Preparation of highly substituted pyrrolidines via an organometallic dipole

Article abstract of DOI:10.1039/b605329g

Highly substituted pyrrolidines are prepared by formal cycloaddition of imines to a metal-stabilised 'Nicholas' dipole derived from an alkyne-cyclopropane dicobalt complex. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605329g

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Preparation of highly substituted pyrrolidines via an organometallic dipole†
Steven D. R. Christie,* Ryan J. Davoile and Raymond C. F. Jones*
Received 13th April 2006, Accepted 1st June 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b605329g
Highly substituted pyrrolidines are prepared by formal cy-
cloaddition of imines to a metal-stabilised ‘Nicholas’ dipole
derived from an alkyne–cyclopropane dicobalt complex.
The use of transition metal-promoted reactions of small rings
has been reported as the key step in a number of useful
transformations. Of particular relevance to this paper are vinyl
cyclopropanes, which have seen use as substrates for palladium-
mediated transformations in a number of different reactions.
Tsuji and coworkers’ original use of vinyl cyclopropanes in the
preparation of cyclopentane units1 has been followed by other
reactions with, for example, isocyanates.2 In related chemistry, Ma
=
Scheme 2 Reagents: (i) XCH CHCO2Me (X = H, CO2Me), Lewis acid;
and Jiao have recently reported the use of allenic cyclopropanes
in reaction with imines to produce pyrrolidines.3
(ii) H2C CHCHO, BF3·OEt2, CH2Cl2, 0 ◦C.
=
We recently reported the use of an organometallic dipole in a
formal cycloaddition to produce tetrahydrofurans.4 The metal–
alkyne cyclopropane 1 is unique in that it provides access to a
Nicholas carbocation5 through the novel cleavage of a carbon–
carbon sigma bond. The formal anionic terminus of the dipole
is stabilised by a malonate unit. We found that reaction of this
species under Lewis acid conditions with a series of aldehydes pro-
duced tetrahydrofuran products wherein the dicobalt alkyne unit
remained intact, Scheme 1. We now report an extension of this
methodology to the synthesis of other heterocyclic systems.6
propenoate was attempted in various solvents with a variety of
Lewis acids, including BF3·OEt2, TiCl4, SnCl4, AlCl3 and ZnBr2,
but none of these produced the desired carbocyclic product, and
only BF3·OEt2 and AlCl3 produced small amounts of the lactone
by-product 2 that we had noted previously, presumably from
intramolecular cyclisation. The other Lewis acids succeeded only
in decomposing the starting material. Initial studies with propenal,
in an attempt to find a more reactive substrate, showed that while
we could indeed gain access to the carbocycle 3, this was produced
in almost equal amounts with the corresponding tetrahydrofuran
4 (Scheme 2). Interestingly, the carbocycle showed a 2 : 1 ratio of
diastereoisomers, while the tetrahydrofuran was produced as a 1 :
1 mixture. Prompted by this tendency towards carbon–heteroatom
addition, we turned our attention to the reaction with imines.
We envisaged that reaction with imines would provide a short
and regiocontrolled access to pyrrolidines. Pyrrolidines remain a
ubiquitous building unit in organic chemistry, with application
in the pharmaceutical industry and are seen in numerous natural
products. Cycloadditions to generate pyrrolidines are well known,
but based almost exclusively on a CNC (azomethine ylide)
plus CC strategy,7 whereas our approach offers an alternative
CCC plus CN disconnection.8 A further intriguing aspect of this
chemistry is the use of a nitrogen nucleophile to quench the formal
propargylic carbocation. While the use of oxygen nucleophiles in
the Nicholas reaction is well documented,9 the analogous nitrogen-
based chemistry has not been examined to the same extent.10 This
work will thus both expand the scope of our new cycloaddition
and increase the utility of nitrogen in the Nicholas reaction. Imines
do not to date appear to have been reported as substrates in either
the Pd-mediated vinyl cyclopropane reactions, or cycloadditions
with donor–acceptor cyclopropanes.11
Scheme 1
The propensity of cyclopropane 1 towards carbon–heteroatom
cycloaddition was highlighted by the outcome of studies designed
to produce carbocycles. We initially anticipated that an electron-
deficient alkene could act as a Michael acceptor for the malonate,
with the resultant enolate cyclising on to the Nicholas carbocation,
Scheme 2. Thus, reaction with dimethyl maleate or methyl
Chemistry Department, Loughborough University, Loughborough, Leics,
LE11 3TU, UK. E-mail: S.D.Christie@lboro.ac.uk, R.C.F.Jones@lboro.
ac.uk; Fax: +44 1509 223926; Tel: +44 1509 222587 (S. D. R. Christie);
Tel: +44 1509 222557 (R. C. F. Jones)
Alkynyl cyclopropane complex 1 was readily prepared in four
steps from 1,4-dibromobut-2-ene and diethyl malonate as we
have described previously.4 The required imines were prepared
† Electronic supplementary information (ESI) available: Experimental
details for compounds 5a–e, 6. See DOI: 10.1039/b605329g
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1
they were measured from 1H NMR spectroscopy. In all cases
the identifications of the cis and trans isomers were consistent
with previous work.4 Variation in reaction temperature had no
predictable effect on yield or diastereoselectivity.
=
Table 1 Reaction of imines R CH NR with alkynylcyclopropane di-
cobalt complex 1
Product R1
R
T/◦C Yielda (%) trans:cis
In order to access the metal-free heterocycle, we have looked
briefly at the removal of the cobalt unit. As illustrated in Scheme 4,
reaction of one of the cycloaddition products 5c with ceric
ammonium nitrate (Et3N, acetone) cleanly oxidises the metal in
acceptable yield to afford the free alkynyl pyrrolidine 6 (60%; 1 : 1
trans : cis). This procedure could also be used in the work-up of the
cycloaddition reaction to allow access to the metal-free pyrrolidine
products in a two-step, one pot procedure.
5a
5b
5c
5d
5e
CO2Et
4-MeOC6H4
0
25
40
0
25
40
0
25
40
0
25
40
25
40
91
75
91
85
73
80
79
81
85
65
72
69
23
30
1:1
1:1
1:1
2:1
2:1
2:1
1:1
1:1
1:1
1:2
1:3
1:3
2:1
2:1
CO2Et
CO2Et
CO2Et
2,4-(MeO)2C6H3
4-MeC6H4
2-NCC6H4
2-O2NC6H4 C6H5
a Reaction time 10 h.
by standard condensation chemistry, treating the amine with
the aldehyde in diethyl ether at 25 ◦C over molecular sieves for
18 h. The imines were then used directly in the cycloaddition
with dicobalt complex 1 to produce pyrrolidines 5 (Scheme 3).
Optimisation studies revealed BF3·OEt2 as the Lewis acid of choice
from those investigated, and that at least two equivalents of Lewis
acid were required to produce pyrrolidines 5a–e in good yield
(Table 1) and to minimise the formation of the lactone 2, just as
we had observed earlier in the tetrahydrofuran synthesis.
Scheme 4 Reagents: (i) (NH4)2Ce(NO3)6, Et3N, Me2CO.
We have thus demonstrated a novel formal cycloaddition to
produce functionalised pyrrolidines via a CCC/CN strategy. Work
is continuing with the alkynyl cyclopropane complex 1 to further
explore its utility in ring-forming reactions. We acknowledge the
support of the EPSRC (studentship to R. J. D.).
Notes and references
1 J. Tsuji, I. Shimizu and Y. Ohashi, Tetrahedron Lett., 1985, 26, 3825–
3828.
2 K. Yamamoto, T. Ishida and J. Tsuji, Chem. Lett., 1987, 1157–
1158.
1
=
Scheme 3 Reagents: (i) R CH NR, BF3·OEt2, CH2Cl2.
3 S. M. Ma and N. Jiao, Angew. Chem., Int. Ed., 2002, 41, 4737–4740.
4 S. D. R. Christie, R. J. Davoile, M. R. J. Elsegood, R. Fryatt, R. C. F.
Jones and G. J. Pritchard, Chem. Commun., 2004, 2474–2475.
5 K. M. Nicholas and R. Pettit, Tetrahedron Lett., 1971, 12, 3474–3477.
6 For related studies with nitrone dipolarophiles (‘homo[3 + 2]dipolar
cycloaddition’), see: T. P. Lebold, C. A. Carson and M. A. Kerr, Synlett,
2006, 364–368, and references. therein.
7 See for example: L. M. Harwood and R. J. Vickers, in Synthetic Applica-
tions of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products, ed. A. Padwa and W. H. Pearson, Wiley-Interscience,
Hoboken, 2003, pp. 169–252.
In general, yields were good to excellent when an electron-
withdrawing group was present on the imine carbon and an
electron-donating group was present on the nitrogen atom, for
example, in the preparation of 5a–c, where the imine was a
glyoxal derivative of aromatic amines carrying electron-donating
substituents. This would be consistent with ring-opening of the
vinyl cyclopropane to give the formal Nicholas cation/malonate
anion dipole; attack of the malonate nucleophile onto the imine
carbon atom is followed by cyclisation of the amide anion onto
the Nicholas carbocation.12
8 For the transformation of homo[3 + 2]dipolar cycloadducts (ref. 6) into
pyrrolidines, see: I. S. Young, J. L. Williams and M. A. Kerr, Org. Lett.,
2005, 7, 953–955.
Placing an ortho-substituted aryl group on either position gave
an increase in the 2,5-diastereoselectivity in the new pyrrolidine
ring. For pyrrolidine 5d, the ortho-nitrile group gave a maximum
of a 3 : 1 ratio in favour of the cis isomer. In contrast, having an
ortho-nitro group in the aryl group of the imine carbon substituent
gave a 2 : 1 ratio in favour of the trans isomer of pyrrolidine
5e, but in a reduced yield. It is unclear at this point whether
this is due to steric interactions. The diastereoselectivities were
measured directly when the isomers were separable, otherwise
9 See for example: S. D. R. Christie, R. J. Davoile and R. C. F. Jones,
Tetrahedron Lett., 2002, 43, 7167–7170, and references therein.
10 For recent reviews of the Nicholas reaction, see: B. J. Teobald,
Tetrahedron, 2002, 58, 4133–4170; J. R. Green, Curr. Org. Chem., 2001,
5, 809–826.
11 For recent reviews of the chemistry of donor–acceptor cyclopropanes,
see: M. Yu and B. L. Pagenkopf, Tetrahedron, 2005, 61, 321–
347; H.-U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151–
1196.
12 For an alternative mechanistic speculation in the case of homo[3 +
2]dipolar cycloaddition, see ref. 6.
2684 | Org. Biomol. Chem., 2006, 4, 2683–2684
This journal is
The Royal Society of Chemistry 2006
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