Organic Process Research & Development 2006, 10, 149−152
Communications to the Editor
One-Pot Preparation of 7-Hydroxyquinoline
Mark Cameron,*,† R. Scott Hoerrner,*,† James M. McNamara,† Margaret Figus,‡ and Scott Thomas‡
Department of Process Research, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000, Rahway, New Jersey
07065, U.S.A., and Department of Analytical Research, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000,
Rahway, New Jersey 07065, U.S.A.
Abstract:
reaction temperatures afforded a wasteful mixture of 4, 8,
and the N,O-alkylated4 compound 9. Formation of quinolines
via classical Skraup chemistry5 was not a viable option owing
to poor yields and poor regiochemistry. Consequently, we
investigated the reaction between 2 and 4, with the intent of
optimizing the amount of 2 required and developing a process
with no distillations or isolations of intermediates to reduce
the risk of exposure to 2. The study of the reaction between
An efficient one-pot procedure for the four-step preparation
of 7-hydroxyquinoline (1) from 3-N-tosylaminophenol (4) in
60% isolated yield, that reduces the risk of exposure to acrolein
(2), is described.
Introduction
1
7-Hydroxyquinoline (1) is a key intermediate in a number
of pharmaceutically interesting compounds including Vin-
blastine.1 However, it is only commercially available in gram
quantities. Its synthesis (Scheme 1) has been reported in the
literature1,2 and requires a large excess of very highly toxic3
acrolein (2), isolation and purification through chromatog-
raphy of the intermediate N-tosyl 7-hydroxyhydroquinoline
(3), to remove the 5-regioisomer 3a, or final purification of
1 through salt formation1,2 with nitric acid.
For our purposes we required an efficient process whereby
the amount of acrolein (2) was optimized and exposure to 2
minimized. Our study of the conversion (Scheme 3) of 3-N-
tosylaminophenol (4) to 1 by 1H NMR and HPLC led to the
development of an efficient one-pot process, whereby 1 is
directly isolated from the reaction mixture in sufficient
quality to be used without further purification. We now report
our results.
2 and 4, by H NMR led to the optimization of the amount
2 required, as well as the selection of reaction solvent
(Scheme 3). The data6 showed that after 2 h in ethanol at
-5 °C with 5 mol equiv of 2, 95% conversion to the ethyl
acetal 8 (R ) Et) rather than to the aldehyde 5 had occurred.
In contrast in methanol at - 5 °C, 5 mol equiv of 2 afforded
only 65% conversion with product being the aldehyde 5
rather than the methyl acetal 10 (R ) Me). Presumably, in
methanol the addition to acrolein is less efficient because
the major product, aldehyde 5, may undergo a retroaddition
reaction, via the enol 11, back to starting materials 2 and 4
(Scheme 3). In ethanol, however, 5 is readily converted to
the stable acetal 8, and consequently, the reaction is driven
to completion. Further experiments showed the reaction to
be more efficient in ethanol than methanol, and in ethanol
at -5 °C a minimum of 1.5 mol equiv of 2 were required to
achieve 95% conversion after 6 h.
Therefore, the optimum conditions for the addition step
were chosen as 1.5 mol equiv of 2 in ethanol at -5 °C for
Results and Discussion
Initially, to overcome the use of 2 we investigated the
use of 3-halopropylaldehyde diethyl acetals (6 and 7, X )
Cl, I) (Scheme 2) as safer alternatives.
The reaction between 4 with either 6 or 7 under basic
conditions, in various solvents, orders of additions, and
1
(4) Compound 9: H NMR (400 MHz, (CD3)2SO) δ 1.00 (6H, t, J ) 7.2 Hz),
δ 1.06 (6H, t, J ) 7.2 Hz), 1.54 (2H, q, J ) 6.8 Hz), 1.89 (2H, q, J ) 6.8
Hz), 3.32 (3H, s), 3.25-3.55 (10 H, m) 3.83 (2H, t, J ) 6.8 Hz), 4.46 (1H,
t, J ) 5.2 Hz), 4.62 (1H, t, J ) 5.2 Hz), 6.54 (1H, t, J ) 2.0 Hz), 6.58 (1H,
dd, J ) 1.6, 8.4 Hz), 6.85 (1H, dd, J ) 2.43, 8.4 Hz), 7.20 (1H, t, J ) 8.0
Hz) 7.33 (2H, d, J ) 8.4 Hz), 7.42 (2H, d, J ) 8.4 Hz).
(5) Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59.
* To
whom
correspondence
should
be
addressed.
E-mail:
(6) Compound 3: 1H NMR (400 MHz, CD3Cl3) δ 2.35 (3H, s), 4.42 (2H, dd,
J ) 1.6, 4.0 Hz), 5.45 (1H, dt, J ) 4.0, 9.6 Hz), 5.2 (1H, br) 5.95 (1H, dt,
J ) 1.6, 9.6 Hz) 6.7 (1 H, dd, J ) 2.4, 8.4 Hz), 6.8 (1H, d, J ) 8.4 Hz),
7.1 (2H, d, J ) 8.4 Hz) 7.4 (2H, d, J ) 8.4 Hz). Compound 4: 1H NMR
(400 MHz, (CD3)2SO) δ 2.30 (3H, s), 6.35 (1H, dd, J ) 2.0, 8.0 Hz), 6.47
(1H, dd, J ) 2.0, 8.0 Hz), 6.53 (1H, t, J ) 2.0 Hz), 6.90 (1H, t, J ) 8.0
Hz), 7.30 (2H, d, J ) 8.4 Hz), 7.60 (2H, d, J ) 8.4 Hz), 9.36 (1H, br, NH),
10.03 (1H, br OH). Compound 5: 1H NMR (400 MHz, CD3Cl3) δ 2.42
(3H, s), 2.68 (2H, t, J ) 7.2 Hz), 3.85 (2H, t, J ) 7.2 Hz), 6.46 (1 H, d, J
) 8.0 Hz), 6.70 (1H, s), 6.80 (1H, d, J ) 8.0 Hz), 7.13 (1 H, t, J ) 8.0
Hz), 7.25 (2H, d, J ) 8.4 Hz), 7.49 (2H, d, J ) 8.4 Hz). Compound 8: 1H
NMR (400 MHz, CD3Cl3) δ 1.10 (3H, t, J ) 7.2 Hz), 1.53 (2H, q, J ) 6.8
Hz), 2.35 (3H, s) 3.33 (2H, m), 3.43-3.48 (4H, m), 4.45 (1H, t, J ) 5.5
Hz), 6.38 (1H, dd, J ) 1.6, 8.4 Hz), 6.45 (1H, t, J ) 2.1 Hz), 6.86 (1H, dd,
J ) 1.6, 8.0 Hz), 7.08 (1H, t, J ) 8.0 Hz), 7.34 (2H, d, J ) 8.4 Hz), 7.41
(2H, d, t J ) 8.4 Hz), 9.53 (1H, br).
mark_cameron@merck.com; scott-hoerrner@merck.com.
† Department of Process Research, Merck Research Laboratories.
‡ Department of Analytical Research, Merck Research Laboratories.
(1) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama,
H.; Fukuyama. T. Pure. Appl. Chem. 2003, 75, 29-38.
(2) Tokuyama, H.; Sato, M.; Ueda, T.; Fukuyama, T. Heterocycles 2001, 54,
105. Tokuyama, H.; Fukuyama, T. U.S. Patent Application Publication US
2004/0034217 A1.
(3) The Occupational Safety and Health Administration (OSHA) legal airborne
permissible exposure limit (PEL) is 0.1 ppm averaged over an 8-h work
shift, and 0.3 ppm not to be exceeded during any 15-min work period
(National Institute for Occupational Safety and Health). For a summary of
the hazards associated with acrolein, see: Bretherick’s Handbook of ReactiVe
Chemical Hazards, 6th ed.; Urben, P. G., Ed.; Butterworth-Heinemann:
Oxford, 1999; Vol. 1, pp 406-407.
10.1021/op0501545 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/17/2005
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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