Synthesis of Functionalised Azabicycles via a Regiospecific Intramolecular Aldol Reaction

Robert A. Stockman,^a Peter Szeto,^a Stephen H. J. Thompson,^a
Michael S. Hadley,^b David C. Lathbury^c and Timothy Gallagher*^a

^aSchool of Chemistry, University of Bristol, Bristol BS8 1TS U.K.
^b SB Pharmaceuticals, New Frontiers Science Park, Harlow CM19 5AD U.K.
^c SB Pharmaceuticals, Old Powder Mills, Tonbridge TN11 9AN U.K.

Abstract: A series of ketoaldehydes (1) undergo aldol-type cyclisation in the presence of a secondary amine to give the azabicyclic enones (2). Optimal reaction conditions involve use of 2,2,6,6-tetramethylpiperidine followed by silica gel, and participation of an electrophilic iminium species is suggested.

The indolizidine ring system, a structural feature present in a number of important heterocyclic target molecules,¹ continues to provide opportunities for the development of new synthetic methodology.² We have recently described a synthesis of (-)-slaframine which involved, at an early point, a regioselective intramolecular aldol reaction (1a) (2a) to assemble the indolizidine nucleus.³

Enone (2a) was only available in modest (at best 31%) yield. This was surprising given the apparently straightforward nature of the transformation involved and the established utility of related aldol-mediated cyclisations.⁴ While the low efficiency of this step may reflect the known preference of pyrrolidin-3-ones, such as (1a), to undergo enolization towards C(4) rather than C(2),⁵ this type of internal aldol process does, nevertheless, offer potential in the field of heterocyclic chemistry. In this paper we describe significantly improved conditions for achieving this cyclisation reaction and, in addition, the scope of this aldol sequence has also been evaluated using a series of novel ketoaldehydes that are structurally related to (1a).

A series of aldol substrates was obtained by N-acylation of 3,3-dimethoxypyrrolidine (3)⁶ and release of the two carbonyl components was achieved in a stepwise fashion - ketal hydrolysis followed by oxidative alkene cleavage - to give the ketoaldehydes (1a-e).⁷ This represents a flexible and efficient synthetic strategy and is illustrated in Scheme 1 for the simple ketoaldehyde (1b).

Scheme 1. Reagents and conditions: i, 4-pentenoic acid, EDC, CH₂Cl₂; ii, H₃O⁺; iii, NaIO₄, OsO₄, THF, H₂O (85% from (3)).

The key cyclocondensation was then accomplished by exposure of ketoaldehydes (1) (in CHCl₃, CH₂Cl₂ or THF) to a secondary amine (pyrrolidine, piperidine or 2,2,6,6-tetramethylpiperidine (TMP)) to give bicyclic enones (2) in up to 68% yield. It is important to note, however, that this transformation did not occur under a wide variety of more conventional aldol reaction conditions.⁸ In the case of (1b) (2b) we have evaluated over 40 different sets of conditions and successful cyclisation has only been observed when a secondary amine has been used. The optimal procedures involve use of either pyrrolidine, piperidine (both in CH₂Cl₂ or THF at room temperature) or TMP (in CHCl₃ at reflux) and the results of this study are summarised in Table 1. These conditions provide access to a series of indolizidines (2a-c) and the pyrrolo[1,2-a]azepinone and the pyrrolo[1,2-c]pyrimidinone derivatives (2d) and (2f) respectively. Cyclisation of (1a) is especially noteworthy given that use of TMP (1 equiv., CHCl₃, reflux, 4 h) followed by adsorption on silica gel provided the slaframine precursor (2a) in 68% yield; this represents a very significant improvement on our earlier report. Attempts to generate an eight-membered ring by cyclisation of (1e) did, however, fail under all of these conditions and we were also unsuccessful in our efforts to cyclize both (1g, X=NH) and (1h, X=O) (see below).

The mechanism of the cyclisation sequence is currently under study but, in the case of (1b), cyclisation (using pyrrolidine) was readily monitored by ¹H NMR (CDCl₃) to give enone (2b) over the course of 1h. However, TLC analysis of the same reaction mixture showed that the transformation of (1b) (2b) to be essentially complete within minutes and clearly silica gel accelerates a key aspect of the process. This reagent may be involved in promoting the cyclisation step and/or the subsequent amine elimination although other potential acid catalysts did not have a significant impact on the rate of cyclisation.⁸

Addition of pyrrolidine to a CDCl₃ solution of ketoaldehyde (1f) showed complete conversion (as judged by ¹H NMR) to an intermediate which has been assigned as enamine (4) [_H 6.13 (1 H, d, J 12 Hz) and 4.86 (1 H, d, J 12 Hz)] (Scheme 2). However, no trace of (2f) was observed in this NMR experiment, even after 24h, but exposure of the solution of enamine (4) to silica gel resulted in rapid cyclisation to give the pyrrolo[1,2-c]pyrimidinone derivative (2f).

Scheme 2

We suggest that the cyclisation step is mediated via a Mannich-type iminium ion intermediate (corresponding to the protonated form of (4)) as the reacting electrophile, with the likely nucleophile being the C(2) enol form of the keto moiety.⁹ Analogous enamine/iminium ion intermediates derived from (1g) and (1h) may either rapidly tautomerise or be subject to facile cleavage in the presence of SiO₂; this provides a plausible explanation for our failure to observe cyclisation these two substrates; only decomposition products were seen.

In summary, amine-mediated intramolecular aldol reactions based on use of the pyrrolidin-3-one unit provides a very direct route to N-based bicycles incorporating a useful degree of functionality. The inherent preference for C(4) enolization of pyrrolidin-3-ones has been circumvented and, while the scope and mechanism of this reaction will continue to be developed, more effective reaction conditions for achieving the aldol cyclisation have now been identified.

Acknowledgements. We thank SB Pharmaceuticals for financial support.

References

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5. Garst, M. E.; Bonfiglio, J. N.; Grudoski, D. A.; Marks, J. J. Org. Chem. 1980, 45, 2307. For a solution to the problems associated with control of C(2) vs. C(4) regiochemistry in intermolecular aldol reactions of pyrrolidin-3-ones, see Thompson, S. H. J.; Subramanian, R. S.; Roberts, J. K.; Hadley, M. S.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1994, 933 and references therein.

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7. Ketoaldehydes (1a-e) were all obtained using the amide coupling procedure shown in Scheme 1. Ketoaldehyde (1f) was prepared via acylation of (3) using allyl isocyanate. Benzylation (BnBr, NaH) of the initial adduct (1g), prior to ketal hydrolysis and oxidative cleavage, provided the N-benzyl variant. Ketoaldehyde (1h) was prepared via acylation of (3) with allyl chloroformate. All new compounds gave satisfactory spectroscopic data and were characterised by elemental analysis and/or high resolution mass measurement.

8. A wide range of primary and tertiary amines and diamines have been examined, as well as amide, hydride and alkoxide bases in both protic and aprotic media. Likewise, Brønsted acids (TFA, TolSO₃H, dibenzylammonium trifluoroacetate) and Lewis acids (TiCl₄, LiClO₄) have, to date, failed to induce cyclisation.
   General experimental procedure: A solution of the ketoaldehyde (1) in CH₂Cl₂, CHCl₃ or THF was treated with pyrrolidine (up to 1 equivalent) and allowed to stand at r.t. for 1-8 hr. After this time, the reaction mixture was directly adsorbed onto silica gel (Merck 60H) and the product was eluted using EtOAc/petrol. Cyclisations involving TMP (1 equivalent) were carried out in CHCl₃ solution at reflux (1-4 hr). The reaction mixture was washed with 2M HCl prior to being adsorbed onto silica gel (Merck 60H).
   In the case of (1b) (2b), use of pyrrolidine in a catalytic quantity (10 mol%) is viable, but very slow reaction times make this unattractive at present.

9. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1. For an example of an -amino ketone undergoing an intermolecular amine-mediated aldol condensation, see Clemo, G. R.; Hoggarth., E. J. Chem. Soc. 1939, 1241. For a recent review of the intramolecular Mannich reaction see Overman, L. E.; Ricca, D. J. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991, vol. 2, p. 1007.

TABLE 1

Ketoaldehyde (1)	Cyclised Product(2)	Amine
(1a)	(2a)	TMP (68%) pyrrolidine (25%) piperidine (31%)
(1b)	(2b)	TMP (57%) pyrrolidine (42%) piperidine (33%)
(1c)	(2c)	pyrrolidine (63%)
(1d) n=1 (1e) n=2	(2d) No cyclisation observed with (1e)	TMP (68%) pyrrolidine (25%) piperidine (33%)
(1f) X=NBn	(2f)	TMP (40%) pyrrolidine (40%) piperidine (20%)
(1g) X=NH (1h) X=O	No cyclisation observed with (1g) or (1h)

Synthesis of Functionalised Azabicycles via a Regiospecific Intramolecular Aldol Reaction

Robert A. Stockman,^a Peter Szeto,^a Stephen H. J. Thompson,^a Michael S. Hadley,^b David C. Lathbury^c and Timothy Gallagher*^a

^b SB Pharmaceuticals, New Frontiers Science Park, Harlow CM19 5AD U.K.

^c SB Pharmaceuticals, Old Powder Mills, Tonbridge TN11 9AN U.K.

Synthesis of Functionalised Azabicycles via a Regiospecific Intramolecular Aldol Reaction. R. A. Stockman, P. Szeto, S. H. J. Thompson, M. S. Hadley, D. C. Lathbury and T. Gallagher Aldol cyclisation, azabicycles, indolizidines