Preparation of quinolines from resin-bound esters using titanium reagents

Article abstract of DOI:10.1016/j.tetlet.2004.09.170

ortho-Amino homobenzylic thioacetals are prepared from ortho- nitrobenzaldehydes via homologation using an alpha-methoxy Wittig reagent. Titanium reagents are generated from the 1,3-dithianes using a low valent titanium reagent and are then used to alkylidenate resin-bound esters. An N-silylated Boc group protects the ortho-amino functionality. Traceless SPS of quinolines is completed by treating the resulting resin-bound enol ethers with TFA and then oxidizing with manganese dioxide to give 2-substituted quinolines in high purity without the need for chromatography.

Full text of DOI:10.1016/j.tetlet.2004.09.170

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8879–8882
Preparation of quinolines from resin-bound esters using
titanium reagents
Calum Macleod,a Carolyn A. Austin,a Dieter W. Hamprechtb and Richard C. Hartleya,*
aDepartment of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
bGlaxoSmithKline, Centro Ricerche, Via Fleming 4, 37135 Verona, Italy
Received 7 September 2004; accepted 28 September 2004
Available online 14 October 2004
Abstract—ortho-Amino homobenzylic thioacetals are prepared from ortho-nitrobenzaldehydes via homologation using an alpha-
methoxy Wittig reagent. Titanium reagents are generated from the 1,3-dithianes using a low valent titanium reagent and are then
used to alkylidenate resin-bound esters. An N-silylated Boc group protects the ortho-amino functionality. Traceless SPS of quino-
lines is completed by treating the resulting resin-bound enol ethers with TFA and then oxidizing with manganese dioxide to give 2-
substituted quinolines in high purity without the need for chromatography.
Ó 2004 Elsevier Ltd. All rights reserved.
Quinolines are found in many medicinally interesting
compounds1 and for this reason researchers have contin-
ued to improve traditional methods and develop new
strategies for their construction.2 However, in spite of
the importance of solid-phase synthesis (SPS),3 few
methods for the construction4,5 or decoration6 of quino-
lines on solid-phase have been developed. Of these, only
Levacher and co-workersÕ adaptation5 of the Friedla¨n-
der synthesis is traceless.7 Here we describe a method
for terminating traditional SPS in a traceless way by
conversion of an ester linker into a range of quinolines
using novel titanium reagents. This is the first time that
titanium alkylidenes8 have been used in the construction
of quinolines, and the method has potential as in theory
a diverse range of esters could be synthesized by stand-
ard split and mix techniques prior to our termination
sequence.
We have recently shown that titanium benzylidene rea-
gents9–13 1 (Scheme 1) bearing a protected oxygen, nitro-
gen or sulfur nucleophile in the ortho position are easy
to generate from thioacetals using low valent titanium
species, Cp2Ti[P(OEt)3]2, and will benzylidenate resin-
bound esters 2 to give resin-bound enol ethers 3. A range
of functionality is tolerated in the titanium benzylidenes
1, including boronate, acetal, fluoro and some amino
and carbamate groups. Treating the enol ethers 3 with
acid then yields 2-substituted benzofurans9–11 in-
doles11,12 or benzothiophenes13 4 in high purity because
the nature of the linker has been switched from an acid-
stable ester to an acid-sensitive enol ether, ensuring that
no products arise from unreacted resin-bound esters 2.
Furthermore, there is no trace in the products of where
the resin had been attached. Thus, the reagents allow
traceless termination of an SPS to form a range of
Scheme 1.
Keywords: Quinolines; Titanium and compounds; Solid-phase synthesis; Thioacetals; Wittig reaction.
*
Corresponding author. Tel.: +44 01413 304398; fax: +44 01413 304888; e-mail: richh@chem.gla.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.170

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C. Macleod et al. / Tetrahedron Letters 45 (2004) 8879–8882
Scheme 2.
heterocycles from resin-bound esters, and this has great
potential in SPS where a diverse range of esters may be
prepared using automation. At first sight, access to
quinolines using related chemistry would seem more
demanding: the necessary homobenzylic titanium rea-
gents would be expected to be more difficult to generate;
the silylated carbamate protecting groups successful in
the indole series might be less stable towards a titanium
alkylidene tethered by a more flexible chain; and a post-
cleavage oxidation step would be required to aromatize
to the quinolines. However, we here report the success of
this strategy.
oxymethyl triphenylphosphonium chloride14 gave pre-
dominantly E-enol ethers15 6 with the E-selectivity
decreasing with increasing electron-donating ability of
the aromatic ring, which is surprising but consistent with
the E:Z ratios reported for similar reactions.16 Enol
ethers 6 were converted into thioacetals 7 directly fol-
lowing work-up of the Wittig reaction. Reduction17 to
the amines 8 and Boc protection gave carbamates 9,
which were purified by recrystallization so that no chro-
matography was used to prepare these in four or five
steps from aldehydes 5. Silylation of the carbamate
groups was followed by reduction of the dithianes 10
to give the active alkylidenating agents, presumably tita-
nium alkylidenes 11.
The necessary dithiane substrates 10 for titanium alkyl-
idene formation were prepared from commercially
available 2-nitrobenzaldehydes 5 as shown in Scheme
2. Reaction with the Wittig reagent derived from meth-
A selection of quinolines18,19 14 (Scheme 3 and Fig. 1)
were then prepared in high purity from Merrifield-resin-
Scheme 3.
Figure 1.

C. Macleod et al. / Tetrahedron Letters 45 (2004) 8879–8882
8881
bound esters 12a0–d0 by treating the latter with the
titanium alkylidenes 11a–c, washing the resin, releasing
the arylammonium salts 13 under acid conditions and
oxidizing to give the quinolines 14. A solid oxidant
was chosen so that it could be removed simply by
filtration.
produced two 7.2–7.3Hz doublets with chemical shifts as
follows: E-6a at dH 7.05 and 6.39, E-6b at dH 7.07 and
5.62, E-6b at dH 6.95 and 5.52, Z-6a at dH 6.31 and 5.70,
Z-6b at dH 6.26 and 5.03, Z-6c at dH 6.24 and 5.83.
16. Compare (a) Maehr, H.; Smallheer, J. M. J. Org. Chem.
1981, 46, 1752–1755, and (b) Wiegand, S.; Schafer, H. J.
Tetrahedron 1995, 51, 5341–5350.
17. Ramadas, K.; Srinivasan, N. Synth. Commun. 1992, 22,
3189–3195.
Acknowledgements
18. Titanium alkylidenes were generated and used according
to the procedure that we have described for the prepara-
tion of indoles.11 The solid-phase reactions were carried
out in normal glassware, but with resin [particle
size = 150–300lm diameter, derived from Merrifield resin
with loading 1.83meq (of benzylic chloride) gꢀ1] con-
tained within porous polypropylene reactors that had an
internal volume of 2.4mL and a pore size of 74lm
(IRORI macrokans, 0.30mequiv of resin-bound ester per
kan). Cleavage from resin is as previously described.11
Manganese dioxide (0.09g, 1.00mmol) was added to a
solution of each crude arylammonium salt in DCM
(10cm3) and the reaction mixture was heated under reflux
for 1–2h. After this time, the reaction mixture was filtered
through a Celite plug, washing with CH2Cl2 (10cm3). The
combined organic phases were washed with saturated
sodium bicarbonate (20cm3), dried over sodium sulfate,
and concentrated to yield the desired quinolines.
EPSRC and GSK for funding.
References and notes
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19. Characterization data: 2-phenethylquinoline 14aa0 (yellow
oil); data in agreement with literature.2b 8-Methoxy-2-
phenethylquinoline 14ba0 (yellow oil); mmax (thin film)/
cmꢀ1: 3060–2852, 1602, 1564, 1503; dH (400MHz, CDCl3):
3.14–3.18 (2H, m), 3.35–3.39 (2H, m), 4.10(3H, s), 7.05
(1H, d, J 7.5), 7.09–7.31 (6H, m), 7.35–7.44 (2H, m), 8.02
(1H, d, J 8.4); dC (100MHz, CDCl3): 36.1 (CH2), 50.0
(CH2), 56.2 (CH3), 107.8 (CH), 119.5 (CH), 122.0 (CH),
125.9 (CH), 126.0(CH), 128.0(C), 128.4 (CH), 128.5
(CH), 136.2 (CH), 139.8 (C), 141.6 (C), 155.0(C), 161.0
(C); HRMS: M+ requires C18H17NO, 263.1310, found
263.1308. 8-Methoxy-2-(20-methylpropen-1-yl)-quinoline
14bb0 (yellow oil); mmax (thin film)/cmꢀ1: 3047–2835,
1649, 1600, 1556, 1498; dH (400MHz, CDCl3): 2.00 (3H,
d, J 1.2), 2.14 (3H, d, J 1.2), 4.07 (3H, s), 6.62 (1H, m),
7.02 (1H, dd, J 7.5 and 1.2), 7.33–7.44 (3H, m), 8.05 (1H,
d, J 8.5); dC (100MHz, CDCl3): 19.9 (CH3), 27.3 (CH3),
55.9 (CH3), 107.6 (CH), 119.2 (CH), 122.7 (CH), 125.8
(CH), 126.2 (CH), 127.3 (C), 135.5 (CH), 139.8 (C), 141.4
(C), 155.2 (C), 156.6 (C); HRMS: M+ requires C14H15NO,
213.1154, found 213.1153. 2-(40-Fluorophenyl)-8-meth-
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Tetrahedron Lett. 1997, 38, 907–910; (c) Ruhland, T.;
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oxyquinoline 14bc0 (yellow oil); mmax (thin film)/cmꢀ1
:
3002–2836, 1615, 1601, 1559, 1497; dH (400MHz, CDCl3):
4.10(3H, s), 7.07 (1H, d, J 7.4), 7.15–7.21 (2H, m), 7.39–
7.47 (2H, m), 8.02 (1H, d, J 8.6), 8.08–8.13 (3H, m); dC
(100MHz, CDCl3): 56.1 (CH3), 107.2 (CH), 115.7 (d, J
21.4, CH), 119.1 (CH), 119.3 (CH), 126.6 (CH), 128.2 (C),
129.5 (d, J 8.2, CH), 135.9 (C), 136.9 (CH), 140.1 (C),
155.2 (C), 155.5 (C), 163.3 (d, J 249, CF); HRMS: M+
require C16H12FNO, 253.0903, found 253.0904. 6,7-
Methylenedioxy-2-phenethylquinoline 14ca0 (yellow oil);
mmax (thin film)/cmꢀ1: 3032–2856, 1618, 1589, 1512, 1495;
dH (400MHz, CDCl3): 3.10–3.15 (2H, m), 3.19–3.24 (2H,
m), 6.09 (2H, s), 7.02 (1H, s), 7.03 (1H, d, J 8.3), 7.17–7.30
(5H, m), 7.38 (1H, s), 7.85 (1H, d, J 8.3); dC (100MHz,
CDCl3): 36.1 (CH2), 40.6 (CH2), 101.6 (CH2), 102.6 (CH),
105.5 (CH), 119.7 (CH), 123.5 (C), 125.9 (CH), 128.3
(CH), 128.5 (CH), 135.1 (CH), 141.6 (C), 146.1 (C), 147.2
(C), 155.6 (C), 159.5 (C); HRMS: M+requires C18H15NO2,
277.1103, found 277.1102. 2-(40-Fluorophenyl)-6,7-methyl-
enedioxy-quinoline 14cc0 (yellow solid); Mp: 139–142°C;
15. The ratio of geometrical isomers was determined from the
vicinal coupling between signals for the alkene protons in
the 1H NMR spectra of the crude mixtures. The E isomers
produced two 12.8Hz doublets while the Z isomers

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C. Macleod et al. / Tetrahedron Letters 45 (2004) 8879–8882
mmax (Golden Gate)/cmꢀ1: 2962–2784, 1617, 1600, 1498; (yellow solid); Mp: 124–127°C; mmax (Golden Gate)/cmꢀ1
:
dH (400MHz, CDCl3): 6.11 (2H, s), 6.77 (1H, s), 7.17–7.20
2914–2848, 1618, 1577, 1513, 1494; dH (400MHz, CDCl3):
6.09 (2H, s), 7.02 (1H, s), 7.04 (1H, d, J 1.6), 7.37 (1H, s),
7.44 (1H, d, J 8.4), 7.52 (1H, d, J 1.6), 7.93 (1H, d, J 8.4),
8.08 (1H, s); dC (100MHz, CDCl3): 101.8 (CH2), 102.7
(CH), 105.8 (CH), 109.0 (CH), 117.1 (CH), 123.9 (C),
127.5 (C), 135.3 (CH), 141.4 (CH), 143.8 (CH), 146.5 (C),
147.5 (C), 149.6 (C), 150.8 (C); HRMS: M+ requires
C14H9NO3, 239.0582, found 239.0581.
(2H, m), 7.43 (1H, s), 7.66 (1H, d, J 8.5), 8.01 (1H, d, J
8.5), 8.09–8.11 (2H, m); dC (100MHz, CDCl3): 101.7
(CH2), 102.5 (CH), 106.0 (CH), 115.7 (d, J 21.4, CH),
116.9 (CH), 124.0(C), 129.0(d, J 8.6, CH), 135.6 (CH),
146.4 (C), 147.8 (C), 150.9 (C), 154.2 (C), 162.5 (d, J 249,
CF); HRMS: M+ requires C16H10FNO2, 267.0696, found
267.0695. 2-(30-Furyl)-6,7-methylenedioxy-quinoline 14cd0