A highly selective rearrangement of a housane-derived cation radical: An electrochemically mediated transformation

Article abstract of DOI:10.1021/jo070190x

(Chemical Equation Presented) To utilize housane-derived cation radicals as intermediates for the synthesis of the bicyclo (n.3.0) framework of natural products, a highly regioselective [1,2] shift of carbon to either a radical or an electron-deficient site is required. Herein we describe how this has been accomplished, provide a set of guidelines to assess housane oxidizability prior to its synthesis, and describe a synthesis of housane 18 that capitalizes upon the facility of [1,5] hydrogen shifts in substituted cyclopentadienes. The catalytic electrochemically mediated oxidation of 18 leads to a cation radical that engages in a rearrangement leading to the (4.3.0) adduct 23. The appearance of a catalytic current in the cyclic voltammogram of a solution containing the tris(aryl)amine and housane 18 is an excellent indicator that the amminium cation radical 14^?+ is able to oxidize the housane and return the mediator to the original redox couple. DFT calculations show electron density on both the aryl and strained σ framework in the HOMO of housane 18. From the spin density and electrostatic potential map for the cation radical, a picture where the spin resides on the side that is distal to the substituent emerges, while the hole is proximal to it. Both experiment and theory show that the rearrangement is best characterized as a [1,2] carbon shift toward an electron-deficient site and that migration toward the substituent-bearing carbon is much preferred over the alternative pathway.

Full text of DOI:10.1021/jo070190x

A Highly Selective Rearrangement of a Housane-Derived Cation
Radical: An Electrochemically Mediated Transformation
Young Sam Park,† Selina C. Wang,‡ Dean J. Tantillo,‡ and R. Daniel Little*,†
Department of Chemistry & Biochemistry, UniVersity of California, Santa Barbara, California 93106, and
Department of Chemistry, UniVersity of California, DaVis, California 95616
little@chem.ucsb.edu
ReceiVed January 30, 2007
To utilize housane-derived cation radicals as intermediates for the synthesis of the bicyclo (n.3.0)
framework of natural products, a highly regioselective [1,2] shift of carbon to either a radical or an
electron-deficient site is required. Herein we describe how this has been accomplished, provide a set of
guidelines to assess housane oxidizability prior to its synthesis, and describe a synthesis of housane 18
that capitalizes upon the facility of [1,5] hydrogen shifts in substituted cyclopentadienes. The catalytic
electrochemically mediated oxidation of 18 leads to a cation radical that engages in a rearrangement
leading to the (4.3.0) adduct 23. The appearance of a catalytic current in the cyclic voltammogram of a
solution containing the tris(aryl)amine and housane 18 is an excellent indicator that the amminium cation
radical 14•+ is able to oxidize the housane and return the mediator to the original redox couple. DFT
calculations show electron density on both the aryl and strained σ framework in the HOMO of housane
18. From the spin density and electrostatic potential map for the cation radical, a picture where the spin
resides on the side that is distal to the substituent emerges, while the hole is proximal to it. Both experiment
and theory show that the rearrangement is best characterized as a [1,2] carbon shift toward an electron-
deficient site and that migration toward the substituent-bearing carbon is much preferred over the alternative
pathway.
Introduction
stituent appended to the aryl group. Thus, the product ratio is
72:28 when it is methoxy and 80:20 when it is carboethoxy, a
result that is consistent with the stabilization of a bridgehead
radical rather than a carbocation.
In contrast to these cases, no selectivity was observed in the
rearrangement of the cation radical derived from the 2-tri-
methylsilylmethyl-substituted housane 7 (Scheme 2); nearly
equal amounts of 8 and 9 were produced despite the possibility
that γ-silyl stabilization of a cation at CR could have biased
the regiochemical outcome.3
We recently described the rearrangement of the cation radicals
derived from housanes 1-3 and 7.1 Surprisingly, each of the
2-aryl-substituted systems, 1-3, rearranged with modest selec-
tivity, favoring the product of housane ring opening with the
subsequent migration of the labeled methylene group toward
the bridgehead carbon positioned distal to the aryl substituent
(viz. toward CR′). We attributed the selectivity to the existence
of a bridging interaction between the aryl group and the cation
radical (see 6, Scheme 1), much the way a phenyl group bridges
when stabilizing a vicinal carbocation.2 Nearly the same level
of selectivity and same preference for a distal migration was
observed regardless of the electron demand of the para sub-
While fundamentally interesting, these results are unsatisfac-
tory if one wishes to apply the chemistry to the synthesis of
specific structures. One of our objectives, for example, is to
use the transformation in the manner illustrated by the conver-
† University of California, Santa Barbara.
(3) (a) For a review concerning the interaction of silicon with positively
charged carbon at the R, â, γ, and δ positions, see: Lambert, J. B.
Tetrahedron 1990, 46, 2677-2689. (b) Kaimakliotis, C; Fry, A. J. J. Org.
Chem. 2003, 68, 9893-9898; reports a novel silicon γ-aryl effect upon
redox potential.
‡ University of California, Davis.
(1) Gerken, J. B.; Wang, S. C.; Preciado, A. B.; Park, Y. S.; Nishiguchi,
G.; Tantillo, D. J.; Little, R. D. J. Org. Chem. 2005, 70, 4598-4608.
(2) Cram, D. J. J. Am. Chem. Soc. 1964, 86, 3767-3772.
10.1021/jo070190x CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/11/2007
J. Org. Chem. 2007, 72, 4351-4357
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Park et al.
SCHEME 1. Aryl Bridging in the Rearrangement of 2-Aryl-Substituted Housanes
SCHEME 2. The Presence of a γ-Silyl Substituent Affords No Regioselectivity
SCHEME 3. Idealized Transformation Leading to the Bicyclo (n.3.0) Framework
sion of 10 (R * R′) to 13 in order to access the bicyclo (n.3.0)
framework that is common to a variety of natural products
(Scheme 3).4 To do so clearly requires a solution to the
regiochemical control issue; significantly greater preferences
must be achieved.
Herein we (a) provide a solution to the problem of regio-
chemical control and describe (b) qualitative guidelines to assist
in choosing housanes that will be oxidizable, (c) the spin and
charge distribution of the cation radical that was selected for
the present investigation, and (d) a rationale for the observed
regioselectivity.
subsequently, to products 4 and 5. The apparent thermodynamic
impasse is countered by the existence of at least one irreversible
follow-up reaction that drains the equilibrium toward the
products.7 This general phenomenon allows products that might
be oxidized under more harshly oxidizing conditions to be
protected.
Oxidizability. With the tris(p-bromophenyl)amminium cation
radical 14•+ as the oxidant of choice, we considered it prudent
to develop a qualitatively useful means to assess housane
(5) For example, see: (a) Cossy, J.; Belotti, D. Tetrahedron 2006, 62,
6459-6470; Floreancig, P. E. Tetrahedron 2006, 62, 6447-6594 (Sym-
posium-in-Print Number 121). (b) Floreancig, P. E. Synlett. 2007, 191-
203. (c) Roth, H. D. In ReactiVe Intermediate Chemistry; Moss, R. A., Platz,
M. S., Jones, M., Jr., Eds.; John Wiley & Sons: New York, 2004; Chapter
6, pp 205-272. (d) Moeller, K. D. Tetrahedron 2000, 56, 9527-9554. (e)
Rinderhagen, H.; Waske, P. A.; Mattay, J. Tetrahedron 2006, 62, 6589-
6593. (f) Adam, W.; Corma, A.; Miranda, M. A.; Sabater-Picot, M.-J.; Sahin,
C. J. Am. Chem. Soc. 1996, 118, 2380-2386. (g) Booker-Milburn, K. I.;
Cox, B.; Grady, M.; Halley, F.; Marrison, S. Tetrahedron Lett. 2000, 41,
4651-4655. (h) Takemoto, Y.; Furuse, S.-I.; Hayase, H.; Echigo, T.; Iwata,
C.; Tanaka, T.; Ibuka, T. Chem. Commun. 1999, 2515-2516. (i) Bauld, N.
L.; Bellville, D. J.; Harirchian, B.; Lorenz, K. T.; Pabon, R. A., Jr.; Reynolds,
D. W.; Wirth, D. D.; Chiou, H. S.; Marsh, B. K. Acc. Chem. Res. 1987, 20,
371-378.
Results and Discussion
Choice of Oxidizing Agent. A variety of methods have
proven suitable for the oxidation of housanes.5 We prefer to
generate the oxidizing agent in situ via the electrochemical
oxidation of tris(4-bromophenyl)amine (TBA, 14).6 In this
manner, one can operate at a potential that is significantly less
than that required for the direct oxidation of the substrate. For
example, the amine (14) oxidizes at ∼ +0.9 V versus a silver/
silver nitrate reference electrode. In contrast, the 2-phenyl-
substituted housane 1 displays its first oxidation peak at a
potential of +1.3 V. Nevertheless, the arylamminium cation
radical 14•+ smoothly converts 1 to its cation radical and,
(6) (a) Mayers, B. T.; Fry, A. J. Org. Lett. 2006, 8, 411-414 and 1253.
(b) Wend, R.; Steckhan, E. Electrochem. Acta 1997, 42, 2027-2039. (c)
Dapperheld, S.; Steckhan, E. Angew. Chem. 1982, 94, 785. (d) Platen, M.;
Steckhan, E. Chem. Ber. 1984, 117, 1679-1694. (e) Dapperheld, S.;
Steckhan, E.; Brinkhaus, K. H. G.; Esch, T. Chem. Ber. 1991, 124, 2557-
2567.
(4) See, for example, the structures shown in: Wilson, R. M.; Danishef-
sky, S. J. Acc. Chem. Res. 2006, 39, 539-549.
(7) Miranda, J.; Wade, C.; Little, R. D. J. Org. Chem. 2005, 70, 8017-
8026.
4352 J. Org. Chem., Vol. 72, No. 12, 2007

SelectiVe Rearrangement of a Housane-DeriVed Cation Radical
TABLE 1. Calculated HOMO Energies for a Series of Housanes
SCHEME 4. Synthesis of Housane 18
oxidizability prior to spending the time and effort required to
synthesize a substrate. We wanted to be confident that the
system we selected would not be too difficult to oxidize. We
know, for example, that the parent housane 15 is not oxidized
by 14•+, while the 2-aryl-substituted housanes 1-3 are easily
oxidized. Given the correlation between HOMO energies and
oxidizability, we have found it convenient to calculate their
energies and to correlate the calculated values with measured
oxidation potential for housanes whose oxidations we, or others,
have investigated.8
raise the HOMO energy from -6.59 to -6.37, indicating that
17 will be easier to oxidize than 16, a conclusion that accords
nicely with experiment.5f The HOMO energy for the analogous
2-phenyl-substituted housane 1 is still more positive (-6.20).
Thus it ought to be the easiest to oxidize of the systems
portrayed, and this is observed to be true.1 The last entry in the
table is monoalkylated and ought, therefore, to be oxidizable
by 14•+. The calculated HOMO energy supports this notion, so
we felt confident to select 18 as a substrate for the present
investigation.
Synthesis of 2-Benzyloxymethylhousane 18. On the basis
of the ideas discussed in the previous section and in an effort
to impose a bias on the directionality of the rearrangement step,
we elected to synthesize housane 18 (Scheme 4), a system whose
bridgehead substituents are different. To do so, we capitalized
upon the facility of substituted cyclopentadienes to undergo 1,5
hydrogen shifts.10 Thus, the product from alkylation of the
cyclopentadienyl anion with benzyl chloromethyl ether readily
undergoes sigmatropic rearrangement to afford 19. Subsequent
treatment with sodium hydride and 1,4-dibromobutane leads
smoothly to the spirocyclic diene 20. Its conversion to diazene
22 followed a standard protocol involving Diels-Alder cyclo-
addition with diethyl azodicarboxylate, reduction to the back
bond of the resulting adduct, and transformation of the biscar-
bamate linkage to the diazene. When photolyzed, 22 loses
nitrogen and efficiently leads to the desired housane 18.
Catalytic, Electrochemically Mediated Oxidation of
Table 1 illustrates the HOMO energies for a series of
housanes calculated at the B3LYP/6-31G(d) level of theory.9
Since the parent housane, bicyclo[2.1.0]pentane (15), has been
shown to be inert to 14•+ while the bridgehead methyl-
substituted housane 16 undergoes oxidation,5f we conclude that,
for housanes whose HOMO energy is equal to or more positive
than -6.59 eV, 14•+ will be a suitable oxidizing agent.
Somewhere between there and approximately -6.9 eV, it will
fail. The influence of a second bridgehead methyl group is to
(8) Adam, W.; Heidenfelder, T. Chem. Soc. ReV. 1999, 28, 359-366.
(9) (a) All calculations performed at UCSB used the SPARTAN ’04
Macintosh software package, while those performed at UCD used the
GAUSSIAN03 suite of programs (Frisch, M. J.; et al. Gaussian 03; Gaussian,
Inc.: Wallingford, CT, 2003). (b) Geometries and HOMO energies for the
systems illustrated in Table 1 were calculated at the HF/3-21G(d), HF/6-
31G(d), and B3LYP/6-31G(d) levels of theory. The trends in HOMO
energies vary slightly with different levels of theory, but in a manner that
does not change any of our conclusions. See Supporting Information for
additional details on all of these calculations, including pictures of the
computed HOMOs.
(10) Yang, Y.-R.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 8224-8227.
J. Org. Chem, Vol. 72, No. 12, 2007 4353

Park et al.
FIGURE 1. Cyclic voltammograms showing the TBA/TBA cation radical redox couple (pink) and the existence of a catalytic current when the
substrate (18) is added (blue curve). Glassy carbon anode, Pt wire cathode, Ag/AgNO3 reference electrode, 0.1 M n-Bu4NBF4 supporting electrolyte
in acetonitrile solvent, 200 mV/s scan rate.
Housane 18: Rearrangement with Exceptionally High
Regioselectivity. Our plan called for the use of 14•+ to mediate
the oxidation of housane 18. The cyclic voltammogram for the
TBA/TBA cation radical couple is displayed in pink in Figure
1. When the benzyloxymethyl-substituted housane 18 is added
and the scan repeated, there is an increase in current flow that
is attributable to a so-called catalytic current (note the blue
curve).11 Its appearance is an excellent indicator that the
amminium cation radical is able to oxidize the housane and
return the mediator to the original redox couple, as illustrated
by the equations accompanying Figure 1.
substituted bicyclic alkene 23. Thus, in contrast with systems
we had previously studied (vide supra), the rearrangement of
18 proved to be highly regioselective; no evidence for the
formation of a regioisomeric adduct was obtained.13
The preparative scale oxidation of 18 was conveniently
carried out in a beaker-style cell that was fitted with a carbon
cathode (reticulated vitreous carbon) and a platinum anode. The
potential was set to +0.88 V in order to oxidize the 10 mol %
of TBA that was dissolved in acetonitrile, rather than the
housane; the course of the reaction was monitored by TLC.12
We were delighted to discover the formation of a single product
in a 66% isolated yield (89% based upon recovered starting
material) whose spectral data are consistent with the bridgehead
Characterization of the Intermediate and the Rearrange-
ment Pathway. DFT calculations (B3LYP/6-31G(d)) and the
resulting image shown in Figure 2 show that the HOMO for
housane 18 is located on both the benzyloxymethyl and strained
σ framework of the molecule.9 The computed spin density
surface for the ring-opened cation radical shows clearly that
the unpaired spin resides on the side that is distal to the
substituent, while the corresponding electrostatic potential map
indicates that the side bearing the substituent is more positive,
suggesting that the hole resides proximal to the substituent.
One mechanism that emerges from these considerations is
illustrated in Scheme 5. The process begins with the oxidation
(11) (a) Steckhan, E. Angew. Chem. 1986, 98, 681-699. (b) Simonet,
J.; Pilard, J.-F. Electrogenerated Reagents. In Organic Electrochemistry,
4th ed.; Lund, H., Hammerich, O., Eds.; Marcel Dekker: New York, 2001;
Chapter 29. (c) Little, R. D.; Moeller, K. D. Interface 2002, 11, 36-42.
(12) The use of 20 mol % of the mediator leads to a significant rate
increase, thereby allowing the complete consumption of the starting material
in 2 h or less.
(13) Interestingly, GCMS analysis shows that heating 18 to 300 °C for
20 min affords both regioisomers. In the thermal process, the major product
corresponds to the isomer that is not observed electrochemically.
4354 J. Org. Chem., Vol. 72, No. 12, 2007

SelectiVe Rearrangement of a Housane-DeriVed Cation Radical
FIGURE 2. Left: HOMO for 18 determined at the B3LYP/6-31G(d) level of theory. Middle: Spin density for the cation radical (HF/3-21G(d))
derived from 18. Right: Electrostatic potential map for the cation radical (HF/3-21G(d)).
SCHEME 5. Alternative Mechanistic Hypotheses for the Conversion of 18 to 23
of the mediator TBA (14) at ∼0.9 V to afford the TBA cation
radical, 14•+. It subsequently oxidizes the substrate 18 and
regenerates TBA (14). The observation of a catalytic current
supports the existence of this sequence (see Figure 1). One or
more follow-up transformations are required to drive the
unfavorable equilibrium that is established during this electron
transfer (ET) step. We suggest that either the [1,2] carbon
migration of the housane cation radical 18•+ to afford the (4.3.0)
cation radical 24•+ and/or the subsequent back electron transfer
(BET) from TBA to 24•+ fulfill this need while also leading to
the product 23 and regenerating the oxidizing agent, 14•+. An
alternative BET pathway posits that the starting material, 18,
rather than 14 provides the electron to 24•+ to afford 23 and
regenerate 18•+ (shown on the right side of Scheme 5). At
this time, we do not have evidence to favor either of these
options.
much preferred over the alternative pathway. At the B3LYP/
6-31G(d) level, for example, the activation barrier is ∼7 kcal/
mol for the distal pathway, while the proximal pathway is nearly
barrierless. Similarly, single point energy calculations on the
B3LYP/6-31G(d) structures using CCSD/6-31G(d) suggest that
the barrier for the distal pathway is ∼9 kcal/mol and that for
the proximal pathway is again only a fraction of a kcal/mol.14
In keeping with the proposed mechanism, this significant
(14) Geometries for structures involved in the rearrangement were
optimized using the B3LYP/6-31G(d) method (Becke, A. D. J. Chem. Phys.
1993, 98, 5648-5652; Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377;
Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789; Stephens,
P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623-11627) on a model system with the benzyl group replaced by
a methyl group. All structures were characterized by frequency calculations.
Intrinsic reaction coordinate (IRC) calculations (Gonzalez, C.; Schlegel,
H. B. J. Phys. Chem. 1990, 94, 5523-5527; Fukui, K. Acc. Chem. Res.
1981, 14, 363-368) were also used to characterize transition structures.
Note that, as a test of this methodology, we attempted to predict the major
product without prior knowledge of the experimental result; in this case,
the prediction proved to be correct. CCSD/6-31G(d) (Scuseria, G. E.;
Schaefer, H. F., III. J. Chem. Phys. 1989, 90, 3700-3703) single point
calculations were also performed. See Supporting Information for additional
details.
Transition structures for the rearrangement step were gener-
ated at both the Hartree-Fock/3-21G(d) and density functional
levels of theory (B3LYP/6-31G(d)).9,14 Each level of theory
leads to the same conclusion; that is, the rearrangement is best
characterized as a [1,2] carbon shift toward an electron-deficient
site, and migration toward the substituent-bearing carbon is
J. Org. Chem, Vol. 72, No. 12, 2007 4355

Park et al.
ether (100 mL). The organic layer was separated, and the aqueous
layer was extracted with ether (5 × 75 mL). The combined organic
portions were washed with brine (3 × 100 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (petroleum ether/EtOAc 100:1, Rf ) 0.25, UV, vanillin)
to afford 20 as a yellow liquid (4.76 g, 19.85 mmol, 86%).
Additional purification could be achieved by using HPLC (5 micron
silica, 10 mm i.d. × 25 cm), at a flow rate of 1.3 mL/min using
hexane as the eluant: IR (neat) νmax 3031, 2951, 2862, 1452, 1089,
preference is likely to be due to the ability of an alkyl substituent
to better stabilize a positive charge than an unpaired electron.
An alternative rationale for the experimentally observed
regioselectivity posits that, like the cation radicals derived from
the 2-aryl-substituted housanes 1-3, the aryl unit is not an
innocent bystander. It could, for example, bridge to stabilize a
positive charge located at C-1 in the manner illustrated by
structure 25.15 Subsequent Wagner-Meerwein rearrangement
would re-establish aromaticity and generate structure 24•+
(Scheme 6). While additional experiments must be performed
to formally assess the viability of this suggestion, our quantum
calculations show that this type of bridging is not required to
explain the regiochemical preference.
1
1070, 737, 698 cm-1; H NMR (400 MHz, CDCl3) δ 1.76-2.00
(m, 8H), 4.27 (s, 2H), 4.52 (s, 2H), 6.23 (dd, 1H), 6.27 (d, 1H),
6.48 (dd, 1H), 7.27-7.40 (m, 5H); 13C NMR (400 MHz, CDCl3)
δ 22.9, 26.3, 31.8, 32.5, 63.8, 72.1, 127.7, 127.9, 128.4, 128.6,
138.8, 145.5, 150.1; LRMS (EI) m/z 240 (M+, 12), 149 (20), 134
(59), 121 (50), 91 (100); HRMS (EI) m/z found 240.1508, calcd
240.1514 for C17H20O.
SCHEME 6. Alternative Mechanistic Pathway
Diethyl 1-(Benzyloxymethyl)-2,3-diazaspiro[bicyclo[2.2.1]-
heptane-7,1′-cyclopentane]-2,3-dicarboxylate (Biscarbamate 21).
The spirocyclopentyl diene derivative 20 (2.0 g, 8.32 mmol) and
diethyl azodicarboxylate (4.05 mL, 24.96 mmol) were dissolved
in dry CH2Cl2 (80 mL), and the resulting mixture was brought to
reflux with magnetic stirring for 24 h. The orange reaction mixture
was cooled to room temperature and diluted with CH2Cl2 (50 mL),
followed by the addition of dipotassium azodicarboxylate (16.13
g, 83.2 mmol). The reaction vessel was fitted with an addition funnel
and an overhead stirrer. The mixture was cooled to 0 ×bcC, and
diimide was generated in situ by the dropwise addition of glacial
acetic acid (5.9 mL, 104 mmol) for 30 min. Vigorous evolution of
gas occurred during the entire course of the addition. The mixture
was gradually warmed to room temperature and stirred for 12 h.
The solids were removed by filtration, and the remaining solids
were washed with CH2Cl2 (200 mL). The solvent was evaporated
under reduced pressure at room temperature and neutralized with
saturated aqueous NaHCO3. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (75 mL × 5). The
combined organic portions were washed with brine (100 mL × 2),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (petroleum ether/Et2O 6:4, Rf ) 0.30, UV, vanillin) to
provide the biscarbamate 21 as a colorless liquid (1.80 g, 4.33
mmol, 52%): 1H NMR (400 MHz, CDCl3) δ 1.10-1.30 (m, 8H),
1.34-1.38 (m, 1H), 1.40-1.62 (m, 3H), 1.64-1.78 (m, 3H), 1.80-
1.99 (m, 3H), 3.94-4.02 (m, 1H), 4.16-4.30 (m, 6H), 4.49-4.60
(m, 2H), 7.24-7.40 (m, 5H).
1-(Benzyloxymethyl)-2,3-diazaspiro[bicyclo[2.2.1]hept[2]ene-
7,1′-cyclopentane] (Benzyloxymethyldiazene 22). The biscarbam-
ate 21 (1.80 g, 4.33 mmol) was dissolved in EtOH (135 mL), the
solution was degassed with argon for 20 min, and KOH (4.88 g,
87.0 mmol) was added. The resulting mixture was brought to reflux
for 12 h. The reaction mixture was cooled to room temperature
and diluted with EtOH (50 mL), followed by removing reflux
condenser. After cooling to 0 °C, a solution of K3Fe(CN)6 (14.27
g, 43.34 mmol) in water (80 mL) was added slowly via addition
funnel over a period of 1 h, and the mixture was stirred for 12 h at
room temperature. TLC showed that Cu(I) test for the resulting
diazene was positive. After the mixture was diluted with water (50
mL), the product was extracted with Et2O (100 mL × 6) and dried
over anhydrous MgSO4. The crude product was obtained upon
concentration under reduced pressure. Purification by flash chro-
matography on silica gel (petroleum ether/Et2O 7:4, Rf ) 0.28, Cu-
(I) stain, UV, vanillin) to afford the diazene 22 as a colorless liquid
(537 mg, 1.99 mmol, 46%): IR (neat) νmax 3029, 2950, 2865, 1492,
1454, 1097, 737, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.94-
1.01 (m, 2H), 1.18-1.22 (m, 1H), 1.32-1.60 (m, 7H), 1.66-1.75
(m, 2H), 4.09 (d, J ) 10.44 Hz, 1H), 4.30 (d, J ) 10.44 Hz, 1H),
4.70 (d, J ) 6.14 Hz, 2H), 4.76 (t, J ) 2.92 Hz), 7.29-7.89 (m,
5H); 13C NMR (400 MHz, CDCl3) δ 20.5, 23.3, 25.9, 26.0, 28.3,
28.5, 64.2, 68.0, 73.9, 86.2, 88.8, 127.6, 127.7, 128.5, 138.4; LRMS
Concluding Remarks
The utility of catalytic electrochemically mediated processes
as well as the application of simple quantum calculations to
the implementation of the chemistry described herein has been
demonstrated. The insight gained during these investigations
promises to be of utility in designing substrates that will allow
the housane-derived cation radical rearrangement reaction to
be applied to the synthesis of specific structures, particularly,
to those of natural products. Our efforts to apply the chemistry
in this manner will be described in due course.
Experimental Section
1-Benzyloxymethyl-1,3-cyclopentadiene 19. To a stirred sus-
pension of NaH (60% oil, 2.40 g, 60.05 mmol) in dry THF (40
mL) was added slowly a solution of freshly distilled cyclopentadiene
(4.01 mL, 60.0 mmol) in THF (20 mL) over 20 min at -10 °C.
After additional stirring for 30 min, the resulting purple reaction
mixture was cooled to -70 °C, and then a solution of benzyl
chloromethyl ether (10.01 mL, 72.0 mmol) in THF (20 mL) was
added slowly to the reaction vessel over 20 min. The resulting
reaction mixture was warmed to -50 °C and stirred at that
temperature for 40 min, and allowed to warm gradually to 0 °C,
quenched with saturated aqueous NH4Cl (50 mL), and stirred for
an additional 1 h. The organic layer was separated, and the aqueous
layer was extracted with ether (5 × 100 mL). The combined organic
layers were washed with water (2 × 100 mL) and brine (2 × 100
mL), dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure at room temperature. The crude product
was purified by flash chromatography on silica gel (petroleum ether/
Et2O 50:1, Rf ) 0.23, UV, vanillin) to afford the alkylated product
1
19 as a yellow liquid (5.37 g, 28.9 mmol, 48%). H NMR data
matched the literature values.10
1-(Benzyloxymethyl)spiro[4.4]nona-1,3-diene 20. To a stirred
suspension of NaH (60% oil, 2.02 g, 50.62 mmol) in dry DMF (40
mL) was added slowly a solution of the cyclopentadiene derivative
19 (4.287 g, 23.01 mmol) and 1,4-dibromobutane (3 mL, 25.32
mmol) in DMF (15 mL) keeping the temperature of the reaction
mixture below 0 °C. The reaction was stirred for 1 h at 0 °C,
quenched with saturated aqueous NH4Cl (50 mL), and diluted with
(15) Stabilization of an incipient or fully formed cation (or radical) could
also be achieved through participation by the ether oxygen. We have no
evidence to favor or disfavor this possibility.
4356 J. Org. Chem., Vol. 72, No. 12, 2007

SelectiVe Rearrangement of a Housane-DeriVed Cation Radical
(ESI+/TOF) m/z 271 [M + H]+, 293 [M + Na]+, 563 [2M + Na]+;
HRMS found 293.1626, calcd 293.1624 for C17H22N2ONa.
1-(Benzyloxymethyl)spiro[bicyclo[2.1.0]pentane-5,1′-cyclo-
pentane] (Benzyloxymethylhousane 18). The diazene 22 (356 mg,
1.31 mmol) was weighed into a 50 mL Pyrex round-bottomed flask
and dissolved in dry THF (15 mL). The solution was degassed by
bubbling argon through it for 20 min. Then, the solution was
irradiated with UV light of 365 nm from a UV hand lamp placed
adjacent to the flask, and the reaction was followed up by TLC.
After 16 h, the diazene was consumed and the solvent was
evaporated under reduced pressure at room temperature. The crude
product was chromatographed on silica gel (petroleum ether/Et2O
50:1, Rf ) 0.21, UV, vanillin) to afford the benzyloxymethylhousane
18 as a colorless liquid (356 mg, 0.94 mmol, 72%): IR (neat) νmax
3027, 2940, 2858, 1452, 1089, 1069, 733, 696 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.13 (m, 1H), 1.34-1.35 (m, 2H), 1.55-1.77 (m,
8H), 2.01-2.18 (m, 2H), 3.53 (d, J ) 11.21 Hz, 1H), 3.67 (d, J )
11.21 Hz, 1H), 4.47 (d, J ) 12.13 Hz, 1H), 4.58 (d, J ) 12.13 Hz,
1H), 7.29-7.35 (m, 5H); 13C NMR (400 MHz, CDCl3) δ 18.6,
23.7, 24.5, 25.9, 26.8, 29.2, 31.2, 31.5, 36.2, 71.6, 72.4, 127.6,
127.8, 128.5, 139.1; LRMS (EI) m/z 242, 151, 134, 121, 108, 91
(base peak); HRMS found 242.1671, calcd 242.1671 for C17H22O.
Cyclic Voltammetry. Cyclic voltammograms were recorded in
a single cell fitted with three electrodes. A glassy carbon disc
electrode (0.033 cm2 surface area) was used as a working electrode,
and a platinum wire (0.6 cm2 surface area) was used as a counter
electrode. The potential was recorded with the reference electrode
Ag/0.01 M AgNO3 immersed in a 0.1 M solution of n-Bu4NBF4 in
CH3CN that was separated from the medium by a Vycor membrane.
Its potential was +0.35 V versus the aqueous saturated calomel
electrode (SCE). All solutions were deoxygenated with a stream
of argon for 20 min before each experiment. A scan rate of 200
mV/s was used. Cyclic voltammetry (CV) was performed using a
computer-controlled potentiostat (Cypress voltammetric system CS
1200), and data were collected using the software available from
Cypress (version 1.5.5) and exported to an Excel Microsoft
worksheet.
bubbling argon through it for 20 min. A pre-electrolysis was
conducted at constant potential of 880 mV until the current value
dropped to ca. 0.5 mA. We routinely carried out pre-electrolyses
in order to ensure the absence of any redox-active materials at the
time when the substrate was added to the reaction medium.
Housane 18 (100 mg, 0.413 mmol) and 10 mol % of tris(4-
bromophenyl)amine (20 mg, 0.041 mmol) were added to the
solution. When a potential of +880 mV was applied to the cell,
the current flow increased to 7.7 mA, and a blue color appeared
on the surface of the platinum electrode, indicating the oxidation
of the mediator. The reaction was monitored by TLC; the
electrolysis was stopped after the coulometer indicated that 1 F/mol
had passed. The dark yellow solution was poured into an Erlen-
meyer flask containing water (15 mL), and the separated aqueous
layer was extracted with Et2O (40 mL × 5). The combined organic
portions were washed with brine (50 mL × 2), dried over MgSO4,
and concentrated under reduced pressure at room temperature. The
crude product was purified by flash chromatography on Si2O
(petroleum ether/Et2O 50:1, Rf ) 0.39, UV, vanillin) to afford the
bicyclononene 23 as a colorless liquid (66 mg, 0.27 mmol, 66%).
The starting material (23 mg, 0.095 mmol, 23%) was also recovered
and could be reused if desired.
7a-(Benzyloxymethyl)-2,4,5,6,7,7a-hexahydro-1H-indene (Ben-
zyloxymethyl Bicyclononene 23): IR (neat) νmax 3033, 2927, 2850,
1453, 1093, 1027, 908, 732, 696 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.10-1.27 (m, 2H), 1.39-1.55 (m, 3H), 1.74-1.78 (m, 1H),
1.88-1.98 (m, 1H), 2.11-2.22 (m, 3H), 2.25-2.35 (m, 2H), 3.27
(d, J ) 8.91 Hz, 1H), 3.44 (d, J ) 8.91 Hz, 1H), 4.51 (d, J )
12.44 Hz, 1H), 4.58 (d, J ) 12.44 Hz, 1H), 5.33 (q, J ) 2.15, 1H),
7.28-7.36 (m, 5H); 13C NMR (400 MHz, CDCl3) δ 15.5, 22.9,
27.1, 27.7, 29.9, 36.7, 50.7, 66.1, 72.4, 73.4, 122.6, 127.6, 128.5,
139.2, 146.2; LRMS (EI) m/z 241 (3), 199 (7), 151 (21), 121 (100),
91 (57); (CI/CH4) m/z 363 (5), 269 (4), 243 (10), 241 (9), 151 (28),
135 (80), 121 (100); HRMS (CI /CH4) found 243.1758, calcd
243.1749 for [C17H22O + H]+.
Acknowledgment. We thank the Petroleum Research Fund
administered by the American Chemical Society (ACS PRF#
43443-AC1) for its support of this research. The research at
UCD was supported in part by the National Science Foundation
through the Pittsburgh Supercomputer Center.
General Procedure for Preparative Indirect Electrolysis. All
preparative electrolyses were carried out in an undivided cell fitted
with a platinum anode (1 cm2 surface area) as a working electrode
and a reticulated vitreous carbon (RVC) electrode as a counter
electrode. A Ag/0.01 M AgNO3 reference electrode used for the
electrolyses had a potential of +0.35 V versus the aqueous calomel
electrode (SCE) at 25 °C. The separation between each of the
electrodes was ca. 0.5 cm. The potentials of all reactions were
controlled by a potentiostat, and the amount of charge passed was
monitored using a coulometer. In a preparative cell, a 0.1 M solution
of n-Bu4NBF4 in CH3CN (15 mL) was added. All electrodes were
fitted in the cell, and then the solution was deoxygenated by
Supporting Information Available: Additional information for
compounds 18 (1H and 13C) and 20 (1H and 13C), 21 (1H), 22 (1H
and 13C), and 23 (1H and 13C), a CV curve for housane 20 and the
product, 23, as well as additional details concerning the calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070190X
J. Org. Chem, Vol. 72, No. 12, 2007 4357