The synthesis of tetrahydroquinolines related to Virantmycin

Article abstract of DOI:10.1055/s-2004-831234

4-Substituted anilines react with 1-methoxymethyl-1-butyl-3- trimethysilylpropargyl chloride but not with 1,1-dibutyl-3- trimethylsilylpropargyl chloride, to form the corresponding substituted N-propargylanilines. These anilines cyclise, using cuprous chloride, in the presence of trifluoroacetic anhydride, and, when the aniline substituent is electron donating, to give 6-substituted 2-butyl-2-methoxymethyl-1- trifluoroacetyl-1,2-dihydroquinolines. Chlorination, followed by selective dechlorination using sodium cyanoborohydride, of the 6-methyl product yields 2-butyl-2-methoxymethyl-3-chloro-6-methyl-1-trifluoroacetyl-1,2,3, 4-tetrahydroquinoline which has the same relative stereochemistry as that in the antiviral compound, Virantmycin.

Full text of DOI:10.1055/s-2004-831234

PAPER
2685
The Synthesis of Tetrahydroquinolines Related to Virantmycin
T
etrahydroquinol
r
ines Re
l
a
ated to Vira
i
ntmyci
g
n
L. Francis, Natalie M. Williamson, A. David Ward*
Department of Chemistry, University of Adelaide, Adelaide, S.A. 5005, Australia
Fax +61(8)83034358; E-mail: david.ward@adelaide.edu.au
Received 21 June 2004
present in Virantmycin, particularly in terms of size, with
the added advantage that the butyl side chain does not
contain any functional group whose presence may com-
plicate the use of the chemistry that we have established1f
Abstract: 4-Substituted anilines react with 1-methoxymethyl-1-
butyl-3-trimethysilylpropargyl chloride but not with 1,1-dibutyl-3-
trimethylsilylpropargyl chloride, to form the corresponding substi-
tuted N-propargylanilines. These anilines cyclise, using cuprous
chloride, in the presence of trifluoroacetic anhydride, and, when the with the 2,2-dimethyl-substituted quinoline systems.
aniline substituent is electron donating, to give 6-substituted 2-bu-
tyl-2-methoxymethyl-1-trifluoroacetyl-1,2-dihydroquinolines.
Chlorination, followed by selective dechlorination using sodium
cyanoborohydride, of the 6-methyl product yields 2-butyl-2-meth-
oxymethyl-3-chloro-6-methyl-1-trifluoroacetyl-1,2,3,4-tetrahydro-
quinoline which has the same relative stereochemistry as that in the
antiviral compound, Virantmycin.
H
NH2 Cl
N
Me
Me
Me
Me
a
+
R
R
2
3
Cl2
Key words: quinolines, diastereoselectivity, cyclisations, alkyl ha-
lides, alkynes, antiviral agents
COCF3
N
COCF3
N
Me
Me
Cl
Me
Me
Cl
NaBH3CN
For some time we have been interested1 in synthetic ap-
proaches to analogues of the antiviral compound
Virantmycin2 (1) (Figure 1) with a view to establishing vi-
able routes to a range of compounds that would ultimately
provide information on the structural factors necessary for
antiviral activity.
R
R
Cl
a = (i) CuCl; (ii) (CF3CO)2O
Scheme 1
The synthesis of the chloroacetylene 5, needed to prepare
these 2-methoxymethyl-2-butyl-1,2-dihydroquinolines
was initially approached as outlined in Scheme 2. Meth-
oxyacetic acid was converted to the corresponding acid
chloride, which was reacted with butylmanganese iodide,4
prepared from butylmagnesium bromide and manga-
nese(II) iodide, to give the ketone 6 in variable yield, with
the best being 57%. A more direct approach5 using butyl-
lithium (2.2 equiv) and methoxyacetic acid was less suc-
cessful as it gave a mixture of the ketone 6 and the
carbinol 7.
OMe
H
N
HO2C
Cl
1
Figure 1
We have recently described1f the preparation and some
chemistry (Scheme 1) of 2,2-dimethyl-1,2-dihydroquino-
lines 2, and it was of interest to establish whether our re-
sults from this study could be applied to similar systems
containing larger side chains, more related to those
present in Virantmycin, at the 2 position of the dihydro-
quinoline. We have already noted3 that the size of the side
chains at the carbon to which the chlorine is attached in
the chloroacetylene 3 is an important factor in determin-
ing whether these systems will react with anilines, to the
extent that large groups at this position can prevent the re-
OMe
OMe
H
Cl
N
4
5
Figure 2
action from occurring. We chose to investigate a system 4 Because of the variability in the yield of these reactions
(Figure 2) with methoxymethyl and butyl side chains at using organometallic reagents we turned our attention to
the 2 position, as these groups closely resemble those an alternative approach (Scheme 3). 1-Hexene was con-
verted in excellent yield to the bromohydrin 8, which re-
acted readily with sodium methoxide to give the hydroxy
SYNTHESIS 2004, No. 16, pp 2685–2691
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831234; Art ID: P06304SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4
ether 9, which was smoothly oxidised, using Jones re-
agent, to the desired ketone 6. The ketone 6 reacted with
either ethynylmagnesium chloride to give the acetylene

2686
C. L. Francis et al.
PAPER
The acetylenic chloride 12 reacted with a range of p-sub-
stituted anilines to give the substituted amines 13a–e
(Figure 3), using the same conditions we have previously
established5 for the acetylenic chloride 3 (Scheme 1);
however, the reaction times were considerably slower (24
h for the reaction of 12 with p-toluidine compared with 1
h for the reaction of 3 with the same aniline). Attempting
the reactions at higher temperatures resulted in extensive
decomposition. The reaction of ethyl 4-aminobenzoate
with the chloride 12 was incomplete even after 72 h and
the coupled product 13c was obtained in only 41% yield.
However the reaction of 12 with p-anisidine was complete
after 2.5 h, as indicated by TLC, although the coupled
product 13e was only obtained in 38% yield. During the
course of these reactions, or their workup, the trimethyl-
silyl group is removed and the products are monosubsti-
tuted acetylenes.
O
C
O
BuMnI
BuLi
MeOCH2
Bu
MeOCH2
MeOCH2
Scheme 2
C
Cl
6
OH
C
O
C
+
6
MeOCH2
Bu
OH
Bu
7
Br
NBS
H2O
OH
NaOMe
To evaluate further the effect of increasing size of substit-
uents attached to the a-carbon of the acetylene on this
coupling reaction, we prepared the dibutyl system 14
(Figure 4) (from 5-nonanone, using the chemistry shown
in Scheme 4). This acetylenic chloride did not react at all
with p-toluidine and the starting materials were largely re-
covered after 24 h. These results indicate that the coupling
reaction is significantly affected by steric factors, and also
the nature of the 4-substituent of the aniline, with electron
donating groups facilitating the coupling and electron
withdrawing groups retarding it.
OMe
OMe
Jones
oxid'n
O
OH
6
9
Scheme 3
10, or with the lithium salt of trimethylsilylacetylene to
give the acetylenic alcohol 11 (Scheme 4). It became ap-
parent from later reactions that it was advantageous to re-
tain the trimethylsilyl protecting group and remove it at a
later stage, using tetrabutylammonium fluoride if neces-
sary, so our general approach was to use the trimethylsi-
lylacetylene system. The acetylenic alcohol 11 was
readily converted to the corresponding acetylenic chloride
12 using a mixture of cuprous chloride, calcium chloride
and copper bronze in concentrated hydrochloric acid
(Scheme 4).5
Cl
COCF3
Bu
Bu
OMe
N
Bu
R
SiMe3
14
17 a R = Me
b R = OMe
MgCl
OH
Bu
Figure 4
Bu
MeO
MeO
O
The cyclisation of the substituted amine 13a occurred us-
ing the same conditions that had previously been used1f
for the dimethyl substituted systems (Scheme 1). Howev-
er, the dihydroquinoline 15 was obtained in only 21%
yield. Also isolated was the quinoline 16 in 24% yield
(Scheme 5). The dihydroquinoline 15 converts to the
quinoline system 16 (presumably by elimination of di-
methyl ether) on standing. For this reason the cyclisation
of these methoxymethyl substituted systems 13a–e were
attempted using our standard conditions,1f but trifluoro-
acetic anhydride was added to the reaction mixture after
the reaction had cooled and before workup. In this manner
the dihydroquinolines 17a,b were obtained. However, the
products from the attempted cyclisations of 13c–e were
complex mixtures whose NMR spectra did not show any
of the expected signals for the dihydroquinoline products
(particularly the alkene hydrogen signals). The ester 13c
was substantially recovered from a reaction using the
standard cyclisation conditions without the addition of tri-
10
6
Me3Si
Li
Cl
OH
CuCl
Bu
Bu
MeO
MeO
CaCl2
Cu
11
12
SiMe3
SiMe3
Scheme 4
OMe
Bu
13 a R = Me
b R = OMe
c R = CO2Et
d R = Br
H
N
e R = NHAc
R
Figure 3
Synthesis 2004, No. 16, 2685–2691 © Thieme Stuttgart · New York

PAPER
Tetrahydroquinolines Related to Virantmycin
2687
fluoroacetic anhydride. Thus it appears that the presence atom are in a cis arrangement on the heterocyclic ring,
of electron withdrawing groups at the 4-position of the which in turn suggests the stereochemistry shown in 19. It
aniline ring inhibits the cyclisation when the substituents is possible that the stereoselectivity observed in 19 was in-
at the 3-position of the acetylenic chloride are larger than troduced during chlorination of the dihydroquinoline 18.
methyl groups.
Complexation of chlorine by the oxygen of the methoxyl
group could facilitate polarisation of the chlorine mole-
cule as well as favouring delivery from the face corre-
sponding to the side of the double bond that the methoxyl
group is on. It is possible that the participation of the tri-
fluoroacetyl group, leading1f to the cis dichlorides formed
in simpler systems, may also be a factor controlling the
observed stereochemistry.
H
OMe
Bu
N
Me
13a
Tetrahydroquinoline N-trifluoroacetamides are usually
hydrolysed relatively easily under basic conditions,1c,e but
it was anticipated that this type of hydrolysis may pose a
problem with the 3-chloro systems, since the basic condi-
tions could facilitate elimination, and/or the anion on ni-
trogen formed under these conditions could
intramolecularly displace chlorine to form an aziridine
system. This type of aziridine formation has been ob-
served for similar systems,1c,2d and attempts to selectively
ring open the aziridine system resulted in mixtures of tet-
rahydroquinolines and unwanted dihydroindoles.1c The
trifluoroacetamide 19 was unaffected by acidic hydrolysis
conditions and, as expected, basic hydrolysis under reflux
conditions gave a complex mixture of products. However,
stirring the trifluoroacetamide 19 with potassium hydrox-
ide in methanol at room temperature provided the parent
amine 20 in good yield (Scheme 6).
H
OMe
N
N
Bu
Bu
+
Me
Me
24%
16
21%
15
Scheme 5
COCF3
N
COCF3
N
OMe
OMe
Cl2
Bu
Bu
Cl
Me
Me
Cl
17a
18
NaBH3CN
ZnCl2
Our results show that the chemistry described above pro-
vides a convenient methodology for the preparation of a
range of 2,2,3,4-, and 2,2,3-substituted tetrahydroquino-
lines that are closely related to Virantmycin. They also
provide indications of the limitations of some of the key
reactions. Taken together with our previous results they
provide good leads for the synthesis of Virantmycin ana-
logues with a range of substituents at the 2, 3 and 4 posi-
tions of the heterocyclic ring, as well as a variety of
substituents on the aromatic ring.
OMe
COCF3
N
H
N
OMe
OH
r.t.
Bu
Cl
Bu
Cl
Me
Me
20
19
Scheme 6
The N-trifluoroacetyldihydroquinoline 17a was success-
fully chlorinated1f to give the cis-dichlorotetrahydroquin-
oline 18 (J3,4 = 6.2 Hz) which was selectively
dechlorinated1f to give the monochloride 19 in excellent
Melting points were recorded on a Kofler hot stage apparatus
equipped with a Reichert microscope and are uncorrected. Mi-
croanalyses were performed by the Canadian Microanalytical Ser-
vice, Vancouver; Chemical and Microanalytical Services,
Melbourne, or the Chemistry Department, University of Otago.
Flash chromatography refers to nitrogen-pressure driven rapid chro-
matography using Merck silica gel, pore diameter 60 Å. Light pe-
troleum refers to the fraction with bp 66–68 °C. IR spectra were
recorded on a Jasco A102 or a Jasco IRA-1 grating spectrometer. 1H
NMR spectra were recorded on a Bruker ACP300 spectrometer op-
erating at 300 MHz in deuterochloroform solution, with tetrameth-
ylsilane as an internal standard. Electron impact MS were recorded
at 70 eV on an AEI MS3074 or a VG ZAB 2HF spectrometer. Ac-
curate mass measurements (HRMS) were made either on an AEI
MS3074 spectrometer or by the Chemistry Department, University
of Melbourne using a JEOL AX505H spectrometer.
1
yield (Scheme 6). The H NMR spectrum of 19 showed
the three sets of doublet-of-doublets expected for the
CH2CHCl ABX system at d = 3.06 (benzylic hydrogen,
J = 4.3, 16.0 Hz), 3.53 (benzylic hydrogen, J = 7.2, 16.0
Hz) and 4.28 (CHCl, J = 4.3, 7.2 Hz). Irradiation at d =
4.28 resulted in an NOE enhancement of the adjacent ben-
zylic methylene hydrogen only. Irradiation of one of the
doublets of the OCH2 AB quartet at d = 3.90 gave en-
hancement of the signal for the other part of the quartet
only. However, irradiation at d = 1.9 (the methylene group
closest to the nitrogen atom in the butyl chain) gave a
1.7% enhancement of the OCH2 AB doublet-of-doublets
and a 1.4% enhancement of the hydrogen attached to the
chlorine-bearing carbon atom. The latter enhancement
suggests that the butyl group and the methine hydrogen
Methoxyacetyl Chloride
Methoxyacetic acid (15 g, 170 mmol) and thionyl chloride (29.76 g,
250 mmol) were refluxed at 110–120 °C under an atmosphere of ni-
Synthesis 2004, No. 16, 2685–2691 © Thieme Stuttgart · New York

2688
C. L. Francis et al.
PAPER
trogen for 2 h. The mixture was fractionally distilled through a 20
cm Vigreux column.
Yield: 11.40 g (63%); colourless liquid; bp 109–113 °C (lit.6 105–
110 °C).
1H NMR: d = 0.92 (t, 3 H, J = 6.8 Hz, Me), 1.3–1.6 (m, 6 H, CH2),
2.34 [br s (exchanges with D2O), 1 H, OH], 3.39 (dd, 1 H, J = 7.0,
10.4 Hz, 1 H of CH2Br), 3.55 (dd, 1 H, J = 3.2, 10.4 Hz, 1 H of
CH2Br), 3.79 (m, 1 H, CHOH).
MS: m/z (%) = 179/181 (1) [M], 163/165 (50), 123/125 (30), 87
(100).
IR (film): 1800, 1200, 1130, 750 cm–1.
1H NMR: d = 3.50 (s, 3 H, OMe), 4.38 (s, 2 H, OCH2).
1-Methoxy-2-hexanol (9)
1-Methoxyhexan-2-one (6)
Sodium (0.84 g, 36 mmol) was added portionwise to a solution of
the bromohydrin 8 (3.29 g, 18 mmol) in anhyd MeOH (20 mL) and
the resulting mixture refluxed under an atmosphere of nitrogen for
3 h. The reaction mixture was cooled, H2O (20 mL) added, and the
resulting solution extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic extracts were dried and the solvent was removed.
Yield: 2.00 g (84%); pale yellow oil.9
IR (film): 3000–3500, 1060 cm–1.
1H NMR: d = 0.91 (t, 3 H, J = 7.3 Hz, Me), 1.3–1.5 (m, 6 H, CH2),
2.66 [br s (exchanges with D2O), 1 H, OH], 3.24 (dd, 1 H, J = 8.0,
9.6 Hz, 1 H of OCH2), 3.39 (s, 3 H, OMe), 3.41, (dd, 1 H, J = 8.0,
9.6 Hz, 1 H of OCH2), 3.78 (m, 1 H, CHOH).
(a) A solution of butylmagnesium bromide (0.17 mol) in anhyd
Et2O (220 mL) was slowly added to a rapidly stirred suspension of
manganese(II) iodide (53.40 g, 0.17 mol) in anhyd Et2O (300 mL)
at 0 °C under an atmosphere of anhyd nitrogen. The resulting mix-
ture was stirred at 0–5 °C for 10 min then at r.t. for 30 min. After
cooling to –60 °C, a solution of methoxyacetyl chloride (15.00 g,
0.14 mol) in anhyd Et2O (100 mL) was added very slowly and the
resultant mixture was allowed to warm, with stirring, to r.t. over-
night. The reaction was quenched with aq HCl (5%) and the aq layer
was extracted twice with Et2O. The combined organic layers were
washed with aq sodium thiosulfate solution (10%), sat. aq NaHCO3,
dried and concentrated under reduced pressure. Distillation of the
residue provided 6.
MS: m/z (%) = 131 (2) [M – H], 115 (20), 87 (50), 69 (100).
Yield: 10.44 g (57%); colourless oil; bp 82–87 °C /32 mm Hg (lit.7
95 °C /13 mm Hg).
3-Methoxymethyl-1-trimethylsilylhept-1-yn-3-ol (11)
(b) Jones reagent was added dropwise to a stirred solution of the
methoxy alcohol 9 (5.09 g, 39 mmol) in acetone (30 mL) until the
orange colour just persisted. The acetone was removed under re-
duced pressure, the residue treated with H2O (75 mL) and extracted
with CH2Cl2 (3 × 40 mL). The combined organic extracts were
washed with H2O (100 mL), dried, the solvent was removed and the
residue distilled.
BuLi (2.5 M in hexanes; 8.5 mL, 21 mmol) was added dropwise to
a stirred solution of trimethylsilylacetylene (2.26 g, 23 mmol) in an-
hyd THF (40 mL) at –70 °C. The resulting solution was stirred at
this temperature for 10 min, followed by the slow addition of ketone
6 (2.50 g, 19 mmol) in anhyd THF (10 mL) at –70 °C. The mixture
was stirred at –70 °C for 30 min and then quenched at this temper-
ature with sat. aq NH4Cl (40 mL). The organic phase was separated
and combined with ethereal extracts of the aq phase. The combined
organic extracts were dried and the solvent was removed.
Yield: 3.46 g (69%); colourless oil; bp 82–86 °C /30 mm Hg.
IR (film): 1724, 1116 cm–1.
1H NMR: d = 0.91 (t, 3 H, J = 7.3 Hz, Me), 1.25–1.7 (m, 4 H, CH2),
2.43 (t, 2 H, J = 7.4 Hz, CH2), 3.42 (s, 3 H, OMe), 4.03 (s, 2 H,
OCH2).
Yield: 2.16 g (50%); colourless liquid; bp 52–54 °C /0.03 mm Hg.
IR (film): 3200–3600, 2140, 1250 cm–1.
1H NMR: d = 0.17 (s, 9 H, SiMe3), 0.92 (t, 3 H, J = 7.3 Hz, Me),
1.3–1.7 (m, 6 H, CH2), 2.80 [br s (exchanges with D2O), 1 H, OH],
3.38 (d, 1 H, J = 9.3 Hz, 1 H of OCH2), 3.46 (s, 3 H, OMe), 3.48 (d,
1 H, J = 9.3 Hz, 1 H of OCH2).
MS: m/z (%) = 129 (50) [M – H], 97 (10), 85 (50), 81 (50), 69 (100).
Reaction of Methoxyacetic Acid with Butyllithium
BuLi in hexane (2.0 M, 6.95 mL, 13.9 mmol) was added dropwise
to a rapidly stirred solution of methoxyacetic acid (0.5 g, 5.55
mmol) in anhyd THF (50 mL) at 0 °C under a nitrogen atmosphere.
The resulting mixture was stirred under nitrogen at r.t. overnight,
then added slowly, via a cannula, to rapidly stirred aq HCl (5%, 50
mL). The aq layer was extracted with Et2O (2 × 50 mL) and the
combined organic layers were dried and concentrated under re-
duced pressure. Removal of the solvent and distillation of the resi-
due gave a product whose spectral data indicated that it was a
mixture of 6 and 7.
MS: m/z (%) = 228, (1) [M], 212 (30), 211 (100), 184 (40), 183
(100).
HRMS: m/z calcd for C12H240Si [M – O]: 212.1596; found:
212.1604.
3-Methoxymethylhept-1-yn-3-ol (10)
(a) TBAF in THF (1 M; 2 mL, 2 mmol) was added dropwise to a
stirred solution of the alkynol 11 (0.20 g, 0.88 mmol) in THF (2 mL)
at r.t. under an atmosphere of nitrogen and the mixture was stirred
for 30 min. The solvent was removed under reduced pressure and
the residue was extracted with Et2O (20 mL). The extracts were
washed with H2O (6 mL), aq HCl (10%; 6 mL), H2O (6 mL), dried,
and evaporated to give a colourless oil which was chromatographed
[EtOAc (18%) in hexane] to give 10.
Yield: 0.54 g; yellow oil.
IR (film): 3436, 1734, 1458, 1198, 1126 cm–1.
1H NMR: d = 0.7–1.7 (br), 2.4 (m), 3.35 (s), 3.8 (s), 4.0 (s).
Yield: 74 mg (54%); colourless oil; bp 105 °C /25 mm Hg.
IR (film): 3444, 3304, 2120, 1112 cm–1.
1H NMR: d = 0.7–1.6 (br, 9 H, Bu), 2.2 (s, 1 H, alkyne H), 2.5 (br,
1 H, OH), 3.3 (s, 2 H, CH2O), 3.4 (s, 3 H, OMe).
1-Bromo-2-hexanol (8)
A solution of 1-hexene (6.73 g, 80 mmol) and H2O (2.9 mL, 161
mmol) in DMSO (100 mL) was cooled to 10 °C. With stirring, NBS
(29.0 g, 163 mmol) was added in one portion. The mixture was
stirred at r.t. for 1 h, poured into dilute aq NaHCO3 (200 mL) and
extracted with Et2O (2 × 50 mL). The combined organic extracts
were washed with H2O (3 × 50 mL), dried and the solvent was re-
moved.
MS: m/z (%) = 111 (30) [M – CH2OMe], 26 (100).
Anal. Calcd for C9H16O : C, 69.2; H, 10.3. Found: C, 68.6; H, 9.9.
(b) The ketone 6 (17.00 g, 0.13 mol) in anhyd THF (25 mL) was
added slowly to an ice-cooled, stirred solution of ethynylmagne-
sium chloride10 (150 mL) under an atmosphere of nitrogen and the
Yield: 13.92 g (96%); pale yellow oil.8
IR (film): 3000–3500, 1040 cm–1.
Synthesis 2004, No. 16, 2685–2691 © Thieme Stuttgart · New York

PAPER
Tetrahydroquinolines Related to Virantmycin
2689
resulting mixture was allowed to warm to r.t. and then stirred for 20
h. The reaction was quenched with sat. aq NH4Cl and the aq layer
was extracted twice with Et2O. The combined organic layers were
dried and evaporated to give an oil which was chromatographed
[Et2O (35%) in hexane] to give 10.
4-Substituted N-[3-(Methoxymethyl)hept-1-yn-3-yl]anilines 13
a–e
A literature procedure1f was used to prepare the following com-
pounds.
N-[3-(Methoxymethyl)hept-1-yn-3-yl]-4-methylaniline (13a)
Yield: 1.20 g (61%); yellow oil.
Yield: 15.90 g (78%).
3-Chloro-3-methoxymethyl-1-trimethylsilyl-1-hexyne (12)
The alkynol 11 (4.35 g, 19 mmol) was added to a stirred mixture of
cuprous chloride (0.79 g, 7.9 mmol), calcium chloride (1.06 g, 9.5
mmol) and copper bronze powder (0.60 g) in aq HCl (concd; 50
mL) and the resulting mixture stirred at r.t. for 96 h. The mixture
was extracted with CH2Cl2 (3 × 40 mL); the combined organic ex-
tracts were washed with aq HCl (concd; 2 × 40 mL) and H2O
(3 × 30 mL), dried and the solvent was removed. The residue was
purified by flash chromatography (light petroleum–EtOAc, 95:5) to
afford 12.
1H NMR: d = 0.92 (t, 3 H, J = 7.2 Hz, Me), 1.2–1.9 (m, 6 H, CH2),
2.25 (s, 3 H, ArMe), 2.42 (s, 1 H, C≡CH), 3.37 (s, 3 H, OMe), 3.48
(d, 1 H, J = 9.2 Hz, 1 H of OCH2), 3.55 (d, 1 H, J = 9.2 Hz, 1 H of
OCH2), 3.85 [br s (exchanges with D2O), 1 H, NH], 6.92 (d, 2 H,
J = 8.4 Hz, ArH), 6.98 (d, 2 H, J = 8.4 Hz, ArH).
MS: m/z (%) = 245 (5) [M], 200 (100), 158 (10), 156 (10).
HRMS: m/z calcd for C16H23NO: 245.1780; found: 245.1787.
N-[3-(Methoxymethyl)hept-1-yn-3-yl]-4-methoxyaniline (13b)
Yield: 20 mg (38%); orange oil.
IR (CDCl3): 3300, 3125, 1600, 1505, 1105 cm–1.
1H NMR: d = 0.92 (t, 3 H, J = 7.1 Hz, Me), 1.25–1.55 (m, 4 H,
CH2), 1.65–1.85 (m, 2 H, CH2), 2.41 (s, 1 H, C≡CH), 3.39 (s, 3 H,
OMe), 3.43 (d, 1 H, J = 9.2 Hz, 1 H of OCH2), 3.51 (d, 1 H, J = 9.2
Hz, 1 H of OCH2), 3.65 [br s (exchanges with D2O), 1 H, NH], 3.76
(s, 3 H, OMe), 6.78 (d, 2 H, J = 8.8 Hz, ArH), 7.00 (d, 2 H, J = 8.8
Hz, ArH).
Yield: 3.44 g (73%); colourless oil.
1H NMR: d = 0.18 (s, 9 H, SiMe3), 0.94 (t, 3 H, J = 7.3 Hz, Me),
1.3–1.4 (m, 2 H, CH2), 1.5–1.6 (m, 2 H, CH2), 1.9–2.0 (m, 2 H,
CH2), 3.49 (s, 3 H, OMe), 3.64 (s, 2 H, OCH2).
MS m/z (%) = 247/249 (15) [M + H], 231/233 (15), 211 (100), 180
(80).
HRMS: m/z calcd for C12H23ClOSi: 246.1207; found: 246.1194.
MS: m/z (%) = 261 (10) [M], 216 (100), 172 (10), 158 (10), 122
(15).
3-Butyl-1-trimethylsilylhept-1-yn-3-ol
BuLi (2.5 M in hexanes; 3.10 mL, 7.7 mmol) was added dropwise
to a stirred solution of trimethylsilylacetylene (0.83 g, 8.5 mmol) in
anhyd THF (15 mL) at –70 °C. The resulting mixture was stirred at
this temperature for 10 min, followed by the slow addition of a so-
lution of 5-nonanone (1.00 g, 7 mmol) in anhyd THF (5 mL) at –70
°C. The mixture was stirred at this temperature for 20 min and
quenched by the addition of sat. aq NH4Cl (15 mL). The organic
phase was separated and combined with ethereal extracts of the aq
phase. The combined organic extracts were dried and the solvent
was removed. The residue was purified by flash chromatography
(light petroleum–EtOAc, 85:15) to provide the alkynol.
HRMS: m/z calcd for C16H23NO2: 261.1729; found: 261.1731.
Ethyl N-[3-(Methoxymethyl)hept-1-yn-3-yl]-4-aminobenzoate
(13c)
Yield: 50 mg (41%); orange oil.
1H NMR: d = 0.91 (t, 3 H, J = 7.1 Hz, Me), 1.3–2.1 (m, 6 H, CH2),
1.35 (t, 3 H, J = 7.1 Hz, OCH2Me), 2.51 (s, 1 H, C≡CH), 3.38 (s, 3
H, OMe), 3.53 (d, 1 H, J = 9.2 Hz, 1 H of OCH2), 3.62 (d, 1 H,
J = 9.2 Hz, 1 H of OCH2), 4.31 (q, 2 H, J = 7.1 Hz, OCH2Me), 4.54
[br s (exchanges with D2O), 1 H, NH], 6.92 (d, 2 H, J = 8.8 Hz,
ArH), 7.84 (d, 2 H, J = 8.8 Hz, ArH).
Yield: 1.42 g (85%); colourless oil.
IR (film): 3250–3600, 2135, 1255 cm–1.
MS: m/z (%) = 303 (1) [M], 259 (20), 258 (100), 230 (5), 185 (3).
HRMS: m/z calcd for C18H25NO3: 303.1834; found: 303.1818.
1H NMR: d = 0.16 (s, 9 H, SiMe3), 0.93 (t, 6 H, J = 6.8 Hz, Me),
1.25–1.75, (m, 8 H, CH2), 2.10 [br s (exchanges with D2O), 1 H,
OH], 2.40 (t, 4 H, J = 7.3 Hz, CH2).
N-[3-(Methoxymethyl)hept-1-yn-3-yl]-4-bromoaniline (13d)
Yield: 0.30 g (48%); orange oil.
MS: m/z (%) = 223 (80) [M – OH], 183 (100), 150 (15).
1H NMR: d = 0.92 (t, 3 H, J = 7.3 Hz, Me), 1.3–1.9 (m, 6 H, CH2),
2.46 (s, 1 H, C≡CH), 2.70 [br s (exchanges with D2O), 1 H, NH],
3.39 (s, 3 H, OMe), 3.49 (d, 1 H, J = 9.3 Hz, 1 H of OCH2), 3.57 (d,
1 H, J = 9.3 Hz, 1 H of OCH2), 6.87 (d, 2 H, J = 8.8 Hz, ArH), 7.26
(d, 2 H, J = 8.8 Hz, ArH).
3-Butyl-3-chloro-1-trimethylsilyl-1-heptyne (14)
The above dibutylcarbinol (1.19 g, 5 mmol) was added to a stirred
mixture of cuprous chloride (0.21 g, 2.1 mmol), calcium chloride
(0.28 g, 2.5 mmol) and copper bronze powder (0.20 g) in aq HCl
(concd; 30 mL) and the resulting mixture stirred at r.t. for 48 h. The
mixture was extracted with CH2Cl2 (3 × 20 mL) and the combined
organic extracts were washed with aq HCl (concd; 2 × 15 mL) and
H2O (3 × 10 mL), dried and the solvent was removed. The residue
was purified by flash chromatography (light petroleum–EtOAc,
95:5) to give 14.
MS: m/z (%) = 309/311 (10) [M], 265/267 (20), 264/266 (100), 251
(15).
HRMS: m/z calcd for C15H20BrNO: 309.0728; found: 309.0741.
N-[3-(Methoxymethyl)hept-1-yn-3-yl]-4-acetamidoaniline(13e)
Yield: 0.079 g (69%); pale yellow needles; mp 106–108 °C.
IR (CDCl3): 3440, 3370, 3300, 1675, 1600, 1505 cm–1.
1H NMR: d = 0.92 (t, 3 H, J = 7.0 Hz, Me), 1.2–1.9 (m, 6 H, CH2),
2.11 (s, 3 H, COMe), 2.45 (s, 1 H, C≡CH), 3.38 (s, 3 H, OMe), 3.47
(d, 1 H, J = 9.2 Hz, 1 H of OCH2), 3.55 (d, 1 H, J = 9.2 Hz, 1 H of
OCH2), 3.9 [br s (exchanges with D2O), NH amine), 6.95 (d, 2 H,
J = 8.7 Hz, ArH), 7.30, (d, 2 H, J = 8.7 Hz, ArH), 7.67 [br s (ex-
changes with D2O), 1 H, NH].
Yield: 1.17 g (91%); colourless oil.
IR (film): 2140, 1250 cm–1.
1H NMR: d = 0.18, (s, 9 H, SiMe3), 0.94 (t, 6 H, J = 7.3 Hz, Me),
1.25–1.7 (m, 8 H, CH2), 1.89 (m, 4 H, CH2).
MS: m/z (%) = 258/260 (10) [M], 243/245 (15), 225 (45), 224
(100), 223 (100).
HRMS: m/z calcd for C14H17ClSi: 258.1570; found: 258.1571.
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2690
C. L. Francis et al.
PAPER
MS: m/z (%) = 288 (25) [M], 244 (20), 243 (100), 231 (5), 201 (7),
IR (CH2Cl2): 1690, 1605, 1550, 1510 cm–1.
149 (15).
1H NMR: d = 0.93 (t, 3 H, J = 6.9 Hz, Me), 1.20–1.55 (m, 4 H,
CH2), 1.70–1.80 (m, 2 H, CH2), 3.42 (s, 3 H, OMe), 3.68 (d, 1 H,
J = 9.6 Hz, 1 H of OCH2), 3.80 (s, 3 H, OMe), 4.23 (d, 1 H, J = 9.6
Hz, 1 H of OCH2), 5.88 (d, 1 H, J = 9.4 Hz, C=CH), 6.50 (d, 1 H,
J = 9.4 Hz, C=CH), 6.83 (d, 1 H, J = 8.9 Hz, ArH), 7.30–7.55 (m, 2
H, ArH).
HRMS: m/z calcd for C17H24N2O2: 288.1838; found: 288.1846.
2-Butyl-2-methoxymethyl-6-methyl-1,2-dihydroquinoline (15)
and 2-Butyl-6-methylquinoline (16)
The N-substituted aniline 13a was cyclised using a literature proce-
dure.1f The residue was purified by flash chromatography (light pe-
troleum–EtOAc, 90:10) to give 15.
MS: m/z (%) = 358 (5) [M + H], 326 (15), 312 (55), 219 (45), 173
(100), 158 (40).
Yield: 0.14 g (21%); unstable orange oil.
2-Butyl-3,4-dichloro-2-methoxymethyl-6-methyl-1-trifluoro-
acetyl-1,2,3,4-tetrahydroquinoline (18)
1H NMR: d = 0.95 (t, 3 H, J = 7.3 Hz, Me), 1.2–1.6 (m, 6 H, CH2),
2.24 (s, 3 H, ArMe), 3.15 (d, 1 H, J = 8.7 Hz, 1 H of OCH2), 3.31
(s, 3 H, OMe), 3.40 (d, 1 H, J = 8.7 Hz, 1 H of OCH2), 5.28 (d, 1 H,
J = 8.9 Hz, C=CH), 6.32 (d, 1 H, J = 8.9 Hz, C=CH), 6.65 (d, 1 H,
J = 1.8 Hz, ArH), 6.74 (dd, 1 H, J = 1.8, 9.6 Hz, ArH), 6.90 (d, 1 H,
J = 9.6 Hz, ArH).
This compound was obtained by a literature chlorination procedure
on 17a.1f
Yield: 57%; unstable, viscous, yellow oil.
1H NMR: d = 0.79 (t, 3 H, J = 7.1 Hz, Me); 1.1–1.7 (m, 6 H, CH2),
2.40 (s, 3 H, ArMe), 3.36 (s, 3 H, OMe), 3.92 (d, 1 H, J = 10.3 Hz,
1 H of OCH2), 4.26 (d, 1 H, J = 10.3 Hz, 1 H of OCH2), 4.39 (d, 1
H, J = 6.2 Hz, CHCl), 5.60 (d, 1 H, J = 6.2 Hz, CHCl), 6.87 (d, 1 H,
J = 7.8 Hz, ArH), 7.13 (dd, 1 H, J = 1.4, 7.8 Hz, ArH), 7.48 (d, 1 H,
J = 1.4 Hz, ArH).
MS: m/z (%) = 246 (15) [M + H], 245 (10) [M], 244 (10) [M – H].
On standing, 15 converted to 16, which was also isolated from the
above reaction.
Yield: 0.16 g (24%); orange oil.
IR (film): 1695, 1605, 1555, 1500 cm–1.
MS: m/z (%) = 411/413/415 (5) [M], 366/368/370 (100), 330/332
1H NMR: d = 0.95 (t, 3 H, J = 7.3 Hz, Me), 1.35–1.50 (m, 2 H,
CH2), 1.65–1.85 (m, 4 H, CH2), 2.50 (s, 3 H, ArMe), 2.90–3.00 (m,
2 H, CH2), 7.24 (d, 1 H, J = 8.4 Hz, ArH), 7.49 (m, 2 H, ArH), 7.94
(m, 2 H, ArH).
(10), 296 (50), 294 (20).
HRMS: m/z calcd for C18H22Cl2F3NO2: 411.0980; found: 411.1040.
2-Butyl-3-chloro-2-methoxymethyl-6-methyl-1-trifluoroacetyl-
1,2,3,4-tetrahydroquinoline (19)
MS: m/z (%) = 200 (5) [M + H], 199 (5) [M], 198 (5) [M – H], 184
(10), 170 (25), 157 (100).
This compound was prepared by a literature selective dechlorina-
tion procedure on 18.1f
HRMS: m/z calcd for C14H17N: 199.1361; found: 199.1355.
Yield: 91%; a viscous, pale yellow oil.
1H NMR: d = 0.80 (t, 3 H, J = 7.2 Hz, Me), 1.0–1.6 (m, 6 H, CH2),
2.24 (s, 3 H, ArMe), 3.06 (dd, 1 H, J = 4.3, 16.0 Hz, 1 H of CH2),
3.35 (s, 3 H, OMe), 3.53 (dd, 1 H, J = 7.2, 16.0 Hz, 1 H of CH2),
3.93 (d, 1 H, J = 10.2 Hz, 1 H of OCH2), 4.22 (d, 1 H, J = 10.2 Hz,
1 H of OCH2), 4.28 (dd, 1 H, J = 4.3, 7.2 Hz, CHCl), 6.8–7.0 (m, 3
H, ArH).
6-Substituted 2-Butyl-2-methoxymethyl-1-trifluoroacetyl-1,2-
dihydroquinolines 17a,b
A stirred mixture of the N-substituted aniline 13a or 13b (2.3 mmol)
and cuprous chloride (200 mg) in toluene (10 mL) was refluxed un-
der an atmosphere of nitrogen for 30 min. The reaction mixture was
cooled and trifluoroacetic anhydride (0.5 mL, 3.5 mmol) was added
under an atmosphere of nitrogen. The resulting mixture was stirred
under an atmosphere of nitrogen at r.t. for 1.5 h. H2O (15 mL) was
added and the organic phase separated and combined with the
CH2Cl2 extracts of the aq phase. The combined organic extracts
were dried and the solvent was removed. The residue was purified
by flash chromatography.
MS: m/z (%) = 377/379 (25) [M], 332/334 (100), 296 (30).
HRMS: m/z calcd for C18H25ClF3NO2: 377.1369; found: 377.1376.
2-Butyl-3-chloro-2-methoxymethyl-6-methyl-1,2,3,4-tetrahy-
droquinoline (20)
A solution of the trifluoroacetamide 19 (50 mg, 0.13 mmol) in KOH
in MeOH (10%; 2 mL) was stirred at r.t. for 2.5 h. H2O (5 mL) was
added and the mixture extracted with CH2Cl2 (4 × 10 mL). The
combined organic extracts were dried and the solvent was removed.
The residue was purified by flash chromatography (light petro-
leum–EtOAc, 90:10) to provide 20.
2-Butyl-2-methoxymethyl-6-methyl-1-trifluoroacetyl-1,2-dihy-
droquinoline (17a)
Yield: 0.49 g (63%); orange oil, after elution with light petroleum–
EtOAc (85:15).
IR (film): 1690, 1600, 1570, 1500 cm–1.
Yield: 28 mg (75%); colourless prisms; mp 65–67 °C.
IR (CDCl3): 3400, 1605, 1500 cm–1.
1H NMR: d = 0.81 (t, 3 H, J = 6.9 Hz, Me), 1.2–1.6 (m, 6 H, CH2),
2.31 (s, 3 H, ArMe), 3.31 (s, 3 H, OMe), 3.70 (d, 1 H, J = 9.4 Hz, 1
H of OCH2), 4.23 (d, 1 H, J = 9.4 Hz, 1 H of OCH2), 5.81 (d, 1 H,
J = 9.8 Hz, C=CH), 6.49 (d, 1 H, J = 9.8 Hz, C=CH), 6.75 (d, 1 H,
J = 8.0 Hz, ArH), 7.14 (br s, 1 H, ArH), 7.30 (m, 1 H, ArH).
1H NMR: d = 0.89 (t, 3 H, J = 9.1 Hz, Me), 1.25–1.36 (m, 4 H,
CH2), 1.54–1.73 (m, 2 H, CH2), 2.21 (s, 3 H, ArMe), 3.00 (dd, 1 H,
J = 6.6, 17.1 Hz, 1 H of CH2), 3.27 (dd, 1 H, J = 5.2, 17.1 Hz, 1 H
of CH2), 3.35 (s, 3 H, OMe), 3.47 (d, 1 H, J = 8.9 Hz, 1 H of OCH2),
3.52 (d, 1 H, J = 8.9 Hz, 1 H of OCH2), 3.90 [br s (exchanges with
D2O), 1 H, NH], 4.32 (dd, 1 H, J = 5.2, 6.6 Hz, CHCl), 6.47 (d, 1 H,
J = 8.0 Hz, ArH), 6.79 (s, 1 H, ArH), 6.83 (d, 1 H, J = 8.0 Hz, ArH).
MS: m/z (%) = 342 (40) [M + H], 310 (40), 297 (75), 296 (100), 283
(15).
HRMS: m/z calcd for C18H22F3NO2: 341.1603; found: 341.1588.
2-Butyl-2-methoxymethyl-6-methoxy-1-trifluoroacetyl-1,2-di-
hydroquinoline (17b)
MS m/z (%) = 281/283 (11) [M], 236/238 (84), 200 (41), 170 (19),
157 (100).
Yield: 60%; orange oil, after elution with light petroleum–EtOAc
(80:20).
HRMS: m/z calcd for C16H24ClNO: 281.1546; found: 281.1559.
Synthesis 2004, No. 16, 2685–2691 © Thieme Stuttgart · New York

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Tetrahydroquinolines Related to Virantmycin
2691
Hirano, A.; Shibukawa, N.; Kojima, Y.; Omura, S. J.
Acknowledgment
Antibiot. 1981, 34, 1408. (d) Hill, M. L.; Raphael, R. A.
Tetrahedron 1990, 46, 4587. (e) Morimoto, Y.; Oda, K.;
Shirahama, H.; Matsumoto, T.; Omura, S. Chem. Lett. 1988,
6, 909. (f) Pearce, C. M.; Sanders, J. K. M. J. Chem. Soc.,
Perkin Trans. 1 1990, 409. (g) Morimoto, Y.; Shirahama,
H. Tetrahedron 1996, 52, 10631.
NMW gratefully acknowledges the award of an Australian Postgra-
duate Research Award (Priority).
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Synthesis 2004, No. 16, 2685–2691 © Thieme Stuttgart · New York