J . Org. Chem. 1996, 61, 7937-7939
7937
of alternatives, we came upon a solution to this problem
first identified more than a century ago.7 We recognized
the conversion of benzaldehydes to phenylpyruvic acids
(9) via their azalactones (7) as a source of considerable
structural diversity in “phenylacetaldehyde equivalents”,
which could then be utilized in a Pictet-Spengler tet-
rahydro-â-carboline synthesis to drive our SAR studies.3,6
“P ictet-Sp en gler -lik e” Syn th esis of
Tetr a h yd r o-â-ca r bolin es u n d er Hyd r olytic
Con d ition s. Dir ect Use of Aza la cton es a s
P h en yla ceta ld eh yd e Equ iva len ts
J ames E. Audia,* J ames J . Droste, J effrey S. Nissen,
Gwyn L. Murdoch, and Deborah A. Evrard
Lilly Research Laboratories, A Division of Eli Lilly &
Company, Indianapolis, Indiana 46285
Received J anuary 12, 1996 (Revised Manuscript Received J uly
30, 1996 )
The Pictet-Spengler reaction has been employed rou-
tinely to provide access to a variety of isoquinolines (2)
and tetrahydro-â-carbolines (4).1 While traditional pro-
tocols call for the condensation of tryptamines and
phenethylamines with aldehydes and reactive ketones,
variants have emerged that employ alternative electro-
philic components such acetals,2 R-keto acids,3 and
activated alkynes,4 further broadening the scope of
targets accessible with this methodology.
(2)
As anticipated, the azalactone syntheses were straight-
forward, with unoptimized yields typically 50-70% of
material isolated by simple filtration.8 However, in our
hands, the two-stage (base followed by acid) hydrolysis
to the phenylpyruvic acids was problematic and low-
yielding, primarily due to difficulties with product isola-
tion and the necessity for both acid and base stability of
accompanying functionality. To further complicate is-
sues, the subsequent Pictet-Spengler reaction with
tryptamines (typically carried out in alcoholic solvent)
was accompanied by the production of varying amounts
of the esterified analog of acid 5, thereby precluding
decarboxylation, making final product isolation tedious
and necessitating chromatographic purification.3 Our
observation that a single-stage acidic hydrolysis of the
azalactones was feasible10 suggested to us a short-circuit
approach and prompted us to attempt an in situ acidic
hydrolysis of the azalactone in the presence of the
tryptamine, thereby avoiding issues of R-keto acid stabil-
ity and isolation. Further, the use of aqueous medium
for the reaction would preclude the possibility for esteri-
fication prior (or subsequent) to cyclization. In the event,
admixture of the tryptamine HCl salt and a slight excess
of the azalactone in 1 N HCl and heating to reflux for
12-72 h allowed for complete conversion to the tetrahy-
dro-â-carboline (Table 1). Reaction progress could be
monitored by TLC or by visual observation of cessation
of CO2 evolution. Product typically could be isolated in
pure form (as its HCl salt) in useful yields directly from
the reaction mixture by filtration, in many cases avoiding
the necessity for chromatographic purification (method
A for direct isolation, method B for neutralization,
extraction, and chromatography).11 Although the phe-
nylpyruvic acid 9 could be detected in solution, the direct
involvement of enamide 8 (or protonated 7) in imine
formation cannot be excluded.
(1)
In the course of our investigation of the structure-
activity relationship (SAR) of a series of serotonin 2B
receptor antagonists,5 we required a robust and general
synthesis of tetrahydro-â-carbolines possessing CH2-aryl
substituents at C-1. While the Pictet-Spengler reaction
of tryptamines with phenylacetaldehyde itself is well-
behaved, the variety of readily available substituted
phenylacetaldehydes is quite limited.6 In our exploration
(1) Pictet, A., Spengler, T. Ber. 1922, 44, 2030. Whaley, W.;
Govindochari, T. Organic Reactions; J ohn Wiley & Sons, Inc.: New
York, 1951; Vol. VI, p 74. Whaley, W.; Govindochari, T. Organic
Reactions; J ohn Wiley & Sons, Inc.: New York, 1951; Vol. VI, p 151.
Sundberg, R. The Chemistry of Indoles; Academic Press: New York,
1970; p 236. Abramovitch, R.; Spencer, I. Advances in Heterocyclic
Chemistry; Academic Press: New York, 1964; Vol. 3, p 79. Ungemach,
F.; Cook, J . M. Heterocycles 1978, 9, 1089.
(2) Valls, N.; Segarra, V. M.; Bosch, J . Heterocycles 1986, 24, 943.
(3) Knabe, J .; Suggau, R. Arch. Pharmaz. 1973, 306, 500. Hudlicky,
T.; Kutchan, T. M.; Shen, G.; Sutliff, V. E.; Coscia, C. J . J . Org. Chem.
1981, 46, 1738.
Thus, the protocol met our criteria for simplicity and
generality and has provided us with a vehicle for prepa-
ration of a diverse set of compounds for SAR evaluation.
(4) Vercauteren, J .; Lavaud, C.; Levy, J .; Massiot, G. J . Org. Chem.
1984, 49, 2278.
(5) Audia, J . E.; Evrard, D. A.; Murdoch, G. R.; Droste, J . J .; Nissen,
J . S.; Schenck, K. S.; Fludzinski, P.; Cohen, M. L. J . Med. Chem. 1996,
39, 2773.
(6) ACD database searching indicated commercial availability of only
the parent phenylacetaldehyde. Conversely, a similar ACD database
search indicated commercial availability of >500 benzaldehyde deriva-
tives.
(7) Plo¨chl, E. Ber. 1883, 16, 2815.
(8) We note the exception of 2,6-disubstituted benzaldehydes in
which azalactone formation fails, presumably due to steric factors.
(9) Snyder, H. R.; Buck, J . S.; Ide, W. S. Organic Syntheses; Blatt,
A. H., Ed.; J ohn S. Wiley & Sons: New York, 1943; Collect. Vol. II, p
333.
(10) Our observation was that single stage hydrolysis was an
effective, albeit slow, means of preparation of the phenylpyruvic acids.
See: MacDonald, S. F. J . Chem. Soc. 1948, 376.
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