Generation and trapping of alkene radical cations under nonoxidizing conditions: Formation of six-membered rings by exo- and endo-mode cyclizations

Article abstract of DOI:10.1021/ol026204x

(Matrix presented) It is demonstrated that alkene radical cations generated by the radical ionic fragmentation of β-(phosphatoxy)alkyl radicals undergo efficient nucleophilic capture by amines in either the 6-exo or 6-endo modes, leading to six-membered n

Full text of DOI:10.1021/ol026204x

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2573-2575
Generation and Trapping of Alkene
Radical Cations under Nonoxidizing
Conditions: Formation of Six-Membered
Rings by Exo- and Endo-Mode
Cyclizations
David Crich* and Santhosh Neelamkavil
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received May 17, 2002
ABSTRACT
It is demonstrated that alkene radical cations generated by the radical ionic fragmentation of â-(phosphatoxy)alkyl radicals undergo efficient
nucleophilic capture by amines in either the 6-exo or 6-endo modes, leading to six-membered nitrogen heterocycles. Suitable placement of an
alkene enables the juxtaposition of a radical cyclization resulting in the formation of both the indolizidine and 1-azabicyclo[3.2.1]octane skeleta.
â-(Phosphatoxy)alkyl radicals,1,2 generated from a variety
of sources, provide, by rapid radical-ionic fragmentation,3 a
convenient source of alkene radical cations under nonoxi-
dizing conditions.4 To date we have demonstrated how alkene
radical cations obtained in this manner may be trapped inter-
and intramolecularly by alcohols and amines leading to the
formation of carbon-oxygen and carbon-nitrogen bonds.5-8
The use of allyl alcohols and amines as nucleophiles permits
synthetically useful radical/polar crossover sequences in
which nucelophilic attack on the radical cation is followed
by radical cyclization,7,8 as exemplified by our entry into
the pyrrolizidine nucleus.8,9 In the more useful intramolecular
sequences we have so far limited ourselves to 5-exo processes
at the level of both the nucleophilic attack and the subsequent
radical cyclization. Here, we describe the extension of the
method to the formation of six-membered rings and, ad-
ditionally, show how even highly stabilized â-(phosphatoxy)-
alkyl radicals may be induced to undergo the radical ionic
fragmentation given the appropriate reaction conditions.
As in the earlier 5-exo/5-exo synthesis of the pyrrolizidine
nucleus,8 a number of factors combined to focus our attention
on the nitro group as the optimal radical precursor. First,
â-nitro alcohols, the immediate precursors to the phosphates,
are very readily assembled by the Henry reaction. Second,
the strongly electron-withdrawing nitro group effectively
prevents any detrimental solvolysis of the phosphate esters.
Third, tertiary nitroalkanes are convenient precursors to free
radicals in stannane-mediated systems.10 Scheme 1 sets out
(1) Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yao, Q. Chem. ReV.
1997, 97, 3273.
(2) Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2; p 188.
(3) Newcomb, M.; Horner, J. H.; Whitted, P. O.; Crich, D.; Huang, X.;
Yao, Q.; Zipse, H. J. Am. Chem. Soc. 1999, 121, 10685.
(4) For more classical entries into alkene radical cations under oxidizing
conditions see: Hintz, S.; Heidbreder, A.; Mattay, J. In Topics in Current
Chemistry; Mattay, J., Ed.: Springer: Berlin, 1996; Vol. 177, p 77;
Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2550.
(5) Crich, D.; Gastaldi, S. Tetrahedron Lett. 1998, 39, 9377.
(6) Crich, D.; Huang, X.; Newcomb, M. Org. Lett. 1999, 1, 225.
(7) Crich, D.; Huang, X.; Newcomb, M. J. Org. Chem. 2000, 65, 523.
(8) Crich, D.; Ranganathan, K.; Huang, X. Org. Lett. 2001, 3, 1917.
(9) The use of allyl alcohols in this manner was first employed as a
probe of mechanism: Giese, B.; Beyrich-Graf, X.; Burger, J.; Kesselheim,
C.; Senn, M.; Schafer, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1742.
10.1021/ol026204x CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/20/2002

Scheme 1. Preparation of Indolizidine Precursor 6
Scheme 3. Preparation of Precursors for 6-Endo Ring
Closures
the synthesis of a substrate for a 6-exo/5-exo tandem
nucleophilic/radical cyclization protocol whereas the cy-
clization itself is shown in Scheme 2.
introduction of a substituent at the proximal position of the
alkene radical cation.
Scheme 2. Formation of Indolizidines by a Tandem
Nucleophilic 6-Exo/Radical 5-Exo Cyclization Protocol
Scheme 4. Formation of a Piperidine by a Nucleophilic
6-Endo Cyclization of an Alkene Radical Cation
Aside from the successful high-yielding nature of the
tandem cyclization (Scheme 2), and the associated increase
in molecular complexity typically seen in sequenced reac-
tions, this approach to the indolizidine nucleus is noteworthy
for the rapid assembly of the very simple acyclic radical
cation precursor 6 from three readily available components:
δ-valerolactone, allylamine, and 2-nitropropane.
Cyclization of 18 under the same conditions resulted in
the formation of the 1-azabicyclo[3.2.1]octane 22 in 78%
yield along with 17% of 21 (Scheme 5). The bicyclic product
Having demonstrated the feasibility of the 6-exo nucleo-
philic trapping of the alkene radical cations, we turned our
attention to the 6-endo mode and the concomitant need to
suppress the competing 5-exo cyclization. We reasoned that
this might best be addressed through the use of steric
hindrance and so constructed the simple probe 17 as outlined
in Scheme 3. Again we stress the very straightforward
chemistry used to assemble this substrate and the availability
of the three key building blocks: angelicalactone, benzy-
lamine, and formaldehyde.
Scheme 5. Formation of the 1-Aza[3.2.1]bicyclooctane
Nucleus by a Tandem Nucleophilic 6-Endo/Radical 5-Exo
Cyclization
Treatment of 17 in benzene at reflux with tributyltin
hydride and AIBN provided the known N-benzylpiperidine
19 in 90% yield (Scheme 4). There was no evidence for the
formation of the known isomeric pyrrolizidine 20 in this
reaction. The 5-exo cyclization mode may therefore be
readily suppressed in favor of the 6-endo-mode through the
22 was isolated as an inseparable mixture of two stereoiso-
mers in the ratio of 2:1. It is noteworthy in this tandem
process that it is the radical cyclization11 which is responsible
for slight reduction in yield with respect to the prototype of
Scheme 4, and not the radical ionic fragmentation and 6-endo
(11) For a rare, related example of the cyclizations of a 3-allylcyclohexyl
type radical leading to the formation of the bicyclo[3.2.1]octane type
skeleton, see Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1982, 47, 4403.
(10) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.;
Kaji, A. Tetrahedron 1985, 41, 4013.
2574
Org. Lett., Vol. 4, No. 15, 2002

cyclization. The 1-azabicyclo[3.2.1]octane skeleton consti-
tutes the nucleus of the 5,11-methanomorphanthridine (mon-
tanine) class of the Amaryllidaceae alkaloids12 and of the
novel Lycopodium alkaloid lyconadin A.13 Moreover,
1-azabicyclo[3.2.1]octane derivatives have been found to be
potent muscarinic agonists with antipsycotic-like activity14
and to be dopamine transporter inhibitors.15,16 The basic
tandem cyclization set out in Scheme 5 therefore provides a
novel entry into a valuable class of molecules and has the
potential to provide access to new substitution patterns for
medicinal chemistry research.
Scheme 7. 6-Endo-Mode Cyclization Illustrating a Relatively
Unfavorable Radical Ionic Fragmentation
In the event attempted cyclization in benzene at reflux
failed and resulted only in the formation of 29, thereby
emphasizing the difficulty inherent in this particular frag-
mentation. However, when the reaction was conducted in a
mixture of benzene and acetonitrile at reflux the tetrahydro-
pyran 28 was obtained in a yield of 30%. Given the difficulty
of the fragmentation in this case, this result bodes well for
the further development of the general methodology.
Finally, the limits of the radical ionic fragmentation were
pushed through the synthesis (Scheme 6) and cyclization
Scheme 6. Preparation of the Tetrahydropyran Precursor 27
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.
OL026204X
(12) Martin, S. F. Alkaloids; Academic Press: New York, 1987; Vol.
30, p 251.
(13) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org. Chem.
2001, 66, 5901.
(Scheme 7) of a probe for the formation of tetrahydropyrans
via 6-endo-cyclization of an alcohol onto a proximally
substituted alkene radical cation. In this example the proximal
substituent driving the regioselectivity of the cyclization is
the phenyl ring which also provides a severe test for the
radical ionic fragmentation. In effect, the radical formed on
homolytic removal of the nitro group from 27 is a relatively
stable tertiary benzylic one and the C-O bond to be
heterolyzed a primary one. This cleavage is therefore the
most uphill of all the radical ionic fragmentations that we
have examined to date.
(14) Sauerberg, P.; Jeppesen, L.; Olesen, P. H.; Rasmussen, T.; Swedberg,
M. D. B.; Sheardown, M. J.; Fink-Jensen, A.; Thomsen, C.; Thørgersen,
H.; Rimvall, K.; Ward, J. S.; Calligaro, D. O.; DeLapp, N. W.; Bymaster,
F. P.; Shannon, H. E. J. Med. Chem. 1998, 41, 4378.
(15) Tamiz, A. P.; Smith, M. P.; Enyedy, I.; Flippen-Anderson, J.; Zhang,
M.; Johnson, K. M.; Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2000,
10, 1681.
(16) Indeed, Scifinder Scholar locates >2000 substances containing the
1-azabicyclo[3.2.1]octane nucleus with the majority in the medicinal and
patent literature, suggesting that this may be an example of a “privileged
structure”: Ariens, E. J.; Beld, A. J.; Rodriguez, de Miranda, J. F.; Simonis,
A. M. In The Receptors, A ComprehensiVe Treatise; O’Brien, R. D., Ed.;
Plenum Press: New York, 1979; p 33.
Org. Lett., Vol. 4, No. 15, 2002
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