The choice of the residues on the aldehyde, the structure
of allyl reagents, and the nucleophiles would build piper-
idines with substituents at C-2, C-3, and C-6. As these
heterocycles are present in several natural products and
have important roles in medicinal chemistry, simple gen-
eral synthetic approaches are desirable.5 In this paper, we
propose a new strategy, in line with this objective, based on
CHC reactions.
To prepare intermediates III (Scheme 1), the Barbier-
type allylation of N-alkylimines with allyl bromide and
indium in alcoholic medium6 was explored. (R)-Phenyl-
glycinol has been reported in this reaction as a useful chiral
auxiliary for the construction of optically active amines.7
Aldehydes 1ꢀ8 reacted with allylbromide 12 in the
presence of indium (9) and (R)-phenylglycinol (10) or
(1R,2S)-1-amino-2-indanol (11) in MeOH giving homo-
allyl alcohols 15ꢀ22 in good yields and stereoselectivity
(Table 1, entries 1ꢀ8). This result encouraged us to explore
the reaction with more synthetically useful bromides 13 or
14.8 In this case, the formation of only two of the four
possible diastereomers was observed. However, with (R)-
phenylglycinol (10) and aliphatic aldehydes, a good stereo-
selectivity was obtained wheras a 1:1 mixture was observed
with benzaldehyde (entry 10, compound 24). Using the
more hindered auxiliary 11 the expected product were
always formed with high stereoselectivity (entries 11ꢀ14
(25ꢀ28) in Table 1).9
After some experimentations, we were pleased to discover
that CHC occurred using Rh(CO)2acac in the presence of
biphephos (5 mol % of Rh catalyst, 1:5 ratio with the
phosphite) under H2/CO (8 bar) in THF at 70 °C (4ꢀ
12 h).9 This result is accounting for the capability of
biphephos to coordinately embrace Rh(I). Variations of
the reaction temperature or use of microwave dielectric
heating, in order to shorten the reaction time, did not
produce an improvement at all. The diastereoselectivity in
the CHC reaction was dependent from the nature of the
chiral auxiliary. With (R)-phenylglycinol, acceptable dr were
obtained exclusively when an aromatic fragment was present
at C-2 (compare entry 1 with entries 2ꢀ4 in Table 1) Better
results were again achieved when the (1R,2S)-1-amino-2-
indanol moiety was attached to the substrates. On products
23ꢀ28, derived from crotyl bromides 13 or 14, CHC oc-
curred with the same trend previously observed on 15ꢀ22. In
the case of CHC products derived from crotyl bromides 13
and 14, the relative stereochemistry was established through
the X-ray analysis of crystalline 39 (Figure 1).
Compounds 15ꢀ23 and 25ꢀ28, each bearing a terminal
alkene, were then submitted to hydroformylation using
syngas (H2/CO 1/1) in the presence of Rh(I). As the linear
aldehyde was desired in our initial specifications, a selec-
tion of the appropriate ligand for Rh(I) has to be made.
The domino hydroformylation cyclization on alkenes with
amino alcohol appendages has never been explored before,
as we2,3 and others1dꢀf have mostly described the reaction
on the corresponding amides passing through a reactive
acyliminium ion. Indeed, the present substrates 15ꢀ28,
encompassing heteroatoms (O or N), could possibly com-
pete as ligand for the metal during the hydroformylation.
Figure 1. X-ray structure of compound 39.
A cis relation between the hydrogens at C-1, C-2, and
C-10 was revealed, whereas at the ring junction, the
hydrogen at C-4a has a trans relationship in respect to
the ones at C-1 and C-2. In compound 39, NOE interac-
tions were found between H1ꢀH2 and H1ꢀH10, and
similar interactions could be found with compounds 38,
40, and 41 confirming that their respective stereochemis-
tries are similar to the one found in 39.
(4) Agami, C.; Couty, F; Evano, G Tetrahedron: Asymmetry 2000,
11, 4639–4643.
(5) Recent reviews on piperidine synthesis: (a) Cossy, J. Chem. Rec.
2005, 5, 70–80. (b) Escolano, C.; Amat, M.; Bosch, J. Chem.;Eur. J.
2006, 12, 8198–8207. (c) Kaellstroem, S.; Leino, R. Bioorg. Med. Chem.
2008, 16, 601–635. (d) De Risi, C.; Fanton, G.; Pollini, G. P.; Trapella,
C.; Valente, F.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19, 131–155.
(6) Valaivan, T.; Winotapan, C.; Bancphavichit, V.; Shinada, T.;
Ohfune, Y. J. Org. Chem. 2005, 70, 3464–3471.
Perhydro-oxazolopyridines obtained with this process
can be elaborated in different ways. Using hydrogenolysis
of the auxiliary in substrates 29 or 38, (S)-(þ)-coniine 42,
and 2,3-disubstituted piperidine 43 were obtained in good
yields (Scheme 2).
(7) Reviews: (a) Kargbo, R. B; Cook, G. R. Curr. Org. Chem. 2007,
11, 1287–1309. (b) Kouznetsov, V. V.; Mendez, L. Y. V. Synthesis 2008,
491–506. (c) Roy, U. K.; Roy, S. Chem. Rev. 2010, 110, 2472–2535.
Selected recent papers:(d) Jang, T. S.; Ku, I. W.; Jang, M. S.; Keum, G.;
Kang, S. B.; Chung, B. Y.; Kim, Y. Org. Lett. 2006, 8, 195–198. (e)
Black, D. A; Arndtsen, B. A. Org. Lett. 2006, 8, 1991–1993. (f) Babu,
S. A.; Yasuda, M.; Baba, A. Org. Lett. 2007, 9, 405–408. (g) Kim, S. H.;
Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1696–
1698. (h) Kim, S. H.; Kim, S. H.; Lee, K. Y; Kim, J. N. Tetrahedron Lett.
2009, 50, 5744–5747. (i) Delaye, P. O.; Pradhan, T. K.; Lambert, E.;
Vasse, J.-L.; Szymoniak, J. Eur. J. Org. Chem. 2010, 3395–3406. (j)
Thirupathi, P.; Kim, S. S. Tetrahedron. 2010, 66, 8623–8628.
(8) Valaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y. Tetrahe-
dron Lett. 2001, 42, 9073–9076.
Scheme 2
Alternatively, the oxazolidine ring can be opened with a
nucleophile in order to introduce an additional substituent
at C-6. When oxazolidines 35 or 36 were submitted to
(9) Allylation chemistry was carried out at rt (20 °C), as
lower temperatures decreased yields without improvements in
stereoselectivity.
Org. Lett., Vol. 13, No. 9, 2011
2295
Arena, Giada
