Generation and reaction of alkene radical cations under nonoxidizing conditions: Synthesis of the pyrrolizidine nucleus

Article abstract of DOI:10.1021/ol015965h

(equation presented) Stable β-phosphatoxy nitroalkanes, readily assembled by the Henry reaction and subsequent phosphorylation, serve as good precursors to alkene radical cations on treatment with triphenyltin or tributyl hydride and AIBN in benzene at re

Full text of DOI:10.1021/ol015965h

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1917-1919
Generation and Reaction of Alkene
Radical Cations under Nonoxidizing
Conditions: Synthesis of the
Pyrrolizidine Nucleus
David Crich,* Krishnakumar Ranganathan, and Xianhai Huang
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received April 9, 2001
ABSTRACT
Stable â-phosphatoxy nitroalkanes, readily assembled by the Henry reaction and subsequent phosphorylation, serve as good precursors to
alkene radical cations on treatment with triphenyltin or tributyl hydride and AIBN in benzene at reflux. When the â-phosphatoxy nitroalkane
is suitably functionalized with nucleophilic groups, substitutions can be achieved with the formation of heterocyclic rings. When the nucleophile
is an allylamine, tandem processes occur giving pyrrolizidines.
Direct spectroscopic evidence for the fragmentation of â-aryl-
â-(phosphatoxy)alkyl radicals (1)1 into styrene radical cations
(3) in polar solvents has recently been provided. In nonpolar
solvents the same radicals are observed to undergo rear-
rangement to the benzylic radicals 2, but the linearity of plots
of log(k) for the fragmentation and/or rearrangement against
the ET(30) solvent polarity scale lead to the conclusion that
all such reactions of 1 have the same rate-determining step,
viz. radical ionic fragmentation to an alkene radical cation/
phosphate anion contact ion pair (CIP).2 In nonpolar solvents
the caged radical ion pair rapidly collapses to give the benzyl
radicals (2), whereas in more polar solvents it is in equilib-
rium with solvent separated ion pairs (SSIP) and, eventually,
observable free ions (Scheme 1).2 Subsequent experiments,
in which the diffusion-controlled oxidation of triarylamines
by alkene radical cations was used to probe the formation
of the latter, revealed that R-alkoxy-â-(phosphatoxy)radicals
behave in a comparable manner.3
Given that the initial radicals (1) may be generated from
a wide variety of precursors, it may be readily appreciated
that a new versatile source of alkene radical cations is at
hand. Such alkene radical cations have only previously been
Scheme 1. General Mechanistic Scheme for Fragmentation and
Rearrangement of â-(Phosphatoxy)alkyl Radicals
(1) Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yao, Q. Chem. ReV.
1997, 97, 3273.
(2) (a) Newcomb, M.; Horner, J. H.; Whitted, P. O.; Crich, D.; Huang,
X.; Yao, Q.; Zipse, H. J. Am. Chem. Soc. 1999, 121, 10685. (b) Whitted,
P. O.; Horner, J. H.; Newcomb, M.; Huang, X.; Crich, D. Org. Lett. 1999,
1, 153. (c) Bales, B. C.; Horner, J. H.; Huang, X.; Newcomb, M.; Crich,
D.; Greenberg, M. M. J. Am. Chem. Soc. 2001, 123, 3623.
10.1021/ol015965h CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/22/2001

accessible from alkenes under strongly oxidizing conditions,
which has limited practical applications of their colorful
chemistry.4 In a first demonstration of the potential of the
new method, we studied trapping by alcohols, both intra-
and intermolecularly, leading to the formation of tetrahy-
drofurans.5 We now describe our preliminary results on the
extension of this chemistry to a radical/ionic cascade
sequence involving intramolecular nucleophilic capture of
the radical cation by an allylamine followed by radical
cyclization leading, overall, to the formation of pyrrolizidines
(Scheme 2).
tetrahydrofuran 95b in 59% yield. This product arises from
regioselective trapping of the â,â-dimethylstyrene radical
cation by allyl alcohol and subsequent radical cyclization.5b
In a second proof of concept, benzaldehyde was condensed
with nitroethane and the resulting nitroaldol converted to the
THP derivative 10 in 99% overall yield. Stirring of 10 with
DBU and methyl acrylate in acetonitrile then afforded 11 in
80% yield. Removal of the THP group in the standard
manner and phosphorylation provided 12 in 63% yield, which
on saponification gave 13 quantitatively. When this substance
was exposed to triphenyltin hydride,11 with AIBN initiation
in benzene at reflux, the γ-lactone 14 was obtained in 90%
yield. In this chemistry the vicinal nitrophosphate serves as
the precursor to the alkene radical cation, which suffers
nucleophilic attack by the acid. The benzyl radical, formed
in the course of the cyclization, is quenched by the stannane.
This example serves to highlight the further significant
advantage of the use of the nitro group as radical precursor,
namely, the ease with which the substrates can be assembled
by simple condensations and alkylations using very well
known chemistry.
Scheme 2. Cascade Sequence for the Formation of
Pyrrolizidines from â-(Phosphatoxy)alkyl Radicals
In reducing Scheme 2 to practice, we were immediately
confronted by the need for a precursor to radical 4 compatible
with the presence of the nucleophilic amine. Evidently,
halides were not suitable, nor were Barton esters,6 which
would be likely to undergo lactamization. Phenyl sulfides
were considered insufficiently reactive toward stannyl radi-
cals7 to permit smooth chain propagation, and we have
generally found 2-phenylselenoalkyl phosphates to be un-
stable, with respect to alkene formation,8 unless formation
of an episeleninium ion is stereochemically prevented.9
Ultimately tertiary nitroalkanes were selected as the precur-
sors of choice, being readily accessible, electron withdrawing
and therefore likely to stabilize the benzylic phosphates, and
good radical precursors in tin hydride mediated chain
sequences.10 To test this idea, 8 was assembled by condensa-
tion of 2-nitropropane with benzaldehyde followed by
reaction with diphenyl chlorophosphate. As expected, it
was found to be stable in benzene at reflux, to silica gel
chromatography and, on reaction with allyl alcohol and
triphenyltin hydride11 in benzene at reflux, to afford the
A suitable precursor (19) to radical 4 was readily as-
sembled from 12 as outlined in Scheme 3. Treatment of 19
with triphenyltin hydride and AIBN in benzene at reflux
gave, after recycling of the tin hydride with sodium boro-
hydride12 and silica gel chromatography, four diastereomeric
Scheme 3. Preparation of Radical Precursor 19a
(3) Newcomb, M.; Miranda, N.; Huang, X.; Crich, D. J. Am. Chem. Soc.
2000, 122, 6128.
(4) (a) Mattay, J. Synthesis 1989, 233. (b) Hintz, S.; Heidbreder, A.;
Mattay, J. In Topics in Current Chemistry; Mattay, J., Ed.; Springer: Berlin,
1996; Vol. 177, p 77. (c) Schmittel, M.; Burghart, A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2550. (d) Bauld, N. L.; Bellville, D. J.; Harirchian, B.;
Lorenz, K. T.; Pabon, R. A.; Reynolds, D. W.; Wirth, D. D.; Chiou, H.-S.;
Marsh, B. K. Acc. Chem. Res. 1987, 20, 269. (e) Lewis, F. D. Acc. Chem.
Res. 1986, 19, 401.
(5) (a) Crich, D.; Huang, X.; Newcomb, M. Org. Lett. 1999, 1, 225. (b)
Crich, D.; Huang, X.; Newcomb, M. J. Org. Chem. 2000, 65, 523.
(6) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
a (a) (i) Allylamine, (ii) Boc2O; (b) LiAlH4; (c) Ph3P, I2,
imidazole; (d) (i) TsOH, (ii) (PhO)2POCl, DMAP; (e) tmsOTf,
lutidine.
1918
Org. Lett., Vol. 3, No. 12, 2001

pyrrolizidines (20a-d) in a combined yield of 85% and ratio
2.7:1.6:1:1 (Scheme 4). The general concept of Scheme 2
was therefore shown to be viable.
A further substrate (28) for cyclization was readily
prepared as outlined in Scheme 5 with the key feature again
Scheme 5. Preparation of Radical Precursor 28a
Scheme 4. Cyclization of 19
The four diastereomers were separated by careful chro-
matography and assigned the structures in Figure 1 on the
a (a) Allylamine; (b LiAlH4; (c) Boc2O; (d) PCC; (e) (i)
Me2CHNO2, KOBut, (ii) (PhO)2POCl, DMAP; (f) tmsOTf, lutidine.
being the rapid assembly by the Henry reaction with a simple
aldehyde and subsequent phosphorylation.
Treatment of 28 with tributyltin hydride11 and AIBN in
benzene at reflux led to a 75% isolated yield of the
pyrrolizidines 29 and 30 as a 1:1 mixture of two diastere-
oisomers (Scheme 6).
Figure 1. Products (20a-d) and corresponding transition states
(21a-d) for the cyclization of 19.
Scheme 6. Cyclization of 28
basis of extensive NOE studies. The two major isomers
(20a,b) have the phenyl group on the exo-surface of the
bicyclic system and differ in the relative configurations of
the two stereocenters formed in the final cyclization. As is
typical in 1-phenyl-5-hexenyl-type cyclizations,13 the major
isomer (20a) has the trans-configuration about the newly
formed bond. We propose therefore that the major isomer
arises from a boatlike transition state (21a) that is a
consequence of the preference of the phenyl group for the
exo-surface and of the nascent bond to be trans. The second
major product issues from the chairlike transistion state 21b,
whereas the two minor products are the result of chair- and
boatlike transition states with the phenyl group on the more
hindered endo-surface of the bicyclic system.
This last example serves to focus attention on two key
points. First, benzylic stabilization is not necessary in this
chemistry. Second, and very important in terms of synthetic
planning, the key radical cation intermediates may be entered
from both sides. More explicitly, the departing phosphate
may be displaced in either a cine fashion, as in Schemes 2
and 4, or directly as in Scheme 6.5b Further cascade type
polycyclizations of reductively generated alkene radical
cations are under investigation and will be reported on in
due course.
(7) Beckwith, A. L. J.; Pigou, P. E. Aust. J. Chem. 1986, 39, 77.
(8) (a) Filzen, G. F. Ph.D. Thesis, University of Illinois at Chicago, 1996.
(b) Huang, X. Ph.D. Thesis, University of Illinois at Chicago, 2000.
(9) Crich, D.; Yao, Q.; Filzen, G. F. J. Am. Chem. Soc. 1995, 117, 11455.
(10) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.;
Kaji, A. Tetrahedron 1985, 41, 4013.
Acknowledgment. We thank the NSF (CHE 9986200)
for support of this work.
Supporting Information Available: Description of ex-
perimental procedures and full characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) In this chemistry tributyl- and triphenyltin hydride may be used
interchangeably. Triphenyltin hydride has the obvious advantage of not
obscuring the upfield region of the 1H NMR spectrum, which facilitates
interpretation of spectra of crude reaction mixtures.
(12) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200.
(13) (a) Walling, C.; Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6064. (b)
Taber, D. F.; Wang, Y.; Pahutski, T. F. J. Org. Chem. 2000, 65, 3861.
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