Preparation of 8-alkyl 7-(2-imidazolinylamino)quinolines via palladium mediated alkylations

Article abstract of DOI:10.1081/SCC-120004853

A convenient preparation of 8-alkyl substituted 7-(2-imidazo linylamino)quinolines from the corresponding 8-trifluoro-methanesulfonates, utilizing palladium cross-coupling reactions is described.

Full text of DOI:10.1081/SCC-120004853

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PREPARATION OF 8-ALKYL 7-(2-
IMIDAZOLINYLAMINO)QUINOLINES VIA PALLADIUM
MEDIATED ALKYLATIONS
Nick Nikolaides a , Sophie E. Bogdan a & James S. Szalma a
a Procter & Gamble Pharmaceuticals , 8700 Mason-Montgomery Road, Mason, OH, 45040,
U.S.A.
Published online: 16 Aug 2006.
To cite this article: Nick Nikolaides , Sophie E. Bogdan & James S. Szalma (2002) PREPARATION OF 8-ALKYL 7-(2-
IMIDAZOLINYLAMINO)QUINOLINES VIA PALLADIUM MEDIATED ALKYLATIONS, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:13, 2027-2033, DOI: 10.1081/SCC-120004853
To link to this article: http://dx.doi.org/10.1081/SCC-120004853
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SYNTHETIC COMMUNICATIONS, 32(13), 2027–2033 (2002)
PREPARATION OF 8-ALKYL
7-(2-IMIDAZOLINYLAMINO)QUINOLINES
VIA PALLADIUM MEDIATED
ALKYLATIONS
*
Nick Nikolaides, Sophie E. Bogdan,
andJames S. Szalma
Procter & Gamble Pharmaceuticals,
8700 Mason-Montgomery Road, Mason, OH 45040, USA
ABSTRACT
A convenient preparation of 8-alkyl substituted 7-(2-imidazo-
linylamino)quinolines from the corresponding 8-trifluoro-
methanesulfonates, utilizing palladium cross-coupling
reactions is described.
During the course of our efforts to design and synthesize ꢀ2 adrenergic
agonists, 8-ethyl-7-(2-imidazolinylamino)quinoline, 1, was identified as a
potent and selective compound. As illustrated in Scheme 1, the initial
synthetic route to the desired quinoline progressed through classical
construction of the quinoline ring system via a modified Doebner–Miller
reaction.[1] Starting with commercially available 4-ethylbenzoic acid (2),
*Corresponding author. E-mail: nikolaidesn@pg.com
2027
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

2028
NIKOLAIDES, BOGDAN, AND SZALMA
dinitration in the presence of fuming nitric acid and sulfuric acid gave rise to
dinitrobenzoic acid 3 in high yield (96%). Treatment of 3 with copper
bronze in refluxing quinoline provided the decarboxylated 2,6-dinitroethyl-
benzene (4) in poor yield (24%). Attempts to optimize the decarboxylation
failed to produce higher isolated yields of the desired ethylbenzene 4.
Catalytic reduction to diamine 5, followed by treatment with 1,1,3-tri-
methoxypropane in the presence of FeCl3, ZnCl2, and 1N HCl in absolute
ethanol afforded quinoline 6 in low yield (36%). Attempts to optimize this
step consistently provided isolated yields in the 32–38% range. Construction
of the aminoimidazoline proceeded through formation of the isothiocyanate
7 by treatment with di-2-pyridylthionocarbonate (98% yield), conversion to
thiourea 8 with ethylenediamine and finally cyclization to the imidazoline by
treatment with mercuric acetate to provide 8-ethyl-7-(2-imidazolinylamino)-
quinoline (1) as the acetate salt in good overall yield from the isothiocyanate
(81%). Kilolab scale-up feasibility studies of this process identified it as
much too costly, owing largely to the poor chemical yields and the failure
to optimize both the decarboxylation and quinoline ring formation steps.
Clearly, a new process needed to be identified.
Scheme 1.
Although the literature is rich with methods aimed towards preparing
8-alkyl substituted quinolines via ring forming reactions,[2] these methods all
offer limitations in their scope, essentially making them undesirable for
scale-up. In determining a suitable starting material for the new process, a
cornerstone of thought included having the quinoline ring system in place at

8-ALKYL 7-(2-IMIDAZOLINYLAMINO)QUINOLINES
2029
the start, thus avoiding the need for ring formation. Stille reported the
coupling of aryltrialkylstannanes to 8-quinolyl trifluoromethanesulfonate[3]
and Crisp and Papadopoulos described the coupling of trialkylaluminum
reagents to 2-quinolyl trifluoromethanesulfonate,[4] both via palladium
mediated cross-couplings. However, in both cases, no additional substitu-
tion on the quinoline ring system was examined. With this precedent in
mind, we viewed commercially available 5-chloro-8-hydroxyquinoline (9)
as a suitable starting material. As illustrated in Scheme 2, nitration of 9
with 1.1 equivalents of KNO3 in concentrated H2SO4 at 5–10ꢀC gave rise to
5-chloro-8-hydroxy-7-nitroquinoline (10) in good yield (86%), which was
then treated with 1.0 equivalents of triflic anhydride in the presence of
triethylamine in CH2Cl2 to provide triflate 11 (90%). Reaction of triflate
11 with tetraethyltin (1.04 equiv) in the presence of PdCl2(PPh3)2
(0.02 equiv) and LiCl (3.0 equiv) in DMF at 80ꢀC gave rise to the desired
8-ethyl substituted quinoline 12 in good yield (75%). Contrary to the reports
of Crisp and Papadopoulos,[4] alkyl transfer from organostannanes did
occur, with this transfer most likely being attributed to the activating
effect of the nitro group ortho to the trifluoromethanesulfonate. In fact,
when triethylaluminum was used as the alkyl source (1.5equiv Et 3Al, 0.05
equiv PdCl2(PPh3)2, 1.3 equiv LiCl, DMF), the reaction proceeded at room
temperature, providing 12 in good yield (74%). Finally, catalytic reduction
of the nitro group, along with concomitant reduction of the chloro moiety
furnish 7-amino-8-ethylquinoline (8, 68%), which was then carried on to the
desired 7-(2-imidazolinyl)quinoline as previously described.
Pursuant to an ongoing study requiring access to a series of
8-alkyl substituted 7-(2-imidazolinylamino)quinolines, the palladium
Scheme 2.

2030
NIKOLAIDES, BOGDAN, AND SZALMA
Table 1. Palladium Mediated Alkylations of Compound 11
Temperature
(ꢀC)
Entry R3Al/R4Sn
Catalyst
Solvent
Product
% Yield
1
2
3
4
5
6
Et4Sn
Et3Al
Et3Al
n-Pr3Al
n-Bu4Sn
n-Bu4Sn
PdCl2(PPh3)2 DMF
PdCl2(PPh3)2 DMF
80
rt
rt
rt
100
100
12a, R¼Et
12a, R¼Et
12a, R¼Et
12b, R¼n-Pr
75
74
28
65
Pd(PPh3)4
PdCl2(PPh3)2 DMF
Pd(PPh3)4 Dioxane
PdCl2(PPh3)2 DMF
DMF
12c, R¼n-Bu no reaction
12c, R¼n-Bu
60
cross-coupling reaction described above was considered as a quick and facile
method to expand the structure-activity relationships of this class of ꢀ2
agonists. As illustrated in Table 1, quick access to the n-propyl (Entry 4)
and n-butyl (Entry 6) analogs was now possible. A brief survey of the scope
of this coupling indicated that triethylaluminum coupled more efficiently in
the presence of PdCl2(PPh3)2 (Entry 2) than in the presence of Pd(PPh3)4
(Entry 3). Moreover, coupling proceeded at room temperature when using
the alkylaluminum reagents, (Entries 2–4) whereas elevated temperatures
were required when utilizing alkylstannanes (Entries 1, 5, 6). The overall
improvement of the new synthetic route was directly measured by the
enhancement of overall isolated yield of 1 (4%, Doebner–Miller strategy
vs. 44%, Pd mediated coupling strategy). Although the palladium mediated
coupling described above seemed plausible for the kilolab campaign, further
development of quinoline 1 was halted, thus no attempt was made to ex-
amine this process on the kilogram scale.
EXPERIMENTAL SECTION
General Methods
Proton NMR spectra were taken on a GE QE-300 (300 MHz)
spectrometer or a Bruker AC-300 (300 MHz) quad-nuclei probe system.

8-ALKYL 7-(2-IMIDAZOLINYLAMINO)QUINOLINES
2031
All chemical shifts were reported in d scale as parts per million downfield
from (CH3)4Si. Spectra taken in CDCl3 were referenced either to (CH3)4Si
or to residual CHCl3 (7.24 ppm). Spectra taken in D2O were referenced to
HOD (4.80 ppm), those in (CD3)2CO were referenced to residual (CH3)2CO
(2.04 ppm), those in CD3OD were referenced to residual CH3OH
(3.30 ppm), and those in (CD3)2SO were referenced to residual (CH3)2SO
(2.49 ppm). Carbon-13 spectra were taken on a GE QE-300 (75MHz) spec-
trometer or a Bruker AC-300 (75MHz) quad-nuclei probe system. Spectra
taken in CDCl3 were referenced to solvent (78 ppm), those in CD3OD were
referenced to solvent (49 ppm), those in (CD3)2SO were referenced to solvent
(39.7 ppm), and those in (CD3)2CO were referenced to solvent (206.5,
29.8 ppm). Mass spectra were determined on a Fision’s Trio 2000 equipped
with a robotic probe. Chemical ionization spectra were obtained using
methane and/or ammonia as a reagent gas. Thin layer chromatography
was performed on silica gel 60 F-254 precoated plates. Flash chromatogra-
phy was performed using silica gel 60 (Merck, 230–400 mesh). Melting
points were obtained with an Electrothermal IA9200 and are uncorrected.
Elemental analysis were obtained from Oneida Research Services,
Whiteboro, NY. Unless otherwise stated, all commercially available
reagents were used without further purification. All reactions were normally
run under an inert atmosphere (argon or nitrogen). Brine referred to satu-
rated aqueous sodium chloride. Residual solvent was removed under
vacuum (ca. 0.03 mm Hg) at rt.
5-Chloro-8-hydroxy-7-nitroquinoline 10: To a 250 mL round bottom
flask was added 5-chloro-8-hydroxyquinoline 9 (7.07 g, 0.039 mol) and
H2SO4 (70 mL). This mixture was cooled to 5–10ꢀC and solid KNO3
(4.14 g, 0.041 mol) was slowly added over a period of one hour. Upon com-
pletion of addition, the reaction mixture was poured over 1 liter of ice/water
and an orange precipitate formed. The solid was filtered and dried in a
vacuum oven to give rise to 5-chloro-8-hydroxy-7-nitroquinoline 10 (7.5g,
86%). m.p. 198.5–199.4ꢀC; 1H-NMR (DMSO-d6): 9.08–9.03 (1H, dd,
J ¼ 4.1, 1.0 Hz), 8.57–8.51 (1H, dd, J ¼ 8.5, 0.9 Hz), 8.12 (1H, s), 7.91–7.86
(1H, dd, J ¼ 8.5–4.3 Hz); 13C-NMR (DMSO): 150.82, 150.45, 140.35,
133.93, 132.67, 128.91, 126.28, 122.27, 118.38.
5-Chloro-7-nitro-8-trifluoromethanesulfonylquinoline 11: To a 500 mL
round bottom flask was added 5-chloro-8-hydroxy-7-nitroquinoline 10
(5.0 g, 0.02 mol) and methylene chloride (200 mL). This heterogeneous mix-
ture was cooled to 0ꢀC and neat triethylamine (3.1 mL, 0.02 mol) was added
via syringe. The resulting mixture was stirred at 0ꢀC for approximately
30 min (or until all solids have dissolved). Neat triflic anhydride was
slowly added over a period of ten minutes and the resulting mixture was
stirred at 0ꢀC for ten minutes. The reaction mixture was filtered through

2032
NIKOLAIDES, BOGDAN, AND SZALMA
a plug of SiO2 (eluted with 300 mL 60 : 40 hexane : ethyl acetate) and the
resulting organic fraction was concentrated in vacuo to give rise to 5-chloro-
7-nitro-8-trifluoromethanesulfonylquinoline 11 (6.98 g, 90%). m.p.
111.0–112.5ꢀC; 1H-NMR (CDCl3): 9.23–9.21 (1H, dd, J ¼ 4.0, 1.5Hz),
8.69–8.66 (1H, dd, J ¼ 8.5, 1.5 Hz), 8.22 (1H, s), 7.85–7.80 (1H, dd,
J ¼ 8.5, 4.0 Hz); 13C-NMR (CDCl3): 153.39, 141.24, 140.20, 138.10,
133.18, 132.08, 129.70, 125.50, 121.09, 120.73, 116.48.
5-Chloro-8-ethyl-7-nitroquinoline 12a: To a 25mL round bottom flask
under N2 was added 5-chloro-7-nitro-8-trifluoromethanesulfonylquinoline
11 (500 mg, 1.4 mmol), DMF (7 mL), Et4Sn (0.29 mL, 1.45mmol), LiCl
(178 mg, 4.2 mmol), and Pd(Cl)2(PPh3)2 (20 mg, 0.028 mmol). The mixture
was heated to 80ꢀC for 18 h. The resulting reaction mixtures was then cooled
to room temperature and diluted with diethyl ether (100 mL), washed with
sat’d KF (3 Â 75mL), H 2O (2 Â 75mL), and brine (1 Â 75mL). The organic
phase was dried (MgSO4), filtered and concentrated to give rise to a yellow
residue. The residue was chromatographed (90 : 10 hexane : ethyl acetate) to
give rise to 5-chloro-8-ethyl-7-nitroquinoline 12a (249 mg, 75%). m.p.
88.3–89ꢀC; H-NMR (CDCl3): 9.1 (1H, dd), 8.6 (1H, dd), 8.0 (1H, s), 7.65
1
(1H, dd), 3.45(2H, q), 1.4 (3H, t); 13C-NMR (CDCl3): 151.54, 138.04, 133.15,
128.10, 123.66, 121.07, 20.78, 15.00. Anal. Calcd for C11H9ClN2O2: C, 55.83;
H, 3.83; N, 11.84. Found: C, 55.96; H, 3.94; N, 11.99.
5-Chloro-7-nitro-8-n-propylquinoline 12b: To a 100 mL round bottom
flask under N2 was added 5-chloro-7-nitro-8-trifluoromethanesulfonylqui-
noline 11 (1.0 g, 2.8 mmol), DMF (20 mL), LiCl (154 mg, 3.6 mmol),
Pd(Cl)2(PPh3)2 (98 mg, 0.01 mmol), and (n-propyl)3Al (660 mg, 4.2 mmol).
The mixture was stirred at rt for 48 h. The resulting reaction mixture was
poured into 150 mL ice/H2O and then partitioned between H2O and diethyl
ether (100 mL). The aqueous phase was washed with diethyl ether
(3 Â 100 mL). The combined organic fractions were washed with brine
(1 Â 100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give rise
to an orange solid. The residue was chromatographed (90 : 10 hexane : ethyl
acetate) to give rise to 5-chloro-7-nitro-8-n-propylquinoline 12b as an off-
1
white solid (460 mg, 65%). H-NMR (CDCl3): 9.10–9.08 (1H, dd, J ¼ 4.2,
1.8 Hz), 8.61–8.58 (1H, dd, J ¼ 8.5, 1.8 Hz), 7.97 (1H, s), 7.66–7.61 (1H, dd,
J ¼ 8.5, 4.3 Hz), 3.45–3.42 (2H, dd, J ¼ 9.2, 7.7 Hz), 1.81–1.73 (2H, m), 1.08
(3H, t, J ¼ 7.4 Hz); 13C-NMR (CDCl3): 151.46, 148.58, 147.16, 137.08,
132.99, 129.98, 128.00, 123.60, 121.07, 28.97, 24.12, 14.46. CIMS (NH3, CH4)
m/e 253 (M þ 3), 251 (Mþ1), 221 (M-NO); Anal. Calcd for C12H11ClN2O2:
C, 57.50; H, 4.42; N, 11.17. Found: C, 57.52; H, 4.81; N, 11.48.
5-Chloro-8-n-butyl-7-nitroquinoline 12c: To a 100 mL round bottom
flask under N2 was added 5-chloro-7-nitro-8-trifluoromethanesulfonylqui-
noline 11 (1.0 g, 0.0028 mol), DMF (20 mL), (n-Bu)4Sn (1.01 g, 0.0029 mol),

8-ALKYL 7-(2-IMIDAZOLINYLAMINO)QUINOLINES
2033
LiCl (0.356 g, 0.0084 mol), and Pd(Cl)2(PPh3)2 (39 mg, 0.39 mmol). The mix-
ture was heated to 100ꢀC for 22 h. The resulting reaction mixture was then
cooled to room temperature and diluted with diethyl ether (100 mL) then
washed with sat’d KF (3 Â 75mL), H 2O (2 Â 75mL), and brine (1 Â 75mL).
The organic phase was dried (MgSO4), filtered and concentrated to give rise
to a yellow residue. The residue was chromatographed (95: 5 hexane : ethyl
acetate) to give rise to 5-chloro-8-n-butyl-7-nitroquinoline 12c as a white
solid (462 mg, 57%). 1H-NMR (CDCl3): 9.10–9.08 (1H, dd, J ¼ 4.2, 1.8 Hz),
8.61–8.58 (1H, dd, J ¼ 8.5, 1.8 Hz), 7.97 (1H, s), 7.66–7.61 (1H, dd, J ¼ 8.5,
4.3 Hz), 3.48–3.43 (2H, dd, J ¼ 9.2, 7.7 Hz), 1.73–1.66 (2H, m), 1.54–1.47
(2H, m), 0.97 (3H, t, J ¼ 7.4 Hz); 13C-NMR (CDCl3): 151.46, 148.58, 147.16,
137.08, 132.99, 129.98, 128.00, 123.60, 121.07, 32.84, 26.82, 23.15, 13.74.
Anal. Calcd for C13H13ClN2O2: C, 58.99; H, 4.95; N, 10.58. Found: C,
59.02; H, 4.99; N, 10.74.
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Received in the USA July 24, 2001