An Efficient Lewis Acid Catalyzed Povarov Reaction for the One-Pot Stereocontrolled Synthesis of Polyfunctionalized Tetrahydroquinolines

Article abstract of DOI:10.1055/s-0036-1589104

An easy and efficient synthetic methodology for the one-pot stereocontrolled synthesis of tetrahydroquinolines through Lewis acid activated Povarov reaction is described. The protocol takes advantage of the very cheap, easy to handle, and environmentally

Full text of DOI:10.1055/s-0036-1589104

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
paper
A
en
C. Cimarelli et al.
Paper
Synthesis
An Efficient Lewis Acid Catalyzed Povarov Reaction for the
One-Pot Stereocontrolled Synthesis of Polyfunctionalized
Tetrahydroquinolines
Cristina Cimarelli*a
Samuele Bordia
Pamela Piermatteia
Maura Pelleia
Fabio Del Bellob
Enrico Marcantonia
X
O
R2
R3
CeCl3•7H2O/NaI
method A or B
R2
R1
N
X
H
+
+
H
R1
N
R3
R1 = Ar, HetAr
R2 = H, 4-OMe, 4-Br
3 = H, Me, Bn
R
17 examples
up to 96% yield
method A: MeCN, 50 °C; syn/anti up to 15:85
method B: neat, –10 °C; syn/anti up to 87:13
a School of Science and Technology - Chemistry Division,
University of Camerino, Via S. Agostino 1, 62032 Camerino,
Italy
cristina.cimarelli@unicam.it
b School of Pharmacy - Medicinal Chemistry Unit, University
of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Received: 13.07.2017
Accepted after revision: 09.08.2017
Published online: 07.09.2017
role. Trivalent rare earth compounds salts, such as Ce(III)
exhibit characteristic acid properties, and they activate
Lewis base functionalities to promote useful organic trans-
formations. For this reason numerous reactions and meth-
odologies have been developed that involves cerium(III) as
CeCl3, its more available source, as key component.9
DOI: 10.1055/s-0036-1589104; Art ID: ss-2017-t0457-op
Abstract An easy and efficient synthetic methodology for the one-pot
stereocontrolled synthesis of tetrahydroquinolines through Lewis acid
activated Povarov reaction is described. The protocol takes advantage
of the very cheap, easy to handle, and environmentally friendly cerium
trichloride as catalyst and allows to obtain either the anti- or the syn-
isomer of the final tetrahydroquinoline with good selectivity, by per-
forming the reaction in solvent or solventless conditions. The scope of
the reaction is expanded to the one-pot synthesis of N-alkyltetrahydro-
quinolines through a very efficient iminium-Povarov approach. A deep-
er insight on the reaction system was provided by the study on the side
reactions occurring in the reaction conditions and on the nature of the
stereoselectivity.
Cerium trichloride has become interesting because of
its high efficiency, low toxicity, and cost and for the ease of
application also in non-anhydrous conditions.10 Further-
more, this environment friendly, cheap, highly efficient
Lewis acid has just been widely applied as catalyst for
the synthesis of heterocyclic compounds.11 Even if the
CeCl3·7H2O has been used as catalyst in multicomponent re-
actions12 for generating new products in a single step and
avoiding large amounts of solvents and expensive purifica-
tion techniques,13 to the best of our knowledge there is no
report on its use in the cyclization of acyclic precursors to
fused-ring heterocycles. Often reactions catalyzed by
CeCl3·7H2O require a stoichiometric amount of this Lewis
acid and long reaction times. A more reactive form of
this catalyst is represented by the promoting system
CeCl3·7H2O/NaI in 1:1 ratio,14 used in catalytic amount in a
wide range of reactions.15
As part of our ongoing efforts on the synthesis of het-
erocycles, and considering that lanthanides have just been
used in imino-Diels–Alder reactions16 and that a number of
biologically active compounds with interesting properties
have their structures based on the tetrahydroquinoline
scaffold,17 we thought about exploring the application of
the CeCl3·7H2O/NaI system as Lewis acid catalyst in the
Povarov reaction, for the one-pot synthesis of a series of
substituted pyranotetrahydroquinolines.
Key words tetrahydroquinoline derivatives, Povarov reaction, Lewis
acid catalysis, cerium, solventless reactions
The Povarov reaction,1,2 – the aza-Diels–Alder reaction
of electron-poor 2-azabutadienes with electron-rich dieno-
philes – is one of the more common pathways for the syn-
thesis of fused-ring heterocyclic compounds, both in the
two and three components version, depending on the pre-
formation of the imine or the direct mixing of all the start-
ing materials. Many catalysts have been used to activate the
reagents: Brønsted3 and Lewis4 acids, also supported,5,6 and
enzyme catalysis7 were investigated with different results.
Efforts are made to develop new methodologies, orient-
ed towards more efficient and environment friendly Lewis
acids, and to bypass the step of pre-formation of imines,
compounds that are difficult to synthesize and unstable in
many cases.
In the last years, the search for economic and environ-
mentally benign synthetic methodologies has stimulated
the use of nontoxic and inexpensive catalytic systems, and
in this perspective Lanthanides8 have played an important
Indeed pyranequinoline skeleton is present in a series of
natural products and biologically active compounds with
interesting pharmaceutical activities namely anti-Alzhei-
mer,18 antiallergic,19 anti-inflammatory,20 and some mole-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

B
C. Cimarelli et al.
Paper
Synthesis
cules with this structure find application in mammalian
cell imaging.19 In addition, several heterocycles for industri-
al application contain this framework11 contributing to
make the synthesis of these derivatives an important chal-
lenge.
The reaction was studied in solvent and under solvent-
less conditions and the method has been extended also to
other dienophiles and N-substituted anilines.
The pilot reaction was carried out in different condi-
tions using aniline (1a), benzaldehyde (2a), and 3,4-dihy-
dro-2H-pyran (3a, DHP), exploring CeCl3·7H2O/NaI as pro-
moting system to find the best reaction conditions, as de-
scribed in Table 1. Given that the required 2-azabutadienes
are not stable in the presence of moisture, we chose to pre-
pare them in situ. To avoid the formation of by-products
from the reaction between aniline and dihydropyran,22 1a
and 2a were stirred in the solvent, in the presence of mag-
nesium sulfate, and after the quantitative formation of the
corresponding imine, monitored by TLC and GC and by
NMR in some cases, DHP (3a) and the catalyst were added.
The reaction was monitored by GC-MS and TLC until the
starting reagents were consumed or a constant composition
of the mixture was reached, and the final tetrahydroquino-
lines 4aa and 5aa were obtained as racemates in syn/anti-
diastereomer mixture. The results obtained are reported in
Table 1.
In acetonitrile at room temperature, the reaction with
an equimolecular amount of CeCl3·7H2O/NaI, with respect
to the substrates, gave 67% yield, while with a 30% mol
amount of catalyst a very similar 70% yield was obtained in
a slightly longer reaction time (Table 1, entries 1, 2). The re-
action is anti-diastereoselective, with a syn/anti ratio of
28:72 in the first case and the ratio increased to 18:82 in
the second. A further lowering to 10% mol of the catalyst
system resulted again in a comparable yield, but the reac-
tion time rose to 24 hours with a lower diastereoselectivity
(entry 3). The reaction performed in toluene or 1,4-dioxane
led to lower yields and with very long reaction times (en-
Table 1 Solvent, Catalyst, and Temperature Optimization of the Pilot Reaction
O
O
O
Ph
O
MgSO4
N
3a
PhNH2
+
+
Ph
H
N
H
Ph
N
H
solvent, r.t.
catalyst
Ph
Ph
1a
2a
(
)-4aa
syn
(
)-5aa
anti
Entry
Catalyst
Amount (mol%) Solvent
Temp (°C)
Time (h)
Yield (%)a
4aa/5aab
1
2
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI
CeCl3·7H2O/NaI/SiO2
CeCl3·7H2O/NaI
CeCl3·7H2O/NaIf
anhyd CeCl3/NaI
CeCl3·7H2O/CuI
CeCl3·7H2O
100
30
10
30
30
30
30
30
100
30
30
30
30
30
30
MeCN
MeCN
MeCN
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
4
5
67
70
68
56
60
9d
28:72
18:82
25:75
3
24
48
48
48
1
c
4
toluene
1,4-dioxane
H2O
–
5
9:91
c
6
–
7
MeCN
82
49
0
15:85
47:53
–
8
MeCN
–10
r.t.
r.t.
–10
50
48
24
0.5
2
e
9
solventless
solventless
solventless
anhyd MeCN
MeCN
10
11
12
13
14
15
16
50
73
40
66
20
57
0
56:44
77:23
8:92
1.5
5
r.t.
r.t.
r.t.
r.t.
33:67
c
MeCN
48
72
72
–
c
NaI
MeCN
–
f
MgSO4
–
MeCN
–
a Isolated yields.
b Ratio determined by 1H NMR analysis of the crude mixture.
c Not determined.
d GC yield.
e Catalyst prepared according to literature.21
f Amount used: 0.200 g.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

C
C. Cimarelli et al.
Paper
Synthesis
tries 4, 5). Really poor yields were obtained in water, afford-
ing to a synthetically useless result (entry 6); on the other
hand anhydrous CeCl3/NaI in anhydrous acetonitrile at
50 °C led to an excellent syn/anti ratio of 8:92, but in only
40% yield (entry 12). Both yield and diastereoselectivity in-
creased when the reaction was performed at 50 °C and the
reaction time decreased to 1 hour (entry 7). Although the
yield obtained using CuI as efficient iodide source instead of
NaI23 was comparable, the corresponding diastereoselectiv-
ity was lower (entry 13). The reaction was attempted also
under solventless conditions with interesting results (en-
tries 9–11). The SiO2 supported CeCl3·7H2O/NaI system24
gave no reaction, but the solventless reaction without SiO2,
performed by adding the dienophile and 30% mol of the
catalytic mixture CeCl3·7H2O/NaI to the preformed imine,
afforded 50% yield at room temperature with a slight pref-
erence for the syn-diastereomer. Lowering the temperature
to –10 °C allowed to obtain a 73% yield with an interesting
inverted diastereoselectivity with respect to reaction per-
formed in solvent (entries 7, 11). Further, although in our
previous papers, SiO2 has been introduced as a support that
facilitates the workup of the reaction mixture and to
change the environment of the catalyst active site,25,26 un-
der our present conditions the Povarov reaction did not
take place in the presence of SiO2.
confirmed by data of the reactions performed in the same
conditions of time and temperature, in 5 and 10 mL of sol-
vent, that showed an increasing anti selectivity of 35:65
and 17:83, respectively. After 4 hours, all the reaction mix-
tures were left to reach room temperature and stirred over-
night, and all resulted enriched in the anti-diastereomer.
These observations confirm that under kinetically con-
trolled conditions at high concentrations and at low tem-
peratures, the syn product is favored, and low concentra-
tion, long reaction times and high dilutions favor the for-
mation of the anti-diastereomer.
The issue of the different stability of the two diastereo-
mers in the reaction mixture was addressed with a further
experiment. A mixture of the two diastereomers (syn/anti =
41:59) was dissolved in MeCN, the catalyst was added and
left stirring overnight at room temperature. After this peri-
od, the diastereomers were isolated as a mixture, and the
yield and the d.r. were determined. The syn/anti ratio
passed to 32:68, showing that the mixture was enriched in
the anti-diastereomer. At the same time, only the 82% of the
initial amount of the mixture was recovered, that in more
detail revealed a 5% loss of the anti-product and a 37% loss
of the syn (Scheme 1).
O
O
The components of the promoting system14 work in
synergy, and we encountered no difficulty to perform our
reaction under solventless conditions because one of the
components is always liquid: the results obtained with
CeCl3·7H2O or NaI alone were really worse and required lon-
ger reaction times than that obtained with both compo-
nents together (Table 1, entries 14, 15). Magnesium sulfate
was not removed from the reaction system after the imine
formation step, because it has no effect on the following re-
action (entry16).
Generally the reactions performed in solvent show a
strong preference for the anti-diastereomer together with
slightly lower yields with respect to those under solventless
conditions. This difference may depend on a different selec-
tivity of the reaction itself and at the same time on a differ-
ent stability of the two diastereomers in the reaction mix-
ture.
Experiments were made to ascertain if the selectivity
depends on a kinetic or thermodynamic control of the reac-
tion system in the different conditions. Generally high con-
centration and low temperatures favor the kinetic control
of a reaction, while high dilution condition and higher tem-
perature allow the thermodynamic control.
We performed the reaction in different conditions of
solvent and temperature, monitoring the diastereomer ratio
at different reaction times and stopping the reaction at 4
hours, unless differently stated. We observed that at –10 °C
only 5 equivalents of solvent are enough to decrease the syn
selectivity shown in the reaction under solventless condi-
tions (Table 1, entry 11) from 77:23 to 54:46. The trend is
CeCl3•7H2O/NaI (30 mol%)
MeCN, r.t.
N
H
Ph
N
H
Ph
(
)-4aa, ( )-5aa
(
)-4aa, ( )-5aa
d.r. 41:59
82%; d.r. 32:68
Scheme 1 Stability of the syn/anti-diastereomers in the reaction mix-
ture
These results confirm that the selectivity of this reac-
tion depends both on kinetic and thermodynamic control
under the different reaction conditions and on a different
stability of the two diastereomers in the reaction mixture.
At the same time they parallel the results reported by
Shen’s group on the samarium diiodide catalyzed Povarov
reaction for the synthesis of pyranoquinolines.4c
The generality of the reaction was explored with a se-
ries of anilines 1a–c and aromatic aldehydes 2a–g that were
tested using both solvent and solventless optimized meth-
ods, as depicted in Scheme 2 (method A or B), obtaining in
most cases good to excellent yields of the desired tetrahy-
droquinolines 4 and 5. Preliminary data obtained using ali-
phatic aldehydes gave poor results; further experiments are
in progress in our laboratory. The reaction has a good func-
tional group tolerance, performing better with electron-
withdrawing groups on the aldehyde, while it is sluggish in
the case of very electron-rich aldehydes (i.e., 3,4,5-trime-
thoxybenzaldehyde) or very electron-poor anilines (i.e., 4-
nitroaniline). GC-MS analysis of the reaction mixture of
these aldehydes revealed only traces of the corresponding
tetrahydroquinolines 4 and 5 even after 24 hours. This ef-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

D
C. Cimarelli et al.
Paper
Synthesis
X
X
NH2
O
CeCl3•7H2O/NaI
method A or B
X
R1
R1
R1
+
+
+
H
R2
R2
R2
N
H
N
H
1a–c
3a: 2,3-dihydropyran
3b: 2,3-dihydrofuran
3c: N-vinylpyrrolidone
2a–g
(
(
(
)-4
)-6
)-8
(
(
(
)-5
)-7
)-9
(
(
)-4aa
)-5aa
(
(
)-4ab
)-5ab
(
(
)-4ac
)-5ac
(
(
)-4ad
)-5ad
O
O
O
O
N
H
N
H
N
H
N
H
NO2
MeO
OMe
A: 1 h, 82% (15:85)b
B: 2 h, 73% (77:23)
A: 1 h, 73% (19:81)
B: 5 h, 69% (87:13)
A: 5 h, 86% (15:85)
B: 12 h, 71% (76:24)
A: 6 h, 88% (25:75)
B: 18 h, 60% (60:40)
(
(
)-4ae
)-5ae
(
(
)-4af
)-5af
(
(
)-4ag
)-5ag
(
(
)-4ba
)-5ba
O
O
O
O
MeO
N
H
N
H
N
H
N
H
O
NTs
F
A: 2 h, 58% (19:81)
B: 8 h, 46% (76:24)
A: 3 h, 74% (22:78)
B: 7 h, 69% (81:19)
A: 4 h, 86% (32:68)
B: -
A: 6 h, 60% (22:78)
B: 18 h, 60% (81:19)
c
(
(
)-4ca
)-5ca
(
(
)-8
)-9
(
(
)-6
)-7
O
O
O
N
Br
N
H
N
N
H
H
A: 0.5 h, 66% (98:2)d
B: 3 h, 51% (95:5)
A: 8 h, 66% (15:85)
B: - c
A: 0.5 h, 82% (50:50)
B: 1 h, 54% (50:50)
Scheme 2 Synthesis of tetrahydroquinolines and N-alkyltetrahydroquinolines by CeCl3·7H2O/NaI catalyzed Povarov reaction. a Reagents and conditions:
Method A: aniline 1a–c (1 mmol), aldehyde 2a–g (1 mmol), dienophile 3a–c (1.2 mmol), CeCl3·7H2O (0.3 mmol), NaI (0.3 mmol), and MgSO4 (200
mg), stirred together in MeCN (5 mL) at 50 °C. Method B: pure isolated imine synthesized from aniline 1 and aldehyde 2 (1 mmol), dienophile 3 (1.5
mmol), CeCl3·7H2O (0.3 mmol), and NaI (0.3 mmol) stirred at –10 °C without solvent. b Syn/anti ratio determined by 1H NMR spectroscopy of the crude.
c Not determined due to the stickiness of the mixture. d Reaction performed at r.t.
fect is enhanced in the solvent-free reaction, that seems to
proceed very slowly or not at all in the examples cited
above.
drawbacks of this methodology: the synthesis of the start-
ing benzotriazole derivative and a little atom economy. Fur-
ther applications of our approach are under study.
The scope of the reaction was extended also to dieno-
philes other than DMP (3a). Beyond the classical candidate
2,3-dihydrofuran (3b), N-vinylpyrrolidone (3c) was also
used under conditions according to both methods A and B.
2,3-Dihydrofuran derivatives syn-6 and anti-7 were ob-
tained in short reaction times, probably because of the
higher energy of the more strained double bond in the five-
membered ring, but unfortunately the reaction was unse-
lective in both conditions, because of the reduced steric
hindrance of the furan ring with respect to pyran. Different
results were obtained with N-vinylpyrrolidone (3c), that af-
forded products syn-8 and anti-9 with acceptable yields
and with a strong preference for the syn-product.
N-Methylaniline (1d) or N-benzylaniline (1e), formalde-
hyde (2h) or ethyl glyoxylate (2i) and dienophiles 3a–c
were mixed in acetonitrile and stirred together at room
temperature with the catalytic system, according to meth-
od A. To our delight, reactions were complete in 0.5–5
hours, giving yields up to 96% of the desired N-alkyltetrahy-
droquinolines 10a–d, as depicted in Scheme 3.
This approach was applied to the synthesis of juloli-
dine-type compound 11. A probable reaction pathway is
described in Scheme 4: the imine formed by the reaction of
aniline with formaldehyde reacts according to Povarov
mechanism with dihydrofuran. The amino group contained
into the intermediate dihydroquinoline can form an imini-
um ion by reaction with a second molecule of formaldehyde
and then a second Povarov reaction takes place, yielding
product 11. Also another julolidine-type synthesis through
The good results obtained with the classical Povarov re-
action prompted us to test iminium ions as heterodienes,
similar to the benzotriazole approach reported by Katritz-
ky’s group,27 with the result of overcoming the two main
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E
C. Cimarelli et al.
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Synthesis
X
R1
R1
CeCl3•7H2O/NaI
O
N
R2
X
R1
+
+
N
OH
H
MeCN, r.t.
N
H
H
R2
N
R1
R2
12 1–10% (GC)
13 2–15% (GC)
1d R1 = Me
1e R1 = Bn
2h R2 = H
2i R2 = COOEt
3a–c
10a–d
Figure 1 Recurrent by-products observed in GC-MS analysis of the
crude
O
O
N
O
by mixing 1a together with a two-fold excess of 3a under
the reaction conditions, and observing that product 14 was
formed in 45% of isolated yield, as described in Scheme 5.
O
N
N
N
N
COOEt
Ph
Lewis
acid
12a
10b
10da
36%, 1 h
10a
10c
78%, 1 h
60%, 2 h
96%, 0.5 h
N
H
O
N
OH
Scheme 3 Synthesis of N-alkyltetrahydroquinolines by CeCl3·7H2O/NaI
catalyzed Povarov reaction. Reagents and conditions: 1d–e (1 mmol),
2h–i (1.2 mmol), 3a–c (1.2 mmol), CeCl3·7H2O, NaI (0.3 mmol), and
MgSO4 (200 mg) were stirred together in MeCN (5 mL) at r.t. a Product
10d was obtained as a 53:47 syn/anti mixture.
O
3a
[4+2]
+
NH2
3a (2 equiv)
1a
O
CeCl3•7H2O, NaI, MgSO4
O
CeCl3•7H2O/NaI
O
O
MeCN, 50 °C
45%
N
H
OH
+
+
MgSO4, MeCN
50 °C, 2 h, 66%
syn/anti = 56:44
H
H
NH2
N
14
3b
1a
2h
O
Scheme 5 Formation of by-product 12a and further reaction with 3a
11
3b [4+2]
– H2O
2h
On the other hand, by-products like 13 were already re-
ported in the Povarov reaction. The coordination of Cerium
with the oxygen atom in tetrahydroquinolines 4 and 5 fa-
vors the ether ring opening,30 then the iminodiene acts as
hydrogen acceptor in the oxidation to quinoline by an hy-
drogen transfer mechanism.31
O
O
2h
3b
[4+2]
N
N
– H2O
N
H
Scheme 4 One-pot synthesis of the julolidine 11. Reagents and condi-
tions: 1a (1 mmol), 2h (2.2 mmol), 3b (2.4 mmol), CeCl3·7H2O, NaI (0.3
mmol), and MgSO4 (200 mg) were stirred together in MeCN (5 mL) at
50 °C for 2 h.
Furthermore tetrahydropyranylation of the free hydrox-
yl groups could occur, because of the known ability of
CeCl3·7H2O/NaI to catalyze this kind of protection of alco-
hols.32 The crude mixture of the preparation of compounds
4ae and 5ae was submitted to ESI-MS analysis and the
presence of all the hypothesized by-products, which cannot
be identified by GC-MS analysis, was clearly shown (see
Supporting Information).
In conclusion, a one-pot methodology for the stereose-
lective synthesis of tetrahydroquinolines, based on the
Povarov reaction catalyzed by the scarcely toxic, easily han-
dled and efficient Lewis acid CeCl3·7H2O, in combination
with NaI, was developed. A series of tetrahydroquinolines
was obtained, in good yields, from aromatic amines, aro-
matic aldehydes, and DHP. The stereoselectivity of the reac-
tion can be driven toward the anti- or the syn-diastereomer
by choosing solvent or solventless reaction conditions. The
analysis of the reaction mixture allowed the identification
of the different reaction pathways that may take place in
the system and consequently the main by-products, re-
sponsible for the sometimes troublesome purification of
the products. The ability of iminium ions to act as Povarov
Povarov reaction is known in literature28 that takes place in
the absence of any catalyst, but is performed in the more
toxic and expensive trifluoroethanol.
Despite the good outcomes of these reactions, yields
rarely rose above 90%, because of some side reactions that
generated byproducts, making the purification more diffi-
cult as well. In these reactions, especially using 3a as dieno-
phile, we observed products 12 and 13 (Figure 1) in signifi-
cant amounts during the GC-MS analysis of the reaction
crude.
By-product 12 is due to opening of the tetrahydropyran
ring by the starting aniline that leads to an imine by-prod-
uct, which reacts as a diene with another dihydropyran
molecule according to the Povarov mechanism and affords
tetrahydroquinoline 14.29 This hypothesis was confirmed
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F
C. Cimarelli et al.
Paper
Synthesis
activated dienes in this protocol was also explored, leading
to up to 96% yield of the desired N-alkyltetrahydroquinoline
products. In addition to demonstrating the efficiency of our
CeCl3·7H2O/NaI catalytic system in the formation of new
carbon–carbon bonds by a multicomponent method, our
present methodology has evidenced its further application
in organic synthesis in the cyclization to fused-ring hetero-
cycles. Further studies in order to explore the application of
our protocol in heterocyclic systems with more different
heteroatoms are currently underway.
(±)-(4aS,5S,10bS)-5-(Furan-2-yl)-3,4,4a,5,6,10b-hexahydro-2H-
pyrano[3,2-c]quinoline (4ae)
Prepared from aniline (1a), 2-furancarbaldehyde (2e), and 2,3-dihy-
dropyran (3a) according to the general procedure; yield: 114 mg
(47%); white solid; mp 156–158 °C.
FT-IR (neat): 3322, 2938, 1602, 1483, 1063, 752, 723 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.43 (d, J = 7.5 Hz, 1 H), 7.42–7.41 (m, 1
H), 7.12–7.08 (m, 1 H), 6.82 (t, J = 7.5 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H),
6.40–6.39 (m, 1 H), 6.31 (dd, J = 3.3, 0.8 Hz, 1 H), 5.24 (d, J = 5.6 Hz, 1
H), 4.72 (d, J = 2.6 Hz, 1 H), 4.00 (br s, 1 H), 3.63–3.59 (m, 1 H), 3.43
(td, J = 11.8, 1.9 Hz, 1 H), 2.42–2.36 (m, 1 H), 1.70–1.46 (m, 4 H).
13C NMR (CDCl3, 100 MHz): δ = 154.3, 144.6, 141.8, 128.3, 127.9,
120.3, 118.8, 114.8, 110.4, 106.3, 72.0, 60.9, 54.0, 36.5, 25.5, 19.0.
GC-MS (EI, 70 eV): m/z = 255 [M+], 196 (100%), 184, 168, 167, 130.
All reagents and solvents were purchased from commercial suppliers
and used without further purification, unless mentioned otherwise.
Formaldehyde was used as a 37% wt. solution in H2O. All reactions
were monitored by TLC using EMD/Merck silica gel 60 precoated
plates (0.25 mm), and the compounds were visualized either by using
UV light (254 nm), and/or I2 vapors, vanillin, or KMnO4 stains as de-
veloping agents. Purification of the reaction products was carried out
by column flash chromatography using silica gel (0.040–0.063 mesh).
1H, 13C, and 19F NMR spectra were recorded on a Varian Mercury 400
(400 MHz, 100 MHz, or 377 MHz, respectively). Chemical shifts are
given in ppm with reference to residual H in deuterated solvents as
the internal standard. Coupling constants J are reported in hertz (Hz).
Diastereomeric ratio was determined by integration of 1H NMR sig-
nals of H-1 and H-6. Mass spectra were obtained using a gas chro-
matograph Agilent 6850 equipped with a HP5MS column (0.25 mm
diameter) and a mass-selective detector Agilent 5973N, or using a LC-
MS Hewlett Packard series 1100 MSD. Microanalyses were performed
with an EA1108 CHNS-D Fisons Instrument. Melting points were de-
termined in open capillary tubes on a Büchi 535 melting point appa-
ratus and are uncorrected.
Anal. Calcd for C16H17NO2 (255.317): C, 75.27; H, 6.71; N, 5.49. Found:
C, 75.25; H, 6.64; N, 5.58.
(±)-(4aS,5R,10bS)-5-(Furan-2-yl)-3,4,4a,5,6,10b-hexahydro-2H-
pyrano[3,2-c]quinoline (5ae)
Prepared from aniline (1a), 2-furancarbaldehyde (2e), and 2,3 dihy-
dropyran (3a) according to the general procedure; yield: 45 mg (18%);
white solid; mp 126–128 °C.
FT-IR (neat): 3317, 2925, 2856, 1626, 1265, 1124, 1073, 1026, 749
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.42–7.41 (m, 1 H), 7.22 (dd, J = 7.6, 1.5
Hz, 1 H), 7.11–7.07 (m, 1 H), 6.72 (t, J = 7.4 Hz, 1 H), 6.56 (d, J = 8.1 Hz,
1 H), 6.37–6.36 (m, 1 H), 6.33 (d, J = 3.2 Hz, 1 H), 4.83 (d, J = 10.5 Hz, 1
H), 4.42 (d, J = 2.9 Hz, 1 H), 4.07–4.02 (m, 2 H), 3.71 (td, J = 11.2, 2.5
Hz, 1 H), 2.30–2.25 (m, 1 H), 1.86–1.71 (m, 2 H), 1.58–1.54 (m, 1 H),
1.43–1.37 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 155.2, 144.1, 142.5, 130.9, 129.5,
121.0, 118.2, 114.8, 110.4, 107.8, 74.3, 68.4, 49.2, 37.3, 24.6, 22.3.
GC-MS (EI, 70 eV): m/z = 255 [M+], 196 (100%), 184, 168, 167, 130.
The analytical and spectral data of known products 4aa, 5aa; 4ab,
5ab; 4ac, 5ac; 4ad, 5ad; 4ba, 5ba, 4ca, 5ca; and 6–8 are provided in
the Supporting Information.
Anal. Calcd for C16H17NO2 (255.317): C, 75.27; H, 6.71; N, 5.49. Found:
C, 75.32; H, 6.60; N, 5.62.
Tetrahydroquinolines 4 and 5
Method A
(±)-(4aS,5S,10bS)-5-(2-Fluorophenyl)-3,4,4a,5,6,10b-hexahydro-
2H-pyrano[3,2-c]quinoline (4af)
In a round-bottomed flask, N-arylamine 1a–c (1 mmol) and aldehyde
2a–g (1 mmol) were stirred together in MeCN (5 mL) in the presence
of anhyd MgSO4 (200 mg). The mixture was stirred until imine was
completely formed (heating when required). Then, CeCl3·7H2O (112
mg, 0.3 mmol) and NaI (45 mg, 0.3 mmol) were added, followed by
the chosen dienophile 3a–c (1.2 mmol) and the mixture was stirred
at 50 °C until consumption of starting materials (TLC, hexane/EtOAc,
vanillin stain). The mixture was diluted with CH2Cl2 (10 mL) and
washed with aq 0.5 M HCl (10 mL). The aqueous layer was extracted
with CH2Cl2, then treated with sat. aq NaHCO3 until basic pH was
reached, and extracted again with CH2Cl2. The organic layers were
combined, washed with brine, and dried (anhyd Na2SO4). The crude
was purified by flash chromatography over silica gel (eluent hex-
ane/EtOAc) to afford the pure desired tetrahydroquinoline product.
Prepared from aniline (1a), 2-fluorobenzaldehyde (2f), and 2,3 dihy-
dropyran (3a) according to the general procedure; yield: 157 mg
(56%); white solid; mp 159–164 °C.
FT-IR (neat): 3301, 2942, 1492, 1226, 1071, 746 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.65–7.58 (m, 1 H), 7.47–7.42 (m, 1 H),
7.34–7.25 (m, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.13–7.04 (m, 2 H), 6.85–
6.77 (m, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 5.33 (d, J = 5.6 Hz, 1 H), 5.03 (d,
J = 2.3 Hz, 1 H), 3.76 (br s, 1 H), 3.64–3.57 (m, 1 H), 3.49–3.36 (m, 1 H),
2.34–2.27 (m, 1 H), 1.66–1.39 (m, 3 H), 1.36–1.18 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 160.2 (d, JC,F = 246.7 Hz), 145.3, 129.0
(d, JC,F = 8.4 Hz), 128.4 (d, JC,F = 11.9 Hz), 128.3, 128.2 (d, JC,F = 4.2 Hz),
127.9, 124.0 (d, JC,F = 3.5 Hz), 120.3, 118.8, 115.7 (d, JC,F = 21.6 Hz),
114.9, 72.6, 60.8, 52.4 (d, JC,F = 3.0 Hz), 36.6, 25.6, 18.6.
19F NMR (CDCl3, 377 MHz): δ = –119.5.
GC-MS (EI, 70 eV): m/z = 283 [M+], 252, 224 (100%), 212, 130, 109, 77.
Method B
In a closed vial, pure isolated N-arylimine (1 mmol, prepared from
1a–c and 2a–g), dienophile 3a–c (1.5 mmol), CeCl3·7H2O (112 mg, 0.3
mmol), and NaI (45 mg, 0.3 mmol) were stirred together at –10 °C in
an ice-salt bath until consumption of the starting imine. Workup and
purification follow the procedure reported in Method A.
Anal. Calcd for C18H18FNO (283.346): C, 76.30; H, 6.40; N, 4.94. Found:
C, 76.34; H, 6.47; N, 4.87.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

G
C. Cimarelli et al.
Paper
Synthesis
(±)-(4aS,5R,10bS)-5-(2-Fluorophenyl)-3,4,4a,5,6,10b-hexahydro-
2H-pyrano[3,2-c]quinoline (5af)
LC-MS (ESI): m/z = 457 [M – H]–.
Anal. Calcd for C27H26N2O3S (458.576): C, 70.72; H, 5.72; N, 6.11; S,
6.99. Found: C, 70.57; H, 5.44; N, 6.23; S, 6.89.
Prepared from aniline (1a), 2-fluorobenzaldehyde (2f), and 2,3-dihy-
dropyran (3a) according to the general procedure; yield: 155 mg
(56%); white foamy solid; mp 47–50 °C.
5-Methyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (10a)
FT-IR (neat): 3354, 2938, 2852, 1610, 1483, 1079, 748 cm–1
.
Prepared from N-methylaniline (1d), formaldehyde (2h), and 2,3-di-
hydrofuran (3b) according to the general procedure at r.t.; yield: 180
mg (96%); pale yellow oil.
FT-IR (neat): 2937, 2863, 2818, 1607, 1497, 1294, 748 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.36 (dd, J = 7.5, 1.6 Hz, 1 H), 7.25–7.18
(m, 1 H), 6.78 (td, J = 7.4, 1.0 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 4.60 (d,
J = 5.5 Hz, 1 H), 3.95 (td, J = 8.4, 5.9 Hz, 1 H), 3.82 (td, J = 8.8, 6.3 Hz, 1
H), 3.02 (dd, J = 11.2, 5.3 Hz, 1 H), 2.90 (s, 3 H), 2.80 (t, J = 11.1 Hz, 1
H), 2.54 (dqd, J = 13.5, 5.4, 2.8 Hz, 1 H), 2.34–2.18 (m, 1 H), 1.80–1.73
(m, 1 H).
1H NMR (CDCl3, 400 MHz): δ = 7.54 (td, J = 7.5, 1.6 Hz, 1 H), 7.34–7.24
(m, 2 H), 7.18 (td, J = 7.5, 1.1 Hz, 1 H), 7.14–7.04 (m, 2 H), 6.74 (td, J =
7.4, 1.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 5.13 (d, J = 10.4 Hz, 1 H), 4.43
(d, J = 2.9 Hz, 1 H), 4.10–4.04 (m, 1 H), 4.09 (br s, 1 H), 3.72 (td, J =
11.3, 2.6 Hz, 1 H), 2.21–2.11 (m, 1 H), 1.92 (qt, J = 12.5, 4.2 Hz, 1 H),
1.72 (tt, J = 13.2, 4.7 Hz, 1 H), 1.56–1.46 (m, 1 H), 1.44–1.35 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 161.3 (d, JC,F = 246.8 Hz), 144.7, 130.9,
129.5, 129.4 (d, JC,F = 8.4 Hz), 129.2 (d, JC,F = 4.0 Hz), 124.8 (d, JC,F = 3.4
Hz), 120.8, 118.0, 115.7 (d, JC,F = 22.5 Hz), 114.5, 74.3, 68.4, 47.9, 38.6,
24.6, 22.5.
.
13C NMR (CDCl3, 100 MHz): δ = 147.1, 131.1, 129.0, 121.7, 117.4,
111.8, 75.8, 65.1, 52.5, 39.3, 35.9, 30.0.
GC-MS (EI, 70 eV): m/z = 189 [M+], 158, 146, 144 (100%).
19F NMR (CDCl3, 377 MHz): δ = –118.6.
GC-MS (EI, 70 eV): m/z = 283 [M+], 252, 224 (100%), 212, 130, 109, 77.
Anal. Calcd for C18H18FNO (283.346): C, 76.30; H, 6.40; N, 4.94. Found:
C, 76.28; H, 6.45; N, 4.98.
Anal. Calcd for C12H15NO (189.258): C, 76.16; H, 7.99; N, 7.40. Found:
C, 76.25; H, 8.17; N, 7.47.
(±)-(4aS,5S,10bS)-5-(1-Tosyl-1H-indol-3-yl)-3,4,4a,5,6,10b-hexahy-
dro-2H-pyrano[3,2-c]quinoline (4ag)
1-(1-Methyl-1,2,3,4-tetrahydroquinolin-4-yl)pyrrolidin-2-one
(10b)
Prepared from aniline (1a), N-tosylindole-3-carboxaldehyde (2g), and
2,3-dihydropyran (3a) according to the general procedure; yield: 257
mg (58%); white solid; mp 121 °C (dec.).
Prepared from N-methylaniline (1d), formaldehyde (2h), and N-vin-
ylpiyrrolidone (3c) according to the general procedure at r.t.; yield:
176 mg (78%); white solid; mp 87–88 °C.
FT-IR (neat): 3380, 2931, 1605, 1368, 1168, 743, 568, 536 cm–1
.
FT-IR (neat): 2950, 2872, 2819, 1671, 1500, 1418, 1287, 748 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.03 (dd, J = 8.3, 0.8 Hz, 1 H), 7.78 (d, J =
8.2 Hz, 2 H), 7.64 (s, 1 H), 7.53 (dd, J = 7.8, 0.7 Hz, 1 H), 7.45 (d, J = 7.6
Hz, 1 H), 7.37–7.34 (m, 1 H), 7.28–7.26 (m, 1 H), 7.23 (d, J = 8.6 Hz, 2
H), 7.14–7.11 (m, 1 H), 6.83 (t, J = 7.5 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H),
5.35 (d, J = 5.6 Hz, 1 H), 4.95–4.94 (m, 1 H), 3.91 (br s, 1 H), 3.60–3.57
(m, 1 H), 3.42 (td, J = 11.4, 2.6 Hz, 1 H), 2.35 (s, 3 H), 2.33–2.27 (m, 1
H), 1.53–1.41 (m, 3 H), 1.16–1.12 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 145.2, 145.1, 135.7, 135.3, 130.1,
129.1, 128.4, 127.9, 127.0, 125.3, 123.6, 123.5, 123.0, 120.4, 119.8,
119.0, 114.9, 114.2, 72.5, 60.8, 52.4, 36.7, 25.5, 21.8, 18.7.
1H NMR (CDCl3, 400 MHz): δ = 7.15–7.11 (m, 1 H), 6.88–6.86 (m, 1 H),
6.67–6.62 (m, 2 H), 5.41 (dd, J = 9.3, 6.0 Hz, 1 H), 3.34 (ddd, J = 11.7,
9.7, 3.4 Hz, 1 H), 3.26–3.18 (m, 2 H), 3.15–3.09 (m, 1 H), 2.88 (s, 3 H),
2.50–2.46 (m, 2 H), 2.19–2.10 (m, 1 H), 2.07–1.93 (m, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 175.6, 147.6, 128.7, 127.7, 119.9,
116.9, 112.0, 49.7, 48.1, 43.7, 39.5, 31.7, 26.9, 18.5.
GC-MS (EI, 70 eV): m/z = 230 [M+], 201, 159, 144 (100%), 130.
Anal. Calcd for C14H18N2O (230.311): C, 73.01; H, 7.88; N, 12.16.
Found: C, 73.25; H, 7.94; N, 12.08.
LC-MS (ESI): m/z = 457 [M – H]–.
6-Benzyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline
(10c)
Anal. Calcd for C27H26N2O3S (458.576): C, 70.72; H, 5.72; N, 6.11; S,
6.99. Found: C, 70.64; H, 5.38; N, 5.94; S, 7.12.
Prepared from N-benzylaniline (1e), formaldehyde (2h), and 2,3-di-
hydropyran (3a) according to the general procedure at r.t.; yield: 163
mg (60%); white solid; mp 126–127 °C.
(±)-(4aS,5R,10bS)-5-(1-Tosyl-1H-indol-3-yl)-3,4,4a,5,6,10b-hexahy-
dro-2H-pyrano[3,2-c]quinoline (5ag)
FT-IR (neat): 2902, 2838, 1602, 1506, 1453, 1046, 743 cm–1
.
Prepared from aniline (1a), N-tosylindole-3-carboxaldehyde (2g), and
2,3-dihydropyran (3a) according to the general procedure; yield: 120
mg (28%); white solid; mp 223–225 °C.
FT-IR (neat): 3375, 2935, 1605, 1368, 1176, 744, 572, 535 cm–1
1H NMR (CDCl3, 400 MHz): δ = 8.03 (dd, J = 8.3, 0.7 Hz, 1 H), 7.77–7.73
(m, 3 H), 7.58 (s, 1 H), 7.36–7.32 (m, 1 H), 7.26–7.18 (m, 4 H), 7.12–
7.08 (m, 1 H), 6.73 (td, J = 7.5, 1.0 Hz, 1 H), 6.52 (d, J = 8.0 Hz, 1 H), 4.97
(d, J = 10.9 Hz, 1 H), 4.41 (d, J = 2.8 Hz, 1 H), 4.13–4.08 (m, 2 H), 3.72
(td, J = 11.5, 2.5 Hz, 1 H), 2.38–2.33 (m, 1 H), 2.36 (s, 3 H), 1.86–1.76
(m, 1 H), 1.63 (tt, J = 13.1, 4.6 Hz, 1 H), 1.42–1.27 (m, 2 H).
1H NMR (CDCl3, 400 MHz): δ = 7.34–7.23 (m, 5 H), 7.10–7.05 (m, 1 H),
6.66 (t, J = 7.3 Hz, 1 H), 6.56 (d, J = 8.3 Hz, 1 H), 4.52 (d, J = 16.9 Hz, 1
H), 4.49 (br s, 1 H), 4.47 (d, J = 17.0 Hz, 1 H), 4.03–3.99 (m, 1 H), 3.75–
3.68 (m, 2 H), 3.09 (dd, J = 11.2, 4.1 Hz, 1 H), 2.26–2.19 (m, 1 H), 1.97–
1.88 (m, 1 H), 1.85–1.75 (m, 2 H), 1.50–1.43 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 145.7, 138.9, 131.1, 129.7, 128.8,
127.1, 126.8, 121.3, 116.5, 111.6, 74.5, 67.6, 55.4, 49.7, 32.4, 25.6,
22.7.
.
GC-MS (EI, 70 eV): m/z = 279 [M+], 220, 188, 144, 130, 91 (100%).
13C NMR (CDCl3, 100 MHz): δ = 145.3, 144.7, 136.0, 135.2, 131.1,
130.1, 129.6, 129.4, 127.0, 125.2, 124.9, 123.4, 121.4, 121.0, 118.0,
114.5, 114.2, 74.6, 68.7, 48.1, 37.0, 24.5, 22.1, 21.8.
Anal. Calcd for C19H21NO (279.383): C, 81.68; H, 7.58; N, 5.01. Found:
C, 81.74; H, 7.62; N, 5.29.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

H
C. Cimarelli et al.
Paper
Synthesis
Ethyl (±)-(3aS,4S,9bS)-5-Methyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-
c]quinoline-4-carboxylate (syn-10d)
(3bS,6aS,9aS,12aS)-3b,5,6,6a,7,9,9a,10,11,12a-Decahydrofuro[3,2-
c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (anti-11)
Prepared from N-methylaniline (1d), ethyl glyoxylate (2i), and 2,3-di-
hydrofuran (3b) according to the general procedure at r.t.; yield: 47
mg (19%); colorless oil.
Prepared from 1a, 2h, and 3b according to the above procedure; yield:
74 mg (29%); white solid; mp 112–113 °C.
FT-IR (neat): 2929, 2833, 1601, 1486, 1290, 1053, 1033, 787, 767 cm–1
.
FT-IR (neat): 3389, 2878, 1721, 1497, 1185, 1026, 748 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.32 (d, J = 7.5 Hz, 2 H), 6.80 (t, J = 7.5
Hz, 1 H), 4.53 (d, J = 4.9 Hz, 2 H), 3.96 (td, J = 8.4, 6.1 Hz, 2 H), 3.82 (td,
J = 8.9, 6.0 Hz, 2 H), 2.94 (dd, J = 10.5, 4.8 Hz, 2 H), 2.63–2.58 (m, 2 H),
2.55–2.48 (m, 2 H), 2.32–2.23 (m, 2 H), 1.76–1.69 (m, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 144.3, 131.4, 121.8, 118.3, 76.1, 65.3,
51.5, 35.6, 30.4.
1H NMR (CDCl3, 400 MHz): δ = 7.32 (dd, J = 7.6, 1.2 Hz, 1 H), 7.26–7.20
(m, 1 H), 6.79 (td, J = 7.4, 1.1 Hz, 1 H), 6.74 (d, J = 8.3 Hz, 1 H), 4.60 (d,
J = 5.1 Hz, 1 H), 4.12–3.99 (m, 2 H), 3.88 (d, J = 6.0 Hz, 1 H), 3.84–3.68
(m, 2 H), 2.91 (s, 3 H), 2.88–2.78 (m, 1 H), 2.48–2.40 (m, 1 H), 2.19–
2.10 (m, 1 H), 1.13 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 171.4, 145.9, 130.5, 129.4, 121.3,
118.0, 112.2, 75.1, 65.6, 63.2, 61.1, 39.7, 39.1, 27.6, 14.2.
GC-MS (EI, 70 eV): m/z = 257 [M+], 226, 214, 212 (100%), 182, 168,
167, 144, 55.
GC-MS (EI, 70 eV): m/z = 261 [M+], 188 (100%), 158, 144.
Anal. Calcd for C16H19NO2 (257.333): C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.68; H, 7.47; N, 5.41.
Anal. Calcd for C15H19NO3 (261.321): C, 68.94; H, 7.33; N, 5.36. Found:
C, 68.87; H, 7.39; N, 5.48.
Ethyl (±)-(3aS,4R,9bS)-5-Methyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-
c]quinoline-4-carboxylate (anti-10d)
Funding Information
This work was supported by grants from University of Camerino
(Fondo di Ateneo per la Ricerca 2014-2015).
Prepared from N-methylaniline (1d), ethyl glyoxylate (2i), and 2,3-di-
hydrofuran (3b) according to the general procedure at r.t. The product
anti-10d was obtained as an enriched diastereomeric mixture.
)(
1H NMR (CDCl3, 400 MHz): δ = 7.29–7.26 (m, 1 H), 7.18 (td, J = 8.2, 1.7
Hz, 1 H), 6.80–6.75 (m, 1 H), 6.66 (d, J = 8.3 Hz, 1 H), 4.94 (d, J = 7.6 Hz,
1 H), 4.14 (qdd, J = 7.1, 2.1, 0.8 Hz, 2 H), 3.92–3.70 (m, 3 H), 3.00 (ddd,
J = 16.9, 8.1, 4.1 Hz, 1 H), 2.95 (s, 3 H), 2.23–2.15 (m, 1 H), 2.06 (dq, J =
12.1, 8.2 Hz, 1 H), 1.19 (td, J = 7.1, 0.8 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589104.
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GC-MS (EI, 70 eV): m/z = 261 [M+], 188 (100%), 158, 144.
References
syn-11 and anti-11
(1) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
Aniline (1a; 1 mmol), formaldehyde (2h; 2.2 mmol), 2,3-dihydrofuran
(3b; 2.4 mmol), CeCl3·7H2O (0.3 mmol), NaI (0.3 mmol), and
MgSO4 (200 mg) were stirred together in MeCN (5 mL) at 50 °C for 2 h.
After consumption of the starting aniline, the reaction was stopped
and the workup was done according to the general procedure. The an-
ti/syn configuration of compounds 11 were assigned according to
those reported28 for 2-methyl-3b,6,7,7a,10a,12,13,14a-octahydro-
5H,8H,10H,11H-pyrano[3,2-c]pyrano[2′,3′:4,5]pyrido[3,2,1-ij]quino-
line.
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(3bR,6aR,9aS,12aS)-3b,5,6,6a,7,9,9a,10,11,12a-Decahydrofuro[3,2-
c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (syn-11)
Prepared from 1a, 2h, and 3b according to the above procedure; yield:
93 mg (37%); white solid; mp 87–88 °C.
FT-IR (neat): 2949, 2863, 1601, 1491, 1445, 1043, 1018, 751 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.26 (d, J = 7.5 Hz, 2 H), 6.79 (t, J = 7.5
Hz, 1 H), 4.75 (d, J = 6.5 Hz, 2 H), 3.88 (td, J = 8.4, 5.2 Hz, 2 H), 3.79 (td,
J = 8.3, 7.1 Hz, 2 H), 2.98 (dd, J = 11.3, 4.4 Hz, 2 H), 2.82 (dd, J = 11.4,
7.7 Hz, 2 H), 2.64–2.56 (m, 2 H), 2.20–2.12 (m, 2 H), 1.96–1.87 (m, 2
H).
13C NMR (CDCl3, 100 MHz): δ = 144.1, 130.9, 122.5, 118.5, 75.8, 66.0,
51.7, 36.5, 29.8.
GC-MS (EI, 70 eV): m/z = 257 [M+], 226, 214, 212 (100%), 182, 168,
167, 144, 55.
Anal. Calcd for C16H19NO2 (257.333): C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.64; H, 7.53; N, 5.38.
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