Influence of guanidinium salts and other ionic liquids on the three-component Aza-Diels-alder reaction

Article abstract of DOI:10.1002/hlca.201200655

The three-component reaction of aniline, benzaldehyde, and dienophiles such as 2,3-dihydrofuran, ethyl vinyl ether, 2,3-dihydropyran, and cyclopentadiene can be promoted by ionic liquids like imidazolium salts and guanidinium salts under thermal as well a

Full text of DOI:10.1002/hlca.201200655

Helvetica Chimica Acta – Vol. 96 (2013)
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Influence of Guanidinium Salts and Other Ionic Liquids on the Three-
Component Aza-DielsꢀAlder Reaction
by Fadime Mert-Balci, Hans-Georg Imrich, Jꢀrgen Conrad, and Uwe Beifuss*
Bioorganische Chemie, Institut fꢀr Chemie, Universitꢁt Hohenheim, Garbenstrasse 30,
DE-70599 Stuttgart
(phone: þ 49-711-459-22171; fax: þ 49-711-459-22951; e-mail: ubeifuss@uni-hohenheim.de)
The three-component reaction of aniline, benzaldehyde, and dienophiles such as 2,3-dihydrofuran,
ethyl vinyl ether, 2,3-dihydropyran, and cyclopentadiene can be promoted by ionic liquids like
imidazolium salts and guanidinium salts under thermal as well as microwave conditions. The chemical
yield as well as the diastereoselectivity of the Povarov reaction strongly depend on the ionic liquid
employed. The guanidinium salts can be recycled and reused several times without loss of reactivity.
Introduction. – The inverse electron-demand aza-DielsꢀAlder reaction of an
electron-poor, positively charged, or neutral 2-azabutadiene with an electron-rich
alkene, the so-called Povarov reaction, is one of the most efficient and flexible routes
for the synthesis of tetrahydroquinolines [1]. Two methods, i.e., the use of preformed 2-
azabutadienes and the in situ preparation of 2-azabutadienes, have been developed to
supply the required 2-azabutadienes. Many aza-DielsꢀAlder reactions reported so far
make use of a preformed N-arylimine as the heterodiene, which can be generated by
condensation of an aromatic amine with a carbonyl compound [2]. However, the use of
preformed imines as heterodienes is often hampered by their instability. In fact, many
imines are unstable at higher temperatures and rapidly hydrolyze upon contact to H2O.
Their purification by distillation or chromatography can sometimes be difficult [3]. The
in situ generation of 2-azabutadienes by reaction of an amine with a CO compound in
the presence of a dienophile not only circumvents the problems encountered with the
instability of preformed 2-azabutadienes, it also allows the synthesis of tetrahydroqui-
nolines and related heterocycles in one pot [4]. This type of three-component reaction
can be promoted by numerous reagents such as SmI2 [4a], SbCl3 [4b], phosphomo-
lybdic acid [4c], TMSCl [4d], I2 [4e], sulfamic acid [4f], InCl3 [4g][4j], Sc(OTf)3 [4g],
SelectfluorTM [4h], fluorinated alcohols [4i], Dy(OTf)3 [4k][4m], GdCl3 [4l], Ln(OTf)3
[4n], and CF3CO2H [4o][4p].
Recently, the application of ionic liquids as solvents and catalysts in organic
transformations has become very popular [5]. Ionic liquids have negligible vapor
pressure, are thermally and chemically stable, have a wide operating temperature
range, and can be reused. This is why they represent a more sustainable, environ-
mentally safe alternative to volatile traditional organic solvents. However, the attention
which ionic liquids have received in organic synthesis is not only due to their solvent
properties but also to their catalytic effects. It has been demonstrated that ionic liquids
ꢂ 2013 Verlag Helvetica Chimica Acta AG, Zꢀrich

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exert a strong influence on the kinetics or the stereoselectivity of reactions [5c][5f][6].
These effects probably can be attributed to polar interactions between the ionic liquids,
and the substrates, the transition states, or the intermediates. Apart from the well-
studied imidazolium salts, there are a number of other ionic liquids such as pyridinium,
phosphonium, and ammonium salts [5]. Recently, guanidinium salt-based ionic liquids
have received considerable attention. Guanidinium salts can easily be synthesized by a
number of efficient and reliable methods [7]. They have been used as solvents or
catalysts for a number of transformations such as the aldol reaction [8], the
condensation of indoles with aldehydes to produce bis(indolyl)methanes [9], the
Knoevenagel reaction [10], the Mannich reaction [11], the asymmetric a-aminoxylation
of CO compounds [12], the Henry reaction [13], the fixation of CO2 by epoxides [14],
the Heck reaction [15], the hydrogenation [16], the hydroformylation [17], the
oxidation of benzylic alcohols [18], and the Sharpless dihydroxylation [19].
Ionic liquids have also been employed to promote aza-DielsꢀAlder reactions
[20][21]. Yadav et al. reported the three-component synthesis of pyrano- and
ˇ
furoquinolines using [bmim]BF4 as ionic liquid [20d]. Jurcꢀk and Wilhelm have shown
that aza-DielsꢀAlder reactions between preformed 2-azabutadienes and alkenes can be
catalyzed by an imidazolinium hexafluorophosphate as the ionic liquid [20c]. Li et al.
reported the synthesis of pyrano- and furoquinolines via the three-component reaction
between an imidazolium tetrafluoroborate bound benzaldehyde, an aniline, and a cyclic
enol ether [20b]. In addition, it has been established that aza-DielsꢀAlder reactions
with imines as the dienophile can be performed in the presence of ionic liquids
[20c][21].
Results and Discussion. – Close inspection of the results published led to the
assumption that yields and stereoselectivities of the aza-DielsꢀAlder reaction for the
synthesis of furoquinolines depend on the ionic liquid and the reaction conditions. This
prompted us to study the influence of different ionic liquids on the outcome of a typical
aza-DielsꢀAlder reaction under different reaction conditions. As part of a program
devoted to the development of new ionic liquids for application in organic synthesis, we
were particularly interested whether guanidinium salts can be used as solvents and/or
catalysts for the aza-DielsꢀAlder reaction.
The three-component reaction between aniline (1), 2,3-dihydrofuran (2), and
benzaldehyde (3) was studied first. For comparison, this reaction was performed
initially in the presence of an imidazolium salt. When 1 equiv. of 1, 2 equiv. of 2, and
1 equiv. of 3 were reacted in [bmim]BF4 (¼1-butyl-3-methylimidazolium tetrafluoro-
borate) under Yadavꢃs conditions [20d], i.e., at room temperature for 3.5 h, 63% of a
4 :1 mixture of the endo- and the exo-furoquinolines, 4a and 4b, respectively, was
1
formed (Scheme 1). The endo/exo ratio was determined by H-NMR analysis of the
mixture after column filtration on SiO2. This result is in contrast to the findings of
Yadav et al. who reported the exclusive formation of the endo-isomer 4a in 92% yield.
Apart from 2,3-dihydrofuran (2) as the dienophile, the Povarov reaction in
[bmim]BF4 was also performed with ethyl vinyl ether (5), 2,3-dihydropyran (6) and
cyclopentadiene (7) as dienophiles. When 1 equiv. of 1, 2 equiv. of ethyl vinyl ether (5),
and 1 equiv. of 3 were reacted in 5.4 equiv. of [bmim]BF4 for 20 h at room temperature,
24% of the endo-4-ethoxy-1,2,3,4-tetrahydro-2-phenylquinoline (8a) were isolated

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Scheme 1. [bmim]BF4-Promoted Reaction between 1, 2, and 3
(Scheme 2). It should be noted that the yield of 8a could be improved to 66%, when the
experiment was repeated in the presence of CaSO4 to remove H2O formed during the
condensation of aniline (1) and benzaldehyde (3).
Scheme 2. [bmim]BF4-Promoted Reaction between 1, 3, and Ethyl Vinyl Ether (5)
The highly diastereoselective Povarov reaction between 1 equiv. of 1, 2 equiv. of
2,3-dihydropyran (6), and 1 equiv. of 3, in the presence of 5.4 equiv. of [bmim]BF4 and
4 equiv. of CaSO4, delivered 51% of the endo-isomer 9a after 6 d at room temperature
(Scheme 3).
Scheme 3. [bmim]BF4-Promoted Reaction between 1, 3, and 2,3-Dihydropyran (6)
The Povarov reaction was also performed with cyclopentadiene (7) as the
dienophile. When 1.2 equiv. of 1, 2 equiv. of 7, and 1 equiv. of 3 were reacted with
5.4 equiv. of [bmim]BF4 and 4 equiv. of CaSO4, 50% of a 95 :5 endo/exo mixture, 10a/b,
were formed (Scheme 4). In addition to the cycloadducts 10a and 10b, 4% of N-
benzylaniline (11) were obtained. First, the endo-isomer 10a could be separated by
recrystallization of the product mixture. N-Benzylaniline (11) and the exo-isomer 10b
were volatile enough to be separated via bulb-to-bulb distillation. The exo-isomer 10b
could be obtained in pure form by flash chromatography of the distillate.

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Scheme 4. [bmim]BF4-Promoted Reaction between 1, 3, and Cyclopentadiene (7)
The three-component reaction between aniline (1), 2,3-dihydrofuran (2), and
benzaldehyde (3) was selected as a model reaction to study the influence of different
ionic liquids and microwave irradiation on the outcome of the Povarov reaction. First,
the [bmim]BF4-promoted reaction was studied under microwave conditions (Table 1)
[22]. It was found that the reaction with 5.4 equiv. of the ionic liquid could be brought to
completion within 7 min to yield 69% of 4a/4b (endo/exo 75 :25; Table 1, Entry 1).
Reduction of the amount of [bmim]BF4 was associated with longer reaction times and
decreasing yields, but an improved endo/exo ratio, 4a/4b (Table 1, Entries 2 and 3).
When the reaction was performed in the absence of any ionic liquid under microwave
conditions (150 W, 708, 5 min), not a trace of the aza-DielsꢀAlder product was formed.
This control experiment clearly underlined the importance of the ionic liquid for this
transformation.
Table 1. Influence of the Amount of [bmim]BF4 on Yield and Selectivity of the Synthesis of 4a/4b under
Microwave Conditionsa)
Entry
[bmim]BF4 [equiv.]
t [min]
Yield [%]
4a (endo)/4b (exo)
1
2
3
5.4
1.0
0.1
7
10
15
69
57
51
75 : 25
83 : 17
84 : 16
a) The reactions were performed in sealed vials. Conditions: 1 (1 equiv.) þ 2 (2 equiv.) þ 3 (1 equiv.), in
the presence of [bmim]BF4, at 708; microwave, 10 W.
To determine the influence of the microwave irradiation on the outcome of this
reaction, it was also studied under thermal conditions in a sealed vial at 708 (Table 2).
Interestingly, in terms of diastereoselectivity there was no difference between the
reactions under thermal and microwave conditions (Table 1, Entries 1 and 3, and
Table 2, Entries 1 – 3). However, the yield of 4a/4b under thermal conditions was
slightly better than under microwave conditions (Table 1, Entry 1, and Table 2,
Entry 1). This is why all further experiments were performed in sealed vials in oil
bath. Variation of the amounts of the substrates revealed that best yields were obtained
when 1.2 equiv. of 1, 2 equiv. of 2 and 1 equiv. of 3 were reacted in 5.4 equiv. of
[bmim]BF4 under the conditions indicated in Table 2, Entry 5.

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Table 2. [bmim]BF4-Promoted Synthesis of 4a/4b under Thermal Conditionsa)
Entry 1 [equiv.] 2 [equiv.] 3 [equiv.] [bmim]BF4 [equiv.] t [min] Yield [%] 4a (endo)/4b (exo)
1
2
3
4
5
6
7
1
1
1
1.2
1.2
1.2
1.2
2
2
2
2
2
2.2
2.4
1
1
1
1
1
1
1
5.4
0.1
0.1
5.4
5.4
5.4
5.4
5
14
60
5
7
7
76
44
43
78
81
75
76
75 : 25
84 : 16
84 : 16
75 : 25
78 : 22
76 : 24
75 : 25
7
a) The reactions were performed in sealed vials. Conditions: 1 þ 2 þ 3, in the presence of [bmim]BF4, at
708, in an oil bath.
In further experiments, the influence of the reaction temperature on the reaction
time, the chemical yield, and the endo/exo selectivity was studied by reacting 1, 2, and 3
in [bmim]BF4 as the ionic liquid in a sealed vial under thermal conditions (Table 3). It
was found that the reaction time could be substantially reduced when the reaction
temperature was changed from 08 to 1608. Simultaneously, the amount of the exo-
isomer 4b increased. At 1608, it took only 3 min to obtain a 67:33 mixture 4a/4b in
quantitative yield (Table 3, Entry 4). To summarize, using [bmim]BF4 as the ionic
liquid led under all reaction conditions to endo/exo mixtures 4a/4b. Interesting to note
is that lower reaction temperatures favored the formation of the endo-isomer. The
influence of microwave irradiation on yield and selectivity seems to be negligible.
a
Table 3. Influence of the Reaction Temperature on the Formation of 4a/4b in the Presence of [bmim]BF4
)
Entry
T [8]
t [min]
Yield [%]
4a (endo)/4b (exo)
1
2
3
4
0
r.t.
70
1140
210
7
79
90
81
quant.
85 : 15
81 : 19
78 : 22
67: 33
160
3
a) The reactions were performed in sealed vials. Conditions: 1 (1.2 equiv.) þ 2 (2 equiv.) þ 3 (1 equiv.),
in the presence of 5.4 equiv. [bmim]BF4, in an oil bath.
During the search for ionic liquids favoring the formation of either the endo-isomer
4a or the exo-isomer 4b, we came across the guanidinium salts. These ionic liquids are
easily available as they can be prepared efficiently by well-elaborated synthetic
protocols [7]. Another advantage is that guanidinium salts are known to be highly
stable [7]. Therefore, the synthesis of 4a/4b was studied in different guanidinium salts
12, starting with the reaction between 1.2 equiv. of 1, 2 equiv. of 2, and 1 equiv. of 3
with 5.4 equiv. of the guanidinium salts 12a – 12r under thermal conditions (1608, 3 min;
Table 4). It was found that the yield as well as the endo/exo ratio, 4a/4b, strongly depend
on the structure of the guanidinium cation, as well as that of the counter ion. With the
guanidinium chlorides the exo-product 4b was formed preferentially, while the
guanidinium tetrafluoroborates delivered the endo-isomer 4a in excess. A particularly

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striking example was the reaction in 12g, which resulted in the exclusive formation of
the exo-isomer 4b, albeit at low yields (Table 4).
Using the guanidinium salts 12g and 12p as examples, it could be demonstrated that
the chemical yield as well as the endo/exo ratio depend on the concentration of the
guanidinium salt (Table 5). It was particularly interesting to note that the trans-

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Table 4. Influence of Different Guanidinium Salts on the Synthesis of 4a/4ba)
Compound 12 Yield [%]
4a (endo)/4b (exo) Compound 12 Yield [%] 4a (endo)/4b (exo)
12a
12b
12c
12d
12e
12f
12g
12h
12i
7
14
5
36 : 64
32 : 68
32 : 68
12j
12k
12l
12m
12n
12o
12p
12q
12r
20
47
45
37
67
43
74
81
74
41 : 59
77: 23
78 : 22
40 : 60
68 : 32
53 : 47
83 : 17
88 : 12
83 : 17
no reaction
5
12
21
12
25
44 : 56
41 : 59
0 : 100
49 : 51
71 : 29
a) The reactions were performed in sealed vials. Conditions: 1 (1.2 equiv.) þ 2 (2 equiv.) þ 3 (1 equiv.),
in the presence of 5.4 equiv. 12, at 1608, 3 min.
formation could be performed with catalytic amounts of the guanidinium salts
(0.1 equiv.) in the absence of any solvent (Table 5, Entries 1 – 5). It turned out that the
reactions could be run under thermal (Table 5, Entries 1, 4, and 5) as well as microwave
conditions (Table 5, Entries 2 and 3). In addition, the chemical yields as well as the
endo/exo ratios depend on the reaction temperature. It should also be emphasized that
no cycloadducts 4 were formed, when the microwave-assisted reaction between 1, 2,
und 3 was run in the absence of an ionic liquid (Table 5, Entry 6). These results
underline that ionic liquids cannot only be used as solvents but can also be employed as
catalysts for this chemical transformation.
Table 5. Influence of Catalytic Amounts (0.1 equiv.) of 12g and 12p on the Synthesis of 4a/4ba)
Entry
Ionic liquid
Reaction conditions
Yield 4 [%]
4a (endo)/4b (exo)
1
2
3
4
5
6
12g
12g
12p
12g
12p
–
1608, 3 min
36
64
86
72
97
–
35 : 65
79 : 21
79 : 21
81 : 19
88 : 12
–
Microwave, 708, 40 min
Microwave, 708, 40 min
708, 40 min
708, 40 min
Microwave, 708, 5 min
a) The reactions were performed in sealed vials. Conditions: 1 (1.2 equiv.) þ 2 (2 equiv.) þ 3 (1 equiv.),
in the presence of 0.1 equiv. 12g or 12p.
And finally, it was demonstrated that guanidinium salts can be used for several
successive cycles with comparable yields and diastereoselectivities, and without
significant loss of catalytic activity (Table 6). The results presented here clearly
demonstrate the potential of guanidinium salts as solvents and catalysts for the aza-
DielsꢀAlder reaction.
The structures of isomers 4a and 4b were elucidated by mass spectrometry and
1
NMR-spectroscopic methods, including H,13C-COSY, HSQC, and HMBC experi-
ments. The relative configurations of the products were established based on the

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Table 6. Recycling and Reuse of Guanidinium Salt 12pa)
No. of runs
1st
2nd
3rd
4th
Yield [%]
70
65
75
74
endo/exo
82 : 18
80 : 20
83 : 17
81 : 19
a) The reactions were performed in sealed vials. Conditions: 1 (1.2 equiv.) þ 2 (2 equiv.) þ 3 (1 equiv.),
in the presence of 5.4 equiv. 12p, at 1608, 3 min.
coupling constants between HꢀC(3a) and HꢀC(4). In 4a (endo), the vicinal coupling
constant J(3a,4) amounts to 3.2 Hz and is significantly smaller than the corresponding
coupling constant in 4b (exo), which amounts to 10.9 Hz (Fig.).
Figure. Structures of the endo-Isomer 4a and the exo-Isomer 4b
Conclusions. – In summary, it has been demonstrated that the three-component
reaction between aniline, benzaldehyde, and 2,3-dihydrofuran can be catalyzed by ionic
liquids such as imidazolium and guanidinium salts under thermal as well as under
microwave conditions. The chemical yield as well as the diastereoselectivity of the one-
pot aza-DielsꢀAlder reaction strongly depend on the ionic liquid employed. The
guanidinium salts can be used for several successive cycles without significant loss of
yield, diastereoselectivity, and loss of activity.
We thank Drs. A. Job and R. Krahwinkel (Saltigo GmbH), Prof. Dr. W. Kantlehner, and Drs. B. Iliev
and U. Jꢁger (Hochschule Aalen), as well as Dr. L. Gharnati and Prof. Dr. M. Dçring (Forschungszen-
trum Karlsruhe) for guanidinium salts. We thank Dr. H. Leutbecher for recording mass spectra, and Ms. S.
Mika for recording NMR spectra. Financial support by the BMBF (01R105181) is greatly acknowledged.
Experimental Part
General. Aniline was distilled from KOH, benzaldehyde from MgSO4, and 2,3-dihydrofuran from
CaH2. Cyclopentadiene was obtained by heating dicyclopentadiene. Reactions were performed using a
DiscoverTM Explorer microwave synthesizer (CEM Corp.), producing continuous irradiation at
2450 MHz. All experiments were conducted under Ar. TLC: TLC aluminum roll silica gel 60 F254
(Merck); visualization with UV light (l 254 nm). M.p.: Kofler apparatus (Reichert, Austria);
uncorrected. UV Spectra: Varian Cary 50; l in nm (log e). IR Spectra: Spectrum One FT-IR
Spectrometer (Perkin Elmer); ˜n in cmꢀ1. NMR Spectra: in CDCl3 on 300- and 500-MHz spectrometers;
the chemical shifts referenced to residual solvent signals at d(H) 7.26 and d(C) 77 ppm relative to TMS; d
in ppm, J in Hz. MS: MAT95 at 70 eV; m/z.

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General Procedure for the Three-Component Reaction between Aniline (1), 2,3-Dihydrofuran (2),
and Benzaldehyde (3). 1.2 Equiv. of 1 (0.6 mmol), 2.0 equiv. of 2 (1 mmol), 1.0 equiv. of 3 (0.5 mmol),
and 5.4 equiv. of a guanidinium salt 12 (2.7 mmol) were placed in a 10-ml microwave reaction vial that
had been heated and cooled under Ar. The vial was sealed with a septum and heated in an oil bath at 1608
for 3 min. After completion of the reaction (TLC), the mixture was allowed to cool to r.t. and extracted
with Et2O (5 ꢁ 5 ml). The combined extracts were concentrated in vacuo and the resulting crude product
was purified by flash chromatography (FC; SiO2; CH2Cl2/petroleum ether (PE) 10 :3) to afford a mixture
of the furoquinolines, 4a/4b, in anal. pure form (for the ratio of 4a/4b, see Table 4).
(3aRS,4RS,9bRS)-2,3,3a,4,5,9b-Hexahydro-4-phenylfuro[3,2-c]quinoline (4a). Rf (PE/AcOEt 8 :2)
0.48. M.p. 98 – 1008. 1H-NMR (500 MHz): 1.53 (dd, J ¼ 11.7, 6.8, 1 HꢀC(3)); 2.22 (dd, J ¼ 11.8, 9.5,
1 HꢀC(3)); 2.80 (dddd, J ¼ 9.4, 8.0, 7.0, 3.2, HꢀC(3a)); 3.70 – 3.75 (m, 1 HꢀC(2)); 3.80 – 3.86 (m,
1 HꢀC(2)); 3.84 (br. s, NH); 4.71 (d, J ¼ 3.2, HꢀC(4)); 5.29 (d, J ¼ 8.0, HꢀC(9b)); 6.61 (dd, J ¼ 7.9, 0.7,
HꢀC(6)); 6.82 (ddd, J ¼ 7.5, 7.5, 1.0, HꢀC(8)); 7.10 (ddd, J ¼ 7.6, 6.9, 1.5, HꢀC(7)); 7.30 – 7.34 (m,
HꢀC(4’)); 7.36 (d, J ¼ 7.4, HꢀC(9)); 7.38 – 7.42 (m, HꢀC(3’), HꢀC(5’)); 7.46 – 7.49 (m, HꢀC(2’), HꢀC(6’)).
13C-NMR (125 MHz): 24.6 (C(3)); 45.8 (C(3a)); 57.5 (C(4)); 66.8 (C(2)); 75.9 (C(9b)); 114.9 (C(6));
119.2 (C(8)); 122.7 (C(9a)); 126.5 (C(2’), C(6’)); 127.6 (C(4’)); 128.3 (C(7)); 128.6 (C(3’), C(5’)); 130.1
(C(9)); 142.2 (C(1’)); 144.9 (C(5a)). EI-MS: 251 (75, Mþ), 232 (36), 218 (82), 206 (100), 174 (31), 146
(19), 130 (29), 115 (30), 91 (45), 77 (42), 65 (17), 51 (26).
(3aRS,4SR,9bRS)-2,3,3a,4,5,9b-Hexahydro-4-phenylfuro[3,2-c]quinoline (4b). Rf (PE/AcOEt 8 :2)
0.41. 1H-NMR (500 MHz): 1.73 (dd, J ¼ 13.5, 1.0, 1 HꢀC(3)); 2.02 (dd, J ¼ 13.1, 7.5, 1 HꢀC(3)); 2.47
(dddd, J ¼ 10.9, 7.6, 5.1, 1.0, HꢀC(3a)); 3.81 (d, J ¼ 10.9, HꢀC(4)); 3.82 – 3.87 (m, 1 HꢀC(2)); 4.01 – 4.07
(m, 1 HꢀC(2)); 4.14 (br. s, NH); 4.61 (d, J ¼ 5.1, HꢀC(9b)); 6.63 (dd, J ¼ 8.1, 0.7, HꢀC(6)); 6.81 (ddd, J ¼
7.5, 7.5, 1.1, HꢀC(8)); 7.13 (ddd, J ¼ 7.8, 7.8, 1.5, HꢀC(7)); 7.33 – 7.37 (m, HꢀC(4’)); 7.38 – 7.41 (m,
HꢀC(3’), HꢀC(5’)); 7.39 – 7.42 (m, HꢀC(9)); 7.44 – 7.46 (m, HꢀC(2’), HꢀC(6’)). 13C-NMR (125 MHz):
28.8 (C(3)); 43.4 (C(3a)); 57.8 (C(4)); 65.2 (C(2)); 76.2 (C(9b)); 114.7 (C(6)); 118.4 (C(8)); 120.0
(C(9a)); 128.1 (C(4’)); 128.3 (C(2’), C(6’)); 128.7 (C(3’), C(5’)); 128.9 (C(7)); 131.2 (C(9)); 141.7 (C(1’));
145.4 (C(5a)). EI-MS: 251 (85, Mþ), 220 (17), 206 (100), 182 (27), 174 (18), 144 (16), 130 (18), 115 (15),
91 (29), 77 (16).
Three-Component Reaction between 1, Ethyl Vinyl Ether (5), and 3. A mixture of 1 equiv. of 1
(1 mmol), 2 equiv. of 5 (2 mmol), and 1 equiv. of 3 (1 mmol) in 5.4 equiv. of [bmim]BF4 (5.4 mmol) was
stirred under Ar at r.t. for 20 h. After completion of the reaction (TLC), the mixture was extracted with
tBuOMe (6 ꢁ 7 ml). The combined org. phases were washed with NaCl soln. (3 ꢁ 10 ml), dried
(Na2SO4), and concentrated in vacuo. The resulting crude product was purified by prep. layer
chromatography (SiO2; PE/acetone 100 :1) to afford 8a.
(2RS,4RS)-4-Ethoxy-1,2,3,4-tetrahydro-2-phenylquinoline (8a). Rf (PE/TBME 10 :1) 0.51. M.p. 76 –
788. UV (MeCN): 207 (4.15), 255 (4.20), 322 (3.49). IR (ATR): 2923, 1597, 1553, 1507, 1489, 1446, 1422,
1319, 1283, 1124, 1023, 828, 792, 730, 689. 1H-NMR (300 MHz): 1.26 (t, J ¼ 6.9, Me); 2.08 (ddd, J ¼ 11.5,
11.5, 11.5, HaxꢀC(3)); 2.42 (ddd, J ¼ 12.3, 5.6, 5.6, HeqꢀC(3)); 3.58 (dq, J ¼ 9.2, 7.0, OCH2); 3.94 (br. s,
NH); 4.54 (dd, J ¼ 11.5, 2.5, HꢀC(2)); 4.82 (dd, J ¼ 10.5, 5.6, HꢀC(4)); 6.50 – 6.55 (m, HꢀC(8)); 6.72 –
6.79 (m, HꢀC(6)); 7.03 – 7.10 (m, HꢀC(7)); 7.27 – 7.49 (m, HꢀC(5), 5 arom. H). 13C-NMR (75 MHz):
15.6 (Me); 37.1 (C(3)); 55.9 (C(2)); 63.5 (OCH2); 74.0 (C(4)); 114.0 (C(8)); 117.8 (C(6)); 122.6 (C(4a));
126.6 (C(2’), C(6’)); 127.2 (C(5)); 127.8 (C(4’)); 128.2 (C(7)); 128.7 (C(3’), C(5’)); 143.7 (C(2’)); 144.6
(C(8a)). EI-MS: 253 (<1, Mþ), 205 (100), 176 (7), 149 (6), 128 (2), 102.5 (10), 102 (18), 88 (5), 57 (3), 28
(24).
Three-Component Reaction between 1, 2,3-Dihydropyran (6), and 3. A mixture of 1 equiv. of 1
(1 mmol), 2 equiv. of 6 (2 mmol), 1 equiv. of 3 (1 mmol), and 4 equiv. anh. CaSO4 (4 mmol) in 5.4 equiv.
of [bmim]BF4 (5.4 mmol) was stirred under Ar at r.t. for 6 d. After completion of the reaction (TLC),
t
the mixture was extracted with BuOMe (7 ꢁ 7 ml). The combined org. phases were washed with NaCl
soln. (3 ꢁ 10 ml), dried (Na2SO4), and concentrated in vacuo. The resulting crude product was purified
by FC (SiO2; PE/AcOEt 40 :1) to afford 9a.
(4aRS,5RS,10bRS)-3,4,4a,5,6,10b-Hexahydro-5-phenyl-2H-pyrano[3,2-c]quinoline (9a). Rf (PE/
AcOEt 8 :2) 0.48. M.p. 126 – 1288. UV (MeCN): 214 (4.33), 249 (4.00), 304 (3.34). IR (ATR): 3330,
2942, 1606, 1482, 1352, 1317, 1273, 1144, 1084, 1071, 1033, 970, 929, 840, 774, 700, 704. 1H-NMR

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Helvetica Chimica Acta – Vol. 96 (2013)
(500 MHz): 1.29 – 1.34 (m, HꢀC(4)); 1.40 – 1.49 (m, HꢀC(3)); 1.50 – 1.60 (m, HꢀC(4)); 1.50 – 1.60 (m,
HꢀC(3)); 2.13 – 2.22 (m, HꢀC(4a)); 3.44 (dt, J ¼ 11.4, 2.1, HaxꢀC(1)); 3.60 (ddt, J ¼ 11.4, 4.0, 1.5,
HeqꢀC(2)); 3.88 (br. s, NH); 4.70 (d, J ¼ 2.3, HꢀC(5)); 5.34 (d, J ¼ 5.6, HꢀC(10b)); 6.61 (dd, J ¼ 7.7, 1.2,
HꢀC(7)); 6.80 (ddd, J ¼ 7.4, 7.4, 1.2, HꢀC(9)); 7.10 (dddd, J ¼ 8.0, 7.4, 1.6, 0.8, HꢀC(8)); 7.31 (br. t, J ¼ 7.2,
HꢀC(4’)); 7.39 (br. t, J ¼ 7.8, HꢀC(3’), HꢀC(5’)); 7.42 (br. d, J ¼ 7.2, HꢀC(2’), HꢀC(6’)); 7.44 (ddd, J ¼ 7.5,
1.6, 0.8, HꢀC(10)). 13C-NMR (125 MHz): 18.0 (C(4)); 25.4 (C(3)); 38.9 (C(4a)); 59.3 (C(5)); 60.6 (C(2));
72.8 (C(10b)); 114.4 (C(7)); 118.3 (C(9)); 119.9 (C(10a)); 126.8 (C(2’), C(6’)); 127.5 (C(4’)); 127.6
(C(10)); 128.1 (C(8)); 128.4 (C(3’), C(5’)); 141.1 (C(1’)); 145.2 (C(6a)). HR-EI-MS: 265.1481 (Mþ,
C18H19NOþ; calc. 265.1461).
Three-Component Reaction between 1, Cyclopentadiene (7), and 3. A mixture of 1.2 equiv. of 1
(1.2 mmol), 2 equiv. of 7 (2 mmol), 1 equiv. of 3 (1 mmol), and 4 equiv. of anh. CaSO4 (4 mmol) in
5.4 equiv. of [bmim]BF4 (5.4 mmol) was stirred under Ar at r.t. for 4.5 h. After completion of the reaction
(TLC), the mixture was extracted with tBuOMe (7 ꢁ 7 ml). The combined org. phases were washed with
NaCl soln., dried (Na2SO4), and concentrated in vacuo. First, endo-isomer 10a was separated by
recrystallization of the mixture from MeOH. N-benzylaniline (11) and the exo-isomer 10b were volatile
enough to be separated via bulb-to-bulb distillation. The exo-isomer 10b was obtained in pure form by FC
(SiO2; PE/AcOEt 19 :1) of the distillate.
(3aSR,4RS,9bRS)-3a,4,5,9b-Tetrahydro-4-phenyl-3H-cyclopenta[c]quinoline (10a). Rf (PE/AcOEt
8 :2) 0.60. M.p. 123 – 1258. UV (MeCN): 209 (4.57), 251 (3.85), 298 (3.38). IR (ATR): 3355, 3025, 1605,
1587, 1498, 1474, 1449, 1361, 1286, 1260, 1137, 1110, 1026, 1005, 929, 844, 778, 745, 700. 1H-NMR
(500 MHz): 1.83 (dddd, J ¼ 16.3, 8.7, 2.6, 1.5, HꢀC(3)); 2.66 (dddd, J ¼ 16.4, 9.2, 2.4, 2.4, HꢀC(3)); 3.03
(dddd, J ¼ 9.0, 9.0, 9.0, 3.3, HꢀC(3a)); 3.76 (s, NH); 4.13 (br. d, J ¼ 8.6, HꢀC(9b)); 4.66 (d, J ¼ 3.1,
HꢀC(4)); 5.64 – 5.68 (m, HꢀC(2)); 5.84 – 5.88 (m, HꢀC(1)); 6.64 (d, J ¼ 7.4, HꢀC(6)); 6.77 (ddd, J ¼ 7.3,
7.3, 1.4, HꢀC(8)); 7.00 (ddd, J ¼ 7.7, 7.7, 1.8, HꢀC(7)); 7.08 (ddd, J ¼ 7.6, 1.6, 1.0, HꢀC(9)); 7.29 (t, J ¼ 7.4,
HꢀC(4’)); 7.39 (t, J ¼ 7.4, HꢀC(3’), HꢀC(5’)); 7.45 (d, J ¼ 7.4, HꢀC(2’), HꢀC(6’)). 13C-NMR (125 MHz):
31.5 (C(3)); 46.0 (C(3a)); 46.4 (C(9b)); 58.1 (C(4)); 115.9 (C(6)); 119.2 (C(8)); 126.1 (C(9a)); 126.3
(C(7)); 126.5 (C(2’), C(6’)); 127.2 (C(4’)); 128.5 (C(3’), C(5’)); 129.0 (C(9)); 130.4 (C(2)); 134.0 (C(1));
142.8 (C(1’)); 145.6 (C(5a)). EI-MS: 247 (100, Mþ), 218 (10), 206 (15), 193 (7), 170 (21), 156 (36), 129
(10), 115 (7), 91 (4), 77 (5), 44 (8), 28 (26).
(3aSR,4SR,9bRS)-3a,4,5,9b-Tetrahydro-4-phenyl-3H-cyclopenta[c]quinoline (10b). Rf (PE/AcOEt
8 :2) 0.60. UV (MeCN): 209 (4.50), 251 (3.92), 299 (3.41). IR (ATR): 3368, 3052, 2929, 2847, 1608, 1588,
1495, 1474, 1454, 1421, 1346, 1315, 1296, 1264, 1252, 1173, 1109, 1064, 1029, 923, 871, 807, 747, 717, 701, 669.
1H-NMR (500 MHz): 2.11 (br. d, J ¼ 16.8, HꢀC(3)); 2.46 (dm, J ¼ 16.8, HꢀC(3)); 2.75 (br. ddd, J ¼ 10.5,
7.2, 7.2, HꢀC(3a)); 3.73 (d, J ¼ 10.5, HꢀC(4)); 3.90 (br. s, NH); 4.02 (br. d, J ¼ 7.5, HꢀC(9b)); 5.68 – 5.72
(m, HꢀC(2)); 5.93 – 5.96 (m, HꢀC(1)); 6.58 (dd, J ¼ 8.0, 1.2, HꢀC(6)); 6.79 (ddd, J ¼ 7.4, 7.4, 1.2, HꢀC(8));
7.02 (dddd, J ¼ 8.1, 7.3, 1.6, 0.8, HꢀC(7)); 7.26 (br. d, J ¼ 7.5, HꢀC(9)); 7.31 – 7.35 (m, HꢀC(4’)); 7.36 – 7.40
(m, HꢀC(3’), HꢀC(5’)); 7.41 – 7.44 (m, HꢀC(2’), HꢀC(6’)). 13C-NMR (125 MHz): 35.8 (C(3)); 43.1
(C(3a)); 46.8 (C(9b)); 58.4 (C(4)); 114.8 (C(6)); 118.4 (C(8)); 124.1 (C(9a)); 126.5 (C(7)); 127.8 (C(4’));
128.1 (C(1)); 128.5 (C(2’), C(6’), C(3’), C(5’)); 129.4 (C(9)); 136.1 (C(2)); 142.9 (C(1’)); 145.7 (C(5a)).
N-Benzylaniline (11). Rf (PE/AcOEt 8 :2) 0.60. M.p. 36 – 388. UV (MeCN): 202 (4.48), 248 (4.12),
297 (3.29). IR (ATR): 3417, 3027, 1600, 1508, 1492, 1449, 1429, 1328, 1276, 1180, 1118, 1065, 1027, 984,
1
858, 735, 688. H-NMR (500 MHz): 4.04 (br. s, NH); 4.34 (s, CH2); 6.64 (d, J ¼ 8.6, HꢀC(2), HꢀC(6));
6.70 – 6.74 (m, HꢀC(4)); 7.18 (dd, J ¼ 8.5, 7.4, HꢀC(3), HꢀC(5)); 7.28 (t, J ¼ 7.3, HꢀC(4’)); 7.35 (t, J ¼ 7.4,
HꢀC(3’), HꢀC(5’)); 7.38 (br. d, J ¼ 7.5, HꢀC(2’), HꢀC(6’)). 13C-NMR (125 MHz): 48.3 (C(7’)); 112.8
(C(2), C(6)); 117.6 (C(4)); 127.2 (C(4’)); 127.5 (C(2’), C(6’)); 128.6 (C(3’), C(5’)); 129.3 (C(3), C(5));
139.4 (C(1’)); 148.1 (C(1)).
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Received December 20, 2012