Tandem polar/radical crossover sequences for the formation of fused and bridged bicyclic nitrogen heterocycles involving radical ionic chain reactions, and alkene radical cation intermediates, performed under reducing conditions: Scope and limitations

Article abstract of DOI:10.1021/ja035639s

It is demonstrated that phosphorylated forms of β-nitro alcohols provide an excellent means of entry into β-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux. These radicals then undergo heterolytic cleavage of t

Full text of DOI:10.1021/ja035639s

Published on Web 06/10/2003
Tandem Polar/Radical Crossover Sequences for the
Formation of Fused and Bridged Bicyclic Nitrogen
Heterocycles Involving Radical Ionic Chain Reactions, and
Alkene Radical Cation Intermediates, Performed under
Reducing Conditions: Scope and Limitations
David Crich,* Krishnakumar Ranganathan, Santhosh Neelamkavil, and
Xianhai Huang
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received April 15, 2003; E-mail: dcrich@uic.edu
Abstract: It is demonstrated that phosphorylated forms of â-nitro alcohols provide an excellent means of
entry into â-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux.
These radicals then undergo heterolytic cleavage of the phosphate group to yield alkene radical cation/
phosphate anion contact ion pairs which are trapped intramolecularly in a tandem polar/radical crossover
sequence involving radical ionic chain reactions by allylic and propargylic amines. The substitution pattern
of the alkene radical cation dictates the cyclization mode, and this may be engineered to form fused ring
systems by an initial exo-mode nucleophilic cyclization or bridged bicyclic systems when the nucleophilic
attack takes place in the endo-mode.
Scheme 1. Resonance Stabilization in Alkene Radical Cations
Introduction
Tandem sequences offer some of the most powerful and direct
approaches to complex molecular frameworks;1 they have the
potential to be especially so when two normally orthogonal
modes of reactivity can be combined into one sequence. Murphy
has called one set of such sequences tandem radical/polar
crossover reactions and has demonstrated their utility in a
number of concise alkaloid syntheses.2 Alkene radical cations,
delocalized, positively charged, open-shell intermediates (Scheme
1), are ideal triggers for tandem polar/radical crossover se-
quences, but this aspect of their chemistry has rarely been
exploited, with the majority of preparative sequences focusing
on their potential in cycloaddition reactions.3 One reason for
the apparent exclusivity of polar/radical crossover sequences
and alkene radical cations arises from the oxidizing conditions
hitherto required to generate the open-shell intermediate. Thus,
nucleophilic attack on the alkene radical cation generates the
radical required for the tandem sequence, but under oxidizing
conditions this is typically converted to the corresponding cation
before it may be used to advantage in any radical process.4 The
general underexploitation of alkene radical cations in synthesis,
when compared to radicals themselves, can also be attributed
Scheme 2. Fragmentation of the â-Acetoxy-R-methoxyethyl
Radical in Water
in large part to the oxidizing conditions required for their
generation from alkenes. In effect, the alkene precursor to the
radical cation must be the HOMO of the substrate which clearly
limits the range of compatible nucleophiles.
An alternative, nonoxidative means of generating alkene
radical cations would clearly offer many advantages, including
the potential to engineer tandem polar/radical crossover se-
quences which are the subject of this Article. The possibility
of such an entry to alkene radical cations was first recognized
by Gilbert and Norman, who suggested that the transformation
of radical 1 to 2 in aqueous acid was best explained by an initial
fragmentation to an alkene radical cation and an acetate anion
followed by trapping with water (Scheme 2).5
(1) (a) Malacria, M. Chem. ReV. 1996, 96, 289. (b) Ryu, I.; Sonoda, N.; Curran,
D. P. Chem. ReV. 1996, 96, 177.
Subsequently, it was recognized that a similar fragmentation
could be used to rationalize the cleavage of DNA, by expulsion
(2) (a) Bashir, N.; Patro, B.; Murphy, J. A. AdV. Free Radical Chem. 1999, 2,
123. (b) Murphy, J. A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, p 298.
(3) (a) Hintz, S.; Heidbreder, A.; Mattay, J. In Topics in Current Chemistry;
Mattay, J., Ed.; Springer: Berlin, 1996; Vol. 177, p 77. (b) 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,
371. (c) Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 2550.
(4) Of course, it is certainly possible to take advantage of this second oxidation
as illustrated by Moeller’s recent synthesis of nemorensic acid: Liu, B.;
Duan, S.; Sutterer, A. C.; Moeller, K. D. J. Am. Chem. Soc. 2002, 124,
10101.
(5) Gilbert, B. C.; Larkin, J. P.; Norman, R. O. C. J. Chem. Soc., Perkin Trans.
2 1972, 794.
9
7942
J. AM. CHEM. SOC. 2003, 125, 7942-7947
10.1021/ja035639s CCC: $25.00 © 2003 American Chemical Society

Tandem Polar/Radical Crossover Sequences
A R T I C L E S
Scheme 3. General Mechanism Relating the â-(Phosphatoxy)alkyl
Radical and Alkene Radical Cations
successful implementation of this general scheme in the
formation of a number of fused and bicyclic heterocyclic amines.
Results and Discussion
In the planning of radical chain reactions, knowledge of the
kinetics of the individual steps and of their competitors is
extremely advantageous.13 The same will evidently be true in
the design of radical ionic chain reactions, and, accordingly,
we open this discussion with a consideration of the relevant,
available data. The rate constants of immediate interest are those
concerning the (i) fragmentation of â-(phosphatoxy)alkyl radi-
cals to alkene radical cations,7,8,14 (ii) addition of nucleophiles
to alkene radical cations,7b,14c,15 and (iii) recombination within
contact ion pairs, that is, the competing rearrangement reac-
tions.7,8,16 The situation, however, is complex, with different
kinetic methods often yielding disparate results because of their
probing the radical cation at different stages of solvation.17
Nevertheless, it is evident from the available literature that
fragmentations are accelerated in more polar solvents and that
nucleophilic attack patterns reflect those of closed-shell systems.
Initial experiments with allyl alcohol as an intermolecular
nucleophile trapping a fragmentation generated â,â-dimethyl-
styrene radical cation/diphenyl phosphate anion pair revealed
that high concentrations of the nucleophile were required to out
compete recombination leading to the rearrangement prod-
uct.18,19 We therefore focused on the considerably more nu-
cleophilic allylamines20 and targeted intramolecular systems as
these typically permit the assembly of more complex systems.
In designing the desired sequences, we determined that a
suitable radical precursor compatible with the presence of a
nucleophile was required. The radical precursor must further-
more be consistent with, and preferentially stabilize, the adjacent
leaving group. In an earlier tandem system with a built-in alcohol
as a nucleophile, we overcame this problem by employing a
C-H bond as a radical precursor and by making double usage
of the oxygen, first as an alkoxyl radical to bring about 1,5-
hydrogen abstraction, thereby generating desired radical, and,
of a 3′-O-phosphate, following hydrogen atom abstraction from
the C4′ under conditions of ionizing radiation.6 In the intervening
years, much indirect evidence has been advanced in support of
the radical ionic fragmentation of radicals with good leaving
groups â- to the radical7 culminating in the direct observation
of certain radical cations by the time-resolved laser flash
photolysis technique in polar solvents.8,9 Strong kinetic evidence
has been advanced that supports the intermediacy of alkene
radical cations in the rearrangements of â-(phosphatoxy)alkyl8,10
and, probably, â-(acyloxy)alkyl radicals8,10d,11 even in nonpolar
media such as benzene. A model has been put forward to unify
all of the various rearrangement and fragmentation reactions of
â-(phosphatoxy)alkyl and related radicals in which the first step
is radical ionic fragmentation to an alkene radical cation/anion
contact ion pair (Scheme 3).8b,12 The subsequent evolution of
this contact ion pair to either fragmentation or rearrangement
products, or indeed back to the starting radical, is a function of
substituent and solvent which leaves considerable room for the
synthetic chemist to maneuver. Indeed, this model underpins
all of our current thinking in the area, including the design of
the systems presented below.
On the basis of the above analysis, we have designed a
number of systems in which a built-in allylamine traps an alkene
radical cation, generated by the fragmentation approach, with
the formation of a first ring. In the second leg of this tandem
polar/radical crossover sequence, a radical cyclization closes
the final ring. This is followed by hydrogen abstraction from a
stannane which completes the product formation and regenerates
a stannyl radical. The complete sequence may therefore be
termed a radical ionic chain reaction. We describe here the
(13) (a) Ingold, K. U.; Griller, D. Acc. Chem. Res. 1980, 13, 317. (b) Newcomb,
M. Tetrahedron 1993, 49, 1151. (c) Newcomb, M. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, p 317.
(14) (a) Koltzenburg, G.; Behrens, G.; Schulte-Frohlinde, D. J. Am. Chem. Soc.
1982, 104, 7311. (b) Cozens, F. L.; O’Neill, M.; Bogdanova, R.; Schepp,
N. J. Am. Chem. Soc. 1997, 119, 10652. (c) Horner, J. H.; Taxil, E.;
Newcomb, M. J. Am. Chem. Soc. 2002, 124, 5402.
(15) (a) Johnston, L. J.; Schepp, N. P. J. Am. Chem. Soc. 1993, 115, 6564. (b)
Johnston, L. J.; Schepp, N. P. Pure Appl. Chem. 1995, 67, 71. (c) Johnston,
L. J.; Schepp, N. P. AdV. Electron-Transfer Chem. 1996, 5, 41.
(16) (a) Crich, D.; Jiao, X.-Y. J. Am. Chem. Soc. 1996, 118, 6666. (b) Choi,
S.-Y.; Crich, D.; Horner, J. H.; Huang, X.; Newcomb, M.; Whitted, P. O.
Tetrahedron 1999, 59, 3317.
(17) For example, time-resolved LFP studies of alkene radical cations generated
according to Scheme 3 using a nanosecond laser only detect the diffusively
free radical cation and so are unable to provide data on the rates of formation
of contact ion pairs or of their trapping. This situation arises because
diffusion out of the contact ion pair is expected to be faster than the
nanosecond time scale of the instrument: Arnold, B. R.; Noukakis, D.;
Farid, S.; Goodman, J. L.; Gould, I. R. J. Am. Chem. Soc. 1995, 117, 4399.
For a discussion, see ref 14c.
(6) (a) von Sonntag, C. The Chemical Basis of Radiation Biology; Taylor and
Francis: London, 1987. (b) von Sonntag, C.; Hagen, U.; Schon-Bopp, A.;
Schulte-Frohlinde, D. In AdVances in Radiation Biology; Lett, J. T., Adler,
H., Eds.; Academic Press: New York, 1981; Vol. 9, p 109.
(7) (a) Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yao, Q. Chem. ReV. 1997,
97, 3273. (b) Gugger, A.; Batra, R.; Rzadek, P.; Rist, G.; Giese, B. J. Am.
Chem. Soc. 1997, 119, 8740.
(8) (a) Whitted, P. O.; Horner, J. H.; Newcomb, M.; Huang, X.; Crich, D.
Org. Lett. 1999, 1, 153. (b) Newcomb, M.; Horner, J. H.; Whitted, P. O.;
Crich, D.; Huang, X.; Yao, Q.; Zipse, H. J. Am. Chem. Soc. 1999, 121,
10685.
(9) The highly delocalized alkene radical cation of 1,1-dimethoxyethene could
be observed directly by ESR spectroscopy following generation by a
fragmentation approach: Behrens, G.; Bothe, E.; Koltzenberg, G.; Schulte-
Frohlinde, D. J. Chem. Soc., Perkin Trans. 2 1980, 883.
(10) (a) Crich, D.; Yao, Q. J. Am. Chem. Soc. 1993, 115, 1165. (b) Crich, D.;
Yao, Q.; Filzen, G. F. J. Am. Chem. Soc. 1995, 117, 11455. (c) Koch, A.;
Lamberth, C.; Wetterich, F.; Giese, B. J. Org. Chem. 1993, 58, 1083. (d)
Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 2, p 188.
(11) (a) Surzur, J.-M.; Teissier, P. C. R. Acad. Sci. Fr. Ser. C 1967, 264, 1981.
(b) Tanner, D. D.; Law, F. C. J. Am. Chem. Soc. 1969, 91, 7535.
(12) A closely related scheme was also advanced earlier by Sprecher: Sprecher,
M. Chemtracts: Org. Chem. 1994, 7, 115.
(18) This is not surprising given that the bimolecular rate constant for the addition
of methanol to the â,â-dimethylstyrene radical cation is only 2 × 105 M-1
s-1 (at 20 °C in trifluoroethanol),15a whereas the unimolecular rate constant
for â-(phosphatoxy)alkyl rearrangement of the â-(diphenylphosphatoxy)-
â-phenyl-R,R-dimethyl radical, that is, the rearrangement proceeding via
the same contact ion pair, is 1.2 × 106 s-1 in benzene and 1.8 × 107 s-1
in acetonitrile (both at 20 °C).16b
(19) For the use of allyl alcohol as a probe for alkene radical cations, see: Giese,
B.; Beyrich-Graf, X.; Burger, J.; Kesselheim, C.; Senn, M.; Schafer, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1742.
(20) The bimolecular rate constant for the addition of butylamine to the
p-methoxystyrene radical cation in acetonitrile at 20 °C is much faster at
2.1 × 109 M-1 s-1 15b
.
9
J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7943

A R T I C L E S
Crich et al.
Scheme 4. Intermolecular Formation of a Tetrahydrofuran
Figure 1. Transition states for the formation of 16.
Scheme 5. Cyclization Leading to a γ-Lactone
Scheme 6. Precursor Synthesis for a cine-exo/exo-Mode Tandem
Cyclization
second, as a nucleophile to capture the ensuing alkene radical
cation. A parallel scheme with a nitrogen nucleophile would
make use of hydrogen atom abstraction by an aminium radical
cation as, in the Hoffmann-Loeffler-Freytag reaction, unfor-
tunately this leaves the amine in the form of an ammonium salt
and, so, incapable of taking part in a subsequent nucleophilic
reaction step.21 A suitable solution to the problem was found
in the shape of nitroalkanes which react nicely with stannyl
radicals, especially when tertiary.22 The use of a nitro group as
a radical precursor additionally permits the rapid assembly of
â-nitro alcohols by the Henry reaction, and the strongly electron-
withdrawing nature of the nitro group stabilizes the â-nitro-
phosphates by retarding any premature solvolysis. In a test case,
2-nitropropane was condensed with benzaldehyde, and the
product converted to the diphenyl phosphate 3, which was stable
to silica gel chromatography. On treatment with tributyltin
hydride23 in 3:1 mixture of benzene and allyl alcohol at reflux,
smooth conversion to a 1/10 trans/cis-mixture of 2,2,4-trimethyl-
3-phenyltetrahydrofuran (4) was observed (Scheme 4), and it
is apparent that the system generates the same alkene radical
cation as was obtained previously by the decarboxylative
approach.24,25
from the nitronate. Treatment of the acid 9 with triphenyltin
hydride and AIBN in benzene at reflux led to the isolation of
the γ-lactone 10 in 90% yield by a process involving radical
generation, fragmentation to the alkene radical cation, capture
by the acid, and chain transfer with the stannane (Scheme 5).
An initial substrate for a tandem cyclization was prepared as
outlined in Scheme 6, starting from the alcohol 11, which was
accessed by lithium aluminum hydride reduction of 8.
Treatment of 15 with triphenyltin hydride and AIBN in
benzene at reflux resulted in the formation of the pyrrolizidine
16 as a mixture of four diastereomers in the ratio of 2.7:1.6:1:1
and 85% overall yield (Table 1). After separation, the stereo-
chemistry of the various isomers was assigned, as designated
in Figure 1, by extensive NOE studies. The two major isomers
(16a, 16b) 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 radical cyclization. As is
typical in 5-hexenyl type cyclizations of benzylic radicals,26 and
indeed as is seen in the formation of 4 (Scheme 4), the major
isomer has the trans-configuration about the newly formed C-C
bond. We propose therefore that the major isomer arises from
a boatlike transition state (17a) that is a consequence of the
preference of the phenyl group for the exo-surface and of the
nascent C-C bond to be trans. The second major product arises
from the chairlike transition state (17b), whereas the two minor
products are the result of chair- and boatlike transition states
with the phenyl on the more hindered endo-surface of the
bicyclic system.
An intramolecular test involved the synthesis of the phos-
phorylated nitro acid 9, as set out in Scheme 5, now taking
advantage of the ability of nitronate anions to participate in
conjugate additions. Especially noteworthy here is the predomi-
nance of the Michael addition over any competing â-elimination
(21) Neutral aminyl radicals are insufficiently electrophilic to achieve rapid
intramolecular hydrogen abstraction: Musa, O. M.; Horner, J. H.; Shahin,
H.; Newcomb, M. J. Am. Chem. Soc. 1996, 118, 3862.
(22) (a) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.; Kaji,
A. Tetrahedron 1985, 41, 4013. (b) Ono, N. The Nitro Group in Organic
Synthesis; Wiley-VCH: New York, 2001.
(23) In this chemistry, tributyl- and triphenyltin hydride may be used inter-
changeably. 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.
The formation of 16 may be viewed as a 5-exo-mode
nucleophilic attack on the alkene radical cation derived from
15 followed by a 5-exo-radical cyclization, and we therefore
categorize it as a 5-exo/5-exo tandem cyclization. We further
denote this cyclization as having occurred with an effective cine-
(24) Crich, D.; Huang, X.; Newcomb, M. J. Org. Chem. 2000, 65, 523.
(25) For preliminary communications, see: (a) Crich, D.; Ranganathan, K.;
Huang, X. Org. Lett. 2001, 3, 1917. (b) Crich, D.; Neelamkavil, S. Org.
Lett. 2002, 4, 2573.
(26) (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. (c) Miranda,
L. D.; Zard, S. Z. Chemm Commun. 2001, 1068.
9
7944 J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003

Tandem Polar/Radical Crossover Sequences
A R T I C L E S
Table 1. Tandem Reactions for the Formation of Fused and Bicyclic Heterocycles
a Overall displacement of the phosphate leaving group by the nucleophile. b Nucleophilic attack/radical cyclization. c Bonds formed by the nucleophilic
attack are in bold blue, and those achieved by radical cyclization are in bold red. d No cyclization was observed.
substitution of the phosphate group.27 The delocalized nature
of the intermediate alkene radical cation in these cyclizations
(Scheme 1) suggests reactions may be set up with either overall
cine- or ipso-substitution of the original leaving group; indeed,
this was demonstrated to be the case in our earlier work on
capture with allyl alcohol.24 In pursuing tandem cyclizations
beyond the formation of 16 from 15, we have generally found
it more convenient and straightforward to prepare substrates for
the ipso-mode. Scheme 7 sets out very straightforward protocols
(27) It should be noted that Zipse has considered substitutions closely related
to the ones employed here as concerted displacements accelerated by the
adjacent radical rather than as dissociative mechanisms. The balance of
the experimental evidence, however, favors the dissociative pathway, and
the computations continue to move in this direction with each successive
cycle of refinement: Zipse, H. Acc. Chem. Res. 1999, 32, 571.
9
J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7945

A R T I C L E S
Crich et al.
Scheme 7. Precursor Synthesis for ipso-exo/exo-Mode Tandem
Cyclizations Leading to Pyrrolizidine and Indolizidine Skeletons
Scheme 8. Precursor Synthesis for ipso-endo/exo-Mode Tandem
Cyclizations Leading to Bridged Systems
for the preparation of 28 and 29, precursors to pyrrolizidine
and indolizidine skeletons by 5-exo/5-exo and 6-exo/5-exo
sequences, respectively, both of which employ the overall ipso-
substitution. The cyclizations of 28 and 29 both proceed in good
yield (Table 1) and result in the formation of approximately
1:1 mixtures of diastereoisomers.
By adjusting the substitution pattern on the alkene radical
cation, it was thought possible to divert the initial nucleophilic
cyclization to an endo-, rather than the hitherto employed exo-,
mode. A test case for a 6-endo cyclization (44) was obtained
from angelica lactone and benzylamine, as set out in Scheme
8. On heating to reflux in benzene with tributyltin hydride and
AIBN, the piperidine 47 was obtained in 90% yield by the
anticipated ipso-6-endo-process. It is instructive to compare the
cyclizations of 15 and 44: both involve alkene radical cations
doubly substituted at the proximal position; yet the nucleophilic
attack in the first example takes place in the exo-mode, whereas
in the latter case the endo-mode is highly favored. In the case
of 15, it appears that the regioselectivity is determined by a
combination of the trisubstituted nature of the alkene radical
cation, which serves to retard the endo-mode attack, and the
benzylic nature of the radical formed. Encouraged by the
successful formation of the piperidine 47 from 44, we obtained
two substrates for tandem cyclization (45 and 46) by similar
routes (Scheme 8). The first of these provided the 1-aza-[3.2.1]-
bicyclooctane system 48 in good yield together with a minor
amount of the piperidine 49 (Table 1) when exposed to the usual
cyclization conditions. It is noteworthy that the slightly reduced
yield in the formation of 48 is due to the follow-up radical
cyclization, not to the initial nucleophilic attack.28 This is readily
understood in terms of the transition state for the radical
cyclization which requires the allyl group to adopt a pseudoaxial
position. The more interesting cyclization, though, is obviously
that of 46 which leads to the formation of the 1-aza[4.2.1]-
bicyclononane skeleton 50 by means of a 7-endo nucleophilic
cyclization followed up by the usual 5-exo radical ring closure:
the slightly reduced yield here obviously reflects the slower
nature of the 7-endo cyclization. Both bicyclic sys-
tems (48 and 50) were formed as approximately 2:1 mixtures
of diastereomers in the final radical step which remain unas-
signed because of difficulties in separation and the complexity
of the spectra. The 1-azabicyclo[3.2.1]octane skeleton constitutes
the nucleus of the 5,11-methanomorphanthridine (montanine)
class of the Amaryllidaceae alkaloids29 and of the novel
Lycpodium alkaoid lyconadin A.30 Moreover, 1-azabicyclo-
[3.2.1]octane derivatives have been found to be potent musca-
rinic agonists with antipsycotic-like activity31 and to be dopam-
ine transporter inhibitors.32,33 The 1-azabicyclo[4.2.1]nonane
skeleton constitutes the nucleus of the Iboga alkaloids such as
catharanthine.34 Additionally, certain medicinally useful vin-
blastine-type (vincorine) alkaloids also embody this skeleton.35
The basic tandem cyclizations of 45 and 46 (Table 1) coupled
with their ready preparation therefore provide novel entries into
valuable classes of molecules with the potential to afford new
substitution patterns for medicinal chemistry research.
(29) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego,
1987; Vol. 30, p 252.
(30) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Am. Chem. Soc.
2001, 123, 5901.
(31) Sauerberg, P.; Jeppesen, L.; Olesen, P. H.; Rasmussen, T.; Swedberg, M.
D. B.; Sheardown, M. J.; Fink-Jensen, A.; Thomsen, C.; Thogersen, H.;
Rimvall, K.; Ward, J. S.; Calligaro, D. O.; Delapp, N. W.; Bymaster, F.
P.; Shannon, H. E. J. Med. Chem. 1998, 41, 4378.
(32) 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.
(33) 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”: (a) Ariens, E. J.; Beld, A. J.; Rodrigues de Miranda, J. F.;
Simonis, A. M. In The Receptors: A ComprehensiVe Treatise; O’Brien,
R. D., Ed.; Plenum: New York, 1979; Vol. 1, pp 33. (b) Evans, B. E.;
Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W.
L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J.
P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(28) For a related, rare, example of the cyclization of a 3-allylcyclohexyl 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.
(34) Popik, P.; Skolnick, P. Alkaloids 1999, 52, 197.
(35) Atta-Ur-Rahman; Iqbal, I.; Nasir, H. Stud. Nat. Prod. Chem. 1994, 14, 805.
9
7946 J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003

Tandem Polar/Radical Crossover Sequences
A R T I C L E S
Scheme 10. Possible Cleavage Modes of a 4-Aminoalkene
Scheme 9. Precursor Synthesis for ipso-endo/exo-dig-Mode
Tandem Cyclizations
Radical Cation
Scheme 11. Synthesis of a Tetrahydropyran Precursor
With a view for retaining more functionality in the tandem
products, a sequence terminating in a 5-exo-dig radical cycliza-
tion was also pursued. The substrate (61) for this reaction, while
potentially available by an obvious minor variation in Scheme
7, was obtained from commercially available 4-aminobutyral-
dehyde diethylacetal as shown in Scheme 9. In this instance
(Table 1), the product (63) was obtained as a 5.7/1 E:Z mixture
of isomers, assigned by NOE measurements, with the major
E-isomer arising with approach of the stannane to the more
exposed side of the rapidly inverting vinyl radical.36
A final substrate (62), intended to probe the limits of the
system, was also obtained by the general pathway of Scheme
9. Unfortunately, when this compound was subjected to the stan-
dard cyclization conditions, a complex mixture was obtained
from which no cyclized products, neither 4-exo/5-exo nor any
other possible regioisomers, could be isolated (Table 1). We
believe this failure to be the result of the slower nature of the
4-exo cyclization coupled with the possibility of C-C bond
cleavage in the intermediate alkene radical cation (Scheme
10).3c,37
As a final test of the nucleophilic trapping of fragmentation
generated alkene radical cations, we prepared substrate 68 as
shown in Scheme 11. Radical ionic fragmentation of this system
would clearly push the limits as it involves fragmentation of
strong, primary C-O by a stabilized, tertiary benzylic radical.
In the event, in benzene, no cyclization was observed,
suggesting either no fragmentation or an equilibrium between
the contact ion pair and the initial radical that favored the latter
to such an extent that ring closure on the radical cation by the
weakly nucleophilic alcohol was not kinetically competent. To
overcome this, we conducted the reaction in a 1:1 mixture of
benzene and acetonitrile and were rewarded by the isolation of
30% of the cyclized product 69 (Scheme 12). This dramatic
Scheme 12. Formation of a Tetrahydropyran
solvent effect can obviously be understood in terms of stabiliza-
tion of the contact ion pair in the more polar solvent, thereby
bringing about a shift in the initial equilibrium which enables
capture of the contact ion pair by the alcohol.38
In summary, alkene radical cations derived from the frag-
mentation of â-(phosphatoxy)alkyl radicals provide for a very
versatile series of tandem polar/radical crossover sequences
involving radical ionic chain reactions and leading to a broad
selection of fused and bridged nitrogen heterocycles. Nitroal-
kanes are ideal radical precursors in this system, permitting rapid
assembly of the substrates by virtue of the rich chemistry of
the nitro group and preventing premature displacement of the
leaving group by their strongly electron-withdrawing nature. The
substitution patterns can be engineered so as to favor nucleo-
philic attack on the radical cations in either the exo- or the endo-
cyclic modes.
Acknowledgment. We thank the NSF (CHE 9986200) for
support of our work in this area.
Supporting Information Available: Complete experimental
details and characterization data (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA035639S
(38) It is interesting to note that, although tributyltin hydride is not soluble in
acetonitrile, and indeed partitioning between acetonitrile and hexanes is a
favorite method for the removal of organotin byproducts from more polar
products,39 there is sufficient solubility in a hot 1/1 mixture of benzene
and acetonitrile for chain reactions to proceed smoothly.
(36) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions;
VCH: Weinheim, 1996.
(37) For the application of related fragmentations in synthesis, see: Aubele, D.
L.; Floreancig, P. E. Org. Lett. 2002, 4, 3443.
(39) Berge, J. M.; Roberts, S. M. Synthesis 1979, 471.
9
J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7947