Experimental evidence for intramolecular ipso substitution of alkyl groups

Article abstract of DOI:10.1002/ejoc.200400356

An acid-mediated intramolecular Friedel-Crafts intramolecular alkene alkylation of the ortho-alkyl group in the N-aryl-amino moiety of various N-(1-allylcycloalkyl)-N-arylamines resulting in alkyl-substituted 3′,4′-dihydro-1′H-spiro[cycloalkane-1,2′-quino

Full text of DOI:10.1002/ejoc.200400356

FULL PAPER
Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups[‡]
Fedor I. Zubkov,*[a] Eugenia V. Nikitina,[a] Vladimir V. Kouznetsov,[b] and
Luz Dary Avellaneda Duarte[b]
Keywords: Electrophilic substitution / Alkylation / Allylic compounds / Spiro compounds / N heterocycles / ipso
substitution
An acid-mediated intramolecular Friedel−Crafts intramolec- The scope and limitations of this reaction were determined.
ular alkene alkylation of the ortho-alkyl group in the N-aryl- As a conclusive proof of the proposed mechanism, previously
amino moiety of various N-(1-allylcycloalkyl)-N-arylamines
resulting in alkyl-substituted 3Ј,4Ј-dihydro-1ЈH-spiro[cycloal-
kane-1,2Ј-quinolines] is described. The mechanistic details
of this intramolecular Friedel−Crafts alkylation by an alkene
moiety can be explained by an intramolecular alkylation with
ipso substitution of alkyl groups and their 1,2-rearrangement.
unknown interesting by-products, dispiro[quino[6,7-f]quino-
line-3,1Ј:9,1ЈЈ-bis(cycloalkanes), were isolated and character-
ized.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
tion of the tetra- or dihydroquinoline rings spiro-annulated
at position C-2 with cycloalkanes[4dϪ4g] or other hetero-
cycles. Thus, the chemistry and biological activity of this
type of spiro-heterocyclic compounds remain largely unex-
plored. As part of our research program towards the prep-
aration of drug-like heterocyclic molecules from imines, we
developed a practical synthesis of the 3Ј,4Ј-dihydro-4Ј-
methyl-1ЈH-spiro[cycloalkane-1,2Ј-quinolines] based on the
reactivity of accessible ketimines[5] (Scheme 1). The ket-
imines are transformed into the corresponding gem-allyl-N-
(arylamino)cycloalkanes through an addition of the Grig-
nard reagent, allylmagnesium bromide. These amines, pos-
sessing a π-electron-rich aromatic ring, a basic nitrogen
atom and an allyl fragment (an electrophilic C3 synthon),
represent versatile synthetic intermediates for the construc-
tion of quinolines spiro-annulated at C-2.
Electrophilic aromatic substitution via Wheland com-
plexes is the classical method for functionalizing aromatic
and heteroaromatic compounds. FriedelϪCrafts alkylation
differs from all other aryl SE reactions in that the reaction
products are better nucleophiles than the starting material.
This decreases the synthetic value of this method. However,
there is a beautiful possibility for improving this situation.
An intramolecular version of the FriedelϪCrafts alkylation,
promoted by Brønsted or Lewis acids[1] has become an ef-
ficient method for the rapid construction of many carbo-
and heterocyclic compounds,[2] including many biologically
and pharmacologically active quinoline and tetrahydro-
quinoline derivatives.[3] The most general method to obtain
these compounds involves an intramolecular cyclisation
starting from a suitably substituted aniline derivative.
Moreover, many new methods for the synthesis of tetra-
hydroquinoline derivatives have been developed.[4] However,
there are very few publications that describe the construc-
[‡]
Intramolecular FriedelϪCrafts Alkylation of N-(ortho-
Scheme 1
Alkylaryl)-N-(1-allylcycloalkyl)amines as an Entry to the
Synthesis of Alkyl-Substituted 3Ј,4Ј-Dihydro-1ЈH-spiro[cyclo-
alkane-1,2Ј-quinolines], 1
While the synthetic potential of intramolecular
FriedelϪCrafts alkylation is well documented, there have
been no reports of intramolecular alkene alkylation in
which ipso attack at a carbon atom attached to an alkyl
group plays a pivotal role in the preparation of alkyl-substi-
tuted dihydro-1ЈH-spiro[cycloalkane-1,2Ј-quinolines]. We
recently reported an unprecedented intramolecular
FriedelϪCrafts alkylation with an alkene group in the series
[a]
Organic Chemistry Department of the Russian Peoples
Friendship University,
6 Miklukho-Maklayia St, Moscow 117198, Russian Federation
Fax: (internat.) ϩ 7-095-955-0779
E-mail: fzubkov@sci.pfu.edu.ru
[b]
´
´
Laboratorio de Sıntesis Organica Fina, CIBIMOL, Escuela de
´
Quımica, Universidad Industrial de Santander,
A. A. 678, Bucaramanga, Colombia
Fax: (internat.) ϩ 5776-349069-358210
E-mail: kouznet@uis.edu.co
5064
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400356
Eur. J. Org. Chem. 2004, 5064Ϫ5074

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups
FULL PAPER
Scheme 2
of ortho-methyl(or -ethyl)-substituted N-(1-allylcycloalkyl)-
However, cyclisation of the ortho-ethyl-substituted ana-
N-(ortho-R-aryl)amines.[6] Now we describe our investi- logs 2f,g gave the desired 8-ethyl-substituted tetrahydro-
gations, which include some mechanistic details on this in- quinolines 3f,g (in 59 and 61% yields, respectively) together
tramolecular FriedelϪCrafts alkylation that easily undergo with the unexpected 5-ethyl-substituted 1,2,3,4-tetrahydro-
the ipso substitution of methyl or ethyl groups and a practi- quinolines 4f,g (17 and 23% yields, respectively) (Scheme 4).
cal synthesis of 5Ј,8Ј-dimethyl(or -diethyl)-3Ј,4Ј-dihydro- Compounds 3f,g and 4f,g were purified and separated by
1ЈH-spiro[cycloalkane-1,2Ј-quinolines], which can serve as alumina column chromatography as colorless oils with simi-
useful semiproducts in drug preparation.
lar retention factors. The mass and IR spectra of the iso-
meric quinolines 3f,g and 4f,g were virtually the same (see
Exp. Sect.).
Results and Discussion
Starting ketimines 1aϪn were easily prepared from the
corresponding anilines and cycloalkanones in boiling tolu-
ene in the presence of catalytic amounts of glacial AcOH
(1aϪi) or pTsOH (1kϪn) using a DeanϪStark apparatus.
According to our approach to 3Ј,4Ј-dihydro-1ЈH-spiro[cy-
cloalkane-1,2Ј-quinolines], the homoallylamines 2aϪn were
obtained easily from accessible cycloalkanone imines and
allylmagnesium bromide in an overall yield of 36Ϫ82%
(from the anilines, calculated after distillation and purifi-
cation processes) (Scheme 2).
Cyclisation of the key substrates 2aϪn was performed
using a seven-fold excess of concd. H2SO4 over 3Ϫ5 h in
boiling chloroform. The cyclisation of (o-methylphenyl)-
amines 2aϪe proceeded smoothly to give 8-alkyl-substi-
tuted quinolines 3aϪe in 66Ϫ84% yields (Scheme 3). The
Scheme 4
1
The H and 13C NMR spectroscopic data allowed only
an unambiguous statement of the formation of the 4-meth-
yltetrahydroquinoline ring. Thus, the H NMR spectra dis-
played the signals of the three aromatic protons. The posi-
tion of the ethyl group could be differentiated between the
pairs 3f/4f and 3g/4g using NOE experiments (Figure 1).
1
so-obtained
8Ј-methyl-substituted
dihydrospiro[cyclo-
alkane-1,2Ј-quinolines] are of interest in our investigations
into spiro analogs of marine alkaloids.[7] It is noteworthy
that in all cases, GC-MS analysis of the crude reaction
mixtures in the formation of 3aϪe did not show any ap- Figure 1. Results of NOE experiments on 3f/4f and 3g/4g
preciable amounts of side products.
Moreover, the X-ray crystal structures of hydrochloride
4f,g unambiguously confirmed their structures as the 3Ј,4Ј-
dihydro-5Ј-ethyl-4Ј-methyl-1ЈH-spiro[cycloalkane-1,2Ј-
quinolines]. The salt of 4g occurs in two forms A and B
(Figure 2).[8] The crystallographically independent cations
A and B have similar geometrical parameters, and differ
only in the orientation of the ethyl group [torsion angles
C(9)ϪC(10)ϪC(16)ϪC(17) and C(11)ϪC(10)ϪC(16)Ϫ
C(17) have values of 154.6 and Ϫ30.3° (A), and Ϫ123.4 and
53.8° (B), respectively]. The projections of forms A and B
Scheme 3
with superimposed phenyl groups are shown in Figure 2.
Eur. J. Org. Chem. 2004, 5064Ϫ5074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5065

F. I. Zubkov, E. V. Nikitina, V. V. Kouznetsov, L. D. A. Duarte
FULL PAPER
Figure 2. X-ray crystal structure of 4g (Forms A and B)
The spirocyclohexane ring has a chair conformation, and orthoЈ position have not been observed. Usually, a proton
the piperidine part of the molecule possesses a half-chair is replaced by the electrophile, but in an ipso substitution,
conformation with the respective deviations of the C(1) and another substituent is replaced. In most cases, the nucleo-
C(7) atoms from the plane of the four atoms philic carbon atom of the arene has a hydrogen atom at-
C(8),C(9),C(14),N(1) being Ϫ0.85 and Ϫ0.20A in cation A tached.[9] Moreover, intermolecular ipso attack[10] has
˚
and Ϫ0.70 and 0.05A in cation B. The bond C(1)ϪN(1) has mostly been studied for nitration[10a,10b] and halogen-
˚
a pseudo-equatorial orientation, and C(1)ϪC(7) is pseudo- ation[10c,10d] reactions. A plausible mechanism for this type
axial. These cations are linked to the chloride anions by of intramolecular FriedelϪCrafts alkene alkylation pro-
NϪH···Cl hydrogen bonds in this crystal. These structural moted by Brønsted acid is proposed in Scheme 5. Thus, the
interactions result in dimeric cationϪanion pairs {A···Cl}2 Wheland intermediates 3*a,g were formed as the result of
and {B···Cl}2.
electrophilic attack at the free ortho position. Loss of Hϩ
These results could be explained by an intramolecular al- from C-4a then afforded the 8-alkyl-substituted tetrahydro-
kylation with ipso substitution of the ethyl group in 2f,g. It quinolines 3a,g. However, when the carbocation formed
is noteworthy that cases of intramolecular ipso substitution from the allyl fragment attacks at the carbon atom attached
of the ortho-alkyl group in the presence of a second free to the alkyl group, ipso attack occurs, resulting in the for-
5066
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5064Ϫ5074

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups
FULL PAPER
mation of the alternative Wheland intermediates 4*a,g. A
1,2-shift of the ethyl group from C-4a to C-5, followed by
loss of Hϩ, gives rise to the isomeric 5-ethyl-substituted
tetrahydroquinoline 4g. We assume that methyl group in the
ethyl radical can stabilize the three-center cationic species
4*g by both induction and hyperconjugation effects.[11] In
the case of 2a, the formation of intermediate 4*a is difficult
because the hydrogen atom cannot stabilize the cationic
center (Scheme 5).
Scheme 7
The intermediate 4*i, resulting from ipso attack, would
be likely to eliminate a stable benzyl cation rather than a
proton. The benzyl elimination process is also favored by
the presence of a peri interaction between the 5-benzyl and
4-methyl groups in the anticipated structure 4i (whose for-
mation has not been observed).
These interesting results stimulated us to investigate the
intramolecular alkene alkylation process in another series,
the ortho,orthoЈ-dialkyl-substituted compounds 2kϪn. To
our surprise, treatment of the ortho,orthoЈ-diethyl-substi-
tuted allyl(arylamino)cyclohexane 2n under the same con-
ditions readily afforded the 5,8-diethyl-substituted spirane
3n in an almost quantitative yield (94%) (Scheme 8). In this
case, as both ortho-carbon atoms attached to ethyl groups
are equivalent, ipso attack proceeded smoothly, and was fol-
lowed by a 1,2-shift of an ethyl group and loss of Hϩ to
reconstitute the aromatic system.
Scheme 5
Next, we tested specially synthesized ortho-isopropyl and
ortho-benzyl derivatives 2h and 2i in acid-mediated alkene
alkylation. We anticipated that the presence of these groups
in the N-arylamino moiety of N-(1-allylcycloalkyl)-N-aryla-
mines would increase the stability of the alkyl cation com-
pared to the ethyl-substituted analogs. However, our experi-
ments gave unexpected results. Thus, acid-mediated cyclis-
ation of 2h led to the 8-isopropyl-substituted tetrahydro-
quinoline 3h in good yield by formation of the Wheland
intermediate 3*h (Scheme 6). No by-products were ob-
served in the crude reaction mixture. In this case, we assume
that the ipso attack at the carbon atom attached to the
bulky isopropyl group does not occur because of the high
steric barrier towards the formation of intermediate 4*h.
Scheme 8
We were very surprised by the result of the intramolecu-
lar alkylation in the cases of ortho,orthoЈ-dimethyl-substi-
tuted allyl(arylamino)cyclohexanes 2k,l. Besides the ipso-
substitution products 3k,l, which were obtained in 53Ϫ56%
yield, we isolated the polyheterocycles 6k,l (16Ϫ26%),
which had an unprecedented spiro structure. Their spectro-
scopic data (1H and 13C NMR and MS data) did not allow
an unambiguous assignment of their structures. However,
X-ray analysis of the product 6l[7] proved its dimeric nature.
As shown in Figure 3, the central bicyclo[2.2.2]octene frag-
ment of 6l is endo-fused to a piperidine ring, and exo-fused
Scheme 6
From the cyclisation of ortho-benzyl derivative 2i, in ad- to a cyclohexene moiety. The spirocycloalkane fragments of
dition to the ‘‘common’’ 8-substituted product 3i (61% polyheterocycle 6l have chair conformations, and the re-
yield), we observed and isolated the debenzylation[12] prod- duced six-membered quinoline rings, unexpectedly spiro-
uct 5[13] (13% yield) (Scheme 7).
substituted by the cycloalkane moieties at C(1) and C(23),
Eur. J. Org. Chem. 2004, 5064Ϫ5074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5067

F. I. Zubkov, E. V. Nikitina, V. V. Kouznetsov, L. D. A. Duarte
FULL PAPER
Figure 3. X-ray crystal structure of 6l
adopt ‘‘envelope’’ conformations in which atoms C(8) and it by alumina column chromatography met with failure. As
C(21) lie away from the mean planes of the other five atoms shown in Scheme 9, this compound has a cis-diene structure
˚
in the rings by 0.67 and 0.61A, respectively (crystallo- and presumably exists long enough to dimerize, acting as
graphic numbering is used throughout). The methyl groups both a diene and a dienophile. It is noteworthy that this
attached to C(8) and C(21) are orientated equatorially. dimerization process is highly stereoselective for the endo
They deviate from the corresponding planes by 0.63 and adduct 6l.
˚
0.53A, respectively. The vicinal methyl groups at C(8) and
It is noteworthy that the cyclisation of 2m, which bears
C(9) have a cis orientation. The other methyl groups at two different ortho substituents, occurs with no regioselec-
C(20) and C(21) are orientated in a similar manner. tivity, giving two isomeric tetrahydroquinolines 3m and 4m
This interesting finding could be also interpreted by the in a ratio of ca. 1:1 in an overall yield of 77% (Scheme 10).
intramolecular ipso attack at the carbon atom attached to The two possible ipso attacks are probably equivalent in
the methyl group. A plausible mechanistic explanation for this case.
the formation of this product 6l is proposed in Scheme 9.
The Wheland intermediate 3*l, formed by ipso attack, can
be stabilized not only by a 1,2-shift of the methyl group to
give the 5,8-dimethyl-substituted spirane 4l (route A), but
also by loss of Hϩ from the resonance-stabilized structure
7*l (route B), resulting in the 2,3,4,4a-tetrahydroquinoline
7l, a precursor of polycyclic product 6l.
Scheme 10
All attempts to isolate these isomeric products by alum-
ina column chromatography met with failure because their
physical and chemical properties are similar. Analysis of
their structures was carried out by means of correlation 1H-
13C NMR spectra of the isomeric mixture. It is interesting
to note that only the ortho,orthoЈ-dimethyl derivatives 2k,l
could form dimers (6k,l); the diethyl analogue 2n and simi-
lar derivative 2m did not give the corresponding dimers.
The ethyl group appears to give significant steric hindrance
in the transition state of the diene dimerization reaction.
To determine the scope and limitations of acid-mediated
intramolecular alkene alkylation of N-(arylamino)cyclohex-
anes bearing an alkene moiety, we synthesized another
Scheme 9
series of methallyl-substituted (arylamino)cyclohexanes
9a,b from ketimines 8a,b (Scheme 11). The ortho,orthoЈ-di-
The presence of compound 7l in the reaction mixture was methyl derivative 9a was prepared by refluxing the corre-
proved by 1H NMR spectroscopy, but all attempts to isolate sponding imine (8a) and (methallyl)magnesium chloride in
5068
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5064Ϫ5074

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups
FULL PAPER
an Et2O/THF mixture in poor yield (35%). Ketimine 8c 3,1Ј:9,1ЈЈ-bis(cycloalkanes)], were isolated and charac-
(R1 ϭ R2 ϭ Et) did not react with (methallyl)magnesium terized. Efforts are in progress to elucidate the mechanistic
chloride in either THF or dioxane at reflux. Finally, it is details of this intramolecular FriedelϪCrafts alkene alky-
noteworthy that a conventional procedure for imine forma- lation and to study the chemical behavior of the dispiro-
tion (condensation of reagents in boiling toluene in the [quino[6,7-f]quinoline-3,1Ј:9,1ЈЈ-bis(cycloalkanes)] 6k and
presence of pTsOH) turned out to be more convenient for 6l.
the synthesis of the hindered ketimines 8aϪc and 1kϪm
derived from o,oЈ-dialkylanilines than the recently described
imine synthesis where the keto form reaction was used.[14]
Experimental Section
General Remarks: All reagents for synthesis were purchased from
Acros Chemical Co. All solvents were used without further purifi-
cation. Melting points were determined using a FisherϪJohns melt-
ing point apparatus and are uncorrected. IR spectra were obtained
with a UR-20 spectrometer using KBr pellets for solids and thin
films for oils. 1H and 13C NMR spectra were recorded with Bruker
WP-200 (1H 200 MHz), WH-400 or Varian UNITYϩ400 (1H
400 MHz, 13C 100.6 MHz) spectrometers with solutions (2%) in
deuteriochloroform or [D6]DMSO at 30 °C, and using TMS as an
internal standard. Chemical shifts are reported in ppm, and coup-
(a) (b) (c) (d) (e)
ling constants (J) are quoted in Hz. Designations
,
,
,
,
indicate possible reverse assignment of the marked signals. Mass
spectra were obtained by electron impact at 70 eV with a Varian
MAT-112 spectrometer or Finnegan MAT95XL chromatomass
spectrometer. Microanalyses were performed with a PerkinϪElmer
2400 Series II analyzer. The purity of the obtained substances and
the composition of the reaction mixtures were monitored by TLC
Silufol UV254 or Sorbfil plates (using hexane/ethyl acetate, 10:1 as
eluent). X-ray data of compounds 4g and 6l were collected with a
‘‘Cad-4’’ 3-circle diffractometer at 293 K using graphite-monochro-
˚
mated Mo-Kα radiation (λ ϭ 0.71073 A, ω-scan, 2° Յ 2θ Յ 60°).
Scheme 11
The software packages used were: SMART[15] for collecting frames
of data, indexing, integration of intensity of reflections and scaling;
SADABS[16] for empirical absorption correction for structure 4g
and 6l. The structures were solved by direct methods using the
SHELXS-97 program and refined against F2 in an anisotropic
approximation for metal and chlorine atoms using the SHELXL-97
package.[16b,16c] The H atoms were located at calculated positions.
Atomic coordinates, bond lengths, bond angles and thermal par-
ameters of these molecules have been deposited at the Cambridge
Crystallographic Data Centre (CCDC).[8]
The chemical behavior of substrates 9a,b was studied un-
der the previously described conditions of cyclisation. In
the case of 9a (R1 ϭ Et, R2 ϭ H), cyclisation proceeded
smoothly at the free orthoЈ position to give the 8-ethyl-sub-
stituted 1,2,3,4-tetrahydroquinoline 10 in good yield, while
similar treatment of 9b (R1 ϭ R2 ϭ Me) led only to the
degradation product 2,6-dimethylaniline 11 in poor yield
(Scheme 11). In both cases, we did not observe any ipso
substitution products. Such an outcome could be due to
the poor electrophilic reactivity of the tertiary carbocation
generated from the methallyl fragment compared to the
secondary carbocation derived from an allyl radical.
Preparation of Homoallylamines 2aϪn and Methallyl Derivatives
9a,b. General Procedure: The corresponding aldimine (0.30 mol)
(see Discussion Ϫ Schemes 2 and 11) was slowly added dropwise to
a stirred solution of allylmagnesium bromide, prepared from allyl
bromide (39 mL, 0.45 mol) and magnesium turnings (22.0 g, 0.90
mol), in absolute ether (300 mL) at reflux (for amines 2aϪn), or to
a solution of (methallyl)magnesium chloride, prepared from me-
thallyl chloride (41 mL, 0.45 mol) and magnesium turnings (22.0 g,
0.90 mol) in a mixture of THF/ether (1:1; 300 mL) at reflux (for
amines 9a,b). After the addition of the Schiff base, the reaction
mixture was stirred at room temperature for 1 h. The cooled reac-
tion mixture was taken up in saturated aqueous NH4Cl solution
(300 mL) under ice cooling, and the mixture was extracted with
diethyl ether (3 ϫ 120 mL). The organic layer was dried with
MgSO4 and concentrated. The residue was distilled in vacuo to give
the products, 2aϪn or 9a,b, as a colorless oils [except for N-(1-
allylcyclohexyl)-N-(2Ј-benzylphenyl)amine (2i), which was recrys-
tallized from hexane after removal of ether].
Conclusion
We have studied the chemical behavior of the 1-[(ortho-
alkylaryl)amino]-1-allyl(methallyl)cycloalkanes under acidic
conditions. Whilst carrying out classical intramolecular
FriedelϪCrafts alkene alkylation reactions, we discovered a
previously unknown alkylation process in which intramol-
ecular ipso substitution of the ortho-alkyl group in the N-
arylamino moiety of the N-(1-allylcycloalkyl)-N-arylamines
takes place. Intramolecular ipso attack at the carbon atom
attached to the methyl (ethyl) group provides an attractive
alternative route to alkyl-substituted C-2-spiro-annulated
1,2,3,4-tetrahydroquinolines. During this study, previously
N-(1-Allylcyclopentyl)-N-(2Ј-methylphenyl)amine (2a): Yield 73%,
Rf ϭ 0.62, b.p. 122Ϫ125 °C/1.5 Torr. IR (film): ν˜ ϭ 3437 (NH),
unknown by-products, the dispiro[quino[6,7-f]quinoline- 1635 (CϭC) cmϪ1
.
1H NMR (CDCl3, 200 MHz): δ ϭ 1.55Ϫ2.05
Eur. J. Org. Chem. 2004, 5064Ϫ5074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5069

F. I. Zubkov, E. V. Nikitina, V. V. Kouznetsov, L. D. A. Duarte
FULL PAPER
(m, 8 H, cycloalkyl H), 2.07 (s, 3 H, 2Ј-Me), 2.55 (d, J ϭ 7.3 Hz,
7.05 (d, J ϭ 7.5 Hz, 1 H, 3Ј-H), 7.06 (dt, J ϭ 7.5, 0.5 Hz, 1 H, 5Ј-
2 H, 1-Hallyl), 3.53 (br. s, 1 H, NH), 4.92 (m, J ϭ 17.1, 2.4 Hz, 1 H) ppm. C16H23N (229.4): calcd. C 83.84, H 10.04, N 6.11; found
H, 3-HZallyl), 5.00 (m, J ϭ 10.4, 2.4 Hz, 1 H, 3-HEallyl), 5.73 (ddt, C 83.70, H 10.04, N 6.17.
J ϭ 17.1, 10.4, 7.3 Hz, 1 H, 2-Hallyl), 6.59 (dt, J ϭ 7.3, 0.9 Hz, 1
N-(1-Allylcyclohexyl)-N-(2Ј-ethylphenyl)amine (2g): Yield 82%,
Rf ϭ 0.71, b.p. 135Ϫ136 °C/1.5 Torr; n2D2 ϭ 1.5462. IR (film): ν˜ ϭ
H, 4Ј-H), 6.77 (dd, J ϭ 7.3, 0.9 Hz, 1 H, 6Ј-H), 7.02 (dd, J ϭ 7.3,
0.9 Hz, 1 H, 3Ј-H), 7.04 (dt, J ϭ 7.3, 0.9 Hz, 1 H, 5Ј-H) ppm.
C15H21N (215.4): calcd. C 83.72, H 9.77, N 6.51; found C 83.81,
H 9.95, N 6.61.
1
3448 (NH), 1636 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ
1.25 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 1.63Ϫ1.18 (m, 8 H, cycloalkyl
H), 2.00 (m, 2 H, cycloalkyl H), 2.49 (q, J ϭ 7.4 Hz, 2 H,
CH2CH3), 2.52 (d, J ϭ 7.3 Hz, 2 H, 1-Hallyl), 3.45 (br. s, 1 H, NH),
4.97 (d, J ϭ 17.0 Hz, 1 H, 3-HZallyl), 5.01 (d, J ϭ 9.8 Hz, 1 H, 3-
HEallyl), 5.74 (ddt, J ϭ 17.0, 9.8, 7.3 Hz, 1 H, 2-Hallyl), 6.67 (br. t,
J ϭ 7.7 Hz, 1 H, 4Ј-H), 6.86 (d, J ϭ 7.7 Hz, 1 H, 6Ј-H), 7.05 (d,
J ϭ 7.7 Hz, 1 H, 3Ј-H), 7.04 (t, J ϭ 7.5 Hz, 1 H, 5Ј-H) ppm.
C17H25N (243.4): calcd. C 83.95, H 10.29, N 5.76; found C 84.16,
H 10.18, N 5.64.
N-(1-Allylcyclohexyl)-N-(2Ј-methylphenyl)amine (2b): Yield 81%,
Rf ϭ 0.65, b.p. 118Ϫ122 °C/2 Torr; n2D3 ϭ 1.5494. IR (film): ν˜ ϭ
1
3445 (NH), 1638 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ
1.64Ϫ1.32 (m, 8 H, cycloalkyl H), 2.06Ϫ2.01 (m, 2 H, cycloalkyl
H), 2.19 (s, 3 H, 2Ј-Me), 2.56 (d, J ϭ 7.3 Hz, 2 H, 1-Hallyl), 3.38
(br. s, 1 H, NH), 5.02 (dd, J ϭ 17.4, 2.2 Hz, 1 H, 3-HZallyl), 5.06
(dd, J ϭ 10.2, 2.2 Hz, 1 H, 3-HEallyl), 5.79 (ddt, J ϭ 17.4, 10.2,
7.3 Hz, 1 H, 2-Hallyl), 6.65 (t, J ϭ 7.3 Hz, 1 H, 4Ј-H), 6.90 (d, J ϭ
7.3 Hz, 1 H, 6Ј-H), 7.02 (d, J ϭ 7.3 Hz, 1 H, 3Ј-H), 7.10 (br. t, J ϭ
7.3 Hz, 1 H, 5Ј-H) ppm. C16H23N (229.4): calcd. C 83.84, H 10.04,
N 6.11; found C 83.75, H 10.13, N 6.17.
N-(1-Allylcyclohexyl)-N-(2Ј-isopropylphenyl)amine (2h): Yield 65%,
Rf ϭ 0.72, b.p. 156Ϫ158 °C/4 Torr; n2D2 ϭ 1.5420. IR (film): ν˜ ϭ
1
3455 (NH), 1644 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ
1.26 [d, J ϭ 6.8 Hz, 6 H, CH(CH3)2], 1.58Ϫ1.43 (m, 8 H, cycloalkyl
H), 2.03Ϫ1.93 (m, 2 H, cycloalkyl H), 2.86 [sept, J ϭ 6.8 Hz,
CH(CH3)2, 1 H], 2.53 (br. d, J ϭ 7.2 Hz, 2 H, 1-Hallyl), 3.53 (br. s,
1 H, NH), 4.97 (m, J ϭ 17.5, 1.0 Hz, 1 H, 3-HZallyl), 5.01 (m, J ϭ
10.3, 1.0 Hz, 1 H, 3-HEallyl), 5.74 (ddt, J ϭ 17.5, 10.3, 7.2 Hz, 1 H,
2-Hallyl), 6.68 (dt, J ϭ 7.5, 1.6 Hz, 1 H, 4Ј-H), 6.87 (dd, J ϭ 7.5,
1.6 Hz, 1 H, 6Ј-H), 7.13 (dd, J ϭ 7.5, 1.6 Hz, 1 H, 3Ј-H), 7.02 (br.
dt, J ϭ 7.5, 1.6 Hz, 1 H, 5Ј-H) ppm. C18H27N (257.4): calcd. C
84.05, H 10.51, N 5.45; found C 83.95, H 10.60, N 5.41.
N-(1-Allylcycloheptyl)-N-(2Ј-methylphenyl)amine (2c): Yield 82%,
Rf ϭ 0.62, b.p. 125Ϫ127 °C/1.5 Torr. IR (film): ν˜ ϭ 3439 (NH),
1642 (CϭC) cmϪ1 1H NMR (CDCl3, 200 MHz): δ ϭ 1.50Ϫ1.78
.
(m, 10 H, cycloalkyl H), 1.99 (m, 2 H, cycloalkyl H), 2.15 (s, 3 H,
2Ј-Me), 2.54 (d, J ϭ 7.5 Hz, 2 H, 1-Hallyl), 3.39 (br. s, 1 H, NH),
4.98 (br. d, J ϭ 17.1 Hz, 1 H, 3-HZallyl), 5.00 (br. s, J ϭ 10.6 Hz, 1
H, 3-HEallyl), 5.75 (ddt, J ϭ 17.1, 10.6, 7.5 Hz, 1 H, 2-Hallyl), 6.62
(t, J ϭ 7.5 Hz, 1 H, 4Ј-H), 6.86 (d, J ϭ 7.5 Hz, 1 H, 6Ј-H), 7.05
(d, J ϭ 7.5 Hz, 1 H, 3Ј-H), 7.06 (t, J ϭ 7.5 Hz, 1 H, 5Ј-H) ppm.
C17H25N (243.4): calcd. C 83.95, H 10.29, N 5.76; found C 83.80,
H 10.17, N 5.59.
N-(1-Allylcyclohexyl)-N-(2Ј-benzylphenyl)amine (2i): White crystals,
yield 52%, Rf ϭ 0.72, m.p. 67Ϫ69 °C (from hexane). IR (KBr): ν˜ ϭ
1
3429 (NH), 1638 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ
N-(1-Allylcyclohexyl)-N-(2Ј,4Ј-dimethylphenyl)amine (2d): Yield
70%, Rf ϭ 0.61, b.p. 144Ϫ145 °C/ 1.5 Torr; n2D3 ϭ 1.5461. IR (film):
1.35Ϫ1.15 (m, 8 H, cycloalkyl H), 1.79 (m, 2 H, cycloalkyl H), 2.39
(dd, J ϭ 7.3, 1.0 Hz, 2 H, 1-Hallyl), 3.30 (br. s, 1 H, NH), 3.89 (br.
s, 2 H, CH2Ph), 4.84 (m, J ϭ 17.5, 1.5 Hz, 1 H, 3-HZallyl), 4.82 (m,
J ϭ 10.2 and 1.5 Hz, 1.0 Hz, 1 H, 3-HEallyl), 5.39 (ddt, J ϭ 17.5,
10.2, 7.3 Hz, 1 H, 2-Hallyl), 6.65 (dt, J ϭ 7.5, 1.1 Hz, 1 H, 4Ј-H),
6.84 (d, J ϭ 7.5 Hz, 1 H, 6Ј-H), 7.29Ϫ7.08 (m, 7 H, 5ЈϪH, 3Ј-H,
CH2Ph) ppm. C22H27N (305.5): calcd. C 86.56, H 8.85, N 4.59;
found C 86.55, H 8.88, N 4.60.
1
ν˜ ϭ 3448 (NH), 1639 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz):
δ ϭ 1.60Ϫ1.45 (m, 8 H, cycloalkyl H), 1.96 (m, 2 H, cycloalkyl H),
2.12 (s, 3 H, 2Ј-Me), 2.20 (s, 3 H, 4Ј-Me), 2.47 (d, J ϭ 7.2 Hz, 2
H, 1-Hallyl), 3.19 (br. s, 1 H, NH), 4.97 (m, J ϭ 17.6, 1.2 Hz, 1 H,
3-HZallyl), 5.01 (m, J ϭ 10.2, 1.2 Hz, 1 H, 3-HEallyl), 5.75 (ddt, J ϭ
17.6, 10.2, 7.2 Hz, 1 H, 2-Hallyl), 6.76 (d, J ϭ 7.9 Hz, 1 H, 6Ј-H),
6.86 (br. s, 1 H, 3Ј-H), 6.85 (br. d, J ϭ 7.9 Hz, 1 H, 5Ј-H) ppm.
C17H25N (243.4): calcd. C 83.95, H 10.29, N 5.76; found C 83.87,
H 10.13, N 5.59.
N-(1-Allylcyclopentyl)-N-(2Ј,6Ј-dimethylphenyl)amine (2k): Yield
36%, Rf ϭ 0.78, b.p. 145Ϫ147 °C/4 Torr; n2D5 ϭ 1.5430. IR (film):
1
ν˜ ϭ 3440 (NH), 1638 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz):
N-(1-Allylcyclohexyl)-N-(2Ј,3Ј-dimethylphenyl)amine (2e): Yield
82%, Rf ϭ 0.71, b.p. 161Ϫ165 °C/3 Torr; n2D0 ϭ 1.5517. IR (film):
δ ϭ 1.22 (t, J ϭ 7.6 Hz, 3 H, CH2CH3), 1.82Ϫ1.61 (m, 6 H, cyclo-
alkyl H), 1.98Ϫ1.89 (m, 2 H, cycloalkyl H), 2.42 (q, J ϭ 7.6 Hz, 2
H, CH2CH3), 2.56 (d, J ϭ 7.3 Hz, 2 H, 1-Hallyl), 3.67 (br. s, 1 H,
NH), 4.95 (m, J ϭ 17.2, 1.1 Hz, 1 H, 3-HZallyl), 5.00 (m, J ϭ 10.2,
1.1 Hz, 1 H, 3-HEallyl), 5.74 (ddt, J ϭ 17.2, 10.2, 7.3 Hz, 1 H, 2-
Hallyl), 6.65 (dt, J ϭ 7.5, 0.5 Hz, 1 H, 4Ј-H), 6.78 (d, J ϭ 7.5 Hz, 1
H, 6Ј-H), 7.05 (d, J ϭ 7.5 Hz, 1 H, 3Ј-H), 7.06 (dt, J ϭ 7.5, 0.5 Hz,
1 H, 5Ј-H) ppm. C16H23N (229.4): calcd. C 83.84, H 10.04, N 6.11;
found C 83.92, H 10.18, N 6.22.
1
ν˜ ϭ 3440 (NH), 1641 (CϭC) cmϪ1. H NMR (CDCl3, 200 MHz):
δ ϭ 1.65Ϫ1.20 (m, 8 H, cycloalkyl H), 1.99 (m, 2 H, cycloalkyl H),
2.05 (s, 3 H, 2Ј-Me), 2.26 (s, 3 H, 3Ј-Me), 2.49 (d, J ϭ 7.3 Hz, 2
H, 1-Hallyl), 3.33 (br. s, 1 H, NH), 4.97 (m, J ϭ 16.5, 2.4 Hz, 1 H,
3-HZallyl), 4.99 (m, J ϭ 10.7, 2.4 Hz, 1 H, 3-HEallyl), 5.75 (ddt, J ϭ
16.5, 10.7, 7.3 Hz, 1 H, 2-Hallyl), 6.53 (d, J ϭ 7.6 Hz, 1 H, 4Ј-H),
6.75 (d, J ϭ 7.6 Hz, 1 H, 6Ј-H), 6.92 (t, J ϭ 7.6 Hz, 1 H, 5Ј-H)
ppm. C17H25N (243.4): calcd. C 83.95, H 10.29, N 5.76; found C
83.83, H 10.17, N 5.77.
N-(1-Allylcyclohexyl)-N-(2Ј,6Ј-dimethylphenyl)amine (2l): Yield
N-(1-Allylcyclopentyl)-N-(2Ј-ethylphenyl)amine (2f): Yield 69%, 65%, Rf ϭ 0.70, b.p. 135Ϫ136 °C/2 Torr. IR (film): ν˜ ϭ 3360 (NH),
Rf ϭ 0.80, b.p. 132Ϫ133 °C/2.5 Torr; n2D3 ϭ 1.5459. IR (film): ν˜ ϭ
1640 (CϭC) cmϪ1 1H NMR (CDCl3, 400 MHz): δ ϭ 1.71Ϫ1.42
.
1
3432 (NH), 1635 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ (m, 10 H, cycloalkyl H), 2.35 (s, 6 H, 2Ј-Me and 6Ј-Me), 2.40 (d,
1.22 (t, J ϭ 7.6 Hz, 3 H, CH2CH3), 1.82Ϫ1.61 (m, 6 H, cycloalkyl J ϭ 7.4 Hz, 2 H, 1-Hallyl), 2.78 (br. s, 1 H, NH), 5.09 (m, J ϭ
H), 1.98Ϫ1.89 (m, 2 H, cycloalkyl H), 2.42 (q, J ϭ 7.6 Hz, 2 H,
17.4 Hz, 1 H, 3-HZallyl), 5.11 (m, J ϭ 10.3 Hz, 1 H, 3-HEallyl), 5.96
CH2CH3), 2.56 (d, J ϭ 7.3 Hz, 2 H, 1-Hallyl), 3.67 (br. s, 1 H, NH), (ddt, J ϭ 17.4, 10.3, 7.4 Hz, 1 H, 2-Hallyl), 6.86 (t, J ϭ 7.4 Hz, 1
4.95 (m, J ϭ 17.2, 1.1 Hz, 1 H, 3-HZallyl), 5.00 (m, J ϭ 10.2, 1.1 Hz, H, 4Ј-H), 6.99 (d, J ϭ 7.4 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. C17H25N
1 H, 3-HEallyl), 5.74 (ddt, J ϭ 17.2, 10.2, 7.3 Hz, 1 H, 2-Hallyl), 6.65 (243.4): calcd. C 83.95, H 10.29, N 5.76; found C 83.89, H 10.10,
(dt, J ϭ 7.5, 0.5 Hz, 1 H, 4Ј-H), 6.78 (d, J ϭ 7.5 Hz, 1 H, 6Ј-H), N 5.77.
5070
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5064Ϫ5074

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups
N-(1-Allylcyclohexyl)-N-(2Ј-ethyl-6Ј-methylphenyl)amine (2m):
FULL PAPER
187 (14), 186 (79), 172 (15), 158 (8), 157 (14). 1H NMR (CDCl3,
200 MHz): δ ϭ 1.85Ϫ1.59 (m, 8 H, cycloalkyl H), 1.41 (d, J ϭ
6.8 Hz, 3 H, 4Ј-Me), 1.65 (dd, J ϭ 12.8, 11.4 Hz, 1 H, 3Ј-HB), 1.84
Yield 51%, Rf ϭ 0.71, b.p. 145Ϫ148 °C/3.5 Torr. IR (film): ν˜ ϭ
1
3365 (NH), 1643 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ
1.16 (t, J ϭ 7.5 Hz, 3 H, CH2CH3), 1.48Ϫ1.38 (m, 6 H, cycloalkyl (dd, J ϭ 12.8, 5.6 Hz, 1 H, 3Ј-HA), 2.12 (s, 3 H, 8Ј-Me), 3.01 (ddq,
H), 1.63Ϫ1.57 (m, 4 H, cycloalkyl H), 2.33 (s, 3 H, 6Ј-Me), 2.35 J ϭ 11.4, 6.8, 5.6 Hz, 1 H, 4Ј-H), 3.60 (br. s, 1 H, NH), 6.63 (t,
(q, J ϭ 7.5 Hz, 2 H, CH2CH3), 2.35 (d, J ϭ 7.5 Hz, 2 H, 1-Hallyl), J ϭ 7.5 Hz, 1 H, 6Ј-H), 6.93 (d, J ϭ 7.5 Hz, 1 H, 7Ј-H), 7.10 (d,
2.88 (br. s, 1 H, NH), 5.11 (m, J ϭ 17.1 Hz, 1 H, 3-HZallyl), 5.12
(m, J ϭ 10.6 Hz, 1 H, 3-HEallyl), 5.96 (m, J ϭ 17.1, 10.6, 7.5 Hz, 1
H, 2-Hallyl), 6.93 (t, J ϭ 7.3 Hz, 1 H, 4Ј-H), 7.00 (d, J ϭ 7.3 Hz, 1
H, 3Ј-H), 7.04 (d, J ϭ 7.3 Hz, 1 H, 5Ј-H) ppm. C18H27N (257.4):
calcd. C 84.05, H 10.51, N 5.45; found C 84.10, H 10.61, N 5.62.
J ϭ 7.5 Hz, 1 H, 5Ј-H) ppm. C15H21N (215.4): calcd. C 83.72, H
9.77, N 6.51; found C 83.82, H 9.67, N 6.32.
3Ј,4Ј-Dihydro-4Ј,8Ј-dimethyl-1ЈH-spiro[cyclohexane-1,2Ј-quinoline]
(3b): Yield 84%, Rf ϭ 0.62, b.p. 125Ϫ128 °C/1.5 Torr. IR (film):
ν˜ ϭ 3415 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ 229 (39) [Mϩ],
214 (41), 200 (8), 186 (100), 173 (9), 170 (7), 158 (12), 143 (10), 130
N-(1-Allylcyclohexyl)-N-(2Ј,6Ј-diethylphenyl)amine (2n): Yield 50%,
Rf ϭ 0.73, b.p. 147Ϫ157 °C/4 Torr. IR (film): ν˜ ϭ 3378 (NH), 1641
1
(5), 115 (5). H NMR (CDCl3, 200 MHz): δ ϭ 1.85Ϫ1.40 (m, 10
(CϭC) cmϪ1 1H NMR (CDCl3, 400 MHz): δ ϭ 1.17 (t, J ϭ H, cycloalkyl H), 1.46 (d, J ϭ 6.7 Hz, 3 H, 4Ј-Me), 1.50 (t, J ϭ
.
7.5 Hz, 6 H, CH2CH3), 1.37Ϫ1.48 (m, 6 H, cycloalkyl H),
1.64Ϫ1.54 (m, 4 H, cycloalkyl H), 2.35 (d, J ϭ 7.5 Hz, 2 H, 1-
12.7, 12.5 Hz, 1 H, 3Ј-HB), 1.98 (dd, J ϭ 12.7, 5.4 Hz, 1 H, 3Ј-HA),
2.23 (s, 3 H, 8Ј-Me), 3.05 (ddq, J ϭ 12.5, 6.7, 5.4 Hz, 1 H, 4Ј-H),
Hallyl), 2.74 (q, J ϭ 7.5 Hz, 4 H, CH2CH3), 2.89 (br. s, 1 H, NH), 3.84 (br. s, 1 H, NH), 6.64 (t, J ϭ 8.0 Hz, 1 H, 6Ј-H), 6.95 (d, J ϭ
5.11 (m, J ϭ 16.1 Hz, 1 H, 3-HZallyl), 5.12 (m, J ϭ 10.7 Hz, 1 H, 8.0 Hz, 1 H, 7Ј-H), 7.11 (d, J ϭ 8.0 Hz, 1 H, 5Ј-H) ppm. C16H23N
3-HEallyl), 5.95 (m, J ϭ 16.1, 10.7, 7.5 Hz, 1 H, 2-Hallyl), 7.06Ϫ6.97 (229.4): calcd. C 83.84, H 10.04, N 6.11; found C 83.68, H 9.95,
(m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H) ppm. C19H29N (271.4): calcd. C 84.13,
N 6.12.
H 10.70, N 5.17; found C 84.21, H 10.78, N 5.13.
3Ј,4Ј-Dihydro-4Ј,8Ј-dimethyl-1ЈH-spiro[cycloheptane-1,2Ј-quinoline]
N-(2Ј-Ethylphenyl)-N-(1-methallylcyclohexyl)amine (9a): Yield 74%, (3c): Yield 79%, Rf ϭ 0.67, b.p. 128Ϫ130 °C/1.5 Torr. IR (film):
Rf ϭ 0.66, b.p. 139Ϫ143 °C/2.5 Torr; n2D3 ϭ 1.5470. IR (film): ν˜ ϭ
ν˜ ϭ 3370 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ 243 (33) [Mϩ],
1
1
3367 (NH), 1646 (CϭC) cmϪ1. H NMR (CDCl3, 400 MHz): δ ϭ 228 (62), 186 (100), 200 (19), 173 (10), 158 (13). H NMR (CDCl3,
1.25 (t, J ϭ 7.5 Hz, 3 H, CH2CH3), 1.62Ϫ1.40 (m, 8 H, cycloalkyl 400 MHz): δ ϭ 1.85Ϫ1.40 (m, 12 H, cycloalkyl H), 1.32 (d, J ϭ
H), 1.72 (br. s, 2 H, 1-Hallyl), 2.10Ϫ2.06 (m, 2 H, cycloalkyl H), 6.7 Hz, 3 H, 4Ј-Me), 1.76 (dd, J ϭ 12.6, 8.6 Hz, 1 H, 3Ј-HB), 1.91
2.48 (q, J ϭ 7.5 Hz, 2 H, CH2CH3), 2.50 (br. s, 3 H, 2-MEallyl),
(dd, J ϭ 12.6, 5.5 Hz, 1 H, 3Ј-HA), 2.09 (s, 3 H, 8Ј-Me), 2.91 (ddq,
3.47 (br. s, 1 H, NH), 4.59 (m, J ϭ 1.4 Hz, 1 H, 3-HAallyl), 4.83 (m, J ϭ 8.6, 6.7, 5.5 Hz, 1 H, 4Ј-H), 3.65 (br. s, 1 H, NH), 6.59 (t, J ϭ
J ϭ 1.4 Hz, 1 H, 3-HBallyl), 6.63 (br. t, J ϭ 7.5 Hz, 1 H, 5Ј-H), 6.86 7.5 Hz, 1 H, 6Ј-H), 6.89 (d, J ϭ 7.5 Hz, 1 H, 7Ј-H), 7.06 (d, J ϭ
(d, J ϭ 7.5 Hz, 1 H, 6Ј-H), 7.04 (t, J ϭ 7.5 Hz, 1 H, 4Ј-H), 7.05 7.5 Hz, 1 H, 5Ј-H) ppm. C17H25N (243.4): calcd. C 83.95, H 10.29,
(d, J ϭ 7.5 Hz, 1 H, 3Ј-H) ppm. C18H27N (257.4): calcd. C 84.05,
N 5.76; found C 84.15, H 10.15, N 5.82.
H 10.51, N 5.45; found C 84.23, H 10.62, N 5.68.
3Ј,4Ј-Dihydro-4Ј,6Ј,8Ј-trimethyl-1ЈH-spiro[cyclohexane-1,2Ј-quin-
N-(2Ј,6Ј-Dimethylphenyl)-N-(1-methallylcyclohexyl)amine
Yield 35%, Rf ϭ 0.74, b.p. 175Ϫ185 °C/9 Torr. IR (film): ν˜ ϭ 3345 1.5560. IR (film): ν˜ ϭ 3440 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ
(NH), 1648 (CϭC) cmϪ1 1H NMR (CDCl3, 400 MHz): δ ϭ 243 (33) [Mϩ], 228 (35), 214 (4), 200 (100), 187 (10), 184 (9), 172
1.75Ϫ1.41 (m, 10 H, cycloalkyl H), 1.97 (s, 3 H, 2-Meallyl), 2.35 (s,
(16), 157 (11). 1H NMR (CDCl3, 400 MHz): δ ϭ 1.75Ϫ1.45 (m, 10
6 H, 2Ј-Me and 6Ј-Me), 2.38 (br. s, 2 H, 1-Hallyl), 2.93 (br. s, 1 H, H, cycloalkyl H), 1.43 (d, J ϭ 6.9 Hz, 3 H, 4Ј-Me), 1.52 (dd, J ϭ
(9b):
oline] (3d): Yield 83%, Rf ϭ 0.48, b.p. 154Ϫ155 °C/2.5 Torr; nD23
ϭ
.
NH), 4.87 (br. s, J ϭ 1.3 Hz, 1 H, 3-HAallyl), 5.00 (m, J ϭ 1.3 Hz,
12.9, 12.0 Hz, 1 H, 3Ј-HB), 1.96 (dd, J ϭ 12.9, 5.4 Hz, 1 H, 3Ј-HA),
1 H, 3-HBallyl), 6.90 (t, J ϭ 7.4 Hz, 1 H, 4Ј-H), 7.03 (d, J ϭ 7.4 Hz, 2.20 (s, 3 H, 8Ј-Me), 2.32 (s, 3 H, 6Ј-Me), 3.01 (ddq, J ϭ 12.0, 6.9,
2 H, 3Ј-H and 5Ј-H) ppm. C18H27N (257.4): calcd. C 84.05, H 5.4 Hz, 1 H, 4Ј-H), 3.77 (br. s, 1 H, NH), 6.83 (s, 1 H, 7Ј-H), 6.98
10.51, N 5.45; found C 83.92, H 10.49, N 5.49.
(s, 1 H, 5Ј-H) ppm. C17H25N (243.4): calcd. C 83.95, H 10.29, N
5.76; found C 84.05, H 10.33, N 5.81.
4Ј-Methyl-3Ј,4Ј-dihydro-1ЈH-spiro[cycloalkane-1,2Ј-quinolines]
3a؊n, 4f, 4g, 5, 10, Aniline 11 and Cycloadducts 6k,l. Typical Pro-
cedure: Sulfuric acid (97%; 37 mL, 0.7 mol) was added rapidly to
a stirred solution of the homoallylamine 2aϪn (0.1 mol) (or me-
thallyl derivatives 9a,b) in CHCl3 (80 mL) at 50Ϫ60 °C. The re-
sulting mixture was heated at 60Ϫ65 °C for 3Ϫ5 h while stirring
vigorously. The reaction progress was monitored by TLC (until the
disappearance of the starting material spot). At the end of the reac-
tion, ice (ca. 200 mL) was added to the cooled reaction mixture,
3Ј,4Ј-Dihydro-4Ј,7Ј,8Ј-trimethyl-1ЈH-spiro[cyclohexane-1,2Ј-quin-
oline] (3e): Yield 83%, Rf ϭ 0.73, b.p. 151Ϫ153 °C/2 Torr; nD19
ϭ
1.5620. IR (film): ν˜ ϭ 3428 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ
243 (46) [Mϩ], 228 (36), 214 (3), 200 (100), 187 (6), 172 (10), 157
1
(6). H NMR (CDCl3, 400 MHz): δ ϭ 1.75Ϫ1.40 (m, 10 H, cyclo-
alkyl H), 1.40 (d, J ϭ 6.8 Hz, 3 H, 4Ј-Me), 1.42 (dd, J ϭ 12.8,
12.1 Hz, 1 H, 3Ј-HB), 1.94 (dd, J ϭ 12.8, 5.5 Hz, 1 H, 3Ј-HA), 2.12
(s, 3 H, 8Ј-Me), 2.33 (s, 3 H, 7Ј-Me), 3.01 (ddq, J ϭ 12.1, 6.8,
and then concentrated ammonium hydroxide solution (ca. 110 mL) 5.5 Hz, 1 H, 4Ј-H), 3.91 (br. s, 1 H, NH), 6.60 (d, J ϭ 7.9 Hz, 1 H,
was added until pH ϭ 10Ϫ11. Three 70-mL extractions with 6Ј-H), 7.04 (d, J ϭ 7.9 Hz, 1 H, 5Ј-H) ppm. C17H25N (243.4): calcd.
chloroform were performed. The organic layers were combined, C 83.95, H 10.29, N 5.76; found C 84.13, H 10.18, N 5.88.
dried (MgSO4) and concentrated. The oily residue was distilled in
8Ј-Ethyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclopentane-1,2Ј-quin-
oline] (3f) and 5Ј-Ethyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclopen-
tane-1,2Ј-quinoline] (4f): After fractional distillation of the reaction
mixture, separation of the products 3f, 4f was carried out by col-
vacuo to give the products 3aϪh, 10 as pale yellow oils or was
purified by column chromatography on alumina to give the prod-
ucts 3i, 3k, 3l, 3n, 3m, 4m, 5, 6k, 6l, 11.
3Ј,4Ј-Dihydro-4Ј,8Ј-dimethyl-1ЈH-spiro[cyclopentane-1,2Ј-quinoline] umn chromatography on Al2O3 (using hexane/ethyl acetate, 20:1 as
(3a): Yield 66%, Rf ϭ 0.60, b.p. 128Ϫ129 °C/1.5 Torr, m.p. (ϫ HCl)
176Ϫ178 °C; n2D0 ϭ 1.5621. IR (film): ν˜ ϭ 390 (NH) cmϪ1. EI-MS
(70 eV): m/z (%) ϭ 215 (36) [Mϩ], 214 (7), 201 (13), 200 (100),
eluent). 3f: Yield 59%, Rf ϭ 0.72, b.p. 139Ϫ140 °C/3 Torr, m.p. (ϫ
HCl) 164Ϫ166 °C (acetone). IR (film): ν˜ ϭ 3428 (NH) cmϪ1. EI-
MS (70 eV): m/z (%) ϭ 229 (39) [Mϩ], 214 (100), 200 (80), 186 (12),
Eur. J. Org. Chem. 2004, 5064Ϫ5074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5071

F. I. Zubkov, E. V. Nikitina, V. V. Kouznetsov, L. D. A. Duarte
22.31, 22.06 (C cycloalkyl) ppm. C17H25N (243.4): calcd. C 83.95,
FULL PAPER
172 (10), 156 (8). H NMR (CDCl3, 400 MHz): δ ϭ 1.33 (t, J ϭ
1
7.5 Hz, 3 H, CH2CH3), 1.9Ϫ1.6 (m, 8 H, cycloalkyl H), 1.45 (d, H 10.29, N 5.76; found C 83.97, H 10.17, N 5.83.
J ϭ 6.8 Hz, 3 H, 4Ј-Me), 1.72 (dd, J ϭ 12.6, 11.9 Hz, 1 H, 3Ј-HB),
3Ј,4Ј-Dihydro-8Ј-isopropyl-4Ј-methyl-1ЈH-spiro[cyclohexane-1,2Ј-
1.87 (dd, J ϭ 12.6, 5.5 Hz, 1 H, 3Ј-HA), 2.51 (q, J ϭ 7.5 Hz, 2 H,
quinoline] (3h): Yield 65%, Rf ϭ 0.67, b.p. 173Ϫ177 °C/4 Torr; nD23
ϭ
CH2CH3), 3.06 (m, J ϭ 11.9, 6.8, 5.5 Hz, 1 H, 4Ј-H), 3.82 (br. s, 1
H, NH), 6.74 (t, J ϭ 7.6 Hz, 1 H, 6Ј-H), 7.00 (dd, J ϭ 7.6, 1.1 Hz,
1 H, 7Ј-H), 7.16 (br. d, J ϭ 7.6 Hz, 1 H, 5Ј-H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ ϭ 60.6 (C-2Ј spiro), 42.2(a) (C-3Ј), 28.70
(C-4Ј), 126.0(b) (C-4aЈ), 124.5 (C-5Ј), 116.0 (C-6Ј), 125.3 (C-7Ј),
125.2(b) (C-8Ј), 141.0 (C-8aЈ), 20.6 (4Ј-Me), 23.6 (MeCH2), 12.7
(MeCH2), 41.1(a), 39.0, 23.6, 23.3 (C cycloalkyl) ppm. C16H23N
(229.4): calcd. C 83.84, H 10.04, N 6.11; found C 84.01, H 10.18,
N 6.41. 4f: Yield 17%, Rf ϭ 0.44, b.p. 139Ϫ140 °C/3 Torr, m.p. (ϫ
HCl) 201Ϫ204 °C (acetone). IR (film): ν˜ ϭ 3380 (NH) cmϪ1. EI-
MS (70 eV): m/z (%) ϭ 229 (32) [Mϩ], 214 (100), 200 (90), 186 (19),
1.5526. IR (film): ν˜ ϭ 3432 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ
257 (25) [Mϩ], 242 (34), 228 (4), 214 (100), 201 (6), 198 (7), 186
(10), 170 (6), 162 (6). 1H NMR (CDCl3, 400 MHz): δ ϭ 1.26 [d,
J ϭ 6.8 Hz, 3 H, CH(CH3)2], 1.27 [d, J ϭ 6.8 Hz, 3 H, CH(CH3)2],
1.67Ϫ1.44 (m, 10 H, cycloalkyl H), 1.34 (d, J ϭ 6.7 Hz, 3 H, 4Ј-
Me), 1.35 (dd, J ϭ 12.9, 11.8 Hz, 1 H, 3Ј-HB), 1.87 (dd, J ϭ 12.9,
5.1 Hz, 1 H, 3Ј-HA), 2.83 [sept, J ϭ 6.8 Hz, 1 H, CH(CH3)2], 2.93
(m, J ϭ 11.8, 6.7, 5.1 Hz, 1 H, 4Ј-H), 4.00 (br. s, 1 H, NH), 6.66
(dd, J ϭ 7.6, 1.3 Hz, 1 H, 6Ј-H), 6.99 (t, J ϭ 7.6 Hz, 1 H, 7Ј-H),
7.05 (dd, J ϭ 7.6, 1.3 Hz, 1 H, 5Ј-H) ppm. C18H27N (257.4): calcd.
C 84.05, H 10.51, N 5.45; found C 84.18, H 10.63, N 5.38.
1
172 (13), 156 (12), 143 (8). H NMR (CDCl3, 400 MHz): δ ϭ 1.32
(t, J ϭ 7.6 Hz, 3 H, CH2CH3), 1.6Ϫ1.9 (m, 8 H, cycloalkyl H),
1.39 (d, J ϭ 7.1 Hz, 3 H, 4Ј-Me), 1.88 (dd, J ϭ 13.4, 3.5 Hz, 1 H,
3Ј-HB), 2.17 (dd, J ϭ 13.4, 6.0 Hz, 1 H, 3Ј-HA), 2.66 and 2.75 (m,
J ϭ 7.6 Hz, 2 H, CH2CH3), 3.26 (m, J ϭ 7.1, 6.0, 3.5 Hz, 1 H, 4Ј-
H), 3.77 (br. s, 1 H, NH), 6.38 (br. d, J ϭ 7.9 Hz, 1 H, 8Ј-H), 6.62
(br. d, J ϭ 7.7 Hz, 1 H, 6Ј-H), 7.01 (t, J ϭ 7.8 Hz, 1 H, 7Ј-H) ppm.
13C NMR (CDCl3, 100.6 MHz): δ ϭ 60.1 (C-2Ј spiro), 41.1 (C-3Ј),
27.6 (C-4Ј), 124.1 (C-4aЈ), 142.0 (C-5Ј), 116.8 (C-6Ј), 126.3 (C-7Ј),
111.8 (C-8Ј), 143.2 (C-8aЈ), 21.8 (4Ј-Me), 24.6 (MeCH2), 15.5
(MeCH2), 41.9, 40.9, 24.0, 22.5 (C cycloalkyl) ppm. C16H23N
(229.4): calcd. C 83.84, H 10.04, N 6.11; found C 84.10, H 10.12,
N 6.38.
8Ј-Benzyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclohexane-1,2Ј-
quinoline] (3i) and 3Ј,4Ј-Dihydro-4Ј-methyl-1ЈH-spiro[cyclohexane-
1,2Ј-quinoline] (5): After the removal of chloroform, the residue
crystallized. The resulting crystals of 3i were recrystallized from a
hexane/ethyl acetate mixture. The mother liquor was concentrated
and the resulting residue was purified by column chromatography
on Al2O3 (using hexane/ethyl acetate, 20:1, as eluent) to give com-
pound 5. 3i: white crystals, yield 61%, Rf ϭ 0.67, m.p. 125Ϫ127 °C
(from hexane/ethyl acetate). IR (KBr): ν˜ ϭ 3430 (NH) cmϪ1. EI-
MS (70 eV): m/z (%) ϭ 305 (41) [Mϩ], 290 (39), 262 (100), 234 (7),
1
156 (10), 130 (14), 91 (13). H NMR (CDCl3, 400 MHz): δ ϭ 0.47
(br. q, 1 H, cycloalkyl H), 1.36Ϫ1.10 (m, 8 H, cycloalkyl H), 1.48
(m, 1 H, cycloalkyl H), 1.31 (d, J ϭ 6.7 Hz, 3 H, 4Ј-Me), 1.4 (br.
t, J ϭ 13.0 Hz, 1 H, 3Ј-HB), 1.71 (dd, J ϭ 13.0, 5.3 Hz, 1 H, 3Ј-HA),
2.91 (m, J ϭ 12.1, 6.7, 5.3 Hz, 1 H, 4Ј-H), 3.81 (d, J ϭ 15.7 Hz, 1
H, CHAHBPh), 3.91 (d, J ϭ 15.7 Hz, 1 H, CHAHBPh), 3.84 (br. s,
1 H, NH), 6.65 (t, J ϭ 7.5 Hz, 1 H, 6Ј-H), 6.95 (br. d, J ϭ 7.5 Hz,
1 H, 7Ј-H), 7.11 (br. d, J ϭ 7.5 Hz, 1 H, 5Ј-H), 7.30Ϫ7.18 (m, 5
H, CH2Ph) ppm. C22H27N (305.5): calcd. C 86.56, H 8.85, N 4.59;
found C 86.48, H 8.89, N 4.62. 5: Pale yellow oil, yield 13%, Rf ϭ
0.80. Its constants are in agree to those reported in the ref.[13]
8Ј-Ethyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclohexane-1,2Ј-quin-
oline] (3g) and 5Ј-Ethyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclohex-
ane-1,2Ј-quinoline] (4g): After fractional distillation of the reaction
mixture, separation of the products 3g, 4g was carried out by col-
umn chromatography on Al2O3 (using hexane/ethyl acetate, 20:1,
as eluent). 3g: Yield 61%, Rf ϭ 0.70, b.p. 142Ϫ143 °C/2 Torr, m.p.
(ϫ HCl) 172Ϫ174 °C (acetone). IR (film): ν˜ ϭ 3433 (NH) cmϪ1
.
EI-MS (70 eV): m/z (%) ϭ 243 (22) [Mϩ], 228 (30), 200 (100), 214
(5), 187 (8), 172 (10). 1H NMR (CDCl3, 400 MHz): δ ϭ 1.34 (t,
3Ј,4Ј-Dihydro-4Ј,5Ј,8Ј-trimethyl-1ЈH-spiro[cyclopentane-1,2Ј-quin-
J ϭ 7.5 Hz, 3 H, CH2CH3), 1.74Ϫ1.42 (m, 10 H, cycloalkyl H), oline] (3k) and 1,2,3,6a,7,9,10,11,11a,12,12a,12b-Dodecahydro-
1.41 (d, J ϭ 6.8 Hz, 3 H, 4Ј-Me), 1.40 (t, J ϭ 12.8 Hz, 1 H, 3Ј-
1,5,7,11,11a,12b-hexamethyl-7,12-ethenodispiro[quino[6,7-f]quin-
HB), 1.94 (dd, J ϭ 12.8, 5.5 Hz, 1 H, 3Ј-HA), 2.54 (q, J ϭ 7.5 Hz, oline-3,1Ј:9,1ЈЈ-bis(cyclopentane)] (6k): After the removal of chloro-
2 H, CH2CH3), 3.00 (ddq, J ϭ 12.8, 6.8, 5.5 Hz, 1 H, 4Ј-H), 3.97 form, the residue was purified by column chromatography on
(br. s, 1 H, NH), 6.70 (t, J ϭ 7.5 Hz, 1 H, 6Ј-H), 6.99 (dd, J ϭ 7.5,
Al2O3 (using hexane as eluent) to give compound 3k. The polycycle
1.1 Hz, 1 H, 7Ј-H), 7.13 (dd, J ϭ 7.5, 1.1 Hz, 1 H, 5Ј-H) ppm. 13C 6k was eluted with chloroform. 3k: Pale yellow oil, yield 53%, Rf ϭ
NMR (CDCl3, 100.6 MHz): δ ϭ 50.25 (C-2Ј spiro), 42.70 (C-3Ј), 0.78. IR (film): ν˜ ϭ 3430 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ
26.80 (C-4Ј), 125.90 (C-4aЈ), 124.38 (C-5Ј), 115.82 (C-6Ј), 125.35 229 (50) [Mϩ], 214 (100), 200 (84), 186 (17), 184 (18), 171 (29), 158
(C-7Ј), 125.27 (C-8Ј), 140.68 (C-8aЈ), 20.48 (4Ј-Me), 23.69 (10), 156 (9), 130 (7), 115 (7). 1H NMR (CDCl3, 400 MHz): δ ϭ
(MeCH2), 12.66 (MeCH2), 40.02, 35.88, 25.87, 21.82, 22.12 (C
cycloalkyl) ppm. C17H25N (243.4): calcd. C 83.95, H 10.29, N 5.76;
found C 83.91, H 10.33, N 5.82. 4g: Yield 23%, Rf ϭ 0.42, b.p.
1.85Ϫ1.64 (m, 8 H, cycloalkyl H), 1.29 (d, J ϭ 7.2 Hz, 3 H, 4Ј-
Me), 1.78 (dd, J ϭ 13.3, 3.7 Hz, 1 H, 3Ј-HB), 2.09 (dd, J ϭ 13.3,
6.4 Hz, 1 H, 3Ј-HA), 2.05 (s, 3 H, 8Ј-Me), 2.26 (s, 3 H, 5Ј-Me), 3.13
142Ϫ143 °C/2 Torr, m.p. (ϫ HCl) 208Ϫ210 °C (acetone). IR (film): (ddq, J ϭ 7.2, 6.4, 3.7 Hz, 1 H, 4Ј-H), 3.66 (br. s, 1 H, NH), 6.42
ν˜ ϭ 3385 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ 243 (21) [Mϩ],
(d, J ϭ 7.5 Hz, 1 H, 6Ј-H), 6.78 (d, J ϭ 7.5 Hz, 1 H, 7Ј-H) ppm.
228 (31), 214 (4), 200 (100), 187 (7), 172 (9). 1H NMR (CDCl3, C16H23N (229.4): calcd. C 83.84, H 10.04, N 6.11; found C 83.98,
400 MHz): δ ϭ 1.26 (t, J ϭ 7.6 Hz, 3 H, CH2CH3), 1.69Ϫ1.38 (m, H 9.88, N 6.07. 6k: White crystals, yield 16%, m.p. 172Ϫ175 °C
10 H, cycloalkyl H), 1.33 (d, J ϭ 7.2 Hz, 3 H, 4Ј-Me), 1.83 (dd,
(chloroform). IR (KBr): ν˜ ϭ 1649 and 1622 (NϭC and CϭC)
J ϭ 13.6, 4.9 Hz, 1 H, 3Ј-HB), 1.88 (dd, J ϭ 13.6, 6.4 Hz, 1 H, 3Ј-
cmϪ1. LC-MS: m/z (%) ϭ 459 ([M ϩ H]ϩ, 100), 230 (13). 1H NMR
HA), 2.65 (m, J ϭ 7.6 Hz, 2 H, CH2CH3), 3.18 (ddq, J ϭ 7.2, 6.4, (CDCl3, 400 MHz): δ ϭ 0.67 (s, 3 H, 11a-Me), 0.84 (d, J ϭ 6.8 Hz,
4.9 Hz, 1 H, 4Ј-H), 3.56 (br. s, 1 H, NH), 6.41 (dd, J ϭ 7.2, 1.2 Hz,
3 H, 1-Me), 0.86 (d, J ϭ 6.7 Hz, 3 H, 11-Me), 0.88 (s, 3 H, 12b-
1 H, 6Ј-H), 6.99 (t, J ϭ 7.2 Hz, 1 H, 7Ј-H), 6.60 (dd, J ϭ 7.2, Me), ca. 1.37 (m, 2 H, 2-H), 1.43 (dd, J ϭ 12.8, 13.8 Hz, 1 H, 10-
1.2 Hz, 1 H, 8Ј-H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ 50.95 HB), 1.39 (s, 3 H, 7-Me), 1.53 (dd, J ϭ 4.5, 13.8 Hz, 1 H, 10-HA),
(C-2Ј spiro), 42.06 (C-3Ј), 26.90 (C-4Ј), 125.40 (C-4aЈ), 142.05 (C- 1.72 (m, 3 H, 5-Me), 1.88 (m, 1 H, 11-H), 2.13 (m, 1 H, 1-H), 2.25
5Ј), 117.61 (C-6Ј), 126.23 (C-7Ј), 112.60 (C-8Ј), 143.52 (C-8aЈ), (d, J ϭ 8.3 Hz, 1 H, 12a-H), 2.33 (m, 1 H, 6a-H), 2.74 (d, J ϭ
22.07 (4Ј-Me), 24.89 (MeCH2), 15.49 (MeCH2), 39.51, 38.75, 25.57,
6.6 Hz, 1 H, 12-H), 5.69 (dd, J ϭ 1.4, 8.1 Hz, 1 H, 1ЈЈЈ-H), 5.77
5072
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5064Ϫ5074

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups
FULL PAPER
(dq, J ϭ 4.1, 1.4 Hz, 1 H, 6-H), 6.04 (dd, J ϭ 6.6, 8.1 Hz, 1 H, (C-5Ј), 118.7(c) (C-6Ј), 125.0(d) (C-7Ј), 124.3 (C-8Ј), 139.7 (C-8aЈ),
2ЈЈЈ-H), 1.8Ϫ1.2 (m, 16 H, cycloalkyl H) ppm. 13C NMR (CDCl3, 21.3(e) (4Ј-Me), 23.5 (MeCH2), 13.0 (MeCH2), 19.4 (5-Me) ppm.
100.6 MHz): δ ϭ 29.6 (C-1), 38.2 (C-2), 65.4(a) (C-3), 166.1 (C-4a), 4m: 1H NMR (CDCl3, 400 MHz): δ ϭ 1.28 (t, J ϭ 7.6 Hz, 3 H,
135.4 (C-5), 129.3 (C-6), 48.2 (C-6a), 49.1 (C-7), 176.2 (C-7a), CH2CH3), 1.4Ϫ1.8 (m, 10 H, cycloalkyl H), 1.36 (d, J ϭ 7.1 Hz, 3
55.8(a) (C-9), 38.8 (C-10), 28.2 (C-11), 39.7(b) (C-11a), 41.5 (C-12), H, 4Ј-Me), 1.89 (d, J ϭ 5.7 Hz, 2 H, 3Ј-H), 2.19 (s, 3 H, 8Ј-Me),
41.6 (C-12a), 42.1(b) (C-12b), 136.6 (C-1ЈЈЈ), 130.6 (C-2ЈЈЈ), 15.44 2.63 and 2.71 (m, J ϭ 7.6 Hz, 2 H, CH2CH3), 3.24 (m, J ϭ 7.6,
(1-Me), 19.8 (5-Me), 18.8 (7-Me), 15.48 (11-Me), 17.7 (11a-Me),
22.7 (12b-Me), 43.5, 42.7, 42.4, 40.0, 24.8, 24.5, 23.98, 23.19 (C-
cyclopentyl) ppm. C32H46N2 (458.7): calcd. C 83.84, H 10.04, N
6.11; found C 83.59, H 10.00, N 6.21.
5.7 Hz, 1 H, 4Ј-H), 3.84 (br. s, 1 H, NH), 6.57 (d, J ϭ 7.6 Hz, 1
H, 6Ј-H), 6.93 (d, J ϭ 7.6 Hz, 1 H, 7Ј-H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ ϭ 50.9(a) (C-2Ј spiro), 42.2 (C-3Ј), 27.4 (C-4Ј),
125.1(b) (C-4aЈ), 140.7 (C-5Ј), 116.6(c) (C-6Ј), 127.5(d) (C-7Ј), 118.4
(C-8Ј), 141.3 (C-8aЈ), 22.1(e) (4Ј-Me), 24.8 (MeCH2), 15.6
(MeCH2), 17.0 (8Ј-Me) ppm. Spirocyclohexane carbon signals of
the isomers 3m and 4m in the 13C NMR spectrum: δ ϭ 39.7, 39.4,
39.1, 38.3, 25.6, 25.57, 22.52, 22.4, 22.2, 22.1 ppm.
3Ј,4Ј-Dihydro-4Ј,5Ј,8Ј-trimethyl-1ЈH-spiro[cyclohexane-1,2Ј-quin-
oline] (3l) and 1,2,3,6a,7,9,10,11,11a,12,12a,12b-Dodecahydro-
1,5,7,11,11a,12b-hexamethyl-7,12-ethenodispiro[quino[6,7-f]quin-
oline-3,1Ј:9,1ЈЈ-bis(cyclohexane)] (6l): After the removal of chloro-
form, the residue was purified by column chromatography on
Al2O3 (using hexane as eluent) to give compound 3l. The polycycle
6l was eluted with chloroform. 3l: Pale yellow oil, yield 56%, Rf ϭ
0.73. IR (film): ν˜ ϭ 3433 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ
243 (25) [Mϩ], 228 (38), 214 (6), 200 (100), 187 (8), 184 (9), 172
(22), 158 (12). 1H NMR (CDCl3, 400 MHz): δ ϭ 1.69Ϫ1.33 (m, 10
H, cycloalkyl H), 1.28 (d, J ϭ 7.0 Hz, 3 H, 4Ј-Me), 1.76 (dd, J ϭ
13.5, 5.4 Hz, 1 H, 3Ј-HB), 1.88 (dd, J ϭ 13.5, 7.1 Hz, 1 H, 3Ј-HA),
2.11 (s, 3 H, 8Ј-Me), 2.26 (s, 3 H, 5Ј-Me), 3.09 (tq, J ϭ 7.0, 5.4 Hz,
1 H, 4Ј-H), 3.76 (br. s, 1 H, NH), 6.45 (d, J ϭ 7.5 Hz, 1 H, 6Ј-H),
6.80 (d, J ϭ 7.5 Hz, 1 H, 7Ј-H) ppm. C17H25N (243.4): calcd. C
83.95, H 10.29, N 5.76; found C 84.01, H 10.44, N 5.89. 6l: White
crystals, yield 26%, m.p. 173Ϫ175 °C (chloroform). IR (KBr): ν˜ ϭ
1656 and 1616 (NϭC and CϭC) cmϪ1. LC-MS: m/z (%) ϭ 487
5Ј,8Ј-Diethyl-3Ј,4Ј-dihydro-4Ј-methyl-1ЈH-spiro[cyclohexane-1,2Ј-
quinoline] (3n): Colorless oil, yield 94%, Rf ϭ 0.78. IR (film): ν˜ ϭ
3420 (NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ 271 (38) [Mϩ], 256
(41), 242 (6), 228 (100), 200 (12), 184 (8), 170 (6), 156 (4). 1H NMR
(CDCl3, 400 MHz): δ ϭ 1.21 (t, J ϭ 7.5 Hz, 3 H, 5Ј-CH2CH3),
1.26 (t, J ϭ 7.5 Hz, 3 H, 8Ј-CH2CH3), 1.72Ϫ1.33 (m, 10 H, cyclo-
alkyl H), 1.28 (d, J ϭ 7.1 Hz, 3 H, 4Ј-Me), 1.79 (dd, J ϭ 13.6,
6.2 Hz, 1 H, 3Ј-HB), 1.83 (dd, J ϭ 13.6, 4.7 Hz, 1 H, 3Ј-HA), 2.47
(q, J ϭ 7.5 Hz, 2 H, 8Ј-CH2CH3), 2.68Ϫ2.51 (m, J ϭ 7.5 Hz, 2 H,
5Ј-CH2CH3), 3.18 (m, J ϭ 7.1, 6.2, 4.7 Hz, 1 H, 4Ј-H), 3.86 (br. s,
1 H, NH), 6.55 (d, J ϭ 7.7 Hz, 1 H, 6Ј-H), 6.88 (d, J ϭ 7.7 Hz, 1
H, 7Ј-H) ppm. C19H29N (271.5): calcd. C 84.13, H 10.70, N 5.17;
found C 84.14, H 10.74, N 5.22.
8Ј-Ethyl-3Ј,4Ј-dihydro-4Ј,4Ј-dimethyl-1ЈH-spiro[cyclohexane-1,2Ј-
quinoline] (10): Yield 68%, Rf ϭ 0.78, b.p. 141Ϫ144 °C/1.5 Torr;
n2D3 ϭ 1.5539. IR (film): ν˜ ϭ 3427 (NH) cmϪ1. EI-MS (70 eV): m/
z (%) ϭ 257 (30) [Mϩ], 242 (41), 228 (18), 214 (100), 200 (46),
1
(100) [M ϩ H]ϩ, 244 (32). H NMR (CDCl3, 400 MHz): δ ϭ 0.67
(s, 3 H, 11a-Me), 0.83 (d, J ϭ 6.8 Hz, 3 H, 1-Me), 0.85 (d, J ϭ
6.8 Hz, 3 H, 11-Me), 0.87 (s, 3 H, 12b-Me), 1.09 (t, J ഠ 13.2 Hz,
1 H, 2-HB), 1.22 (t, J ϭ 12.8, 13.9 Hz, 1 H, 10-HB), 1.38 (s, 3 H,
7-H), 1.58 (dd, J ϭ 4.2, 13.9 Hz, 1 H, 10-HA), 1.61 (dd, J ϭ 3.1,
13.6 Hz, 1 H, 2-HA), 1.72 (m, 3 H, 5-Me), 1.86 (m, 1 H, 11-H),
2.12 (m, 1 H, 1-H), 2.24 (d, J ϭ 8.2 Hz, 1 H, 12a-H), 2.32 (m, 1
H, 6a-H), 2.73 (d, J ϭ 6.8 Hz, 1 H, 12-H), 5.69 (dd, J ϭ 1.1, 8.1 Hz,
1 H, 1ЈЈЈ-H), 5.79 (dq, J ϭ 4.1, 1.4 Hz, 1 H, 6-H), 6.02 (dd, J ϭ
6.6, 8.1 Hz, 1 H, 2ЈЈЈ-H), 1.8Ϫ1.2 (m, 20 H, cyclohexyl H) ppm.
13C NMR (CDCl3, 100.6 MHz): δ ϭ 27.1 (C-1), 36.5 (C-2), 55.9(a)
(C-3), 166.4 (C-4a), 135.5 (C-5), 129.3 (C-6), 48.5 (C-6a), 49.2 (C-
7), 176.3 (C-7a), 56.4(a) (C-9), 38.3 (C-10), 27.4 (C-11), 40.1(b) (C-
11a), 41.6 (C-12), 41.6 (C-12a), 42.6(b) (C-12b), 136.5 (C-1ЈЈЈ), 130.7
(C-2ЈЈЈ), 15.58 (1-Me), 19.8 (5-Me), 18.9 (7-Me), 15.5 (11-Me), 17.9
(11a-Me), 22.9 (12b-Me), 42.1, 40.9, 39.7, 36.9, 26.3, 26.0, 22.5,
22.3, 22.0, 21.8 (C cyclohexyl) ppm. C34H50N2 (486.8): calcd. C
83.95, H 10.29, N 5.76; found C 83.91, H 10.42, N 5.79.
1
186 (11), 172 (11), 143 (10), 130 (10), 115 (10). H NMR (CDCl3,
400 MHz): δ ϭ 1.27 (t, J ϭ 7.6 Hz, 3 H, CH2CH3), 1.58Ϫ1.36 (m,
10 H, cycloalkyl H), 1.32 (s, 6 H, 4Ј-Me), 1.73 (s, 2 H, 3Ј-H), 2.49
(q, J ϭ 7.6 Hz, 2 H, CH2CH3), 3.94 (br. s, 1 H, NH), 6.67 (t, J ϭ
7.6 Hz, 1 H, 6Ј-H), 6.91 (br. d, J ϭ 7.6 Hz, 1 H, 7Ј-H), 7.09 (dd,
J ϭ 7.6, 1.3 Hz, 1 H, 5Ј-H) ppm. C18H27N (257.4): calcd. C 84.05,
H 10.51, N 5.45; found C 83.78, H 10.33, N 5.48.
2,6-Dimethylaniline (11): Yield 33%. Spectroscopic data are in
agreement with those reported in the literature.
Acknowledgments
The authors would like to thank Konstantin F. Turchin (Center
for Chemistry of Drugs Ϫ All-Russian Institute for Chemical and
Pharmaceutical Research, Moscow, Russia), Grigorii G. Aleksand-
rov (Kurnakov Institute of General and Inorganic Chemistry, Rus-
sian Academy of Sciences, Moscow, Russia) and Dr. Alan England,
KBSI (Korean Basic Science Institute) for useful discussions during
the preparation of the manuscript. Partial financial support from
the Colombian Institute for Science and Research (Colciencias,
proyecto 1115-05-353-96) is acknowledged.
8Ј-Ethyl-3Ј,4Ј-dihydro-4Ј,5Ј-dimethyl-1ЈH-spiro[cyclohexane-1,2Ј-
quinoline] (3m) and 5Ј-Ethyl-3Ј,4Ј-dihydro-4Ј,8Ј-dimethyl-1ЈH-spiro-
[cyclohexane-1,2Ј-quinoline] (4m): Yellow oil, an inseparable mix-
ture of isomers, ca. 1:1, yield 77%, Rf ϭ 0.70. IR (film): ν˜ ϭ 3430
(NH) cmϪ1. EI-MS (70 eV): m/z (%) ϭ 257 (47) [Mϩ], 242 (61), 228
(12), 214 (100), 186 (9), 157 (5), 130 (4). C18H27N (257.4): calcd. C
84.05, H 10.51, N 5.45; found C 83.89, H 10.49, N 5.48. 1H and
13C NMR spectra were recorded for a mixture of isomers 3m and
[1] [1a]
1
G. A. Olah, R. Krishnamurti, G. K. S. Prakash,
4m. 3m: H NMR (CDCl3, 400 MHz): δ ϭ 1.33 (t, J ϭ 7.5 Hz, 3
‘‘FriedelϪCrafts Alkylations’’ in Comprehensive Organic Syn-
thesis (Eds.: B. M. Trost, I. Fleming) Pergamon Press, Oxford,
1991, vol. 3, pp. 293Ϫ300. [1b] H. Heaney, ‘‘The Intramolecular
Aromatic FriedelϪCrafts Reaction’’ in Comprehensive Organic
H, CH2CH3), 1.4Ϫ1.8 (m, 10 H, cycloalkyl H), 1.39 (d, J ϭ 7.1 Hz,
3 H, 4Ј-Me), 1.85 (dd, J ϭ 13.5, 5.3 Hz, 1 H, 3Ј-HB), 1.94 (dd, J ϭ
13.5, 7.0 Hz, 1 H, 3Ј-HA), 2.34 (s, 3 H, 5Ј-Me), 2.54 (q, J ϭ 7.5 Hz,
2 H, CH2CH3), 3.19 (ddq, J ϭ 7.1, 7.0, 5.3 Hz, 1 H, 4Ј-H), 3.94
(br. s, 1 H, NH), 6.57 (d, J ϭ 7.6 Hz, 1 H, 6Ј-H), 6.90 (d, J ϭ
7.6 Hz, 1 H, 7Ј-H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ
50.7(a) (C-2Ј spiro), 42.2 (C-3Ј), 27.0 (C-4Ј), 124.7(b) (C-4aЈ), 133.6
Synthesis (Eds.: B. M. Trost, I. Fleming) Pergamon Press, Ox-
[1c]
ford, 1991, vol. 2, pp. 753Ϫ768.
R. M. Roberts, A. A.
Khalaf, FriedelϪCrafts Alkylation Chemistry: A Century of
Discovery, Marcel Dekker, New York, 1984.
Eur. J. Org. Chem. 2004, 5064Ϫ5074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5073

F. I. Zubkov, E. V. Nikitina, V. V. Kouznetsov, L. D. A. Duarte
FULL PAPER
[2] [2a]
¯
J. B. Beck, R. N. Booher, A. C. Brown, R. Kwok, A. Poh-
C17H26ClN, M ϭ 279.84, space group P1, triclinic, a ϭ
land, J. Am. Chem. Soc. 1967, 89, 3934Ϫ3935. [2b] R. T. Conley,
11.002(3), b ϭ 12.954(6), c ϭ 14.058(8) A, α ϭ 90.51(3), β ϭ
˚
[2c]
3
˚
W. N. Knopka, J. Org. Chem. 1964, 29, 496Ϫ497.
Plostnieks, U. S. 3,706,522, 1973 (Chem. Abstr. 1973, 78,
J.
112.40(3), γ ϭ 113.73(3)°, Z ϭ 4, V ϭ 1664.3(13) A , ρcalcd.
ϭ
1.117 g ϫ cmϪ3, µ ϭ 0.219 cmϪ1, F(000) ϭ 608. Intensities
of 8882 reflections with I Ն 0.5σ(I) (8349 are independent of
symmetry) were measured. Final R1 value 0.0539 [wR2(F2) ϭ
0.2041] for 2013 reflections with I Ն 2σ(I) (Rint ϭ 0.0223),
GOOF ϭ 0.998. Crystal data for 6l: Crystal dimensions: 0.81
ϫ 0.31 ϫ 0.12 mm, colorless rhombuses, C34H50N2, M ϭ
486.76, space group P2(1)/c monoclinic, a ϭ 12.510(3), b ϭ
[2d]
29641f).
116, 4979Ϫ4980.
K. Yang, Tetrahedron: Asymmetry 2000, 11, 781Ϫ787.
G. Majetich, Y. Zhang, J. Am. Chem. Soc. 1994,
[2e]
Y. Gan, A. Li, X. Pan, A. S. C. Chan, T.-
[3] [3a]
G. Jones, ‘‘Quinolines’’ in The Chemistry of Heterocyclic
Compounds (Eds.: A. Weissberger, E. C. Taylor), John Wiley &
Sons, Chichester, 1977, vol. 32, part 1, pp. 93Ϫ318. [3b]V. V.
Kouznetsov, A. R. Palma, C. A. Ewert, A. V. Varlamov, J. Het-
erocycl. Chem. 1998, 35, 761Ϫ785. [3c] A. R. Katritzky, S. Rach-
wal, B. Rachwal, Tetrahedron 1996, 52, 15031Ϫ 15070.
˚
10.140(2), c ϭ 22.570(5) A, β ϭ 102.16(3)°, Z ϭ 4, V ϭ
2798.8(11) A , ρcalcd. ϭ 1.155 g ϫ cmϪ3, µ ϭ 0.660 cmϪ1
,
3
˚
F(000) ϭ 1072. Intensities of 4407 reflections with I Ն 0.5σ(I)
(4212 are independent of symmetry) were measured. The final
R1 value was 0.0747 [wR2(F2) ϭ 0.2359] for 1614 reflections
with I Ն 2σ(I) (Rint. ϭ 0.1238), GOOF ϭ 1.096.
[4] [4a]
S. Talukdar, C.-T. Chen, J. Org. Chem. 2000, 65,
3148Ϫ3153.
[4b]
M. Arisawa, C. Theeraladanon, A. Nishida,
[4c]
M. Nakagawa, Tetrahedron Lett. 2001, 42, 8029Ϫ8033.
R.
[9] [9a]
C. L. Perrin, D. A. Skinner, J. Am. Chem. Soc. 1971, 93,
Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, Eur. J. Org.
[9b]
3389Ϫ3394.
937Ϫ941.
J. G. Traynham, J. Chem. Educ. 1983, 60,
Chem. 2002, 1184Ϫ1190. [4d] H.-J. Knölker, R. Boese, K. Hart-
[4e]
mann, Tetrahedron Lett. 1991, 32, 1953Ϫ1956.
H.-J.
[10] [10a]
R.B. Moodie, K. Schofield, Acc. Chem. Res. 1976, 9,
[4f]
Knölker, H. Gössel, K. Hartmann, Synlett 1991, 428Ϫ430.
[10b]
287Ϫ292.
65, 6807Ϫ6818.
2002, 41, 1699Ϫ1700.
S. M. Hubig, J. K. Kochi, J. Org. Chem. 2000,
[4g]
H.-J. Knölker, Synlett 1992, 371Ϫ387.
H.-J. Knölker, E.
[10c]
F. Effenberger, Angew. Chem. Int. Ed.
Baum, H. Goesmann, H. Gössel, K. Hartmann, M. Kosub, U.
Locher, T. Sommer, Angew. Chem. Int. Ed. 2000, 39, 781Ϫ784.
[10d]
D. E. Pearson, M. G. Frazer, V. S.
Frazer, L. C. Washburn, Synthesis 1976, 621Ϫ624.
[5] [5a]
A. R. Palma, W. Rozo, E. Stashenko, D. Molina, V. Kouz-
[11] [11a]
F. A. Carrol, in Perspectives on Structure and mechanism
[5b]
netsov, J. Heterocycl. Chem. 1998, 35, 183Ϫ 186.
Palma, L. Y. Vargas, J. Silva, V. Kouznetsov, Heterocycl. Com-
mun. 1998, 4, 455Ϫ462.
V. Kouznetsov, E. Stashenko, A. Bahsas, J. Amaro-Luis, Tetra-
A. R.
in Organic Chemistry, Brooks/Cole Publishing Company, New
[11b]
York, 1998, p. 268.
R. Brückner, in Advanced Organic
[5c]
A. Palma, A. J. Silva, C. Carrillo,
Chemistry, Academic Press, New York, 2002, p. 66Ϫ67.
B. Love, K. M. Snader, J. Org. Chem. 1965, 30, 1914Ϫ1916.
N. S. Prostakov, V. V. Kuznetsov, E. E. Stashenko, Khim. Geter-
otsikl. Soedin. (Russ.) 1989, 1514Ϫ1519 (Chem. Abstr. 1990,
113, 40.424z).
[12]
[13]
[5d]
hedron 2002, 58, 8719Ϫ8727.
V. Kouznetsov, A. Palma, W.
Rozo, E. Stashenko, A. Bahsas, J. Amaro-Luis, Tetrahedron
2003, 59, 419Ϫ425.
V. V. Kouznetsov, F. I. Zubkov, E. V. Nikitina, L. D. A. Duarte,
Tetrahedron Lett. 2004, 45, 1981Ϫ1984.
V. Kouznetsov, F. Zubkov, A. Palma, G. Restrepo, Tetrahedron
Lett. 2002, 43, 4707Ϫ4709.
[6]
[7]
[8]
[14]
[15]
J. T. Lai, Tetrahedron Lett. 2002, 43, 1965Ϫ1967.
SMART (control) and SAINT (integration) software, version
5.0 Bruker AXS Inc., Madison, WI, 1997.
[16] [16a]
G. M. Sheldrick, SADABS, program for scaling and cor-
Crystallographic data for structures 4g and 6l have been de-
posited with the Cambridge Crystallographic Data Centre
(CCDC) as supplementary publication numbers CCDC-
220116 (4g) and -220117 (6l). Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223-336-
033; E-mail: deposit@ccdc.cam.ac.uk]. Crystal data for 4g:
Crystal dimensions: 0.30 ϫ 0.45 ϫ 0.85 mm, colorless prisms,
rection of area detector data, University of Göttingen, 1997
(based on the method of: H. Blessing, Acta Crystallogr., Sect.
A 1995, 51, 33). [16b] G. M. Sheldrick, SHELXL-97 Ϫ Program
for the refinement of crystal structures, University of Göttingen,
Germany, 1997. [16c] G. M. Sheldrick, SHELXS-97 Ϫ Program
for the Solution of Crystal Structures, University of Göttingen,
Germany, 1997.
Received May 20, 2004
5074
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5064Ϫ5074