The preparation and some chemistry of 2,2-dimethyl-1,2-dihydroquinolines

Article abstract of DOI:10.1016/j.tet.2004.10.035

The cyclisation of N-(1,1-dimethylpropargyl) anilines, using cuprous chloride in refluxing toluene, yields 6-substituted-2,2-dimethyl-1,2- dihydroquinolines. The reactivity of the double bond in the heterocyclic ring of these products is exemplified by chlorination, to yield 6-substituted-3,4-cis- dichloro-2,2-dimethyl-1,2,3,4-tetrahydroquinolines which can be selectively dechlorinated to provide 6-substituted-3-chloro-2,2-dimethyl-1,2,3,4- tetrahydroquinolines; epoxidation to yield an epoxide, which can be hydrogenolysed to the corresponding 3-hydroxy product and in turn oxidised to the 3-keto derivative; and oxymercuration to provide a 4-hydroxy product and hence a 4-keto derivative. Dehydrochlorination of a 3,4-dichloro product provides a 3-chloro-1,2-dihydroquinoline which can be hydrolysed to a 3-keto system. The formation of cis 3,4-dichloro products from the chlorination, as well as the formation of a cis chlorohydrin from the chlorination of N-acetyl-2,2,6-trimethyl-1,2-dihydroquinoline in partially aqueous solution, suggests that N-acetyl, or N-trifluoroacetyl groups, participate in the addition process. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.035

Tetrahedron 61 (2005) 155–165
The preparation and some chemistry of
2,2-dimethyl-1,2-dihydroquinolines
*
Natalie M. Williamson and A. David Ward
Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia
Received 15 June 2004; revised 21 September 2004; accepted 14 October 2004
Available online 5 November 2004
Abstract—The cyclisation of N-(1,1-dimethylpropargyl) anilines, using cuprous chloride in refluxing toluene, yields 6-substituted-2,2-
dimethyl-1,2-dihydroquinolines. The reactivity of the double bond in the heterocyclic ring of these products is exemplified by chlorination,
to yield 6-substituted-3,4-cis-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroquinolines which can be selectively dechlorinated to provide
6-substituted-3-chloro-2,2-dimethyl-1,2,3,4-tetrahydroquinolines; epoxidation to yield an epoxide, which can be hydrogenolysed to the
corresponding 3-hydroxy product and in turn oxidised to the 3-keto derivative; and oxymercuration to provide a 4-hydroxy product and hence
a 4-keto derivative. Dehydrochlorination of a 3,4-dichloro product provides a 3-chloro-1,2-dihydroquinoline which can be hydrolysed to a
3-keto system. The formation of cis 3,4-dichloro products from the chlorination, as well as the formation of a cis chlorohydrin from the
chlorination of N-acetyl-2,2,6-trimethyl-1,2-dihydroquinoline in partially aqueous solution, suggests that N-acetyl, or N-trifluoroacetyl
groups, participate in the addition process.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lines. We have previously noted5 that the size of the
substituents attached to the carbon bearing the nitrogen
atom affects the coupling of the amine to the acetylenic
chloride (Scheme 1) such that when these groups are
sufficiently bulky the coupling does not occur and for this
reason we chose initially to investigate the chemistry of
2,2-dimethyl-1,2-dihydroquinolines in order to establish
the range of reactions that these least sterically hindered
2,2-substituted-1,2-dihydroquinolines would undergo.
Any addition reaction to the double bond that creates a
3-substituted product has also created a neopentyl system at
the 3-position which has ramifications for substitutions at
this position. Having established the chemistry of the
dimethyl substituted dihydroquinolines we would then be in
a position to evaluate how well these reactions would work
when more bulky substituents, needed for the development
of Virantmycin analogues, were present.
The availability of 2,2-disubstituted-1,2-dihydroquino-
lines,1–3 1, via the copper catalysed cyclisation of N-(1,1-
substitutedpropargyl) anilines,4,5 (Scheme 1) makes these
compounds of interest as starting materials for the
preparation of 2,2,3,4- and 2,2,3- or 2,2,4-substituted
tetrahydroquinolines and related compounds. We have
been interested for some time3,6–9 in the development of
general synthetic approaches to analogues of the antiviral
compound Virantmycin,10–16 2, and we were, as a
consequence, particularly interested in methodology that
would lead to 2,2-disubstituted-3-chlorotetrahydroquino-
2. Results and discussion
Chlorination of the dihydroquinolines, 1, was expected to be
difficult to control as, at least in cases where an aromatic
substituent that is electron donating is present, chlorination
of both the double bond and the aromatic ring would be
expected. Even the N-acetyl compound, 3, gave the
expected dichloro compound, 4, together with some of the
ring chlorinated material, 5. Aromatic chlorination did
not occur, however, when the N-protecting group was
trifluoroacetyl rather than acetyl. Consequently a range of
Scheme 1.
Keywords: N-propargylanilines; Dihydroquinolines; Tetrahydroquinolines;
Addition; Synthesis.
* Corresponding author. Tel.: C61 8 8303 5496; fax: C61 8 8303 4358;
e-mail: david.ward@adelaide.edu.au
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.035

156
N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
N-trifluoroacetyl derivatives, 6a–6h, were prepared to
investigate the reactivity of the dichloro compounds.
This cis geometry of these dichlorotetrahydroquinolines, 7,
can be rationalised by invoking the participation of the
N-protecting group, as shown in Scheme 2. The benzylic
carbocation, 8, and/or the corresponding chloronium ion,
may be trapped by the carbonyl oxygen of the acyl
group, giving the trans-intermediate, 9, which is then
attacked at the benzylic position by chloride ion to give the
cis-product.
Scheme 2.
Support for this protecting-group participation explanation
was provided by the chlorination, in acidic solution, of the
unprotected dihydroquinoline, 1a, which gave a dichloro
product, 10, whose coupling constant, J3,4, was 9.2 Hz,
typical of that expected for a trans product and showing
that in the absence of the protecting group the chlori-
nation proceeds via the expected chloronium ion mecha-
nism.
The ester-substituted dihydroquinoline, 1j, cannot be N-pro-
tected due to the delocalisation of the lone electron pair on
the nitrogen atom by the ester substituent. Attempts to
chlorinate the dihydroquinoline double bond of the
unprotected ester, 1j, resulted in a complex mixture.
However the iodo-substituted dihydroquinoline, 6h, could
be carbonylated to yield the methyl ester, 6i, in moderate
yield as well as a small amount of the deprotected
compound, 1k. This deprotection possibly involves metha-
nolysis of the trifluoroacetamide facilitated by the triethyl-
amine present in the reaction mixture.
The dichloro compounds, 7, were, in general, unstable
and were used as soon as they had been isolated. The
N-acetyldichloro compound, 4, slowly crystallised on
standing exposed to the atmosphere. Recrystallisation of
this material gave the alcohol, 11, whose structure, and the
trans geometry of the chlorine and hydroxyl groups in the
heterocyclic ring, were confirmed by an X-ray crystal
structure determination.17 In the solid state the heterocyclic
ring is in a twist boat conformation. Such a conformation in
solution would facilitate substitution of the benzylic
chlorine by the carbonyl oxygen of either the acetyl or the
trifluoroacetyl group. The coupling constant, J3,4, was
9.7 Hz for the trans chlorohydrin, 11, a value which is
very similar to that of the trans dichloride, 10, but
considerably higher than the coupling constants of the cis
dichlorides, 7.
Chlorination of the N-trifluoroacetyldihydroquinolines
6a–6i proceeded smoothly to give excellent yields of the
3,4-dichlorotetrahydroquinolines, 7a–7i. The 1H NMR
spectra of the dichloro compounds showed two doublets at
approximately d 4.5 and 5.2, corresponding to the two
methine hydrogens attached to chlorine-bearing carbon
atoms. The coupling constants for these doublets were
small, ranging from 4–6 Hz, suggesting cis stereochemistry.
By the same criteria cis chlorination was also observed for
the N-acetyl compound, 3, and for its corresponding 6-meth-
oxy substituted analogue.
Bromination of the N-acetyl dihydroquinoline, 3, gave an
unstable dibromo compound, 12, in high yield. A coupling
constant of 3.9 Hz for the H3 and H4 doublets suggested
that cis-addition had also occurred with bromine.
The facile conversion of the dichloride, 4, to the
chlorohydrin, 11, prompted an examination of the chlori-
nation in partially aqueous solvents. When the chlorination

N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
157
of 3 was conducted in a tetrahydrofuran/water mixture
the chlorohydrin, 11, was produced in 96% yield. The
N-trifluoroacetyl compound, 6a, gave only a 36% yield of
the corresponding chlorohydrin, 13, under these conditions
but the cis-3,4-dichloro compound, 7a, was also obtained in
a 47% yield. The trans geometry of the chlorohydrins, 11
and 13, can either arise from the displacement of the
benzylic chlorine in the cis dichloride or from attack on the
intermediate, 9, as shown in Scheme 3.
the diastereotopic hydrogens of the benzylic methylene
group were now well-defined doublets at d 3.36 and 3.87.
The signal for H5 was at d 7.11.
The alcohol, 16, was subjected to Mitsunobu conditions in
attempts to introduce a halogen atom into the 3-position.
However using zinc chloride and tetrabutylammonium
bromide or chloride as the halide source produced only
the trifluoroacetate, 18, presumably formed via trifluoro-
acetyl group transfer from the nitrogen atom to the oxygen
atom. TLC and 1H NMR of a sample of the alcohol, 16, that
had been standing for a few weeks revealed that the
trifluoroacetyl transfer from the nitrogen atom to the oxygen
atom is a relatively facile process as it also occurs on
standing. Hydrolysis of the trifluoroacetate, 18, using
10% methanolic potassium bicarbonate, provided the
aminoalcohol, 19. Treatment of this aminoalcohol with
thionyl chloride13 gave only an intractable product mixture
Scheme 3.
Treatment of the dichloro compounds, 7, with zinc-modified
cyanoborohydride18 gave the corresponding 3-chlorotetra-
hydroquinolines, 14, in moderate to excellent yields. The
nature of the aromatic substituent was found to affect the
rate of dechlorination, with electron-withdrawing substitu-
ents such as bromo, iodo and ester groups slowing the
reaction to such an extent that only 50% conversion was
observed after 10–12 days reaction time. Two doublet of
doublets in the region d 3.0–3.2, both with a large geminal
coupling constant (15–16 Hz) and a smaller vicinal coupling
constant (3–6 Hz), and a third doublet of doublets, at
approximately d 4.2, with two small vicinal coupling
constants confirmed the removal of the benzylic chlorine
in these products.
1
as evidenced by tlc and H NMR in which signals for the
expected chloro compound could not be detected.
Direct SN2 displacement of the trifluoroacetyl moiety of 18
with chloride ion (using tetrabutylammonium chloride as
the chloride source) was very slow and the 3-chloroquino-
line product, 20, was unable to be separated from the
starting trifluoroacetate. Evidence for the presence of the
chloro compound, 20, was seen in the 1H NMR of the crude
mixture. Two doublet of doublets were observed at d 5.10
and 4.08, assigned to the methine hydrogen atoms of the
trifluoroacetate, 18, and the monochloride, 20, respectively.
A mass spectrum of the mixture showed molecular ions for
both the trifluoroacetate, 18, (m/z 287) and the chloro
compound, 20, (m/z 209/211).
Epoxidation of the double bond of 6a, to yield the epoxide
15, was achieved using meta-chloroperoxybenzoic acid.
Hydrogenolysis of the epoxide provided the alcohol, 16, in
good yield. The 1H NMR spectrum of 16 resembled that of
the related 3-chloro system, 14a.
Oxidation of the alcohol, 16, to the ketone, 17, proceeded
smoothly using Jones reagent. However, the 1H NMR
spectrum of the ketone did not show the expected sharp
signals for the geminal dimethyl groups or the hydrogens of
the benzylic methylene group, but rather four very broad
singlets at d 1.3, 1.7, 3.3 and 3.8, respectively, suggesting
that a ring flipping process of the heterocyclic ring was
creating two separate magnetic environments for the
hydrogens attached to it, causing the broadening observed
at room temperature. Heating the NMR sample to 50 8C saw
coalescence of the two pairs of broadened signals to single
resonances at d 1.51 and 3.58, assigned to the hydrogens of
the geminal dimethyl groups and the benzylic methylene
group respectively. Cooling the sample to 0 8C caused all
signals to sharpen considerably with the signals for the
hydrogens of the two geminal dimethyl groups now
appearing as two sharp singlets at d 1.34 and 1.70, while
It was also of interest to establish whether the double bond
in the heterocyclic ring of the dihydroquinoline systems
could undergo hydration and, if so, which carbon of the
double bond was functionalised. Hydroboration of 3 gave a
mixture of the N-ethyldihydroquinoline from reduction of
the amide together with starting material. Hydroboration of
the unprotected amine, 1a, with excess diborane was
unsuccesful with starting material being recovered. Oxy-
mercuration of 3 gave a poor yield of an alcohol, 21, whose
NMR spectrum was quite different to that of the alcohol, 16.
In particular, the benzylic methylene hydrogens of 16 occur
as two doublet of doublets at d 2.82 and 2.94, with both

158
N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
showing a vicinal and a geminal coupling, whereas the
methylene signals of 21 were less deshielded and appeared
as a multiplet in the region d 2.1–2.4. The structure of this
alcohol was confirmed by its oxidation to the ketone, 22, in
which the NMR signal for H5 showed the characteristic
downfield shift (d 7.75) expected for the anisotropic effect
of the adjacent carbonyl. Oxidation of the chlorohydrin, 11,
gave the corresponding ketone, 25, whose H5 signal in the
NMR spectrum was at d 7.85 (d, JZ2 Hz).
d in parts per million and coupling constants (J) are given in
Hertz (Hz). Electron impact mass spectra (m/z) were
recorded at 70 eV on a VG ZAB 2HF spectrometer.
Accurate mass measurements (HRMS) were made using
electron impact on either an AEI MS3074 spectrometer or
by the University of Melbourne on a JEOL AX505H
spectrometer. Where a formula contains bromine or chlorine
atoms the accurate mass measurement was conducted on the
major molecular ion peak corresponding to the halogen
atom (or atoms) of lowest atomic weight. Flash chroma-
tography refers to nitrogen pressure driven rapid chroma-
tography19 using Merck silica gel, pore diameter 60A.
Organic extracts were dried using anhydrous magnesium
sulfate.
4.2. General procedure for the synthesis of 2,2-dimethyl-
1,2-dihydroquinolines 1a–1j
A stirred mixture of the N-substituted aniline4,5 (11 mmol)
and cuprous chloride (250 mg) in toluene (10 mL) was
refluxed under an atmosphere of nitrogen for 0.5–16 h. The
reaction mixture was cooled and water (10 mL) was added.
The organic phase was separated and combined with the
dichloromethane extracts of the aqueous phase. The
combined organic extracts were dried and the solvent
removed. The residue was purified by flash chromotogra-
phy; elution with light petroleum/ethyl acetate gave the
dihydroquinolines, which partially decomposed, and/or
rearranged, on attempted distillation under reduced pres-
sure. By this method the following compounds were
prepared:
The dichloride, 4, could be dehydrochlorinated using
potassium tertiary butoxide and gave the vinyl chloride,
23. Confirmation of this structure was provided by its
hydrolysis to the ketone, 24, in which the NMR signal for
H5 was at ca d 7.2.
4.2.1. 2,2,6-Trimethyl-1,2-dihydroquinoline 1a. (56%) as
white needles, mp 36–37 8C (lit.3 mp 36–37 8C).
3. Conclusion
6-Substituted 2,2-dimethyl-1,2-dihydroquinolines can be
readily prepared by the cyclisation of 4-substituted N-(1,1-
dimethylpropargyl)anilines using cuprous chloride in
refluxing toluene. These dihydroquinolines serve as con-
venient substrates from which to prepare 3-, 4- and 3,4-
functionalised 2,2-dimethyl-1,2,3,4-tetrahydroquinolines
with substituents at the 6-position of the quinoline system.
4.2.2. 6-Methoxy-2,2-dimethyl-1,2-dihydroquinoline 1b.
(41%) as a yellow oil; dH 6.35–6.60 (3H, m, ArH), 6.20 (1H,
d, JZ9.1 Hz, C]CH), 5.45 (1H, d, JZ9.1 Hz, C]CH),
3.70 (3H, s, OMe), 2.25 (1H, br s (exchanges with D2O),
NH), 1.25 (6H, s, Me); m/z 189 (M, 20%), 174 (100), 159
(15), 131 (40); HRMS: M, found 189.1150. C12H15NO
requires 189.1154.
4.2.3. 6-Bromo-2,2-dimethyl-1,2-dihydroquinoline 1c.
(43%) as orange prisms, mp 59–61 8C; dH 6.9–7.1 (2H, m,
ArH), 6.28 (1H, d, JZ8.3 Hz, ArH), 6.18 (1H, d, JZ9.7 Hz,
C]CH), 5.49 (1H, d, JZ9.7 Hz, C]CH), 3.50 (1H, br s
(exchanges with D2O), NH), 1.29 (6H, s, Me); m/z 237/239
(M, 15%), 222/224 (100), 143 (50); HRMS: M, found
237.0146. C11H12BrN requires 237.0153.
4. Experimental
4.1. General
Melting points were determined on a Kofler hot stage
apparatus equipped with a Reichert microscope and are
uncorrected. Infrared spectra were recorded on a Jasco A102
grating spectrometer. N-acetyl-tetrahydro- and dihydro-
quinolines and N-trifluoroacetyl-tetrahydro- and dihydro-
quinolines showed carbonyl absorption in the region 1680–
1705 cmK1. The double bond in the heterocyclic ring of the
4.2.4. 2,2-Dimethyl-6-trimethylsilyloxy-1,2-dihydro-
quinoline 1d. (54%) as an unstable orange oil; dH 6.49
(1H, dd, JZ2.7, 8.3 Hz, ArH), 6.43 (1H, d, JZ2.7 Hz,
ArH), 6.31 (1H, d, JZ8.3 Hz, ArH), 6.20 (1H, d, JZ9.6 Hz,
C]CH), 5.50 (1H, d, JZ9.6 Hz, C]CH), 3.50 (1H, br s
(exchanges with D2O), NH), 1.28 (6H, s, Me), 0.22 (9H, s,
SiMe3); m/z 247 (M, 15%), 232 (100), 160 (25), 73 (10);
HRMS: M, found 247.1385. C14H21NOSi requires
247.1392.
dihydroquinolines absorbed in the region 1630–1640 cmK1
.
The NH of N-unsubstituted di- and tetrahydroquinolines
absorbed in the region 3370–3400 cmK1. Only absorptions
above 1600 cmK1, other than those, are provided for
individual compounds. Proton NMR spectra (dH) were
recorded on a Bruker ACP300 spectrometer operating at
300 MHz in deuterochloroform solution using tetramethyl-
silane as an internal standard. Chemical shifts are quoted as
4.2.5. N-(2,2-Dimethyl-1,2-dihydro-6-quinolyl)aceta-
;
mide 1e. (78%) as an orange oil. nmax (CDCl3) 1675 cmK1

N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
159
dH 7.98 (1H, br s (exchanges with D2O), NH amide), 6.87–
7.05 (2H, m, ArH), 6.33, (1H, d, JZ8.2 Hz, ArH), 6.15 (1H,
d, JZ9.8 Hz, C]CH), 5.48 (1H, d, JZ9.8 Hz, C]CH),
3.50 (1H, br s (exchanges with D2O), NH amine), 2.02 (3H,
s, COMe), 1.24 (6H, s, Me); m/z 216 (M, 15%); 201 (100);
160 (10); 159 (15); HRMS: M, found 216.1252. C13H16N2O
requires 216.1263.)
carbon monoxide for 10 min. Palladium acetate (15 mg,
0.66 mmol) was added and the resulting mixture stirred at
100 8C under an atmosphere of carbon monoxide for 4 h.
The reaction mixture was cooled and ether (5 mL) was
added. Brine (5 mL) was added and the organic phase
separated and combined with ethereal extracts of the
aqueous phase. The combined organic extracts were washed
with water (3!15 mL) and brine (2!15 mL), dried and
the solvent removed. The residue was purified by flash
chromatography; elution with light petroleum/ethyl acetate
(80:20) provided the N-substituted ester, 6i, (16 mg, 39%)
as colourless needles, mp 92–94 8C; nmax (CH2Cl2)
1690 cmK1; dH 7.85 (1H, dd, JZ2.0, 8.2 Hz, ArH), 7.78
(1H, d, JZ2.0 Hz, ArH), 6.88 (1H, d, JZ8.2 Hz, ArH), 6.45
(1H, d, JZ9.7 Hz, C]CH), 5.81 (1H, d, JZ9.7 Hz,
C]CH), 3.92 (3H, s, OMe), 1.57 (6H, s, Me); m/z 313
(M, 5%), 298 (100), 170 (31), 157 (16), 115 (22); HRMS:
M, found 313.0934. C15H14F3NO3 requires 313.0926.
4.2.6. 2,2-Dimethyl-6-trimethylsilyl-1,2-dihydroquino-
line 1f. (30%) as an unstable orange oil; dH 7.07 (2H, m,
ArH), 6.39 (1H, d, JZ9.7 Hz, C]CH), 6.26 (1H, d, JZ
9.5 Hz, ArH), 5.45 (1H, d, JZ9.7 Hz, C]CH), 3.70 (1H, br
s (exchanges with D2O), NH), 1.30 (6H, s, Me), 0.20 (9H, s,
SiMe3); m/z 231 (M, 1%), 216 (2), 178 (3), 158 (20), 144
(100).
4.2.7. 2,2-Dimethyl-1,2-dihydroquinoline 1g. Obtained
from the same reaction. (21%) as an orange oil; dH 6.95
(1H, t, JZ7.9 Hz, ArH), 6.87 (1H, d, JZ7.5 Hz, ArH), 6.57
(1H, t, JZ7.5 Hz, ArH), 6.40 (1H, d, JZ7.9 Hz, ArH), 6.26
(1H, d, JZ9.6 Hz, C]CH), 5.46 (1H, d, JZ9.6 Hz,
C]CH), 3.64 (1H, br s (exchanges with D2O), NH), 1.30
(6H, s, Me); m/z 159 (M, 15%), 145 (15), 144 (100), 143
(10), 128 (5); HRMS: M, found 159.1043. C11H13N requires
159.1048.
Further elution gave the N-unsubstituted ester, 1k (10 mg,
25%) as unstable tan prisms, mp 85–87 8C; nmax (CDCl3)
3400, 1705 cmK1; dH 7.65 (1H, dd, JZ1.9, 8.4 Hz, ArH),
7.55 (1H, d, JZ1.9 Hz, ArH), 6.34 (1H, d, JZ8.4 Hz, ArH),
6.26 (1H, d, JZ9.8 Hz, C]CH), 5.46 (1H, dd, JZ1.9,
9.8 Hz, C]CH), 4.13 (1H, br s (exchanges with D2O), NH),
3.83 (3H, s, OMe), 1.33 (6H, s, Me); m/z 217 (M, 8%), 202
(100), 143 (20), 115 (10); HRMS: M, found 217.1092.
C13H15NO2 requires 217.1103.
4.2.8. Ethyl 2-(2,2-dimethyl-1,2-dihydro-6-quinolyl)ace-
tate 1h. (57%) as an unstable orange oil; nmax (CDCl3)
1720 cmK1; dH 6.87 (1H, dd, JZ1.9, 8.0 Hz, ArH), 6.80
(1H, d, JZ1.9 Hz, ArH), 6.36 (1H, d, JZ8.0 Hz, ArH), 6.23
(1H, d, JZ9.7 Hz, C]CH), 5.46 (1H, d, JZ9.7 Hz,
C]CH), 4.12 (2H, q, JZ7.1 Hz, OCH2), 3.64 (1H, br s
(exchanges with D2O), NH), 3.43 (2H, s, CH2), 1.29 (6H, s,
Me), 1.24 (3H, t, JZ7.1 Hz, Me); m/z 246 (MCH, 80%),
245 (M, 20), 244 (MKH, 35), 230 (100), 202 (35), 172 (65),
157 (45).
4.2.12. 1-Acetyl-2,2,6-trimethyl-1,2-dihydroquinoline 3.
To a stirred solution of 2,2,6-trimethyl-1,2-dihydroquino-
line,1,31a, (5.8 mmol) in pyridine (10 mL) and dichloro-
methane (10 mL) cooled to 0 8C was added acetyl chloride
(8.7 mmol) dropwise. The resultant mixture was stirred
under nitrogen at room temperature for 1 h. Water (10 mL)
was added and the organic layer was separated and washed
with hydrochloric acid (5%, 4!25 mL). The organic layer
was dried and the solvent removed. The residue was purified
by flash chromatography; elution with ethyl acetate/light
petroleum yielded a yellow oil that crystallised on standing.
Recrystallisation from ethanol/water afforded the aceta-
mide, 3, (1.00 g, 80%) as white needles, mp 67–68 8C; dH
6.50–7.05, (3H, m, ArH), 6.25 (1H, d, JZ10 Hz, C]CH),
5.65 (1H, d, JZ10 Hz, C]CH), 2.30 (3H, s, ArMe), 2.15
(3H, s, COMe), 1.55 (6H, s, Me); m/z 215 (M, 50%), 214
(25), 200 (10), 158 (50), 107 (100); HRMS: M, found
215.1301. C14H17NO requires M, 215.1310.
4.2.9. 6-Iodo-2,2-dimethyl-1,2-dihydroquinoline 1i.
(40%) as a light-sensitive orange oil; dH 7.19 (1H, d, JZ
2.0 Hz, ArH), 7.15 (1H, dd, JZ2.0, 8.3 Hz, ArH), 6.19 (1H,
d, JZ8.3 Hz, ArH), 6.15 (1H, d, JZ9.8 Hz, C]CH), 5.46
(1H, d, JZ9.8 Hz, C]CH), 3.66 (1H, br s (exchanges with
D2O), NH), 1.29 (6H, s, Me); m/z 285 (M, 22%), 270 (100),
144 (90), 114 (10); HRMS: M, found 285.0024. C11H12IN
requires 285.0016.
4.2.10. Ethyl 2,2-dimethyl-1,2-dihydroquinoline-6-carb-
oxylate 1j. (56%) as pale yellow prisms after crystallisation
from ethanol/water, mp 106–107 8C; [Found: C, 72.6; H,
7.7; N, 6.0. C14H17NO2 requires C, 72.7; H, 7.4; N, 6.1%];
nmax (CDCl3) 1690 cmK1; dH 7.50 (2H, br s, ArH), 6.30 (1H,
d, JZ7.5 Hz, ArH), 6.20 (1H, d, JZ9.5 Hz, C]C–H), 5.40
(1H, d, JZ9.5 Hz, C]C–H), 4.30 (2H, q, JZ7.2 Hz, CH2),
3.45 (1H, br s, NH), 1.35 (3H, t, JZ7.2 Hz, Me), 1.30 (6H,
s, Me); m/z 231 (M, 50%).
4.3. General procedure for the synthesis of N-trifluoro-
acetyl dihydroquinolines
Trifluoroacetic anhydride (2.30 mmol) was added dropwise
under an atmosphere of nitrogen to a solution of the
corresponding dihydroquinoline (1.53 mmol) in dry dichlor-
omethane (10 mL) and pyridine (0.5 mL) at 0 8C. The
reaction was stirred at ambient temperature for 30–60 min,
then quenched by the slow addition of water (10 mL). The
organic phase was separated, washed with hydrochloric acid
(10%, 3!15 mL) and water (15 mL), dried and the solvent
removed. The residue was purified by flash chroma-
tography; elution with light petroleum/ethyl acetate pro-
vided the N-trifluoroacetyldihydroquinolines. By this
method, the following compounds were prepared:
4.2.11. Methyl 2,2-dimethyl-1-trifluoroacetyl-1,2-dihy-
droquinoline-6-carboxylate 6i and methyl 2,2-dimethyl-
1,2-dihydroquinoline-6-carboxylate 1k. A mixture of the
6-iododihydroquinoline, 1i (50 mg, 0.13 mmol), triphenyl-
phosphine (100 mg, 0.39 mmol), triethylamine (37 ml,
0.26 mmol), methanol (0.5 mL) and dimethylformamide
(1.5 mL) was purged with nitrogen for 10 min and then with

160
N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
4.3.1. 1-Trifluoroacetyl-2,2,6-trimethyl-1,2-dihydroquino-
line 6a. (75%) as an orange oil; dH 6.96 (1H, dd, JZ1.5,
8.0 Hz, ArH), 6.91 (1H, d, JZ1.5 Hz, ArH), 6.76 (1H, d,
JZ8.0 Hz, ArH), 6.35 (1H, d, JZ9.7 Hz, C]CH), 5.73
(1H, d, JZ9.7 Hz, C]CH), 2.32 (3H, s, ArMe), 1.54 (6H, s,
Me); m/z 269 (M, 5%), 254 (64), 172 (15), 157 (83), 156
(39), 115 (34), 69 (100); HRMS: M, found 269.1011.
C14H14F3NO requires 269.1027.
dihydroquinoline 6h. (75%) as a light-sensitive yellow
oil; dH 7.48 (1H, dd, JZ2.0, 8.3 Hz, ArH), 7.42 (1H, d, JZ
2.0 Hz, ArH), 6.61 (1H, d, JZ8.3 Hz, ArH), 6.32 (1H, d,
JZ9.7 Hz, C]CH), 5.79 (1H, d, JZ9.7 Hz, C]CH), 1.55
(6H, s, Me); m/z 381 (M, 15%), 366 (100), 269 (12), 240
(35), 170 (22); HRMS: M, found 380.9821. C13H11F3INO
requires 380.9838.
4.4. General procedure for the preparation of 3,4-
dichlorotetrahydroquinolines
4.3.2. 1-Trifluoroacetyl-6-methoxy-2,2-dimethyl-1,2-
dihydroquinoline 6b. (43%) as an orange oil; dH 6.82
(1H, d, JZ8.4 Hz, ArH), 6.68 (2H, m, ArH), 6.35 (1H, d,
JZ9.7 Hz, C]CH), 5.78 (1H, d, JZ9.7 Hz, C]CH), 3.81
(3H, s, OMe), 1.55 (6H, s, Me); m/z 286 (MCH, 20%), 272
(100), 173 (55), 158 (15), 130 (15); HRMS: (MCH), found
286.1061. C14H15F3NO2 requires 286.1055.
A solution of chlorine in carbon tetrachloride (2.4 M,
0.83 mmol) was added dropwise under an atmosphere of
nitrogen to a stirred solution of the corresponding
dihydroquinoline (0.67 mmol) in dry dichloromethane
(5 mL) and the mixture stirred at ambient temperature for
15–30 min. The solvent and excess chlorine were removed
under reduced pressure and the residue purified by flash
chromatography; elution with light petroleum/ethyl acetate
gave the 3,4-dichloro compounds as unstable solids or oils.
By this method, the following compounds were prepared.
4.3.3. 6-Bromo-1-trifluoroacetyl-2,2-dimethyl-1,2-dihy-
droquinoline 6c. (86%) as an orange oil; dH 7.2–7.3 (2H,
m, ArH), 6.74 (1H, d, JZ8.4 Hz, ArH), 6.33 (1H, d, JZ
9.7 Hz, C]CH), 5.81 (1H, d, JZ9.7 Hz, C]CH), 1.55
(6H, s, Me); m/z 333/335 (M, 100), 221/223 (40), 170 (15);
HRMS: M, found 332.9965. C13H11BrF3NO requires
332.9976.
4.4.1. 1-Acetyl-3,4-dichloro-2,2,6-trimethyl-1,2,3,4-tetra-
hydroquinoline 4. (75%) as an unstable viscous yellow
liquid; dH 6.80–7.35 (3H, m, ArH), 5.20 (1H, d, JZ5.5 Hz,
CHCl), 4.50 (1H, d, JZ5.5 Hz, CHCl), 2.40 (3H, s, ArMe),
2.10 (3H, s, COMe), 1.85 (3H, s, Me), 1.40 (3H, s, Me); m/z
285/287/289 (M, 30%), 250/252/254 (30), 243/245/247
(30), HRMS: M, found 285.0675. C14H17NOCl2 requires
285.0689.
4.3.4. 1-Trifluoroacetyl-6-hydroxy-2,2-dimethyl-1,2-di-
hydroquinoline 6d. (86%) as pale orange needles, mp
117–120 8C; nmax (CDCl3) 3150 cmK1; dH 6.78 (1H, d, JZ
8.6 Hz, ArH), 6.64 (2H, m, ArH), 6.33 (1H, d, JZ9.7 Hz,
C]CH), 5.78 (1H, d, JZ9.7 Hz, C]CH), 5.33 (1H, br s
(exchanges with D2O), OH), 1.55 (6H, s, Me); m/z 271 (M,
25%), 256 (100), 159 (50), 130 (15), 69 (25); HRMS: M,
found 271.0810. C13H12F3NO2 requires 271.0820.
4.4.2. 1-Acetyl-3,4,8-trichloro-2,2,6-trimethyl-1,2,3,4-
tetrahydroquinoline 5. Obtained from the same reaction.
(0.17 g, 13%) as a slightly impure yellow oil; dH 6.90–7.15,
(2H, m, ArH), 5.10 (1H, d, JZ4.5 Hz, CHCl), 4.70 (1H, d,
JZ4.5 Hz, CHCl), 2.40 (3H, s, ArMe), 2.05 (3H, s, COMe),
2.00 (6H, s, Me); m/z 321/323/325 (M, 15%).
4.3.5. N-(2,2-Dimethyl-1-trifluoroacetyl-1,2-dihydro-6-
quinolyl)acetamide 6e. (51%) as orange needles, mp
157–159 8C; nmax (CDCl3) 1670 cmK1; dH 7.92 (1H, br s
(exchanges with D2O), NH), 7.51 (1H, d, JZ2.3 Hz, ArH),
7.20 (1H, dd, JZ2.3, 8.5 Hz, ArH), 6.81 (1H, d, JZ8.5 Hz,
ArH), 6.34 (1H, d, JZ9.7 Hz, C]CH), 5.77 (1H, d, JZ
9.7 Hz, C]CH), 2.18 (3H, s, COMe), 1.54 (6H, s, Me); m/z
312 (M, 15%), 298 (100), 255 (15),158 (50); HRMS: M,
found 312.1092. C15H15F3N2O2 requires 312.1086.
4.4.3. 3,4-Dichloro-1-trifluoroacetyl-6-methoxy-2,2-
dimethyl-1,2,3,4-tetrahydroquinoline 7b. (88%) as an
unstable yellow oil; dH 7.04 (1H, d, JZ2.8 Hz, ArH), 6.94
(1H, d, JZ8.8 Hz, ArH), 6.88 (1H, dd, JZ2.8, 8.8 Hz,
ArH), 4.47 (1H, d, JZ4.5 Hz, CHCl), 5.19 (1H, d, JZ
4.5 Hz, CHCl), 3.84 (3H, s, OMe), 1.81 (3H, s, Me), 1.51
(3H, s, Me); m/z 355/357/359 (M, 100%), 322/324/326 (70),
280/282 (100), 272 (50), 230 (55), 188 (55); HRMS: M,
found 355.0343. C14H14Cl2F3NO2 requires 355.0354.
4.3.6. 1-Trifluoroacetyl-2,2-dimethyl-1,2-dihydroquino-
line 6f. (67%) as a pale orange oil; dH 7.14 (3H, m, ArH),
6.87 (1H, d, JZ7.3 Hz, ArH), 6.40 (1H, d, JZ9.7 Hz,
C]CH), 5.76 (1H, d, JZ9.7 Hz, C]CH), 1.56 (6H, s, Me);
m/z 255 (M, 15%), 240 (100), 170 (15), 143 (35); HRMS:
M, found 255.0865. C13H12F3NO requires 255.0871.
(Attempted trifluoroacetylation of 1f produced only the
reduced compound, 6f).
4.4.4. 6-Bromo-3,4-dichloro-1-trifluoroacetyl-2,2-di-
methyl-1,2,3,4-tetrahydroquinoline 7c. (90%) as an
unstable pale yellow oil; dH 7.48 (1H, dd, JZ2.1, 8.3 Hz,
ArH), 6.85 (1H, d, JZ8.3 Hz, ArH), 6.68 (1H, d, JZ2.1 Hz,
ArH, 5.21 (1H, d, JZ4.4 Hz, CHCl), 4.44 (1H, d, JZ
4.4 Hz, CHCl), 1.77 (3H, s, Me), 1.56 (3H, s, Me); m/z 403/
405/407 (M, 40%), 368/370/372 (100), 247 (60); HRMS: M,
found 402.9334. C13H11BrCl2F3NO requires 402.9353.)
4.3.7. Ethyl 2-(2,2-dimethyl-1-trifluoroacetyl-1,2-dihy-
dro-6-quinolyl)acetate 6g. (72%) as a yellow oil; nmax
(CDCl3) 1720 cmK1; dH 7.08 (2H, m, ArH), 6.82 (1H, d, JZ
8.0 Hz, ArH), 6.37 (1H, d, JZ9.7 Hz, C]CH), 5.76 (1H, d,
JZ9.7 Hz, C]CH), 4.17 (2H, q, JZ7.1 Hz, OCH2), 3.58
(2H, s, CH2), 1.55 (6H, s, Me), 1.27 (3H, t, JZ7.1 Hz, Me);
m/z 341 (M, 10%), 326 (100), 202 (40), 156 (60); HRMS:
M, found 341.1227. C17H18F3NO3 requires 341.1239.
4.4.5. 3,4-Dichloro-1-trifluoroacetyl-6-hydroxy-2,2-di-
methyl-1,2,3,4-tetrahydroquinoline 7d. (100%) as
unstable pale yellow needles, mp 100–102 8C; nmax
(CDCl3) 3160 cmK1; dH 7.03 (1H, d, JZ2.6 Hz, ArH),
6.90 (1H, d, JZ8.6 Hz, ArH), 6.84 (1H, dd, JZ2.6, 8.6 Hz,
ArH), 6.25 (1H, br s (exchanges with D2O), OH), 5.16 (1H,
4.3.8.
1-Trifluoroacetyl-6-iodo-2,2-dimethyl-1,2-

N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
161
d, JZ4.6 Hz, CHCl), 4.45 (1H, d, JZ4.6 Hz, CHCl), 1.81
(3H, s, Me), 1.53 (3H, s, Me); m/z 341/343/345 (M, 100%),
306 (75), 266 (30), 264 (90), 216 (60), 174 (90).
hydroxide solution (10%) and extracted with dichloro-
methane (3!10 mL). The combined organic extracts were
dried and the solvent removed. The residue was purified by
flash chromatography; elution with light petroleum/ethyl
acetate (85:15) gave the dichloro compound, 10, (33 mg,
47%) as unstable white prisms, mp 107–109 8C; dH 7.25
(1H, d, JZ1.5 Hz, ArH), 6.92 (1H, dd, JZ1.5, 8.1 Hz,
ArH), 6.49 (1H, d, JZ8.1 Hz, ArH), 4.76 (1H, d, JZ9.2 Hz,
CHCl), 3.98 (1H, d, JZ9.2 Hz, CHCl), 2.60 (1H, br s
(exchanges with D2O), NH), 2.25 (3H, s, ArMe), 1.39 (3H,
s, Me), 1.24 (3H, s, Me); m/z 243/245/247 (M, 1%), 208/210
(25), 192/194 (100).
4.4.6. N-(3,4-Dichloro-2,2-dimethyl-1-trifluoroacetyl-
1,2,3,4-tetrahydro-6-quinolyl)acetamide 7e. (75%) as
unstable pale yellow needles, mp 145–147 8C; nmax
(CDCl3) 1670 cmK1; dH 8.14 (1H, br s (exchanges with
D2O), NH), 7.84 (1H, d, JZ2.2 Hz, ArH), 7.52 (1H, dd, JZ
2.2, 8.7 Hz, ArH), 6.93 (1H, d, JZ8.7 Hz, ArH), 5.20 (1H,
d, JZ4.4 Hz, CHCl), 4.46 (1H, d, JZ4.4 Hz, CHCl), 2.20
(3H, s, COMe), 1.79 (3H, s, Me), 1.53 (3H, s, Me); m/z 382/
384/386 (M, 100%), 347/349 (75), 312 (100), 305/307 (90),
297 (100); HRMS: M, found 382.0476. C15H15Cl2F3N2O2
requires 382.0463.
4.4.12. 1-Acetyl-3-chloro-2,2,6-trimethyl-1,2,3,4-tetra-
hydroquinolin-4-ol 11. A solution of chlorine in carbon
tetrachloride (2.4 M, 0.15 mL, 0.35 mmol) was added
dropwise to a solution of the dihydroquinoline, 3, (50 mg,
0.23 mmol) in tetrahydrofuran (2 mL) and water (2 mL) and
the resulting mixture stirred vigorously under an atmos-
phere of nitrogen for 24 h. Water (5 mL) was added and the
mixture extracted with dichloromethane (3!10 mL). The
combined organic extracts were dried and the solvent
removed. The residue was purified by flash chromatog-
raphy; elution with light petroleum/ethyl acetate (1:1)
provided the chlorohydrin, 11, (60 mg, 96%) as cream
prisms, mp 139–141 8C; nmax (CDCl3) 3575 cmK1; dH 7.39
(1H, d, JZ1.8 Hz, ArH), 7.07 (1H, dd, JZ1.8, 8.1 Hz,
ArH), 6.84 (1H, d, JZ8.1 Hz, ArH), 4.71 (1H, dd, JZ3.0,
9.5 Hz, CHOH), 3.67 (1H, d, JZ9.5 Hz, CHCl), 2.84 (1H,
br s (exchanges with D2O), OH), 2.37 (3H, s, ArMe), 2.11
(3H, s, COMe), 1.69 (3H, s, Me), 1.68 (3H, s, Me); m/z
267/269 (M, 44%), 225/227 (60), 210/212 (100), 198 (46);
HRMS: M, found 267.1018. C14H18ClNO2 requires
267.1026.)
4.4.7. 3,4-Dichloro-1-trifluoroacetyl-2,2-dimethyl-1,2,
3,4-tetrahydroquinoline 7f. (83%) as an unstable yellow
oil; dH 7.54 (1H, dd, JZ3.7, 5.8 Hz, ArH), 7.36 (2H, m,
ArH), 6.98 (1H, m, ArH), 5.27 (1H, d, JZ4.5 Hz, CHCl),
4.48 (1H, d, JZ4.5 Hz, CHCl), 1.80 (3H, s, Me), 1.55 (3H,
s, Me); m/z 325/327/329 (M, 25%), 290/292 (100), 253 (20),
239 (40); HRMS: M, found 325.0245. C13H12Cl2F3NO
requires 325.0248.
4.4.8. Ethyl 2-(3,4-dichloro-1-trifluoroacetyl-2,2-di-
methyl-1,2,3,4-tetrahydro-6-quinolyl)acetate 7g. (92%)
as an unstable yellow oil; nmax (CDCl3) 1720 cmK1; dH 7.48
(1H, d, JZ1.8 Hz, ArH), 7.28 (1H, dd, JZ1.8, 8.0 Hz,
ArH), 6.93 (1H, d, JZ8.0 Hz, ArH), 5.25 (1H, d, JZ4.5 Hz,
CHCl), 4.45 (1H, d, JZ4.5 Hz, CHCl), 4.18 (2H, q, JZ
7.0 Hz, OCH2), 3.65 (2H, s, CH2), 1.78 (3H, s, Me), 1.55
(3H, s, Me), 1.27 (3H, t, JZ7.0 Hz, Me); m/z 411/413/415 (M,
35%), 376/378 (100), 340 (25), 326 (55), 260 (40); HRMS: M,
found 411.0596. C17H18Cl2F3NO3 requires 411.0616.
This compound also formed slowly from the dichloride, 4, if
it was left exposed to the atmosphere.
4.4.9.
3,4-Dichloro-1-trifluoroacetyl-6-iodo-2,2-di-
methyl-1,2,3,4-tetrahydroquinoline 7h. (68%) as unstable
white prisms, mp 75–77 8C; dH 7.86 (1H, d, JZ1.9 Hz,
ArH), 7.66 (1H, dd, JZ1.9, 8.4 Hz, ArH), 6.70 (1H, d, JZ
8.4 Hz, ArH), 5.19 (1H, d, JZ4.4 Hz, CHCl), 4.43 (1H, d,
JZ4.4 Hz, CHCl), 1.77 (3H, s, Me), 1.56 (3H, s, Me); m/z
451/453/455 (M, 60%), 416/418 (55), 368 (22), 290 (26),
247 (22), 69 (100).
4.4.13. 3-Chloro-1-trifluoroacetyl-2,2,6-trimethyl-1,2,
3,4-tetrahydroquinolin-4-ol 13, and 1-trifluoroacetyl-
3,4-dichloro-1,2,3,4-tetrahydroquinoline 7a. The chloro-
hydrin, 13, was prepared, from 6a, in a similar manner
(43 mg, 36%) as a pale yellow gum; nmax (CDCl3)
3595 cmK1; dH 7.43 (1H, d, JZ1.6 Hz, ArH), 7.11 (1H,
dd, JZ1.6, 8.4 Hz, ArH), 6.89 (1H, d, JZ8.4 Hz, ArH),
4.74 (1H, d, JZ9.2 Hz, CHOH), 3.69 (1H, d, JZ9.2 Hz,
CHCl), 2.85 (1H, br s (exchanges with D2O), OH), 2.39 (3H,
s, ArMe), 1.68 (3H, s, Me), 1.67 (3H, s, Me); m/z 321/323
(M, 100%), 244 (54), 216 (45), 203 (63), 162 (86); HRMS:
M, found 321.0733. C14H15ClF3NO2 requires 321.0743.)
4.4.10. Methyl 3,4-dichloro-2,2-dimethyl-1-trifluoroace-
tyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 7i. (80%)
as unstable yellow prisms, mp 104–106 8C; nmax (CDCl3)
1695 cmK1; dH 8.23 (1H, d, JZ1.9 Hz, ArH), 8.02 (1H, dd,
JZ1.9, 8.3 Hz, ArH), 6.99 (1H, d, JZ8.3 Hz, ArH), 5.32
(1H, d, JZ4.3 Hz, CHCl), 4.48 (1H, d, JZ4.3 Hz, CHCl),
3.95 (3H, s, OMe), 1.77 (3H, s, Me), 1.59 (3H, s, Me); m/z
383/385/387 (M, 22%), 348/350 (100), 312 (13), 298 (20),
258 (16), 216 (15); HRMS: M, found 383.0303. C15H14-
Cl2F3NO3 requires 383.0303.
4.4.14. 7a. Also obtained from this reaction was the
dichloride. (59 mg, 47%) as a pale yellow oil; dH 7.33
(1H, d, JZ1.5 Hz, ArH), 7.14 (1H, dd, JZ1.5, 8.3 Hz,
ArH), 6.87 (1H, d, JZ8.3 Hz, ArH), 5.22 (1H, d, JZ4.4 Hz,
CHCl), 4.47 (1H, d, JZ4.4 Hz, CHCl). 2.38 (3H, s, ArMe),
1.79 (3H, s, Me), 1.52 (3H, s, Me); m/z 339/341/343 (M,
32%), 304/306 (77), 262 (45), 214 (34), 172 (50), 69 (100);
HRMS: M, found 339.0402. C14H14Cl2F3NO requires
339.0404.)
4.4.11. 3,4-Dichloro-2,2,6-trimethyl-1,2,3,4-tetrahydro-
quinoline 10. A solution of chlorine in carbon tetrachloride
(2.4 M, 0.18 mL, 0.43 mmol) was added dropwise to a
stirred solution of the dihydroquinoline, 1a, (0.05 g,
0.29 mmol) in concentrated hydrochloric acid (5 mL) and
the resulting mixture stirred vigorously at room temperature
for 30 min. The mixture was neutralised with sodium
4.4.15. 1-Acetyl-3,4-dibromo-2,2,6-trimethyl-1,2,3,4-tet-
rahydroquinoline 12. Bromine (0.44 g, 2.7 mmol) was

162
N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
added dropwise to a stirred solution of the dihydroquinoline,
3, (0.59 g, 2.7 mmol) in dry dichloromethane (5 mL) and
the resulting mixture stirred at ambient temperature for 1 h.
The solvent and excess bromine were removed under
reduced pressure and the residue purified by flash
chromatography; elution with light petroleum/ethyl acetate
(60:40) provided the dibromo compound, 12, (0.94 g, 91%)
as an unstable orange oil; dH 7.23 (1H, d, JZ1.7 Hz, ArH),
7.11 (1H, dd, JZ1.7, 8.2 Hz, ArH), 6.90 (1H, d, JZ8.2 Hz,
ArH), 5.55 (1H, d, JZ3.9 Hz, CHBr), 4.89 (1H, d, JZ
3.9 Hz, CHBr), 2.36 (3H, s, COMe), 2.10 (3H, s, ArMe),
1.91 (3H, s, Me), 1.37 (3H, s, Me); m/z 373/375/377 (M,
2%), 314/316/318 (25), 294/296 (10), 236/238 (15), 200
(20), 158 (100).
4.5.4. 3-Chloro-2,2-dimethyl-6-hydroxy-1-trifluoro-
acetyl-1,2,3,4-tetrahydroquinoline 14d. (88%) as a white
powder, mp 118–119 8C; [Found: C, 50.5; H, 4.1; N, 4.7.
C13H13ClF3NO2 requires C, 50.7; H, 4.3; N, 4.6%]; nmax
(CDCl3) 3155 cmK1; dH 6.89 (1H, d, JZ8.3 Hz, ArH), 6.73
(1H, dd, JZ2.7, 8.3 Hz, ArH), 6.70 (1H, d, JZ2.7 Hz,
ArH), 5.91 (1H, br s (exchanges with D2O), OH), 4.18 (1H,
dd, JZ3.5, 6.2 Hz, CHCl), 3.17 (1H, dd, JZ3.5, 15.4 Hz,
1H of CH2), 3.04 (1H, dd, JZ6.2, 15.4 Hz, 1H of CH2), 1.67
(3H, s, Me), 1.65 (3H, s, Me); m/z 307/309 (M, 30%), 272
(5), 230 (100), 218 (25), 174 (12).
4.5.5. N-(3-Chloro-2,2-dimethyl-1-trifluoroacetyl-1,2,
3,4-tetrahydro-6-quinolyl)acetamide 14e. (55%) as pale
yellow prisms, mp 146–148 8C; [Found: C, 51.4; H, 4.5; N,
7.7. C15H16ClF3N2O2 requires C, 51.6; H, 4.6; N, 8.0%];
nmax (CDCl3) 1675 cmK1; dH 7.78 (1H, br s (exchanges with
D2O), NH), 7.65 (1H, d, JZ2.3 Hz, ArH), 7.26 (1H, dd, JZ
2.3, 8.6 Hz, ArH), 6.93 (1H, d, JZ8.6 Hz, ArH), 4.19 (1H,
dd, JZ3.5, 5.9 Hz, CHCl), 3.21 (1H, dd, JZ3.5, 15.6 Hz,
1H of CH2), 3.07 (1H, dd, JZ5.9, 15.6 Hz, 1H of CH2), 2.19
(3H, s, COMe), 1.67 (3H, s, Me), 1.63 (3H, s, Me); m/z 348/
350 (M, 35%), 313 (5), 271 (60), 254 (45), 223 (100).
4.5. General procedure for the synthesis of 3-chloro-
tetrahydroquinolines
Sodium cyanoborohydride (1.75 mmol) was added to a
solution of freshly dried zinc chloride18 (0.87 mmol) in dry
ether (10 mL) and the mixture stirred at ambient tempera-
ture under an atmosphere of nitrogen for 20 min. A solution
of the dichlorotetrahydroquinoline (0.87 mmol) in dry ether
(4 mL) was then added under an atmosphere of nitrogen
and the resulting mixture stirred at ambient temperature for
3–10 days. The reaction was quenched with saturated
sodium bicarbonate solution (15 mL), the organic phase
separated and washed with water (15 mL) and brine (3!
15 mL), dried and the solvent removed. The residue was
purified by flash chromatography; elution with light
petroleum/ethyl acetate provided the 3-chloro compounds.
By this method, the following compounds were prepared.
4.5.6. 3-Chloro-2,2-dimethyl-1-trifluoroacetyl-1,2,3,4-
tetrahydroquinoline 14f. (66%) as colourless prisms, mp
40–42 8C; [Found: C, 53.8; H, 4.4; N, 4.7. C13H13ClF3NO
requires C, 53.5; H, 4.5; N, 4.8%]; dH 7.24 (2H, m, ArH),
6.99 (2H, m, ArH), 4.19 (1H, dd, JZ3.6, 6.3 Hz, CHCl),
3.25 (1H, dd, JZ3.6, 15.5 Hz, 1H of CH2), 3.12 (1H, dd,
JZ6.3, 15.5 Hz, 1H of CH2), 1.68 (3H, s, Me), 1.65 (3H, s,
Me); m/z 291/293 (M, 20%), 256 (5), 240 (10), 214 (100),
202 (25), 158 (15).
4.5.1. 1-Acetyl-3-chloro-2,2,6-trimethyl-1,2,3,4-tetra-
hydroquinoline. As white plates after crystallisation from
light petroleum (0.26 g, 65%), mp 74–76 8C; [Found: C,
67.0; H, 7.5; N, 5.6. C14H18NOCl requires C, 66.9; H, 7.2;
N, 5.6%.]; dH 6.96–7.02 (2H, m, ArH), 6.85 (1H, d, JZ
8 Hz, ArH), 4.15 (1H, dd, JZ3.4, 6.7 Hz, CHCl), 3.15 (1H,
dd, JZ3.4, 15.3 Hz, 1H of CH2), 3.01 (1H, dd, JZ6.7,
15.3 Hz, 1H of CH2–), 2.33 (3H, s, ArMe),2.11 (3H, s,
COMe), 1.68 (6H, s, Me); m/z 251/253 (M, 60%), 9/211
(70), 196 (75), 194 (100).
4.5.7. Ethyl 2-(3-chloro-2,2-dimethyl-1-trifluoroacetyl-
1,2,3,4-tetrahydro-6-quinolyl)acetate 14g. (76%) as a
viscous, pale yellow oil; nmax (CDCl3) 1720 cmK1; dH
7.15 (2H, m, ArH), 6.94 (1H, br s (not exchangeable with
D2O), ArH), 4.17 (3H, m, CHCl and OCH2), 3.61 (2H, s,
ArCH2), 3.23 (1H, dd, JZ6.4, 15.6 Hz, 1H of CH2), 3.11
(1H, dd, JZ3.7, 15.6 Hz, 1H of CH2), 1.67 (3H, s, Me), 1.64
(3H, s, Me), 1.26 (3H, t, JZ7.2 Hz, Me); m/z 378/380 (MC
H, 35%), 342 (7), 300 (20), 288 (25), 226 (100); HRMS: M,
found 377.0994. C17H19ClF3NO3 requires 377.1005.)
4.5.2. 3-Chloro-2,2-dimethyl-6-methoxy-1-trifluoro-
acetyl-1,2,3,4-tetrahydroquinoline 14b. (78%) as a pale
yellow oil; dH 6.93 (1H, d, JZ8.8 Hz, ArH), 6.75 (2H, m,
ArH), 4.17 (1H, dd, JZ3.6, 6.3 Hz, CHCl), 3.81 (3H, s,
OMe), 3.19 (1H, dd, JZ3.6, 15.3 Hz, 1H of CH2), 3.05
(1H, dd, JZ6.3, 15.3 Hz, 1H of CH2), 1.66 (6H, s, Me); m/z
321/323 (M, 60%), 286 (15), 270 (10), 244 (100), 232 (25),
188 (15); HRMS: M, found 321.0749. C14H15ClF3NO2
requires 321.0743.
4.5.8. 3-Chloro-2,2-dimethyl-6-iodo-1-trifluoroacetyl-
1,2,3,4-tetrahydroquinoline 14h. (33%) as a viscous,
pale yellow oil; dH 7.56 (1H, br s (not exchangeable with
D2O), ArH), 7.24 (1H, m, ArH), 6.72 (1H, d, JZ8.8 Hz,
ArH), 4.19 (1H, dd, JZ3.6, 5.8 Hz, CHCl), 3.22 (1H, dd,
JZ3.6, 15.8 Hz, 1H of CH2), 3.07 (1H, dd, JZ5.8, 15.8 Hz,
1H of CH2), 1.67 (3H, s, Me), 1.62 (3H, s, Me); m/z 417/419
(M, 40%), 382 (5), 340 (40), 291 (20), 258 (25), 214 (85), 69
(100); HRMS: M, found 416.9585. C13H12ClF3INO
requires 416.9606.
4.5.3. 6-Bromo-3-chloro-2,2-dimethyl-1-trifluoroacetyl-
1,2,3,4-tetrahydroquinoline 14c. (20%) as white needles,
mp 78–80 8C; [Found: C, 42.5; H, 3.3; N, 3.7. C13H12-
BrClF3NO requires C, 42.1; H, 3.3; N, 3.8%]; dH 7.37 (2H,
m, ArH), 6.86 (1H, dd, JZ0.8, 8.9 Hz, ArH), 4.21 (1H, dd,
JZ3.5, 5.8 Hz, CHCl), 3.24 (1H, dd, JZ3.5, 15.8 Hz, 1H of
CH2), 3.09 (1H, dd, JZ5.8, 15.8 Hz, 1H of CH2), 1.67 (3H,
s, Me), 1.63 (3H, s, Me); m/z 369/371/373 (M, 50%), 292/
294 (75), 279/281 (25), 213 (100).
4.5.9. Methyl 3-chloro-2,2-dimethyl-1-trifluoroacetyl-
1,2,3,4-tetrahydroquinoline-6-carboxylate 14i. (34%) as
a colourless oil; nmax (CH2Cl2) 1690 cmK1; dH 7.92 (2H, m,
ArH); 7.02 (1H, d, JZ7.9 Hz, ArH), 3.93 (3H, s, OMe),
4.24 (1H, dd, JZ3.7, 5.6 Hz, CHCl), 3.19 (1H, dd, JZ3.7,
16.0 Hz, 1H of CH2), 3.13 (1H, dd, JZ5.6, 16.0 Hz, 1H of
CH2), 1.69 (3H, s, Me), 1.63 (3H, s, Me); m/z 349/351

N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
163
(M, 38%), 272 (100), 260 (49), 240 (20), 228 (42); HRMS:
M, found 349.0692. C15H15ClF3NO3 requires 349.0693.)
(0.18 g, 1.1 mmol) in dry tetrahydrofuran (1 mL) were
added consecutively with stirring. The resulting mixture
was stirred under an atmosphere of nitrogen for 2 h, the
solvent removed in vacuo and the residue purified by flash
chromatography; elution with light petroleum/ethyl acetate
(80:20) gave the trifluoroacetate, 18, (78 mg, 78%) as an
unstable pale yellow oil; nmax (CDCl3) 1780 cmK1; dH 6.84
(1H, d, JZ8.1 Hz, ArH), 6.81 (1H, s, ArH), 6.46 (1H, d, JZ
8.1 Hz, ArH), 5.10 (1H, dd, JZ5.5, 7.4 Hz, CHO), 3.56
(1H, br s (exchanges with D2O), NH), 2.86 (1H, dd, JZ7.4,
16.9 Hz, 1H of CH2), 2.22, (3H, s, ArMe), 1.22 (3H, s, Me),
1.20 (3H, s, Me); m/z 287 (M, 9%), 272 (7), 173 (26), 158
(100), 132 (41).
4.5.10. 3,4-Epoxy-1-trifluoroacetyl-2,2,6-trimethyl-1,2,
3,4-tetrahydroquinoline 15. Sodium bicarbonate
(255 mg, 3.0 mmol) and m-chloroperoxybenzoic acid
(80%, 0.55 g, 2.4 mmol) were added to a solution of the
dihydroquinoline, 6a, (0.50 g, 1.9 mmol) in dichloro-
methane (25 mL) and the resulting mixture stirred under
an atmosphere of nitrogen for 41 h. The mixture was diluted
with dichloromethane (10 mL), washed with saturated
sodium bicarbonate solution (3!15 mL) and water (2!
15 mL), dried and the solvent removed. The residue was
purified by flash chromatography; elution with light
petroleum/ethyl acetate (70:30) afforded the epoxide, 15,
(0.39 g, 74%) as a pale orange oil; dH 7.26 (1H, d, JZ
1.8 Hz, ArH), 7.12, (1H, dd, JZ1.8, 8.1 Hz, ArH), 6.77 (1H,
d, JZ8.1 Hz, ArH), 3.86 (1H, d, JZ4.2 Hz, CHO), 3.41
(1H, d, JZ4.2 Hz, CHO), 2.37 (3H, s, ArMe), 1.88 (3H, s,
Me), 1.21 (3H, s, Me); m/z 285 (M, 46%), 214 (100), 145
(29), 144 (28), 69 (48); HRMS: M, found 285.0980.
C14H14F3NO2 requires 285.0977.
Other attempts at the above reaction using the same
conditions but replacing the zinc chloride with either
tetrabutylammonium chloride or tetrabutylammonium bro-
mide also gave the trifluoroacetate, 18, as the sole product.
4.5.14. 2,2,6-Trimethyl-1,2,3,4-tetrahydroquinolin-3-ol
19. An aqueous solution of potassium bicarbonate (10%,
2.5 mL, 2.4 mmol) was added dropwise to a solution of the
trifluoroacetate, 18, (77 mg, 0.27 mmol) in methanol (5 mL)
and the resulting mixture stirred at room temperature under
an atmosphere of nitrogen for 40 min. Water (5 mL) was
added and the mixture extracted with dichloromethane (3!
10 mL). The combined organic extracts were dried and the
solvent removed. The residue was purified by flash
chromatography; elution with light petroleum/ethyl acetate
(60:40) provided the aminoalcohol, 19, (40 mg, 78%) as
4.5.11. 1-Trifluoroacetyl-2,2,6-trimethyl-1,2,3,4-tetra-
hydroquinolin-3-ol 16. A solution of the epoxide, 15,
(0.39 g, 1.4 mmol) in ethyl acetate (10 mL) was stirred with
5% palladium on carbon (100 mg) under an atmosphere of
hydrogen for 23 h. The mixture was filtered through a pad of
celite and the solvent removed. The residue was purified by
flash chromatography; elution with light petroleum/ethyl
acetate (1:1) provided the alcohol, 16, (0.27 g, 69%) as a
colourless, unstable oil nmax (CDCl3) 3600 cmK1; dH 7.04
(2H, m, ArH), 6.91 (1H, d, JZ7.9 Hz, ArH), 3.89 (1H, m,
CHOH), 2.82 (1H, dd, JZ5.5, 14.4 Hz, 1H of CH2), 2.94
(1H, dd, JZ2.4, 14.4 Hz, 1H of CH2), 2.35 (3H, s, ArMe),
1.59 (3H, s, Me), 1.56 (3H, s, Me), 1.43 (1H, d, JZ7.8 Hz
(exchanges with D2O), OH); m/z 287 (M, 84%), 271 (48),
217 (25), 216 (30), 190 (35), 158 (100); HRMS: M, found
287.1123. C14H16F3NO2 requires 287.1133.
cream prisms, mp 73–74 8C; nmax (CDCl3) 3500, 3370 cmK1
;
dH 6.81 (2H, m, ArH), 6.43 (1H, d, JZ8.7 Hz, ArH), 3.63
(1H, t, JZ4.4 Hz, CHOH), 3.46, (1H, br s (exchanges with
D2O), NH), 2.99 (1H, dd, JZ4.4, 17.0 Hz, 1H of CH2), 2.71
(1H, dd, JZ4.4, 17.0 Hz, 1H of CH2), 2.21 (3H, s, ArMe),
2.18 (1H, br s (exchanges with D2O), OH), 1.20 (3H, s, Me),
1.11 (3H, s, Me); m/z 191 (M, 69%), 176 (100), 158 (31),
146 (34), 132 (36); HRMS: M, found 191.1314. C12H17NO
requires 191.1310.
4.5.12. 1-Trifluoroacetyl-2,2,6-trimethyl-1,2,3,4-tetra-
hydro-3-quinolone 17. Jones reagent was added dropwise
to a solution of the alcohol, 16, (10 mg, 35 mmol) in acetone
(5 mL) until the orange colour just persisted. Water (5 mL)
was added and the mixture extracted with dichloromethane
(3!10 mL). The combined organic extracts were dried and
the solvent removed. The residue was purified by flash
chromatography; elution with light petroleum/ethyl acetate
(80:20) afforded the ketone, 17, (7.3 mg, 74%) as a pale
yellow oil; nmax (CDCl3) 1730 cmK1; dH (acquired at 0 8C)
7.11 (2H, m, ArH), 7.01 (1H, d, JZ8.0 Hz, ArH), 3.87 (1H,
d, JZ13.8 Hz, 1H of CH2), 3.36 (1H, d, JZ13.8 Hz, 1H of
CH2), 2.31 (3H, s, ArMe), 1.79 (3H, s, Me), 1.34 (3H, s,
Me); m/z 285 (M, 30%), 257 (60), 242 (58), 188 (50), 160
(90), 145 (100); HRMS: M, found 285.0970. C14H14F3NO2
requires 285.0977.
4.5.15. 3-Chloro-2,2,6-trimethyl-1,2,3,4-tetrahydro-
quinoline 20. A mixture of the trifluoroacetate, 18,
(20 mg, 0.07 mmol), tetrabutylammonium chloride (28 mg,
0.10 mmol) and tetrahydrofuran (5 mL) was refluxed for
24 h. The reaction mixture was cooled, diluted with
dichloromethane (5 mL), washed with water (2!10 mL)
and brine (5 mL), dried and the solvent removed. The
residue was purified by flash chromatography; elution with
light petroleum/ethyl acetate (60:40) gave an inseparable
mixture of the starting trifluoroacetate, 18, and the 3-chloro
compound, 20, (6.5 mg); spectroscopic data for 20; dH 6.83
(2H, m, ArH), 6.45 (1H, d, JZ8.0 Hz, ArH), 4.08 (1H, dd,
JZ5.4, 8.4 Hz, CHCl), 3.60 (1H, br s (exchanges with
D2O), NH), 3.23 (1H, dd, JZ5.4, 16.9 Hz, 1H of CH2), 3.03
(1H, dd, JZ8.4, 16.9 Hz, 1H of CH2), 2.21 (3H, s, ArMe),
1.30 (3H, s, Me), 1.25 (3H, s, Me); m/z 209/211 (M, 29%),
194 (1), 174 (1), 158 (2).
4.5.13. 2,2,6-Trimethyl-1,2,3,4-tetrahydro-3-quinolyl tri-
fluoroacetate 18. The alcohol, 16, (100 mg, 0.35 mmol)
and triphenylphosphine (270 mg, 1.1 mmol) were dissolved
in dry tetrahydrofuran (5 mL) under an atmosphere of
nitrogen. Anhydrous zinc chloride (48 mg, 0.35 mmol) in
dry tetrahydrofuran (1 mL) and diethyl azodicarboxylate
4.5.16. 1-Acetyl-2,2,6-trimethyl-1,2,3,4-tetrahydroquino-
line-4-ol 21. To a stirred solution of mercuric acetate
(0.15 g, 0.5 mmol) in water (1 mL) was added tetrahydro-
furan (1 mL); the resulting suspension was vigorously
stirred and then the acetamide, 3, (0.10 g, 0.5 mmol) was

164
N. M. Williamson, A. D. Ward / Tetrahedron 61 (2005) 155–165
added and the resultant mixture was stirred at room
temperature for 24 h. Sodium hydroxide (3.0 M, 0.5 mL)
was added followed by a solution of sodium borohydride
(0.5 M) in sodium hydroxide (3.0 M, 0.5 mL). After 45 min
the organic layer was separated and combined with
dichloromethane extracts of the aqueous phase. The
combined organic extracts were dried and the solvent
removed. The residue was purified by flash chromatog-
raphy; elution with ethyl acetate/light petroleum (1:1)
afforded an orange oil that solidified on standing. Recrys-
tallisation of this solid from dichloromethane/light petro-
leum yielded the alcohol, 21, (0.018 g, 15%) as cream-
residue was purified by flash chromatography; elution with
ethyl acetate/light petroleum (1:4) yielded a fraction which
contained predominantly the ketone, 24, (0.10 g, 70%) as a
yellow oil; nmax (CDCl3) 1730 cmK1; dH 6.67–7.32 (3H, m,
ArH), 3.06 (2H, s, CH2), 2.32 (3H, s, ArMe), 2.23 (3H, s,
COMe), 2.18 (6H, s, Me); m/z 231 (M, 20%), 189 (15), 188
(29), 174 (100).
4.5.20. 1-Acetyl-3-chloro-2,2,6-trimethyl-1,2,3,4-tetra-
hydroquinoline-4-one 25. A solution of chromium trioxide
in sulfuric acid (30%, 0.07 mL, 0.19 mmol) was added to a
stirred solution of the chlorohydrin, 11, (0.05 g, 0.19 mmol)
in acetone (2 mL) and the mixture stirred under nitrogen for
24 h. The mixture was diluted with water (5 mL) and
extracted with dichloromethane (2!10 mL). The combined
organic extracts were dried and the solvent removed. The
residue was purified by flash chromatography; elution with
ethyl acetate/light petroleum (3:7) yielded the ketone, 25,
coloured prisms, mp 123–125 8C; nmax (CDCl3) 3550 cmK1
;
dH 7.27 (1H, br s, ArH), 7.01, (1H, d, JZ7.9 Hz, ArH), 6.83
(1H, d, JZ7.9 Hz, ArH), 4.76 (1H, br d, JZ11.2 Hz, CHO),
2.10–2.40 (2H, m, CH2), 2.37 (3H, s, ArMe), 2.10 (3H, s,
COMe), 1.73 (3H, s, Me), 1.53 (3H, s, Me), 1.46 (1H, br s,
OH); m/z 233 (M, 50%), 217 (10), 176 (100), 158 (95);
HRMS: M, Found 233.1426. C14H19NO2 requires 233.1416.
(0.036 g, 73%) asapaleyellowoil;nmax (CDCl3) 1740 cmK1
;
dH 7.85 (1H, d, JZ2.2 Hz, ArH), 7.30 (1H, dd, JZ2.2,
8.0 Hz, ArH), 6.85 (1H, d, JZ8.0 Hz, ArH), 4.10 (1H, s,
CHCl), 2.35 (3H, s, ArMe), 2.30 (3H, s, COMe), 1.70 (3H, s,
Me), 1.40 (3H, s, Me); m/z 265/267 (M, 20%), 223/225 (30),
208/210 (50), 138 (100); HRMS: M, found 265.0863.
C14H16ClNO2 requires 265.0870.
4.5.17. 1-Acetyl-2,2,6-trimethyl-1,2,3,4-tetrahydroquino-
line-4-one 22. A solution of chromium trioxide in sulfuric
acid (30%, 0.014 mL, 0.04 mmol) was added to a stirred
solution of the alcohol, 21, (0.01 g, 0.04 mmol) in acetone
(2 mL) and the mixture was stirred under nitrogen for 2 h.
Water (3 mL) was then added and the mixture was extracted
with dichloromethane (3!5 mL). The combined organic
extracts were dried and the solvent removed. The residue
was purified by flash chromatography; elution with ethyl
acetate/light petroleum (1:1) yielded the ketone, 22, (7 mg,
71%) as a yellow oil; nmax (CDCl3) 1710 cmK1; dH 7.75
(1H, d, JZ2.0 Hz, ArH), 7.25 (1H, dd, JZ2.0, 8.2 Hz,
ArH), 6.80 (1H, d, JZ8.2 Hz, ArH), 2.70 (2H, s, CH2), 2.35
(3H, s, ArMe), 2.25 (3H, s, COMe), 1.51 (3H, s, Me), 1.50
(3H, s, Me); m/z 231 (M, 20%), 174 (100), 128 (50), 127 (25);
HRMS: M, found 231.1251. C14H17NO2 requires 231.1260.
Acknowledgements
N. M. W. acknowledges, with gratitude, the award of an
Australian Postgraduate Research Award (Priority).
References and notes
4.5.18. 1-Acetyl-3-chloro-2,2,6-trimethyl-1,2-dihydro-
quinoline 23. Potassium tert-butoxide (0.17 g, 1.2 mmol)
was added to a stirred solution of the dichloro compound, 4,
(0.22 g, 0.77 mmol) in tetrahydrofuran (10 mL) and the
resultant mixture was stirred under nitrogen for 24 h. Water
(10 mL) was added and the mixture extracted with
dichloromethane (3!15 mL). The combined organic
extracts were dried and the solvent removed. The residue
was purified by flash chromatography; elution with ethyl
acetate/light petroleum (1:4) yielded the vinyl chloride, 23,
(0.065 g, 74%) as a yellow oil; dH 7.35 (1H, br s, ArH),
6.80–7.00 (2H, m, ArH), 5.85 (1H, s, C]CH), 2.40 (3H, s,
ArMe), 2.15 (3H, s, COMe), 1.60 (6H, s, Me); m/z 249/251
(M, 20%), 234/236 (55), 192/194 (100); HRMS: M, found
249.0911. C14H16ClNO requires 249.0920.
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