New types of reactivity of α,β-unsaturated N,N- dimethylhydrazones: Chemodivergent diastereoselective synthesis of functionalized tetrahydroquinolines and hexahydropyrrolo[3,2-b]indoles

Article abstract of DOI:10.1002/chem.201103562

The indium trichloride-catalyzed reaction between aromatic imines and α,β-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl₃ with BF ₃·Et₂O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB′C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation. Copyright

Full text of DOI:10.1002/chem.201103562

DOI: 10.1002/chem.201103562
New Types of Reactivity of a,b-Unsaturated N,N-Dimethylhydrazones:
Chemodivergent Diastereoselective Synthesis of Functionalized
Tetrahydroquinolines and HexahydropyrroloACTHUNRTGNEUNG[3,2-b]indoles
Vellaisamy Sridharan,[a] Pascual Ribelles,[a] Verꢀnica Estꢁvez,[a] Mercedes Villacampa,[a]
M. Teresa Ramos,[a] Paramasivan T. Perumal,[a, b] and J. Carlos Menꢁndez*[a]
Abstract: The indium trichloride-cata-
lyzed reaction between aromatic
imines and a,b-unsaturated N,N-dime-
thylhydrazones in acetonitrile afforded
stitutes the first example of an a,b-un-
saturated dimethylhydrazone that be-
drazone in CHCl3 with BF3·Et2O as
catalyst afforded polysubstituted
1,2,3,3a,4,8b-hexahydropyrrolo[3,2-
b]indoles as major products through
a fully diastereoselective ABB’C four-
component domino process that gener-
ates two cycles, three stereocenters,
haves as
a
dienophile in
a
hetero
ACHTUNGTRENNUNG
Diels–Alder reaction. The related reac-
tion between anilines, aromatic alde-
hydes, and methacrolein dimethylhy-
1,2,3,4-tetrahydroquinolines
a hydrazone function at C4 through
one-pot diastereoselective domino
bearing
a
À
À
process that involves the formation of
two C C bonds, and two C N bonds in
a single operation.
Keywords: domino reactions · het-
erocycles · Lewis acids · multicom-
ponent reactions · stereoselectivity
À
two C C bonds and the controlled gen-
eration of two stereocenters, one of
which is quaternary. This reaction con-
Introduction
an excellent Michael acceptor, the azomethine nitrogen
atom is a good nucleophile, and the C=N double bond can
be cleaved under hydrolytic, oxidative, and reductive condi-
tions to release the free carbonyl group. Finally, the use of
chiral substituents at the nitrogen atom attached to the aza-
diene system allows asymmetric induction in some of the
previously mentioned reactions[4] (Scheme 1).
Chemodivergent reactions are one of the keys for the gener-
ation of molecular diversity and complexity from simple and
inexpensive starting materials. This type of chemistry is one
of the most promising paradigms in the discovery of new
bioactive compounds and has also become one of the main
challenges for organic synthesis.[1] Herein, we present an ex-
ample of chemodivergence associated with the reaction con-
ditions and catalyst in the diastereoselective synthesis of two
classes of synthetically and biologically relevant nitrogen
heterocycles.
a,b-Unsaturated N,N-dialkylhydrazones are versatile
building blocks in organic synthesis that have attracted in-
tense interest recently.[2] The 1-azadiene unit is employed in
hetero Diels–Alder reactions with
a normal electron
Scheme 1. Main types of reactivity of a,b-unsaturated N,N-dialkylhydra-
zones.
demand, thanks to the electron-releasing effect of the dial-
kylamino substituent.[3] Furthermore, the b-carbon atom is
Quinoline and its derivatives are among the most impor-
tant nitrogen heterocycles.[5] 1,2,3,4-Tetrahydroquinolines in
particular show a wide range of interesting biological activi-
ties,[6] and therefore much effort has been devoted to their
preparation.[7] One of the most versatile methods for the
synthesis of 1,2,3,4-tetrahydroquinolines is the Povarov reac-
tion, that is, the formal imino Diels–Alder reaction between
N-arylimines and electron-rich dienophiles in the presence
of Lewis acids.[8] As previously mentioned, a,b-unsaturated
imines can be employed as the diene component in hetero
Diels–Alder reactions with a normal electron demand, thus
leading to pyridine and fused-pyridine derivatives. Because
[a] Dr. V. Sridharan, P. Ribelles, V. Estꢀvez, Prof. M. Villacampa,
Prof. M. T. Ramos, Prof. P. T. Perumal, Prof. J. C. Menꢀndez
Departmento de Quꢁmica Orgꢂnica y Farmacꢀutica
Universidad Complutense
Facultad de Farmacia, 28040 Madrid (Spain)
Fax : (+34)91-3941822
E-mail: josecm@farm.ucm.es
[b] Prof. P. T. Perumal
Organic Chemistry Division
Central Leather Research Institute
Chennai 600 020 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103562.
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Chem. Eur. J. 2012, 18, 5056 – 5063

FULL PAPER
Table 1. Catalyst optimization for the synthesis of 3a.[a]
this type of reaction requires the unsaturated imines to be
electron rich, the imines have to be modified by the intro-
duction of electron-releasing groups on the nitrogen atom,
normally dimethylamino,[9] and in some other cases acetyla-
mino[10] or 1-tert-butyldimethylsilyloxy,[11] substituents to
compensate for the electron-withdrawing effect of the nitro-
gen atom. We reasoned that the same electron-releasing
effect should be expected to increase the electron density of
Entry
Catalyst
Catalyst
t [h]
3a/4a/5a[b]
loading [mol%]
1
2
3
4
5
6
7
8
CAN
5
5
1
24
2
2
1
5
5
3
28:19:53
33:15:52
51:11:38
48:trace:52
46:16:38
47:12:41
28:14:58
33:12:55
Sc
Sc
U
10
10
10
10
10
10
Yb
Dy
Dy
N
À
KHSO4
the C2 C3 bond of the hydrazone sufficiently to allow its
triphenylphosphonium
perchlorate
BF3·Et2O
participation in Povarov-type chemistry. This expectation
was supported by ab initio calculations at the B3LYP-6-
31G* level, which reveal a very similar electron density for
the carbon atoms in this bond and for the C=C bond in
9
10
10
10
1
2
38:15:47
64:5:31
InCl3
[a] Solvent was acetonitrile. [b] Calculated from the 1H NMR spectra of
the crude reaction products. All reactions proceeded in 100% conver-
sion. CAN=cerium(IV) ammonium nitrate, OTf=trifluoromethanesulfo-
nate.
ethyl vinyl ether,
a typical Povarov dienophile (see
Scheme 2 and the Supporting Information). This study re-
quired the prior determination of the conformation of unsa-
turated dimethylhydrazones, which was established to be s-
trans by NOE interaction studies.[12]
at maximizing the yield of tetrahydroquinoline 3 and are
summarized in Table 1. We first studied the effect of other
Lewis acids, such as scandium, ytterbium, and dysprosium
triflates, which all afforded tetrahydroquinoline 3a and 4a
in yields of around 50 and 10–15%, respectively, together
with the transimination product 5 in amounts similar to
those of 3a (Table 1, entries 2–6). These results were not im-
proved in the presence of less conventional catalysts, such as
potassium hydrogen sulfate, triphenylphosphonium perchlo-
rate, or boron trifluoride etherate (Table 1, entries 7–9, re-
spectively). Indium trichloride was the only catalyst that fur-
nished 3a as the major product (Table 1, entry 10). This re-
agent is a mild and water-tolerant Lewis acid that is highly
efficient in activating nitrogen-containing compounds such
as imines and hydrazones[18] and was chosen for further stud-
ies aimed at the synthesis of derivatives of 3.
Scheme 2. a) Comparison of Mulliken atomic charges for 2 and ethyl
vinyl ether. b) Conformational study of 2.
Results and Discussion
We first undertook the study of the reaction between aro-
matic imine 1a and methacrolein dimethylhydrazone (2)
and hoped to use the latter compound as the dienophile
rather than the diene for the first time in an imino Diels–
Alder reaction, which would lead to an aza version of
a type-1 vinylogous Povarov reaction,[13] a previously un-
known transformation.[14] Besides the mechanistic novelty of
this reaction, it would also be synthetically relevant because
it could generate tetrahydroquinolines bearing a functional
group and a quaternary stereocenter at C4. The correspond-
ing, simpler reaction with alkyl vinyl ethers that leads to 4-
alkoxy-2-aryl-1,2,3,4-tetrahydroquinolines has been report-
ed.[15]
Due to our interest in cerium(IV) ammonium nitrate
(CAN) as a catalyst in synthesis,[16,17] we started our investi-
gation by studying the reaction in its presence with acetoni-
trile as the solvent (Table 1, entry 1). Unfortunately, the de-
sired tetrahydroquinoline 3a was obtained only in moderate
yields accompanied by two additional products, namely,
a small amount of an unexpected product, later identified as
indolopyrrole 4a, and benzaldehyde N,N-dimethylhydrazone
(5a), a transimination compound that arises from the ex-
change of the hydrazone unit of 2 and the aldehyde unit of
1, which was isolated as the major product. The results ob-
tained in our optimization study of the reaction were aimed
We briefly examined the model reaction in several sol-
vents with varying polarities to optimize the reaction
medium (Table 2); however, we found no improvement over
the original solvent of acetonitrile, which was employed for
the subsequent reactions directed at the preparation of tet-
rahydroquinolines.
Table 2. Solvent optimization for the synthesis of 3a.[a]
Entry
Solvent
t [h]
3a/4a/5a[b]
1
2
3
4
5
CH3CN
THF
CH2Cl2
CHCl3
EtOH
2
6
6
6
6
64:5:31
0:0:22[c]
27:17:44[d]
38:15:47
51:14:35
[a] Catalyst: 10 mol% InCl3. [b] Calculated from the 1H NMR spectra of
the crude reaction products. All the reactions proceeded with 100% con-
version, except for entries 2 and 3. [c] Compound 1a was recovered in
78% yield. [d] Compound 1a was recovered in 12% yield.
We next examined the scope of the reaction in terms of
the electron density on both aromatic rings by starting from
diarylimines containing both electron-releasing and - with-
drawing groups on both aryl rings (e.g., 1) and compound 2.
Chem. Eur. J. 2012, 18, 5056 – 5063
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5057

J. C. Menꢀndez et al.
Scheme 3. Two- and three-component versions of the reaction between imines (or anilines plus aldehydes) and methacrolein dimethylhydrazone (2).
The main general conclusion that may be obtained from the
data shown in Scheme 3 and Table 3 is that electron-releas-
ing substituents on the imine ring that came from an aryla-
mine diminished the side products, thus leading to excellent
yields of the C4-functionalized tetrahydroquinolines 3. On
the other hand, electron-withdrawing substituents afforded
transimination compounds 5 as the major products. The
nature of the substituents on the ring that came from the ar-
omatic aldehydes affected neither the rate of the reaction
nor the product ratio. In summary, the reaction gave access
to tetrahydroquinolines with combinations of substituents at
all the possible carbon atoms, except C3, and always in fully
diastereoselective fashion regarding the substitution at C2
and C4. We also studied a three-component version of the
reaction and started from anilines 6, aldehydes 7, and unsa-
turated hydrazone 2. This one-pot protocol increased the
yield of 4, but it also increased the amount of undesired 5
(see the second half of Table 3). The use of two equivalents
of the arylamine and changes to the order of reagent addi-
tion did not alter these results significantly.
Some additional reactions were carried out to further
extend the generality of the method, and the products ob-
Table 3. Synthesis of tetrahydroquinolines through two- and three-component InCl3-catalyzed reactions of 2.
Entry Compound R1
R2
R3
R4
R5
Two-component reaction
Three-component reaction
t [h] Yield of 3 [%][a] 3/4/5[b]
t [h] Yield of 3 [%][a] 3/4/5[b]
Conditions[e]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
Me
H
H
H
H
H
H
H
OMe
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Me
Cl
Cl
Me
Cl
OMe
OMe
OMe
Cl
OMe
Me
Br
H
2
2
2
2
2
2
2
2
2
2
2
3
2
3
2
2
2
3
3
5
3
–
5
1.5
2
58
71
90
60[c]
56
80
34
27
71
71
76
87
93
70
51
72
80
79
83
81
80
–
64:5:31
73:9:18
93:0:7
2
2
2
–
2
–
–
2
–
–
2
3
3
2
–
2
–
3
3
5
3
2
5
–
–
37
30
19
–
27
–
–
11
–
41:18:41
35:23:42
23:23:54
–
34:27:39
–
B
B
A
–
A
–
–
A
–
Me
OMe
H
H
Me
F
Cl
H
H
Me
OMe
OMe
H
64:11:25
64:11:25
83:0:17
38:0:62
33:0:67
77:5:18
75:7:18
81:0:19
91:0:9
–
13:0:87
–
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
–
–
40
56
33
64
–
46:16:38
64:7[d]: 29
39:14[d]: 47
71:0:29
–
C
C
A
B
–
95:0:5
75:0:25
57:11:32
78:0:22
86:0:14
87:0:13
88:0:12
87:0:13
88:0:12
–
H
Me
OMe
Me
Me
Me
Me
H
H
NMe2
H
53
–
60:10[d]:30
–
A
–
H
Me
Me
Me
Me
Me
Me
H
73
76
60
72
61
63
–
81:0:19
83:0:17
67:0:33
80:0:20
71:0:29
83:0:17
–
A
B
B
A
B
B
–
s
t
u
v
w
x
y
Cl
H
64
68
72
84:0:16
78:0:22
75:10:15
H
OMe
OMe Me
–
–
–
1
[a] Yield of the isolated product. [b] Calculated from the H NMR spectra of the crude reaction products. All the reactions proceeded with 100% conver-
sion. [c] The imine used for this reaction was 90% pure. [d] In these cases, the minor compound 4 could not be isolated in pure form. [e] See the Experi-
mental Section for details.
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Chem. Eur. J. 2012, 18, 5056 – 5063

Synthesis of Tetrahydroquinolines in a One-Pot Diastereoselective Domino Process
FULL PAPER
terials but contains four different structural units, two of
which come from one component that acts with two differ-
ent chemical roles in a chemodifferentiated fashion. Process-
es of this type have attracted much attention recently be-
cause of their ability to generate molecular diversity and
complexity from a limited number of starting materials.[21] In
an effort to increase the product selectivity in favor of 4, we
employed our previous optimization studies to select
BF3·Et2O/CHCl3 as the most promising catalyst/solvent com-
bination and carried out the reactions using a three-compo-
nent protocol. According to our expectations, the yield of 4
under these conditions rose up to 93%, although they were
still accompanied by transimination products and, in most
cases, by small amounts of the corresponding tetrahydroqui-
nolines (Table 4). In an effort to further optimize the yield
of 4, we reasoned that the formation of these compounds in-
volves an intermolecular nucleophilic attack that competes
with the intramolecular attack, thus leading to 3 (see the
mechanistic proposal in Scheme 5). For this reason, we
hoped that by carrying out the reaction in a more concen-
Scheme 4. Additional examples that increase the scope of the two-com-
ponent tetrahydroquinoline synthesis that use Method A in all cases.
tained are summarized in Scheme 4. These examples, which
were carried out through the two-component protocol, show
that the tetrahydroquinoline synthesis tolerates substituents
other than a methyl group at C4 (i.e., 3z), aromatic substitu-
ents other than a phenyl ring (i.e., 3aa and 3ab), and also
nonaromatic (i.e., 3ac–3ae) and acyl substituents at C2 (i.e.,
3af). Some attempts were made to employ C3-substituted
dimethylhydrazones, thus leading to C3-substituted tetrahy-
droquinolines, although only complex mixtures were ob-
tained.
Table 4. Improved synthesis of 4.[a]
The reaction that leads to 4 is interesting because the
Entry
Cmpd
R2
R3
R4
R5
Yield [%][b]
1,2,3,3a,4,8b-hexahydropyrroloACTHNUGRTNEUNG[3,2-b]indole system is almost
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4k
4o
H
H
H
Me
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Cl
OMe
68
59
58[c]
75
93
38
59
unknown[19] in spite of the considerable synthetic and phar-
macological interest of the regioisomeric hexahydropyrrolo-
Me
OMe
H
H
Me
H
ACHTUNGTRENNUNG[2,3-b]indole species, which is present in a large number of
alkaloids.[20] This transformation is also important because it
can be considered to be one of the very few examples of
a reaction taking place through an ABB’C multicomponent
mechanism. The final product arises from three starting ma-
H
[a] Conditions: CHCl3, BF3·Et2O, RT, 2 h. [b] Yield of isolated products.
[c] Obtained as an approximate 1:1 mixture of diastereomers.
Scheme 5. Mechanistic proposal for the formation of 3 and 4.
Chem. Eur. J. 2012, 18, 5056 – 5063
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5059

J. C. Menꢀndez et al.
trated solution we could achieve better product selectivity in
favor of 4. Although this assumption turned out to be cor-
rect, these conditions had the disadvantage of decreasing
the diastereoselectivity of the process that led to 4 and af-
forded the other possible diastereomers 8, which was shown
by 1H NMR spectroscopic analysis of the crude reaction
mixtures. Although this result was not synthetically useful,
we isolated two of the compounds 8 to fully characterize
them (Scheme 6). This result serves to introduce a note of
Scheme 6. Structure of two examples of derivatives of 8.
caution over the use of highly concentrated conditions in
Lewis acid-catalyzed cyclization reactions due to the possi-
ble loss of diastereoselectivity. It is relevant to mention at
this point that the reaction that started from para-anisidine
also lacked diastereoselectivity, even under the normal dilu-
tion conditions, and afforded an equimolecular mixture of
4c and 8c. The use of a larger excess of aniline was also at-
tempted as a way to increase the yield of 4, but it mainly fa-
vored the transimination reaction.
The structures and relative configurations of 3 and 4 were
determined by spectroscopic analysis combined with single-
crystal X-ray diffraction data (Figure 1). Compounds 3 have
a cis relationship between the C2 hydrogen atom and the C4
methyl group. This relationship was initially established by
NOE interactions studies that showed a correlation peak be-
À
tween the H2 and C4 CH3 signals, which is only consistent
Figure 1. ORTEP plot for compounds 3b (top) and 4e (bottom).
with a cis arrangement for these substituents because both
are axial. Subsequently, this conclusion was confirmed by an
X-ray diffraction study of 3b (Figure 1). Compounds 4 were
also isolated in diastereomerically pure form, and their pro-
posed stereochemistry is based on the NOESY correlations
between the methyl group and the two hydrogen atoms at-
tached to the stereogenic carbon atoms, which was con-
firmed by X-ray diffraction studies of 4e. The most charac-
teristic 1H NMR signals of 4 were the singlet at approxi-
mately d=5.2 ppm due to the 8b proton, and the 13C NMR
signals at approximately d=65, 70, and 75 ppm due to the
three carbon atoms adjacent to the nitrogen atoms.
accept a second arylamine molecule to generate intermedi-
ate B. This attack takes place from the face of the hydra-
zone C=N opposite to the carbon chain containing the aryl
and arylamino substituents, thereby explaining the observed
diastereoselectivity provided that A is in the conformation
shown in Scheme 5, which would be stabilized by intramo-
lecular hydrogen bonding. Indium trichloride activates the
cyclization of B to the pyrrolidine intermediate C, which
subsequently furnishes the observed indolopyrrole 4, pre-
sumably by elimination of a dimethylhydrazine molecule to
give an intermediate iminium cation that finally undergoes
a Friedel–Crafts-type intramolecular cyclization reaction.
The generation of an iminium cation from C should be fa-
vored by the presence of electron-releasing substituents at
the aniline ring and is supported by the observation that 4
was not obtained at all when the reactions were carried out
with aniline compounds bearing electron-withdrawing
groups (Table 1, entry 1 versus entries 7 and 8). The pro-
The mechanism proposed for the formation of 3 and 4 is
summarized in Scheme 5. The Lewis acid-activated imine is
attacked by the electron-rich hydrazone to afford the Mi-
chael acceptor A, which may then undergo a Friedel–Crafts-
type cyclization reaction to afford the Povarov product 3,
which takes place through a chairlike transition state and
leads to a preference for an equatorial arrangement of the
bulky dimethylhydrazono and aryl substituents, thus giving
the observed stereochemistry of 3. Alternatively, A can
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Chem. Eur. J. 2012, 18, 5056 – 5063

Synthesis of Tetrahydroquinolines in a One-Pot Diastereoselective Domino Process
FULL PAPER
posed mechanism is consistent with the fact that ortho-sub-
stituted arylamines failed to give indolopyrroles 4 (Table 3,
entries 6, 14, and 18–23) because the Michael addition of ar-
ylamines to the corresponding intermediates A is sterically
hindered. The lower diastereoselectivity found for the for-
mation of 4 in more concentrated solutions can be explained
by the increased probability of attack of the second aniline
molecule by the “inner” side of the Michael acceptor
through coordination of the nucleophile with the Lewis acid
and any of the two electron-rich nitrogen atoms of inter-
mediate B (Scheme 7). This proposal would also account for
the lack of diastereoselectivity in the case of 4c, in which
the presence of a strong electron donor (i.e., OMe group)
para to the aniline nitrogen atom and the NH group in inter-
mediate B would favor this type of coordination.
tion and the first type-I vinylogous Povarov reaction. The
presence of the dimethylhydrazone group is interesting in
that it may allow further functionalization, either directly or
with prior cleavage.[2] Modified reaction conditions (i.e.,
CHCl3 as the solvent and BF3·Et2O as the catalyst) allowed
the
hexahydropyrrolo
an ABB’C four-component reaction that generates two
isolation
of
polysubstituted
1,2,3,3a,4,8b-
AHCTUNGTRENNG[UN 3,2-b]indoles as major products through
À
À
cycles, two C C bonds, and two C N bonds in a single oper-
ation, while creating three stereocenters, one of which is
quaternary, in a fully diastereoselective fashion.
Experimental Section
General: See the Supporting Information for the general experimental
details.
General protocol for the synthesis of tetrahydroquinoline derivatives 3
by reactions of imines 1 and methacrolein dimethylhydrazone (2): Imines
1 were prepared by the standard procedure of heating equimolecular
amounts of the appropriate aniline and aldehydes to reflux in ethanol for
3 h. The solid that formed by precipitation was removed by filtration
after cooling. InCl3 (10 mol%) was added to a stirred solution of pure
imine 1 (3 mmol) and 2[24] (3.6 mmol) in acetonitrile (20 mL). The reac-
tion mixture was stirred for the time period specified in Table 3. After
completion of the reaction as indicated by TLC analysis, the reaction
mixture was diluted with water (10 mL) and extracted with CH2Cl2 (4ꢄ
10 mL). The extracts were dried over anhydrous Na2SO4 and evaporated.
Purification was achieved by column chromatography on silica gel with
petroleum ether/ethyl acetate (95:5, v/v) as the eluent.
Scheme 7. Proposed explanation of the decreased diastereoselectivity of
4 in concentrated solutions. LA=Lewis acid.
The source of the second aniline molecule must be ex-
plained to rationalize the formation of 4 in the two-compo-
nent protocol. Although the Lewis acid-catalyzed hydrolysis
of starting imine 1 from traces of water in the solvent might
be invoked, we have never observed the other hydrolysis
product, namely, aldehyde 7. Furthermore, in an independ-
ent experiment, imine 1a was recovered after being submit-
ted to our usual reaction conditions for several hours in the
absence of the other reaction component 2. Related transi-
mination reactions have been explained through a [2+2] cy-
cloaddition/retrocycloaddition sequence,[22] which would
afford the observed products 5 and N-arylmethacroleini-
mines in our case. These compounds are known to be highly
unstable[23] and therefore can be expected to rapidly evolve
to the corresponding aniline and a methacrolein molecule,
the volatility of which would preclude its isolation.
General protocols for the three-component reactions between anilines 6,
aldehydes 7, and a,b-unsaturated dimethylhydrazones:
Method A: Equimolar quantities of the appropriate aniline 6 and alde-
hyde 7 were mixed well without any solvent for 5–10 min. The reaction
mixture was dissolved in acetonitrile (20 mL for a scale of 3 mmol) and
stirred. InCl3 (10 mol%) followed by 2 (1.2 equiv) were added to this so-
lution, which was stirred for the time period specified in Table 3. After
completion of the reaction, as indicated by TLC analysis, workup and pu-
rification were performed as mentioned in the two-component method.
Method B: An equimolar mixture of the appropriate aniline 6 and alde-
hyde 7 was heated to reflux in ethanol for 1 h. The ethanol was evaporat-
ed, and the reaction mixture was dissolved in acetonitrile (20 mL for
a
scale of 3 mmol) and stirred. Compound 2 (1.2 equiv) and InCl3
(10 mol%) were added to the reaction mixture, which was stirred for the
time period specified in Table 3. After completion of the reaction, as in-
dicated by TLC analysis, workup and purification were performed as in
the two-component method.
Method C: An equimolar mixture of the appropriate aniline 6 and alde-
hyde 7 was dissolved in a minimum amount of CH2Cl2 (1 mL for 3 mmol
of reactant). The solution was mixed well and became solid within 1 or
2 min. The solid was dissolved in acetonitrile (20 mL for a scale of
3 mmol) and stirred. Compound 2 (1.2 equiv) and InCl3 (10 mol%) were
added to the reaction mixture, which was stirred for the time period
specified in Table 3. After completion of the reaction, as indicated by
TLC analysis, workup and purification were performed as in the two-
component method.[25]
Conclusion
The indium trichloride-catalyzed Povarov-type reaction be-
tween aromatic imines and a,b-unsaturated N,N-dimethylhy-
drazones in acetonitrile gives ready access to biologically
and synthetically relevant 1,2,3,4-tetrahydroquinolines bear-
ing a hydrazone function at C4 through a one-pot diastereo-
selective domino process that involves the formation of two
Characterization data for representative compounds are given below. For
data corresponding to the full set of compounds, see the Supporting In-
formation.
(Æ)-(2S*,4S*)-4-[(2,2-Dimethylhydrazono)methyl]-4-methyl-2-phenyl-
1,2,3,4-tetrahydroquinoline (3a): M.p. 72–738C; 1H NMR (CDCl3,
250 MHz): d=1.66 (s, 3H), 1.91 (dd, J=13.1, 2.5 Hz, 1H), 2.15 (dd, J=
13.1, 11.8 Hz, 1H), 2.82 (s, 6H), 4.21 (brs, 1H), 4.63 (dd, J=11.8, 2.5 Hz,
1H), 6.63–6.80 (m, 3H), 7.09–7.17 (m, 2H), 7.31–7.55 ppm (m, 5H);
À
C C bonds and the controlled generation of two stereocen-
ters, one of which is quaternary. This reaction constitutes
the first example of an a,b-unsaturated dimethylhydrazone
that behaves as a dienophile in a hetero Diels–Alder reac-
Chem. Eur. J. 2012, 18, 5056 – 5063
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5061

J. C. Menꢀndez et al.
13C NMR (CDCl3, 62.9 MHz): d=28.4, 41.2, 43.9, 44.6, 53.5, 115.0, 118.1,
127.2, 127.9, 128.2, 129.2, 129.3, 144.5, 144.8, 145.1 ppm (two aromatic sig-
nals are merged); IR (neat) n˜ =3376.7, 2967.6, 2850.3, 1603.8, 1483.8,
1313.8, 1157.7, 1011.1 cmÀ1; elemental analysis (%) calcd for C19H23N3: C
77.78, H 7.90, N 14.32; found: C 77.97, H 7.68, N 13.99.
1504.4, 1232.0, 1042.9 cmÀ1 ; elemental analysis (%) calcd for C17H25N3O3:
C 63.93, H 7.89, N 13.16; found: C 63.94, H 7.63, N 13.03.
Synthesis of hexahydropyrroloACHTUNTRGNEU[GN 3,2-b]indoles 4: The suitable aniline 7
(2 equiv) and aldehyde 6 (1 equiv) were mixed well without any solvent
for 5–10 min. The reaction mixture was dissolved in CHCl3 (15 mL for
a scale of 3 mmol) and stirred. BF3·Et2O (10 mol%) followed by 2
(1.2 equiv) were added to the reaction mixture, which was stirred for the
time period specified in Table 3. After completion of the reaction, as in-
dicated by TLC analysis, the reaction mixture was mixed with water
(10 mL) and extracted with CHCl3 (3ꢄ10 mL). The extracts were dried
over anhydrous Na2SO4 and evaporated. Purification was achieved by
column chromatography on silica gel with petroleum ether/ethyl acetate
(95:5, v/v) as the eluent.[25]
(Æ)-(2S*,4S*)-4-[(2,2-Dimethylhydrazono)methyl]-4,7-dimethyl-2-
phenyl-1,2,3,4-tetrahydroquinoline (3d): Viscous liquid; 1H NMR
(CDCl3, 250 MHz): d=1.60 (s, 3H), 1.86 (dd, J=12.9, 2.7 Hz, 1H), 2.08
(dd, J=12.9, 11.8 Hz, 1H), 2.29 (s, 3H), 2.77 (s, 6H), 4.12 (brs, 1H), 4.58
(dd, J=11.8, 2.7 Hz, 1H), 6.45 (d, J=1.1 Hz, 1H), 6.57 (dd, J=7.8,
1.1 Hz, 1H), 6.82 (s, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.34–7.51 ppm (m,
5H); 13C NMR (CDCl3, 62.9 MHz): d=21.6, 28.3, 40.9, 43.9, 44.7, 53.4,
115.5, 119.1, 124.3, 127.1, 128.1, 129.1, 129.2, 137.7, 144.5, 144.6,
145.3 ppm; IR (neat) n˜ =3366.3, 2966.4, 2852.0, 1618.0, 1577.5, 1469.8,
1317.3, 1179.7, 1010.4 cmÀ1; elemental analysis (%) calcd for C20H25N3: C
78.14, H 8.20, N 13.67; found: C 78.22, H 7.97, N 13.40.
(Æ)-(2R*,3aR*,8bR*)-3a-Methyl-1,2-diphenyl-1,2,3,3a,4,8b-
hexahydropyrroloACTHNUTRGNEUNG
[3,2-b]indole (4a): M.p. 174–1758C; 1H NMR (CDCl3,
250 MHz): d=1.57 (s, 3H), 2.21 (dd, J=12.3, 9.2 Hz, 1H), 2.53 (dd, J=
12.3, 7.0 Hz, 1H), 3.90 (brs, 1H), 4.88 (dd, J=9.2, 7.0 Hz, 1H), 5.16 (s,
1H), 6.69 (d, J=7.8 Hz, 1H), 6.77–6.84 (m, 3H), 6.91 (td, J=7.5, 0.8 Hz,
1H), 7.18–7.29 (m, 8H), 7.64 ppm (d, J=7.5 Hz, 1H); 13C NMR (CDCl3,
62.9 MHz): d=25.5, 50.1, 64.6, 69.3, 74.8, 111.3, 113.5, 117.3, 120.1, 126.0,
126.2, 127.3, 129.1, 129.4, 129.5, 131.6, 144.0, 147.9, 149.4 ppm; IR (neat)
n˜ =3356.5, 2960.3, 2866.9, 1597.9, 1501.8, 1351.6, 1251.7, 1152.0 cmÀ1; ele-
mental analysis (%) calcd for C23H22N2: C 84.63, H 6.79, N 8.58; found:
C 84.41, H 6.80, N 8.76.
(Æ)-(2S*,4S*)-2-(4-Chlorophenyl)-4-[(2,2-dimethyl-hydrazono)methyl]-4-
methyl-1,2,3,4-tetrahydroquinoline (3i): M.p. 90–918C; 1H NMR (CDCl3,
250 MHz): d=1.59 (s, 3H), 1.83 (dd, J=13.2, 2.0 Hz, 1H), 2.06 (dd, J=
13.2, 11.1 Hz, 1H), 2.78 (s, 6H), 4.13 (brs, 1H), 4.57 (dd, J=11.1, 2.0 Hz,
1H), 6.62 (d, J=8.4 Hz, 1H), 6.67 (s, 1H), 6.74 (t, J=7.1 Hz, 1H), 7.04–
7.12 (m, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.43 ppm (d, J=8.6 Hz, 2H);
13C NMR (CDCl3, 62.9 MHz): d=28.5, 41.1, 43.8, 44.6, 52.9, 115.1, 118.4,
127.2, 127.9, 128.6, 129.3, 133.6, 143.1, 144.5, 144.7 ppm (two aromatic sig-
nals are merged); IR (neat) n˜ =3374.3, 2965.0, 2851.2, 1603.9, 1488.2,
1312.5, 1257.7, 1090.4, 1013.8 cmÀ1; elemental analysis (%) calcd for
C19H22ClN3: C 69.61, H 6.76, N 12.82; found: C 69.59, H 6.62, N 12.83.
(Æ)-(2R*,3aR*,8bR*)-7-Methoxy-3a-methyl-1-(4-methoxyphenyl)-2-
phenyl-1,2,3,3a,4,8b-hexahydropyrrolo
[3,2-b]indole
(4c):
M.p. 147–
1488C; 1H NMR (CDCl3, 250 MHz): d=1.60 (s, 3H), 2.03 (dd, J=12.6,
9.3 Hz, 1H), 2.50 (dd, J=12.6, 6.2 Hz, 1H), 3.53 (s, 3H), 3.71 (s, 3H),
4.64 (dd, J=9.3, 6.2 Hz, 1H), 5.39 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 6.57–
6.77 (m, 6H), 7.17–7.33 ppm (m, 5H); 13C NMR (CDCl3, 62.9 MHz): d=
27.3, 52.9, 55.8, 56.1, 62.7, 69.3, 75.4, 110.9, 113.1, 114.3, 115.3, 121.3,
127.0, 127.1, 128.8, 129.5, 140.1, 143.3, 145.2, 153.0, 153.3 ppm; IR (neat)
n˜ =3355.0, 2956.4, 2830.5, 1602.9, 1510.4, 1491.2, 1239.8, 1036.7 cmÀ1; ele-
mental analysis (%) calcd for C25H26N2O2: C 77.69, H 6.78, N 7.25;
found: C 77.83, H 6.72, N 7.35.
(Æ)-(2S*,4S*)-4-[(2,2-Dimethylhydrazono)methyl]-2-(4-methoxyphenyl)-
4,6-dimethyl-1,2,3,4-tetrahydroquinoline (3p): M.p. 119–1208C; 1H NMR
(CDCl3, 250 MHz): d=1.59 (s, 3H), 1.80 (dd, J=13.1, 2.6 Hz, 1H), 2.07
(dd, J=13.1, 11.6 Hz, 1H), 2.25 (s, 3H), 2.78 (s, 6H), 3.85 (s, 3H), 4.00
(brs, 1H), 4.51 (dd, J=11.6, 2.6 Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 6.70 (s,
1H), 6.86–6.89 (m, 2H), 6.93 (d, J=8.7 Hz, 2H), 7.40 ppm (d, J=8.7 Hz,
2H); 13C NMR (CDCl3, 62.9 MHz): d=20.9, 28.4, 41.2, 43.9, 44.8, 52.9,
55.8, 114.4, 115.0, 127.1, 127.2, 128.2, 128.5, 129.6, 136.7, 142.5, 145.5,
159.5 ppm; IR (neat) n˜ =3366.4, 2956.1, 2852.5, 1612.1, 1506.5, 1467.1,
1247.4, 1172.8, 1034.2 cmÀ1; elemental analysis (%) calcd for C21H27N3O:
C 74.74, H 8.06, N 12.45; found: C 74.35, H 7.93, N 12.41.
(Æ)-(2S*,3aR*,8bR*)-7-Methoxy-3a-methyl-1-(4-methoxyphenyl)-2-
phenyl-1,2, 3,3a,4,8b-hexahydropyrroloACTHNUTRGNEU[GN 3,2-b]indole (8c): M.p. 108–
1118C; 1H NMR (CDCl3, 250 MHz): d=1.51 (s, 3H), 2.13 (dd, J=12.2,
9.8 Hz, 1H), 2.45 (dd, J=12.2, 6.7 Hz, 1H), 3.75 (s, 3H), 3.81 (s, 3H),
4.74 (dd, J=9.8, 6.7 Hz, 1H), 5.01 (s, 1H), 6.60–6.83 (m, 6H), 7.15–
7.25 ppm (m, 6H); 13C NMR (CDCl3, 62.9 MHz): d=24.7, 49.5, 55.7,
56.1, 64.4, 69.1, 75.4, 111.7, 112.5, 113.7, 114.2, 114.7, 125.6, 126.8, 128.6,
133.8, 141.8, 142.2, 143.5, 151.5, 151.6 ppm; IR (neat) n˜ =3343.4, 2927.2,
1510.2, 1489.0, 1242.8, 1037.3, 815.0 cmÀ1; elemental analysis (%) calcd
for C25H26N2O2: C 77.69, H 6.78, N 7.25; found: C 77.34, H 6.54, N 6.98.
(Æ)-(2RS,4RS)-4-[(2,2-Dimethylhydrazono)methyl]-2-(4-methoxyphen-
yl)-6-methoxy-4-methyl-1,2,3,4-tetrahydroquinoline (3q): M.p. 94–958C;
1H NMR (CDCl3, 250 MHz): d=1.60 (s, 3H), 1.81 (dd, J=13.2, 2.5 Hz,
1H), 2.08 (dd, J=13.2, 11.6 Hz, 1H), 2.77 (s, 6H), 3.76 (s, 3H), 3.85 (s,
3H), 3.89 (bs, 1H), 4.48 (dd, J=11.6, 2.5 Hz, 1H), 6.56 (dd, J=7.5,
1.4 Hz, 1H), 6.67–6.70 (m, 3H), 6.93 (d, J=8.7 Hz, 2H), 7.40 ppm (d, J=
8.7 Hz, 2H); 13C NMR (CDCl3, 62.9 MHz): d=28.6, 41.6, 43.9, 44.7, 53.0,
55.8, 56.3, 113.9, 114.4, 114.8, 115.9, 128.2, 128.5, 136.7, 139.1, 145.1,
152.5, 159.5 ppm; IR (neat) n˜ =3363.2, 2950.8, 2831.5, 1611.1, 1503.3,
1466.3, 1246.4, 1172.4, 1035.5 cmÀ1; elemental analysis (%) calcd for
C21H27N3O2: C 71.36, H 7.70, N 11.89; found: C 71.28, H 7.48, N 11.95.
(Æ)-(2R*,3aR*,8bR*)-1-(3,5-Dimethylphenyl)-3a,6,8-trimethyl-2-phenyl-
1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indole
(4e):
M.p. 216–2178C;
1H NMR (CDCl3, 250 MHz): d=1.47 (s, 3H), 2.19 (dd, J=11.8, 10.5 Hz,
1H), 2.26 (s, 6H), 2.30 (s, 3H), 2.42 (s, 3H), 2.43 (dd, J=11.8, 7.3 Hz,
1H), 3.85 (brs, 1H), 4.81 (dd, J=10.5, 7.3 Hz, 1H), 5.21 (s, 1H), 6.36 (s,
1H), 6.48 (s, 3H), 6.54 (s, 1H), 7.20–7.32 ppm (m, 5H); 13C NMR
(CDCl3, 62.9 MHz): d=19.8, 21.8, 22.3, 24.4, 49.3, 66.4, 69.3, 74.6, 110.0,
112.1, 119.6, 123.5, 126.0, 126.5, 127.2, 129.1, 136.2, 138.6, 138.9, 145.2,
149.2, 149.9 ppm; IR (neat) n˜ =3346.2, 2961.6, 2919.4, 1597.2, 1454.1,
1352.4, 1298.2, 1206.1, 1152.3, 1065.2 cmÀ1; elemental analysis (%) calcd
for C27H30N2: C 84.77, H 7.90, N 7.32; found: C 84.59, H 7.95, N 7.39.
(Æ)-(2S*,4S*)-4-[(2,2-Dimethylhydrazono)methyl]-2-(2-furyl)-6-methoxy-
4-methyl-1,2,3,4-tetrahydroquinoline (3aa): Pale-orange viscous liquid;
1H NMR (CDCl3, 250 MHz): d=1.56 (s, 3H), 2.00 (dd, J=13.1, 2.6 Hz,
1H), 2.23 (t, J=12.9 Hz, 1H), 2.78 (s, 6H), 3.75 (s, 3H), 4.03 (brs, 1H),
4.61 (dd, J=11.5, 2.4 Hz, 1H), 6.28 (dt, J=3.2, 0.7 Hz, 1H), 6.38 (dd, J=
3.2, 1.8 Hz, 1H), 6.55–6.73 (m, 4H), 7.41 ppm (dd, J=1.8, 0.8 Hz, 1H);
13C NMR (CDCl3, 63 MHz): d=27.9, 39.9, 40.4, 43.3, 46.8, 55.7, 105.1,
110.2, 113.4, 114.1, 115.9, 128.3, 137.5, 141.7, 144.3, 152.3, 156.4 ppm; IR
(neat) n˜ =3362.2, 2952.5, 2851.4, 1504.6 cmÀ1; elemental analysis (%)
calcd for C18H23N3O2: C 68.98, H 7.40; N 13.41; found: C 69.12, H 7.47, N
13.41.
(Æ)-(2R*,3aR*,8bR*)-2-(4-Methoxyphenyl)-3a-methyl-1-phenyl-
1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indole
(4o):
M.p. 148–1498C;
1H NMR (CDCl3, 250 MHz): d=1.52 (s, 3H), 2.15 (dd, J=12.2, 9.3 Hz,
1H), 2.47 (dd, J=12.2, 7.0 Hz, 1H), 3.76 (s, 3H), 4.80 (dd, J=9.3, 7.0 Hz,
1H), 5.10 (s, 1H), 6.65–6.90 (m, 6H), 7.11–7.28 (m, 6H), 7.59 ppm (d, J=
7.4 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz): d=25.4, 50.2, 55.6, 64.0, 69.2,
74.7, 111.3, 113.4, 114.4, 117.2, 120.0, 126.1, 127.1, 129.3, 129.5, 135.9,
147.8, 149.3, 158.9 ppm; IR (neat) n˜ =3357.8, 2958.7, 2836.0, 1597.7,
1501.8, 1464.2, 1353.8, 1245.2, 1170.5, 1035.1 cmÀ1; elemental analysis (%)
calcd for C24H24N2O: C 80.87, H 6.79, N 7.86; found: C 80.66, H 6.95, N
8.09.
(Æ)-(2RS,4RS)-Ethyl 4-[(2,2-dimethylhydrazono)methyl]-4-methyl-6-me-
thoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate (3ac): Pale yellow vis-
1
cous liquid; H NMR (CDCl3, 250 MHz): d=1.34 (t, J=7.1 Hz, 3H), 1.51
(s, 3H), 1.97 (dd, J=12.8, 11.8 Hz, 1H), 2.11 (dd, J=12.8, 3.3 Hz, 1H),
2.79 (s, 6H), 3.73 (s, 3H), 4.13 (dd, J=11.8, 3.3 Hz, 1H), 4.27 (q, J=
7.1 Hz, 2H), 6.60–6.67 ppm (m, 4H); 13C NMR (CDCl3, 62.9 MHz): d=
14.6, 27.4, 37.8, 40.8, 43.7, 51.6, 56.2, 61.8, 113.9, 114.2, 116.4, 128.4, 136.9,
143.7, 152.6, 173.6 ppm; IR (neat) n˜ =3387.6, 2978.0, 2853.4, 1738.2,
5062
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5056 – 5063

Synthesis of Tetrahydroquinolines in a One-Pot Diastereoselective Domino Process
FULL PAPER
M. Ahmadian, J. A. Scherschel, Tetrahedron Lett. 1997, 38, 2211–
2214.
Acknowledgements
[12] These experiments also provided independent confirmation of the
previously established E configuration of these compounds at the
C=N bond; see: L. Ghosez, B. Serckx-Poncin, M. Rivera, P. Bayard,
F. Sainte, A. Demoulin, A.-M. Hesbain-Frisque, A. Mockel, L.
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[13] For a proposal for the systematization of vinylogous Povarov reac-
tions, see: V. Sridharan, C. AvendaÇo, J. C. Menꢀndez, Synlett 2007,
1079–1082.
We thank MICINN (grant CTQ2009–12320-BQU) and UCM (Grupos de
Investigaciꢅn Consolidados, grant GR35/10 A-920234) for financial sup-
port of this research. The stay of P.T.P. in Madrid was supported by a fel-
lowship from the Santander-UCM “Programa de Visitantes Distingui-
dos”, which is also gratefully acknowledged.
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Received: November 11, 2011
Published online: March 5, 2012
Chem. Eur. J. 2012, 18, 5056 – 5063
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5063