Highly regioselective friedlaender reaction

Article abstract of DOI:10.1021/ol006785v

Matrix presented A highly regioselective Friedlaender reaction is described. By introduction of a phosphonate group at one of the α-carbons of a ketone, regioselectivity can be perfectly controlled.

Full text of DOI:10.1021/ol006785v

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1101-1103
Highly Regioselective Friedla1nder
Reaction
Yi Hsiao,* Nelo R. Rivera, Nobuyoshi Yasuda, David L. Hughes, and
Paul J. Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
yi_xiao@merck.com
Received October 26, 2000
ABSTRACT
A highly regioselective Friedla1nder reaction is described. By introduction of a phosphonate group at one of the r-carbons of a ketone,
regioselectivity can be perfectly controlled.
In connection with our research interests, we needed a
general method to prepare 2-substituted [1,8]naphthyridines.
There are two general methods for making naphthyridines,
namely, the Skraup reaction and the Friedla¨nder reaction.
The former is a powerful method for the syntheses of
quinolines and many naphthyridines.1 However, it is very
substrate dependent and has not been suitable for the
preparation of 2-substituted [1,8]naphthyridines.2 On the
other hand, the Friedla¨nder reaction is one of the most
important methods for synthesizing pyridines, quinolines, and
naphthyridines.3 This method typically provides products
with high yields, but one of the major drawbacks is that
unsymmetrical ketones give both regioisomeric products,
generally with little or no selectivity (Scheme 1). Although
undergo the Friedla¨nder reaction regioselectively to provide
2,3-disubstituted pyridines and their derivatives with excel-
lent yields.4
Herein, we report a novel, highly regioselective Friedla¨nder
reaction leading to 2-substituted [1,8]naphthyridines in high
yield. This new method should be applicable not only to
naphthyridines but also to other heterocycles such as quino-
lines.
Our initial approach to controlling regioselectivity was to
differentiate the two R-positions of a ketone by regioselective
enolate formation. Exploratory work along these lines
focused on use of Lewis acids such as TiCl4 to form terminal
enols of methyl ketones, so that the Friedla¨nder reaction
would occur at the terminal (methyl) position. Unfortunately,
even though some increase in regioselectivity was observed,
it remained very low.
To differentiate between the two R-carbons of ketones,
we decided to introduce at one of the R-positions of the
ketone an acidifying directing group, which was not only a
good electron-withdrawing group but also a good leaving
group. A phosphonate group was chosen since it should serve
Scheme 1. Friedla¨nder Reaction
(1) For a review, see: Hamada, Y.; Takeuchi, I. Yakugaku Zasshi 2000,
120, 206.
(2) Hamada, Y.; Takeuchi, I. Chem. Pharm. Bull. 1971, 19, 1857.
(3) For the newest review, see: Cheng, C.-C.; Yan, S.-J. In The
Friedla¨nder Synthesis of Quinolines; Dauben, W. C., Ed.; Organic Reactions;
J. Wiley & Sons: New York, 1982; Vol. 28, p 37.
(4) (a) Breitmaier, E.; Bayer, E. Tetrahedron 1970, 26, 5907. (b)
Veronese, A. C.; Callegari, R.; Salah, S. A. A. Tetrahedron Lett. 1990, 31,
3485. (c) Veronese, A. C.; Callegari, R.; Morelli, C. F. Tetrahedron 1995,
51, 12277.
this reaction was discovered more than a century ago, this
regioselectivity problem has never been effectively addressed.
For this reason, application of the Friedla¨nder reaction has
been limited. In fact, only â-ketoesters and 1,3-diketones
10.1021/ol006785v CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/20/2001

both functions. We envisioned that the R-carbon of the
phosphonate would react with the aldehyde selectively, and
therefore, the reaction with â-keto phosphonates5 would
provide the desired 2-substituted [1.8]naphthyridines as the
sole regioisomer. To test this hypothesis, â-keto phospho-
nates 2a,6 2b,7 and 2c8 were chosen as substrates. The
Friedla¨nder reaction with 2-amino-3-formylpyridine (3)9 was
carried out in MeOH in the presence of aqueous NaOH at
room temperature. For comparison, the corresponding methyl
ketones (1a, 1b, and 1c) were also examined (Scheme 2).
Table 1. Friedla¨nder Reaction
Scheme 2. Ketones and â-Keto Phosphonates
entry
substrate
yield, %
selectivity 4:5
1
2
3
4
5
6
1a
2a
1b
2b
1c
2c
91
95
94
90
89
85
64:36
100:0
13:87
100:0
67:33
100:0
ate stage by using THF as solvent instead of methanol. Thus,
the intermediate was isolated and identified as the trans-
Horner-Emmons product 7. The desired 2-substituted [1.8]-
naphthyridine was smoothly obtained when 7 was subjected
to the original reaction conditions (aqueous NaOH in
MeOH).
All reactions were carried out in MeOH and NaOH at
room temperature.10 Reaction yields and selectivities were
determined by NMR with mesitylene as internal standard.
On the basis of these observations, we believe that the
Friedla¨nder reaction of â-keto phosphonates occurs via the
trans-Horner-Emmons intermediate. More importantly, the
cis-trans isomerization of 7 is promoted by methanol,
possibly through the methanol adduct 8. Either the cis
compound 6 or the adduct 8 can undergo cyclization and
subsequent aromatization to give the desired product 4
(Scheme 3). It is also worth mentioning that slow addition
of 2-amino-3-formylpyridine (3) provided better results by
In the case of methylketones, the Friedla¨nder reactions
gave naphthyridines with low regioselectivity, and the ratio
of 4:5 ranged from 67:33 to 13:87. In strong contrast to
methyl ketones, all three Friedla¨nder reactions using â-keto
phosphonates resulted in single regioisomers 4 with excellent
isolated yields (Table 1). Of particular note, for the 4-meth-
oxyphenylacetone example, the regioselectivity was dramati-
cally reversed from 13:87 to 100:0 (entries 3 and 4).
In this newly developed Friedla¨nder reaction, an interme-
diate was typically observed by HPLC analysis. As the
reaction progressed, the intermediate grew in and then was
converted to the product. All attempts to isolate the inter-
mediate failed under the standard reaction conditions.
However, we were able to stop the reaction at the intermedi-
Scheme 3. Reaction Mechanism
1102
Org. Lett., Vol. 3, No. 8, 2001

preventing the second Friedla¨nder reaction between the
intermediate 7 and 3 to give compound 9.
Acknowledgment. We thank Drs. M. S. Jensen, M.
Palucki, D. R. Gauthier, and M. E. Duggan for helpful
discussions and Mr. R. A. Reamer and Ms. L. M. DiMichele
for NMR support.
In conclusion, we have discovered a new method for
obtaining perfect control of regioselectivity in the Friedla¨nder
reaction by attaching a phosphonate activating group at one
of the R-carbons of a ketone. To the best of our knowledge,
this is the first example using a â-keto phosphonate for the
Friedla¨nder reaction. The reaction proceeds through the trans
Horner-Emmons intermediate 7, and methanol is likely
involved in the cis-trans isomerization, which is critical for
this reaction.
Supporting Information Available: Characterization
data for compounds 4 and 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006785V
(9) Rivera, N. R.; Hsiao, Y.; McWilliams, C.; Cowen, J. A.; Armstrong,
J.; Yasuda, N.; Hughes, D. L. Synth. Commun. In press.
(5) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654.
(6) Commercially available from Aldrich.
(10) Typical Experimental Procedure. Into a methanol solution of the
â-keto phosphonate (1.1 equiv, concentration 0.44 M) was added 2-amino-
3-formylpyridine (0.8 equiv). Aqueous NaOH (1.2 equiv, 50 wt %) was
then added slowly over a 10 min period such that Tmax e 41 °C. The solution
was stirred for 30 min, after which the remainder of the aldehyde (0.2 equiv)
was added over 3 min. The reaction was allowed to stir overnight at room
temperature (20 °C). The crude mixture was concentrated, and the residue
was dissolved in EtOAc. After a water wash, the organic solution was
concentrated to give the desired naphthyridine product.
(7) The synthesis of 2b followed a standard procedure: (a) Kanemasa,
S.; Otsuka, T.; Doi, K.; Tsuge, O.; Wada, E. Synthesis 1990, 1167. (b)
Shapiro, G.; Buechler, D.; Hennet, S. Tetrahedron Lett. 1990, 31, 5733.
1H NMR (CDCl3) δ 7.12 (m, 2H), 6.86 (m, 2H), 3.82 (s, 2H), 3.79 (s, 3H),
3.78 (d, J ) 11.1 Hz, 6H), 3.09 (d, J ) 22.6 Hz, 2H); 13C NMR (CDCl3)
δ 199.4 (d, JCP = 6.1 Hz), 158.5, 130.3, 125.1, 113.8, 54.8, 52.5 (d, JCP
6.4 Hz), 49.4 (d, JCP = 1.2 Hz), 39.6 (d, JCP = 128.3 Hz).
(8) Delamarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453.
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