Convenient synthesis of julolidines using benzotriazole methodology

Article abstract of DOI:10.1021/jo9519118

Reaction of N,N-bis[(benzotriazol-1-yl)methyl]aniline (2) with 1-vinylpyrrolidin-2-one gives a mixture of diastereomeric 1,7-bis(2-oxopyrrolidin-1-yl)julolidines 3. After reduction of 3 with LAH, the predominant trans diastereomer of 1,7-di(pyrrolidin-1-yl)julolidine (4) is separated. Reaction of 2 with ethyl vinyl ether yields predominantly trans-1,7-di(benzotriazol-1-yl)julolidine (11). Stepwise synthesis from tetrahydroquinoline 15 gives access to julolidines with two different substituents on C-1 and C-7. Reaction of 1-[(benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydroquinoline (25) with enolizable aldehydes gives a mixture of tetrahydroquinolines 26-29 which are converted into single julolidine products upon treatment with sodium hydride, LAH, or phenylmagnesium bromide. Reactions of 1,2,3,4-tetrahydroquinolines with benzotriazole and 2 molar equiv of enolizable aldehydes gives 1,2,3-trisubstituted julolidines 38-41, which with lithium aluminum hydride, sodium hydride, or a Grignard reagent produce single diastereomers of products 42, 43, and 45, respectively.

Full text of DOI:10.1021/jo9519118

J . Org. Chem. 1996, 61, 3117-3126
3117
Con ven ien t Syn th esis of J u lolid in es Usin g Ben zotr ia zole
Meth od ology
Alan R. Katritzky,* Bogumila Rachwal, and Stanislaw Rachwal
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Khalil A. Abboud
Department of Chemistry, University of Florida, Gainesville, Florida 32611
Received October 26, 1995X
Reaction of N,N-bis[(benzotriazol-1-yl)methyl]aniline (2) with 1-vinylpyrrolidin-2-one gives a mixture
of diastereomeric 1,7-bis(2-oxopyrrolidin-1-yl)julolidines 3. After reduction of 3 with LAH, the
predominant trans diastereomer of 1,7-di(pyrrolidin-1-yl)julolidine (4) is separated. Reaction of 2
with ethyl vinyl ether yields predominantly trans-1,7-di(benzotriazol-1-yl)julolidine (11). Stepwise
synthesis from tetrahydroquinoline 15 gives access to julolidines with two different substituents
on C-1 and C-7. Reaction of 1-[(benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydroquinoline (25) with
enolizable aldehydes gives a mixture of tetrahydroquinolines 26-29 which are converted into single
julolidine products upon treatment with sodium hydride, LAH, or phenylmagnesium bromide.
Reactions of 1,2,3,4-tetrahydroquinolines with benzotriazole and 2 molar equiv of enolizable
aldehydes gives 1,2,3-trisubstituted julolidines 38-41, which with lithium aluminum hydride,
sodium hydride, or a Grignard reagent produce single diastereomers of products 42, 43, and 45,
respectively.
Ch a r t 1
In tr od u ction
J ulolidine (1a ), 2,3,6,7-tetrahydro-1H,5H-benzo[ij]-
quinolizine, has been known for over a century (Chart
1).1 This compound and its derivatives have found recent
interest as photoconductive materials,2 chemilumines-
cence substances,3 chromogenic substrates in analytical
redox reactions,4,5 dye intermediates,6-8 potential anti-
depressants and tranquilizers,9 nonlinear optical materi-
als,10 high sensitivity photopolymerizable materials,11
and for improving color stability in photography.12 Su-
perior second-order nonlinear optical properties were
shown for julolidine derivative 1b.13 The traditional
synthetic path for julolidines involves alkylation of a
1,2,3,4-tetrahydroquinoline with 3-chloro-1-bromopro-
pane;14 a more recent version reacts aniline with an
excess of 3-chloro-1-bromopropane.15 We now present
novel syntheses of julolidines based on benzotriazole
methodology, which allow the preparation of a variety
of substituted derivatives.
Resu lts a n d Discu ssion
N-Vin yl-2-p yr r olid in on e. In a previous paper, we
reported that N-alkyl-N-[(benzotriazol-1-yl)methyl]ani-
lines react with N-vinylamides to give N-alkyl-4-amido-
1,2,3,4-tetrahydroquinolines.16 We now find that, under
similar conditions, the reaction of N,N-bis[(benzotriazol-
1-yl)methyl]aniline17 (2) with 1-vinyl-2-pyrolidinone yields
julolidine 3 in high yield (Scheme 1). According to NMR,
the crude product 3 was a mixture of two diastereomers
in an approximate ratio of 2:1. Because the asymmetric
carbon atoms are relatively distant from each other, the
NMR spectral properties of the individual diastereomers
were insufficiently different to allow definitive assign-
ment of their geometries. A sample highly enriched in
the predominant diastereomer (90%) was characterized
by NMR. In a literature example, chemical shifts of the
corresponding carbon resonances in diastereomeric cis-
and trans-2,6-dihydroxyjulolidines do not differ more
X Abstract published in Advance ACS Abstracts, April 1, 1996.
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S0022-3263(95)01911-6 CCC: $12.00 © 1996 American Chemical Society

3118 J . Org. Chem., Vol. 61, No. 9, 1996
Katritzky et al.
Sch em e 1
F igu r e 1.
of 8 which, upon recrystallization from ethanol, gave the
predominant isomer 11. The trans configuration of the
substituents in 11 was assigned on the basis of its C-3
resonance (δ 46.3) in a higher field than that of the minor
diastereomer (δ 46.6), in agreement with the rule deduced
from the spectra of compounds 3 and 4. Phenyl substit-
uents do not cause sufficient differentiation in the physi-
cal properties of diastereomers 13 to allow their separa-
tion; even the chemical shifts of their aliphatic 13C NMR
resonances are almost identical (∆δ < 0.1 ppm). The
relatively long distance between the asymmetric carbon
atoms in 14 prevented separation of its diastereomers.
We rationalize the formation of two alternative prod-
ucts 8 and 10 by postulating a stepwise reaction of 2 with
the two molecules of ethyl vinyl ether giving initially
tetrahydroquinoline 6.22 Reaction with the second mol-
ecule of ethyl vinyl ether proceeds via protonation of the
N-3 atom of the benzotriazole ring bound via a methylene
bridge to the tetrahydroquinoline nitrogen atom in 6 and
subsequent elimination of benzotriazole with formation
of the corresponding methyleneimmonium cation. This
cation attacks ethyl vinyl ether to produce carboxonium
cation 7, followed by one of two possible conversions: (i)
electrophilic attack on the aromatic ring giving 9 or (ii)
attack on the benzotriazole system giving 10. Compound
10 is stable, but under the reaction conditions, the ethoxy
group on 9 is substituted by benzotriazole, giving deriva-
tive 8.22 N,N-Bis(methoxymethyl)aniline and ethyl vinyl
ether are reported to give 1,7-diethoxyjulolidine (45%) in
a reaction similar to that depicted in Scheme 2.23
Un sym m et r ica lly 1,7-Disu b st it u t ed J u lolid in es.
Constructing the saturated rings of julolidines in a
stepwise manner enables the introduction of two different
substituents in positions 1 and 7 (cf. 1). Thus, condensa-
tion of 4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquino-
line16 (15) with 1-(hydroxymethyl)benzotriazole gave
derivative 16 which upon reaction with N-vinylacetamide
was converted to unsymmetrical julolidines 20 and 21
(Scheme 3). The reaction mechanisms involves an elec-
trophilic attack of the methyleneimmonium cation de-
rived from 16 on the vinyl group of N-vinylacetamide
leading to intermediate 18, in analogy to the case of the
tetrahydroquinolines previously discussed in detail.16 In
the following step, electrophilic attack of 18 on the ortho
position of the aromatic ring gives julolidine 20. Alter-
than 0.5 ppm;18 however, the diastereomers could be
separated by HPLC.19,20
Fortunately, reduction of the carbonyl groups of mixed
diastereomers 3 gave a mixture of the corresponding
amines 5 from which the predominant diastereomer 4
was separated by recrystallization. As the NMR spectra
could not determine the molecular geometry of 4, the
trans configuration of the substituents was determined
by X-ray crystallography (Figure 1).21 Thus, the pre-
dominant diastereomer of 3 must also be trans.
The definitive establishment of the structures of com-
pounds 3 and 5, followed by analysis of their NMR
spectra, allowed the formulation of rules which were then
used to assign the molecular geometry of similar com-
pounds obtained subsequently. The C-3 and H-3 (cf.
structure 1) resonances are the most sensitive to the
molecular geometry and were used diagnostically. Thus,
in the case of 4, the trans isomer (δ 44.6) exhibits the
C-3 signal at a higher field than the cis isomer (δ 45.9)
and the individual H-3 resonances of the cis isomer (δ
3.05 and 3.64) are more separated than those of the trans
isomer (δ 3.12 and 3.47).
Eth yl Vin yl Eth er . Reaction of 2 with ethyl vinyl
ether gave a complex and inseparable mixture of benzo-
triazolyl derivatives 8 and 10. Due to two asymmetric
centers, and three possible sets of benzotriazol-1-yl and
-2-yl substituents,17 8 and 10 each exist in several
different forms. The composition of the mixture was
determined by its treatment with lithium aluminum
hydride, eliminating the benzotriazole residues and the
asymmetric centers and converting 8 into julolidine (1)
and 10 into tetrahydroquinoline 12. This mixture could
be easily separated by column chromatography. In
another experiment, substitution of the benzotriazolyl by
phenyl groups in a reaction with phenylmagnesium
bromide eliminated the problem of benzotriazol-1-yl and
benzotriazol-2-yl isomerism, reduced dramatically the
number of the mixture components, and allowed separa-
tion of the main products, 13 and 14, each, as a mixture
of diastereomers (Scheme 2).
Column chromatography allowed separation of a frac-
tion consisting exclusively of isomers and diastereomers
(21) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK(.22) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J . Org. Chem. 1995,
60, 2588.
(18) Silhankova, A.; Trska, P.; Vlkova, D.; Ferles, M. Collect. Czech.
Chem. Commun. 1985, 50, 1048.
(19) Podzimek, S.; Dobas, I.; Svestka, S.; Horalek, J .; Tkaczyk, M.;
Kubin, M. J . Appl. Polym. Sci. 1990, 41, 1151.
(20) Podzimek, S.; Dobas, I.; Svestka, S.; Eichler, J .; Kubin, M. J .
Appl. Polym. Sci. 1991, 42, 791.
(23) Shono, T.; Matsumura, Y.; Inoue, K.; Ohmizu, H.; Kashimura,
S. J . Am. Chem. Soc. 1982, 104, 5753.

Convenient Synthesis of J ulolidines
J . Org. Chem., Vol. 61, No. 9, 1996 3119
Sch em e 2
natively, substitution of the acetamide by benzotriazole
via intermediate 17 gives cation 19 which leads then to
julolidine 21. The rotational isomerization of 20 caused
by the N-methylacetamido group hindered interpretation
of its NMR. However, 20 was smoothly converted to
julolidine 22 by lithium aluminum hydride.
NMR spectra showed formation of exclusively one
diastereomer for each of 21 and 22. By analogy to the
predominant diastereomer 4, compounds 21 and 22 were
assigned trans configurations. Treatment of 21 with
lithium aluminum hydride removed the benzotriazolyl
substituent and reduced the carbonyl group converting
21 into monosubstituted julolidine 23. J ulolidine 23 was
also obtained from 1,2,3,4-tetrahydroquinoline by react-
ing it with 1-(hydroxymethyl)benzotriazole followed by
1-vinyl-2-pyrrolidinone to give 24 and then reduction of
the carbonyl group in 24.
(δ 61.1, 18%), 28a (δ 69.3, 17%), 29a (δ 681, 5%). Three
major isomers, 26a -28a were separated by column
chromatography of the reaction mixture and fully char-
acterized. Column chromatography of a crude mixture
of 26b-29b gave a fraction consisting of benzotriazol-1-
yl isomers 26b (H-1, δ 5.94, d, J ) 9.4 Hz; CH3, δ 0.93,
d, J ) 6.6 Hz) and 27b (H-1, δ 6.04, d, J ) 4.5 Hz; CH3,
δ 0.78, d, J ) 6.9 Hz) in the ratio of 3:1. Isomer 26b
was characterized by complete 13C NMR data and 27b
by the 13C NMR of its aliphatic carbon resonances. The
trans configuration of the substituents in 26b was
confirmed by NOE; thus, irradiation of the methyl group
doublet at δ 0.93 produced 13% enhancement of the
H-1 doublet at δ 5.94. Mixtures of 26c and 27c and
26d and 27d were also separated and similarly charac-
terized. In the case of the derivatives of acetaldehyde
(R ) H), two isomers, 26e and 28e, were separated in
pure forms.
Treatment with lithium aluminum hydride converted
each of the mixtures of four isomers 26-29 into the
corresponding monosubstituted julolidine 31 in high
yields. 2-(Dialkylamino)julolidines (analogs of 31, R )
NR′2) found recent interest as central nervous system
agents; their reported synthesis from 8-(bromomethyl)-
quinoline is rather complex,25,26 but they should be
easily prepared from 25 and, e.g., commercially available
phthalimidoacetaldehyde diethyl acetal.
E n oliza b le Ald eh yd es. As recently reported,24
N-[(benzotriazol-1-yl)methyl]anilines react with enoliz-
able aldehydes to provide a convenient synthesis for 3,4-
disubstituted 1,2,3,4-tetrahydroquinolines. We now find
that this reaction can be effectively applied to the
synthesis of unsymmetrically substituted julolidines.
Thus, tetrahydroquinoline derivative 25 was reacted with
various aldehydes to give julolidines 26-29 in quantita-
tive yields, with the trans benzotriazol-1-yl isomer (26)
strongly predominanting (Scheme 4). For example,
integration of the C-1 peaks in the 13C NMR spectrum of
crude 26a -29a allowed estimation of the relative abun-
dance of the isomers as follows: 26a (δ 63.2, 60%), 27a
(25) Moon, M. W.; Heier, R. F.; Morris, J . K. PCT Int. Appl. WO, 90
15,058, 1990; Chem. Abstr. 1991, 114, 143420v.
(26) Moon, M. W.; Morris, J . K.; Heier, R. F.; Chidester, C. G.;
Hoffmann, W. E.; Piercey, M. F.; Althaus, J . S.; VonVoigtlander, P.
F.; Evans, D. L.; Figur, L. M.; Lahti, R. A. J . Med. Chem. 1992, 35,
1076.
(24) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J . Org. Chem. 1995,
60, 7631.

3120 J . Org. Chem., Vol. 61, No. 9, 1996
Katritzky et al.
Sch em e 3
did not react with oxygen during workup and was easily
separated and characterized. None of the hydroxy de-
rivatives 34a -c could be isolated pure. However, their
intermediacy in the reaction sequence is postulated on
the basis of previous results with 1,2,3,4-tetrahydro-
quinolines.24
2,3-Disu bstitu ted J u lolid in es. The new synthetic
methods for julolidines discussed so far involve building
of the C(1)-C(2)-C(3) bridge from two fragments: (i) the
CH2 group originating from formaldehyde and (ii) a vinyl
group from N-vinylamide, ethyl vinyl ether, or enolizable
aldehyde RCH2CHO. The use of aldehyde RCH2CHO
enables introduction of a substituent R at C-2. We have
also found that the method can be further extended by
use of higher aldehydes instead of formaldehyde as
fragment i. Thus, condensations of 1,2,3,4-tetrahydro-
quinolines with two molecules of aldehydes RCH2CHO
produced mixtures of isomeric julolidines 38-41. The
reaction is believed to proceed in two steps: (a) conden-
sation of 1,2,3,4-tetrahydroquinoline with an aldehyde
and benzotriazole giving 36, an analog of the formalde-
hyde derivative 25; (b) nucleophilic attack of immonium
cation 37 on the R carbon atom of an aldehyde in its enol
form, followed by cyclocondensation to produce julolidines
38-41 (Scheme 5).
Despite three asymmetric carbon atoms and benzo-
triazol-1-yl-benzotriazol-2-yl isomerization giving rise to
eight possible isomers, only four structures (38-41) were
detected in the product mixtures by NMR methods. The
benzotriazol-1-yl derivative 38 appeared to strongly
predominate in all instances. Thus, in the case of R )
Me, the crude product mixture consisted of 38b (70%, δ
(H-1) 5.83, J 1,2 ) 7.7 Hz), 39b (25%, δ (H-1) 6.00, J 1,2
)
11.9 Hz), 40b (4%, δ (H-1) 5.74, J 1,2 ) 6.2 Hz), and 41b
(1%, δ (H-1) 5.84, J 1,2 ) 10.8 Hz). Trans-trans config-
uration of the substituents in 38b was assigned by NOE;
thus, irradiation of the methyl group at C-2 (δ 0.95) gave
13% enhancement of the H-1 doublet at δ 5.83 and also
13% enhancement of the H-3 multiplet at δ 2.84. In a
second experiment, the H-3 (4%) and methyl group
signals (1%) were enhanced by irradiation of the H-1
doublet. All other structural assignments in this group
of derivatives were made accordingly.
Crude mixtures of 38-41 were each reduced with
lithium aluminum hydride, giving in each case a single
diastereomer 42. The trans configuration of the substit-
uents in 42b was confirmed by irradiation of the ethyl
methylene multiplet at δ 1.35, producing 3% NOE
enhancement of the H-2 multiplet at δ 2.00. Single
products (43) were also obtained from the reactions of
38-41 with sodium hydride.
Reaction of 38a with methylmagnesium iodide pro-
duced exclusively the trans,trans 1,2,3-trisubstituted
julolidine 45a . This can be explained by steric interaction
with the C-2 phenyl group during nucleophilic attack of
the Grignard reagent on the ionic intermediate 44.
Reaction of the mixture 38b-41b with phenylmagnesium
bromide also gave the single diastereomer, julolidine 45b,
supporting the intermediacy of cation 44. The trans,-
trans orientation of the substituents in 45b was proved
by NOE; irradiation of the C-2 methyl group doublet at
δ 0.95 gave 10% enhancement of the H-1 resonance at δ
3.67. Formation of diastereomer mixtures on cyclization
(38-41) but only trans,trans diastereomers (45) after
the Grignard addition reflects a general trend in tet-
rahydroquinoline systems; thus, condensation of N-
methylaniline with hydroxyethanal gives predominantly
Reactions of each of the crude mixtures of isomers 26-
29 with phenylmagnesium bromide produced exclusively
trans 1,2-disubstituted julolidines 32 in analogy to a
similar reaction of 3,4-disubstituted 1,2,3,4-tetrahydro-
quinolines.24 As examples of two such products, 32a (R
) Ph) and 32b (R ) Me) were investigated. The trans
configuration of the substituents in julolidine 32b was
confirmed by NOE; thus, irradiation of the methyl
doublet at δ 0.89 produced 12% enhancement of the H-1
doublet at δ 3.60 (J 1,2 ) 9.0 Hz). A similar value of the
coupling constant in the case of 32a (J 1,2 ) 8.4 Hz)
suggests that this also has a trans configuration of the
phenyl substituents. Reaction of a mixture of 26e and
28e with the same reagent gave 1-phenyljulolidine (32e).
Reactions with sodium hydride19 also eliminated the
asymmetry of julolidines 26-29 by conversion into
enamino derivatives 30. Enamine 30a was stable enough
to be separated, purified, and characterized. Upon
workup, 30b,c rearranged into imino derivatives 33b,c
which then were oxidized to alcohols 34b,c and dehy-
drated to products 35b,c. Compound 33e with R ) H

Convenient Synthesis of J ulolidines
J . Org. Chem., Vol. 61, No. 9, 1996 3121
Sch em e 4
under nitrogen and distilled immediately before use. Column
chromatography was conducted with silica gel grade 60-200
mesh.
cis,trans-1-methyl-2-(hydroxymethyl)-3-hydroxy-4-(meth-
ylphenylamino)-1,2,3,4-tetrahydroquinoline,27 whereas a
trans,trans isomer of 1,2,3,4-tetrakis(trimethylsilyl)-
1,2,3,4-tetrahydroquinoline is formed exclusively in a
reaction of quinoline with trimethylsilyl chloride and
lithium.28
1,7-Di(2-oxop yr r olid in -1-yl)ju lolid in e (3). p-Toluene-
sulfonic acid (0.04 g, 0.2 mmol) was added to a mixture of 2
(3.75 g, 10 mmol) and 1-vinyl-2-pyrrolidinone (2.50 g, 22
mmol), preheated to 130 °C (oil bath) and stirred under
nitrogen. The stirring at 130 °C was continued for an
additional 10 min. After cooling, the reaction mixture was
dissolved in chloroform and purified by column chromatogra-
phy to give a 2:1 mixture of trans and cis isomers of 3 (3.05 g,
90%). Repeated column chromatography of 3 (hexane/trieth-
ylamine) gave a fraction additionally enriched in the trans
isomer (90%), allowing its full NMR characterization: 1H NMR
δ 1.99 (m, 4 H), 2.11 (m, 4 H), 2.48 (t, J ) 8.1 Hz, 4 H), 3.14
(m, 4 H), 3.24 (m, 4 H), 5.35 (t, J ) 6.8 Hz, 2 H), 6.60 (t, J )
7.2 Hz, 1 H), 6.79 (d, J ) 7.5 Hz, 2 H); 13C NMR δ 18.3 (2 C),
26.9 (2 C), 31.4 (2 C), 44.2 (2 C), 47.4 (2 C), 47.9 (2 C), 116.8,
119.4 (2 C), 127.5 (2 C), 144.5, 175.1(2 C). Anal. Calcd for
C20H25N3O2: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.50; H,
7.42; N, 12.48.
Con clu sion s
The novel julolidine syntheses presented in this paper,
based on benzotriazole intermediates of type Ar-N-C-
Bt, offer both convenience and versatility. The method
is especially useful for the preparation of symmetrically
and asymmetrically 1,7-disubstituted julolidines as well
as for the introduction of one, two, or three substituents,
in any combination, at C-1, C-2, and C-3 in the julolidine
system.
Exp er im en ta l Section
tr a n s-1,7-Di(P yr r olid in -1-yl)ju lolid in e (4). A solution
of crude 3 (3.39 g, 10 mmol) and lithium aluminum hydride
(0.76 g, 20 mmol) in THF (20 mL) was stirred at 22 °C under
nitrogen for 1 h. The reaction mixture was poured into ice-
cold 10% NaOH (100 mL) and extracted with ether (3 × 100
mL). The combined extracts were dried over Na2CO3 and
evaporated to give a pure mixture of diastereomers 5 (2.20 g,
70%). Recrystallization from hexane/triethylamine (9:1) gave
pure trans diastereomers 4 as colorless plates: mp 113-114
Gen er a l. Melting points were determined on a capillary
melting point apparatus and are uncorrected. NMR spectra
were taken for solution in CDCl3 with tetramethylsilane as
internal standard for 1H (300 MHz) and 13C (75 MHz).
Solvents for the Grignard reactions and reductions (ether,
THF, toluene) were dried by reflux with sodium benzophenone
(27) Turner, A. B.; McBain, B. I.; Howie, R. A.; Cox, P. J . J . Chem.
Soc., Perkin Trans. 1 1986, 1151.
(28) Grignon-Dubois, M.; Fialeix, M.; Rezzonico, B. Can. J . Chem.
1990, 68, 2153.
1
°C; H NMR δ 1.73 (m, 8 H), 1.84 (tdd, J ) 13.2, 5.4, 3.3 Hz,
2 H), 2.10 (dq, J ) 13.5, 3.3 Hz, 2 H), 2.40 (m, 4 H), 2.67 (m,
4 H), 3.12 (ddd, J ) 11.1, 7.8, 2.7 Hz, 2 H), 3.17 (t, J ) 3.3 Hz,

3122 J . Org. Chem., Vol. 61, No. 9, 1996
Katritzky et al.
Sch em e 5
2 H), 3.47 (ddd, J ) 12.6, 11.1, 3.9 Hz, 2 H), 6.34 (t, J ) 7.2
Hz, 1 H), 6.90 (d, J ) 7.5 Hz, 2 H); 13C NMR δ 23.4 (4 C), 25.6
(2 C), 44.6 (2 C), 51.8 (4 C), 61.4 (2 C), 111.6, 121.3 (2 C), 129.7
(2 C), 140.9. Anal. Calcd for C20H29N3: C, 77.12; H, 9.38; N,
13.49. Found: C, 77.25; H, 9.53; N, 13.34.
subjected to column chromatography (hexane) to give julolidine
1 (0.72 g, 41%) as the first fraction: plates, mp 38 °C [lit.1 mp
40 °C].
After separation of 1, the column was eluted with chloroform
to give 12 (1.16 g, 51%) as a colorless oil: 1H NMR δ 1.22 (t,
J ) 7.1 Hz, 3 H), 1.85 (q, J ) 6.3 Hz, 2 H), 1.93 (m, 2 H), 2.75
(t, J ) 6.3 Hz, 2 H), 3.27 (t, J ) 5.7 Hz, 2 H), 3.36 (t, J ) 7.1
Hz, 2 H), 3.44-3.51 (m, 4 H), 6.54 (td, J ) 7.2, 0.9 Hz, 1 H),
6.60 (d, J ) 8.2 Hz, 1 H), 6.92 (d, J ) 6.8 Hz, 1 H), 7.03 (td, J
) 7.2, 1.2 Hz, 1 H); 13C NMR δ 15.2, 22.3, 26.9, 28.2, 48.3,
49.5, 66.2, 68.1, 110.6, 115.3, 122.2, 127.1, 129.1, 145.4. HRMS
calcd for C14H21NO (M+ + 1) 219.1623, found 219.1616.
1,7-Dip h en ylju lolid in e (13) a n d 1-(3-Eth oxy-3-p h en yl-
p r op yl)-4-p h en yl-1,2,3,4-tetr a h yd r oqu in olin e (14). An
ethereal solution of phenylmagnesium bromide (25 mL, 50
mmol) was added to a crude mixture of 8 and 10 (obtained
from 10 mmol of 2 according to the procedure given for 11)
and dissolved in toluene (50 mL). The ether was distilled off,
and the remaining toluene solution was heated at reflux under
nitrogen for 2 h. The reaction mixture was poured into ice-
water (100 g), neutralized with 10% acetic acid, and extracted
with ether (2 × 50 mL). The extract was washed with water
followed by 10% Na2CO3 (50 mL) and dried over anhydrous
Na2CO3. The solvent was evaporated under reduced pressure,
and the residue was subjected to column chromatography
(toluene) to give 13 (0.76 g, 23%) as the first fraction: colorless
oil; 1H NMR δ 2.12 (m, 2 H), 2.27 (m, 2 H), 3.13 (m, 4 H), 4.16
(m, 2 H), 6.39 (m, 1 H), 6.61 (m, 2 H), 7.16 (m, 5 H), 7.30 (m,
5 H); 13C NMR δ 30.6 (2 C), 43.4 (2 C), 47.2 (2 C), 115.6 (2 C),
123.4, 126.0 (2 C), 128.2 (4 C), 128.5 (2 C), 128.6 (4 C), 143.2,
146.9 (2 C). Anal. Calcd for C24H23N: C, 88.57; H, 7.12; N,
4.30. Found: C, 88.40; H, 7.26; N, 4.50.
tr a n s-1,7-Di(Ben zotr ia zol-1-yl)ju lolid in e (11). p-Tolu-
enesulfonic acid (0.04 g, 0.2 mmol) was added to a solution of
2 (3.55 g, 10 mmol) and ethyl vinyl ether (2.1 mL, 22 mmol)
in THF (40 mL), and the obtained solution was set aside at
22 °C for 18 h. The reaction mixture was poured into ice-
water (50 g) and extracted with chloroform (2 × 30 mL). The
combined extracts were washed with 10% Na2CO3 (50 mL)
followed by water and dried over Na2CO3. Evaporation of the
solvent gave a mixture of 8 and 10 (1:1). The mixture was
separated into 10 (first fraction) and 8 (second fraction) using
column chromatography with ethyl acetate as eluent. Careful
rechromatography of the fraction containing two diastereomers
of the di(benzotriazol-1-yl) isomer of 8 and recrystallization
of this fraction from ethanol gave pure trans isomer 11 (0.57
1
g, 14%) as fine needles: mp 197-198 °C; H NMR δ 2.64 (m,
4 H), 3.37 (m, 4 H), 6.33 (t, J ) 6.6 Hz, 2 H), 6.48 (t, J ) 7.5
Hz, 2 H), 6.83 (d, J ) 7.6 Hz, 2 H), 7.25-7.50 (m, 5 H), 8.08
(d, J ) 8.1 Hz, 2 H); 13C NMR δ 28.7 (2 C), 46.3 (2 C), 56.2 (2
C), 110.7 (2 C), 117.0, 117.3 (2 C), 119.8 (2 C), 123.8 (2 C),
127.3 (2 C), 130.4 (2 C), 132.3 (2 C), 144.1, 146.2 (2 C). Anal.
Calcd for C24H21N7: C, 70.74; H, 5.19; N, 24.06. Found: C,
70.42; H, 5.22; N, 23.67.
1-(3-Eth oxypr opyl)-1,2,3,4-tetr ah ydr oqu in olin e (12) an d
J u lolid in e (1). A crude mixture of 8 and 10, obtained from
the reaction of 2 (3.55 g, 10 mmol) with ethyl vinyl ether, was
treated with lithium aluminum hydride (0.76 g, 20 mmol) in
refluxing anisole (20 mL) under nitrogen for 5 h. After cooling,
the reaction mixture was poured into ice-cold 20% NaOH (100
mL) and extracted with ether (2 × 50 mL). The extract was
washed with 10% NaOH, dried over Na2CO3, and evaporated
under atmospheric pressure to remove ether and then under
reduced pressure (1 Torr) to remove anisole. The residue was
The second fraction (the same eluent) gave 14 (0.74 g, 20%)
as a colorless oil: 1H NMR δ 1.19 (m, 3 H), 1.90-2.10 (m, 3
H), 2.20 (m, 1 H), 3.15-3.55 (m, 6 H), 4.12 (t, J ) 5.3 Hz, 1
H), 4.27 (m, 1 H), 6.51 (t, J ) 7.3 Hz, 1 H), 6.65 (d, J ) 8.3 Hz,
1 H), 6.76 (d, J ) 7.1 Hz, 1 H), 7.09 (d, J ) 8.1 Hz, 2 H), 7.15-
7.35 (m, 9 H); 13C NMR δ 15.3, 30.5, 35.1, 43.3, 45.8, 47.9,

Convenient Synthesis of J ulolidines
J . Org. Chem., Vol. 61, No. 9, 1996 3123
64.1, 79.8, 110.7, 115.4, 123.9, 126.0, 126.4 (2 C), 127.5, 127.6,
128.2 (2 C), 128.4 (2 C), 128.6 (2 C), 130.2, 142.7, 145.4, 146.5.
Anal. Calcd for C26H29NO: C, 84.06; H, 7.87; N, 3.77.
Found: C, 84.11; H, 7.92; N, 4.00.
1-[(Ben zotr ia zol-1-yl)m eth yl]-1,2,3,4-tetr a h yd r oqu in o-
lin e (25). A solution of 1-(hydroxymethyl)benzotriazole (14.92
g, 100 mmol) and 1,2,3,4-tetrahydroquinoline (12.6 mL, 100
mmol) in tetrahydrofuran (100 mL) was stored over molecular
sieves (4 Å, 40 g) for 20 h. Some crystals of precipitating 25
were manually separated, dried, and submitted for analysis.
The remaining crystals were dissolved by addition of chloro-
form (100 mL), and the obtained solution was evaporated to
give 25 (contaminated with its benzotriazol-2-yl isomer)sthis
mixture was used for further reactions. Pure 25 was obtained
1-[(Ben zotr ia zol-1-yl)m eth yl]-4-(2-oxop yr r olid in -1-yl)-
1,2,3,4-tetr a h yd r oqu in olin e (16). A mixture of 15 (2.17 g,
10 mmol) and 1-(hydroxymethyl)benzotriazole (1.49 g, 10
mmol) in toluene (50 mL) was refluxed under a Dean-Stark
trap for 1 h. The toluene solution was evaporated to give a
crude mixture of 16 and its benzotriazol-2-yl isomer.
Rea ction of 16 w ith N-Vin yla ceta m id e. A mixture of
crude 16 (3.48 g, 10 mmol) and N-vinylacetamide (0.99 g, 10
mmol) was preheated to 120 °C, and then p-toluenesulfonic
acid monohydrate (0.02 g, 0.1 mmol) was added. The heating
at 120 °C was continued for 10 additional minutes, and the
mixture was allowed to cool to room temperature. The
obtained mass was dissolved in chloroform (50 mL) and
washed with 10% Na2CO3 (50 mL). The solution was dried
(Na2CO3) and evaporated under reduced pressure. The residue
was subjected to column chromatography (ethyl acetate) to give
21 as the first fraction: glassy material; 1H NMR δ 2.00-2.30
(m, 4 H), 2.55 (m, 4H), 3.10-3.50 (m, 6 H), 5.56 (dd, J ) 6.1,
9.5 Hz, 1 H), 6.26 (t, J ) 4.9 Hz, 1 H), 6.56 (t, J ) 7.6 Hz, 1
H), 6.74-6.82 (m, 2 H), 6.91 (d, J ) 7.5 Hz, 1 H), 7.29 (m, 2
H), 8.04 (m, 1 H); 13C NMR δ 18.3, 26.1, 29.7, 31.4, 43.4, 46.3,
47.7, 48.4, 56.6, 110.9, 116.6, 117.1, 119.9, 120.0, 123.6, 127.2,
128.4, 129.6, 132.3, 144.2, 146.2, 175.5. Anal. Calcd for
C22H23N5O: C, 70.76; H, 6.21; N, 18.75. Found: C, 71.01; H,
6.26; N, 18.76.
1
as large colorless prisms: mp 139-140 °C; H NMR δ 1.86-
1.94 (m, 2 H), 2.72 (t, J ) 6.3 Hz, 2 H), 3.52 (t, J ) 5.5 Hz, 2
H), 6.13 (s, 2 H), 6.75 (td, J ) 6.9, 1.6 Hz, 1 H), 7.00 (d, J )
7.3 Hz, 1 H), 7.12-7.21 (m, 2 H), 7.32-7.51 (m, 3 H), 8.06
(dd, J ) 0.8, 8.3 Hz, 1 H); 13C NMR δ 21.7, 27.6, 49.3, 65.1,
110.0, 112.6, 118.6, 119.8, 123.8 (2 C), 127.1, 127.4, 129.7,
132.5, 143.0, 146.1. Anal. Calcd for C16H16N4: C, 72.70; H,
6.10; N, 21.20. Found: C, 72.61; H, 6.14; N, 21.26.
1-(2-Oxopyr r olidin -1-yl)ju lolidin e (24). p-Toluenesulfon-
ic acid monohydrate (20 mg, 0.1 mmol) was added to a mixture
of 25 (2.64 g, 10 mmol) and 1-vinyl-2-pyrrolidinone (1.25 g, 11
mmol) preheated to 120 °C. The mixture was kept at 120 °C
for 10 min, cooled, and dissolved in chloroform (50 mL). The
solution was washed with 10% Na2
CO3. The solvent was
evaporated, and the residue was subjected to column chroma-
tography (ethyl acetate) to give as the first fraction pure 24
(2.15 g, 84%) as a sticky oil:
1H NMR δ 1.95-2.15 (m, 6 H),
2.50 (t, J ) 7.9 Hz, 2 H), 2.70-2.86 (m, 2 H), 3.06-3.28 (m, 6
H), 5.41 (dd, J ) 7.2 and 8.3 Hz, 1 H), 6.55 (td, J ) 7.4 and
1.1 Hz, 1 H), 6.71 (d, J ) 7.6 Hz, 1 H), 6.86 (d, J ) 6.6 Hz, 1
H); 13C NMR δ 18.2, 21.9, 26.4, 27.3, 31.4, 43.6, 47.9, 48.2,
50.0, 116.3, 118.7, 122.3, 125.6, 128.3, 143.8, 175.3. Anal.
Calcd for C16H20N2O: C, 74.97; H, 7.87; N, 10.93. Found: C,
74.66; H, 8.19; N, 10.79.
The second fraction from column chromatography (eluted
with ethyl acetate/triethylamine, 9:1) gave 20 (1.31 g, 42%)
as a mixture of two rotamers: oil. The product was character-
ized after reduction of its carbonyl groups.
1-(N-E t h yl-N-m et h yla m in o)-7-(p yr r olid in -1-yl)ju loli-
d in e (22). A solution of 20 (0.95 g, 3 mmol) and LiAlH4 (0.23
g, 6 mmol) in THF (10 mL) was refluxed under nitrogen for
10 min. The reaction mixture was poured into 10% NaOH
and extracted with ether (2 × 20 mL). The combined extracts
were washed with 10% NaOH (20 mL), dried over Na2CO3,
and evaporated. The residue was purified by column chro-
matography (ethyl acetate/triethylamine, 9:1) to give a pure
diastereomer 22 (0.30 g, 33%): oil; 1H NMR δ 1.06 (t, J ) 7.1
Hz, 3 H), 1.73 (m, 5 H), 1.85 (m, 1 H), 2.00 (m, 1 H), 2.12 (m,
1 H), 2.24 (s, 3 H), 2.44 (m, 3 H), 2.64 (m, 3 H), 3.01 (m, 1 H),
3.18 (t, J ) 3.4 Hz, 1 H), 3.23 (ddd, J ) 4.5, 6.9, 11.4 Hz, 1 H),
3.31 (ddd, J ) 4.2, 7.8, 11.4 Hz, 1 H), 3.47 (ddd, J ) 3.5, 11.0,
12.6 Hz, 1 H), 3.72 (dd, J ) 4.6, 8.0 Hz, 1 H), 6.46 (t, J ) 7.4
Hz, 1 H), 6.91 (dd, J ) 1.7, 7.4 Hz, 1 H), 7.20 (ddd, J ) 0.9,
1.7, 7.5 Hz, 1 H); 13C NMR δ 12.8, 21.1, 23.3 (2 C), 25.5, 37.9,
45.3, 47.1, 47.5, 51.5 (2 C), 60.0, 60.7, 113.2 (2 C), 128.3 (2 C),
129.5, 142.3. Anal. Calcd for C19H29N3: C, 76.21; H, 9.76; N,
14.03. Found: 76.45; H, 9.83; N, 14.02.
1-(P yr r olid in -1-yl)ju lolid in e (23). Meth od A. A solution
of 21 (0.37 g, 1 mmol) and LiAlH4 (0.12 g, 3 mmol) in anisole
(5 mL) was heated at reflux under nitrogen for 30 min. The
reaction mixture was poured into 20% NaOH (10 mL) and
extracted with ether (2 × 10 mL). The extract was dried over
Na2CO3, and the solvents were evaporated using rotavapor
and then under 1 Torr (oil vacuum pump) to give 23 (0.21 g,
88%) as a colorless oil: 1H NMR δ 1.68-2.00 (m, 7 H), 2.10
(dq, J ) 13.5, 3.9 Hz, 1 H), 2.39-2.47 (m, 2 H), 2.62-2.75 (m,
4 H), 3.00 (dt, J ) 8.2, 4.1 Hz, 1 H), 3.11-3.30 (m, 3 H),
3.48 (td, J ) 11.6, 3.6 Hz, 1 H), 6.42 (t, J ) 7.4 Hz, 1 H), 6.81
(dd, J ) 0.8, 7.3 Hz, 1 H), 6.89 (dd, J ) 1.2, 7.5 Hz, 1 H); 13C
NMR δ 21.7, 23.3 (2 C), 25.0, 27.8, 45.6, 49.6, 51.2 (2 C), 60.5,
113.5, 120.9, 121.3, 127.9, 128.2, 141.8. Anal. Calcd for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.07; H,
9.08; N, 11.87.
1-Ben zotr ia zolyl-2-p h en ylju lolid in es (26a -29a ). A so-
lution of 25 (2.64 g, 10 mmol), phenylacetaldehyde (1.2 mL,
10 mmol), and p-toluenesulfonic acid monohydrate (20 mg, 0.1
mmol) in THF (20 mL) was stored over molecular sieves (5 g,
4 Å) for 2 h with occasional shaking. The solution was
decanted, and the molecular sieves were washed with THF (2
× 10 mL). The solution and the washings were combined and
evaporated under reduced pressure to give a crude mixture of
26a -29a . Column chromatography (chloroform) of the mix-
ture gave trans-1-(benzotriazol-2-yl)-2-phenyljulolidine (28a )
(0.51 g, 14%) as cuboids (from ether): mp 141-143 °C; 1H
NMR δ 1.95-2.20 (m, 2 H), 2.75-2.87 (m, 2 H), 3.19 (ddd, J
) 3.6, 9.3, 11.1 Hz, 1 H), 3.28-3.35 (m, 1 H), 3.45 (dd, J )
4.4, 11.9 Hz, 1 H), 3.54 (dd, J ) 10.3, 11.8 Hz, 1 H), 4.22 (td,
J ) 10.1, 4.4 Hz, 1 H), 6.30 (d, J ) 7.7 Hz, 1 H), 6.38 (d, J )
10.1 Hz, 1 H), 6.43 (t, J ) 7.7 Hz, 1 H), 6.90 (d, J ) 10.1 Hz,
1 H), 7.19 (s, 5 H), 7.31 (m, 2 H), 7.81 (m, 2 H); 13C NMR δ
21.9, 27.5, 44.8, 50.0, 54.5, 69.4, 116.6, 118.3 (2 C), 119.3, 122.4,
125.7, 126.0 (2 C), 127.3, 127.4 (2 C), 128.7 (2 C), 129.2, 139.8,
142.4, 144.1 (2 C). Anal. Calcd for C24H22N4: C, 78.66; H,
6.05; N, 15.29. Found: C, 78.48; H, 6.06; N, 15.05.
The second fraction from column chromatography yielded
trans-1-(benzotriazol-1-yl)-2-phenyljulolidine (26a ) (2.23 g,
61%) as cuboids (from ether): mp 133-135 °C; 1H NMR δ
2.01-2.25 (m, 2 H), 2.79-2.98 (m, 2 H), 3.23 (td, J ) 7.6, 3.4
Hz, 1 H), 3.30 (t, J ) 4.4 Hz, 1 H), 3.37 (dd, J ) 3.9, 11.8 Hz,
1 H), 3.62 (dd, J ) 10.9, 11.8 Hz, 1 H), 3.96 (td, J ) 10.7, 3.8
Hz, 1 H), 6.29 (d, J ) 7.6 Hz, 1 H), 6.42 (m, 2 H), 6.93 (d, J )
7.4 Hz, 1 H), 7.00 (m, 2 H), 7.15 (m, 3 H), 7.27 (m, 3 H), 7.99
(m, 1 H); 13C NMR δ 22.0, 27.4, 44.3, 50.1, 55.0, 63.3, 110.7,
117.0, 118.5, 120.1, 122.6, 123.6, 125.9, 127.0, 127.2 (2 C),
127.5, 128.8 (2 C), 129.3, 132.0, 139.3, 143.0, 146.4. Anal.
Calcd for C24H22N4: C, 78.66; H, 6.05; N, 15.29. Found: C,
78.73; H, 6.13; N, 15.07.
Meth od B. Lithium aluminum hydride (0.76 g, 20 mmol)
was added to a solution of 24 in tetrahydrofuran (20 mL). The
obtained mixture was stirred at 22 °C under nitrogen for 2 h
and then poured into 20% NaOH (50 mL). The combined
extracts were washed with 10% NaOH, dried over Na2CO3,
and evaporated. The residue was purified by column chro-
matography (ethyl acetate) to give 23 (1.94 g, 80%) as a
colorless oil.
cis-1-(Ben zotr ia zol-1-yl)-2-p h en ylju lolid in e (27a ) was
obtained as the third fraction from column chromatography
(0.58 g, 16%): powder; mp 210-212 °C; 1H NMR δ 2.05-2.20
(m, 2 H), 2.75-3.05 (m, 2 H), 3.26 (ddd, J ) 1.5, 3.9, 11.4 Hz,
1 H), 3.32-3.41 (m, 1 H), 3.49 (ddd, J ) 4.2, 9.1, 11.4 Hz, 1
H), 3.80 (dt, J ) 12.6, 4.2 Hz, 1 H), 4.08 (dd, J ) 11.5, 12.6
Hz, 1 H), 6.06 (d, J ) 4.5 Hz,1 H), 6.48 (t, J ) 7.5 Hz, 1 H),
6.64 (d, J ) 8.0 Hz, 2 H), 6.75 (d, J ) 7.1 Hz, 1 H), 6.90 (d, J

3124 J . Org. Chem., Vol. 61, No. 9, 1996
Katritzky et al.
) 7.3 Hz, 1 H), 6.98 (m, 3 H), 7.15 (m, 3 H), 7.91 (d, J ) 7.3
Hz, 1 H); 13C NMR δ 21.9, 27.8, 44.4, 49.2, 50.0, 61.2, 109.5,
116.1, 116.8, 119.6, 122.4, 123.2, 126.6, 127.3, 127.4 (2 C),
128.3, 128.4 (2 C), 129.8, 134.1, 138.3, 143.1, 145.2. Anal.
Calcd for C24H22N4: C, 78.66; H, 6.05; N, 15.29. Found: C,
78.48; H, 6.06; N, 15.05.
) 7.7 Hz, 2 H), 6.79 (t, J ) 7.3 Hz, 1 H), 6.87 (d, J ) 7.4 Hz,
1 H), 7.06 (d, J ) 7.8 Hz, 1 H), 7.15 (t, J ) 7.7 Hz, 2 H), 7.20-
7.31 (m, 5 H); 13C NMR δ 21.6, 27.0, 49.9, 55.0, 115.9 (2 C),
117.3, 119.0, 120.3, 122.3 (2 C), 123.3, 126.6 (2 C), 127.2, 128.5
(2 C), 129.0 (3 C), 131.5, 138.3, 143.1, 146.4. Anal. Calcd for
C24H22N2: C, 85.17; H, 6.25; N, 8.28. Found: C, 85.14, H, 5.95;
N, 8.17.
2-P h en ylju lolid in e (31a ). A solution of crude 26a -29a
(10 mmol) and lithium aluminum hydride (0.34 g, 10 mmol)
in anisole (20 mL) was heated at reflux under nitrogen for 1
h. After cooling, methanol (10 mL) was added dropwise, and
the flask contents were poured into 10% NaOH (50 mL). The
mixture was extracted with ether (2 × 50 mL). The combined
extracts were dried over Na2CO3, and the solvent was evapo-
rated (first ether under atmospheric pressure and then anisole
under high vacuum). Column chromatography of the residue
(hexane/ether, 4:1) gave pure julolidine 31a (2.25 g, 90%) as a
yellowish oil: 1H NMR δ 1.93-2.05 (m, 3 H), 2.69-2.82 (m, 3
H), 2.98 (m, 2 H), 3.16 (m, 1 H), 3.22 (bs, 2 H), 6.53 (t, J ) 7.4
Hz, 1 H), 6.82 (d, J ) 7.4 Hz, 2 H), 7.20-7.35 (m, 5 H); 13C
NMR δ 22.1, 27.6, 35.3, 38.6, 50.0, 56.3, 115.9, 121.4, 121.5,
126.6, 127.0, 127.1 (3 C), 128.5 (2 C), 142.2, 143.9. Anal. Calcd
for C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C, 87.08; H,
7.63; N, 5.55.
2-Meth ylju lolid in e (31b). Starting from crude 26b-29b
and following a procedure as above, julolidine 31b (1.48 g, 79%)
was obtained as colorless oil: 1H NMR δ 1.00 (d, J ) 6.6 Hz,
3 H), 1.82-2.00 (m, 2 H), 2.00-2.15 (m, 1 H), 2.38 (dd, J )
10.5, 15.9 Hz, 1 H), 2.65-2.80 (m, 4 H), 3.00 (ddd, J ) 2.3,
3.8, 11.0 Hz, 1 H), 3.05-3.10 (m, 2 H), 6.46 (t, J ) 7.4 Hz, 1
H), 6.74 (d, J ) 7.4 Hz, 2 H); 13C NMR δ 19.1, 22.0, 26.9, 27.6,
36.1, 49.8, 57.0, 115.6, 121.1 (2 C), 126.7, 126.8, 142.2. Anal.
Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found; C, 83.06;
H, 8.95; N, 7.84.
1-Ben zotr ia zolyl-2-m eth ylju lolid in es (26b -29b). A so-
lution of 25 (2.64 g, 10 mmol), propionaldehyde (0.9 mL, 12
mmol), and p-toluenesulfonic acid monohydrate (20 mg, 0.1
mmol) in THF (10 mL) was stored over molecular sieves for 2
h with occasional shaking. Workup as above gave a crude
mixture of 26b-29b. Column chromatography (toluene) gave
a fraction consisting of 26b and 27b (3:1): oil; 13C NMR (26b)
δ 16.2, 21.7, 27.2, 32.8, 49.9, 54.9, 64.1, 111.0, 116.5, 117.1,
119.8, 122.2, 123.5, 126.0, 126.8, 129.0, 131.6, 142.9, 146.5;
13C NMR (27b, aliphatic) 14.7, 21.7, 27.6, 33.0, 49.6, 52.3, 60.7;
HRMS calcd for C19H20N4 (M+) 304.1688, found 304.1676.
1-Ben zotr ia zolyl-2-p r op ylju lolid in es (26c-29c). Start-
ing from valeraldehyde (1.1 mL, 10 mmol) and following a
procedure analogous to that from 26a -29a , a crude mixture
of 26c-29c was obtained.
Column chromatography (toluene) gave a fraction consisting
of 26c and 27c (3:1): oil; 13C NMR (26c) δ 13.9, 19.6, 21.8,
27.3, 32.8, 37.6, 50.1, 52.4, 62.8, 111.0, 116.6, 116.9, 119.9,
122.2, 123.5, 126.7, 126.8, 129.1, 131.8, 143.2, 146.5; 13C NMR
(27c, aliphatic) δ 13.9, 20.0, 21.8, 27.6, 31.3, 37.8, 49.7, 50.4,
59.9. Anal. Calcd for C21H24N4: C, 75.87; H, 7.28; N, 16.80.
Found: C, 75.83; H, 7.45; N, 16.76.
1-Ben zot r ia zolyl-2-(p h en ylm et h yl)ju lolid in es (26d -
29d ). This product was obtained by condensation of 25 (2.64
g, 10 mmol) with hydrocinnamaldehyde (1.3 mL, 10 mmol)
according to the procedure for 26a -29a . Column chromatog-
raphy of the crude reaction mixture (toluene) gave a fraction
consisting of 26d and 27d (3:1): oil; 13C NMR (26d ) δ 21.8,
27.4, 36.9, 39.9, 50.0, 50.8, 61.8, 110.8, 115.9, 116.7, 120.0,
122.3, 123.6, 126.4, 127.0, 127.4, 128.4 (2 C), 129.0 (2 C), 129.5,
132.1, 138.6, 143.1, 146.5; HRMS calcd for C25H24N4 (M+)
380.2001, found 380.2026.
1-(Ben zotr ia zol-2-yl)ju lolid in e (28e). Starting from 25
(2.64 g, 10 mmol) and acetaldehyde (0.8 mL, 15 mmol), crude
product 26e-28e was obtained according to a procedure
analogous to that for 26a -29a . Column chromatography of
this crude product (chloroform) gave as the first fraction
analytically pure 28e (0.35 g, 12%): prisms (ether) mp 122-
123 °C; 1H NMR δ 2.03 (m, 2 H), 2.51 (m, 1 H), 2.64 (m, 1 H),
2.81 (m, 2 H), 3.23 (m, 3 H), 3.50 (ddd, J ) 3.4, 10.3, 11.6 Hz,
1 H), 6.14 (t, J ) 5.3 Hz, 1 H), 6.47 (t, J ) 7.5 Hz, 1 H), 6.72
(d, J ) 7.6 Hz, 1 H), 6.90 (d, J ) 7.2 Hz, 1 H), 7.34 (m, 2 H),
7.86 (m, 2 H); 13C NMR δ 21.9, 27.6, 29.1, 46.1, 50.0, 62.9,
116.1, 118.2 (2 C), 122.5 (2 C), 126.0 (2 C), 127.7, 129.6, 143.2,
144.2 (2 C). Anal. Calcd for C18H18N4: C, 74.46; H, 6.25; N,
19.30. Found: C, 74.67; H, 6.28; N, 19.23.
The second fraction gave 1-(ben zotr ia zol-1-yl)-ju lolid in e
(26e): 2.20 g, 76%; prisms (EtOH/Et2O, 1:1); mp 103-104 °C;
1H NMR δ 2.07 (m, 2 H), 2.47 (m, 1 H), 2.60 (m, 1 H), 2.86 (t,
J ) 6.3 Hz, 2 H), 3.14-3.35 (m, 4 H), 6.31 (t, J ) 7.1 Hz, 1 H),
6.46 (m, 1 H), 6.56 (d, J ) 7.5 Hz, 1 H), 6.95 (d, J ) 7.4 Hz, 1
H), 7.03 (m, 1 H), 7.28 (m, 2 H), 8.06 (m, 1 H); 13C NMR δ
21.8, 27.4, 29.3, 46.9, 49.9, 57.0, 110.9, 116.3, 119.8, 122.4 (2
C). 123.5, 126.8, 127.1, 129.5, 132.3, 143.4, 146.3. Anal. Calcd
for C18H18N4: C, 74.46; H, 6.25; N, 19.30. Found: C, 74.49;
H, 6.34; N, 19.27.
1-(P h en ylim in o)-2,3,6,7-t et r a h yd r o-1H ,5H -b en zo[ij]-
qu in olizin e (30a ). Sodium hydride (0.34 g, 10 mmol) was
added to a solution of crude 26a -29a (3.66 g, 10 mmol) in
dioxane (20 mL), and the obtained mixture was heated at
reflux under nitrogen for 14 h. The reaction mixture was
poured into ice-water (50 g), acidified with acetic acid to pH
5, and extracted with toluene (2 × 30 mL). The combined
extracts were washed with water (50 mL), dried over MgSO4,
and evaporated. The residue was subjected to column chro-
matography (toluene). Finally, the product was recrystallied
from toluene to give pure compound 30a (2.75 g, 81%) as
cuboids: mp 146-147 °C; 1H NMR δ 2.12 (quintet, J ) 6.3
Hz, 2 H), 2.81 (t, J ) 6.3 Hz, 2 H), 3.12 (t, J ) 5.2 Hz, 2 H),
4.11 (s, 2 H), 5.26 (s, 1 H), 6.51 (t, J ) 7.5 Hz, 1 H), 6.62 (d, J
2-P r op ylju lolid in e (31c). Starting from crude 26c-29c
and following a procedure as above, julolidine 31c (1.75 g, 81%)
was obtained as a colorless oil: 1H NMR δ 0.93 (t, J ) 7.4 Hz,
3 H), 1.25-1.50 (m, 4 H), 1.85-2.05 (m, 3 H), 2.39 (dd, J )
10.7, 15.9 Hz, 1 H), 2.65-2.85 (m, 4 H), 3.02-3.20 (m, 3 H),
6.47 (t, J ) 7.3 Hz, 1 H), 6.75 (d, J ) 7.2 Hz, 2 H); 13C NMR
δ 14.2, 19.9, 22.1, 27.6, 31.8, 34.3, 36.3, 50.0, 55.6, 115.7, 121.2
(2 C), 126.8, 126.9, 142.6. Anal. Calcd for C15H21N: C, 83.67;
H, 9.83; N, 6.50. Found: C, 83.99; H, 9.80; N, 6.61.
2-(P h en ylm eth yl)ju lolid in e (31d ). A crude mixture of
26d -29d (10 mmol) was converted to julolidine 31d (2.28 g,
87%) according to a procedure analogous to that above:
1
yellowish oil; H NMR δ 1.82-2.00 (m, 2 H), 2.22-2.35 (m, 1
H), 2.48 (dd, J ) 8.8, 15.7 Hz, 1 H), 2.61 (d, J ) 7.4 Hz, 2 H),
2.65-2.85 (m, 5 H), 3.03 (m, 2 H), 6.47 (t, J ) 7.5 Hz, 1 H),
6.75 (t, J ) 7.1 Hz, 2 H), 7.10-7.38 (m, 5 H); 13C NMR δ 22.0,
27.6, 33.9 (2 C), 40.1, 49.9, 54.4, 115.8, 120.6, 121.3, 125.9,
126.9, 127.1, 128.2 (2 C), 129.0 (2 C), 140.2, 142.5. Anal. Calcd
for C19H21N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.39; H,
8.15; N, 5.51.
tr a n s-1,2-Dip h en ylju lolid in e (32a ). An ethereal solution
of phenylmagnesium bromide (10 mL, 20 mmol) was added to
a solution of crude 26a -29a (3.66 g, 10 mmol) in toluene (50
mL). The ether was distilled off, and the residue was heated
at reflux under nitrogen for 1 h. After cooling, the reaction
mixture was poured into ice-water (100 g), acidified with 5%
acetic acid to pH 6, and extracted with ether (2 × 50 mL). The
ethereal solution was washed with water followed by 10% Na2-
CO3 and dried over Na2CO3. Column chromatography of the
residue (hexane/ether, 4:1) gave julolidine 32a (2.95 g, 91%)
as a greenish oil: 1H NMR δ 1.98-2.20 (m, 2 H), 2.75-2.95
(m, 2 H), 3.10-3.40 (m, 5 H), 4.22 (d, J ) 8.4 Hz, 1 H), 6.49
(m, 2 H), 6.85 (d, J ) 7.3 Hz, 1 H), 6.95-7.25 (m, 10 H); 13C
NMR δ 22.1, 27.7, 47.4, 50.3, 51.2, 55.4, 116.3, 121.7, 125.3,
126.0, 126.4, 127.3, 127.8 (2 C), 128.0 (2 C), 128.3 (2 C), 128.4,
129.2 (2 C), 142.8, 143.2, 145.2. Anal. Calcd for C24H23N: C,
88.57; H, 7.12; N, 4.30. Found: C, 88.18; H, 7.09; N, 4.07.
tr a n s-2-Meth yl-1-p h en ylju lolid in e (32b). Reaction of
crude 26b-29b (3.04 g, 10 mmol) with phenylmagnesium
bromide (15 mL, 30 mmol) according to the above procedure
gave julolidine 32b (2.27, 86%) as a colorless oil: 1H NMR δ
0.89 (d, J ) 6.9 Hz, 3 H), 1.92-2.08 (m, 2 H), 2.15-2.26 (m, 1

Convenient Synthesis of J ulolidines
J . Org. Chem., Vol. 61, No. 9, 1996 3125
H), 2.75-2.82 (m, 2 H), 2.87 (dd, J ) 9.0, 11.1 Hz, 1 H), 3.05-
3.14 (m, 2 H), 3.15-3.24 (m, 1 H), 3.60 (d, J ) 9.0 Hz, 1 H),
6.41 (m, 2 H), 6.78 (m, 1 H), 7.10-7.30 (m, 5 H); 13C NMR δ
18.2, 22.0, 27.7, 34.7, 50.2, 52.0, 55.7, 115.9, 121.2, 124.5, 126.1,
127.1, 128.2 (2 C), 128.3, 129.2 (2 C), 142.9, 145.9. Anal. Calcd
for C19H21N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.32; H,
7.93; N, 5.28.
1-P h en ylju lolid in e (32e). Reaction of a crude mixture of
26e and 28e (2.90 g, 1 0 mmol) with phenylmagnesium
bromide (15 mL, 30 mmol) according to the above procedure
gave julolidine 32e (2.15 g, 86%) as a colorless oil: 1H NMR δ
2.00 (m, 2 H), 2.05 (m, 1 H), 2.20 (m, 1 H), 2.80 (t, J ) 6.5 Hz,
2 H), 3.09 (m, 2 H), 3.16 (t, J ) 5.4 Hz, 2 H), 4.10 (t, J ) 5.6
Hz, 1 H), 6.43 (t, J ) 7.4 Hz, 1 H), 6.54 (d, J ) 7.4 Hz, 1 H),
6.81 (d, J ) 7.2 Hz, 1 H), 7.10-7.30 (m, 5 H); 13C NMR δ 22.1,
27.8, 30.9, 43.5, 47.4, 50.2, 115.6, 121.5, 123.6, 126.0, 127.4,
128.0, 128.2 (2 C), 128.6 (2 C), 143.1, 146.9. Anal. Calcd for
C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C, 86.66; H, 7.86;
N, 5.56.
1-(P h en ylim in o)ju lolid in e (33e). Sodium hydride (0.48
g, 20 mmol) was added to a solution of 26e (2.90 g, 10 mmol)
in dioxane (20 mL), and the obtained mixture was stirred and
heated to reflux under nitrogen for 2 h. After cooling, the
reaction mixture was poured into ice-water (100 g), acidified
with acetic acid to pH 5, and extracted with chloroform (2 ×
20 mL). The combined extracts were washed with water (50
mL), dried over MgSO4, and evaporated. Column chromatog-
raphy of the residue (toluene) gave pure 33e (2.12 g, 81%) as
yellow prisms (from toluene/ether): mp 103-104 °C; 1H NMR
δ 2.04 (quintet, J ) 6.3 Hz, 2 H), 2.61 (t, J ) 6.1 Hz, 2 H),
2.79 (t, J ) 6.6 Hz, 2 H), 3.13 (m, 4 H), 6.68 (t, J ) 7.9 Hz, 1
H), 6.80 (d, J ) 8.4 Hz, 2 H), 7.05 (m, 2 H), 7.32 (m, 2 H), 8.03
(d, J ) 7.9 Hz, 1 H); 13C NMR δ 21.8, 27.0, 28.8, 49.6, 50.3,
117.1, 120.1 (2 C), 120.2, 122.9, 123.2, 124.8, 128.8 (2 C), 132.1,
146.8, 151.4, 162.5. Anal. Calcd for C18H18N2: C, 82.41; H,
6.92; N, 10.68. Found: C, 82.06; H, 6.93; N, 10.44.
(dt, J ) 11.8, 9.3 Hz, 1 H), 3.44-3.58 (m, 1 H), 3.72 (m, 1 H),
3.78 (q, J ) 4.5 Hz, 1 H), 6.14 (d, J ) 5.0 Hz, 1 H), 6.53 (m, 2
H), 6.65 (m, 2 H), 6.82 (m, 1 H), 6.99-7.15 (m, 9 H), 7.27 (m,
2 H), 8.05 (m, 1 H); 13C NMR δ 22.1, 28.2, 36.7, 47.1, 48.7,
61.6, 63.9, 110.8, 115.1, 116.1, 120.0, 123.1, 123.6, 126.2, 127.1
(2 C), 127.5 (2 C), 127.9, 128.3 (2 C), 128.7 (2 C), 128.9 (2 C),
129.6, 132.8, 138.0, 141.9, 142.1, 146.2. Anal. Calcd for
C31H28N4: C, 81.55; H, 6.18; N, 12.27. Found: C, 81.95; H,
6.32; N, 11.92.
tr a n s,tr a n s-1-(Ben zotr ia zol-1-yl)-2-m eth yl-3-eth ylju lo-
lid in e (38b) a n d Its Isom er s 39b-41b. Using a procedure
as above, condensation of 1,2,3,4-tetrahydroquinoline (1.3 mL,
10 mmol) with propionaldehyde (1.8 mL, 25 mmol) and
benzotriazole (1.19 g, 10 mmol) produced a crude mixture of
38b-41b. Column chromatography of the mixture gave a
fraction (0.35 g) containing 60% of 40b in a mixture with other
isomers: 13C NMR (aliphatic) δ 8.3, 17.9, 22.2, 28.1, 34.9, 47.8,
50.2, 53.5, 69.2.
The second fraction gave a mixture of 38b and 39b (1.91
g). Trituration of the mixture with ether (10 mL) caused
precipitation of 38b (0.95 g, 29%) as colorless prisms: mp 114
°C; 1H NMR δ 0.64 (t, J ) 7.4 Hz, 3 H), 0.95 (d, J ) 6.8 Hz, 3
H), 1.45 (m, 1 H), 1.58 (m, 1 H), 1.95 (m, 1 H), 2.07 (m, 1 H),
2.70-2.94 (m, 3 H), 3.20 (m, 2 H), 3.45 (m, 1 H), 5.83 (d, J )
4.3 Hz, 1 H), 6.33-6.46 (m, 2 H), 6.88 (m, 1 H), 6.94 (d, J )
6.1 Hz, 1 H), 7.29 (m, 2 H), 8.06 (m, 1 H); 13C NMR δ 7.7, 17.4,
22.1, 22.3, 28.0, 34.4, 47.2, 63.2, 63.3, 111.3, 115.7, 120.0, 123.0
(2 C), 123.6, 126.8, 126.9, 129.2, 132.3, 142.6, 146.4. Anal.
Calcd for C21H24N4: C, 75.87; H, 7.28; N, 16.85. Found: C,
76.25; H, 7.49; N, 16.83.
Evaporation of the filtrate from 38b gave a mixture of 39b
and 38b (0.96 g, ratio 2:1): 13C NMR δ of 39b 13.1, 15.4, 21.1,
22.3, 27.9, 35.8, 50.2, 62.1, 64.6, 111.2, 115.3, 116.6, 120.0,
122.3, 123.6, 125.8, 126.8, 128.9, 131.6, 141.1, 146.8.
tr a n s,tr a n s-1-(Ben zotr ia zol-1-yl)-3-bu tyl-2-p r op ylju lo-
lid in e (38c). Using the procedure above, condensation of
1,2,3,4-tetrahydroquinoline (1.3 mL, 10 mmol) with valeral-
dehyde (2.2 mL, 20 mmol) and benzotriazole (1.19 g, 10 mmol)
gave a crude mixture of 38c-41c. Column chromatography
(toluene) of the mixture gave a fraction containing 70% of 38c
allowing its characterization: 13C NMR δ 13.3, 14.1, 20.2, 21.8,
22.2, 27.3, 28.3, 29.9, 34.9, 39.3, 48.9, 60.7, 61.2, 111.7, 115.1,
119.7, 122.0 (2 C), 123.2, 126.7, 129.9 (2 C), 132.8, 141.7, 146.1.
Anal. Calcd for C25H32N4: C, 77.28; H, 8.30; N, 14.42.
Found: C, 77.46; H, 8.69; N, 14.28.
1-(P h en ylim in o)-2-m eth yl-6,7-dih ydr o-1H,5H-ben zo[ij]-
qu in olin e(35b). Sodium hydride (0.48 g, 20 mmol) was added
to a solution of 26b-29b (3.04 g, 10 mmol) in dioxane (50 mL).
The obtained mixture was stirred and heated at reflux under
nitrogen for 2 h. After cooling, the mixture was poured into
ice-water (100 g), acidified with 10% acetic acid to pH 5, and
extracted with chloroform (2 × 50 mL). The extract was
washed with water (2 × 50 mL), dried over MgSO4, and
evaporated under reduced pressure. The residue was sub-
jected to column chromatography (toluene) to give pure 35
1-(Ben zotr iazol-1-yl)-3-m eth ylju lolidin es (38d an d 39d).
Using the procedure above, condensation of 1,2,3,4-tetrahyd-
roquinoline (1.3 mL, 10 mmol) with acetaldehyde (1.7 mL, 30
mmol) and benzotriazole (1.19 g, 10 mmol) gave a crude
mixture of 38d -41d . Column chromatography of the mixture
gave the main fraction consisting of 38d and 39d (ap-
proximately 1:1): 13C NMR δ (16.5), 20.0, (21.9), 22.2, (27.7),
27.7, (34.6), 37.4, 45.8, (47.5), (52.0), 52.1, (55.0), 57.2, (111.1),
111.2, (115.6), 116.5, 118.0, 119.8, (119.8), 122.4, 123.5, (123.5),
(125.1), 125.5, (125.7), 126.7, (128.0), (128.8), 129.1, (129.3),
131.6, (131.6), (141.5), 143.3, 146.5 (146.5); HRMS calcd for
1
(2.26 g, 82%) as yellow prisms: mp 150-152 °C; H NMR δ
1.72 (s, 3 H), 2.12 (m, 2 H), 2.97 (t, J ) 6.1 Hz, 2 H), 3.90 (t,
J ) 5.7 Hz, 2 H), 6.82-6.94 (m, 4 H), 7.00 (dd, J ) 7.2, 8.2
Hz, 1 H), 7.19-7.27 (m, 3 H), 8.12 (d, J ) 8.5 Hz, 1 H); 13C
NMR δ 18.8, 21.3, 27.4, 50.9, 111.2, 120.4 (2 C), 120.6, 121.8,
123.3, 124.8 (2 C), 125.8, 128.2 (2 C), 129.3, 137.8, 152.9, 153.9.
Anal. Calcd for C19H18N2: C, 83.18; H, 6.61; N, 10.21.
Found: C, 83.50; H, 6.73; N, 10.03.
1-(P h en ylim in o)-2-p r opyl-6,7-d ih ydr o-1H,5H-ben zo[ij]-
qu in olin e (35c). By a procedure analogous to 35b, compound
35c (2.53 g, 84%) was prepared from a crude mixture of 26c-
C19
H20N4 (M+) 304.1688, found 304.1690.
1
29c (3.32 g, 10 mmol) as yellow grains: mp 146 °C; H NMR
tr a n s-2-P h en yl-3-(p h en ylm eth yl)ju lolid in e (42a ). Re-
duction of a crude mixture of 38a -41a (4.56 g, 10 mmol) with
lithium aluminum hydride (0.76 g, 20 mmol) according to the
procedure for 31a and recrystallization of the crude product
from ethanol gave pure 42a (2.95 g, 87%) as fine colorless
needles: mp 98-100 °C; 1H NMR δ 1.70-1.90 (m, 2 H), 2.64-
2.86 (m, 4 H), 2.91-3.04 (m, 2 H), 3.13 (dd, J ) 5.7, 13.5 Hz,
1 H), 3.23 (ddd, J ) 3.6, 9.6, 11.1 Hz, 1 H), 3.33-3.44 (m, 2
H), 6.53 (t, J ) 7.5 Hz, 1 H), 6.81-6.97 (m, 3 H), 7.00 (m, 2
H), 7.08-7.19 (m, 3 H), 7.20-7.40 (m, 4 H); 13C NMR δ 21.9,
28.2, 28.5, 37.4, 38.4, 49.3, 65.3, 115.1, 118.6, 121.4, 125.9,
126.2, 126.8, 127.4 (3 C), 128.1 (2 C), 128.5 (2 C), 129.2 (2 C),
139.3, 141.1, 145.6. Anal. Calcd for C25H25N: C, 88.45; H,
7.42; N, 4.13. Found: C, 88.44; H, 7.60; N, 4.27.
δ 0.71 (m, 3 H), 1.38 (m, 2 H), 2.13 (m, 4 H), 2.94 (m, 2 H),
3.90 (m, 2 H), 6.78-6.96 (m, 5 H), 7.12-7.28 (m, 3 H), 7.96
(d, J ) 6.8 Hz, 1 H); 13C NMR δ 13.7, 21.2, 22.3, 27.4, 32.8,
50.8, 117.5, 119.6 (2 C), 120.2, 121.1, 123.0, 124.8, 126.0, 128.5
(2 C), 129.1, 136.6 (2 C), 152.2, 154.2. Anal. Calcd for
C21H22N2: C, 83.40; H, 7.33; N, 9.26. Found: C, 83.26; H, 7.42;
N, 9.16.
tr a n s,tr a n s-1-(Ben zot r ia zol-1-yl)-2-p h en yl-3-(p h en yl-
m eth yl)ju lolid in e (38a ). A solution of 1,2,3,4-tetrahydro-
quinoline (1.3 mL, 10 mmol), benzotriazole (1.19 g, 10 mmol),
phenylacetaldehyde (2.4 mL, 20 mmol), and p-toluenesulfonic
acid monohydrate (20 mg, 0.1 mmol) in THF was shaken for
2 h with molecular sieves (4 Å, 5 g), filtered, and evaporated
to give crude product (a mixture of 38a -41a ). Trituration of
the crude product with ether (20 mL) produced crystals of pure
isomer 38a (1.92 g, 42%): tiny needles (toluene); mp 187-
188 °C; 1H NMR δ 1.90-2.15 (m, 2 H), 2.59 (dd, J ) 7.7, 16.4
Hz, 1 H), 2.81 (dd, J ) 5.0, 14.3 Hz, 1 H), 2.88 (m, 2 H), 3.15
tr a n s-2-Meth yl-3-eth ylju lolid in e (42b). Reduction of a
crude mixture of 38b-41b (3.32 g, 10 mmol) with lithium
aluminum hydride (0.76 g, 20 mmol) according to the proce-
dure for 31a and column chromatography of the crude product
(hexane) gave pure 42b (1.85 g, 86%) as an oil: 1H NMR δ

3126 J . Org. Chem., Vol. 61, No. 9, 1996
Katritzky et al.
0.90 m, 6 H), 1.36 (m, 1 H), 1.64 (m, 1 H), 1.90 (m, 2 H), 2.00
(m, 1 H), 2.28 (d, J ) 16.2 Hz, 1 H), 2.66 (m, 1 H), 2.73 (m, 2
H), 2.89 (dd, J ) 5.3, 16.2 Hz, 1 H), 3.13 (dt, J ) 11.5, 4.7 Hz,
1 H), 3.41 (ddd, J ) 7.4 Hz, 1 H), 6.41 (t, J ) 7.3 Hz, 1 H),
6.76 (d, J ) 7.3 Hz, 2 H); 13C NMR δ 10.5, 19.3, 22.1, 25.2,
26.3, 28.3, 30.1, 49.6, 65.7, 114.2, 118.1, 120.4, 126.7, 127.8,
140.6. Anal. Calcd for: C15H21N: C, 83.67; H, 9.83; N, 6.50.
Found: C, 83.30; H, 9.91; N, 6.65.
tr a n s-2-P r op yl-3-bu tylju lolid in e (42c). Reduction of a
crude mixture of 38c-41c (3.89 g, 10 mmol) with lithium
aluminum hydride (0.76 g, 20 mmol) according to the proce-
dure for 31a and column chromatography of the crude product
(hexane) gave pure 42c (2.45 g, 90%): oil; 1H NMR δ 0.88 (m,
6 H), 1.20-1.45 (m, 9 H), 1.65 (m, 1 H), 1.80 (m, 1 H), 1.93
(m, 2 H), 2.40 (d, J ) 16.3 Hz, 1 H), 2.74 (m, 2 H), 2.80-2.94
(m, 2 H), 3.14 (m, 1 H), 3.42 (m, 1 H), 6.43 (t, J ) 7.4 Hz, 1 H),
6.77 (m, 2 H); 13C NMR δ 14.1, 14.2, 20.5, 22.1, 22.9, 28.1,
28.3, 28.5, 32.0, 32.2, 34.9, 49.5, 62.3, 114.2, 118.2, 120.3, 126.7,
127.7, 140.7. Anal. Calcd for C19H29N: C, 84.07; H, 10.77; N,
5.16. Found: C, 83.72; H, 10.94; N, 5.08.
3-Meth ylju lolid in e (42d ). Reduction of a crude mixture
of 38d -41d (3.04 g, 10 mmol) with lithium aluminum hydride
(0.76 g, 20 mmol), according to the procedure for 31a , and
column chromatography of the crude product (hexane/ether,
9:1) gave pure 42d (1.74 g, 93%): colorless oil; 1H NMR δ 1.11
(d, J ) 6.4 Hz, 3 H), 1.71 (qt, J ) 6.4, 3.7 Hz, 1 H), 1.92 (m, 3
H), 2.57-2.86 (m, 4 H), 3.04 (dt, J ) 11.3, 5.0 Hz, 1 H), 3.25-
3.38 (m, 2 H), 6.44 (t, J ) 7.4 Hz, 1 H), 6.76 (m, 2 H); 13C
NMR δ 17.3, 22.1, 23.7, 27.8, 28.1, 47.8, 52.7, 114.8, 120.8,
121.2, 126.8, 127.0, 141.6. Anal. Calcd for C13H17N: C, 83.37;
H, 9.15; N, 7.48. Found: C, 83.38; H, 9.31; N, 7.44.
and sodium hydride (0.48 g, 20 mmol) and following a
procedure analogous to that for 35b produced crude 43c.
Column chromatography of the crude product (toluene) gave
pure 42c (3.15 g, 87%) as a yellow powder: mp 90-92 °C; 1H
NMR δ 0.71 (t, J ) 7.2 Hz, 3 H), 0.88 (t, J ) 7.5 Hz, 3 H),
1.04-1.68 (m, 10 H), 1.98 (m, 2 H), 2.57 (m, 1 H), 2.74 (m, 2
H), 2.95 (m, 1 H), 3.22 (m, 1 H), 3.42 (m, 1 H), 6.55 (t, J ) 6.9
Hz, 1 H), 6.76 (d, J ) 7.8 Hz, 2 H), 7.01 (m, 2 H), 7.29 (m, 2
H), 7.83 (d, J ) 7.8 Hz, 1 H); 13C NMR δ 13.9, 14.0, 20.1, 21.7,
22.8, 27.5, 28.4, 29.7, 32.9, 38.4, 49.4, 61.8, 115.0, 117.0, 119.9
(2 C), 121.8, 122.5, 125.3, 128.5 (2 C), 131.7, 142.7, 151.5, 165.9.
Anal. Calcd for C25H32N2: C, 83.28; H, 8.95; N, 7.77. Found:
C, 883.32; H, 9.07; N, 7.75.
3-Meth yl-1-(p h en ylim in o)ju lolid in e (43d ). Reaction of
a crude mixture of 38d -41d (3.04 g, 10 mmol) with sodium
hydride (0.48 g, 20 mmol), according to a procedure analogous
to that for 35b, gave a crude product which was purified by
column chromatography (toluene) to give pure 43d (2.42 g,
87%) as fine yellow needles: mp 118-119 °C; 1H NMR δ 1.08
(d, J ) 6.3 Hz, 3 H), 2.02 (m, 2 H), 2.52 (dd, J ) 3.3, 15.0 Hz,
1 H), 2.63 (dd, J ) 5.1, 15.3 Hz, 1 H), 2.77 (m, 2 H), 3.15 (m,
1 H), 3.25-3.50 (m, 2 H), 6.62 (t, J ) 7.5 Hz, 1 H), 6.78 (d, J
) 7.5 Hz, 2 H), 7.04 (m, 2 H), 7.32 (t, J ) 7.7 Hz, 2 H), 7.95 (d,
J ) 7.5 Hz, 1 H); 13C NMR δ 14.6, 21.8, 27.4, 34.5, 47.8, 53.8,
115.9, 119.1, 120.1 (2 C), 122.7, 122.9, 124.6, 128.7 (2 C), 132.2,
144.0, 151.6, 161.6. Anal. Calcd for C19H20N2: C, 82.57; H,
7.29; N, 10.14. Found: C, 82.37; H, 7.64; N, 10.02.
tr a n s,tr a n s-1-Met h yl-3-p h en yl-2-(p h en ylm et h yl)ju lo-
lid in e (45a ). Reaction of pure 38a (1.85 g, 4 mmol) with
methylmagnesium iodide (10 mL of an ethereal solution, 20
mmol), according to the procedure for 32a , gave 45a (0.95 g,
1
tr a n s-2-P h en yl-3-(p h en ylm eth yl)-1-(p h en ylim in o)ju lo-
lid in e (43a ). Reaction of a crude mixture of 38a -41a (4.56
g, 10 mmol) with sodium hydride (0.48 g, 20 mmol), according
to a procedure analogous to that for 35b, gave crude 43a which
was purified by recrystallization from toluene to give pure 43a
67%) as tiny needles: mp 109 °C; H NMR δ 1.34 (d, J ) 7.2
Hz, 3 H), 1.83 (m, 1 H), 1.95 (m, 1 H), 2.74 (t, J ) 5.6 Hz, 2
H), 2.81 (t, J ) 5.0 Hz, 1 H), 2.88-3.03 (m, 4 H), 3.31 (ddd, J
) 4.2, 9.7, 11.0 Hz, 1 H), 3.55 (q, J ) 6.3 Hz, 1 H), 6.61 (t, J
) 7.4 Hz, 1 H), 6.88 (d, J ) 7.3 Hz, 1 H), 7.00 (dd, J ) 1.6, 8.1
Hz, 2 H), 7.10-7.30 (m, 9 H); 13C NMR δ 22.1, 22.5, 28.3, 36.0,
37.6, 48.8, 50.0, 65.5, 115.7, 122.8, 125.5, 126.0, 126.1, 126.5,
126.6, 127.7 (2 C), 128.3 (4 C), 129.3 (2 C), 139.6, 141.3, 146.3.
Anal. Calcd for: C26H27N: C, 88.34; H, 7.70; N, 3.96. Found:
C, 88.18; H, 7.86; N, 3.95.
1
(3.95 g, 92%) as yellow prisms: mp 128 °C; H NMR δ 1.60-
1.80 (m, 2 H), 2.66 (m, 2 H), 2.74 (dd, J ) 8.0, 13.5 Hz, 1 H),
2.80-2.93 (m, 2 H), 3.09 (dd, J ) 6.9, 13.2 Hz, 1 H), 3.40 (m,
1 H), 3.71 (s, 1 H), 6.54 (d, J ) 7.7 Hz, 2 H), 6.68 (t, J ) 7.4
Hz, 1 H), 6.88 (m, 2 H), 6.94 (t, J ) 6.8 Hz, 1 H), 7.05-7.30
(m, 11 H), 8.11 (d, J ) 7.9 Hz, 1 H); 13C NMR δ 21.5, 27.5,
36.7, 45.2, 49.8, 67.9, 115.7, 118.5, 120.4 (2 C), 122.8, 123.0,
125.3, 126.4, 126.5, 127.6 (2 C), 128.2 (2 C), 128.37 (2 C), 128.43
(2 C), 129.3 (2 C), 132.0, 138.3, 141.0, 143.2, 150.5, 161.9. Anal.
Calcd for C31H28N2: C, 86.88; H, 6.59; N, 6.54. Found: C,
86.58; H, 6.62; N, 6.37.
tr a n s,tr a n s-3-Eth yl-2-m eth yl-1-p h en ylju lolid in e (45b).
An ethereal solution of phenylmagnesium bromide (15 mL, 30
mmol) was added to a solution of crude 38a -41a (3.32 g, 10
mmol) in toluene (40 mL), stirred under nitrogen, and heated
to reflux. The ether was distilled off, and the residue was
additionally heated at reflux for 30 min. After being cooled
to room temperature, the reaction mixture was poured into
ice-water (100 g), neutralized with 10% acetic acid, and
extracted with ether, followed by 10% Na2CO3, and dried over
anhydrous Na2CO3. The solvent was evaporated, and the
residue was purified by column chromatography (hexane/ether,
5:1) to give pure 45a (2.46 g, 84%) as a colorless powder: mp
70-76 °C; 1H NMR δ 0.67 (t, J ) 7.4 Hz, 3 H), 0.95 (d, J ) 6.7
Hz, 3 H), 1.40-1.65 (m, 3 H), 1.80-2.15 (m, 2 H), 2.31 (m, 1
H), 2.77 (m, 1 H), 2.90 (m, 1 H), 3.05 (m, 1 H), 3.42 (ddd, J )
4.0, 8.7, 11.0 Hz, 1 H), 3.67 (d, J ) 6.9 Hz, 1 H), 6.45 (m, 2 H),
6.84 (m, 1 H), 7.10-7.40 (m, 5 H); 13C NMR δ 8.3, 20.3, 22.6,
22.8, 28.3, 35.9, 47.7, 49.6, 65.1, 114.9, 122.0, 123.1, 125.9,
127.0, 128.1 (2 C), 128.2, 129.2 (2 C), 142.4, 145.3. Anal. Calcd
for C21H25N: C, 86.55; H, 8.65; N, 4.81. Found: C, 86.71; H,
8.79; N, 4.76.
tr a n s-3-Eth yl-2-m eth yl-1-(ph en ylim in o)ju lolidin e (43b).
Reaction of a crude mixture of 38b-41b (3.32 g, 10 mmol) with
sodium hydride (0.48 g, 20 mmol) according to a procedure
analogous to that for 35b gave a crude 43b which was
recrystallized from toluene to give pure 43b (2.53 g, 83%) as
yellow prisms: mp 126-127 °C; 1H NMR δ 0.80 (t, J ) 7.5
Hz, 3 H), 1.10 (d, J ) 6.9 Hz, 3 H), 1.41 (m, 1 H), 1.66 (m, 1
H), 1.99 (m, 2 H), 2.65-2.77 (m, 4 H), 3.25 (dt, J ) 11.6, 4.6
Hz, 1 H), 3.43 (dt, J ) 11.2, 6.1 Hz, 1 H), 6.56 (t, J ) 7.5 Hz,
1 H), 6.78 (dd, J ) 1.2, 8.4 Hz, 2 H), 7.00-7.07 (m, 2 H), 7.31
(t, J ) 7.8 Hz, 2 H), 7.86 (dd, J ) 1.6, 7.9 Hz, 1 H); 13C NMR
δ 10.7, 17.8, 21.7, 22.7, 27.6, 33.0, 49.6, 67.0, 115.0, 116.5, 119.8
(2 C), 121.9, 122.6, 125.4, 128.7 (2 C), 131.8, 142.6, 151.6, 166.2.
Anal. Calcd for C21H24N2: C, 82.85; H, 7.95; N, 9.20. Found:
C, 82.62; H, 8.09; N, 9.24.
tr a n s-3-Bu tyl-2-pr opyl-1-(ph en ylim in o)ju lolidin e (43c).
Starting from a crude mixture of 38c-41c (3.89 g, 10 mmol)
J O9519118