The aza-xylylene Diels-Alder approach for the synthesis of naturally occurring 2-alkyl tetrahydroquinolines

Article abstract of DOI:10.1016/S0040-4020(03)00915-3

The recently discovered intramolecular aza-xylylene Diels-Alder reaction, based on a 1,4-dehydrohalogenation reaction, was extended in terms of substrates and leaving groups allowing the assembly of tetrahydroquinolines in two synthetic steps. Intramolecular cleavage of a thiocarbamate using triphenylphosphine and tetrachloromethane (Appel conditions) to give chloromethyl phenylisocyanate has been presented for the first time. The synthetic feasibility of this process was demonstrated in the first total syntheses of the alkaloids rac-Angustureine and 1-methyl-2-propyltetrahydroquinoline.

Full text of DOI:10.1016/S0040-4020(03)00915-3

Tetrahedron 59 (2003) 6785–6796
The aza-xylylene Diels–Alder approach for the synthesis of
naturally occurring 2-alkyl tetrahydroquinolines
a
Frank Avemaria, Sylvia Vanderheiden and Stefan Brase
a
b
,
*
¨
a
´
¨ ¨
Kekule-Institut fur Organische Chemie and Biochemie, Rheinische Friedrich-Wilhelms-Universitat Bonn, Gerhard-Domagk-Straße 1,
D-53121 Bonn, Germany
¨ ¨
Institut fur Organische Chemie, Universitat Karlsruhe, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
b
Received 2 April 2003; revised 9 June 2003; accepted 10 June 2003
Dedicated to Professor K. C. Nicolaou for his achievements in the total synthesis of complex natural products
Abstract—The recently discovered intramolecular aza-xylylene Diels–Alder reaction, based on a 1,4-dehydrohalogenation reaction, was
extended in terms of substrates and leaving groups allowing the assembly of tetrahydroquinolines in two synthetic steps. Intramolecular
cleavage of a thiocarbamate using triphenylphosphine and tetrachloromethane (Appel conditions) to give chloromethyl phenylisocyanate has
been presented for the first time. The synthetic feasibility of this process was demonstrated in the first total syntheses of the alkaloids rac-
Angustureine and 1-methyl-2-propyltetrahydroquinoline.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
phenyl carbamates having an internal or external dieno-
phile. The scope of this reaction was demonstrated in the
total synthesis of the anti-viral Virantmycin.14
Tetrahydroquinolines play an important role in material
sciences and as key elements in many natural products.
Numerous ring-annulated or 3- and 4-substituted tetrahy-
droquinolines can be found in nature and can be prepared
efficiently via a Grieco type reaction.1 Much simpler 2-alkyl
tetrahydroquinolines which are not directly accessible by
this route are present in a recently discovered relatively
small class of natural products 2b,2 3b,3 4b,4 5b5 and 6b3
(Fig. 1). Some members of this family have interesting
pharmacological properties.3,6
In order to expand the scope of this useful reaction, we
explored the access to building blocks suitable for the
intramolecular cyclization. The carbamate structure can be
assembled by the reaction of isocyanates with alcohols or
via the reaction of anilines with chloroformates. Since only
few unsaturated chloroformates are commercially available
and, moreover, only (Z)-configured double bonds are
suitable dienophiles,12 the synthesis of carbamates using
isocyanates as starting material was more promising with
regards to the anticipated solid-phase reaction. Therefore,
an alternative route to chloromethyl phenylisocyanates was
investigated. Some thirty years ago, Appel described the
cleavage of arylthiocarbamates by means of triphenylpho-
sphine/tetrachloromethane to yield alkyl chlorides and
arylisocyanates.15 This transformation and in particular
the subsequent reaction with external nucleophiles has, to
our knowledge, never been described since. However, an
intramolecular Appel reaction on arylthiocarbamates would
enable an access to chloromethyl arylisocyanates. The
required known 1,4-dihydro-benzo[d][1,3]oxazine-2-thione
8 was synthesized using carbon disulfide under standard
conditions.16 Other entries to this class of compounds such
as the conversion of the corresponding carbamate using
Lawesson reagent have not met with success. The reaction
of the thiocarbamate 8 with triphenylphosphine in the
presence of tetrachloromethane yielded the desired
2-chloromethylphenylisocyanate (9)17 in quantitative yield
Owing to our interest in heterocyclic chemistry, in particular
using solid-phase chemistry7 and searching for new lead
structures in combinatorial drug discovery based on natural
products, we envisaged a general synthesis of this class of
compounds.8 We were intrigued by the smooth generation
of substituted tetrahydroquinolines using the base-induced
1,4-elimination aza-xylylene9 Diels–Alder10 approach
lately explored by Nishiyama et al.11 and Corey and
Steinhagen.12 Nicolaou et al. very recently used a novel
access to o-imidoquinones and their Diels–Alder reaction to
generate benzomorpholines13 (Y¼O, Scheme 1).
An elegant approach to tetrahydroquinoline systems is
based on the 1,4-dehydrohalogenation of 2-chloromethyl-
Keywords: tetrahydroquinolines; aza-xylylene; Diels–Alder reaction.
*
Corresponding author. Tel.: þ49-721-608-2903; fax: þ49-721-608-8581;
e-mail: braese@uni-bonn.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00915-3

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F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
Figure 1. Naturally occurring 2-alkyltetrahydroquinolines.
Scheme 1. Aza-xylylene and imidoqinone synthesis and subsequent Diels–Alder reactions towards tetrahydroquinolines and benzomorpholines, respectively.
according to gas chromatographic analysis. Crucial for the
complete conversion was the employment of elevated
temperature (508C). At lower temperature, e.g. at 08C
triphenylphosphine oxide was isolated next to the expected
by-product triphenylphosphine sulfide. Presumably, a
phosphine-promoted rearrangement serves as source for
triphenyl phosphine oxide.
in good to excellent yields. This transformation turns into a
viable method for combinatorial synthesis as in principle
any dienophile possessing a suitable nucleophilic group
reacting with isocyanates might be used. This reaction is
promising and was demonstrated in the present work for
allyl alcohol and homoallyl alcohol19 (Scheme 2).
For the envisaged solid-phase synthesis of tetrahydroqui-
nolines having a triazene linkage20 a different leaving group
for this reaction was also explored. Since carbonates act as
potential leaving groups displaying a leaving tendency
This bis-electrophile 9, which also is a useful building block
for 2-amino-4H-benzo[d][1,3]oxazines,18 can be converted
into the desired carbamates 11 with different allyl alcohols
Scheme 2. Synthesis of 2-chloromethyl isocyanate (9) via an intramolecular Appel reaction and its conversion to carbamates 11a,b.

F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
6787
Scheme 3. Synthesis of cyclic carbamates 12. Alloc¼allyloxycarbonyl.
similar to chlorides,21 2-amino benzylalcohol (7) was
converted into the corresponding mixed carbamates/car-
bonates 14 with unsaturated chloroformates. The utilization
of carbonates as leaving groups in an intramolecular aza-
xylylene Diels–Alder reaction either by base-induced
elimination11 as well as by pyrolysis22 has been described
earlier. Gratifyingly, the cyclization of the carbonate 14a
using cesium carbonate as a base at elevated temperature
proceeded smoothly to generate the tetrahydroquinoline 12a
in 69% yield. Although the overall yield of this route is
somewhat lower compared to the previously described route
using the benzylic chloride 11a this access allows the
assembly of the tetrahydroquinoline 12a in just two steps.
Furthermore, acid sensitive material might be used in this
case.
internal dienophile inhibits the Diels–Alder reaction to a
considerable extent (Scheme 3).
With the cyclic carbamates 12 at hand, model reactions for
the synthesis of the targeted natural products have been
performed. The nearly quantitative conversion of the
carbamate 12a into the amino alcohol 1725 was carried
out with sodium hydroxide in ethanol,26 while reduction of
the carbamates 12a,b with lithium aluminium hydride
furnished the N-methylated alcohols 16a,27 16b in very
good yields. Standard transformations to the corresponding
bromides 18a, 20a and iodides 18b,25 19b, 20b, respect-
ively, were also met with success (Scheme 4).
The bromide 18a was converted to its lithio derivative 18c
by treatment with n-butyl lithium in THF at 2788C and
warming this mixture to room temperature within 12 hours.
After aqueous work-up, N-(2-but-3-enylphenyl)-N-butyl-N-
methylamine (21e) was isolated as the major product (55%)
(Scheme 5, Table 1, entry 2). The alkylated product
1-methyl-2-pentyl tetrahydroquinoline (18e) could not be
detected. The butenyl derivative 21e derives from a
The cyclization of the chlorides 11, either prepared from the
alcohols 1323 or by the above-mentioned route, delivers the
tetrahydroquinolines 12a,b. However, this cyclization
furnished the homologous butenyl substituted material in
lesser yields due to the formation of the benzazetine 15b as a
by-product.24 Apparently, a longer spacer within the
Scheme 4. Ring opening and subsequent transformations of cyclic carbamates.

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F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
Scheme 5. Synthesis and ring opening of 2-lithiomethyl tetrahydroquinoline 18c.
Table 1. Addition of nucleophilic reagents at tetrahydroquinolyl derivatives 18 and 19
Entry
1
Starting material
Conditions
Product
Yield (%)a
18a
MeLi, THF, 2788C to rt, 12 h
18d
21f
21e
18g
18e (3b)
21e
21f
14
26
85 (55)b
67
15
28
49
2
3
4
18a
18a
18a
BuLi, THF, 2788C to rt, 12 h
PhLi, THF, 2788C to rt, 12 h
CuBr·SMe2, BuLi, Et2O, 2788C to rt, 12 h
5
6
7
18a
18a
18b
CuI, BuLi, Et2O, 2788C to rt, 12 h
Li2CuCl4, EtMgBr, THF, 258C to rt, 5 h
CuI, BuLi, Et2O, 2788C to rt, 12 h
18e (3b)
21e
21f
18f (1b)
18g
21f
21e
21f
18i
18
12
47
4
76 (40)b
14 (5)b
34
58
61 (27)b
–
52 (47)b
96 (67)b
8
9
10
11
18b
18b
19b
19b
Li2CuCl4, C2H3MgBr, THF, 258C to rt, 24 h
PPh3, MeCN, reflux, 4 days
Li2CuCl4, PhMgBr, THF, 258C to rt, 24 h
Li2CuCl4, MeMgBr, THF, 258C to rt, 24 h
–
18h
18f (1b)
a
Product ratio according to GC–MS.
Isolated yield.
b
metal–halogen exchange and a subsequent unexpected28
elimination of the 2-lithiotetrahydroquinoline 18c. Finally,
alkylation with the formed bromobutane gave the amine
21e. According to gas chromatic analysis, the rearrange-
ment to any benzo[b]azepine did not occur. To our
knowledge, the 2-piperidinylmethyl-3-azepinyl rearrange-
ment, which is quite common,29 has not been observed for
the 2-benzannelated series.25 The reaction of 18a with
methyl lithium at 2788C yielded predominantly N-(2-but-3-
enylphenyl)-N-methylamine 21f after warming to room
temperature. As a side product (approx. 14%), 2-ethyl-1-
methyltetrahydroquinoline 18d was detected (Scheme 5,
Table 1, entry 1).30
of butyl lithium gave similar results with the bromide 18a,
while the iodide 18b gives rise only to ring-opened material
32
(Table 1, entries 5, 7). Lithium chloro cuprate Li2CuCl4
facilitates the transfer of a vinyl group to iodide 18b
effectively using vinyl magnesium bromide to furnish allyl
tetrahydroquinoline 18i in good selectivity (Scheme 6,
Table 1, entry 8). However, ethyl magnesium bromide leads
to reduction of the bromide group, presumably via a
b-hydride transfer (Table 1, entry 6).
The reaction with other nucleophiles such as triphenyl
phosphine with bromide 18a failed even at elevated
temperatures due to the neopentyl type structure of 18a
and diminished nucleophilicity of the phosphine (Table 1,
entry 9).
The cuprate generated from copper-(I)-bromide dimethyl
sulfide complex and butyl lithium (1:2)31 introduces a butyl
moiety to furnish racemic Angustureine (3b¼18e) in 15%
yield (Scheme 6, Table 1, entry 4). Major product is the
ring-opened 21f (R¼H). Copper-(I)-iodide in the presence
Gratifyingly, the reaction of the iodide 19b with carbon
nucleophiles such as methyl magnesium bromide or phenyl
magnesium bromide smoothly proceeds in the presence of
Scheme 6. Synthesis of substituted tetrahydroquinolines 18.

F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
6789
copper salts to give rise to substituted tetrahydroquinolines
18f and 18h, respectively (Table 1, entries 10, 11).
Hence, the homologous haloethyl tetrahydroquinolines 19
are apparently more suitable substrates for nucleophilic
displacement since the ring-opening reaction to yield aniline
derivatives was not observed.
ether 1:1). Yield 270 mg (40%). TLC: Rf¼0.72 (pentane/
ether, 1:1). GC: Rt¼4.42 min. HPLC [MeOH/H2O 70:30,
1.0 ml/min]: Rt¼1.55 min. IR (neat): n¼3249 (w), 3181
(m), 3132 (m), 3060 (w), 3014 (m), 2967 (m), 1623 (m),
1530 (m), 1492 (m), 1449 (m), 1412 (m), 1315 (m), 1222
(m), 1150 (s, CvS), 1104 (m), 969 (m), 890 (m), 856 (m),
750 (s) cm21. 1H NMR (400 MHz, CD3OD): d¼4.86 (s, 1H,
3
Although 2-alkyl tetrahydroquinolines can in principle be
prepared by the classical Reissert type addition of
nucleophiles to quinolines,33 the preparation via aminoben-
zyl alcohol is advantageous in terms of substitution pattern
at the arene core as well as possible (cyclic) dienophiles
leading to tri- and tetrasubstituted carbamates.
NH), 5.29 (s, 2H, CH2), 6.92 (bd, J¼7.52 Hz, 1H, Ar-H),
3
4
7.12 (ddd, J¼7.52, 7.52 Hz, J¼1.00 Hz, 1H, Ar-H), 7.18
3
3
(bd, J¼7.52 Hz, 1H, Ar-H), 7.29 (dd, J¼7.52, 7.52 Hz,
1H, Ar-H). 13C NMR (100 MHz, CD3OD): d¼71.0 (þ,
CH2), 115.5 (2, C-Ar), 120.9 (quart, Cquart-Ar), 126.4 (2,
C-Ar), 126.7 (2, C-Ar), 131.8 (2, C-Ar), 135.8 (quart,
Cquart-Ar), 188.4 (quart, CvS). MS (70 eV, EI), m/z (%):
165 (100) [Mþ], 132 (11), 104 (41), 78 (28), 63 (3), 51 (8).
C8H7NOS (165.02): calcd C 58.16, H 4.27, N 8.48, S 19.41;
found C 58.11, H 4.17, N 8.51, S 19.16.
In summary, a rapid access to tetrahydroquinoline deriva-
tives starting from aminobenzylalcohol has been presented.
The first intermolecular cleavage of thiocarbamates using
triphenylphosphine and tetrachloromethane to give chlor-
omethyl phenylisocyanate has been presented. Finally, total
syntheses of some natural occurring 2-alkyl-1-methyltetra-
hydroquinolines have been reported.
2.1.2. (2-Chloromethylphenyl)carbamic acid allyl ester
(11a). (a) From 13a. To a solution of 3.80 g (18.4 mmol) of
(2-hydroxymethylphenyl)carbamic acid allyl ester (13a) in
150 ml of dichloromethane and 2.50 ml (1.85 g, 18.3 mmol)
of triethylamine was added 1.50 ml (2.38 g, 20.2 mmol,
1.1 equiv.) of thionylchloride dropwise at 08C. The reaction
mixture was stirred for 5 h, while warming to room
temperature. It was concentrated to dryness in vacuum
and subsequently dissolved in 50 ml of diethyl ether,
washed with 30 ml of water, dried over sodium sulfate,
filtered and again concentrated to dryness in vacuum.
Compound 11a was furnished as white solid. Yield 4.09 g
(99%).
2. Experimental
2.1. General
All reactions were conducted in dried glassware under an
atmosphere of dry argon. THF (Na, benzophenone),
dichloromethane (CaH2), acetonitrile (CaH2), methanol
(Mg) and tetrachloromethane (K2CO3, molecular sieves)
were distilled from the drying agent indicated in argon
atmosphere. Pentane, hexane, diethyl ether, dichloro-
methane, ethanol and 1,2-dichloroethane were distilled
and used without further purification. Cesium carbonate was
dried before use (408C, 2 h in high vacuum). All chemicals
and solvents were purchased from Aldrich, Acros, Fluka
and Merck (Darmstadt) and used as received unless
otherwise stated. TLC analyses were performed on silica
gel precoated aluminium plates Kieselgel 60 (Merck) UV.
Column chromatography was performed on Kieselgel 60
(Merck). NMR: Bruker AMX-400 or DP 400 (400.13 MHz
(b) From 8. To a stirred solution of 504 mg (3.05 mmol) of
1,4-dihydro-benzo[d][1,3]oxazine-2-thione(8)in10 mlofdry
acetonitrile was added 962 mg (3.67 mmol, 1.20 equiv.) of
triphenylphosphine and 0.40 ml (636 mg, 4.19 mmol,
1.37 equiv.) of tetrachloromethane at room temperature.
The reaction mixture was stirred at 508C for 3 h. During that
time, the colour of the solution changed from colourless to
deep red. The reaction mixture was cooled to 08C, 0.35 ml
(298 mg, 5.13 mmol, 1.67 equiv.) of allyl alcohol (10a)
were added and stirred again at 508C for 6 h. The reaction
mixture was concentrated to dryness in vacuum and
compound 11a was isolated as white solid after column
chromatography on silica (30 g, 2.5£18 cm, hexane/ether
2:1). Yield 611 mg (89%). Mp: 638C. TLC: Rf¼0.30
(pentane/ether, 3:1). GC: Rt¼4.08 min. HPLC [MeOH/
H2O 70:30, 1.0 ml/min]: Rt¼2.56 min. IR (KBr): n¼2993
(m), 2978 (m), 2938 (m), 2870 (m), 2769 (w), 2369 (w),
2345 (w), 2285 (w), 2196 (w), 1972 (w), 1845 (w), 1698
(vs), 1647 (s), 1609 (s), 1593 (s), 1531 (vs), 1487 (s), 1458
(s), 1450 (s), 1410 (s), 1300 (vs), 1250 (vs), 1110 (s), 1090
1
for H), CDCl3 and CD3OD as solvents, dH (CHCl3)¼7.27
and dH (CD3OD)¼3.31. Abbreviations for1H NMR: s¼
singlet, d¼doublet, t¼triplet and DEPT multiplicities for
13C NMR. Infrared spectra were recorded on a Perkin–
Elmer FTIR 1750. Mass spectra were recorded on a
KRATOS MS 50 (70 eV) or KRATOS MS 890A (70 eV)
respectively. HPLC: Lichrospher 100 (Merck) RP-18,
1 ml/min. GC: column HP-1 (cross-linked Methyl Siloxane)
12 m£0.25 mm£0.33 mm film thickness. Init. temp: 608C,
init. time: 0.5 min, rate: 508C/min. Elemental analysis:
elementar vario EL at the Mikroanalytisches Labor des
1
(s), 1060 (s), 1010 (s) cm21. H NMR (400 MHz, CDCl3):
d¼4.59 (s, 2H, CH2Cl), 4.68 (dt, 3J¼5.72 Hz, 4J¼1.35 Hz,
¨
Instituts fu¨r Organische Chemie der Universitat Bonn.
Melting points are corrected.
2
3
2H, CH2OCO), 5.27 (dd, J¼2.87 Hz, J¼10.45 Hz, 1H,
CHvCH2), 5.37 (ddd, 2J¼2.87 Hz, 3J¼17.19 Hz,
3
4J¼1.35 Hz, 1H, CHvCH2), 5.98 (ddd, J¼5.72, 10.45,
2.1.1. 1,4-Dihydrobenzo[d][1,3]oxazine-2-thione (8).16
A
17.19 Hz, 1H, CH), 6.96 (bs, 1H, NH), 7.09 (dd,
3J¼7.64 Hz, 4J¼1.12 Hz, 1H, Ar-H4), 7.27 (dd,
3J¼7.64 Hz, 4J¼1.45 Hz, 1H, Ar-H3), 7.35 (dd,
3J¼8.02 Hz, 4J¼1.45 Hz, 1H, Ar-H5), 7.84 (bd,
3J¼8.02 Hz, 1H, Ar-H6). 13C NMR (100 MHz, CDCl3):
d¼44.0 (þ, Ar-CH2Cl), 66.3 (þ, CH2OCO), 118.5 (þ,
stirred solution of 500 mg (4.06 mmol) of 2-aminobenzy-
lalcohol (7) and 5.00 ml (6.33 g, 83.4 mmol, 20.5 equiv.) of
carbon disulfide in a sealed tube was heated at 808C for 8 h,
cooled to room temperature and concentrated to dryness in
vacuum. Compound 8 was isolated as beige solid after
column chromatography on silica (60 g, 4£15 cm, pentane/

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F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
CHvCH2), 123.1 (2, C6-Ar), 124.6 (2, C4-Ar), 127.5
(quart, CCquart-Ar), 130.1 (2, C-Ar*), 130.2 (2, C-Ar*),
132.5 (2, CHvCH2), 136.7 (quart, NCquart-Ar), 153.6
(quart, CvO). MS (70 eV, EI), m/z (%): 225/227 (96/30)
[Mþ], 184 (83), 166 (86), 148 (50), 132 (100), 118 (27), 104
(68), 91 (14), 77 (50), 58 (15). HRMS C11H12ClNO2: calcd
225.0557; found 225.0552. C11H12ClNO2 (225.06): calcd C
58.54, H 5.36, N 6.21; found C 58.66, H 5.46, N 6.25.
of (2-chloromethylphenyl)carbamic acid allyl ester (11a)
and 24.6 g (75.5 mmol, 3.4 equiv.) of cesium carbonate was
stirred in 170 ml of dry dichloromethane at room tempera-
ture for 3 days. Subsequently, the mixture was filtered over
Celitew and thoroughly washed with dichloromethane. The
filtrate was concentrated to dryness in vacuum. Heterocycle
12a was furnished as beige solid. Yield 3.84 g (91%).
(b) From 14a. A solution of 4.50 g (15.4 mmol) of carbonic
acid allyl ester 2-allyloxycarbonylamino-benzyl ester (14a)
and 15.1 g (46.3 mmol, 3 equiv.) of cesium carbonate was
stirred in 200 ml of dry dichloroethane at 808C for 12 h.
After being cooled to room temperature, the mixture was
filtered over Celitew and thoroughly washed with dichloro-
methane. The filtrate was concentrated to dryness in
vacuum. After column chromatography on silica (100 g,
4£25 cm, pentane/ether 3:1), heterocycle 12a was isolated
as beige solid. Yield 2.02 g (69%). Mp: 848C. TLC:
Rf¼0.11 (pentane/ether, 1:1). GC: Rt¼4.62 min. HPLC
[MeOH/H2O 70:30, 1.0 ml/min]: Rt¼2.04 min. IR (KBr):
n¼2931 (m), 2903 (m), 2847 (m), 1742 (vs), 1700 (s), 1602
(s), 1548 (m), 1495 (vs), 1456 (s), 1400 (vs), 1327 (s), 1298
(s), 1290 (s), 1219 (s), 1186 (m), 1139 (s), 1113 (s), 1087
(m), 1035 (s), 974 (m), 944 (m), 789 (m), 754 (vs), 718
2.1.3. (2-Chloromethylphenyl)carbamic acid but-3-enyl
ester (11b). (a) From 13b. To a solution of 4.90 g
(22.2 mmol) of (2-hydroxymethylphenyl)carbamic acid
but-3-enyl ester (13b) in 50 ml of dichloromethane and
3.00 ml (2.22 g, 22.0 mmol, 1.0 equiv.) of triethylamine
was added 1.80 ml (2.87 g, 24.4 mmol, 1.1 equiv.) of
thionylchloride dropwise at 08C. The reaction mixture was
stirred for 5 h, while warming to room temperature. It was
concentrated to dryness in vacuum and subsequently
dissolved in 50 ml of diethyl ether, washed with 30 ml of
water, dried over sodium sulfate, filtered and again
concentrated to dryness in vacuum. Compound 13b was
furnished as white solid. Yield 5.21 g (98%).
(b) From 8. To a stirred solution of 504 mg (3.05 mmol) of
1,4-dihydro-benzo[d][1,3]oxazine-2-thione (8) in 10 ml of
dry acetonitrile was added 962 mg (3.67 mmol, 1.20 equiv.)
of triphenylphosphine and 0.40 ml (636 mg, 4.19 mmol,
1.37 equiv.) of tetrachloromethane at room temperature.
The reaction mixture was stirred at 508C for 3 h. During that
time, the colour of the solution changed from colourless to
deep red. The reaction mixture was cooled to 08C, 0.45 ml
(0.38 g, 5.26 mmol, 1.72 equiv.) of homoallyl alcohol (10b)
were added and stirred again at 508C for 6 h. The reaction
mixture was concentrated to dryness in vacuum and
compound 11b was isolated as white solid after column
chromatography on silica (30 g, 2.5£18 cm, hexane/ether
2:1). Yield 434 mg (60%). Mp: 698C. TLC: Rf¼0.52
(pentane/ether, 1:1). GC: Rt¼4.28 min. HPLC [MeOH/
H2O 70:30, 1.0 ml/min]: Rt¼3.24 min. IR (KBr): n¼3293
(s), 3076 (w), 2975 (w), 1694 (s), 1592 (m), 1541 (s), 1459
(m), 1255 (s), 1076 (m), 921 (m), 770 (m), 670 (s) cm21. 1H
1
(m) cm21. H NMR (400 MHz, CDCl3): d¼1.79–1.90 (m,
1H, CH2), 2.15–2.21 (m, 1H, CH2), 2.89–3.03 (m, 2H,
CH2), 4.04 (t, J¼8.33 Hz, 1H, CH2), 4.14–4.21 (m, 1H,
3
CH), 4.58 (m, 3J¼8.33 Hz, 1H, CH2), 7.03 (dd, 3J¼7.57 Hz,
3
3J¼7.57 Hz, 1H, Ar-H), 7.13 (bd, J¼7.57 Hz, 1H, Ar-H),
3
3
7.23 (dd, J¼8.28 Hz, J¼7.57 Hz, 1H, Ar-H), 8.23 (bd,
3J¼8.28 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3):
d¼26.7 (þ, CH2), 26.8 (þ, CH2), 54.6 (2, CH), 67.5 (þ,
CH2O), 118.5 (2, C-Ar), 123.6 (2, C-Ar), 124.9 (quart,
CCquart-Ar), 127.3 (2, C-Ar), 129.2 (2, C-Ar), 135.0 (quart,
NCquart-Ar), 154.5 (quart, CvO). MS (70 eV, CI), m/z (%):
189 (100) [Mþ], 144 (53), 130 (30), 117 (40), 103 (6), 90
(10), 77 (11), 65 (3), 51 (6). HRMS C11H11NO2: calcd
189.0790; found 189.0795. C11H11NO2 (189.21) calcd C
69.83, H 5.86, N 7.40; found C 69.54, H 5.94, N 7.33.
2.1.5. 4,4a,5,6-Tetrahydro-3H-[1,3]oxazin[3,4-a]quino-
lin-1-one (12b) and butenyloxy carbonylbenzoazetedine
(15b). A suspension of 4.60 g (19.2 mmol) of (2-chloro-
methylphenyl)carbamic acid but-3-enyl ester (11b) and
15.6 g (47.9 mmol, 2.5 equiv.) of cesium carbonate was
stirred in 350 ml of dry dichloromethane at room tempera-
ture for 3 days. Subsequently, the reaction mixture was
filtered over Celitew and thoroughly washed with dichlor-
omethane. The filtrate was concentrated to dryness in
vacuum. After column chromatography on silica, hetero-
cycle 12b was isolated as white solid. Yield 1.18 g (32%).
Mp: 1018C. TLC: Rf¼0.03 (pentane/ether, 1:1). GC:
Rt¼5.46 min. HPLC [MeOH/H2O 70:30, 1.0 ml/min]:
Rt¼3.64 min. IR (KBr): n¼2922 (s), 2903 (m), 1692 (s),
1604 (w), 1491 (m), 1469 (m), 1410 (m), 1282 (m), 1224
(m), 1205 (w), 1124 (m), 1087 (m), 1020 (w), 960 (m),
3
NMR (400 MHz, CDCl3): d¼2.47 (dq, J¼1.44, 6.76 Hz,
2H, CHCH2), 4.25 (t, 3J¼6.76 Hz, 2H, CH2O), 4.60 (s, 2H,
2
3
CH2Cl), 5.11 (ddd, J¼3.03 Hz, J¼1.23, 10.28 Hz, 1H,
CHvCH2), 5.16 (ddd, 2J¼3.03 Hz, 3J¼1.44, 17.16 Hz,
3
1H, CHvCH2), 5.84 (ddd, J¼6.77, 10.28, 17.16 Hz, 1H,
CHvCH2), 6.91 (bs, 1H, NH), 7.10 (ddd, 3J¼7.61 Hz,
3J¼7.61 Hz, 4J¼1.14 Hz, 1H, Ar-H4), 7.28 (dd,
3J¼7.61 Hz, 4J¼1.39 Hz, 1H, Ar-H3), 7.36 (ddd,
3J¼7.81 Hz, 3J¼7.61 Hz, 4J¼1.39 Hz, 1H, Ar-H5), 7.82
(bd, 3J¼7.81 Hz, 1H, Ar-H6). 13C NMR (100 MHz, CDCl3):
d¼33.5 (þ, CHCH2), 44.0 (þ, CH2Cl), 64.7 (þ, OCH2),
117.5 (þ, CHvCH2), 123.1 (2, C6-Ar), 124.6 (2, C4-Ar),
127.5 (quart, CCquart-Ar), 130.1 (2, C-Ar*), 130.2 (2, C-
Ar*), 133.9 (2, CHvCH2), 136.7 (quart, NCquart-Ar), 153.9
(quart, CvO). MS (70 eV, EI), m/z (%): 239/241 (48/16)
[Mþ], 204 (12), 185 (40), 166 (15), 150 (25), 132 (85), 105
(32), 97 (17), 55 (100). HRMS C12H14ClNO2: calcd
239.0713; found 239.0720. C12H14ClNO2 (239.06): calcd
C 60.13, H 5.89, N 5.84; found C 60.08, H 5.91, N 5.78.
946 (w), 782 (w), 756 (s), 714 (m) cm21 1H NMR
.
(400 MHz, CDCl3): d¼1.81–1.91 (m, 1H, CH2), 1.93–
2.02 (m, 1H, CH2), 2.10–2.17 (m, 1H, CH2), 2.28–2.35 (m,
1H, CH2), 2.87–2.91 (m, 2H, CH2), 3.67–3.75 (m, 1H,
CH), 4.28–4.33 (m, 2H, CH2), 7.02 (ddd, 3J¼7.38 Hz,
3J¼7.38 Hz, 4J¼0.76 Hz, 1H, Ar-H), 7.09 (dd, 3J¼7.38 Hz,
4J¼0.88 Hz, 1H, Ar-H), 7.16 (ddd, 3J¼8.28 Hz,
2.1.4. 3,3a,4,5-Tetrahydrooxazol[3,4,-a]quinolin-1-one
(12a). (a) From 11a. A suspension of 5.00 g (22.2 mmol)

F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
6791
3J¼8.28 Hz, 4J¼0.88 Hz, 1H, Ar-H), 7.76 (dd, 3J¼8.28 Hz,
4J¼0.76 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3):
d¼26.2 (þ, CH2), 30.0 (þ, CH2), 30.7 (þ, CH2), 54.1 (2,
CH), 64.3 (þ, CH2O), 124.3 (2, C-Ar), 124.4 (2, C-Ar),
126.2 (2, C-Ar), 128.3 (quart, CCquart-Ar), 129.2 (2, C-Ar),
138.1 (NCquart-Ar), 152.8 (quart, CvO). MS (70 eV, CI), m/
z (%): 203 (100) [Mþ], 158 (65), 144 (27), 130 (100), 117
(28). HRMS C12H13NO2: calcd 203.0946; found 203.0947.
C12H13NO2 (203.24) calcd C 70.92, H 6.45, N 6.89; found C
70.95, H 6.53, N 6.83. As a side-product, benzazetidine 15b
(2). HRMS C11H13NO3: calcd 207.0895; found 207.0900.
C11H13NO3 (207.9): calcd C 63.76, H 6.32, N 6.76; found C
63.75, H 6.29, N 6.72.
2.1.7. (2-Hydroxymethylphenyl)carbamic acid but-3-
enyl ester (13b). To a solution of 4.58 g (37.2 mmol) of
2-aminobenzylalcohol (7) in 80 ml of dichloromethane and
3.00 ml (2.94 g, 37.2 mmol, 1.0 equiv.) of pyridine was
added 4.60 ml (5.00 g, 37.3 mmol, 1.0 equiv.) of 3-butenyl
chloroformate dropwise at 258C. The reaction mixture was
stirred for 24 h, while warming to room temperature.
Subsequently, the mixture was washed with each 20 ml of
sodium hydrogen carbonate solution, brine and water. The
organic layer was dried over sodium sulfate, filtered and
concentrated to dryness in vacuum. After column chroma-
tography on silica (220 g, 6£22 cm, pentane/ether 1:1),
carbamate 13b was isolated as yellowish oil. Yield 7.65 g
(93%). TLC: Rf¼0.42 (pentane/ether, 1:1). GC:
Rt¼4.83 min. HPLC [MeOH/H2O 70:30, 1.0 ml/min]:
Rt¼2.05 min. IR (KBr): n¼3285 (s), 2955 (m), 2895 (w),
2287 (w), 1692 (s), 1588 (w), 1535 (m), 1481 (w), 1456 (w),
1421 (w), 1376 (m), 1352 (w), 1294 (w), 1253 (m), 1163
1
was isolated. Yield 368 mg (10%). H NMR (300 MHz,
3
C6D6): d¼2.26 (dddd, J¼6.76, 6.76, 1.44, 1.44 Hz, 2H,
3
CHCH2), 4.25 (t, J¼6.76 Hz, 2H, CH2O), 4.70 (s, 2H,
CH2), 4.90 (ddd, 2J¼3.03 Hz, 3J¼1.23, 10.28 Hz, 1H,
CHvCH2), 4.95 (ddd, 2J¼3.03 Hz, 3J¼1.44, 17.16 Hz, 1H,
CHvCH2), 5.84 (ddd, 3J¼6.77, 10.28, 17.16 Hz, 1H,
CHvCH2), 7.10 (ddd, 3J¼7.61 Hz, 3J¼7.61 Hz, 4J¼
1.14 Hz, 1H, Ar-H), 7.28 (dd, 3J¼7.61 Hz, 4J¼1.39 Hz,
1H, Ar-H), 7.36 (ddd, 3J¼7.81 Hz, 3J¼7.61 Hz, 4J¼
3
1.39 Hz, 1H, Ar-H), 7.82 (bd, J¼7.81 Hz, 1H, Ar-H). 13C
NMR (75.5 MHz, CDCl3): d¼33.3 (þ, CHCH2), 67.6 (þ,
OCH2), 68.7 (þ, CH2), 117.1 (þ, CHvCH2), 123.1 (2,
C-Ar), 124.6 (2, C-Ar), 127.5 (quart, CCquart-Ar), 130.1 (2,
C-Ar*), 130.2 (2, C-Ar*), 133.9 (2, CHvCH2), 136.7
(quart, NCquart-Ar), 157.0 (quart, CvO). MS (70 eV, CI),
m/z (%): 203 (50) [Mþ], 149 (53), 132 (21), 118 (23), 105
(100), 77 (33), 55 (27).
(m), 1112 (w), 1070 (w), 1037 (m) cm21 1H NMR
.
3
4
(400 MHz, CDCl3): d¼2.40 (dq, J¼6.76 Hz, J¼1.43 Hz,
2H, OCH2CH2), 3.70 (bs, 1H, OH), 4.13 (t, 3J¼6.82 Hz, 2H,
2
OCH2CH2), 4.54 (t, J¼5.30 Hz, 2H, CH2OH), 5.09 (ddd,
2J¼3.07 Hz, 3J¼1.16, 10.28 Hz, 1H, CHvCH2), 5.13 (ddd,
2J¼3.07 Hz, 3J¼17.18 Hz, 4J¼1.43 Hz, 1H, CHvCH2),
3
2.1.6. (2-Hydroxymethylphenyl)carbamic acid allyl ester
(13a).23 To a solution of 6.00 g (48.8 mmol) of 2-
aminobenzylalcohol (7) in 80 ml of dichloromethane and
4.00 ml (3.88 g, 49.1 mmol, 1.0 equiv.) of pyridine was
added 5.20 ml (5.92 g, 49.3 mmol, 1.0 equiv.) of allyl
chloroformate dropwise at 258C. The reaction mixture
was stirred for 7 h, while warming to room temperature.
Subsequently, the mixture was washed with each 20 ml of
aq. sodium hydrogen carbonate solution, brine and water.
The organic layer was dried over sodium sulfate, filtered and
concentrated to dryness in vacuum. After column chroma-
tography on silica (70 g, 4£14 cm, pentane/ether 1:1)
compound 13 was furnished as white solid. Yield 8.50 g
(84%). Mp: 548C. TLC: Rf¼0.29 (pentane/ether, 1:1). GC:
Rt¼4.20 min. HPLC [MeOH/H2O 70:30, 1.0 ml/min]:
Rt¼1.76 min. IR (KBr): n¼2953 (m), 2895 (m), 2283 (w),
1691 (vs), 1590 (s), 1535 (vs), 1481 (s), 1456 (s), 1421 (s),
1376 (m), 1346 (m), 1295 (s), 1238 (vs), 1163 (m), 1111 (s),
5.80 (ddd, J¼6.76, 10.28, 17.18 Hz, 1H, CHvCH2), 7.00
(d, 3J¼7.46 Hz, 1H, Ar-H4), 7.08 (dd, 3J¼7.46 Hz,
4J¼1.44 Hz, 1H, Ar-H3) 7.25 (dd, 3J¼7.78 Hz,
3
4J¼1.44 Hz, 1H, Ar-H5), 7.79 (bd, J¼7.78 Hz, 1H, Ar-
H6), 8.02 (bs, 1H, NH). 13C NMR (100 MHz, CDCl3):
d¼33.1 (þ, OCH2CH2), 63.5 (þ, CH2OH), 64.2 (þ,
OCH2CH2), 117.2 (þ, CHvCH2), 121.1 (2, C6-Ar),
123.4 (2, C4-Ar), 128.6 (2, C-Ar*), 128.7 (2, C-Ar*),
129.5 (quart, CCquart-Ar), 133.8 (2, CHvCH2), 137.2
(quart, NCquart-Ar), 154.3 (quart, CvO). MS (70 eV, EI), m/
z (%): 221 (41) [Mþ], 149 (19), 132 (36), 122 (100), 105
(37), 94 (11), 78 (16), 55 (49). HRMS C12H15NO3: calcd
211.1052; found 211.1050. C12H15NO3 (221.11): calcd C
65.14, H 6.83, N 6.33; found C 65.02, H 6.86, N 6.38.
2.1.8. Carbonic acid allyl ester 2-allyloxycarbonylamino-
benzyl ester (14a). To a solution of 2.00 g (16.2 mmol) of
2-aminobenzylalcohol (7) in 20 ml of dichloromethane and
3.9 ml (3.84 g, 48.6 mmol, 3.0 equiv.) of pyridine was
added 5.2 ml (5.86 g, 48.6 mmol, 3 equiv.) of allyl chloro-
formate dropwise at room temperature. The reaction
mixture was stirred for 7 h. Subsequently, the mixture was
washed with each 20 ml of sodium hydrogen carbonate
solution, brine and water. The organic layer was dried over
sodium sulfate, filtered and concentrated to dryness in
vacuum. After column chromatography on silica (50 g,
4£14 cm, pentane/ether 4:1), carbamate 14a was isolated as
yellowish oil. Yield 3.55 g (75%). TLC: Rf¼0.22 (pentane/
ether, 4:1). GC: Rt¼5.33 min. HPLC [MeOH/H2O 70:30,
1.0 ml/min]: Rt¼3.06 min. IR (capillary): n¼2984 (w),
2951 (w), 2893 (w), 1739 (vs), 1649 (m), 1609 (m), 1594
(s), 1528 (s), 1483 (m), 1456 (s), 1425 (m), 1388 (s), 1360
(m), 1300 (s), 1255 (vs), 1222 (vs), 1163 (w), 1123 (w),
1070 (s), 1036 (s) cm21 1H NMR (400 MHz, CDCl3):
.
d¼3.46 (bs, 1H, OH), 4.55 (bs, 2H, CH2OH), 4.58 (ddd,
2
3J¼1.47, 5.73 Hz, 2H, OCCH2), 5.23 (ddd, J¼2.77 Hz,
3J¼1.23, 10.41 Hz, 1H, CH2vCH), 5.33 (ddd, 2J¼2.77 Hz,
3
3J¼1.47, 17.23 Hz, 1H, CH2vCH), 5.93 (ddd, J¼5.73,
3
10.41, 17.23 Hz, 1H, CH2vCH), 7.00 (ddd, J¼7.65 Hz,
3J¼7.46 Hz, 4J¼1.05 Hz, 1H, Ar-H4), 7.09 (dd,
3J¼7.46 Hz, 4J¼1.54 Hz, 1H, Ar-H3), 7.25 (ddd,
3J¼7.87 Hz, 3J¼7.65 Hz, 4J¼1.54 Hz, 1H, Ar-H5), 7.80
(bd, 3J¼7.87 Hz, 1H, Ar-H6), 8.05 (bs, 1H, NH). 13C NMR
(100 MHz, CDCl3): d¼63.6 (þ, CH2OH), 65.8 (þ,
COCH2), 118.1 (þ, CH2vCH), 121.1 (2, C6-Ar), 123.6
(2, C4-Ar), 128.7 (2, C-Ar*), 128.8 (2, C-Ar*), 129.4
(quart, CCquart-Ar), 132.4 (2, CHvCH2), 137.2 (quart,
NCquart-Ar), 154.0 (quart, CvO). MS (70 eV, EI), m/z (%):
207 (48) [Mþ], 148 (6), 132 (22) [C8H6NOþ], 122 (100)
[C7H8NOþ], 104 (10) [C7H6Nþ], 94 (17), 77 (18), 65 (4), 52
1
1102 (w), 1056 (s) cm21. H NMR (400 MHz, CDCl3):
3
3
4
d¼4.63 (ddd, J¼5.63 Hz, J¼5.63 Hz, J¼1.23 Hz, 2H,

6792
F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
CH2OCO), 4.68 (ddd, 3J¼5.63 Hz, 3J¼5.63 Hz,
4J¼1.23 Hz, 2H, CH2OCO), 5.17 (s, 2H, Ar-CH2), 5.27
(ddd, 2J¼1.37 Hz, 3J¼10.44 Hz, 4J¼1.23 Hz, 2H,
CHvCH2), 5.34 (ddd, 2J¼1.37 Hz, 3J¼17.20 Hz,
4J¼1.65 Hz, 1H, CHvCH2), 5.38 (ddd, 2J¼1.37 Hz,
suspended in 50 ml of dichloromethane and refluxed for
30 min. After filtration, the organic layers were combined
and washed with each 40 ml of brine and water. The organic
layer was dried over sodium sulfate, filtered and concen-
trated to dryness in vacuum. After column chromatography
on silica (20 g, 1.5£12 cm, hexane/ether 1:1), alcohol 16a
was isolated as yellowish oil. Yield 1.76 g (94%). TLC:
Rf¼0.08 (pentane/ether, 2:1). GC: Rt¼3.79 min. IR (KBr):
n¼3369 (w), 2928 (w), 2877 (w), 1601 (m), 1498 (m), 1479
(m), 1455 (w), 1433 (w), 1328 (w), 1307 (m), 1212 (m),
4
3J¼17.20 Hz, J¼1.65 Hz, 1H, CHvCH2), 5.86–6.04 (m,
2H, CH), 7.12 (ddd, 3J¼7.42 Hz, 3J¼7.42 Hz, 4J¼1.23 Hz,
1H, Ar-H4), 7.36 (dd, 3J¼7.42 Hz, 4J¼1.23 Hz, 1H, Ar-H3),
3
4
7.38 (ddd, J¼7.42 Hz, J¼1.23 Hz, 1H, Ar-H5), 7.67 (bs,
3
1H, NH), 7.84 (bd, J¼7.42 Hz, 1H, Ar-H6). 13C NMR
1
(100 MHz, CDCl3): d¼66.3 (þ, CH2OCO), 67.2 (þ, Ar-
CH2), 69.2 (þ, CH2OCO), 118.4 (þ, CH2CH), 119.5 (þ,
CH2CH), 123.0 (2, C-Ar), 124.6 (2, C-Ar), 125.6 (quart,
Cq-Ar), 130.4 (2, CHCH2), 131.4 (2, CHCH2), 131.5 (2,
C-Ar), 132.7 (2, C-Ar), 137.2 (quart, Cq-Ar), 154.0 (þ,
OCvO), 155.5 (quart, CvO). MS (70 eV, EI), m/z (%): 291
(51) [Mþ], 190 (34) [C11H12NOþ2 ], 148 (100) [C8H6NOþ2 ],
144 (64), 132 (71) [C8H6NOþ], 118 (34), 104 (38), 93 (19),
77 (15), 57 (4), 52 (3). HRMS C15H17NO5: calcd 291.1107;
found 291.1120. C15H17NO5 (291.10): calcd C 61.85, H
5.88, N 4.81; found C 61.70, H 5.90, N 4.77.
1036 (m), 1010 (m) cm21. H NMR (400 MHz, CDCl3):
d¼1.84–1.93 (m, 1H, CHCH2), 2.04–2.10 (m, 1H,
CHCH2), 2.67–2.83 (m, 2H, Ar-CH2), 2.95 (s, 3H, CH3),
3.33–3.39 (m, 1H, CH), 3.61–3.70 (m, 2H, CH2OH), 6.63
(bd, 3J¼7.77 Hz, 1H, Ar-H5), 6.67 (dd, 3J¼7.27 Hz,
3
4J¼1.01 Hz, 1H, Ar-H7), 7.00 (bd, J¼7.27 Hz, 1H, Ar-
3
4
H8), 7.13 (dd, J¼7.77 Hz, J¼1.52 Hz, 1H, Ar-H6). 13C
NMR (100 MHz, CDCl3, coupled): d¼22.9 (þ, t,
J¼129.8 Hz, Ar-CH2), 24.2 (þ, t, J¼126.6 Hz, CHCH2),
38.5 (2, q, J¼135.3 Hz, CH3), 60.0 (2, d, J¼136.6 Hz,
CH), 63.2 (þ, t, J¼126.6 Hz, CH2OH), 111.2 (2, d,
J¼155.9 Hz, C5-Ar), 116.1 (2, d, J¼160.5 Hz, C7-Ar),
122.4 (quart, s, Cquart-Ar), 127.2 (2, d, J¼157.1 Hz, C6-Ar),
128.6 (2, d, J¼154.4 Hz, C8-Ar), 145.5 (s, NCquart-Ar). MS
(70 eV, EI), m/z (%): 177 (16) [Mþ], 146 (100), 131 (15),
118 (6), 91 (3), 77 (3). HRMS C11H15NO: calcd 177.1154;
found 177.1153. C11H15NO (177.24) calcd C 74.54, H 8.53,
N 7.90; found C 74.52, H 8.59, N 7.93.
2.1.9. Carbonic acid 3-butenyl ester 3-butenyloxycarbo-
nylamino-benzyl ester (14b). To a solution of 1.53 g
(1.24 mmol) of 2-aminobenzylalcohol (7) in 30 ml of
dichloromethane and 3.0 ml (2.94 g, 37.2 mmol,
3.0 equiv.) of pyridine was added 5.00 g (37.2 mmol,
3 equiv.) of 3-butenyl chloroformate dropwise at room
temperature. The reaction mixture was stirred for 12 h.
Subsequently, the mixture was washed with each 20 ml of
sodium hydrogen carbonate solution, brine and water. The
organic layer was dried over sodium sulfate, filtered and
concentrated to dryness in vacuum. After column chroma-
tography on silica (120 g, 4£20 cm, pentane/ether 4:1),
carbamate 14b was isolated as yellowish oil. Yield 3.66 g.
(92%). TLC: Rf¼0.42 (pentane/ether, 1:1). GC:
Rt¼5.79 min. IR (KBr): n¼3078 (w), 2981 (w), 2962 (w),
2906 (w), 1739 (s), 1527 (m), 1456 (m), 1397 (m), 1300 (m),
1252 (s), 1219 (s), 1065 (m), 921 (m), 790 (w), 768
2.1.11. (1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)etha-
nol (16b). To a solution of 97 mg (0.48 mmol) of
4,4a,5,6-tetrahydro-3H-[1,3]oxazin[3,4-a]quinolin-1-one
(12b) in 30 ml of dry tetrahydrofuran was added 127 mg
(3.3 mmol, 7 equiv.) of lithium aluminum hydride and
refluxed for 4 h. After being cooled to room temperature, the
mixture was treated with water in small portions and
filtered. The white solid was suspended in 50 ml of
dichloromethane and refluxed for 30 min. After filtration,
both fractions were combined and washed with each 40 ml
of brine and water. The organic layer was dried over sodium
sulfate, filtered and concentrated to dryness in vacuum.
After column chromatography on silica (8 g, 1£16 cm,
pentane/ether 1:1), alcohol 16b was isolated as yellowish
oil. Yield 81 mg (89%). TLC: Rf¼0.10 (pentane/ether, 1:1).
1
(m) cm21. H NMR (400 MHz, CDCl3): d¼2.38–2.48 (m,
4H, CH2), 4.17–4.24 (m, 4H, CH2), 5.06–5.17 (m, 6H,
CH2), 5.70–5.88 (m, 2H, CHvCH2), 7.10 (dd, J¼1.01,
7.57 Hz, 1H, Ar-H), 7.33–7.38 (m, 2H, Ar-H), 7.61 (bs, 1H,
NH), 7.82 (bd, 3J¼6.13 Hz, 1H, Ar-H). 13C NMR (100 MHz,
CDCl3): d¼33.0 (þ, CH2), 33.5 (þ, CH2), 64.5 (þ, Ar-CH2),
66.8 (þ, CH2), 67.5 (þ, CH2), 117.4 (þ, CH2CH), 117.8 (þ,
CH2CH), 122.8 (2, C-Ar) 124.3 (2, C-Ar), 125.4 (quart,
Cquart-Ar), 130.2 (2, C-Ar), 131.3 (2, CHCH2), 133.3 (2,
CHCH2), 134.1 (2, C-Ar), 137.1 (quart, Cquart-Ar), 154.2
(quart, CvO), 155.6 (quart, CvO). MS (70 eV, EI), m/z (%):
319 (83) [Mþ], 204 (20), 149 (43), 132 (100), 122 (18), 105
(59), 91 (6), 77 (11), 55 (67). HRMS C17H21NO5: calcd
319.1420; found 319.1425. C17H21NO5 (319.35) calcd C
63.94, H 6.63, N 4.39; found C 64.03, H 6.70, N 4.45.
1
GC: Rt¼4.57 min. H NMR (400 MHz, CDCl3): d¼1.55–
1.65 (m, 2H, CH2), 1.80–1.55 (m, 3H, CH2), 2.50–2.60 (m,
1H, Ar-CH2), 2.70–2.80 (m, 1H, Ar-CH2), 3.40 (s, 3H,
3
CH3), 3.61–3.70 (m, 2H, CH2OH), 6.63 (bd, J¼7.77 Hz,
1H, Ar-H5), 6.67 (ddd, 3J¼7.27 Hz, 3J¼7.27 Hz,
3
4J¼1.01 Hz, 1H, Ar-H7), 7.00 (bd, J¼7.27 Hz, 1H, Ar-
3
3
4
H8), 7.13 (ddd, J¼7.77 Hz, J¼7.27 Hz, J¼1.52 Hz, 1H,
Ar-H6). 13C NMR (100 MHz, CDCl3): d¼23.6 (þ, Ar-
CH2), 24.7 (þ, CHCH2), 34.5 (þ, CHCH2), 38.9 (2, CH3),
56.1 (2, CH), 60.4 (þ, CH2OH), 111.8 (2, C5-Ar), 116.1
(2, C7-Ar), 122.1 (quart, Cquart-Ar), 127.4 (2, C6-Ar),
128.8 (2, C8-Ar), 145.3 (quart, NCquart-Ar). MS (70 eV,
EI), m/z (%): 191 (20) [Mþ], 146 (100) [C10H12N], 131 (10),
118 (6), 91 (3), 77 (3). HRMS C12H17NO: calcd 191.1310;
found 191.1309. C12H17NO (191.27) calcd C 75.35, H 8.96,
N 7.32; found C 75.02, H 8.89, N 7.62.
2.1.10. (1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)-
methanol (16a).27 To a solution of 2.00 g (10.6 mmol) of
3,3a,4,5-tetrahydrooxazol[3,4,-a]quinolin-1-one (12a) in
70 ml of dry tetrahydrofuran was added 1.2 g (31.8 mmol,
3 equiv.) of lithium aluminum hydride and refluxed for
4.5 h. After being cooled to room temperature, the mixture
was treated with water in small portions to furnish a white
precipitate and filtered. The remaining white solid was
2.1.12. (1,2,3,4-Tetrahydroquinolin-2-yl)methanol
(17).25 500 mg (2.64 mmol) of 3,3a,4,5-tetrahydro-

F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
6793
oxazol[3,4,-a]quinolin-1-one (12a) in 20 ml of a 10%
solution of sodium hydroxide in ethanol were refluxed for
3 h. After being cooled, the mixture was added to 50 ml of
dichloromethane and washed with each 40 ml of brine and
water. The organic layer was dried over sodium sulfate,
filtered and concentrated to dryness in vacuum. Heterocycle
17 was furnished as yellow oil without further purification.
Yield 410 mg (95%). TLC: Rf¼0.08 (pentane/ether, 1:1).
GC: Rt¼3.74 min. IR (KBr): n¼3373 (s), 2927 (m), 2844
(w), 1601 (m), 1496 (s), 1435 (w), 1310 (m), 1209 (w), 1029
added 360 mg (5.29 mmol, 1.88 equiv.) of imidazole, 1.33 g
(5.07 mmol, 1.79 equiv.) of triphenylphosphine and 1.30 g
(5.12 mmol, 1.82 equiv.) of iodine at room temperature. The
reaction mixture was stirred at room temperature for 24 h
and then treated in small portions with sat. aq. Na2S2O3
solution until the reaction mixture got colourless. It was
added 50 ml of ether, the organic layer was separated and
washed with each 30 ml of aq. sodium hydrogen carbonate
solution, brine and water. The organic layer was dried over
sodium sulfate, filtered and concentrated to dryness in
vacuum. After column chromatography on silica (30 g,
2.5£18 cm, hexane/ether 2:1) compound 18b was furnished
as yellowish oil. Yield 487 mg (60%). TLC: Rf¼0.78
(hexane/ether, 1:1). GC: Rt¼4.38 min. 1H NMR (400 MHz,
CDCl3): d¼1.91–2.02 (m, 1H, CHCH2), 2.38–2.46 (m, 1H,
CHCH2), 2.73–2.80 (m, 2H, Ar-CH2), 3.05 (s, 3H, CH3),
3.10–3.15 (m, 1H, CH2I), 3.39–3.43 (m, 1H, CH2I), 3.58–
1
(w) cm21. H NMR (400 MHz, CDCl3): d¼1.64–1.77 (m,
1H, CHCH2), 1.86–1.95 (m, 1H, CHCH2), 2.70–2.91 (m,
2H, Ar-CH2), 3.39–3.47 (m, 1H, CH), 3.54 (dd,
2J¼10.36 Hz, 3J¼7.65 Hz, 1H, CH2OH), 3.72 (dd,
2J¼10.36 Hz, 3J¼3.74 Hz, 1H, CH2OH), 6.54 (bd,
3J¼7.91 Hz, 1H, Ar-H5), 6.66 (d, 3J¼7.34 Hz, 1H, Ar-
H7), 6.96–7.04 (m, 2H). 13C NMR (100 MHz, CDCl3):
d¼24.4 (þ, Ar-CH2), 25.9 (þ, CHCH2), 52.8 (2, CH), 66.7
(þ, CH2OH), 114.6 (2, C5-Ar), 117.5 (2, C7-Ar), 121.5
(quart, Cquart-Ar), 126.9 (2, C6-Ar), 129.3 (2, C8-Ar),
141.2 (quart, NCquart-Ar). MS (70 eV, EI), m/z (%): 163 (20)
[Mþ], 132 (100) [C9H9Nþ], 119 (18). HRMS C10H13NO:
calcd 163.0997; found 163.1001. C10H13NO (163.10) calcd
C 73.59, H 8.03, N 8.58; found C 73.11, H 8.22, N 8.50.
3
3.65 (m, 1H, CH), 6.62 (bd, J¼8.04 Hz, 1H, Ar-H), 6.71
3
3
(dd, J¼7.04, 7.52 Hz, 1H, Ar-H), 7.06 (bd, J¼7.04 Hz,
1H, Ar-H), 7.16 (dd, J¼7.52, 8.04 Hz, 1H, Ar-H). 13C
3
NMR (100 MHz, CDCl3): d¼7.7 (þ, CH2I), 22.6 (þ, Ar-
CH2), 23.9 (þ, CHCH2), 37.9 (2, CH3), 59.9 (2, CH),
110.6 (2, C-Ar), 116.3 (2, C-Ar), 121.8 (quart, CCquart-Ar),
127.4 (2, C-Ar), 128.9 (2, C-Ar), 144.1 (quart, NCquart
-
Ar). MS (70 eV, EI), m/z (%): 287 (41) [Mþ], 159 (52), 146
(100), 131 (55), 117 (44), 91 (57), 77 (54), 65 (37). HRMS
C11H14IN: calcd 287.0171; found 287.0175.
2.1.13. 2-Brommethyl-1-methyl-1,2,3,4-tetrahydroqui-
noline (18a). To a solution of 500 mg (2.8 mmol) of (1-
methyl-1,2,3,4-tetrahydroquinolin-2-yl)-methanol (12a) in
15 ml of dry tetrahydrofuran and 0.78 ml (570 mg,
5.64 mmol, 2.0 equiv.) of triethylamine was added 420 mg
(3.67 mmol, 1.3 equiv.) of mesylchloride dropwise at
2408C. The reaction mixture was stirred at 2408C for
1.5 h and subsequently treated with 980 mg (11.3 mmol,
4.0 equiv.) of lithium bromide, dissolved in 10 ml of dry
tetrahydrofuran. After stirring additional 30 min at 2408C,
the mixture was warmed to room temperature within 4 h.
The mixture was dissolved in 70 ml of dichloromethane and
washed with each 50 ml of aq. sodium hydrogen carbonate
solution and brine. After back extraction of the aqueous
layer with dichloromethane, the combined organic layers
were dried over sodium sulfate, filtered and concentrated to
dryness in vacuum. After column chromatography on silica
(70 g, 3£30 cm, pentane/ether 1:1), compound 18a was
furnished as yellowish oil. Yield 573 mg (86%). TLC:
Rf¼0.59 (pentane/ether, 9:1). 1H NMR (400 MHz, CDCl3):
d¼1.90–2.00 (m, 1H, CHCH2), 2.20–2.30 (m, 1H,
CHCH2), 2.55–2.80 (m, 2H, CH2), 3.00 (s, 3H, CH3),
3.35–3.45 (m, 1H, CH), 3.55–3.80 (m, 2H), 6.40 (bd,
3J¼7.80 Hz, 1H, Ar-H), 6.67 (dd, 3J¼7.30 Hz, 3J¼7.30 Hz,
1H, Ar-H), 7.00 (d, 3J¼7.30 Hz, 1H, Ar-H), 7.13 (dd,
3J¼7.30 Hz, 3J¼7.80, 1H, Ar-H). 13C NMR (100 MHz,
CDCl3): d¼22.8 (þ, Ar-CH2), 31.1 (þ, CHCH2), 38.1 (2,
CH3), 43.1 (þ, CH2Br), 60.0 (2, CH), 110.5 (2,C5-Ar),
116.3 (2, C7-Ar), 121.7 (quart, Cquart-Ar), 127.3 (2, C6-
Ar), 128.8 (2,C8-Ar), 144.2 (quart, NCquart-Ar). HRMS
C11H14NBr: calcd 239.0310; found 239.0309. C11H14NBr
(240.14) calcd C 55.02, H 5.88, N 5.83; found C 55.54, H
5.95, N 5.96.
2.1.15. 2-(2-Iodo-ethyl)-1-methyl-1,2,3,4-tetrahydroqui-
noline (19b). To a stirred solution of 202 mg (1.06 mmol) of
2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-ethanol (16b)
in 15 ml of a mixture of ether and acetonitrile (3:2) was
added 136 mg (1.99 mmol, 1.87 equiv.) of imidazole,
498 mg (1.89 mmol, 1.78 equiv.) of triphenylphosphine
and 489 mg (1.92 mmol, 1.81 equiv.) of iodine at room
temperature. The reaction mixture was stirred at room
temperature for 24 h and then treated in small portions with
sat. aq. Na2S2O3 solution until the reaction mixture got
colourless. It was added 50 ml of ether and the organic layer
was separated and washed with each 30 ml of aq. sodium
hydrogen carbonate solution, brine and water. The organic
layer was dried over sodium sulfate, filtered and concen-
trated to dryness in vacuum. After column chromatography
on silica (74.0 g, 3£19 cm, pentane/ether 50:1) compound
19b was furnished as yellowish oil. Yield 215 mg (68%).
1
TLC: Rf¼0.23 (pentane/ether, 50:1). GC: Rt¼5.09 min. H
NMR (400 MHz, CDCl3): d¼1.82–1.98 (m, 3H), 2.12–
2.20 (m, 1H, CH2), 2.70–2.78 (m, 2H, CH2), 3.00 (s, 3H,
CH3), 3.13–3.19 (m, 1H, CH2), 3.25–3.31 (m, 1H, CH2),
3
3.41–3.47 (m, 1H, CH), 6.56 (bd, J¼8.14 Hz, 1H, Ar-H),
6.63 (dd, 3J¼7.19, 7.70 Hz, 1H, Ar-H), 6.98 (bd,
3
3J¼7.19 Hz, 1H, Ar-H), 7.10 (dd, J¼7.70, 8.14 Hz, 1H,
Ar-H). 13C NMR (100 MHz, CDCl3): d¼2.9 (þ, CH2I),
23.5 (þ, CH2), 24.0 (þ, CH2), 35.4 (þ, CH2), 38.4 (2,
CH3), 59.0 (2, CH), 111.1 (2, C-Ar), 115.9 (2, C-Ar),
121.4 (quart, CCquart-Ar), 127.2 (2, C-Ar), 128.8 (2, C-Ar),
145.0 (quart, NCquart-Ar). GC–MS (70 eV, EI), m/z (%):
301 (35) [Mþ], 173 (4), 146 (100), 130 (30), 118 (14), 103
(6), 91 (10), 77 (9), 65 (6), 51 (5).
2.1.14. 2-Iodmethyl-1-methyl-1,2,3,4-tetrahydroquino-
line (18b). To a stirred solution of 500 mg (2.82 mmol) of
1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-methanol (16a)
in 15 ml of a mixture of ether and acetonitrile (3:2) was
2.1.16. Reaction of 18a with BuLi. A solution of 48.0 mg
(0.20 mmol, 1.0 equiv.) of bromide 18a in 2 ml of THF was
treated with 128 ml (0.20 mmol, 1.0 equiv.) 1.6 M BuLi in

6794
F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
hexanes at 2788C. After warming to room temperature
within 12 h, the mixture was quenched with aq. sodium
hydroxide solution. Aqueous workup and chromatography
on silica (8.0 g, 1£17 cm, pentane/ether 20:1), provided
(2-but-3-enylphenyl)butylmethylamine (21e) as colourless
liquid. Yield 24.0 mg (55%). TLC: Rf¼0.59 (pentane/ether,
(100 MHz, CDCl3): d¼24.3 (þ, CH2), 29.7 (þ, CH2),
35.9 (þ, CH2), 37.8 (2, NCH3), 58.7 (2, CHNCH3), 110.5
(2, C-Ar), 115.5 (2, C-Ar), 117.0 (þ, CHvCH2), 121.8
(quart, CCquart-Ar), 127.1 (2, C-Ar), 128.6 (2, C-Ar), 135.4
(2, CHvCH2), 145.2 (quart, NCquart-Ar). GC–MS (70 eV,
EI), m/z (%): 187 (16) [Mþ], 146 (100), 131 (20), 118 (8), 91
(6), 77 (5), 65 (2).
1
9:1). H NMR (400 MHz, CDCl3): d¼0.91 (t, J¼7.32 Hz,
3H), 1.29–1.38 (m, 2H, CH2), 1.45–1.54 (m, 2H, CH2),
2.36–2.42 (m, 2H, CH2), 2.63 (s, 3H, NCH3), 2.77–2.86
(m, 4H, CH2), 4.97 (dd, J¼3.39, 10.27 Hz, 1H, CHvCH2),
5.05 (dd, J¼3.39, 17.02 Hz, 1H, CHvCH2), 5.91 (ddd,
J¼6.60, 10.27, 17.02 Hz, 1H, CHvCH2), 7.01 (dd, J¼1.51,
7.26 Hz, 1H, Ar-H), 7.11 (dd, J¼1.51, 7.95 Hz, 1H, Ar-H),
7.14–7.21 (m, 2H, Ar-H). 13C NMR (100 MHz, CDCl3):
d¼14.1 (2, CH3), 20.5 (þ, CH2), 30.2 (þ, CH2), 30.3 (þ,
CH2), 34.7 (þ, CH2), 43.0 (2, CH3), 57.1 (þ, CH2), 114.5 (þ,
CHvCH2), 121.1 (2, C-Ar), 123.6 (2, C-Ar), 126.6 (2,
C-Ar), 129.7 (2, C-Ar), 137.9 (quart, CCquart-Ar), 139.0 (2,
CHvCH2), 152.7 (quart, NCquart-Ar). GC–MS (70 eV, EI),
m/z (%): 217 (10) [Mþ], 174 (100) [Mþ2C3H7], 159 (12)
[Mþ2C4H10], 146 (20) [Mþ2C5H11], 144 (22)
[Mþ2C5H13], 132 (75) [Mþ2C5H13], 117 (30), 91 (33).
2.1.19. 1,2-Dimethyl-1,2,3,4-tetrahydroquinoline (18g)
and (2-but-3-enylphenyl)-methyl-amine (21f). To a stir-
red solution of 55.0 mg (1.29 mmol, 1.1 equiv.) of lithium
chloride and 81.0 mg (0.60 mmol, 0.5 equiv.) of copper-
(II)-chloride in 6 ml of THF was added 297 mg (1.24 mmol)
of
2-bromomethyl-1-methyl-1,2,3,4-tetrahydroquinoline
(18a) dissolved in 6 ml of THF at 258C. Subsequently,
0.67 ml (2.01 mmol, 1.5 equiv.) of ethyl magnesium
bromide solution (3 M in ether) were slowly added and
stirred for 5 h. After warming slowly to room temperature,
the mixture was quenched with 1 M hydrochloric acid. It
was added 30 ml of ether and the organic layer was
separated and washed with each 20 ml of aq. sodium
hydrogen carbonate solution, brine and water. The organic
layer was dried over sodium sulfate, filtered and concen-
trated to dryness in vacuum. After column chromatography
on silica (40 g, 2.5£16 cm, pentane/ether 40:1) compound
18g was furnished as yellowish oil. Yield 80.0 mg (40%).
1H NMR (400 MHz, CDCl3): d¼1.17 (d, 3J¼6.45 Hz, CH3),
1.76–1.82 (m, 1H, CH2), 1.98–2.07 (m, 1H, CH2), 2.69–
2.76 (m, 1H, CH2), 2.84–2.89 (m, 1H, CH2), 2.94 (s, 3H,
NCH3), 3.44–3.51 (m, 1H, CHCH3), 6.59 (bd, 3J¼8.21 Hz,
1H, Ar-H), 6.63 (dd, 3J¼7.32, 7.83 Hz, 1H, Ar-H), 7.01 (bd,
2.1.17. Reaction of 18a with the cuprate generated from
BuLi and CuBr·Me2S.
A
suspension of 205 mg
(1.00 mmol) of CuBr·Me2S in 2 ml of ether was treated
with 1.3 ml (2.08 mmol, 10.5 equiv.) of BuLi (1.6 M,
hexanes) at 278 and stirred at 2308C for 30 min. After
being cooled again to 2788C, 48.0 mg (0.20 mmol) of
bromide 18a in 2 ml of ether were added. After warming
slowly to room temperature, the mixture was quenched with
a sat. solution of ammonium chloride in aqueous ammonia.
Aqueous workup provided 1-methyl-2-pentyl-1,2,3,4-tetra-
hydroquinoline (18e, 15%) together with 21f (49%) and 21e
(28%) as colourless liquid. 18e: MS (70 eV, EI), m/z (%):
217 (5) [Mþ], 146 (100) [Mþ2C5H11], 130 (10). The
spectroscopic data of 18e are in accordance with the
literature values [3].
3
3J¼7.32 Hz, 1H, Ar-H), 7.12 (dd, J¼7.83, 8.21 Hz, 1H,
Ar-H). 13C NMR (100 MHz, CDCl3): d¼16.5 (2, CHCH3),
22.8 (þ, CH2), 27.1 (þ, CH2), 35.9 (2, NCH3), 52.8 (2,
CHCH3), 109.6 (2, C-Ar), 114.4 (2, C-Ar), 121.0 (quart,
CCquart-Ar), 126.0 (2, C-Ar), 127.5 (2, C-Ar), 144.4 (quart,
NCquart-Ar). GC–MS (70 eV, EI), m/z (%): 161 (98) [Mþ],
146(100), 131(90), 118(48), 91(33), 77(28), 65(17), 51(16).
2.1.18. 2-Allyl-1-methyl-1,2,3,4-tetrahydroquinoline
(18i). To a stirred solution of 97.4 mg (2.29 mmol,
2.2 equiv.) of lithium chloride and 155 mg (1.15 mmol,
1.1 equiv.) of copper-(II)-chloride in 5 ml of THF was
added 300 mg (1.05 mmol) of 2-iodomethyl-1-methyl-
1,2,3,4-tetrahydroquinoline (18b) dissolved in 5 ml of
THF at 258C. Subsequently, 1.57 ml (1.57 mmol,
1.5 equiv.) of vinyl magnesium bromide solution (1 M,
THF) were slowly added and stirred for 24 h. After warming
slowly to room temperature, the mixture was quenched with
sat. ammonia solution (25%, water). It was added 40 ml of
ether and the organic layer was separated and washed with
each 20 ml of sat. ammonium chloride solution, brine and
water. The organic layer was dried over sodium sulfate,
filtered and concentrated to dryness in vacuum. Compound
18i was furnished as yellowish oil. Yield 52.7 mg (27%).
As a second fraction compound 21f was isolated. Yield
1
10.0 mg (5%). H NMR (400 MHz, CDCl3): d¼2.35–2.41
(m, 2H, CH2), 2.55 (d, J¼8.59 Hz, 1H, CH2), 2.57 (d,
J¼10.11 Hz, 1H, CH2), 2.89 (s, 3H, CH3), 3.68 (bs, 1H,
NH), 5.02 (dd, J¼3.17, 10.26 Hz, 1H, CHCH2), 5.09 (dd,
J¼3.17, 17.08 Hz, 1H, CHCH2), 5.91 (ddd, 3J¼6.58, 10.26,
3
17.08 Hz, 1H, CHCH2), 6.64 (bd, J¼7.66 Hz, 1H, Ar-H),
6.70 (dd, 3J¼7.52, 7.66 Hz, 1H, Ar-H), 7.06 (bd,
3
3J¼7.51 Hz, 1H, Ar-H), 7.17 (dd, J¼7.51, 7.52 Hz, 1H,
Ar-H). 13C NMR (100 MHz, CDCl3): d¼30.6 (þ, CH2),
31.0 (2, CH3), 32.7 (þ, CH2), 109.8 (2, C-Ar), 115.1 (þ,
CHCH2), 117.1 (2, C-Ar), 125.6 (quart, CCquart-Ar), 127.4
(2, C-Ar), 128.9 (2, C-Ar), 138.3 (2, CHCH2), 146.9
(quart, NCquart-Ar). GC–MS (70 eV, EI), m/z (%): 161 (40)
[Mþ], 120 (100), 91 (26), 77 (7), 65 (9), 51 (5).
1
GC: Rt¼3.97 min. H NMR (400 MHz, CDCl3): d¼2.12–
2.1.20. 1-Methyl-2-phenethyl-1,2,3,4-tetrahydroquino-
line (18h). To a stirred solution of 32.8 mg (0.77 mmol,
2.2 equiv.) of lithium chloride and 51.9 mg (0.38 mmol,
1.1 equiv.) of copper-(II)-chloride in 15 ml of THF was
added 105 mg (0.35 mmol) of 2-(2-iodoethyl)-1-methyl-
1,2,3,4-tetrahydroquinoline (19b) dissolved in 10 ml of
THF at 258C. Subsequently, 1.00 ml (2.00 mmol,
5.7 equiv.) of phenyl magnesium chloride solution (2 M,
2.20 (m, 1H, CH2), 2.40–2.46 (m, 1H, CH2), 2.64–2.69 (m,
2H, CH2), 2.78–2.85 (m, 2H, CH2), 2.94 (s, 3H, CH3),
3.31–3.36 (m, 1H, CHNCH3), 5.06–5.11 (m, 2H, CH2),
5.81 (dddd, J¼6.49, 8.04, 10.34, 16.88 Hz 1H, CHvCH2),
6.54 (bd, 3J¼8.09 Hz, 1H, Ar-H), 6.60 (dd, 3J¼7.26,
7.39 Hz, 1H, Ar-H), 6.97 (bd, 3J¼7.26 Hz, 1H, Ar-H),
7.07 (dd, 3J¼7.39, 8.09 Hz, 1H, Ar-H). 13C NMR

F. Avemaria et al. / Tetrahedron 59 (2003) 6785–6796
6795
THF) were slowly added and the mixture was stirred for
24 h. After warming slowly to room temperature, the
mixture was quenched with sat. ammonia solution (25%
in water). It was added 40 ml of ether and the organic layer
was separated and washed with each 20 ml of sat.
ammonium chloride solution, brine and water. The organic
layer was dried over sodium sulfate, filtered and concen-
trated to dryness in vacuum. After column chromatography
on silica (29 g, 2.5£20 cm, pentane/ether 50:1) compound
18h was furnished as white solid. Yield 41.0 mg (47%).
1H NMR (400 MHz, CDCl3): d¼1.72–1.83 (m, 1H,
CH2), 1.90–2.01 (m, 3H, CH2), 2.56–2.63 (m, 1H, CH2),
2.67–2.76 (m, 2H, CH2), 2.82–2.89 (m, 1H, CH2), 2.92
(s, 3H, CH3), 3.27–3.32 (m, 1H, CHNCH3), 6.54 (bd,
gratefully acknowledged. We thank Dr Mazen Es-Sayed
(Bayer CropScience, Monheim), Dr Henning Steinhagen
(formerly Bayer, now Aventis) and Professor Dr R. Appel
(Bonn) for helpful discussions and disclosure of unpub-
lished material. We thank Viktor Zimmermann for
technical assistance.
References
1. Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768–1769.
2. Galipinine (¼allocuspareine): Rakotoson, J. H.; Fabre, N.;
3
3J¼8.14 Hz, 1H, Ar-H), 6.60 (dd, J¼7.14, 7.33 Hz, 1H,
´
Jacquemond-Collet, I.; Hannedouche, S.; Fouraste, I.; Moulis,
C. Planta Med. 1998, 64, 762–763.
3. Angustureine, Galipeine: (a) Jacquemond-Collet, I.;
Ar-H), 6.98 (bd, 3J¼7.14 Hz, 1H, Ar-H), 7.08 (dd,
3J¼7.32, 8.14 Hz, 1H, Ar-0H), 7.18–7.21 (m, 3H,
Ar0-H), 7.27–7.30 (m, 2H, Ar -H). 13C NMR (100 MHz,
CDCl3): d¼23.6 (þ, CH2), 24.4 (þ, CH2), 32.3 (þ, CH2),
32.9 (þ, CH2), 38.0 (2, NCH3), 58.4 (2, CHNCH3),
´
Hannedouche, S.; Fabre, N.; Fouraste, I.; Moulis, C.
Phytochemistry 1999, 51, 1167–1170. (b) Jacquemond-
`
Collet, I.; Bessiere, J.-M.; Hannedouche, S.; Bertrand, C.;
110.6 (2, C-Ar), 115.4 (2, C-Ar), 121.8 (quart, CCquart
-
´
Fouraste, C.; Moulis, C. Phytochem. Anal. 2001, 12, 312–319.
4. Cuspareine: Houghton, P. J.; Woldemariam, T. Z.; Watanabe,
Y.; Yates, M. Planta Med. 1999, 65, 250–254.
Ar), 125.8 (2, C-Ar), 127.1 (2, C-Ar), 0128.2 (2, C-Ar0),
128.4 (2, C-Ar0), 128.6 (2, C-Ar ), 142.0 (quart,
CH2Cquart-Ar0), 145.2 (quart, NCquart-Ar). GC–MS
(70 eV, EI), m/z (%): 251 (34) [Mþ], 146 (100), 130
(15), 118 (7), 91 (6), 77 (5), 65 (5).
5. Oxaminquine kills HC-sensitive strains of Schistosoma
mansoni worms, but it is inactive against HC-resistant strains:
El-Hamouly, W.; Pica-Mattoccia, L.; Cioli, D.; Schwartz,
H. M.; Archer, S. J. Med. Chem. 1998, 31, 1629–1631.
6. The drug quinaprilw used to treat high blood pressure and heart
failure contains 1,2,3,4-tetrahydro-quinoline-2-carboxylic
acid.
2.1.21. 1-Methyl-2-propyl-1,2,3,4-tetrahydroquinoline
(18f). To a stirred solution of 30.8 mg (0.73 mmol,
2.1 equiv.) of lithium chloride and 51.1 mg (0.38 mmol,
1.1 equiv.) of copper-(II)-chloride in 15 ml of THF was
added 105 mg (0.35 mmol) of 2-(2-iodoethyl)-1-methyl-
1,2,3,4-tetrahydroquinoline (19b) dissolved in 10 ml of
THF at 258C. Subsequently, 1.00 ml (3.00 mmol,
8.6 equiv.) of methyl magnesium bromide solution (3 M,
ether) were slowly added and the mixture was stirred for
24 h. After warming slowly to room temperature, the
mixture was quenched with sat. ammonia solution (25%,
water). It was added 40 ml of ether and the organic layer
was separated and washed with each 20 ml of sat.
ammonium chloride solution, brine and water. The organic
layer was dried over sodium sulfate, filtered and concen-
trated to dryness in vacuum. Compound 18f was furnished
as yellowish oil. Yield 44.0 mg (67%). GC: Rt¼3.99 min.
1H NMR (400 MHz, CDCl3): d¼0.96 (t, J¼7.12 Hz, 3H,
CH3), 1.28–1.35 (m, 1H, CH2), 1.37–1.47 (m, 2H, CH2),
1.57–1.61 (m, 1H, CH2), 1.88–1.93 (m, 2H, CH2), 2.64–
2.70 (m, 1H, CH2), 2.78–2.84 (m, 1H, CH2), 2.95 (s, 3H,
NCH3), 3.24–3.29 (m, 1H, CHNCH3), 6.54 (bd,
¨
7. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10,
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3
3J¼8.08 Hz, 1H, Ar-H), 6.60 (dd, J¼7.32, 7.32 Hz, 1H,
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Ar-H), 6.98 (bd, 3J¼7.32 Hz, 1H, Ar-H), 7.09 (dd, 3J¼7.32,
8.08 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3): d¼14.4
(2, CH3), 19.4 (þ, CH2), 23.7 (þ, CH2), 24.6 (þ, CH2),
33.7 (þ, CH2), 38.1 (2, NCH3), 58.8 (2, CHNCH3), 110.5
(2, C-Ar), 115.3 (2, C-Ar), 121.9 (quart, CCquart-Ar), 127.1
(2, C-Ar), 128.7 (2, C-Ar), 145.56 (quart, NCquart-Ar).
GC–MS (70 eV, EI), m/z (%): 189 (23) [Mþ], 146 (100),
130 (13), 118 (7), 91 (5), 77 (5), 65 (3).
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¨
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