Diastereoselective intramolecular Ritter reaction: generation of a cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system with 4a,9b-diangular substituents.

Article abstract of DOI:10.1021/ol006248a

Indanol intermediates 5, prepared via Michael addition of 1-indanone beta-ketoester and acrylonitrile followed by reduction or Grignard reaction of the ketone group, were submitted to intramolecular Ritter reaction using various acid reaction conditions t

Full text of DOI:10.1021/ol006248a

ORGANIC
LETTERS
2
000
Vol. 2, No. 20
083-3086
Diastereoselective Intramolecular Ritter
Reaction: Generation of a Cis-Fused
Hexahydro-4aH-indeno[1,2-b]pyridine
Ring System with 4a,9b-Diangular
Substituents
3
†
Kristof Van Emelen, Tom De Wit, Georges J. Hoornaert, and Frans Compernolle*
Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F,
3001 HeVerlee, Belgium
frans.compernolle@chem.kuleuVen.ac.be
Received June 26, 2000
ABSTRACT
Indanol intermediates 5, prepared via Michael addition of 1-indanone â-ketoester and acrylonitrile followed by reduction or Grignard reaction
of the ketone group, were submitted to intramolecular Ritter reaction using various acid reaction conditions to produce tricyclic lactams 4.
This cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system, substituted at both angular positions 4a and 9b, provides access to constrained
1
analogues of non-peptide NK -antagonists with monocyclic piperidine structure.
In our search for improved non-peptide NK
1
-antagonists, we
focus on conformationally constrained modifications of the
1
2
2
,3-substituted piperidines 1 (CP-96345) and 2 (CP-99994).
Considering the structural features of these first-generation
non-peptide NK -antagonists, we envisaged specifically
substituted tricyclic piperidines 3 as target molecules (Figure
). The partial incorporation of the pharmacophoric group,
1
1
3
i.e., the N-benzyl-1-phenyl-1,2-diaminoethane moiety, in a
tricyclic ring system instead of a monocyclic piperidine
†
Current address: Janssen Research Foundation, Turnhoutseweg 30,
2
340 Beerse, Belgium.
1) (a) Snider R. M.; Constantine, J. W.; Lowe, III; J. A.; Longo, K. P.;
(
Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick, F. J.;
Spencer, R. W.; Hess, H.-J. Science 1991, 251, 435. (b) Lowe, J. A., III;
Drozda, S. E.; Snider, R. M.; Longo, K. P.; Bordner, J. Bioorg. Med. Chem.
Lett. 1991, 1, 129.
Figure 1. Piperidine non-peptide NK1-antagonists 1 and 2 and
conformationally constrained target structure 3.
(
2) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider,
R. M. J. Med. Chem. 1992, 35, 4911.
3) Howson, W.; Hodgson, J.; Richardson, R.; Walton, L.; Guard, S.;
Watling, K. Bioorg. Med. Chem. Lett. 1992, 2, 559.
structure should allow us to further define the spacial
requirements for the “bioactive conformation”.
(
1
0.1021/ol006248a CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

In this paper we describe the application of an intramo-
lecular Ritter reaction to 2-(cyanoethyl)-1-hydroxy-2-indane-
carboxylates 5 in order to prepare 9b-substituted 2-oxo-
â-Keto ester 7 was prepared by treatment of 1-indanone
6 with sodium hydride and dimethyl carbonate (Scheme 2).7
1
,2,3,4,5,9b-hexahydro-4aH-indeno[1,2-b]pyridine-4a-car-
boxylates 4 (Scheme 1). Compounds 4 can serve as key
Scheme 2. Conversion of 1-Indanone to Intermediates 5
Scheme 1. Access to Tricyclic Target Structures via
Intramolecular Ritter Reaction
intermediates in the synthesis of target molecules 3, which
will be described in due course.
Little is known about the intramolecular applications of
4
the Ritter reaction to alcohol derivatives. However, the
intermolecular Ritter reaction of both racemic and enantio-
meric forms of 1,2-indanediols with acetonitrile has been
exploited for their regio- and stereocontrolled conversion to
Subsequent Michael addition of 7 to acrylonitrile, using
t-BuOH as a solvent and t-BuOK as a base catalyst, afforded
the keto nitrile 8. When methanol was used instead of
t-BuOH, nucleophilic addition of methoxide to the ketone
function led to opening of the five-membered ring to form
5
cis-amino alcohols. The relative configuration of the newly
8
formed 1-amino function was controlled through intermediate
formation of a cis-methyloxazoline ring involving the
configurationally unmodified C-2 alcohol group. In the
intramolecular Ritter reaction of compounds 5, a similar
control on the ring closing process apparently is exerted by
the stereogenic center at C-2 when forming the carbon-
nitrogen bond in the cis-fused lactam products. Although the
basic indeno[1,2-b]piperidine ring system has been de-
the corresponding diester product. Reduction with NaBH
4
afforded an almost 1:1 mixture of diastereomeric secondary
alcohols 5a. In contrast, upon Grignard reaction of 8 with
freshly prepared alkyl- or arylmagnesium bromide at -78
°
C, the tertiary alcohols 5b-d were produced with diaster-
6
eomeric excesses ranging from 50% (5c) to 98% (5b and
scribed, to our knowledge compounds of type 4 with double
9
5
d). The yields of these nucleophilic addition reactions were
angular substitution have not yet been reported.
universally high despite steric hindrance.
In each case the structure of the major diastereomer was
assigned on the basis of NOE correlations in the H NMR
spectra, observed between a downfield 3-methylene proton
(
4) For a review of the Ritter reaction, see: Krimen, L. I.; Cota, D. J.
Org. React. 1969, 17, 213.
5) (a) Senanayake, C. H.; Robert, F. E.; DiMichele, L. M.; Ryan, K.
1
(
M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.; Larsen, R.
D. Tetrahedron Lett. 1995, 36, 3993 (b) Senanayake, C. H.; DiMichele, L.
M.; Liu, J.; Fredenburgh, L. E.; Ryan, K. M.; Roberts, F. E.; Larsen, R.
D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7615.
and protons located on the variable 1-R substituent, i.e., CH
5b), H-3 of the 2-thienyl group (5d), and the ortho-protons
3
(
of the phenyl group (5c). The downfield 3-methylene proton
was assigned to be cis-disposed with respect to the ester
group by comparison with the spectrum of compound 7.10
(6) Kunstmann, R.; Lerch, U.; Gerhards, H.; Leven, M.; Schacht, U. J.
Med. Chem. 1984, 27, 432
(
7) Binder, B.; Noe, C. R. Monatsh. Chem. 1977, 108, 839.
(8) All new compounds were characterized by analytical data (NMR,
MS, IR) including elemental analysis or exact mass measurement.
9) The diastereomeric excess was determined from integration of the
signals corresponding to the AB pattern of the 5-CH2 protons. 5b, de )
The high degree of diastereoselectivity may be explained
(
2
+
by the formation of a cyclic Mg chelate involving both
the ester and ketone carbonyl group. Inspection of a
2
2
9
8%: 2.83 ppm (d, 0.01H, J ) 16 Hz, H-3); 2.86 ppm (d, 0.99H, J ) 16
2
Hz, H-3). 5c, de ) 50%: 2.96 ppm (d, 0.25H, J ) 16 Hz, H-3); 2.99 (d,
11
conformationally optimized model reveals a nearly flat
2
2
0
.75H, J ) 16 Hz, H-3). 5d, de ) 98%: 2.96 ppm (d, 0.01H, J ) 16 Hz,
2
H-3); 2.99 ppm (d, 0.99H, J ) 16 Hz, H-3).
tricyclic structure with perpendicular orientation for the
cyanoethyl side chain (Figure 2). Accordingly, nucleophilic
attack will occur from the sterically less hindered side,
resulting in a cis-relationship between the ester and the alkyl
or aryl group.
1
(
10) The H NMR spectrum of compound 7 displayed an ABX coupling
3
pattern for H-2 and the two H-3 protons: H-2, 3.73 ppm ( J ) 4 and 8
Hz); H-3 (cis with the ester function), 3.55 ppm ( J ) 17 Hz, J ) 4 Hz);
H-3 (trans with the ester function), 3.37 ppm ( J ) 17 Hz, J ) 8 Hz).
11) Model calculations were carried out using the molecular mechanics
method of HyperChemTM: Release 4.5, Hypercube, Inc.
12) (a) Schwenker, G.; Metz, G. J. Chem. Res., Synop. 1985, 112. (b)
2
3
2
3
(
(
Cyclization of compounds 5 to form the corresponding
lactam compounds 4 was achieved through intramolecular
Ritter reaction, i.e., internal addition of the nitrile group to
Metz, G. J. Chem. Res., Synop. 1985, 382. (c) Metz, G. J. Chem. Res.,
Synop. 1987, 66.
(13) Chang, S.-J Org. Process Res. DeV. 1999, 3, 232.
3084
Org. Lett., Vol. 2, No. 20, 2000

In a similar way, several side products were formed when
applying the polyphosphoric acid procedure to the thienyl
derivative 5d, whereas the desired lactam 4d was isolated
in 85% yield when using methanesulfonic acid. However,
even the latter conditions failed to effect the cyclization of
alcohols 5a and 5b, most probably because of the less
stabilized character of the intermediate carbocations. Con-
sequently, we modified our procedure according to the
conditions reported for the intermolecular Ritter reaction of
1
3
secondary alcohols. This modification involved the use of
chlorobenzene as a solvent and heating with methanesulfonic
acid at 70 °C, which effected conversion of alcohols 5a and
5
b into tricyclic lactams 4a and 4b in 71% and 67% yields,
respectively.
In all cases, the ring closure was shown to proceed
diastereoselectively as only one stereoisomer was detected
by TLC and H NMR analysis of crude compounds 4a-d.
Figure 2. Cyclic Mg2+ chelate postulated as intermediate in the
Grignard reaction of â-ketoester 8.
1
However, the relative configuration, i.e., the cis or trans ring
1
fusion, could not be determined from H NMR NOE
a stabilized carbocation intermediate generated from the
benzylic alcohol group in an acidic medium (Scheme 3). In
view of the higher stability expected for a dibenzylic
carbocation, cyclization was first attempted using compound
difference experiments performed on either the ester com-
pound 4c or the corresponding alcohol, prepared by selective
4
reduction of the ester group with LiAlH .
5c.
An X-ray analysis of 4c unambiguously confirmed the cis
annelation that was expected from the more probable syn
attack of the nitrile on the planar dibenzylic cation (Figure
3). In addition, model calculations revealed the cis ring fusion
Scheme 3. Intramolecular Ritter Reaction of Nitrile
Compounds 5
Typical conditions for the Ritter reaction comprise the
treatment of secondary and tertiary alcohols with concen-
trated sulfuric acid. In our hands, however, yields obtained
under these conditions were low (20%). We investigated
several alternative conditions to optimize the yield. Treatment
of 5c with 80% sulfuric acid at room temperature, as
12
described by Metz for the preparation of mixed dilactams,
afforded the desired lactam 4c in 60% yield besides the
corresponding lactone 9 (20%). The latter may be formed
by attack of the carbonyl oxygen of the primary amide,
generated either directly from nitrile 5c or indirectly from
lactam 4c, on the dibenzylic carbocation intermediate.
Conducting the reaction in polyphosphoric acid at 135 °C
provided 4c in good yield (76%). However, extensive workup
and column chromatography were required and scaling up
this procedure was found to be extremely tedious. Finally,
the cyclization reaction was shown to proceed readily by
treatment of 5c with methanesulfonic acid at room temper-
ature affording 4c in an excellent yield of 92%.
Figure 3. X-ray analysis of compound 4c.
to be largely preferred over the trans one, due to the angular
strain imposed on the trans product by the partially planar
character of the cyclopentene and six-membered lactam ring
1
1
moieties.
The cis relation established between the transformable ester
function in position 4a and the aryl substituents in position
9b of compounds 4c,d is in accordance with target structures
Org. Lett., Vol. 2, No. 20, 2000
3085

3
and with the 2,3-cis substitution pattern characteristic of
Acknowledgment. The authors wish to thank the F.W.O.
(Fonds voor wetenschappelijk onderzoek-Flanders) and the
Janssen Pharmaceutica company for financial support to the
lab. They are also grateful to R. De Boer for mass spectral
analysis, Prof. S. Toppet for NMR spectra, and Prof. L. Van
Meervelt for X-ray analysis. K.V.E. and T.D.W wish to thank
the I.W.T. (Instituut voor wetenschappelijk en technologisch
onderzoek-Flanders) for the fellowships received.
model compounds 1 and 2.
In conclusion, we have defined conditions that allow a
diastereoselective synthesis of novel 9b-substituted 2-oxo-
1
,2,3,4,5,9b-hexahydro-4aH-indeno[1,2-b]pyridine-4a-car-
boxylates 4 via an intramolecular Ritter reaction. This
reaction is applicable to 1-indanol derivatives 5 having either
a secondary or a tertiary alcohol function substituted with a
methyl, aryl, or heteroaryl group. Extension of this meth-
odology to include other heteroaromatic ring systems and
to form the corresponding five-membered ring lactams, and
the eventual transformation of compounds 4a,b into the target
compounds 3, will be reported in due course.
Supporting Information Available: Experimental pro-
cedures and NMR and MS data for compounds 4a-d, 5a-
d, 7, and 8. X-ray data for compound 4c. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL006248A
3086
Org. Lett., Vol. 2, No. 20, 2000