Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a
Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis
of (R, R)-Formoterol Tartrate
H. Scott Wilkinson, Robert Hett, Gerald J. Tanoury,* Chris H. Senanayake,* and Stephen A. Wald
Chemical Research and DeVelopment, Sepracor Inc., 111 Locke DriVe, Marlborough, Massachusetts 01752, U.S.A.
Abstract:
In the synthesis of the
2
-adrenoceptor agonist (R,R)-formterol,
a key step in the synthesis was the development of a highly
chemoselective reduction of (1R)-2-bromo-1-[3-nitro-4-(phenyl-
methoxy)phenyl]ethan-1-ol to give (1R)-1-[3-amino-4-(phenyl-
methoxy)phenyl]-2-bromoethan-1-ol. The aniline product was
isolated as the corresponding formamide. The reaction required
reduction of the nitro moiety in the presence of a phenyl benzyl
ether, a secondary benzylic hydroxyl group, and a primary
bromide, and with no racemization at the stereogenic carbinol
carbon atom. The development of a synthetic methodology using
heterogeneous catalytic hydrogenation to perform the required
reduction was successful when a sulfur-based poison was added.
The chemistry of sulfur-based poisons to temper the reacitivty
of catalyst was studied in depth. The data show that the type
of hydrogenation catalyst, the oxidation state of the poison, and
the substituents on the sulfur atom had a dramatic effect on
the chemoselectivity of the reaction. Dimethyl sulfide was the
poison of choice, possessing all of the required characteristics
for providing a highly chemoselective and high yielding reaction.
The practicality and robustness of the process was demonstrated
by preparing the final formamide product with high chemose-
lectivity, chemical yield, and product purity on a multi-kilogram
scale.
(R,R)-Formoterol (1) is an extremely potent and selective
2
-adrenoceptor agonist
1,2
having rapid onset (1-5 min) and
long duration (12 h) and is 1000 times more active than the
(S,S) isomer.
3
The synthesis of 1 was described earlier,
4
and
is outlined in Scheme 1. Starting with the nitroarene 2,
chemoselective reduction of the nitro group provided 3
(observed by HPLC analysis), which was directly formylated
to give the isolable intermediate formamide 4. Compound 4
was converted in several steps (epoxide formation, epoxide
ring-opening, and debenzylation) to the desired final product,
formoterol (1). Although each step in the total synthesis
contained unique synthetic challenges, of particular interest
to this contribution is the investigation and development of
the chemoselective hydrogenation of nitroarene 2 to the
corresponding aniline 3 in the presence of three reactive and
labile functional groups: the benzyl-protected phenol, the
benzylic hydroxyl group, and the primary bromide.
The mechanism for the hydrogenation of a nitro group is
shown in Scheme 2.
5
The first step is the reduction of the
nitroarene to the corresponding nitroso intermediate. A
typical value for the heat of reaction is -32 kcal/mol. The
second step consists of conversion of the nitroso intermediate
to the hydroxylamine, with a typical accompanying heat of
reaction of -37 kcal/mol. The final step in the mechanism
is reduction to the aniline, having a heat of reaction of -62
kcal/mol. The total heat of reaction for the hydrogenation
of a nitroarene to an aniline is in the range of -131 kcal/
mol. The rate of reaction for each step is different: the nitroso
intermediate is extremely reactive, and the hydroxylamine
reduces slowly and accumulates in the reaction. The order
of reactivity of the various intermediates and starting material
are ArNO > ArNO
2
> ArNHOH. As a result, the conversion
of the hydroxylamine to the aniline becomes the rate-
determining step, and the step of greatest chemoselective
concern. For the hydrogenation of 2, the hydroxylamine
intermediate was observed during the reaction (HPLC
analysis).
The chemoselective catalytic hydrogenation of various
functional groups, especially in the presence of benzyl ethers,
has been demonstrated in the literature.
6,7
However, few
hydrogenation methods exist for the reduction of nitroarenes
to anilines with hydrogenation-sensitive functionalities present.
The most popular methods for effecting the selectivity was
by the addition of a catalyst poison to the reaction mixture
or by careful selection of the reaction solvent. For the
chemoselective reduction of 2 to 3, development of the
proper catalyst system would require consideration of the
other three functional groups.
Initially, platinum- and palladium-catalyzed hydrogena-
tions were investigated for the transformation shown in eq
(1) Nelson, H. S. N. Engl. J. Med. 1995, 333, 499.
(2) For references concerning other 2-adrenoceptor agonists and the biological
activity of their enantiomers, see: (a) Bakale, R. P.; Wald, S. A.; Butler,
H. T.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. Clin. ReV. Allergy Immunol.
1996, 14, 7. (b) Johnson, M. Med. Res. ReV. 1995, 15, 225. Hett, R.; Stare,
R.; Helquist, P. Tetrahedron Lett. 1994, 35, 9375. (c) Waldeck, B. Chirality
1993, 5, 350.
(3) Trofast, J.; O ¨ sterberg, K.; Ka ¨llstro ¨m, B.-L.; Waldeck, B. Chirality 1991,
3, 443.
(4) (a) Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.; Wald,
S. A. Tetrahedron Lett. 1997, 38, 1125. (b) Hett, R.; Fang, Q. K.; Gao, Y.;
Wald, S. A.; Senanayake, C. H. Organic Process Res. DeV. 1998, 1, 96.
(5) Girgis, M. J.; Kiss, K.; Ziltener, C. A.; Prashad, J.; Har, D.; Yoskowitz, R.
S.; Basso, B.; Repic, O.; Blacklock, T. J.; Landau, R. N. Org. Process
Res. DeV. 1997, 1, 339.
(6) For leading reviews and extensive discussions on hydrogenations, see: (a)
Practical Catalytic Hydrogenation Techniques and Applications; Wiley-
Interscience: New York, 1971. (b) Catalytic Hydrogenation in Organic
Synthesis; Academic Press: New York, 1979. (c) Hydrogenation Methods;
Academic Press: New York, 1991. (a) Sajiki, H. Tetrahedron Lett. 1995,
36, 3465. Tamura, R.; Oda, D.; Kurokawa, H. Tetrahedron Lett. 1986, 27,
5759. Greenfield, H.; Dovell, F. S. J. Org. Chem. 1967, 32, 3267.
(7) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465. Tamura, R.; Oda, D.;
Kurokawa, H. Tetrahedron Lett. 1986, 27, 5759. Greenfield, H.; Dovell,
F. S. J. Org. Chem. 1967, 32, 3267.
Organic Process Research & Development 2000, 4, 567-570
10.1021/op000287k CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry Vol. 4, No. 6, 2000 / Organic Process Research & Development • 567
Published on Web 08/08/2000