Reliable Synthesis of Phosphino- and Phosphine Sulfide-1,2,3,4-Tetrahydroquinolines and Phosphine Sulfide Quinolines

Article abstract of DOI:10.1002/ejoc.201700258

The synthesis of phosphino- and phosphine sulfide-1,2,3,4-tetrahydroquinolines and phosphine sulfide quinolines is described. The synthetic route involves a multicomponent reaction of 2-phosphinoaniline or 2-phosphine sulfide-aniline, aldehydes, and styre

Full text of DOI:10.1002/ejoc.201700258

DOI: 10.1002/ejoc.201700258
Full Paper
Phosphorus Quinolines
Reliable Synthesis of Phosphino- and Phosphine Sulfide-1,2,3,4-
Tetrahydroquinolines and Phosphine Sulfide Quinolines
Concepción Alonso,[a] Endika Martín-Encinas,[a] Gloria Rubiales,[a] and Francisco Palacios*[a]
Abstract: The synthesis of phosphino- and phosphine sulfide- phosphine sulfide-1,2,3,4-tetrahydroquinolines and allows for
1,2,3,4-tetrahydroquinolines and phosphine sulfide quinolines the selective generation of two stereogenic centers in a short,
is described. The synthetic route involves a multicomponent efficient, and reliable approach. The selective oxidation of phos-
reaction of 2-phosphinoaniline or 2-phosphine sulfide-aniline, phine sulfide-1,2,3,4-tetrahydroquinolines led to the formation
aldehydes, and styrenes for the preparation of phosphino- or of the phosphine sulfide quinolines.
Introduction
8-phosphinoquinolines I have been prepared in very low yields
(29–36 %), which involved the phosphination of 8-bromoquin-
oline (IIa, X = Br, R = H, Scheme 1a)[11a] or 8-bromo-2-methyl-
Quinoline, a versatile bicyclic scaffold that is present in a large
number of natural products, has a wide variety of therapeutic
properties such as antimicrobial, anti-inflammatory, anti-
diabetic,[1] and anticancer activity.[2] Likewise, the 1,2,3,4-tetra-
hydroquinoline ring system is prevalent in many pharmacologi-
cally active synthetic[3] and natural products.[4] Moreover, or-
ganophosphorus derivatives are interesting compounds from a
biological point of view, as phosphorus substituents may affect
the reactivity of heterocycles and regulate important biological
functions.[5] The incorporation of organophosphorus functional-
ities into simple synthons may provide new strategies for the
preparation of aminophosphonates[6] and phosphorylated aza-
heterocycles.[7] One example is the diphosphonylation of quin-
olines to lead to tetrahydroquinolines.[8]
[13]
quinoline (IIb, X = Br, R = CH3, Scheme 1a) with BuLi/ClPPh2
or the phosphination of quinolyl triflates with PPh3 in the pres-
ence of Pd/C or Pd/Al2O3 as a catalyst to give IIa (X = trifluoro-
methanesulfonate (OTf), R = H, Scheme 1a).[14]
Some quinoline derivatives that contain the phosphine oxide
of a phosphonate group in the 3-position have been previously
reported by our group.[9] However, a phosphino group located
in the 8-position of a quinoline and/or a 1,2,3,4-tetrahydroquin-
oline ring is significant because of its difference in bond
strength as a result of the N–P-donor bonding of the bidentate
hybrid N,P ligands. These substrates combine the favorable in-
fluence of the phosphorus atom on the stability of the catalyst
complex and the stimulating effect of the nitrogen atom on the
catalytic activity. 8-Phosphinoquinolines I (Scheme 1) have
been used not only for the formation of ligands for asymmetric
hydrogenation[10] but also for the formation of Au,[11a] Cu,[11b]
Pd,[11c] Ir,[11d] and Ni complexes[11e] in the hydrogenation of ket-
ones[12a] and/or nitriles,[12b] olefin polymerization,[12c] and cross-
coupling reactions to construct C–C bonds.[12d] Unfortunately,
Scheme 1.
As far as we know, only one example of the corresponding
tetrahydroquinolines such as the 2-alkyl-substituted 8-phos-
phino-1,2,3,4-tetrahydroquinolines have been recently prepared
by the N-carboxy-mediated ortho-lithiation of tetrahydroquin-
olines. Compound IV was employed in a metallation-phos-
phination protocol in the presence of phenyl diphenylphos-
phinite (Scheme 1b) to give the 2-alkyl-substituted product in
moderate yields.[15]
[a] Departamento de Química Orgánica I, Facultad de Farmacia and Centro
de Investigacion Lascaray (Lascaray Research Center), Universidad del País
Vasco/Euskal Herriko Unibertsitatea (UPV/EHU),
Paseo de la Universidad 7, 01006 Vitoria, Spain
E-mail: francisco.palacios@ehu.eus
http://www.ehu.eus/es/web/pfq/hasiera
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700258.
On the basis of these results, the development of highly se-
lective methods to provide efficient access to important mol-
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ecules and prepare phosphino-substituted heterocycles that doublet that corresponds to the methylenic protons at δ =
3
contain a quinolone and/or 1,2,3,4-tetrahydroquinoline skeleton 4.33 ppm with a coupling constant of JH,H = 5.7 Hz, and the
represent an attractive challenge in organic chemistry because 31P NMR spectrum of the same compound has one signal at
of the interest of these molecules in synthetic and medicinal δ = 37.2 ppm. The formation of aminophosphine oxide 6 in-
chemistry. In this context, the hetero-Diels–Alder (HDA) reaction volves the intramolecular addition of phosphine to the imine
is a highly atom-economic alternative for carbon-carbon bond bond of compound 3 to form the phosphazole ring of salt 5.
construction[16] to efficiently generate molecular complexity for The subsequent addition of water gives rise to aminophosphine
industrial applications[17] and is among the most useful ap- oxide 6. Similar behavior has been previously observed when
proach to synthesize six-membered nitrogen heterocycles.[18] phosphinoanilines were treated with pyridine 2-carboxaldehyde
Because multicomponent reactions (MCRs) are widely used in in the presence of Brønsted acids.[25]
medicinal chemistry,[19] the multicomponent version of the Po-
varov reaction[20] (i.e., amine V, aldehyde VI, and alkene VII,
Scheme 1c) has attracted great interest because of its advanta-
ges over classic divergent synthetic strategies.[21] This multi-
component reaction may be considered a powerful tool for the
preparation of quinoline derivatives, in which two or three con-
tiguous stereogenic centers can be generated in a single step
with excellent regioselectivity.
Our research group has previously used different methods
for the synthesis of a wide range of six-membered nitrogen
heterocycles,[22] some of which contained phosphorylated[23] or
fluorinated[24] substituents. Because of the importance of phos-
phine-substituted heterocycles that have a quinoline and/or
1,2,3,4-tetrahydroquinoline ring in medicinal chemistry, their
significance as hybrid bidentade N,P ligands for the formation
of metal complexes, and the preparative limitations of their syn-
thesis,[11–15] a new strategy for the synthesis of these functional-
ized heterocycles is an attractive challenge for chemists. In this
study, we report a new method based on the multicomponent-
modified Povarov reaction for the preparation of phosphoryl-
ated
tetrahydroquinoline
and
quinoline
derivatives
(Scheme 1c). This strategy offers a new route to access un-
known 2,4-disubstituted phosphorylated tetrahydroquinoline
and quinoline compounds and provides control over the stereo-
chemistry at the 2- and 4-positions. A wide variety of products
may be generated because of the broad range of possible alde-
hyde VI and alkene VII substrates, thereby generating potential
biologically active molecules and catalysts with bidentate N,P
ligands.
Scheme 2. Intramolecular cycloaddition of aldimine 3a (MS = molecular
sieves).
The limitations of this approach considerably restrict the
operational simplicity for the preparation of the phosphino-
quinoline derivatives. At this point, we thought that a multi-
component (MCR) protocol may avoid this issue. If the three
components (i.e., amine 1, aldehyde 2, and olefin 4, Scheme 3)
are present in the reaction mixture from the beginning, the
imine, immediately upon formation, could undergo a reaction
with the olefin if not given sufficient time for an intramolecular
reaction to occur. Thus, the corresponding phosphino-1,2,3,4-
tetrahydroquinolines 7 were regioselectively obtained by a mul-
ticomponent reaction of 2-(diphenylphosphino)aniline (1), alde-
hydes 2, and styrenes 3 in the presence of 2 equiv. of BF3·Et2O
in chloroform at reflux over 24 h (Scheme 3, Table 1, Entries 1–
4). According to the NMR analysis of the crude product, we can
assert that under the reaction conditions only the correspond-
ing endo-adducts 7 were stereoselectively obtained, and no sig-
nals that correspond to the exo-adduct were observed (see Sup-
porting Information). Phosphino-1,2,3,4-tetrahydroquinolines 7
were obtained in good yields (Table 1, Entries 1 and 2), whereas
some others were unstable during the purification conditions
and could not be isolated (Table 1, Entries 3 and 4).
Results and Discussion
First, the hetero-Diels–Alder reaction between styrene (4a, R1 =
Ph) and N-(2-diphenylphosphino)aldimine 3a, which was pre-
pared in situ by the reaction of 2-(diphenylphosphino)aniline
(1) and benzaldehyde (2a), in the presence of 2 equiv. of
BF3·Et2O in chloroform at reflux was performed (Scheme 2).
However, aminophosphine oxide 6 was isolated instead of the
expected [4+2] cycloaddition adduct. The progress of the reac-
tion was monitored by 31P NMR spectroscopy, in which the sig-
nal corresponding to aldimine 3a at δ = –13.00 ppm disap-
peared as the appearance of a signal at δ = 39.00 ppm corre-
sponding to phosphonium salt 5 was observed. After a period
of time, this new signal was transformed into another at δ =
37.2 ppm, which corresponds to aminophosphine oxide 6. The
structure of 6 was assigned by 1D and 2D NMR spectroscopic
analysis. Thus, the H NMR spectrum of compound 6 has one compound 7 may be explained by a regio- and stereoselective
The formation of 8-phosphino-1,2,3,4-tetrahydroquinoline
1
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Scheme 3. Multicomponent reaction of amines (i.e., 1 and 10), aldehydes 2, and styrenes 4.
Table 1. Obtained phosphino-1,2,3,4-tetrahydroquinolines 7.
The scope of the reaction was then extended to other alde-
hydes and aromatic olefins that contain electron-donating and
electron-withdrawing groups, including fluorine and trifluoro-
methyl substituents, on the aromatic ring, as several recently
approved drugs contain fluorine in their structure.[26] It is note-
worthy that when olefins that contain substituted aromatic
rings were used, more stable phosphino-1,2,3,4-tetrahydroquin-
olines 7 were obtained and isolated in good yields (Table 1,
Entries 5–9). As far as we know, this strategy represents the
first example for the preparation of disubstituted 8-phosphino-
1,2,3,4-tetrahydroquinolines 7.
Because of highly reactive phosphine group, compounds
7ad and 7ae (Table 1, Entries 3 and 4), which were obtained
from styrene 4a (R1 = Ph), decomposed most likely during the
purification process. In these cases, sulfurization reactions were
performed to transform the phosphorus(III) into phosphorus(V)
derivatives and increase the stability of these heterocyclic com-
pounds. Thus, the crude reaction mixture of compound 7 in
chloroform was treated with 0.28 equiv. of molecular sulfur (S8)
at reflux over 3 h to give the corresponding phosphine sulfide-
1,2,3,4-tetrahydroquinolines 8 (Scheme 3, Table 2).
Entry
Product
R
R1
Yield [%][a]
1
2
3
4
5
6
7
8
9
7aa
7ab
7ad
7ae
7ba
7bb
7ca
7cc
Ph
Ph
Ph
Ph
Ph
69
65
4-CF3C6H4
4-MeOC6H4
4-NO2C6H4
Ph
4-CF3C6H4
Ph
[b]
–
–
[b]
4-FC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
69
56
68
71
72
4-FC6H4
4-CH3OC6H4
7cd
[a] Isolated yields are provided. [b] Product was not isolated but used in next
transformation.
[4+2] cycloaddition reaction between aldimine 3, which was
generated by the condensation reaction of phosphinoamine 1
and aldehyde 2, and styrene 4 followed by a prototropic tau-
tomerization.
The structures of compounds 7 were assigned by 1D and 2D
1
NMR spectroscopy. Characteristic signals in the H NMR spec-
trum of compound 7aa (R = Ph, R1 = Ph) include the doublet
3
of doublet at δ = 4.17 ppm that has coupling constants JH,H
=
Table 2. Phosphine sulfide-1,2,3,4-tetrahydroquinolines 8 and phosphine sulf-
ide quinolines 9 obtained from amines 1 and 10.
3
12.1 Hz and JH,H = 4.1 Hz and corresponds to the proton at
the 2-position of the quinoline ring, one multiplet at δ = 3.66–
3.61 ppm that corresponds to the proton at the 4-position, one
double triplet at δ = 2.00 ppm that has coupling constants
Entry Product
R
R1
% Yield
8
9
1
2
3
4
5
6
7
8
8aa/9aa Ph
Ph
Ph
Ph
Ph
80[a] (76)[b] 9[a] (–)
61[a] (77)[b] – (–)
3
3JH,H = 12.1 Hz and JH,H = 4.1 Hz and corresponds to one of
8ab
8ad
8ae
4-CF3C6H4
4-MeOC6H4
4-NO2C6H4
the methylenic protons at the 3-position, and a quadruplet at
90[a]
95[a]
–
–
3
δ = 1.86 ppm that has a coupling constant JH,H = 4.1 Hz and
8ba/9ba Ph
4-FC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
44[a] (40)[b] 23[a] (36)[b]
corresponds to the other methylenic proton at the 3-position.
The regio- and stereochemistry of compounds 7 were estab-
lished by comparing their data with previously obtained re-
sults.[22b] Moreover, the HMBC spectra were in accordance with
the assigned regiochemistry, and the spectral data of NOESY-
1D experiments were consistent with the relative cis configura-
tion of the protons at the 2- and 4-positions (see Supporting
Information).
8bb
4-CF3C6H4
59[a]
–
8ca
Ph
56[a] (67)[b] – (–)
8cc/9cc
4-FC6H4
48[a] (56)[b] 33[a] (30)[b]
[a] Isolated yields obtained from amine 1. [b] Isolated yields obtained from
amine 10.
For example, the formation of compound 8aa was deter-
mined by 31P NMR spectroscopy, in which the signal of the
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phosphine group of compound 7aa at δ = 29.72 ppm disap-
All attempts, however, of the selective oxidation of the
peared as we observed the appearance of another signal at δ = 1,2,3,4-tetrahydroquinoline ring of 8-phosphino-1,2,3,4-tetra-
40.28 ppm, which corresponds to the phosphine sulfide group hydroquinolines 7 by using treatments such as H2O2 at room
of derivative 8aa. In this case, the analysis of the 31P NMR spec- temperature over 72 h, DDQ in acetonitrile under microwave
trum of the crude reaction mixture also shows an additional irradiation, and 2 equiv. of 2-iodoxybenzoic acid/tetra-n-butyl-
signal that corresponds to compound 9aa (Scheme 3, Table 2, ammonium fluoride (IBX/TBAF) in acetonitrile at room tempera-
Entry 1), the formation of which could be justified by the de- ture did not give the corresponding quinolines 11, and decom-
hydrogenation of compound 8aa under the reaction conditions position products were obtained. Most likely, this was a result
to generate the quinoline ring system. An extension of this of the higher reactivity of the phosphorus(III) compound. When
method to the other phosphino-1,2,3,4-tetrahydroquinolines 7 8-phosphino-1,2,3,4-tetrahydroquinolines 7 were treated with
gave the corresponding phosphine sulfide-1,2,3,4-tetrahydro- the oxidants, several secondary compounds were obtained.
quinolines 8 (Scheme 3, Table 2, Entries 2–8).
Finally, the desulfurization of phosphine sulfide-quinolines 9
to give 8-phosphinoquinolines 11 was explored. Unfortunately,
upon treatment with 1 equiv. of HSiCl3 in toluene, treatment
with 1.2 equiv. of Si2Cl6 in benzene at reflux, or carrying out
the reaction in a sealed tube, no conversion was observed, and
the starting materials were recovered. When the process was
performed with 1 equiv. of LiAlH4 in tetrahydrofuran (THF), de-
composition products were detected by 31P NMR spectroscopic
analysis of the reaction mixture.
Next, we explored whether the phosphine sulfide-1,2,3,4-
tetrahydroquinolines 8 may be directly obtained by employing
phosphine sulfide amine 10 in a multicomponent protocol. In
this case, the three components [i.e., phosphine sulfide amine
10 (X = S), aldehyde 2, and olefin 4, Scheme 3] were combined
in chloroform from the beginning in the presence of a Lewis
acid (BF3·Et2O) at reflux over 24 h, and the corresponding endo-
phosphine sulfide-1,2,3,4-tetrahydroquinolines 8 were regio-
selectively obtained (Scheme 3, Table 2). As above, the forma-
tion of the 8-phosphine sulfide-1,2,3,4-tetrahydroquinolines 8
may be explained by a regio- and stereoselective [4+2] cyclo-
addition reaction between aldimine 3 (X = S), initially generated
by the condensation reaction of phosphine sulfide amine 10
and aldehyde 2, and styrene 4 followed by a prototropic tau-
tomerization. The structures of compounds 8 were in agree-
ment with those previously obtained by sulfurization of phos-
phino-1,2,3,4-tetrahydroquinolines 7 (Scheme 3) using molec-
ular sulfur (S8). These methods represent the first example for
the preparation of disubstituted phosphine sulfide-1,2,3,4-tetra-
hydroquinolines 8.
Conclusions
In summary, the first report of the Povarov reaction for the
synthesis of 1,2,3,4-tetrahydroquinolines and quinolines that
contain a phosphorus substituent involves the multicomponent
reaction of phosphinoanilines, aldehydes, and styrenes. This ap-
proach offers a new strategy for the preparation of bidentate
hybrid N,P ligands such as disubstituted 8-phosphine-1,2,3,4-
tetrahydroquinolines. The subsequent sulfurization of these
functionalized heterocycles can provide access to the corre-
sponding phosphine sulfide 1,2,3,4-tetrahydroquinolines. These
derivative can not only be directly obtained from multicompo-
nent reactions between anilines that have a phosphine sulfide
substituent, aldehydes, and styrenes but can also be used as
the starting material for the preparation of 8-phosphine sulfide-
quinolines.
From a synthetic point of view, the value of these ap-
proaches is not only in its great simplicity, as a multicomponent
process, but also in its considerable potential to form phosphor-
ylated heterocycles. These compounds have not yet been re-
ported to date and contribute to the introduction of structural
diversity at different positions of the resulting scaffold, depend-
ing on the starting amines and commercially available aromatic
aldehydes and olefins. This method allows for the preparation
of quinolines that have a phosphorylated substituent in the
structure. These derivatives are interesting in terms of the bio-
logical activity as phosphorylated heterocycles are present in
compounds that have very interesting biological properties.
To confirm the formation of phosphine sulfide-1,2,3,4-tetra-
hydroquinolines 9, which are a minor product of the sulfur-
ization reaction of heterocycles 8, the phosphine sulfide-1,2,3,4-
tetrahydroquinolines 8 were treated under microwave irradia-
tion with 1 equiv. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in toluene for 1 h. In this manner, the corresponding
phosphine sulfide-1,2,3,4-quinolines 9 were obtained quantita-
tively (Table 3).
Table 3. Phosphine sulfide quinolines 9 obtained by treatment of compounds
8 with 1 equiv. of DDQ under microwave irradiation.
Entry
Product
R
R1
Yield [%][a]
1
2
3
4
5
9aa
9ab
9ba
9bb
9cc
Ph
4-CF3C6H4
Ph
4-CF3C6H4
4-FC6H4
Ph
Ph
89
61
66
59
72
4-FC6H4
4-FC6H4
4-CH3C6H4
[a] Isolated yields are provided.
Experimental Section
The formation of compound 9aa (R = Ph) was determined
by its 31P NMR spectrum, in which the signal at δ = 40.28 ppm,
which corresponds to tetrahydroquinoline 8aa, disappeared as
the appearance of another signal at δ = 44.40 ppm was ob-
served. This strategy represents the first example of the prepa-
ration of 8-phosphine sulfide-quinolines 9.
General Methods: All reagents from commercial suppliers were
used without further purification. All solvents were freshly distilled
from appropriate drying agents before use. All other reagents were
recrystallized or distilled when necessary. Reactions were per-
formed under dry nitrogen. Analytical TLC was performed with silica
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gel 60 F254 plates. Visualization of the developed plates was
achieved under UV light. Column chromatography was carried out
on silica gel 60 (230–400 mesh, ASTM) or neutral alumina (70–
290 mesh, ASTM). Melting points were determined with a digital
BF3·Et2O (3.691 mL, 30 mmol, 3 equiv.) in CHCl3 (25 mL) in the
presence of molecular sieves (4 Å) was stirred and heated at reflux
until TLC, 1H NMR, and 31P NMR analyses indicated the consump-
tion of the starting materials. The molecular sieves were removed
melting point apparatus. The NMR spectroscopic data were re- by filtration, and the resulting solution was diluted with dichloro-
corded at 25 °C with 300 and 400 MHz spectrometers. Chemical methane (50 mL). This solution was washed with NaOH (2 aque-
shifts for 1H NMR spectra are reported in ppm downfield from TMS.
ous solution, 50mL) and water (50mL) and then extracted with di-
Chemical shifts for 13C NMR spectra are recorded in ppm relative to chloromethane (2 × 20mL). The combined organic extracts were
M
internal chloroform (δ = 77.2 ppm for CDCl3), and the chemical
shifts for 19F NMR are reported in ppm downfield from fluorotri-
chloromethane (CFCl3). Coupling constants are reported in Hertz.
The abbreviations m (multiplet), s (singlet), d (doublet), t (triplet), q
(quartet), and br. (broad) were used to report the multiplicity of the
NMR signals. The 13C and 19F NMR spectra were broadband decou-
pled from the hydrogen nuclei. Mass spectrometry was carried out
by electron impact (EI) at an ionizing voltage of 70 eV or by chemi-
cal ionization (CI). High resolution mass spectrometry was per-
formed by positive ion electrospray ionization using a Q-TOF (Q =
quadrupole) mass spectrometer. 2-(diphenylphosphino)aniline (1)
was prepared as previously described.[27]
dried with MgSO4. After filtration, the removal of solvent under vac-
uum led to an oil. This crude product was purified by flash column
chromatography on silica gel (gradient of 10 to 40 % ethyl acetate
in hexane) to afford compound 7.
8-(Diphenylphosphino)-2,4-diphenyl-1,2,3,4-tetrahydroquinol-
ine (7aa): The general procedure was employed by using benzalde-
hyde (1.016 mL, 10 mmol) and compound 4a (2.291 mL, 20 mmol)
for 48 h, which afforded 7aa (3.240 g, 69 % yield) as a white solid;
1
m.p. 110–111 °C (ethyl acetate/hexane). H NMR (300 MHz, CDCl3):
3
2
3
δ = 1.86 (ddd, JH,H = 13 Hz, JH,H = 13 Hz, JH,H = 13 Hz, 1 H, CH2),
3
3
1.97–2.04 (m, 1 H, CH2), 3.63 (dd, JH,H = 3.5 Hz, JH,H = 13 Hz, 1 H,
3
3
CH), 3.90–3.92 (m, 1 H, NH), 4.17 (dd, JH,H = 4.1 Hz, JH,H = 13 Hz,
1 H, CH), 6.49–7.53 (m, 23 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
δ = 45.4 (CH), 61.3 (CH2), 61.9 (CH), 117.4 (d, 3JC,P = 13.1 Hz, HCarom),
N-Benzylidene-2-(diphenylphosphino)aniline (3a): To a solution
of 2-(diphenylphosphino)aniline (1, 2.773 g, 10 mmol) in CHCl3
(30 mL) were added benzaldehyde (1.016 mL, 10 mmol) and trifluo-
roacetic acid (3 drops) in the presence of molecular sieves (4 Å).
The mixture was stirred at reflux for 16 h. Compound 3a was unsta-
ble during distillation and/or chromatography, and thus was used
without purification in the following reactions. 1H NMR (300 MHz,
CDCl3): δ = 6.61–7.44 (m, 17 H, Harom), 7.62–7.71 (m, 2 H, Harom), 8.16
(d, 1 H, Himine) ppm. 31P NMR (120 MHz, CDCl3): δ = –13.21 ppm.
1
120.4 (d, JC,P = 106 Hz, Carom), 126.3–128.4 (m, 14 HCarom), 130.8–
3
131.7 (m, 8 HCarom), 134.9 (d, JC,P = 20 Hz, Carom), 136.4 (Carom),
139.1 (Carom), 143.2 (1JC,P = 72 Hz, 2 Carom), 153.9 (d, JC,P = 3.4 Hz,
2
C
arom) ppm. 31P NMR (120 MHz, CDCl3): δ = 31.03 ppm. HRMS (EI):
calcd. for C33H28NP [M]+ 469.1959; found 469.1954.
8-(Diphenylphosphino)-4-phenyl-2-(4-trifluoromethylphenyl)-
1,2,3,4-tetrahydroquinoline (7ab): The general procedure was
employed by using 4-trifluoromethylbenzaldehyde (1.365 mL,
10 mmol) and compound 4a (2.291 mL, 20 mmol) for 48 h, which
afforded 7ab (3.494 g, 65 % yield) as a white solid; m.p. 114–115 °C
(ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ = 1.72 (ddd,
3JH,H = 12.6 Hz, 2JH,H = 12.6 Hz, 3JH,H = 12.6 Hz, 1 H, CH2), 2.12–2.17
(m, 1 H, CH2), 4.15 (dd, 3JH,H = 3.4 Hz, 3JH,H = 12.6 Hz, 1 H, HC), 4.69
2-(Benzylamino)phenyldiphenylphosphine Oxide (6): Benzalde-
hyde (1.016 mL, 10 mmol) and BF3·Et2O (2.461 mL, 20 mmol,
2 equiv.) were added to a solution of the in situ prepared N-benzyl-
idene-2-(diphenylphosphino)aniline (3a, 10 mmol) in CHCl3 (25 mL).
The mixture was stirred at reflux for 12 h. The reaction mixture was
washed with NaOH (2
M aqueous solution, 50 mL) and water
3
3
(50 mL) and then extracted with dichloromethane (2 × 25 mL). The
combined organic extracts were dried with anhydrous MgSO4. After
filtration, the solvent was removed under vacuum to afford an oil.
The crude oil was purified by silica gel flash column chromatogra-
(dd, JH,H = 4.4 Hz, JH,H = 12.6 Hz, 1 H, HC), 7.02–7.69 (m, 22 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 45.2 (CH), 61.6 (CH2),
62.7 (CH), 119.2 (d, 3JC,P = 15.1 Hz, HCarom), 120.4 (d, 1JC,P = 106 Hz,
1
Carom), 124.3 (q, JC,F = 270 Hz, CF3), 125.3–137.2 (m, 22 HCarom and
1
4 Carom), 143.2 (3JC,P = 22.4 Hz, Carom), 146.8 (Carom), 153.3
(Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 31.03 ppm. 19F NMR
(282 MHz, CDCl3): δ = –62.80 ppm. HRMS (EI): calcd. for C34H27F3NP
[M]+ 537.1833; found 537.1828.
phy to afford product 6. H NMR (300 MHz, CDCl3): δ = 4.39 (s, 1 H,
2
NH), 4.43 (d, JH,H = 5.7 Hz, 2 H, CH2), 6.39–7.64 (m, 19 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 46.7 (CH2), 111.8 (d,
1
2JC,P = 8.7 Hz, HCarom), 112.5 (d, JC,P = 107.7 Hz, Carom), 115.9 (d,
3JC,P = 13.2 Hz, HCarom), 120.6 (HCarom), 125.6–134.0 (m, 16 HCarom
and 2 Carom), 143.7 (HCarom), 152.7 (d, 2JC,P = 4.4 Hz, Carom) ppm. 31
NMR (120 MHz, CDCl3): δ = 37.4 ppm.
P
8-(Diphenylphosphino)-2-(4-methoxylphenyl)-4-phenyl-1,2,3,4-
tetrahydroquinoline (7ad): The general procedure was employed
by using 4-methoxybenzaldehyde (1.219 mL, 10 mmol) and com-
pound 4a (2.291 mL, 20 mmol) for 48 h, which afforded 7ad. This
compound was unstable and, thus, not isolated. It was used directly
in the subsequent reactions.
(2-Aminophenyl)diphenylphosphine Sulfide (10): To a solution
of N-benzylidene-2-(diphenylphosphino)aniline (3a, 2.773 g,
10 mmol) in toluene (30 mL) was added molecular sulfur (S8,
0.0072 g, 0.28 mmol). The mixture was stirred at room temperature
for 48 h. Removal of solvent under vacuum led to a solid that was
purified by flash column chromatography on silica gel. 1H NMR
(300 MHz, CDCl3): δ = 4.94 (s, 2 H, NH2), 6.48–7.89 (m, 14 H,
8-(Diphenylphosphino)-2-(4-nitrophenyl)-4-phenyl-1,2,3,4-
tetrahydroquinoline (7ae): The general procedure was employed
by using 4-nitrobenzaldehyde (1.511 g, 10 mmol) and compound
4a (2.291 mL, 20 mmol) for 48 h, which afforded 7ae. This com-
pound was unstable and, thus, not isolated. It was used directly in
the subsequent reactions.
1
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 112.7 (d, JC,P = 87.7 Hz,
3
3
Carom), 117.5 (d, JC,P = 12.3 Hz, HCarom), 117.8 (d, JC,P = 7.9 Hz,
2
HCarom), 128.7–133.5 (m, 12 HCarom and 2 Carom), 151.03 (d, JC,P
=
4.9 Hz, Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.7 ppm. HRMS
8-(Diphenylphosphino)-4-(4-fluorophenyl)-2-phenyl-1,2,3,4-
tetrahydroquinoline (7ba): The general procedure was employed
by using benzaldehyde (1.016 mL, 10 mmol) and compound 4b
(2.292 mL, 20 mmol) for 48 h, which afforded 7ba (3.3612 g, 69 %
yield) as a white solid; m.p. 115–117 °C (ethyl acetate/hexane). 1H
(EI): calcd. for C25H22NOP [M]+ 383.1439; found 383.1453.
Multicomponent Povarov Reaction – General Procedure for the
Preparation of Phosphino-1,2,3,4-tetrahydroquinolines 7: A
mixture of 2-(diphenylphosphino)aniline (1, 2.773 g, 10 mmol),
freshly distilled aldehyde (10 mmol), styrene 4 (20 mmol), and
NMR (300 MHz, CDCl3): δ = 1.81–2.12 (m, 2 H, CH2), 3.73 (dd, 3JH,H
=
Eur. J. Org. Chem. 2017, 2916–2924
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2920 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
3.4 Hz, JH,H = 12.5 Hz, 1 H, HC), 4.04–4.12 (m, 1 H, NH), 4.25 (dd,
(75 MHz, CDCl3): δ = 21.4 (CH3), 45.0 (CH), 55.5 (OCH3), 61.1 (CH2),
3JH,H = 4.3 Hz, JH,H = 12.5 Hz, 1 H, HC), 6.48–7.87 (m, 22 H,
61.5 (CH), 114.0 (2 HCarom), 118.0 (d, JC,P = 13.5 Hz, HCarom), 120.4
3
3
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 44.3 (CH), 61.3 (CH2), (d, JC,P = 103 Hz, Carom), 126.6–143.2 (m, 18 HCarom and 6 Carom),
1
61.9 (CH), 115.5 (d, 2JC,F = 21.4 Hz, 2 HCarom), 118.2 (d, 3JC,P = 12.8 Hz,
154.3 (d, 3JC,P = 3.4 Hz, Carom), 158.6 (Carom) ppm. 31P NMR (120 MHz,
CDCl3): δ = 30.4 ppm. HRMS (EI): calcd. for C35H32NOP [M]+
513.2222; found 513.2231.
2
HCarom), 120.0–142.4 (m, 19 HCarom, and 6 Carom), 153.9 (d, JC,P
=
3.4 Hz, Carom), 161.6 (d, JC,F = 245.5 Hz, FCarom) ppm. 31P NMR
(120 MHz, CDCl3): δ = 30.6 ppm. 19F NMR (282 MHz, CDCl3): δ =
–116.1 ppm. HRMS (EI): calcd. for C33H27FNP [M]+ 487.1865; found
487.1859.
1
General Procedure A – Preparation of 8-(Diphenylphosphine-
sulfide)-1,2,3,4-tetrahydroquinolines 8: To a solution of phos-
phino-1,2,3,4-tetrahydroquinoline 7 (1 mmol) in CHCl3 (7 mL) was
added molecular sulfur (S8, 0.0072 g, 0.028 mmol). The mixture was
stirred and heated at reflux until TLC, 1H NMR, and 31P NMR analyses
indicated the consumption of starting materials. The removal of
8-(Diphenylphosphino)-4-(4-fluorophenyl)-2-(4-trifluoromethyl-
phenyl)-1,2,3,4-tetrahydroquinoline (7bb): The general proce-
dure was employed by using 4-trifluoromethylbenzaldehyde
(1.365 mL, 10 mmol) and compound 4b (2.292 mL, 20 mmol) for solvent under vacuum led to an oil, which was purified by flash
48 h, which afforded 7bb (3.111 g, 56 % yield) as a white solid; m.p.
245–246 °C (ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ =
1.87 (ddd, 3JH,H = 12.6 Hz, 2JH,H = 12.6 Hz, 3JH,H = 12.6 Hz, 1 H, CH2),
column chromatography on silica gel to afford compound 8.
General Procedure B (Povarov Reaction) – Preparation of 8-(Di-
phenylphosphinesulfide)-1,2,3,4-tetrahydroquinolines 8: A mix-
ture of 2-aminophenyldiphenylphosphine sulfide 10 (3.094 g,
10 mmol), the freshly distilled aldehyde (10 mmol), styrene 4
(20 mmol), and BF3·Et2O (3.691 mL, 30 mmol, 3 equiv.) in CHCl3
(25 mL) in the presence of molecular sieves (4 Å) was stirred and
3
3
2.12–2.20 (m, 1 H, CH2), 3.74 (dd, JH,H = 3.2 Hz, JH,H = 12.6 Hz, 1
3
3
H, HC), 4.12–4.20 (m, 1 H, NH), 4.29 (dd, JH,H = 4.4 Hz, JH,H
=
12.6 Hz, 1 H, HC), 6.71–7.82. (m, 21 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 44.3 (CH), 61.3 (CH2), 62.4 (CH), 115.7 (d, 2JC,F = 21.3 Hz,
2 HCarom), 119.2–138.4 (m, 21 HCarom, CF3, and 3 Carom), 143.0 (2
1
heated at reflux until TLC, H NMR, and 31P NMR analyses indicated
1
Carom), 146.5 (Carom), 153.4 (Carom), 162.3 (d, JC,F = 245.6 Hz,
the consumption of starting materials. The molecular sieves were
removed by filtration, and the resulting solution was diluted with
dichloromethane (50 mL). This solution was washed with NaOH (2
FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 30.9 ppm. 19F NMR
(282 MHz, CDCl3): δ = –115.8, –62.8 ppm. HRMS (EI): calcd. for
C34H26F4NP [M]+ 555.1739; found 555.1743.
M
aqueous solution, 50 mL) and water (50 mL) and then extracted
8-(Diphenylphosphino)-4-(4-methylphenyl)-2-phenyl-1,2,3,4- with dichloromethane (2 × 20 mL). The combined organic extracts
tetrahydroquinoline (7ca): The general procedure was employed
by using benzaldehyde (1.016 mL, 10 mmol) and compound 4c
were dried with MgSO4. After filtration, the removal of solvent un-
der vacuum led to an oil, which was purified by flash column chro-
(2.640 mL, 20 mmol) for 48 h, which afforded 7ca (3.285 g, 68 % matography on silica gel to afford compound 8.
yield) as a white solid; m.p. 129–131 °C (ethyl acetate/hexane). 1H
8-(Diphenylphosphinosulfide)-2,4-bis(phenyl)-1,2,3,4-tetra-
NMR (300 MHz, CDCl3): δ = 1.92–2.43 (m, 5 H, CH2 and CH3), 3.74
hydroquinoline (8aa): General procedure A was employed by us-
ing 7aa (0.469 g, 1 mmol) for a reaction time of 48 h to afford a
mixture of compounds 8aa (0.401 g, 80 % yield) and 9aa (0.044 g,
9 % yield) as white solids. General procedure B was employed by
using benzaldehyde (1.016 mL, 10 mmol) and compound 4a
(2.291 mL, 20 mmol) for a reaction time of 48 h to give 8aa (3.805 g,
3
(dd, 3JH,H = 3.4 Hz, JH,H = 12.3 Hz, 1 H, HC), 3.95–4.15 (m, 1 H, NH),
3
3
4.31 (dd, JH,H = 4.3 Hz, JH,H = 12.3 Hz, 1 H, HC), 6.60–7.86 (m, 22
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 44.9 (CH),
3
61.6 (CH2), 62.3 (CH), 118.2 (d, JC,P = 13.8 Hz, HCarom), 120.7 (d,
1JC,P = 106.3 Hz, Carom), 126.3–137.7 (m, 20 HCarom and 3 Carom),
139.5 (HCarom), 140.5 (Carom), 142.9 (2 Carom), 154.3 (d, 2JC,P = 3.4 Hz,
Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 30.7 ppm. HRMS (EI):
calcd. for C34H30NP [M]+ 483.2116; found 483.2124.
76 % yield); m.p. 102–103 °C (ethyl acetate/hexane). 1H NMR
3
(300 MHz, CDCl3): δ = 1.95–2.23 (m, 3 H, NH, CH2), 4.27 (dd, JH,H
=
=
3
3
3
4.7 Hz, JH,H = 12.6 Hz, 1 H, CH), 4.74 (dd, JH,H = 3.5 Hz, JH,H
8-(Diphenylphosphino)-2-(4-fluorophenyl)-4-(4-methylphenyl)-
1,2,3,4-tetrahydroquinoline (7cc): The general procedure was em-
ployed by using 4-fluorobenzaldehyde (1.072 mL, 10 mmol) and
compound 4c (2.640 mL, 20 mmol) for 48 h, which afforded 7cc
(3.558 g, 71 % yield) as a white solid; m.p. 126–127 °C (ethyl acetate/
12.6 Hz, 1 H, CH), 6.34–8.04 (m, 23 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 41.4 (CH2), 45.1 (CH), 57.04 (CH), 111.6 (d, 1JC,P = 88.2 Hz,
3
Carom), 115.5 (d, JC,P = 13.2 Hz, HCarom), 120.6 (Carom), 126.0–132.9
(m, 22 HCarom and 2 Carom), 143.9 (Carom), 144.5 (Carom), 148.4 (d,
2JC,P = 5.6 Hz, Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.3 ppm.
HRMS (EI): calcd. for C33H28NPS [M]+ 501.1680; found 501.1671. See
below for data of compound 9aa.
1
hexane). H NMR (300 MHz, CDCl3): δ = 1.85–2.42 (m, 5 H, CH2 and
3
3
CH3), 3.69 (dd, JH,H = 3.5 Hz, JH,H = 12.5 Hz, 1 H, HC), 4.01–4.07
(m, 1 H, NH), 4.22 (dd, 3JH,H = 4.2 Hz, 3JH,H = 12.5 Hz, 1 H, HC), 6.59–
7.87 (m, 21 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3),
8-(Diphenylphosphinosulfide)-4-phenyl-2-(4-trifluoromethyl-
phenyl)-1,2,3,4-tetrahydroquinoline (8ab): General procedure A
was employed by using a solution of 7ab (0.538 g, 1 mmol) for a
reaction time of 48 h to afford 8ab (0.347 g, 61 % yield) as a white
solid. General procedure B was employed by using 4-trifluorometh-
ylbenzaldehyde (1.365 mL) and compound 4a (2.291 mL, 20 mmol)
for a reaction time of 48 h to afford 8ab (4.386 g, 77 % yield); m.p.
141–142 °C (ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ =
1.51–2.53 (m, 2 H, CH2), 2.91–3.08 (m, 1 H, NH), 4.44–4.62 (m, 1 H,
CH), 4.86–4.98 (m, 1 H, CH), 6.53–7.96 (m, 22 H, Harom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 40.7 (CH2), 45.9 (CH), 55.9 (CH), 114.1 (d,
1JC,P = 87.1 Hz, Carom), 117.5 (d, 3JC,P = 13.5 Hz, HCarom), 121.7–134.2
(m, CF3, 21 HCarom and 3 Carom), 142.7–147.6 (m, 4 Carom) ppm. 31P
2
44.9 (CH), 61.0 (CH2), 61.7(CH), 115.4 (d, JC,F = 21.1 Hz, 2 HCarom),
3
1
118.6 (d, JC,P = 13.6 Hz, HCarom), 120.6 (d, JC,P = 102.7 Hz, Carom),
2
127.8–142.8 (m, 18 HCarom and 5 Carom), 153.8 (d, JC,P = 3.4 Hz,
Carom), 162.3 (d, JC,F = 244.8 Hz, FCarom) ppm. 31P NMR (120 MHz,
1
CDCl3): δ = 30.6 ppm. 19F NMR (282 MHz, CDCl3): δ = –116.0 ppm.
HRMS (EI): calcd. for C34H29FNP [M]+ 501.2022; found 501.2024.
8-(Diphenylphosphino)-2-(4-methoxyphenyl)-4-(4-methyl-
phenyl)-1,2,3,4-tetrahydroquinoline (7cd): The general proce-
dure was employed by using 4-methoxybenzaldehyde (1.219 mL,
10 mmol) and compound 4c (2.640 mL, 20 mmol) for 48 h, which
afforded 7cd (3.698 g, 72 % yield) as a white solid; m.p. 102–103 °C
(ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ = 1.92–2.52 (m, NMR (120 MHz, CDCl3): δ = 40.1 ppm. 19F NMR (282 MHz, CDCl3):
5 H, CH2 and CH3), 3.82 (s, 3 H, OCH3), 3.94–4.14 (m, 2 H, NH, CH),
δ = –62.8 ppm. HRMS (EI): calcd. for C34H27F3NPS [M]+ 569.1554;
4.27–4.39 (m, 1 H, CH), 6.53–7.99 (m, 21 H, Harom) ppm. 13C NMR found 569.1563.
Eur. J. Org. Chem. 2017, 2916–2924
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
8-(Diphenylphosphinosulfide)-2-(4-methoxyphenyl)-4-phenyl-
8-(Diphenylphosphinosulfide)-4-(4-methylphenyl)-2-phenyl-
1,2,3,4-tetrahydroquinoline (8ad): General procedure A was em-
1,2,3,4-tetrahydroquinoline (8ca): General procedure A was em-
ployed by using a solution of 7ad (0.499 g, 1 mmol) for a reaction ployed by using a solution of 7ca (0.483 g, 1 mmol) for a reaction
time of 48 h to afford 8ad (0.478 g, 90 % yield) as a white solid; time of 48 h to afford 8ca (0.288 g, 56 % yield) as a white solid;
m.p. 81–82 °C (ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ = m.p. 135–136 °C (ethyl acetate/hexane). General procedure B was
1.81 (ddd, 3JH,H = 12.7 Hz, 3JH,H = 12.7 Hz, 2JH,H = 12.7 Hz, 1 H, CH2),
employed by using benzaldehyde (1.016 mL, 10 mmol) and com-
3
2.17–2.21 (m, 1 H, CH2), 3.67 (br. s, 4 H, OCH3, NH), 4.26 (dd, JH,H
=
=
pound 4c (2.640 mL, 20 mmol) for a reaction time of 48 h to afford
3
3
3
1
4.4 Hz, JH,H = 12.7 Hz, 1 H, CH), 4.66 (dd, JH,H = 3.2 Hz, JH,H
8ca (3.446 g, 67 % yield). H NMR (300 MHz, CDCl3): δ = 1.68–2.60
12.7 Hz, 1 H, CH), 6.30–6.81 (m, 6 H, Harom), 6.14–7.97 (m, 16 H,
(m, 6 H, CH3, CH2, NH), 4.12–4.36 (m, 1 H, CH), 4.62–4.76 (m, 1 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.3 (CH2), 44.9 (CH), CH), 6.12–8.08 (m, 21 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
1
2
55.3 (OCH3), 56.3 (CH), 111.5 (d, JC,P = 88.2 Hz, Carom), 113.8 (2
21.1 (CH3), 41.3 (CH2), 44.5 (CH), 57.0 (CH), 112.5 (d, JC,P = 8.0 Hz,
HCarom), 115.2 (d, 3JC,P = 13.5 Hz, HCarom), 126.4–133.9 (m, 19 HCarom HCarom), 112.6 (d, JC,P = 88.9 Hz, Carom), 116.2 (d, JC,P = 12.0 Hz,
1
3
2
and 2 Carom), 135.7 (Carom), 144.4 (Carom), 148.4 (d, JC,P = 3.5 Hz,
Carom), 158.8 (Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.2 ppm.
HRMS (EI): calcd. for C34H30NOPS [M]+ 531.1786; found 531.1792.
HCarom), 125.9–133.7 (m, 20 HCarom and 2 Carom), 138.7 (Carom), 139.5
2
(Carom), 141.2 (Carom), 143.6 (Carom), 148.4 (Carom), 150.1 (d, JC,P
=
5.7 Hz, Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.2 ppm. HRMS
(EI): calcd. for C34H30NPS [M]+ 515.1837; found 515.1841.
8-(Diphenylphosphinosulfide)-2-(4-nitrophenyl)-4-phenyl-
1,2,3,4-tetrahydroquinoline (8ae): General procedure A was em-
ployed by using a solution of 7ae (0.514 g, 1 mmol) for a reaction
time of 48 h to afford 8ae (0.519 g, 95 % yield) as a white solid;
8-(Diphenylphosphinosulfide)-2-(4-fluorophenyl)-4-(4-methyl-
phenyl)-1,2,3,4-tetrahydroquinoline (8cc): General procedure A
was employed by using a solution of 7cc (0.501 g, 1 mmol) for a
reaction time of 48 h to afford a mixture of compounds 8cc
(0.256 g, 48 % yield) and 9cc (0.175 g, 33 % yield) as white solids.
General procedure B was employed by using 4-fluorobenzaldehyde
(1.072 mL, 10 mmol) and compound 4c (2.640 mL, 20 mmol) for
are reaction time of 48 h to give a mixture of compounds 8cc
(2.987 g, 56 % yield) and 9cc (1.590 g, 30 % yield). Data for com-
pound 8cc: M.p. 112–114 °C (ethyl acetate/hexane). 1H NMR
(300 MHz, CDCl3): δ = 1.22–2.39 (m, 6 H, CH3, CH2, NH), 4.16–4.27
(m, 1 H, CH), 4.79–4.89 (m, 1 H, CH), 6.36–8.09 (m, 21 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 41.3 (CH2), 44.7 (CH), 56.5
1
m.p. 129–131 °C (ethyl acetate/hexane). H NMR (300 MHz, CDCl3):
δ = 1.79–2.47 (m, 3 H, NH and CH2), 4.19–4.36 (m, 1 H, CH), 4.74–
4.89 (m, 1 H, CH), 6.57–8.25 (m, 22 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 41.4 (CH2), 44.7 (CH), 56.4 (CH), 112.6 (d, 1JC,P = 84.8 Hz,
3
Carom), 116.4 (d, JC,P = 13.5 Hz, HCarom), 123.9 (2 HCarom), 125.9–
133.5 (m, 19 HCarom and 3 Carom), 143.8 (Carom), 146.0 (Carom), 148.4
2
(d, JC,P = 3.5 Hz, Carom), 151.6 (Carom) ppm. 31P NMR (120 MHz,
CDCl3): δ = 40.2 ppm. HRMS (EI): calcd. for C33H27N2O2PS [M]+
546.1531; found 546.1563.
1
(CH), 111.8 (d, JC,P = 87.3 Hz, Carom), 114.7–115.5 (m, 3 HCarom),
126.5–133.7 (m, 18 HCarom and 3 Carom), 136.6 (Carom), 139.5 (Carom),
8-(Diphenylphosphinosulfide)-4-(4-fluorophenyl)-2-phenyl-
1,2,3,4-tetrahydroquinoline (8ba): General procedure A was em-
ployed by using a solution of 7ba (0.487 g, 1 mmol) for a reaction
time of 48 h to afford a mixture of compounds 8ba (0.226 g, 44 %
yield) and 9ba (0.116 g, 23 % yield) as white solids. General proce-
dure B was employed by using benzaldehyde (1.016 mL, 10 mmol)
and compound 4b (2.292 mL, 20 mmol) for a reaction time of 48 h
to give a mixture of compounds 8ba (2.078 g, 40 % yield) and 9ba
(1.857 g, 36 % yield). Data for 8ba: M.p. 102–103 °C (ethyl acetate/
2
1
141.2 (Carom), 148.2 (d, JC,P = 3.4 Hz, Carom), 162.1 (d, JC,F
=
245.7 Hz, FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.3 ppm.
19F NMR (282 MHz, CDCl3): δ = –112.2 ppm. HRMS (EI): calcd. for
C34H29FNPS [M]+ 533.1742; found 533.1745. See below for data of
compound 9cc.
General Procedure for the Preparation of 8-(Diphenylphos-
phanyl)quinolines 9 by Dehydrogenation with DDQ: To a solu-
tion of the corresponding tetrahydroquinoline 8 (1 mmol) in tolu-
ene (20 mL) was added DDQ (0.3269 g, 1.2 mmol), and the mixture
was irradiated in a microwave at 150 W and 40 °C for 1 h. The
resulting solid was removed by filtration, and the solvent of the
filtrate was removed under vacuum to lead to an oil. The crude oil
was purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:20) to afford compound 9.
1
hexane). H NMR (300 MHz, CDCl3): δ = 1.74–2.36 (m, 3 H, NH and
CH2), 4.10–4.26 (m, 1 H, CH), 4.58–4.68 (m, 1 H, CH), 6.57–8.25 (m,
22 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.5 (CH2), 44.0
1
(CH), 56.6 (CH), 111.8 (d, JC,P = 86.2 Hz, Carom), 114.7–115.5 (m, 3
HCarom), 125.7–133.4 (m, 19 HCarom and 2 Carom), 143.4 (Carom), 146.4
2
1
(Carom), 148.1 (d, JC,P = 3.4 Hz, Carom), 161.5 (d, JC,F = 245.8 Hz,
FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.2 ppm. 19F NMR
(282 MHz, CDCl3): δ = –116.9 ppm. HRMS (EI): calcd. for C33H27FNPS
[M]+ 519.1586; found 519.1583. See below for data of compound
9ba.
8-(Diphenylphosphinosulfide)-2,4-bis(phenyl)quinoline (9aa):
The general procedure was employed with a solution of 8aa
(0.502 g, 1 mmol) to afford 9aa (0.445 g, 89 % yield) as a white
solid; m.p. 104–105 °C (ethyl acetate/hexane). 1H NMR (300 MHz,
CDCl3): δ = 7.24–8.25 (m, 23 H, Harom), 8.58–8.72 (m, 1 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 119.6 (HCarom), 126.1 (d,
8-(Diphenylphosphinosulfide)-4-(4-fluorophenyl)-2-(4-trifluoro-
methylphenyl)-1,2,3,4-tetrahydroquinoline (8bb): General proce-
dure A was employed by using a solution of 7bb (0.555 g, 1 mmol)
for a reaction time of 48 h to afford 8bb (0.346 g, 59 % yield) as a
white solid; m.p. 97–98 °C (ethyl acetate/hexane). 1H NMR (300 MHz,
CDCl3): δ = 1.74–2.42 (m, 3 H, NH and CH2), 4.21–437 (m, 1 H, CH),
4.69–4.83 (m, 1 H, CH), 6.13–8.05 (m, 21 H, Harom) ppm. 13C NMR
3
3JC,P = 14.4 Hz, HCarom), 126.4 (d, JC,P = 6.6 Hz, Carom), 127.9–132.6
1
(m, 21 HCarom and 2 Carom), 134.5 (d, JC,P = 90 Hz, Carom), 138.3
2
(Carom), 138.6 (Carom), 138.9 (d, JC,P = 11.5 Hz, HCarom), 147.7 (d,
2JC,P = 4.5 Hz, Carom), 149.9 (Carom), 155.7 (Carom) ppm. 31P NMR
(120 MHz, CDCl3): δ = 44.4 ppm. HRMS (EI): calcd. for C33H24NPS
[M]+ 497.1377; found 497.1381.
(75 MHz, CDCl3): δ = 41.3 (CH2), 44.1 (CH), 56.5 (CH), 112.5 (d, 1JC,P
=
87.6 Hz, Carom), 115–116.1 (m, 3 HCarom), 122.5–133.2 (m, CF3, 18
2
HCarom, and 4 Carom), 139.8 (Carom), 141.8 (q, JC,F = 38.1 Hz, Carom),
8-(Diphenylphosphinosulfide)-4-phenyl-2-(4-trifluoromethyl-
phenyl)quinoline (9ab): The general procedure was employed
with a solution of 8ab (0.569 g, 1 mmol) to afford 9ab (0.345 g,
61 % yield) as a white solid; m.p. 123–124 °C (ethyl acetate/hexane).
1H NMR (300 MHz, CDCl3): δ = 7.12–8.33 (m, 22 H, Harom), 8.34–8.52
2
1
146.3 (Carom), 148.1 (d, JC,P = 3.5 Hz, Carom), 161.9 (d, JC,F
=
245.2 Hz, FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 40.2 ppm.
19F NMR (282 MHz, CDCl3): δ = –62.8 (CF3), –116.2 (CF) ppm. HRMS
(EI): calcd. for C34H26F4NPS [M]+ 587.1460; found 587.14587.
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(m, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 119.5 (HCarom),
124.2 (q, JC,F = 233.1 Hz, F3C), 125.7–133.7 (m, 21 HCarom and 3
Sustainable Chem. Eng. 2016, 4, 4064–4078; c) H. Yang, H. Zhang, C. Yang,
Y. Chen, Chem. Biodiversity 2016, 13, 807–820; d) E. Vessally, L. Edjlali, A.
Hosseinian, A. Bekhradnia, M. D. Esrafili, RSC Adv. 2016, 6, 49730–49746.
[2] D. Jhanwar, J. Sharma, Int. J. Pharm. Res. Bio-Sci. 2015, 4, 130–148.
[3] For an excellent review, see: V. Sridharan, P. A. Suryavanshi, J. C. Menen-
dez, Chem. Rev. 2011, 111, 7157–7259.
[4] For reviews, see: a) J. S. Bello Forero, J. Jones, F. M. da Silva, Curr. Org.
Synth. 2016, 13, 157–175; b) K. Kaur, M. Jain, R. P. Reddy, R. Jain, Eur. J.
Med. Chem. 2010, 45, 3245–3264.
1
Carom), 134.7 (d, 1JC,P = 87.1 Hz, Carom), 137.9 (Carom), 138.7 (d, 2JC,P
=
2
11.2 Hz, HCarom), 142.0 (d, JC,P = 5.1 Hz, Carom), 147.8 (Carom), 150.4
(Carom), 154.1 (Carom) ppm. 31P NMR (120 MHz, CDCl3): δ = 43.9 ppm.
19F NMR (282 MHz, CDCl3): δ = –62.9 (CF3) ppm. HRMS (EI): calcd.
for C33H23F3NPS [M]+ 565.1241; found 565.1238.
8-(Diphenylphosphinosulfide)-4-(4-fluorophenyl)-2-phenyl-
quinoline (9ba): The general procedure was employed with a solu-
tion of 8ba (0.519 g, 1 mmol) to afford 9ba (0.385 g, 66 % yield) as a
[5]
For reviews, see: a) R. Engel (Ed.), Handbook of Organophosphorus Chem-
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Biologically Active Natural Products (Ed.: H. G. Culter), ACS Symposium
Series 380, American Chemical Society, Washington, D.C., 1988, p. 182.
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For excellent reviews, see: a) S. Van der Jeught, C. V. Stevens, Chem. Rev.
2009, 109, 2672–2702; b) K. Moonen, I. Laureyn, C. V. Stevens, Chem. Rev.
2004, 104, 6177–6215.
1
white-green solid; m.p. 112–114 °C (ethyl acetate/hexane). H NMR
(300 MHz, CDCl3): δ = 6.72–8.24 (m, 22 H, Harom), 8.52–8.74 (m, 1 H,
H
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 116.1 (d, 2JC,F = 21.4 Hz,
[6]
[7]
2 HCarom), 119.6 (HCarom), 122.3–133.8 (m, 19 HCarom, 4 Carom), 134.5
1
2
(d, JC,P = 90.1 Hz, Carom), 138.7 (d, JC,P = 11 Hz, HCarom), 141.6
(Carom), 145.7 (Carom), 146.6 (Carom), 148.8 (Carom), 154.8 (Carom), 163.2
1
(d, JC,F = 246.5 Hz, FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ =
[8]
[9]
a) A. De Blieck, K. G. R. Masschelein, F. Dhaene, E. Rozycka-Sokolowska,
B. Marciniak, J. Drabowicz, C. V. Stevens, Chem. Commun. 2010, 46, 258–
260; b) F. E. A. Van Waes, W. Debrouwer, T. S. A. Heugebaert, C. V. Stevens,
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5947–5964; c) F. Palacios, D. Aparicio, J. García, Tetrahedron 1998, 54,
1647–1656.
44.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –113.1 ppm. HRMS (EI):
calcd. for C33H23FNPS [M]+ 515.1273; found 515.1292.
8-(Diphenylphosphinosulfide)-4-(4-fluorophenyl)-2-(4-trifluoro-
methylphenyl)quinoline (9bb): The general procedure was em-
ployed with solution of 8bb (0.587 g, 1 mmol) to afford 9bb
(0.344 g, 59 % yield) as a white-green solid; m.p. 101–102 °C (ethyl
acetate/hexane). 1H NMR (300 MHz, CDCl3): δ = 6.67–8.34 (br. m, 21
H, Harom), 8.39–8.54 (m, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
[10]
[11]
T. Pullmann, B. Engendahl, Z. Zhang, M. Hoelscher, A. Zanotti-Gerosa, A.
Dyke, G. Francio, W. Leitner, Chem. Eur. J. 2010, 16, 7517–7526.
a) L. Huang, F. Rominger, M. Rudolph, A. S. K. Hashmi, Chem. Commun.
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2
δ = 116.1 (d, JC,F = 21.4 Hz, 2 HCarom), 119.5 (HCarom), 122.5–132.8
1
(m, 16 HCarom, 3 Carom, and CF3), 133.9 (Carom), 134.2 (d, JC,P
=
89.9 Hz, Carom), 139.2 (d, 2JC,P = 10.7 Hz, HCarom), 141.8 (Carom), 144.9
1
(Carom), 146.6 (Carom), 148.8 (Carom), 153.7 (Carom), 163.2 (d, JC,F
=
246.5 Hz, FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 43.8 ppm.
19F NMR (282 MHz, CDCl3): δ = –63.0 (CF3) –112.6 (CF) ppm. HRMS
(EI): calcd. for C34H22F4NPS [M]+ 583.1479; found 583.1481.
[12]
a) Y. Y. Li, S. L. Yu, W. Y. Shen, J. X. Gao, Acc. Chem. Res. 2015, 48, 2587–
2598; b) A. Mukherjee, D. Srimani, S. Chakraborty, Y. Ben-David, D. Mil-
stein, J. Am. Chem. Soc. 2015, 137, 8888–8891; c) H. Mu, L. Pan, D. Song,
Y. Li, Chem. Rev. 2015, 115, 12091–12137; d) A. H. Cherney, N. T. Kadunce,
S. E. Reisman, Chem. Rev. 2015, 115, 9587–9652.
8-(Diphenylphosphinosulfide)-2-(4-fluorophenyl)-4-(4-methyl-
phenyl)quinoline (9cc): The general procedure was employed with
solution of 8cc (0.533 g, 1 mmol) to afford 9cc (0.381 g, 72 % yield)
as a white solid; m.p. 112–114 °C (ethyl acetate/hexane). 1H NMR
(300 MHz, CDCl3): δ = 2.48 (s, 3 H, CH3), 6.67–8.14 (m, 21 H, Harom),
8.39–8.54 (m, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6
[13]
[14]
[15]
[16]
[17]
[18]
L. Canovese, F. Visentin, G. Chessa, P. Uguagliati, C. Santo, A. Dolmella,
Organometallics 2005, 24, 3297–3308.
Y. Wang, C. W. Lai, F. Y. Kwong, W. Jia, K. S. Chan, Tetrahedron 2004, 60,
9433–9439.
S. H. Jun, J. H. Park, C. S. Lee, S. Y. Park, M. J. Go, J. Lee, B. Y. Lee, Organo-
metallics 2013, 32, 7357–7365.
K. M. Shea in Name Reactions for Carbocyclic Ring Formations (Ed.: J. J.
Li), Wiley, Hoboken, 2010, pp. 275–308.
2
(CH3), 115.6 (d, JC,F = 22.6 Hz, 2 HCarom), 120.0 (HCarom), 125.7–
1
134.1 (m, 18 HCarom, 4 Carom), 134.5 (d, JC,P = 90 Hz, Carom), 138.6
2
2
(d, JC,P = 11 Hz, HCarom), 139.1 (Carom), 146.7 (d, JC,P = 4.9 Hz,
1
Carom), 147.8 (Carom), 150.1 (Carom), 154.6 (Carom), 164.7 (d, JC,F
=
245.8 Hz, FCarom) ppm. 31P NMR (120 MHz, CDCl3): δ = 44.1 ppm.
19F NMR (282 MHz, CDCl3): δ = –112.3 (CF) ppm. HRMS (EI): calcd.
for C34H25FNPS [M]+ 529.1429; found 529.1443.
J.-A. Funel, S. Abele, Angew. Chem. Int. Ed. 2013, 52, 3822–3863; Angew.
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Acknowledgments
Financial support from the Dirección General de Investigación
del Ministerio de Economía
y Competitividad (MINECO;
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CTQ2015-67871-R) and by Gobierno Vasco/EJ and Universidad
del País Vasco (GV, IT 992-16; UPV) is gratefully acknowledged.
Servicios Generales de Investigación (SGIker;UPV/EHU) technical
support (MINECO, GV/EJ, European Social Fund) is also grate-
fully acknowledged.
[20]
[21]
Keywords: Multicomponent reactions · Nitrogen
heterocycles · Povarov reaction · Phosphorus · Regioselectivity
[22]
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Received: March 1, 2017
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