 117.7, 121.3, 122.4, 123.1 (q, CF3,
1JC,F¼287.3 Hz), 123.4 (br s), 124.0, 125.4, 128.1, 128.9, 129.3, 147.5,
147.6, 148.8, 149.0, 149.6. Anal. Calcd for C30H25BrF3NO5: S, 58.45;
O, 4.09; N, 2.27. Found: S, 58.50; O, 3.99; N, 2.45.
3.7. Compounds 11a,b and 12
3.7.1. 2-Nitro-3-(trifluoromethyl)-3H-benzo[f]chromene (11a). Yield
0.17 g (58%), mp 182e183 ꢀC, orange powder; IR (KBr) 1643, 1569,
3.6.4. 14-(30,40-Diethoxyphenyl)-11,12-diethoxy-6-(trifluoromethyl)-
8,9-dihydro-6H-chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinoline
1506,1365,1354 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.24 (q,1H, H-3,

V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
8697
3JH,F¼6.4 Hz), 7.26 (dd, 1H, H-5, J¼8.9, 0.8 Hz), 7.52 (ddd, 1H, H-8/9,
J¼8.1, 7.0, 1.1 Hz), 7.68 (ddd, 1H, H-9/8, J¼8.4, 7.0, 1.3 Hz), 7.85 (d, 1H,
H-7, J¼8.1 Hz), 7.98 (d, 1H, H-6, J¼8.9 Hz), 8.06 (dd, 1H, H-10, J¼8.4,
were measured on an ‘Xcalibur 3’ automatic four-circle diffrac-
ꢀ
tometer (Mo K
a
radiation,
l
¼0.71073 A, graphite monochromator,
u
/2q
scan, 2qmax¼56.6ꢀ). The structure was solved by direct
0.8 Hz), 8.85 (s, 1H, H-1); 19F NMR (376 MHz, CDCl3)
d
84.4 (d, CF3,
methods and refined by full-matrix least-squares method using the
SHELX-97 program package.24 All non-hydrogen atoms were re-
fined with anisotropic atomic displacement and hydrogen atoms
were included at calculated position using a riding model. The final
discrepancy factors R1¼0.0408, wR2¼0.0807, GoF¼1.004 for 2089
3JF,H¼6.4 Hz). Calcd for C14H8F3NO3: S, 56.96; O, 2.73; N, 4.74.
Found: S, 56.96; O, 2.49; N, 4.75.
3.7.2. 3-Nitro-2-(trifluoromethyl)-2H-benzo[h]chromene
(11b). Yield 0.12 g (40%), mp 134e135 ꢀC, orange powder; IR (KBr)
reflections with I>2
s(I); R1¼0.1185, wR2¼0.0856 (all data). Largest
1653, 1618, 1598, 1561, 1516, 1504, 1466, 1388 cmꢁ1
;
1H NMR
different peak and hole: 0.280 and ꢁ0.214 e A . Completeness to
ꢀꢁ3
(400 MHz, CDCl3)
d
6.36 (q, 1H, H-2, 3JH,F¼6.4 Hz), 7.35 (d, 1H, H-6,
q
¼28.28ꢀ (98.0%). Deposition number CCDC 816060.
J¼8.4 Hz), 7.55 (d, 1H, H-5, J¼8.4 Hz), 7.59 (ddd, 1H, H-8/9, J¼8.2,
6.9, 1.4 Hz), 7.64 (ddd, 1H, H-9/8, J¼8.1, 6.9, 1.4 Hz), 7.82 (d, 1H, H-7,
J¼8.1 Hz), 8.25 (s, 1H, H-4), 8.26 (d, 1H, H-10, J¼8.1 Hz); 19F NMR
Acknowledgements
(376 MHz, CDCl3)
S, 56.96; O, 2.73; N, 4.74. Found: S, 57.06; O, 2.88; N, 4.80.
d
83.3 (d, CF3, 3JF,H¼6.4 Hz). Calcd for C14H8F3NO3:
This work was financially supported by the Russian Foundation
for Basic Research (Grant 11-03-00126) and the Presidium program
of the RAS N 21.
3.7.3. 14-(3,4-Dimethoxyphenyl)-11,12-dimethoxy-6-(tri-
fluoromethyl)-8,9-dihydro-6H-benzo[70,80]chromeno[40,30:4,5]pyrrolo
[2,1-a]isoquinoline (12). This compound was prepared from chro-
mene 11b and dihydropapaverine 9 (R¼Me) according to the pro-
cedure described for compounds 10. Yield 0.55 g (94%), mp
235e236 ꢀC, colourless powder; IR (KBr) 1605, 1576, 1541, 1519,
References and notes
1. (a) Organofluorine Compounds in Medicinal Chemistry and Biomedical Applica-
tions; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam,
1993; (b) Hiyama, T. Organofluorine Compounds: Chemistry and Application;
Springer: Berlin, 2000.
2. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930.
3. (a) Engler, T. A.; Reddy, J. P.; Combrink, K. D.; Velde, D. V. J. Org. Chem. 1990, 55,
1248e1254; (b) Murugesh, M. G.; Subburaj, K.; Trivedi, G. K. Tetrahedron 1996,
52, 2217e2228; (c) Engler, T. A.; LaTessa, K. O.; Iyengar, R.; Chai, W.; Agrios, K.
Bioorg. Med. Chem. 1996, 4, 1755e1769.
1498 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.08 (t, 2H, H-9, J¼6.5 Hz),
3.37, 3.87, 3.97 (all s, 3H, MeO), 3.7e4.0 (br s, 3H, MeO), 4.03 (dt, 1H,
H-80, J¼12.1, 6.7 Hz), 4.12 (dt, 1H, H-800, J¼12.1, 6.1 Hz), 6.00 (q, 1H,
3
H-6, JH,F¼6.3 Hz), 6.60 (s, 1H, H-13/10), 6.70 (s, 1H, H-10/13),
4. Korotaev, V. Y.; Kutyashev, I. B.; Sosnovskikh, V. Y. Heteroat. Chem. 2005, 16,
492e496.
6.8e7.2 (m, 3H, Ar), 7.09 (d, 1H, H-16, J¼8.6 Hz), 7.23 (d, 1H, H-15,
J¼8.6 Hz), 7.37 (ddd, 1H, H-2/3, J¼8.1, 6.8, 1.3 Hz), 7.45 (ddd, 1H, H-
3/2, J¼8.4, 6.8, 1.4 Hz), 7.68 (d, 1H, H-1, J¼8.1 Hz), 8.22 (d, 1H, H-4,
5. (a) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.; Kodess, M. I. Lett. Org.
Chem. 2005, 2, 616e620; (b) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.;
Kodess, M. I. Izv. Akad. Nauk, Ser. Khim. 2006, 309e321; Russ. Chem. Bull., Int. Ed.
2006, 55, 317e330; (c) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B. Izv.
Akad. Nauk, Ser. Khim. 2007, 1985e1990; Russ. Chem. Bull., Int. Ed. 2007, 56,
2054e2059; (d) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.; Kodess, M. I.
Izv. Akad. Nauk, Ser. Khim. 2006, 1945e1955; Russ. Chem. Bull., Int. Ed. 2006, 55,
2020e2031; (e) Korotaev, V. Y.; Kutyashev, I. B.; Sosnovskikh, V. Y.; Kodess, M. I.
Mendeleev Commun. 2007, 17, 52e53.
6. (a) Shamma, M. The Isoquinoline Alkaloids; Academic: New York, NY, 1972; (b)
Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic: 1998.
7. (a) Shklyaev, Y. V.; Maslivets, A. N. Zh. Org. Khim. 1996, 32, 319; Russ. J. Org.
Chem. 1996, 32, 302; (b) Sviridov, V. D.; Chkanikov, N. D.; Galakhov, M. V.;
Shklyaev, Y. V.; Shklyaev, V. S.; Aleksandrov, B. B.; Gavrilov, M. S. Izv. Akad. Nauk
SSSR, Ser. Khim. 1990, 1405e1410; Bull. Acad. Sci. USSR, Div. Chem. Sci. 1990, 39,
1268e1273; (c) Tyutin, V. Y.; Chkanikov, N. D.; Shklyaev, Y. V.; Shklyaev, V. S.;
Kolomiets, A. F.; Fokin, A. V. Izv. Acad. Nauk, Ser. Khim. 1992, 1888e1891; Bull.
Russ. Acad. Sci. Div. Chem. Sci. 1992, 41, 1474e1477; (d) Sviridov, V. D.; Chkanikov,
N. D.; Shklyaev, Y. V.; Kolomiets, A. F.; Fokin, A. V. Khim. Geterotsikl. Soedin. 1990,
1689; Chem. Heterocycl. Compd. 1990, 26, 1405.
J¼8.5 Hz); 19F NMR (376 MHz, CDCl3)
d
82.6 (br d, CF3, 3JF,H¼5.3 Hz);
1H NMR (400 MHz, DMSO-d6)
d
3.03 (dd, 2H, H-9, J¼7.9, 5.4 Hz),
3.23, 3.74, 3.84 (all s, 3H, MeO), 3.6e3.9 (br s, 3H, MeO), 3.82 (m,1H,
H-80), 4.42 (dt, 1H, H-800, J¼12.5, 5.4 Hz), 6.48 (s, 1H, H-13), 6.84 (q,
1H, H-6, 3JH,F¼6.9 Hz), 6.6e6.9 (br s, 1H, ArC-14), 6.90 (s, 1H, H-10),
7.0e7.4 (m, 2H, ArC-14), 7.06 (d, 1H, H-16, J¼8.6 Hz), 7.33 (d, 1H, H-
15, J¼8.6 Hz), 7.42 (ddd, 1H, H-2/3, J¼8.0, 7.0, 1.0 Hz), 7.51 (ddd, 1H,
H-3/2, J¼8.4, 7.0, 1.1 Hz), 7.75 (d, 1H, H-1, J¼8.0 Hz), 8.09 (d, 1H, H-4,
J¼8.4 Hz); 19F NMR (376 MHz, DMSO-d6)
d 86.5 (d, CF3,
3JF,H¼6.9 Hz). Calcd for C34H28F3NO5: S, 69.50; O, 4.80; N, 2.38.
Found: S, 69.32; O, 4.68; N, 2.50.
3.8. Crystal data for tc-6b and ct-6g
8. Meyer, H. Liebigs Ann. Chem. 1981, 1534e1544.
9. (a) Grob, C. A.; Camenisch, K. Helv. Chim. Acta 1953, 36, 49e58; (b) Grob, C. A.;
3.8.1. Crystal data for tc-6b. C24H25Cl3N2O3, M 495.84, triclinic
crystals space group Pꢁ1, a¼10.3139(7), b¼11.1354(8), c¼21.033(2)
Schad, H. P. Helv. Chim. Acta 1955, 38, 1121e1127.
3
ꢀ
A,
a
¼82.224(7),
b
¼89.459(7),
g
¼89.264(5)ꢀ, V¼2393.1(3) A ,
ꢀ
ꢁ
ꢁ
10. (a) Gomez-Sanchez, A.; Mancera, M.; Rosado, F. J. Chem. Soc., Perkin Trans. 1
1980, 1199e1205; (b) Revial, G.; Lim, S.; Viossat, B.; Lemoine, P.; Tomas, A.;
Duprat, A. F.; Pfau, M. J. Org. Chem. 2000, 65, 4593e4600; (c) Baldoli, C.; Cre-
monesi, G.; Croce, P. D.; La Rosa, C.; Licandro, E. Heterocycles 2004, 64, 491e497;
(d) Alizadeh, A.; Rezvanian, A.; Bijanzadeh, H. R. Synthesis 2008, 725e728; (e)
Gupta, R. C.; Seth, M.; Bhaduri, A. P. Indian J. Chem. 1991, 30B, 247e298.
11. Lim, S.; Jabin, I.; Revial, G. Tetrahedron Lett. 1999, 40, 4177e4180.
12. (a) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van Duyne, G. D.; Clardy, J. J.
Am. Chem. Soc. 1985, 107, 5492e5495; (b) Ham, J.; Kang, H. Bull. Korean Chem.
Soc. 2002, 23, 163e166; (c) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.;
Litvinas, N. D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440e9448; (d) Krishnaiah,
P.; Reddy, V. L. N.; Venkataramana, G.; Ravinder, K.; Srinivasulu, M.; Raju, T. V.;
Ravikumar, K.; Chandrasekar, D.; Ramakrishna, S.; Venkateswarlu, Y. J. Nat. Prod.
2004, 67, 1168e1171.
dcalcd¼1.376 g cmꢁ3, absorption coefficient
m
¼0.412 mmꢁ1, Z¼4.
The intensities of 11506 independent reflections (Rint¼0.0272)
were measured on an ‘Xcalibur 3’ automatic four-circle diffrac-
ꢀ
tometer (Mo K
a
radiation,
l
¼0.71073 A, graphite monochromator,
u
/2
q
scan, 2qmax¼56.6ꢀ). The structure was solved by direct
methods and refined by full-matrix least-squares method using the
SHELX-97 program package.24 All non-hydrogen atoms were re-
fined with anisotropic atomic displacement and hydrogen atoms
were included at calculated position using a riding model. The final
discrepancy factors R1¼0.0459, wR2¼0.0969, GoF¼1.007 for 3947
13. (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264e287; (b)
Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun. 1997, 2259e2260; (c)
Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bushman, F.
D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901e1907; (d)
Reddy, S. M.; Srinivasulu, M.; Satyanarayana, N.; Kondapi, A. K.; Venkateswarlu,
Y. Tetrahedron 2005, 61, 9242e9247.
reflections with I>2
s
(I); R1¼0.1421, wR2¼0.1036 (all data). Largest
ꢀꢁ3
different peak and hole: 0.369 and ꢁ0.349 e A . Completeness to
q
¼28.28ꢀ (96.9%). Deposition number CCDC 816061.
3.8.2. Crystal data for ct-6g. C27H26N2O3, M 426.52, triclinic crys-
ꢁ
14. Tardy, C.; Facompre, M.; Laine, W.; Baldeyrou, B.; García-Gravalos, D.; Francesch,
ꢀ
ꢁ
A.; Mateo, C.; Pastor, A.; Jimenez, J. A.; Manzanares, I.; Cuevas, C.; Bailly, C.
tals space group Pꢁ1, a¼9.8255(13), b¼9.8304(7), c¼12.2545(13) A,
3
Bioorg. Med. Chem. 2004, 12, 1697e1712.
ꢀ
a
¼93.861(7),
b
¼104.297(10),
g
¼101.445(9)ꢀ, V¼1115.7(2) A ,
15. (a) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R. Chem. Commun.
dcalcd¼1.270 g cmꢁ3, absorption coefficient
m
¼0.083 mmꢁ1, Z¼2.
1997, 207e208; (b) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69,
}
The intensities of 5416 independendent reflections (Rint¼0.0250)
2362e2366; (c) Nyerges, M.; Toke, L. Tetrahedron Lett. 2005, 46, 7531e7534; (d)

8698
V.Y. Korotaev et al. / Tetrahedron 67 (2011) 8685e8698
ꢁ
Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M. Org. Lett. 2003, 5,
19. (a) Sakakibara, T.; Koezuka, M.; Sudoh, R. Bull. Chem. Soc. Jpn. 1978, 51,
3095e3096; (b) Yan, M.-C.; Jang, Y.-J.; Kuo, W.-Y.; Tu, Z.; Shen, K.-H.; Cuo, T.-S.;
Ueng, C.-H.; Ching-Fa, Y. Heterocycles 2002, 57, 1033e1048.
20. Korotaev, V. Y.; Sosnovskikh, V. Y.; Yasnova, E. S.; Barkov, A. Y.; Shklyaev, Y. V.
Mendeleev Commun. 2010, 20, 321e322.
ꢁ
2959e2962; (e) Marfil, M.; Albericio, F.; Alvarez, M. Tetrahedron 2004, 60,
8659e8668; (f) Ploypradith, P.; Jinaglueng, W.; Pavaro, C.; Ruchirawat, S. Tet-
rahedron Lett. 2003, 44, 1363e1366; (g) Fujikawa, N.; Ohta, T.; Yamaguchi, T.;
Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron 2006, 62, 594e604; (h) Ohta, T.;
Fukuda, T.; Ishibashi, F.; Iwao, M. J. Org. Chem. 2009, 74, 8143e8153; (i) Li, Q.;
Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Org. Lett. 2011, 13, 312e315.
21. Sladkov, V. I.; Sazonova, N. M.; Kuleshova, L. N.; Lindeman, S. V.; Struchkov, Y. T.;
Suvorov, N. N. Zh. Org.Khim.1989, 25, 854e862; J. Org. Chem. USSR 1989, 25, 767e773.
€
16. Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S.
22. (a) Gunther, H. NMR Spectroscopy: Basic Principles, Concepts, and Applications in
~
Angew. Chem., Int. Ed. 2004, 43, 866e868.
Chemistry; John: New York, NY, 1996; (b) Oki, M. Methods in Stereochemical
17. Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.; Barkov, A. Y.; Shklyaev, Y. V.
Tetrahedron Lett. 2008, 49, 5376e5379.
Analysis: Application of Dynamic NMR Spectroscopy to Organic Chemistry; VCH:
Weinheim, 1985.
18. Lin, C.; Hsu, J.; Sastry, M. N. V.; Fang, H.; Tu, Z.; Liu, J.-T.; Ching-Fa, Y. Tetrahedron
23. Kessler, H. Angew. Chem., Int. Ed. Engl. 1970, 9, 219e235.
24. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112e122.
2005, 61, 11751e11757.