1,4-Hydroxybiradical Behavior Revealed through Crystal Structure-Solid-State Reactivity Correlations

Article abstract of DOI:10.1021/ja039076w

Structure-reactivity correlations for triplet 1,4-hydroxybiradicals in solution are made difficult by the presence of multiple reactive conformers and the possibility of conformation-dependent intersystem crossing. These problems can be overcome by working in the crystalline state, where the conformations of the 1,4-hydroxybiradicals are fixed and determinable by X-ray crystallography of the parent ketones, assuming that hydrogen atom abstraction occurs with little or no change in conformation. This approach is applied to 15 bi- and tricyclic ketones designed to have slightly different biradical conformations, so that the effect of small and incremental changes in geometry on biradical behavior can be tested. The results indicate that, while geometry does have a strong influence on 1,4-hydroxybiradical partitioning between cyclization, cleavage, and reverse hydrogen transfer, a full understanding of the results requires that the strain involved in forming the cyclization products be taken into account.

Full text of DOI:10.1021/ja039076w

Published on Web 03/02/2004
1,4-Hydroxybiradical Behavior Revealed through Crystal
Structure-Solid-State Reactivity Correlations
Dario Braga,‡ Shuang Chen,† Heather Filson,† Lucia Maini,‡ Matthew R. Netherton,†
Brian O. Patrick,† John R. Scheffer,*,† Carl Scott,† and Wujiong Xia†
Contribution from the Department of Chemistry, UniVersity of British Columbia,
VancouVer, Canada V6T 1Z1, and Department of Chemistry G. Ciamician, UniVersity of
Bologna, 40126 Bologna, Italy
Received October 15, 2003; E-mail: scheffer@chem.ubc.ca
Abstract: Structure-reactivity correlations for triplet 1,4-hydroxybiradicals in solution are made difficult by
the presence of multiple reactive conformers and the possibility of conformation-dependent intersystem
crossing. These problems can be overcome by working in the crystalline state, where the conformations
of the 1,4-hydroxybiradicals are fixed and determinable by X-ray crystallography of the parent ketones,
assuming that hydrogen atom abstraction occurs with little or no change in conformation. This approach is
applied to 15 bi- and tricyclic ketones designed to have slightly different biradical conformations, so that
the effect of small and incremental changes in geometry on biradical behavior can be tested. The results
indicate that, while geometry does have a strong influence on 1,4-hydroxybiradical partitioning between
cyclization, cleavage, and reverse hydrogen transfer, a full understanding of the results requires that the
strain involved in forming the cyclization products be taken into account.
1,4-Biradicals are formed as intermediates in a wide variety
of ground- and excited-state reactions and continue to be the
subject of intense experimental1 and theoretical2 interest. Triplet
1,4-biradicals are particularly common in photochemical reac-
tions and have been identified as intermediates in enone-alkene
photocycloadditions,3 the Paterno-Bu¨chi reaction,4,5 and the
Norrish/Yang type II reaction.6 It is with this last reaction that
the present Article is concerned.
Triplet 1,4-hydroxybiradicals formed in the first step of the
photochemical Norrish/Yang type II reaction have three fates:
reverse hydrogen transfer to regenerate the starting ketone in
its ground state, cleavage of the central carbon-carbon bond
to form an alkene and an enol, and Yang cyclization to form a
cyclobutanol derivative.6,7
singlet intersystem crossing, and this has given rise to two subtly
different schools of thought concerning mechanism. The first,
espoused by Wagner and co-workers,8,9 views triplet hydroxy-
biradical partitioning as being controlled by conventional kinetic
barriers in which intersystem crossing accompanies product
formation. The second, more widely accepted view, advanced
originally by Scaiano et al.10 and subsequently elaborated by
Griesbeck and co-workers,11 pictures biradical behavior as being
controlled by intersystem crossing. In this scenario, the singlet
biradical is viewed as reacting immediately following intersys-
tem crossing from the triplet. As a result, the conformation in
which the singlet is born (and from which it reacts) will be the
one that was most favorable for intersystem crossing - a
geometry that may be quite different from that conventionally
thought to favor cleavage, cyclization, or reverse hydrogen
transfer.12 Consequently, while some structural features of
biradical reactivity are well established, such as the requirement
for good overlap during cleavage between the C2-C3 bond and
(6) For a general review of the Norrish type II reaction, see: Wagner, P.; Park,
B.-S. In Organic Photochemistry; Padwa, A., Ed.; Marcel Dekker: New
York, 1991; Vol. 11, Chapter 4.
(7) Cyclobutanol products in Norrish type II photochemistry were first reported
by: Yang, N. C.; Yang, D. H. J. Am. Chem. Soc. 1958, 80, 2913.
(8) Wagner, P. J. Acc. Chem. Res. 1989, 22, 83.
(9) Wagner, P. J.; Meador, M. A.; Zhou, B.; Park, B. S. J. Am. Chem. Soc.
1991, 113, 9630. For related work supporting the idea of intersystem
crossing accompanying product formation, see: Michl, J. J. Am. Chem.
Soc. 1996, 118, 3568.
(10) Scaiano, J. C. Tetrahedron 1982, 38, 819.
(11) (a) Griesbeck, A. G.; Heckroth, H. J. Am. Chem. Soc. 2002, 124, 396. (b)
Griesbeck, A. G. Synlett 2003, 451.
(12) The spin-orbit coupling contribution to intersystem crossing in triplet
biradicals is greatest when the radical-containing orbitals are othogonal to
one another, a geometry that may not be well arranged for cleavage or
cyclization and may even correspond to a nonminimum energy conforma-
tion.4 See also: Carlacci, L.; Doubleday, C., Jr.; Furlani, T. R.; King, H.
F.; McIver, J. W., Jr. J. Am. Chem. Soc. 1987, 109, 5323.
These reactions are necessarily accompanied by triplet to
† University of British Columbia.
‡ University of Bologna.
(1) Kinetics and Spectroscopy of Carbenes and Biradicals; Platz, M. S., Ed.;
Plenum: New York, 1990.
(2) Klessinger, M. Theor. Comput. Chem. 1998, 5, 581.
(3) Andrew, D.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 5647 and
references therein.
(4) Griesbeck, A. G.; Mauder, H.; Stadtmu¨ller, S. Acc. Chem. Res. 1994, 27,
70.
(5) Griesbeck, A. G.; Buhr, S.; Fiege, M.; Schmickler, H.; Lex, J. J. Org. Chem.
1998, 63, 3847.
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J. AM. CHEM. SOC. 2004, 126, 3511-3520
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A R T I C L E S
Braga et al.
the radical-containing orbitals at C1 and C4,13 there is still no
general understanding of how biradical structure affects parti-
tioning among the three possible reaction pathways. To add to
the problem, triplet 1,4-hydroxybiradicals are sufficiently long-
lived to allow conformational equilibration, making identifica-
tion of reactive conformers difficult. For all of the above reasons,
it is apparent that further research correlating 1,4-hydroxybi-
radical structure and reactivity is needed.
By working in the crystalline state, the problems of multiple
reactive conformers and conformation-dependent intersystem
crossing can be avoided, because most organic compounds
crystallize in and are restricted to their lowest energy conforma-
tions. Furthermore, because it is likely that γ-hydrogen abstrac-
tion in the crystalline state occurs with very little motion of the
associated heavy atoms,14,15 the structures of the conformation-
ally locked 1,4-hydroxybiradicals can be inferred from the X-ray
crystal structures of the parent ketones, and this allows direct
structure-reactivity relationships to be established for these
reactive intermediates. In a preliminary communication, we used
this approach to analyze the Norrish/Yang type II photochem-
istry of spirocyclic ketones 13a-c.16 In the present Article, we
report an extension of this work to the eight-ring homologue
13d, as well as to the homologous series 4a-d and 16a-d.
ketones 4a-e from the known compound, methyl bicyclo[3.3.1]-
nonane-9-carboxylate (1).18 Analogous procedures were used
for the preparation of ketones 13a-e and 16a-e, and the details
of the synthesis of these compounds are given in the Supporting
Information. All 15 ketones proved to be crystalline solids, and
each had its crystal and molecular structure determined by direct
methods. Crystallographic information files for all 15 starting
ketones (as well as five photoproducts) are provided in the
Supporting Information. Figure 1 presents ORTEP drawings of
ketones 4a-e at the 30% ellipsoid probability level showing
the conformational differences between them as a function of
spiro ring size.
Photochemistry. Each of the 15 ketones was irradiated in
the crystalline state. The procedure consisted of crushing ca. 5
mg of the ketone to be photolyzed between two Pyrex
microscope slides, taping the plates together, sealing the
resulting sandwiches under nitrogen in polyethylene bags, and
irradiating the ensembles with the output from a water-cooled
450 W medium-pressure mercury lamp. Conversions were
generally kept below ca. 25% to minimize crystal melting during
photolysis. Preparative scale photolyses for the purpose of
product isolation and characterization were carried out in
solution, which led to results essentially identical to those
observed in the solid state. The photoproducts were isolated by
column chromatography, and their structures were established
by high-resolution NMR and other spectroscopic methods. In
some cases (photoproducts 11d, 15c, 15d, 19, and 20), the
structures were corroborated by X-ray crystallography. The
workup and photoproduct isolation and characterization proce-
dures for the photolysis of ketones 4a-e are given in the
Experimental Section. Details of the photolysis of ketone 13e
have been published,15 and, for the remaining nine photolyses,
this information is provided in the Supporting Information.
With a specificity and internal consistency that is little short
of astonishing, the five-membered ring spiroketones 4a, 13a,
and 16a all underwent exclusive cleavage to afford the corre-
sponding ring-opened photoproducts 10a, 14a, and 17a (Scheme
2) as an approximately 1:1 mixture of two diastereomers. These
are formed by nonstereoselective ketonization of the intermedi-
ate enols, which could be detected by 1H NMR in the photolysis
of ketones 4a and 13a. Figure 2a shows the vinyl region of the
1H NMR spectrum of ketone 13a following photolysis at 0 °C
in 2:1 tert-butyl alcohol-d10/benzene d6. The resonances at δ
5.42 and 5.79 ppm are assigned to the vinyl hydrogens of the
enol formed by cleavage of the 1,4-hydroxybiradical. Figure
2b shows a second spectrum taken immediately after the addition
of a trace amount of trifluoroacetic acid. This spectrum contains
vinylic signals for the enol as well as four new resonances (δ
5.34, 5.38, 5.60, and 5.72 ppm) assigned to the two newly
formed epimers of ketone 14a. Another spectrum (Figure 2c)
acquired 5 min later contained no enol signals, indicating that
complete conversion to the keto tautomers had occurred.
Unlike the five-ring spiroketones, the seven-ring, eight-ring,
and nonspirocyclic ketones 4c/13c/16c, 4d/13d/16d, and 4e/
13e/16e reacted predominantly to form cyclized products 11c/
15c/18c, 11d/15d/18d, and 19/21/22, respectively. In those cases
where crystal structures were lacking, the stereochemistry at
the hydroxyl-bearing carbon atom was established by 1H NOE
difference nuclear magnetic resonance spectroscopy (see Sup-
These compounds were chosen for investigation because the
conformation of the 1,4-biradicals formed by γ-hydrogen atom
abstraction could be varied in a regular and incremental fashion
by changing the size of the ketone-containing spiro ring. For
comparison purposes, we also report the results of photolyzing
the nonspirocyclic analogues 4e, 13e, and 16e in the solid state.
The results obtained paint a remarkable picture of how relatively
subtle conformational changes can profoundly affect 1,4-
hydroxybiradical partitioning among cleavage, reverse hydrogen
transfer, and cyclization.17
Results and Discussion
Synthesis of Starting Materials and X-ray Crystallogra-
phy. Scheme 1 shows the approach taken for the synthesis of
(13) Wagner, P. J.; Kemppainen, A. E. J. Am. Chem. Soc. 1968, 90, 5896.
(14) Gudmundsdottir, A. D.; Lewis, T. J.; Randall, L. H.; Scheffer, J. R.; Rettig,
S. J.; Trotter, J.; Wu, C.-H. J. Am. Chem. Soc. 1996, 118, 6167.
(15) Leibovitch, M.; Olovsson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem.
Soc. 1998, 120, 12755.
(16) Cheung, E.; Netherton, M. R.; Scheffer, J. R.; Trotter, J. Org. Lett. 2000,
2, 77.
(17) For related studies carried out in solution, see: (a) Lewis, F. D.; Hilliard,
T. A. J. Am. Chem. Soc. 1972, 94, 3852. (b) Lewis, F. D.; Johnson, R. W.;
Ruden, R. A. J. Am. Chem. Soc. 1972, 94, 4292.
(18) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061.
9
3512 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

1,4-Hydroxybiradicals
A R T I C L E S
Scheme 1
porting Information). In the case of ketones 4c, 4d, and 4e, small
amounts (5-10%) of a second photoproduct (12c, 12d, and 20,
respectively) were also isolated and characterized. These are
presumably formed by a novel disproportionation of the
intermediate 1,4-hydroxybiradicals in which a hydrogen atom
on C5 is transferred to the radical center on C1 (Figure 3a).19
In striking contrast to all of the above results, the six-
membered ring spiroketones 4b, 13b, and 16b proved to be
photochemically inert, giving only trace amounts (<1%) of
unidentified short retention time peaks on GC. The overall
results are summarized in Table 1.
by deuterium labeling studies (in solution) to be due to efficient
reverse hydrogen transfer of the 1,4-hydroxybiradical intermedi-
ate rather than to a failure of initial γ-hydrogen abstraction.
Based on the fact that the γ-hydrogen atom abstraction distances
and angles are nearly identical for all three six-ring spiroke-
tones,20 the same can be confidently assumed for compounds
4b and 16b, even though in these cases attempted trapping of
the biradicals was unsuccessful.21
Based on the crystallographic results, the 1,4-hydroxybiradi-
cals may be modeled as shown in Figure 3. The crystallographic
data reveal that the C1-C2-C3-C4 torsion angle is essentially
As outlined in the preliminary communication,16 the lack of
photoproduct formation in the case of ketone 13b was shown
(20) In fact, all 15 ketones have similar γ-hydrogen atom abstraction geometries,
with d (the CdO‚‚‚Hγ distance) ) 2.47 ( 0.10 Å and ω (the γ-hydrogen
out-of-plane angle) ) 43 ( 16°. These values are typical of ketones known
to take part in the Norrish/Yang type II reaction in the crystalline state.
For a review on this topic, see: Ihmels, H.; Scheffer, J. R. Tetrahedron
1999, 55, 885.
(19) As far as we are aware, this type of disproportionation is unknown for
1,4-hydroxybiradicals, although it has been observed in the case of a 1,5-
hydroxybiradical. See: Wagner, P. J.; Laidig, G. Tetrahedron Lett. 1991,
32, 895.
9
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A R T I C L E S
Braga et al.
The overlap is g80% of maximum for 4a and 13a and
somewhat less for 16a (79% and 58% of maximum). At the
same time that cleavage is favored, cyclization of these biradicals
is disfavored by the poor overlap between the p-orbitals on C1
and C4 (â ) 60-71°). Furthermore, cyclization would lead to
a highly strained pentacyclic ring system,23 and it is thus not
surprising that cleavage is the exclusive mode of reaction
detectable for the five-ring spirocycles.
In contrast, the six-ring (n ) 2) ketones 4b, 13b, and 16b
lead to biradicals in which only the p-orbital on C4 is reasonably
oriented for cleavage, the other (on C1) being very poorly
aligned (2-7% of maximum overlap). The subsequent failure
of these biradicals to cleave is clear evidence that cleavage
requires overlap of both p-orbitals with the cleaving C2-C3
bond. While the geometry for cyclization in these cases is by
no means ideal (â ) 53-61°), it is, as we shall see, adequate.
More important is the fact that cyclization would lead to the
very strained trans-fused 6/4 ring junction-containing photo-
products 11b, 15b, and 18b. The overall result is that both
cleavage and cyclization are disadvantaged relative to reverse
hydrogen transfer, and this becomes the sole process undergone
by these biradicals.
Figure 1. Molecular conformation of ketones 4a-e in the crystalline state.
constant at 63.4 ( 1.8° (gauche) for all 15 compounds
investigated and that the C1‚‚‚C4 distance is likewise invariant
at 3.00 ( 0.06 Å. The major structural difference between
homologues lies in the extent of rotation about the C1-C2 bond,
which varies with the presence or absence of the spiro ring and
the ring size. The effect of this difference is to change the
overlap of the p-orbital on C1 with both the C2-C3 bond and
the p-orbital on C4, and this, we believe, is the key structural
feature affecting biradical reactivity in these systems. Our
hypothesis is that cleavage is favored by good overlap between
the p-orbitals on C1 and C4 with the C2-C3 bond, cyclization
is favored by good overlap of the p-orbitals on C1 and C4 with
each other, and reverse hydrogen transfer dominates when
neither of the above conditions is met and the OH group is close
to C4 (as it is in every case). As we shall see, the crystallographic
data support this hypothesis, but, as will also become apparent,
a full interpretation of the results requires that the strain involved
in forming the cyclization products be taken into account.
For the purposes of discussion, we define æ1 and æ4 as the
dihedral angles between the C2-C3 bond and the p-orbitals on
C1 and C4, respectively. The overlap between these orbitals is
proportional to cos æ1 and cos æ4,22 and, as mentioned earlier,
the best geometry for cleavage can be expected when æ1 and
æ4 ) 0° and cos æ1 ) cos æ4 ) 1. The values of cos æ1 and
cos æ4 for the 15 ketones investigated in the present study are
given in Table 1. Also shown in Table 1 are the values of the
angle â, defined as the dihedral angle between the p-orbital on
C1 and the C2-C4 vector (Figure 3b). The most favorable
geometry for cyclization exists when â ) 0°, that is, when the
p-orbital on C1 is pointing directly at the p-orbital on C4.
As can be seen from Table 1, the three five-ring (n ) 1)
ketones 4a, 13a, and 16a undergo exclusive cleavage from
biradicals in which there is reasonably good overlap between
both radical-containing p-orbitals and the central C2-C3 bond.
Cyclization is the preferred mode of reaction of the biradicals
formed by photolyzing the seven-ring (n ) 3) spiroketones 4c,
13c, and 16c, and this can be understood as being due to three
factors: relatively poor cleavage geometry (cos æ1 ) 34-47%),
relatively favorable cyclization geometry (â ) 29-39°), and
formation of a trans-fused 7/4 ring system that is no longer
prohibitively strained. The same reasoning applies to the
nonspirocyclic systems 4e, 13e, and 16e, which have biradical
geometries similar to those of the seven-ring compounds and
likewise undergo mainly Yang photocyclization in the crystalline
state.
Finally, from Table 1 it can be seen that the geometry of the
biradicals formed by photolysis of the eight-ring (n ) 4) ketones
4d, 13d, and 16d is nearly identical to that of their six-ring (n
) 2) counterparts, yet the former cyclize while the latter react
exclusively via reverse hydrogen transfer. The logical conclusion
from these results is that cyclization is slowed in the six-ring
case, not only by the biradical geometry, but also by the
difficulty in forming a trans-fused 6/4 product, a rate-retarding
effect that is lessened in the eight-ring case.
In summary, the fact that the effect of spirocyclic ring size
on biradical partitioning is the same for three separate ring
systems (4, 13, and 16) argues very strongly for a common
interpretation of the results. This interpretation is based on two
factors: the geometry of the intermediate 1,4-hydroxybiradicals
as deduced from X-ray crystallography of the parent ketones,
and the increase in strain energy accompanying cyclization
(∆Estrain). Molecular mechanics calculations indicate that ∆Estrain
is greatest when n ) 1 and least when n ) 4.24 As a result, the
relative rate of biradical cyclization would be expected to
decrease with decreasing n.25 In agreement with this analysis,
(21) The trapping experiment consisted of irradiating ketones 4b and 16b in
2:1 tert-BuOD/benzene and looking for deuterium incorporation at the
γ-position. While successful in the case of 13b,16 no exchange was
detectable for ketones 4b and 16b. Attempts to observe such exchange in
γ,γ-d2-nonaphenone were similarly unsuccessful. See: Wagner, P. J.; Kelso,
P. A.; Kemppainen, A. E.; McGrath, J. M.; Schott, H. N.; Zepp, R. G. J.
Am. Chem. Soc. 1972, 94, 7506.
(23) The expected cyclization products are cyclobutanols 11a, 15a, and 18a in
which a prohibitively strained trans-fused 5/4 ring system is added to an
existing and moderately strained bi- or tricyclic carbon skeleton.
(24) For example, the increase in strain energy in going from ketone 4a to
cyclobutanol 11a was calculated to be 72.6 kcal/mol. In the case of the 4b
to 11b conversion, ∆Estrain ) 46.4 kcal/mol, which decreased to 29.8 kcal/
mol for the 4c/11c pair and 28.7 kcal/mol for the 4d/11d pair. Calculations
were carried out using the HyperChem/ChemPlus software package, version
5.11/2.0.
(22) Burdett, J. K. Molecular Shapes; Wiley-Interscience: New York, 1980; p
6.
9
3514 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

1,4-Hydroxybiradicals
A R T I C L E S
Scheme 2
9
J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3515

A R T I C L E S
Braga et al.
have very similar geometries in the crystalline state, yet the
latter cyclize while the former undergo reverse hydrogen
transfer.
The added effect of varying the spiro ring size is to change
the orientation of the p-orbital on C1 of the 1,4-hydroxybiradical
with respect to the C2-C3 σ bond involved in cleavage as well
as the p-orbital on C4 involved in cyclization. For n ) 1,
geometric factors favor cleavage, and, because cyclization is
strongly disfavored by ring strain, cleavage predominates.26
When n ) 2, cleavage is strongly disfavored by geometry
because the C2-C3 bond is well aligned with only one of the
two p-orbitals, and cyclization, while geometrically feasible, is
disfavored by ring strain. The result is exclusive reverse
hydrogen transfer. When n ) 3, 4, or acyclic, geometric factors
favor cyclization over cleavage, and, because cyclization is no
longer prohibited by ring strain, this becomes the dominant
observable pathway.26
Experimental Section
General Methods. Commercial spectral grade solvents were used
for photochemical experiments unless otherwise stated. For synthetic
use, tetrahydrofuran and diethyl ether were dried over the sodium ketyl
of benzophenone; dichloromethane was dried over calcium hydride;
acetonitrile was distilled from P2O5. All reactions were performed under
a nitrogen atmosphere unless otherwise noted. Melting points were
determined on a Fisher-Johns hot-stage apparatus and uncorrected.
Analytical TLC was performed on 0.20 mm silica gel 60-F plates and
visualized under UV light and/or by staining with I2 or phosphomo-
lybdic acid. Preparative chromatography was performed using either
the flash column method with silica gel (particle size 230-400 mesh)
or radial elution chromatography on a Harrison Research Chromatotron
(model 7924T) with self-coated silica gel plates (1 mm or 2 mm
thickness with EM Science silica gel 60 PF254 containing gypsum
7749-3). Infrared spectra were recorded on a Perkin-Elmer 1710
Fourier transform spectrometer. Ultraviolet spectra were recorded on
a Perkin-Elmer Lambda-4B UV/vis spectrometer at 25 °C. High-
resolution mass spectra were obtained from a Kratos MS 50 instrument
using electron impact (EI) ionization at 70 eV, or chemical ionization
(CI) with the ionization gas noted. Elemental analyses were performed
by the UBC microanalytical service on a Carlo Erba CHN Model 1106
analyzer. 1H NMR spectra were obtained at either 300 or 400 MHz on
Bruker AV-300 or Bruker AV-400 instruments. 13C NMR spectra were
recorded at either 75 or 100 MHz.
Figure 2. 1H NMR vinyl region (δ 5-6 ppm) after photolysis of ketone
13a showing signals due to the intermediate enol (E) and the two
diastereomers of ketone 14a (K): (a) after photolysis; (b) immediately
following addition of catalytic trifluoroacetic acid; (c) 5 min post addition;
(d) purified sample of 14a.
Figure 3. (a) The gauche 1,4-hydroxybiradical model; (b) the angle â.
Table 1. Solid-State Photolysis Results and Geometric Data for
Ketones 4a-e, 13a-e, and 16a-ea
n
ketone
product
cos æ1
cos æ4
â (deg)
reactionb
1
2
3
4
4a
13a
16a
10a
14a
17a
0.81
0.85
0.79
0.80
0.87
0.58
60
61
71
CL
CL
CL
4b
13b
16b
none
none
none
0.02
0.05
0.07
0.75
0.86
0.53
61
59
53
RHT
RHT
RHT
Methyl 9-Methylbicyclo[3.3.1]nonane-9-carboxylate (2). General
Procedure A. To a cold (-78 °C) solution of LDA (prepared from
19.5 mmol of DIPA and 18.1 mmol of n-butyllithium) in THF (60
mL) was added methyl bicyclo[3.3.1]nonane-9-carboxylate (1)18 (2.54
g, 13.9 mmol) in THF (30 mL) over 15 min. After the mixture was
stirred in the cold for 1.5 h, an additional portion of n-butyllithium
(9.6 mL of a 1.6 M solution in n-hexane, 15.3 mmol) was added
dropwise. The reaction was stirred for 30 min, followed by the addition
of DMPU (5.0 mL, 42 mmol). After 5 min, methyl iodide (9.89 g,
69.7 mmol) was added, and the reaction was stirred in the cold for 3
h before warming slowly to room temperature and stirring overnight.
The reaction was quenched with water and extracted with Et2O. The
combined ethereal extracts were washed with brine, dried (MgSO4),
and the solvent was removed in vacuo. Vacuum distillation afforded
4c
13c
16c
11c (trace 12c)
15c
18c
0.41
0.34
0.47
0.80
0.87
0.53
37
39
29
CY
CY
CY
4d
13d
16d
11d (trace 12d)
15d
18d
0.17
0.09
0.14
0.81
0.86
0.53
49
55
48
CY
CY
CY
acyclic 4e
13e
16e
19 (trace 20)
21
22
0.52
0.48
0.57
0.81
0.87
0.54
28
29
21
CY
CY
CY
a Assumes abstraction of the more favorably oriented γ-hydrogen in each
case. This is unambiguous for the majority of the ketones studied, but for
compounds 4a, 13a, and 16a, where the γ-hydrogens are nearly equidistant
from the carbonyl oxygen, the data represent average values for both
γ-hydrogens. The γ-hydrogen abstraction distances and angles for each
compound are tabulated in the Supporting Information. b CL ) cleavage;
RHT ) reverse hydrogen transfer; CY ) cyclization.
(25) This analysis is based on the reasonable assumption that ∆Sq does not
change appreciably with spiro ring size because (a) a four-membered ring
is being formed in each case, and (b) cyclization occurs in each case from
a fixed conformation with relatively few degrees of freedom. As a result,
∆Hq (difference in strain energy) is expected to be the determining factor
in the rate of ring closure.
no cyclization is observed when n ) 1 or 2. The effect of ring
strain is most clearly seen in the different behavior of the n )
2 and n ) 4 biradicals. The X-ray data show that these biradicals
(26) Because it is undetectable, the extent of reverse hydrogen transfer in the
photochemistry of ketones 4a,c,d,e; 13a,c,d,e; and 16a,c,d,e is unknown.
9
3516 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

1,4-Hydroxybiradicals
A R T I C L E S
the title compound as a colorless liquid (2.24 g, 82%). bp: 96-99
°C/6 mmHg. 1H NMR (CDCl3, 300 MHz): δ 1.23 (s, 3H), 1.34-2.05
(m, 14H), 3.67 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.30,
20.87, 23.83, 26.40, 29.39, 33.260, 46.17, 51.22, 178.80 ppm. IR
benzyl bromide. The crude product was purified by silica gel chroma-
tography (3% Et2O in petroleum ether) to give the title compound (680
mg, 91%) as a white solid. mp: 65-66 °C (Et2O/hexanes). H NMR
(CDCl3, 300 MHz): δ 1.38-2.30 (m, 14H), 3.01 (s, 2H), 3.45 (s, 3H),
7.02-7.26 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.26, 21.02,
26.79, 29.52, 32.22, 41.78, 50.62, 52.18, 126.40, 127.94, 129.33, 138.01,
175.84 ppm. IR (KBr): 2960, 2913, 2866, 1737, 1723, 1490, 1227,
1045, 740, 700 cm-1. HRMS (EI) calcd for C18H24O2 272.1776, found
272.1782. Anal. Calcd for C18H24O2: C, 79.37; H, 8.88. Found: C,
79.18; H, 8.79.
1
(neat): 2988, 2914, 2867, 1731, 1453, 1267, 1232, 1119, 1098 cm-1
HRMS (EI) calcd for C12H20O2 196.1463, found 196.1460.
.
9-Hydroxymethyl-9-methylbicyclo[3.3.1]nonane (3). General Pro-
cedure B. To a solution of ester 2 (2.18 g, 11.1 mmol) in THF (40
mL) was added lithium aluminum hydride (6.1 mL of a 1.0 M solution
in THF, 6.1 mmol). The reaction was allowed to reflux for 16 h. The
reaction was cooled and carefully quenched with aqueous saturated
sodium sulfate solution until large particles of white precipitate were
formed. The reaction mixture was filtered, and removal of THF in vacuo
gave an aqueous residue, which was extracted with Et2O. The combined
ethereal extracts were washed with brine and dried over MgSO4.
Removal of solvent in vacuo gave alcohol 3 (1.85 g, 99%) as a white
Spiro[2H-indene-2,9′-bicyclo[3.3.1]nonan]-1(3H)-one (4a). Gen-
eral Procedure D. To a cold (-78 °C) solution of ester 5a (416 mg,
1.53 mmol) in anhydrous dichloromethane (10 mL) was added boron
trichloride (15.3 mL of a 1.0 M solution in dichloromethane, 15.3 mmol)
over 10 min. The reaction was slowly warmed to 0 °C and stirred for
3 h before being poured onto crushed ice (15 g). Dichloromethane (125
mL) was added, and the mixture was stirred until all of the ice melted.
The organic phase was separated and successively washed with 5%
aqueous sodium carbonate, water, and brine, then dried (MgSO4) and
concentrated in vacuo. Silica gel chromatography (3% Et2O in
petroleum ether) afforded the title compound (323 mg, 88%) as a white
1
solid. mp: 117-119 °C (EtOAc/petroleum ether). H NMR (CDCl3,
300 MHz): δ 1.07 (s, 3H), 1.18 (br, 1H), 1.40-2.04 (m, 14H), 3.61
(s, 2H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.66, 21.43, 21.48, 27.22,
27.50, 32.91, 36.76, 69.45 ppm. IR (KBr): 3299 (br), 2950, 2911, 2868,
1453, 1024 cm-1. HRMS (EI) calcd for C11H20O 168.1514, found
168.1507. Anal. Calcd for C11H20O: C, 78.51; H, 11.98. Found: C,
78.91; H, 12.10.
9-(p-Carbomethoxybenzoyl)-9-methylbicyclo[3.3.1]nonane (4e).
General Procedure C. A mixture of PCC (3.71 g, 17.2 mmol) and
Celite 545 (5.00 g) was ground in a mortar and pestle until homoge-
neous. This solid was added to a solution of alcohol 3 (1.81 g, 10.8
mmol) in anhydrous dichloromethane (120 mL) and stirred for 2 h at
room temperature. The reaction mixture was filtered through a column
of Florisil, and the remaining solids were triturated well with anhydrous
Et2O. Removal of solvent in vacuo gave the corresponding aldehyde
(1.79 g, 99%) as a colorless oil, which was used without further
purification.
To a cold (-40 °C) solution of methyl 4-iodobenzoate (2.85 g, 10.9
mmol) in THF (60 mL) was added isopropylmagnesium chloride (5.7
mL of a 2.0 M solution in THF, 11.4 mmol) over 10 min. The reaction
was stirred in the cold for 1 h. A solution of the aldehyde (1.73 g, 10.4
mmol) obtained above in THF (20 mL) was added dropwise. The
reaction was stirred in the cold for 3 h and quenched with 5% aqueous
NH4Cl. THF was removed in vacuo, and the resultant aqueous phase
was extracted with Et2O. The combined ethereal extracts were washed
with brine, followed by drying (MgSO4) and removal of the solvent in
vacuo. Silica gel chromatography (14% EtOAc in petroleum ether)
afforded corresponding alcohol (2.82 g, 90%) as a white powder.
A mixture of PCC (3.09 g, 14.3 mmol) and Celite 545 (5.0 g) was
ground in a mortar and pestle until homogeneous. This solid was added
to a solution of the alcohol (2.71 g, 8.96 mmol) obtained above in
anhydrous dichloromethane (100 mL), and the reaction was stirred for
12 h at room temperature. The reaction mixture was filtered through a
column of Florisil, and the remaining solids were triturated well with
anhydrous Et2O. Removal of solvent in vacuo gave ketone 4e (2.69 g,
100%) as a white solid. mp: 137-138 °C (EtOAc/hexanes). 1H NMR
(CDCl3, 300 MHz): δ 1.48 (s, 3H), 1.32-1.94 (m, 10H), 2.08 (m,
2H), 2.29 (br, 2H), 3.92 (s, 3H), 7.74 (d, J ) 8.5 Hz, 2H), 8.03 (d, J
) 8.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.10, 20.89,
23.64, 26.71, 29.03, 33.74, 51.04, 52.32, 127.69, 129.27, 131.89, 143.20,
166.36, 209.71 ppm. IR (KBr): 2950, 2906, 2857, 1722, 1666, 1435,
1279, 1190, 1108, 862, 738 cm-1. UV/vis (1.46 × 10-4 M, MeOH):
285 (1459), 330 (194) nm (M-1 cm-1). HRMS (EI) calcd for C19H24O3
300.1725, found 300.1729. Anal. Calcd for C19H24O3: C, 75.97; H,
8.05. Found: C, 75.80; H, 8.00.
1
solid. mp: 105.5-107.5 °C (hexanes). H NMR (CDCl3, 300 MHz):
δ 1.48-2.12 (m, 12H), 2.52 (m, 2H), 3.16 (s, 2H), 7.28-7.69 (m, 4H)
ppm. 13C NMR (CDCl3, 75 MHz): δ 20.48, 20.55, 26.78, 29.37, 33.51,
38.94, 53.16, 123.94, 125.99, 127.10, 134.13, 136.87, 151.15, 209.99
ppm. IR (KBr): 2947, 2917, 2876, 1693, 1281, 936, 764, 727 cm-1
.
UV/vis (1.75 × 10-4 M, MeOH): 294 (2851), 340 (65) nm (M-1 cm-1).
HRMS (EI) calcd for C17H20O 240.1514, found 240.1514. Anal. Calcd
for C17H20O: C, 84.96; H, 8.39. Found: C, 84.59; H, 8.66.
Methyl 9-(2-Phenylethyl)bicyclo[3.3.1]nonane-9-carboxylate (5b).
Compound 5b was prepared by General Procedure A using 7.31 mmol
of LDA, 1.03 g (5.62 mmol) of methyl bicyclo[3.3.1]nonane-9-
carboxylate,18 n-butyllithium (3.9 mL of a 1.6 M solution in n-hexane,
6.18 mmol), 1.36 mL (11.3 mmol) of DMPU, and 1.14 mL (11.3 mmol)
of 2-bromo-1-phenylethane. The crude product was purified by silica
gel chromatography (3% Et2O in petroleum ether) to give the title
compound (1.31 g, 81%) as a colorless oil. 1H NMR (CDCl3, 300
MHz): δ 1.41-2.05 (m, 14H), 2.15 (br, 2H), 2.42 (m, 2H), 3.73 (s,
3H), 7.12-7.31 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.04,
21.29, 26.29, 29.46, 29.99, 31.97, 37.82, 49.74, 51.19, 125.79, 128.28,
128.36, 142.42, 177.03 ppm. IR (neat): 3025, 2950, 2914, 2867, 1728,
1455, 1239, 1197, 1163, 1050, 759, 699 cm-1. HRMS (CI) calcd for
C19H30NO2 (M + NH4+) 304.2277, found 304.2276. Anal. Calcd for
C19H26O2: C, 79.68; H, 9.15. Found: C, 79.61; H, 9.43.
3,4-Dihydrospiro[naphthalene-2(1H),9′-bicyclo[3.3.1]nonan]-1-
one (4b). Compound 4b was prepared by General Procedure D using
1.09 g (3.81 mmol) of ester 5b and 20.0 mL (20.0 mmol, 1.0 M in
dichloromethane) of boron trichloride. The crude product was purified
by silica gel chromatography (3% Et2O in petroleum ether) to give the
title compound (691 mg, 71%) as a white solid. mp: 92-93 °C (Et2O/
petroleum ether). 1H NMR (CDCl3, 300 MHz): δ 1.45-1.65 (m, 6H),
1.75-2.24 (m, 10H), 2.97 (t, J ) 6.3 Hz, 2H), 7.14 (d, J ) 7.6 Hz,
1H), 7.24 (dt, J ) 7.7, 0.9 Hz, 1H), 7.38 (dt, J ) 7.6, 1.5 Hz, 1H),
7.76 (dd, J ) 7.7, 1.1 Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz): δ
20.66, 21.62, 24.24, 27.46, 28.71, 30.74, 31.55, 47.35, 126.39, 127.46,
127.87, 132.00, 134.23, 141.92, 206.80 ppm. IR (KBr): 2926, 2857,
1685, 1286, 1226, 900, 757, 738 cm-1. UV/vis (1.89 × 10-4 M,
MeOH): 285 (2466), 330 (150) nm (M-1 cm-1). HRMS (EI) calcd for
C18H22O 254.1671, found 254.1671. Anal. Calcd for C18H22O: C, 84.99;
H, 8.72. Found: C, 85.15; H, 8.66.
Methyl 9-(2-Propenyl)bicyclo[3.3.1]nonane-9-carboxylate (6).
Compound 6 was prepared by General Procedure A using 21.9 mmol
of LDA, 3.07 g (16.8 mmol) of methyl bicyclo[3.3.1]nonane-9-
carboxylate,18 n-butyllithium (11.6 mL of a 1.6 M solution in n-hexane,
18.5 mmol), 4.1 mL (34 mmol) of DMPU, and 2.9 mL (34 mmol) of
allyl bromide. The crude product was purified by silica gel chroma-
Methyl 9-Benzylbicyclo[3.3.1]nonane-9-carboxylate (5a). Com-
pound 5a was prepared by General Procedure A using 3.56 mmol of
LDA, 500 mg (2.74 mmol) of methyl bicyclo[3.3.1]nonane-9-carboxyl-
ate,18 n-butyllithium (1.9 mL of a 1.6 M solution in n-hexane, 3.01
mmol), 662 µL (5.48 mmol) of DMPU, and 937 mg (5.48 mmol) of
9
J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3517

A R T I C L E S
Braga et al.
tography (3% Et2O in petroleum ether) and bulb-to-bulb distillation to
give the title compound (3.49 g, 93%) as a colorless liquid. bp: 125-
127 °C/6 mmHg. 1H NMR (CDCl3, 300 MHz): δ 1.40-2.00 (m, 12H),
2.05 (br, 2H), 2.43 (d, J ) 7.5 Hz, 2H), 3.68 (s, 3H), 4.98 (m, 2H),
5.65 (m, 1H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.07, 21.16, 26.26,
29.42, 31.80, 40.13, 50.48, 51.00, 117.03, 133.58, 176.52 ppm. IR
Spiro[6H-benzocycloheptene-6,9′-bicyclo[3.3.1]nonan]-5(7H)-
one (9a). General Procedure F. To a solution of ketone 8a (472 mg,
1.60 mmol) in degassed anhydrous dichloromethane (110 mL) was
added a solution of Grubbs’ catalyst (benzylidene-bis(tricyclohexyl-
phosphine)dichlororuthenium) (63 mg, 5 mol %) in degassed anhydrous
dichloromethane over 10 min. The initial purple color was replaced
by a light golden brown color. The reaction was stirred at room
temperature for 12 h. The reaction solution was filtered through Florisil,
and the solvent was removed in vacuo. Silica gel chromatography (8%
Et2O in petroleum ether) afforded the enone 9a (416 mg, 97%) as a
pale yellow solid. Further purification by recrystallization from EtOAc/
petroleum ether provided colorless crystals. mp: 101-102 °C (EtOAc/
petroleum ether). 1H NMR (CDCl3, 300 MHz): δ 1.38-2.03 (m, 12H),
2.19 (br, 2H), 2.62 (dd, J ) 2.8, 5.2 Hz, 2H), 5.81 (dt, J ) 5.2 and
12.2 Hz, 1H), 6.38 (d, J ) 12.2 Hz, 1H), 7.11 (d, J ) 7.5 Hz, 1H),
7.26 (dt, J ) 7.5 and 1.0 Hz, 1H), 7.36 (dt, J ) 7.5 and 1.5 Hz, 1H),
7.50 (d, J ) 7.5 Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz): δ 20.25,
21.48, 26.97, 28.96, 31.31, 35.37, 49.69, 127.21, 127.52, 129.35, 130.01,
130.73, 130.83, 132.87, 138.21, 209.72 ppm. IR (KBr): 3019, 2911,
2869, 1677, 1460, 1261, 925, 779, 764 cm-1. UV/vis (1.95 × 10-4 M,
MeOH): 270 (4049), 310 (2466) nm (M-1 cm-1). HRMS (EI) calcd
for C19H22O 266.1671, found 266.1671. Anal. Calcd for C19H22O: C,
85.67; H, 8.32. Found: C, 85.71; H, 8.44.
(neat): 2960, 2912, 2866, 1731, 1460, 1214, 1186, 1120, 912 cm-1
.
HRMS (EI) calcd for C14H22O2 222.1620, found 222.1620. Anal. Calcd
for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.97; H, 10.14.
9-Hydroxymethyl-9-(2-propenyl)bicyclo[3.3.1]nonane (7). Com-
pound 7 was prepared by General Procedure B using 3.36 g (15.1 mmol)
of ester 6 and 8.3 mL (8.3 mmol, 1.0 M solution in THF) of lithium
aluminum hydride. The crude product was purified by silica gel
chromatography (25% Et2O in petroleum ether) to give the title
compound (2.67 g, 91%) as a white solid. mp: 51-52 °C (Et2O/
1
pentane). H NMR (CDCl3, 400 MHz): δ 1.38-2.10 (m, 14H), 2.37
(d, J ) 7.5 Hz, 2H), 3.75 (s, 2H), 5.02-5.17 (m, 2H), 5.89 (m, 1H)
ppm. 13C NMR (CDCl3, 100 MHz): δ 20.86, 21.07, 26.97, 27.24, 31.02,
37.03, 39.66, 65.10, 116.89, 135.56 ppm. IR (KBr): 3371 (br), 3072,
2911, 2876, 1637, 1487, 1463, 1048, 1009, 910 cm-1. HRMS (CI) calcd
for C13H26NO (M + NH4+) 212.2015, found 212.2015. Anal. Calcd
for C13H22O: C, 80.35; H, 11.41. Found: C, 80.06; H, 11.54.
9-(2-Propenyl)-9-(o-vinylbenzoyl)bicyclo[3.3.1]nonane (8a). Gen-
eral Procedure E. A mixture of PCC (1.42 g, 6.59 mmol) and Celite
545 (3.09 g) was ground in a mortar and pestle until homogeneous.
This solid was added to a solution of alcohol 7 (927 mg, 4.77 mmol)
in anhydrous dichloromethane (150 mL) and stirred for 2 h at room
temperature. The reaction mixture was filtered through a column of
Florisil, and the remaining solids were triturated well with anhydrous
Et2O. Removal of solvent in vacuo gave the corresponding aldehyde
(915 mg, 99%) as a colorless oil, which was used without further
purification.
8,9-Dihydrospiro[6H-benzocycloheptene-6,9′-bicyclo[3.3.1]nonan]-
5(7H)-one (4c). General Procedure G. A suspension of 10% palladium
on charcoal (18 mg) and enone 9a (186 mg, 0.70 mmol) in EtOAc (25
mL) was placed under an atmosphere of H2. The mixture was stirred
for 4 h and filtered through Celite 545. Removal of the solvent in vacuo
afforded ketone 4c (180 mg, 96%) as a white solid. Recrystallization
from Et2O/hexanes provided colorless crystals. mp: 75-76 °C. 1H
NMR (CDCl3, 300 MHz): δ 1.37-1.58 (m, 6H), 1.68-2.10 (m, 12H),
2.84 (m, 2H), 7.08 (m, 1H), 7.18-7.33 (m, 3H) ppm. 13C NMR (CDCl3,
75 MHz): δ 20.06, 21.07, 23.69, 26.53, 28.95, 32.59, 35.77, 36.26,
53.48, 126.03, 128.18, 128.53, 129.25, 137.69, 141.96, 213.51 ppm.
IR (KBr): 2914, 2864, 1679, 1446, 1260, 951, 770, 740 cm-1. UV/vis
(1.49 × 10-4 M, MeOH): 275 (1294), 315 (338) nm (M-1 cm-1).
HRMS (EI) calcd for C19H24O 268.1827, found 268.1827. Anal. Calcd
for C19H24O: C, 85.03; H, 9.01. Found: C, 85.29; H, 9.17.
To a suspension of Mg turnings (570 mg, 23.8 mmol) in THF (30
mL) was added 1,2-dibromoethane (50 µµL). The mixture was gently
heated for 2 min. 2-Bromostyrene (1.83 g, 10.0 mmol) was then added
slowly so as to maintain a gentle reflux, and the reaction was stirred
for 1 h. The aldehyde (915 mg, 4.76 mmol) obtained above in THF
(20 mL) was added dropwise, and the reaction was stirred for 2 h at
room temperature. The reaction was quenched with 1 M HCl and diluted
with Et2O. The organic phase was separated and washed successively
with water and brine. The organic layer was dried (MgSO4), and the
solvent was removed in vacuo. Silica gel chromatography (5% Et2O
in petroleum ether) afforded the corresponding alcohol (1.12 g, 79%
from 7) as a white solid (mp: 80-82 °C Et2O/petroleum ether).
A mixture of PCC (1.20 g, 5.57 mmol) and Celite 545 (2.50 g) was
ground in a mortar and pestle until homogeneous. This solid was added
to a solution of the alcohol (1.10 g, 3.71 mmol) obtained above in
anhydrous dichloromethane (150 mL), and the resulting mixture was
stirred for 12 h at room temperature. The reaction mixture was filtered
through a column of Florisil, and the remaining solids were triturated
well with anhydrous Et2O. Removal of solvent in vacuo and silica gel
chromatography (5% Et2O in petroleum ether) gave ketone 8a (673
mg, 61%) as a colorless oil, which solidified upon standing. mp: 53-
54 °C (Et2O/petroleum ether). 1H NMR (CDCl3, 300 MHz): δ 1.34-
1.71 (m, 8H), 1.83 (m, 2H), 2.08 (m, 2H), 2.29 (br, 2H), 2.78 (d, J )
7.3 Hz, 2H), 5.04 (m, 2H), 5.27 (dd, J ) 11.2 and 11.0 Hz, 1H), 5.70
(m, 2H), 7.00 (dd, J ) 11.0 and 17.4 Hz, 1H), 7.21 (dt, J ) 7.6 and
1.2 Hz, 1H), 7.36 (dt, J ) 7.8 and 1.2 Hz, 1H), 7.55 (dd, J ) 7.8 and
1.2 Hz, 1H), 7.61 (d, J ) 7.9 Hz, 1H) ppm. 13C NMR (CDCl3, 75
MHz): δ 19.81, 20.99, 26.71, 28.94, 32.38, 39.60, 55.20, 116.32,
117.18, 124.85, 126.26, 127.46, 129.82, 133.57, 135.09, 137.63, 139.16,
209.75 ppm. IR (KBr): 3075, 2916, 2867, 1672, 1475, 1216, 994, 914,
769, 739 cm-1. HRMS (EI) calcd for C21H26O 294.1984, found
294.1984. Anal. Calcd for C21H26O: C, 85.67; H, 8.90. Found: C,
85.39; H, 8.94.
9-(2-Propenyl)-9-[o-(2-propenyl)benzoyl]bicyclo[3.3.1]nonane (8b).
Compound 8b was prepared by General Procedure E. PCC (1.50 g,
6.96 mmol) was used to oxidize alcohol 7 (1.08 g, 5.56 mmol) to give
the corresponding aldehyde (1.04 g, 97%) as a colorless oil; Mg turnings
(649 mg, 27.0 mmol), 2-propenylbromobenzene27 (2.26 g, 11.5 mmol),
and this aldehyde (1.04 g, 5.41 mmol) reacted to afford the corre-
sponding alcohol (1.29 g, 75%) as a colorless oil. Oxidation of this
alcohol (1.20 g, 3.86 mmol) with PCC (1.25 g, 5.80 mmol) was
followed by silica gel chromatography (6% Et2O in petroleum ether)
to give the title compound (988 mg, 83%) as a colorless oil, which
1
solidified upon standing. mp: 54-56 °C (Et2O/petroleum ether). H
NMR (CDCl3, 300 MHz): δ 1.35-1.71 (m, 8H), 1.84 (m, 2H), 2.09
(m, 2H), 2.30 (br, 2H), 2.80 (d, J ) 7.3 Hz, 2H), 3.44 (d, J ) 6.8 Hz,
2H), 5.07 (m, 4H), 5.74 (m, 1H), 6.02 (m, 1H), 7.14 (m, 1H), 7.32 (d,
J ) 3.9 Hz, 2H), 7.55 (d, J ) 7.8 Hz, 1H) ppm. 13C NMR (CDCl3, 75
MHz): δ 19.83, 20.97, 26.70, 28.95, 32.33, 37.44, 39.64, 55.17, 115.95,
117.10, 124.77, 124.97, 129.67, 131.27, 133.63, 137.64, 139.61, 139.78,
209.89 ppm. IR (KBr): 3074, 2915, 2868, 1672, 1637, 1460, 1217,
995, 914, 743 cm-1. HRMS (EI) calcd for C22H28O 308.2140, found
308.2139. Anal. Calcd for C22H28O: C, 85.66; H, 9.15. Found: C,
86.00; H, 9.27.
Spiro[6H-benzocyclooctene-6,9′-bicyclo[3.3.1]nonan]-5(7H,10H)-
one (9b). Compound 9b was prepared by General Procedure F using
670 mg (2.17 mmol) of ketone 8b and 54 mg (3 mol %) of Grubbs’
catalyst (benzylidene-bis(tricyclohexylphosphine)dichlororuthenium).
(27) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int.
Ed. 1998, 37, 1701.
9
3518 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

1,4-Hydroxybiradicals
A R T I C L E S
The crude product was purified by silica gel chromatography (5% Et2O
in petroleum ether) to give the title compound (578 mg, 95%) as an
off-white solid. Recrystallization from hexanes provided colorless
isolated was 1-indanone (3 mg, 11%, 17% based on recovered starting
material) resulting from secondary photocleavage of ketone 10a.
1
Ketone 10a (Equal Mixture of Two Epimers). H NMR (CDCl3,
1
crystals. mp: 83-84 °C (hexanes). H NMR (CDCl3, 300 MHz): δ
300 MHz): δ 0.98-1.67 (m, 6H), 1.97-2.43 (m, 5H), 2.63 (m, 1H),
2.87 (m, 1H), 3.16 (m, 1H), 5.64 (m, 2H), 7.33 (m, 1H), 7.43 (m, 1H),
7.55 (m, 1H), 7.72 (m, 1H) ppm. 13C NMR (CDCl3, 75 MHz): δ 24.75,
24.86, 25.68, 25.71, 27.93, 28.16, 28.88, 28.94, 29.67, 30.38, 31.30,
34.62, 37.57, 38.63, 54.30, 54.51, 123.56, 123.69, 126.42, 126.47,
127.18 (two accidentally equivalent), 129.66, 130.01, 130.12, 130.57,
134.48 (two accidentally equivalent), 137.89, 138.04, 154.27, 154.67,
208.70, 208.88 ppm. IR (neat): 3013, 2923, 2853, 1709, 1610, 1464,
1282, 750, 732 cm-1. HRMS (EI) calcd for C17H20O 240.1514, found
240.1516. Anal. Calcd for C17H20O: C, 84.96; H, 8.39. Found: C,
85.06; H, 8.61.
1.50-1.75 (br m, 6H), 1.80-2.05 (br m, 6H), 2.21 (br, 1H), 2.45 (br
m, 3H), 3.48 (br m, 2H), 5.57-5.75 (m, 2H), 7.05-7.26 (m, 4H) ppm.
13C NMR (CDCl3, 75 MHz): δ 20.01, 21.38, 26.81 (br), 28.10 (br),
28.32 (br), 30.10 (br), 31.05 (br), 31.73, 32.88 (br), 35.69, 57.33, 124.90,
125.46, 125.89, 128.26, 128.93, 129.84, 135.43, 141.14, 213.58 ppm,
slow conformational exchange at room temperature has broadened and
split some of the carbon signals. IR (KBr): 2912, 2867, 1694, 1458,
1120, 951, 936, 772, 727 cm-1. UV/vis (1.78 × 10-4 M, MeOH): 265
(286), 315 (118) nm (M-1 cm-1). HRMS (EI) calcd for C20H24O
280.1827, found 280.1828. Anal. Calcd for C20H24O: C, 85.67; H, 8.63.
Found: C, 85.59; H, 8.80.
Ketone 10a was also found to be the major product (67%, at 6%
conversion) resulting from irradiation of crystals of spiroketone 4a;
compounds 1-indanone, 1,4-cyclooctadiene, and 1,5-cyclooctadiene
were also observed by GC-MS, presumably through the competitive
enol-keto tautomerization and secondary photolysis seen in solution
(GC).
8,9-Dihydrospiro[6H-benzocyclooctene-6,9′-bicyclo[3.3.1]nonan]-
5(7H,10H)-one (4d). Compound 4d was prepared by General Procedure
G using 249 mg (0.89 mmol) of ketone 9b and 25 mg of 10% palladium
on charcoal. Filtration gave the title compound (241 mg, 96%) as a
white solid. Recrystallization from hexanes provided colorless crystals.
1
mp: 102-103 °C. H NMR (CDCl3, 300 MHz): δ 1.22-2.32 (br m,
Photolysis of Spiroketone 4b. Irradiation (>24 h) of a 2:1 tert-
butyl alcohol/benzene or acetonitrile solution of spiroketone 4b resulted
in only trace amounts (<1%) of unidentified short retention time peaks
on GC. Photolysis of spiroketone 4b in the solid state (>48 h) also led
to no detectable photoproducts.
18H), 2.52-2.96 (br m, 2H), 7.05-7.25 (m, 4H) ppm. 13C NMR
(CDCl3, 75 MHz): δ 19.74, 21.76, 22.06, 25.77 (br), 27.87 (br), 28.10
(br), 29.18, 29.42 (br), 31.80 (br), 32.61, 33.12 (br), 34.04, 55.44,
124.59, 124.92, 128.29, 130.17, 139.70, 140.78, 215.29, slow confor-
mational exchange at room temperature has broadened and split some
of the carbon signals. IR (KBr): 2911, 2867, 1685, 1448, 935, 753
cm-1. UV/vis (1.56 × 10-4 M, MeOH): 265 (247), 315 (95) nm (M-1
cm-1). HRMS (EI) calcd for C20H26O 282.1984, found 282.1983. Anal.
Calcd for C20H26O: C, 85.06; H, 9.28. Found: C, 84.94; H, 9.59.
Photochemical Studies. General Considerations. Both solution and
solid-state photolyses were carried out by using a 450 W Hanovia
medium-pressure mercury lamp in a water-cooled immersion well. Light
from the lamp was filtered through a Pyrex (λ g 290 nm) immersion
well.
Photolysis of Spiroketone 4c. A solution of ketone 4c (70 mg, 0.26
mmol) in 2:1 tert-butyl alcohol/benzene (50 mL) was purged with
nitrogen for 30 min and irradiated (Pyrex filter, 450 W Hanovia) for
56 h. Removal of solvent in vacuo followed by silica gel chromatog-
raphy (6% Et2O in petroleum ether) afforded starting material 4c (14
mg, 20%) and cyclobutanol 11c (37 mg, 53%; 66% based on recovered
starting material) as a colorless oil. Also isolated was a mixture of two
components (2 mg, 3%). Careful examination of the 1H NMR spectrum
of this mixture revealed that one component was cyclobutanol 11c and
another component was an alkene (12c) bearing characteristic vinyl
proton signals similar to those of alkene 20. Further attempts to purify
12c were not successful because of its small quantity and polarity similar
to that of 11c.
For preparative scale solution-state photolyses, samples were dis-
solved in HPLC grade or spectral grade solvents and were purged with
nitrogen for at least 15 min prior to irradiation. In the case of ketones
4a, 13a, and 16a, anhydrous barium oxide was added to scavenge any
acidic impurities that might promote the tautomerization of intermediate
enols to ketone epimers. By doing so, secondary photocleavage of the
ketone epimers was kept to a minimum. The reactions were performed
either in sealed reaction vessels or under a positive pressure of nitrogen.
Yields and conversions were calculated on the basis of the mass of the
isolated products.
1
endo-Arylcyclobutanol 11c. H NMR (C6D6, 400 MHz): δ 0.93
(m, 1H), 1.02 (br, 1H), 1.15 (m, 1H), 1.30-1.79 (m, 9H), 1.91 (m,
1H), 2.04 (m, 2H), 2.20 (m, 1H), 2.44 (m, 1H), 2.59 (m, 1H), 2.79 (m,
1H), 3.25 (m, 1H), 7.01 (m, 3H), 7.19 (m, 1H) ppm. 13C NMR (C6D6,
100 MHz): δ 18.93, 20.98, 22.37, 23.46, 25.72, 27.69, 30.01, 31.90,
36.77, 37.91, 48.21, 48.70, 83.01, 125.39, 125.88, 127.16, 131.57,
142.27, 143.21 ppm. IR (KBr): 3459, 2927, 2874, 1006, 968, 757,
740 cm-1. HRMS (EI) calcd for C19H24O 268.1827, found 268.1829.
Anal. Calcd for C19H24O: C, 85.03; H, 9.01. Found: C, 85.08; H, 9.38.
endo-Arylcyclobutanol 11c and alkene 12c were also found to be
the only two products (96% and 4%, respectively, at 18% conversion)
resulting from irradiation of crystals of spiroketone 4c (GC).
For analytical solid-state photolyses, ground solid samples (5-10
mg) were sandwiched between two microscopic slides. The sample
plates were then fixed to one another with tape and placed in a
polyethylene bag, and heat-sealed under a positive pressure of nitrogen.
Following irradiation, the samples were quantitatively washed from
the plates with an appropriate solvent and concentrated in vacuo. The
samples were analyzed directly by GC and/or NMR spectroscopy.
Yields and conversions of the solid-state reactions were determined
on the basis of the average integration of at least two GC analyses.
The overall precision of the reported GC results is estimated to be (1%.
In the case of ketones 13c and 13d, where GC analyses were hampered
Photolysis of Spiroketone 4d. A solution of ketone 4d (179 mg,
0.63 mmol) in 2:1 tert-butyl alcohol/benzene (50 mL) was irradiated
(Pyrex filter, 450 W Hanovia) for 156 h. Removal of the solvent in
vacuo followed by silica gel chromatography (8% Et2O in petroleum
ether) gave starting material 4d (47 mg, 26%) and an oily mixture of
11d and 12d (92 mg, 51%; 69% based on recovered starting material).
Attempts to separate 11d and 12d failed due to similar polarity of these
two compounds. NMR analysis revealed that this mixture consisted of
one secondary alcohol and one tertiary alcohol. The oxidizing reagent
TPAP (tetrapropylammonium perruthenate)/NMO (4-methylmorpholine
N-oxide)28 was used to oxidize the secondary alcohol component to
the corresponding ketone 12do, which showed a significant difference
in polarity to the tertiary alcohol component. Silica gel chromatography
1
by the thermal lability of the photoproducts, H NMR and 13C NMR
analyses of the crude solid-state photosylates were conducted to
determine their composition.
Photolysis of Spiroketone 4a. A solution of ketone 4a (51 mg, 0.21
mmol) in 2:1 tert-butyl alcohol/benzene (20 mL) containing anhydrous
barium oxide (14 mg) was irradiated (Pyrex filter, 450 W Hanovia
lamp) for 2.5 h at room temperature. Removal of solvent and silica gel
chromatography (5% Et2O in petroleum ether) afforded starting material
4a (19 mg, 37%) and ketone epimers (∼1:1 by 1H NMR) 10a (18 mg,
35%; 56% based on recovered starting material) as a colorless oil. Also
(28) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 7,
639.
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J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3519

A R T I C L E S
Braga et al.
(8% Et2O in petroleum ether) provided 11d (73 mg, 41%; 55% based
on recovered starting material) and 12do (17 mg, 9%; 13% based on
recovered starting material). Oily compound 11d solidified upon
standing, while compound 12do remained an oil.
8.11 (d, J ) 8.2 Hz, 2H) ppm. 13C NMR (C6D6, 100 MHz): δ 17.70,
18.61, 20.46, 22.87, 24.61, 27.73, 36.19, 37.62, 46.42, 46.79, 51.61,
81.87, 125.73, 129.45, 130.32, 149.34, 166.64 ppm. IR (KBr): 3482,
2958, 2927, 2879, 1723, 1609, 1439, 1279, 1106, 861, 781, 712 cm-1
.
1
endo-Arylcyclobutanol 11d. mp: 62-64 °C (hexanes). H NMR
HRMS (EI) calcd for C19H24O3 300.1725, found 300.1726. Anal. Calcd
for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.96; H, 8.28.
(C6D6, 400 MHz): δ 0.99 (m, 1H), 1.04 (br, 1H), 1.21 (m, 1H), 1.30-
1.50 (m, 4H), 1.51-1.70 (m, 5H), 1.75-1.90 (m, 3H), 2.00 (m, 1H),
2.36 (m, 2H), 2.51 (1H, m), 2.61 (m, 1H), 2.70 (m, 1H), 2.90 (m, 1H),
6.98 (m, 1H), 7.04 (m, 2H), 7.13 (m, 1H) ppm. 13C NMR (C6D6, 100
MHz): δ 18.79, 20.75, 22.87, 25.37, 25.69, 27.15, 27.24, 27.80, 32.76,
34.63, 36.57, 48.25, 49.82, 82.17, 126.17, 127.25, 127.26, 131.82,
141.92, 143.48 ppm. IR (KBr): 3471, 2928, 2870, 1455, 983, 964,
771, 740 cm-1. HRMS (EI) calcd for C20H26O 282.1984, found
282.1985. Anal. Calcd for C20H26O: C, 85.06; H, 9.28. Found: C,
85.03; H, 9.63.
Ketone 12do. 1H NMR (C6D6, 400 MHz): δ 1.02-1.80 (m, 13H),
2.32 (br, 2H), 2.46 (br, 1H), 2.81 (m, 1H), 3.14 (m, 1H), 5.60 (m, 1H),
5.86 (m, 1H), 6.90-6.99 (m, 2H), 7.05 (m, 1H), 7.35 (m, 1H) ppm.
13C NMR (C6D6, 100 MHz): δ 16.97, 19.27, 23.32, 29.37, 30.55, 30.82,
31.32, 32.56, 34.56, 54.42, 125.00, 125.80, 128.42, 129.88, 130.41,
132.08, 137.82, 142.89, 212.72 ppm. IR (neat): 3015, 2914, 2865, 1683,
1446, 972, 756, 710 cm-1. HRMS (EI) calcd for C20H24O 280.1827,
found 280.1831. Anal. Calcd for C20H24O: C, 85.67; H, 8.63. Found:
C, 85.67; H, 8.65.
1
Alkene 20. mp: 148-150 °C (CHCl3/hexanes). H NMR (C6D6,
400 MHz): δ 0.85 (s, 3H), 1.03-1.12 (m, 2H), 1.20-1.30 (m, 3H),
1.48-1.80 (m, 4H), 2.35 (br, 1H), 2.53(br, 1H), 3.53 (s, 3H), 4.30 (s,
1H), 5.62 (m, 1H), 5.83 (m, 1H), 7.29 (d, J ) 8.3 Hz, 2H), 8.13 (d, J
) 8.3 Hz, 2H) ppm. 13C NMR (C6D6, 75 MHz): δ 15.71, 16.52, 24.57,
29.36, 32.11, 32.90, 36.16, 40.09, 51.57, 75.22, 128.05, 128.55, 129.04,
129.19, 129.35, 148.50, 166.82 ppm. IR (KBr): 3524, 3017, 2921, 2862,
1723, 1706, 1610, 1436, 1281, 1111, 1016, 860, 772, 724 cm-1. HRMS
(CI) calcd for C19H28NO3 (M + NH4+) 318.2069, found 318.2069. Anal.
Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.89; H, 8.36.
endo-Arylcyclobutanol 19 and alkene 20 were also observed (92%
and 6%, respectively, at 25% conversion) in the solid-state photolysis
of ketone 4e (GC).
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial support.
J.R.S. thanks the Institute of Advanced Studies, University of
Bologna, for sabbatical support in the form of a Senior Guest
Fellowship. D.B. acknowledges MIUR and the University of
Bologna for financial support.
The structure of photoproduct 12d was deduced on the basis of the
spectral data of its derivative ketone 12do.
endo-Arylcyclobutanol 11d and alkene 12d were also found to be
the only two products (81% and 19%, respectively, at 9% conversion)
resulting from irradiation of crystals of spiroketone 4d (GC).
Photolysis of Ketone 4e. A solution of ketone 4e (501 mg, 1.67
mmol) in acetonitrile (50 mL) was irradiated (Pyrex filter, 450 W
Hanovia) for 6 h. Removal of the solvent in vacuo followed by silica
gel chromatography (11% EtOAc in petroleum ether) afforded cy-
clobutanol 19 (446 mg, 89%) and alkene 20 (27 mg, 5%).
endo-Arylcyclobutanol 19. mp: 149-150 °C (EtOAc/petroleum
Supporting Information Available: Crystallographic infor-
mation files (CIF) for previously unreported crystal structures,
experimental details of the synthesis and photochemistry of
ketones 13a-e and 16a-e, table of geometric data showing
the hydrogen atom abstraction geometries for ketones 4a-e,
13a-e, and 16a-e, and a figure showing the NOE interactions
used in establishing the stereochemistry of photoproducts 11c,
18c-d, 21, and 22 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
1
ether). H NMR (C6D6, 400 MHz): δ 0.85 (m, 1H), 0.98 (m, 1H),
1.20 (s, 3H), 1.21-1.35 (m, 3H), 1.45-1.65 (m, 5H), 1.83 (m, 2H),
2.52 (m, 1H), 2.66 (m, 1H), 3.53 (s, 3H), 7.09 (d, J ) 8.2 Hz, 2H),
JA039076W
9
3520 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004