Highly regioselective synthesis of polysubstituted tetrahydroquinolines by an iodine-induced tandem cyclization reaction from propargylic alcohols and amines

Article abstract of DOI:10.1002/asia.201200344

An efficient and rapid synthetic strategy for the naturally occurring polysubstituted tetrahydroquinoline scaffold through an environmentally friendly iodine-induced reaction of propargyl alcohols and aromatic amines is described. The reaction conditions and the scope of the process are examined, and a possible mechanism is proposed (see scheme). Copyright

Full text of DOI:10.1002/asia.201200344

DOI: 10.1002/asia.201200344
Highly Regioselective Synthesis of Polysubstituted Tetrahydroquinolines by
an Iodine-Induced Tandem Cyclization Reaction from Propargylic Alcohols
and Amines
Yu-Ying Ye,[a] Lian-Biao Zhao,[b] Shu-Chun Zhao,[a] Fang Yang,[a] Xue-Yuan Liu,[a] and
Yong-Min Liang*[a]
The tetrahydroquinoline ring system, is a very common
structural motif and is found in numerous biologically active
natural products and pharmacologically relevant therapeutic
agents.[1] Because of the significance of these scaffolds in
drug discovery and medicinal chemistry, the efficient synthe-
sis of tetrahydroquinoline derivatives continues to attract
the interest of synthetic chemists. However, most classical
methods for the synthesis of the complex substituted tetra-
hydroquinolines always need precious metals, high tempera-
tures or prolonged reaction times.[2] To avoid the above limi-
tations, an efficient, convenient, and environmentally friend-
ly method with short reaction times has been developed.
Recently, iodocyclization has emerged as an extremely
useful protocol in the preparation of a variety of five- or six-
membered carbocyclic and heterocyclic ring systems, due to
the efficient, mild and clean reaction conditions.[3–12] Many
important heterocyclic compounds, such as benzo[b]thio-
phenes,[3] benzofurans,[4] 2,3-dihydropyrroles and pyrroles,[5]
furans,[6] indoles,[7] isochromenes,[8] isocoumarins and R-py-
rones,[9] isoquinolines and quinolines,[10] isoxazoles,[11] and
oxazoles,[12] have been synthetized based on this strategy.
Thus, iodine-promoted tandem reactions continue to be an
area of active research in the field of synthetic chemistry.
Herein, we wish to report a simple iodine-induced tandem
cyclization reaction of propargylic alcohols with amines to-
wards the preparation of regioselective 2,2-disubstituted tet-
rahydroquinoline derivatives, which can serve as the struc-
tural basis for progesterone receptor antagonists.[2]
from limited substrates,[13] we found that in the presence of
trace amounts of H+, propargylic alcohols[14] can easily lose
a hydroxy group to afford the intermediate propargyl carbo-
cations. These propargyl carbocations, which may be in equi-
librium with allene cations (Scheme 1a), are good inter-
mediates for a domino cyclization process. Therefore, we hy-
pothesized that propargylic substrate 1 could undergo the
isomerization process in the presence of I2 and then cyclize
to give 3,4-diiodotetrahydroquinoline (Scheme 1b). To our
surprise, the unexpected amination product 2 was generated
in high yield and 3,4-diiodotetrahydroquinoline was not
formed. This reaction employs iodine[15] for the preparation
of the regioselective polysubstituted tetrahydroquinoline de-
rivatives under mild conditions.
In our initial experiments, we treated the mixture of 4-(2-
aminophenyl)-2-methylbut-3-yn-2-ol (1a; 1.0 equiv) with
molecular iodine (1.0 equiv) in wet CH2Cl2 at room temper-
ature. To our delight, the unexpected product 2a was isolat-
ed in 91% yield after 0.5 hours (Table 1, entry 1). The struc-
ture of the product was characterized by spectroscopic anal-
ysis and was further confirmed by X-ray crystal structure
analysis (Figure 1).[16] To improve the reaction efficiency, the
effect of the reaction media was then investigated. Switching
the solvent from CH2Cl2 to CH3OH, 1,2-dichloroethane
(DCE), CH3NO2, CH3CN, tetrahydrofuran (THF), and N,N-
dimethylformamide (DMF) furnished the product in re-
duced yield (Table 1, entries 5–11). Furthermore, the
amount of iodine was investigated in this reaction (Table 1,
entries 2–5). Increasing the amount of I2 to 1.2 equivalents
gave the same yield of 2a (Table 1, entry 2), whereas
1.5 equivalents of I2 gave a slightly decreased yield of 88%
(Table 1, entry 3). When we decreased the amount of I2, we
found that the yields decreased further (Table 1, entries 4
and 5), and no product was observed in the absence of I2
(Table 1, entry 12). After extensive screening, we found that
the optimized reaction conditions for 2a were 1.0 equivalent
of I2 in CH2Cl2 at room temperature.
In a continuation of our ongoing efforts to construct the
complex functionalized heterocyclic structures available
[a] Y.-Y. Ye, Dr. S.-C. Zhao, Dr. F. Yang, X.-Y. Liu,
Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (China)
Fax : (+86)931-8912582
E-mail: liangym@lzu.edu.cn
[b] L.-B. Zhao
In most cases, products having similar structural frame-
works were obtained through alkyne activation with Brønst-
ed acids, iodine, or gold complexes.[17] Therfore, we investi-
gated the reaction in the presence of protic acids such as
AcOH, trifluoroacetic acid (TFA), pyridinium 4-toluenesul-
fonate (PPTS), para-toluenesulfonic acid (p-TsOH), and
College of Natural Sciences
Gansu Agricultural University
Lanzhou 730070 (China)
Fax : (+86)931-7631212
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200344.
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COMMUNICATION
trifluoromethanesulfonic acid
(TfOH) without using iodine
and the experiments indicated
that the desired product can be
obtained in only 20% yield
with PPTS, and trace amounts
of the products were formed in
the presence of other acids
mentioned above. The electro-
philic catalysts, such as AuCl3,
NaAuCl4·2H2O, AuI, AgSbF6,
AgOTf, CuACHTNUTRGNE(UNG OTf)2, and FeCl3
gave the products in trace
amounts, and the desired prod-
uct can be obtained in only
40% yield when using PtCl2 as
the catalyst.
With the optimized condi-
Scheme 1. a) Possible equilibrium. b) Design of the present domino process.
Table 1. Optimization of reaction conditions.[a]
tions in hand, various 4-(2-aminophenyl)-2-methylbut-3- yn-
2-ol derivatives 1a–1i were then subjected to the optimized
conditions, as depicted in Table 2. Thus, the cyclization reac-
tion of 4-(2-aminophenyl)-2-methylbut-3-yn-2-ol derivatives
1a–1i proceeded smoothly to provide the corresponding
products 2a–2i in moderate to excellent yields within
0.5 hours, except for 2e. We first investigated the scope of
the R1 group. It was found that, electron-rich groups showed
slightly better results than those with electron-withdrawing
groups in this cyclization (Table 2, entries 1–4). Substrate 1e
Entry
I2 [equiv]
Solvent[b]
t [h]
Yield [%][c]
1
2
3
4
5
6
7
8
1.0
1.2
1.5
0.8
0.2
1.0
1.0
1.0
1.0
1.0
1.0
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3NO2
THF
CH3OH
DMF
CH3CN
DCE
0.5
0.5
0.5
4
91
91
88
68
20
78
50
86
with
a strong electron-withdrawing gave no reaction
(Table 2, entry 5). Compared with the reaction of substrate
1c, 1d gave a relatively low yield (83%), probably due to
the steric hindrance of the ortho-methyl group (Table 2, en-
tries 3 and 4).
20
0.5
0.5
0.5
0.5
0.5
0.5
20
Furthermore, to expand the scope of this reaction, we also
investigated the influence of alkynols with different R2 and
R3 groups (Table 2, entries 6–9). Substrates such as 1 f and
1g with aromatic groups also gave the corresponding prod-
ucts 2 f and 2g in moderate yield and with only an E confor-
mation (Table 2, entries 6 and 7). When R2 and R3 are cyclo-
alkyl groups, the products are obtained almost exclusively in
one conformation and the six-membered ring alkynol 1i was
formed in higher yield than that of five-membered ring alky-
nol 1h (Table 2, entries 8 and 9), but the reason for the
effect of these substituents is still unclear. According to the
1H NMR data and X-ray diffraction analysis of 2a
(Figure 1), the trans isomers were proven to be the major
products.
9
37
56
10
11
12
84
CH2Cl2
NR[d]
[a] Reaction conditions: 1a (0.40 mmol) and I2 (0.40 mmol, 1.0 equiv) in
CH2Cl2 (4.0 mL) at room temperature. [b] All solvents were wet.
[c] Yield of isolated product. [d] NR=no reaction.
To further expand the scope of the reaction, we investigat-
ed a wide range of aniline derivatives 4 with propargylic al-
cohols 1 in the presence of iodine. To our surprise, when
3.0 equivalents of an aniline derivative were used, the ex-
pected 2,2-disubstituted tetrahydroquinoline derivatives 3
were obtained in moderate to excellent yields, as depicted in
Table 3. The relative configurations of the major isomers
3h, 3i, and 3k were assigned by Nuclear Overhauser Effect
(NOE) analysis.
Figure 1. X-ray structure of 2a.[16]
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Highly Regioselective Synthesis of Polysubstituted Tetrahydroquinolines
Table 2. Synthesis of 2,2-disubstituted-tetrahydroquinoline derivatives
Table 3. Synthesis of 2,2-disubstituted tetrahydroquinoline derivatives
from the propargylic alcohol 1.[a]
from propargylic alcohols 1 and aniline derivatives 4.[a]
Entry
1
4
Product
Yield [%][b] (Z/E)[c]
Entry
1
Substrate
Product
Yield (%)[b] (Z/E)[c]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
R=H
3a
3b
3c
3d
3e
3 f
3g
3h
3i
76 (33:76)
68 (25:75)
73 (13:87)
88 (14:86)
87 (9:91)
83 (<1:99)
92 (<1:99)
78 (<1:99)
66 (<1:99)
2
3
4
5
6
7
8
9
R=2-Me
R=3-Me
R=4-Me
R=2-Cl
R=3-Cl
R=4-Cl
R=4-Br
R=4-OCH3
2a
91
88
96
ACHTUNGTRNE(NUNG 9:91)
2
3
2b
2c
ACHTUNGTRNE(NUNG 23:77)
10
1a
3j
96 (19:81)
AHCTUNGTRENGN(UN 25:75)
11
12
1a
1c
3k
3l
55 (1:99)
78 (9:91)
4
2d
83
ACHTUNGTRNE(NUNG <1:99)
R=H
[a] Reaction conditions: I2 (0.80 mmol, 2.0 equiv) was added to a solution
of 1 (0.20 mmol) and aniline derivative (0.60 mmol, 3.0 equiv) in wet
CH2Cl2 (2.0 mL) at room temperature. [b] Yield of isolated product.
5
6
2e
2 f
NR[d]
1
[c] Determined by H NMR spectroscopy.
trogen double bond with I2 generates intermediate E.[18]
(d) Regioselective intramolecular nucleophilic attack of the
nitrogen of the amino group forms F, which undergoes de-
protonation and protonation to afford the enamine H.
(e) The enamine, which is very unstable immediately isomer-
izes to form I and J (path a). Formation of the trans isomer
J is more likely at room temperature because of steric hin-
drance effects. An alternative mechanism is also possible
(Scheme 2 path b). In the presence of H+, the propargylic
alcohols A generate 3-methyl-1-phenylbut-2-en-1-one K in
situ followed by intramolecular Michael addition to give 2,3-
78
73
ACHTUNGTRNE(NUNG 0:100)
7
2g
ACHTUNGTRNE(NUNG 0:100)
8
9
2h
2i
39
87
ACHTUNGTRNE(NUNG <1:99)
dihydro-2,2-disubstituted-quinolin-4ACTHNUTRGNEUNG
(1H)-one L.[19] Subse-
AHCTUNGTRENGN(UN <1:99)
quently, a condensation reaction of the aniline derivative
with intermediate L gives the products I and J.
[a] Reaction conditions: I2 (0.40 mmol, 1.0 equiv) was added to a solution
of 1 (0.40 mmol) in wet CH2Cl2 (4.0 mL) at room temperature. [b] Yield
of isolated product. [c] Determined by 1H NMR spectroscopy. [d] NR=
no reaction.
In summary, we have developed a versatile, convenient,
and environmentally friendly approach to synthesize 2,2-dis-
ubstituted tetrahydroquinoline by an iodine-induced tandem
cyclization reaction from propargylic alcohols and amines. A
variety of propargylic alcohols and amines are applicable in
this process. In this reaction, the starting materials are readi-
ly available and this reaction proceeds with wide scope
under mild conditions with high efficiency and excellent se-
lectivity. Well tolerated functional groups at different posi-
tions of the substrates are demonstrated. Further investiga-
tions on this iodine-induced cyclization reaction and the ap-
plication of 2,2-disubstituted tetrahydroquinolines are ongo-
ing.
Two mechanisms are plausible for the iodine-induced
tandem cyclization reaction (Scheme 2). Path a: (a) In the
presence of trace amounts of H+, the propargylic alcohols
A easily lose a hydroxy group to afford the intermediate
propargyl carbocations, which may be in equilibrium with
allene cations B. (b) Aniline then subsequently captures the
allene cation to give intermediate C, which loses a proton to
form the intermediate D. (c) Coordination of the carbon–ni-
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COMMUNICATION
Experimental Section
General Procedure for the Synthesis of
2,2-Disubstituted Tetrahydroquinoline
Derivatives
I2 (205.6 mg, 0.40 mmol, 1.0 equiv) was
added to a solution of 1 (0.40 mmol)
in wet CH2Cl2 (4.0 mL) at room tem-
perature. When the reaction was con-
sidered complete as determined by
TLC analysis, the reaction mixture
was quenched by addition of saturated
aqueous sodium thiosulfate and dilut-
ed with CH2Cl2 (40 mL), washed with
water, saturated brine, dried over
Na2SO4, and evaporated under re-
duced pressure. The residue was puri-
fied by chromatography on silica gel
to afford the corresponding N-(2,2-dis-
ubstituted-2,3-dihydroquinolin-4ACTHNUTRGNEUG(N 1H)-
ylidene) aniline compounds 2.
Acknowledgements
We thank the National Science Foun-
dation (NSF-21072080) and the Na-
tional Basic Research Program of
China (973 Program) 2010CB8-33203
for financial support. We also ac-
knowledge support from the “111”
Project.
Keywords: allenes · amines ·
cyclization
·
iodine
·
tetrahydroquinoline
Scheme 2. Proposed reaction mechanism.
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Received: April 16, 2012
Revised: May 9, 2012
Published online: && &&, 0000
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COMMUNICATION
Iodocyclization
Yu-Ying Ye, Lian-Biao Zhao,
Shu-Chun Zhao, Fang Yang,
Xue-Yuan Liu,
Yong-Min Liang*
&&&& — &&&&
Highly Regioselective Synthesis of
Polysubstituted Tetrahydroquinolines
by an Iodine-Induced Tandem Cycliza-
tion Reaction from Propargylic Alco-
hols and Amines
An efficient and rapid synthetic strat-
egy for the naturally occurring poly-
substituted tetrahydroquinoline scaf-
fold through an environmentally
friendly iodine-induced reaction of
propargyl alcohols and aromatic
amines is described. The reaction con-
ditions and the scope of the process
are examined, and a possible mecha-
nism is proposed (see scheme).
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