From dimerization, to cycloaddition, to atom transfer cyclization: The further chemistry of TMM diradicals

Article abstract of DOI:10.1021/jo048717i

We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloadd

Full text of DOI:10.1021/jo048717i

From Dimerization, to Cycloaddition, to Atom Transfer
Cyclization: The Further Chemistry of TMM Diradicals†
Arup Maiti, James B. Gerken, Mohammad R. Masjedizadeh,‡ Yvette S. Mimieux, and
R. Daniel Little*
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
Santa Barbara, California 93106
little@chem.ucsb.edu
Received July 26, 2004
We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely
tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples
of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC,
and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be
the preferred path, and when the two processes will be competitive. Remarkably, a wide variety of
structures can be obtained simply by varying the length of the tether within the diazenes
investigated. DFT calculations were used to probe the energy surfaces for both atom transfer and
cycloaddition. The transition structure for atom transfer involving the captodative system indicates
that it occurs earlier along the reaction coordinate than for a system having only one radical
stabilizing group. This is consistent with the existence of an exothermic process leading from the
initial diyl to the captodatively stabilized distonic diyl. Gratifyingly, theory agrees with observation
and provides substantial insight into the chemistry.
SCHEME 1
Introduction
Cyclopentatrimethylenemethane diradicals 1 (cyclo-
pentaTMM diyls) can be intercepted intermolecularly
by alkenes, alkynes, allenes, azodicarboxylates, and
oxygen, as well as certain aldehydes, ketones, imines, and
thioketones.1 In so doing, both carbo- and heterocyclic
systems can be constructed. These versatile intermedi-
ates also undergo a process we refer to as “atom transfer
cyclization” (ATC).2 This sequence has been less thor-
oughly explored than cycloaddition, and has only once
been applied to total synthesis.3 We wondered whether
there were circumstances wherein ATC and the more
thoroughly investigated intramolecular cycloaddition
(IDTR: intramolecular diyl trapping reaction)4 might be
competitive, and whether it was possible to determine
circumstances under which one or the other of these
reaction pathways would dominate (note Scheme 1). In
this paper we describe [a] the first examples of intramo-
lecular cycloaddition of a TMM diyl to a remotely tethered
aldehyde, [b] the effect of a Lewis acid upon the course
of TMM chemistry, [c] examples of exclusive intramo-
lecular cycloaddition, competitive cycloaddition and ATC,
and exclusive ATC, and [d] a set of predictive guidelines
with which to assess whether cycloaddition or ATC will
be the preferred path, and when the two processes will
be competitive.
Four diyls, 9-12, differing in the length of the meth-
ylene chain, n, and the nature of X, were studied. Their
diazene precursors, 5-8, were synthesized in the manner
portrayed in Scheme 2. As we have described previously,4
the routes have four integral components: (1) assembly
of the alkyl chain, (2) fulvene formation, (3) Diels-Alder
cycloaddition, and (4) conversion of a biscarbamate to a
diazene linkage. Details are illustrated in Scheme 2 and
described in the Experimental Section.
† We dedicate this paper to Professor Jerome Bersonsfriend, mentor,
and the founder of cyclopenta TMM diradical researchson the occasion
of his 80th birthday.
‡ Present address: Roche Palo Alto, Palo Alto, CA.
(1) (a) Little, R. D.; Bode, H.; Stone, K. J.; Wallquist, O.; Dannecker,
R. J. Org. Chem. 1985, 50 (13), 2400. (b) Berson, J. A. In Diradicals;
Borden, W. T., Ed.; Wiley: New York, 1982; Chapter 4.
(2) (a) Billera, C. F.; Little, R. D. J. Am. Chem. Soc. 1994, 116 (12),
5487. (b) Byers, J. Atom Transfer Reactions. In Radicals In Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: New York, 2001;
Vol. 1, Chapter 1.5. (c) Feray, L.; Kuznetsov, N.; Renaud, P. Hydrogen
Atom Abstraction. In Radicals In Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: New York, 2001; Vol. 1, Chapter 3.6.
(3) Carroll, G. L.; Allan, A. K.; Schwaebe, M. K.; Little, R. D. Org.
Lett. 2000, 2 (16), 2531.
(4) (a) Allan, A. K.; Carroll, G. L.; Little, R. D. Eur. J. Org. Chem.
1936, 1, 1. (b) Little, R. D. Chem. Rev. 1996, 96 (1), 93.
10.1021/jo048717i CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
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J. Org. Chem. 2004, 69, 8574-8582

Cyclopentatrimethylenemethane Diradicals
SCHEME 2
now renders the unit susceptible to attack. We suspect
that the product is formed via the attack of a dipolar diyl
(a species with more dipolar character than diradical)7
upon the polarized carbonyl unit to afford 30, which
subsequently collapses to form 31.
SCHEME 4
In contrast to the dimerization that is observed in the
chemistry of the diyl derived from 5, cycloaddition does
occur when the length of the tether is increased by one
methylene unit. Thus, diazene 6 (n ) 2, X ) H) smoothly
and efficiently undergoes cycloaddition. Atom transfer is
not observed. The reaction can be conducted thermally
(in the presence or absence of zinc chloride) or photo-
chemically (450 W Hanovia, Pyrex filter, acetonitrile), the
latter being the cleaner and more efficient process (77-
78% vs 65%). Cycloaddition rather than atom transfer
is also the case starting from the more elaborate diazene
7, despite the fact that atom transfer would have afforded
a captodatively stabilized diradical 34.8 That it did not
occur is consistent with the inability of diyl 35 to achieve
an “appropriate” transfer angle, R (see 35, and note the
discussion that occurs later), between either CF or Cꢀ and
the hydrogen to be transferred. Once again the tether is
too short. In both instances (viz., with 6 and 7) it is ideal
for the formation of a five-membered ring, and this is the
pathway that is observed.
Results and Discussion
In each instance, the TMM diyl was generated by
adding the precursor diazene to a refluxing solution of
toluene. When n ) 1 and X ) H (viz., diazene 5), diyl
dimerization occurs. The tether is simply too short to
allow the requisite centers to attain a geometry that is
suitable for atom transfer (vide infra). That cycloaddition
was not observed is presumably a reflection of the
difference between the π-bond strength of a CdO vs a
CdC bond, or a reversible cyclization of 24.5a This
conjecture is corroborated by the fact that the analogous
diyl 27 containing a C-C π-bond in place of the carbonyl
does undergo cycloaddition.5b
SCHEME 3
SCHEME 5
Interestingly, this limitation can be overcome by using
a Lewis acid.6 Thus, when heated to reflux in THF
containing zinc chloride, 5 is smoothly converted to the
[4.3.0] diene alcohol 31 in yields of 65-70%. Clearly
complexation of the Lewis acid to the carbonyl oxygen
(5) (a) A reviewer has offered a reasonable alternative explanation.
The rationale posits that a reversible cyclization of 24 would lead to
an unstabilized oxygen-centered radical that would quickly revert to
24. In contrast, both the cyclization of 27 and 29 would afford a
stabilized radical. Perhaps, as the reviewer suggested, stabilization
increases the lifetime of the intermediate enough to allow formation
of the second σ-bond to occur. (b) Campopiano, O.; Little, R. D.;
Petersen, J. L. J. Am. Chem. Soc. 1985, 107 (12), 3721.
To investigate these issues further we conducted DFT
calculations using the UB3LYP/6-31G* basis set to probe
(7) Little, R. D.; Brown, L. M.; Masjedizadeh, M. R. J. Am. Chem.
Soc. 1992, 114 (8), 3071.
(8) (a) Beckwith, A. L. J. Chem. Soc. Rev. 1993, 22 (3), 143. (b)
Gaudiano, G.; Koch, T. H. Chem. Res. Tox. 1991, 4 (1), 2. (c) Nootens,
C.; Merenyi, R.; Janousek, Z.; Viehe, H. G. Bull. Soc. Chim. Belg. 1988,
97 (11-12), 1045. (d) Cossy, J.; Madaci, A.; Pete, J. P. Tetrahedron
Lett. 1994, 35 (10), 1541.
(6) The transformations appearing in this paper represent the first
reported examples of the use of Lewis acids in conjunction with TMM
diyl chemistry.
J. Org. Chem, Vol. 69, No. 25, 2004 8575

Maiti et al.
note that our previous studies placed either an R-hydroxy
ester or an R-hydroxy nitrile at the end of the tether. In
8 a single aldehyde unit has replaced the two radical
stabilizing groups. We wondered whether a single ester
would work just as well. It does not. When CHO is
replaced by CO2Me, the resulting diyl dimerizes rather
than engaging in either ATC or cycloaddition.
Like 5, the presence of a Lewis acid changes the course
of the chemistry. Thus, no atom transfer is observed
when diazene aldehyde 8 is heated in refluxing THF
containing zinc chloride. Instead, cycloaddition occurs to
afford a mixture of diastereomeric products, 41. It seems
that the carbonyl π-bond has once again been weakened
sufficiently to allow cycloaddition to occur, and this time,
to also tip the scales entirely toward cycloaddition and
away from ATC.
FIGURE 1. Comparison of energy differences between cy-
cloaddition and atom transfer paths.
the energy surface.9 Transition states for atom transfer
and two cycloaddition paths were modeled, and the
difference between the transition state energy and that
of the starting triplet diyl, ∆E, were compared. As shown
in Figure 1, a 5-exo-trig cyclization is preferred over the
8-endo-trig option, despite the fact that the latter affords
an oxygen-stabilized radical (cf., 37 and 37a). Gratify-
ingly, theory agrees with experiment, placing the cy-
cloaddition pathway substantially below that for atom
transfer. Notice, too, the comparatively small transfer
angle, R ) 132°, a value that is apparently too small to
accommodate atom transfer, for it is not observed.2b,c,10
SCHEME 7
While not a prerequisite for atom transfer, the benefit
of two radical stabilizing groups is evident in the con-
trasting chemistries of the diyls derived from diazenes 8
and 42. Unlike 8, where a mixture of ATC and cycload-
dition is observed, only the ATC pathway is followed
when a captodative radical is generated from diazene 42.
From these results we conclude that the two most
important factors in determining whether ATC will occur
are (1) the length of the tether and (2) the presence of
one or more radical stabilizing groups at the site from
which the hydrogen is being transferred.
SCHEME 6
SCHEME 8
While 6 and 7 undergo cycloaddition exclusively, the
addition of one more methylene unit between the diyl and
site of transfer provides sufficient flexibility to attain the
requisite geometry for atom transfer. Thus ATC consti-
tutes the preferred reaction pathway in the chemistry of
the diyl obtained from 8. This is so despite the fact that
the radical formed following atom transfer, 39, is stabi-
lized by just one substituent (viz., CHO). While previous
reports from these laboratories suggested that two radical
stabilizing groups were needed to achieve atom transfer,
this is clearly not the case.2a To be fair, it is important to
It is interesting to compare the transition structures
for the straight chain and captodative systems, 47 and
48, respectively (see Figures 3 and 4). In so-doing we will
use the three parameters defined in structure 46: d1, the
distance between the hydrogen undergoing transfer and
the carbon from which it is migrating, Cλ; d2, the distance
between the hydrogen being transferred and the carbon
to which it is migrating, Cꢀ; and R, the angle Cλ-H-Cꢀ,
referred to earlier in this paper as the transfer angle.
(9) (a) Calculations were conducted with the Spartan 02 PC Software
program available from Wavefunction, Inc. (b) Monoradicals and TMM
diyls differ in several important ways. In particular, the latter can
exist in more than one spin state (singlet/triplet) whose geometries
(planar/bisected) and chemistries often differ, and second, because they
are diradicals, there are two possible sites to which atom transfer can
occur. That a 1,7-hydrogen transfer is not observed despite the fact
that the transition state for it is calculated to reside only 1 kcal/mol
above that for the 1,5 transfer is consistent with the notion that such
a process is slowed entropically by the necessity to form an eight-
membered ring in the transition structure leading to transfer.
(10) (a) Huang, X. L.; Dannenberg, J. J. J. Org. Chem. 1991, 56 (18),
5421. (b) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115 (14),
6051. (c) Schliesser, C. H.; Skidmore, M. A. Calculations: a Useful
Tool for Synthetic Chemists. In Radicals In Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: New York, 2001; Vol. 1, Chapter 3.2
and references therein.
FIGURE 2. Important geometric parameters for atom trans-
fer reactions.
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Cyclopentatrimethylenemethane Diradicals
FIGURE 3. Comparison of atom transfer transition state
geometries.
Quantum calculations (UB3LYP/6-31G*) of the transi-
tion structure for 1,5-hydrogen transfer within the triplet
diyl of the straight chain aldehyde derived from 8 place
the migrating atom approximately midway between the
origin and terminus, though the length of the bond to
the terminus, d2, is somewhat shorter than that to the
origin, d1 (d2 ) 1.347 Å vs d1 ) 1.379 Å).9b Note, again,
Figures 3 and 4. The C(ꢀ-θ) bond has lengthened from
1.413 Å in the starting structure to 1.464 Å in the
transition structure (47), while the ring bonds have
equalized (C(θ-F) ) 1.405 Å) in consonance with the
development of an allylic radical. Both centers, Cλ and
Cꢀ, are distorted toward pyramidal. The geometry is
reminiscent of that generally associated with γ-hydrogen
atom transfer to the oxygen atom of a triplet carbonyl
excited state in a Norrish Type II photoreaction.11 Of
particular note, and common to both systems, 47 and 48,
is the flattening of the ring that occurs to accommodate
the large transfer angle (R ∼ 154°),10 some 20° greater
than that calculated for transition structure 36, a system
for which atom transfer does not occur.
FIGURE 4. Early transition state leading to captodatively
stabilized distonic diyl.
SCHEME 9
The transition structure for the captodative system,
48, is enlightening. As shown in Figure 3, the hydrogen
being transferred is much closer to the carbon from which
it is migrating (d1) than to the site where it will
eventually reside (d2). The migration has not advanced
nearly as far in this system as it has in 47. That is, the
transition state occurs earlier along the reaction coordi-
nate. This is consistent with the existence of a more
exothermic process leading from the initial diyl to the
captodatively stabilized distonic diyl, rather than to a
system where the newly formed radical is stabilized only
by the aldehyde unit.
As illustrated in Figure 4, calculations corroborate
these suggestions. The captodatively stabilized triplet
diyl 45 (Scheme 8, Z ) CHO, X ) OMe) is calculated to
be ∼11 kcal/mol more stable than the starting TMM diyl
44, while the less stabilized diyl produced from 47 after
atom transfer (viz., 39, Z ) CHO, X ) H, Scheme 6) is 2
kcal/mol less stable than the TMM diyl from which it was
produced.
the odd electron centers located on the ring to allow
σ-bond formation to occur immediately following the atom
transfer event. For the transformation highlighted in
Scheme 9, that bond would be between atoms CF and Cλ
of 39. Of course, this begs the question: How fast is
“immediately”? We do not know, though we do plan to
examine this issue experimentally. At this point, calcula-
tions suggest that the event is not likely to be as fast as
we initially projected. The shortest distance between the
radical site being formed, Cλ, and either of the odd
electron centers on the ring in transition structure 47 is
calculated to be ∼4.3 Å, a value that is certainly too large
to accommodate our original hypothesis. This finding is
consistent with our previous observation that the abso-
lute configuration at Cλ is not retained in the ATC
chemistry of the diyl derived from enantiomerically pure
diazene 49;3 by the time the reactive centers close within
bonding range, the radical has lost its configurational
integrity.
In addition to providing useful insights concerning the
hypersurface for these processes, the calculations have
proven enlightening in other ways. For example, we
previously hypothesized that the newly formed radical
site in ATC reactions would be “close enough” to one of
Concluding Remarks
On the basis of the chemistry described in this paper
we formulate the following guidelines: (1) In the absence
of a Lewis acid, diyl dimerization will occur if the tether
length is too short to allow it to attain the requisite
geometry for atom transfer (viz., n ) 1, Scheme 10). In
the presence of a Lewis acid, however, the chemistry can
(11) (a) Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk,
K. N. J. Am. Chem. Soc. 1991, 113, 4368. (b) Dorigo, A. E.; McCarrick,
M. A.; Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1990, 112,
7508. (c) Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G.
J. Am. Chem. Soc. 1972, 94, 7500.
J. Org. Chem, Vol. 69, No. 25, 2004 8577

Maiti et al.
transition state was analyzed and found to correspond to
movement along the reaction coordinate.
SCHEME 10
Several reactant conformations were used as the initial
geometry from which the transition state searches were begun
at the AM1 level; those that produced the lowest energy
transition states were investigated further at the B3LYP/6-
31G* level of theory. As expected, a pseudoequatorial disposi-
tion of the substituents about the cycle corresponding to the
cyclic transition state for atom transfer led to lower energies
than alternative dispositions.
As in the case of intramolecular atom transfers of mono-
radicals, the tether length is a critical parameter in determin-
ing the energy difference between ground and transition states.
Two possible sites for atom transfer to the diyl exist. One is
to the exocyclic carbon, the other is to one of the endocyclic
radical centers. Reaction between the diyl and the aldehyde
π-system is also possible. These processes were investigated
as well and some transition states were found. Both singlet
and triplet diyls were investigated.
General Procedure A: Preparation of Fulvenes. To a
solution of aldehyde (1.0 mmol) and cyclopentadiene (3.0 mmol)
in MeOH (2.5 mL) at 0 °C was added pyrrolidine (1.5 mmol),
dropwise via syringe. The resulting homogeneous mixture was
allowed to warm to room temperature. After 5 h, the reaction
mixture was cooled to 0 °C, and glacial acetic acid (4.5 mmol)
was added dropwise. After 30 min the solution was diluted
with water (2 mL), and the aqueous layer was extracted with
ether (3 × 10 mL). The combined organic layers were washed
with saturated NaHCO3 (5 mL) and brine (5 mL), dried over
magnesium sulfate, and concentrated in vacuo. Chromatog-
raphy on silica gel (5-10% ether/pentane) afforded each of the
fulvenes as a bright yellow oil.
be diverted in a useful manner even when the tether is
short (e.g., 5 to 11). (2) Cycloaddition will occur when a
five-membered ring can be formed via addition to the
carbonyl carbon of the acceptor aldehyde unit (n ) 2, or
when n ) 3 in the presence of zinc chloride). (3) ATC
predominates when the tether length is long enough to
accommodate a “nearly linear” atom transfer angle, and
is the sole reaction pathway when the radical center
formed after transfer is captodatively stabilized. The two
most important factors in determining whether ATC will
occur are (1) the length of the tether and (2) the presence
of one or more radical stabilizing groups at the site from
which the hydrogen is being transferred.
General Procedure B: Diels-Alder Cycloaddition and
Reduction of ∆ (5,6) π-Bond. To a solution of fulvene (1.0
mmol) in methylene chloride (3.0 mL) was added diethyl
azodicarboxylate (1.5 mmol) at 0 °C. The solution was stirred
for 5-6 h at 0 °C and the progress was monitored by TLC and
continued until the complete disappearance of the fulvene was
noted. The solution was diluted with CH2Cl2 (5.0 mL), followed
by the addition of dipotassium azodicarboxylate (8.0 mmol);
the mixture was stirred with an overhead stirrer. The reaction
mixture was cooled to 0 °C, and glacial acetic acid (9.0 mmol)
in CH2Cl2 (1.0 mL) was added dropwise via addition funnel.
A vigorous gas evolution took place and the reaction mixture
was stirred for 3-4 h after it ceased. The color of the TLC
spots changed from black to blue as the reaction progressed,
appearing at the same Rf as the starting material (vanillin
stain). The solids were removed by filtration through a sintered
glass funnel and were washed thoroughly with CH2Cl2. The
solvent was washed with brine, dried, and removed under
reduced pressure and the very viscous oil was purified by
chromatography on silica gel (20% ether/pentane) to afford
pure carbamate as a white foam.
General Procedure C: Preparation of Carbamate
Alcohols (Scheme 2, Series 1). To a solution of carbamate
(1.0 mmol) in THF (2.5 mL) was added tetrabutylammonium
fluoride (1.5 mL of a 1 M solution in THF, 1.5 mmol) at 0 °C
and the resulting solution was allowed to warm to room
temperature. The mixture was stirred for another 1.5 h.
Saturated NH4Cl solution (1.5 mL) was added, and the
reaction mixture was stirred for 5-10 min. It was then diluted
with water and extracted with EtOAc. The combined organic
layers were washed with brine, dried, and evaporated under
reduced pressure. The crude product was purified by flash
chromatography; elution with ether afforded the carbamate
alcohols 19b, 20b, and 21b as colorless foams.
We find it remarkable that such a wide range of
structures can be obtained from such similar starting
materials. Thus, by simply varying the length of the
tether within diazenes 5-8, one can selectively access
any of the diverse skeletal types illustrated in Scheme
10. These results add considerably to the scope of TMM
diyl chemistry. We hope that it will render the chemistry
of greater utility to us and to others who might wish to
explore it in greater detail, or to use it to help solve
interesting problems.
Experimental Section
Calculations. Computations were conducted with Spartan
‘02 software, available from Wavefunction, Inc. The triplet
ground state of each TMM diyl was minimized (planar
geometry), then various atom transfer and cycloaddition
transition states were found at the AM1 level of theory. The
geometry was then re-optimized by using ab initio methods
at the UHF/3-21G* level. Some geometries were further
investigated with density functional theory and larger basis
sets at the UB3LYP/6-31G* level. This procedure was followed
to rapidly produce approximate geometries for further refine-
ment and minimize the amount of time used in high-level
computations. Unfortunately, the energies calculated by Har-
tree-Fock methods are inaccurate for H-atom transfers even
though the geometry is close to that produced by DFT. On the
basis of comparisons with computations done on monoradical
H-atom transfers, we conclude that B3LYP/6-31G* is suf-
ficiently accurate and is less expensive than higher level MP2/
6-31G* calculations. Energies corresponding to the distonic diyl
intermediates that result from the atom transfer process were
determined for the triplet spin state.
General Procedure D: Diazene Preparation. To a
solution of carbamate (1.0 mmol) in ethanol (1.0 mL) and THF
(0.25 mL) was added a solution of potassium hydroxide (8.0
mmol) in ethanol (2.5 mL) at room temperature. The resulting
mixture was refluxed for 2.5 h and then cooled to room
Minima and transition state geometries were optimized
without imposing constraints. When stationary points were
identified, frequency calculations were performed. The minima
were found to have no imaginary frequencies and the transi-
tion states each had one. The imaginary frequency of each
8578 J. Org. Chem., Vol. 69, No. 25, 2004

Cyclopentatrimethylenemethane Diradicals
temperature. Solvent was evaporated under reduced pressure.
The reaction mixture was diluted with a mixture of DMSO
(2.0 mL) and CH2Cl2 (1.0 mL) and cooled to 0 °C. Iodobenzene
diacetate (3.0 mmol) was added to the solution and stirred for
2-3 h at the same temperature. A saturated solution of
NaHCO3 (5 mL) was added to the reaction mixture and stirred
for another 5-10 min. The solids were removed by filtration
through a sintered glass funnel and washed thoroughly with
ether. The organic phase was separated and the aqueous phase
was extracted several times with ether. Combined solvents
were washed with brine, dried over sodium sulfate, and
removed under reduced pressure and the resulting viscous oil
was purified by chromatography on silica gel (100% ether) to
afford pure diazene as a colorless oil.
General Procedure E: Preparation of Diazene Alde-
hyde (Scheme 2, Series 1). To a stirred solution of diazene
alcohol (1.0 mmol) dissolved in a mixture of dry CH2Cl2 (1.6
mL) and DMSO (2.0 mL) at 0 °C was added triethylamine (5.0
mmol). After 2 min SO3‚Py complex (5.0 mmol) was added in
one portion and the resulting mixture was stirred at 0 °C for
1 h. The reaction mixture was then quenched with water and
extracted with ether and the organic layer was washed with
brine and dried over Na2SO4. The combined ether solutions
were removed under reduced pressure and the resulting oil
was purified by chromatography on silica gel (100% ether) to
afford pure diazene aldehydes (5-8) as colorless oils.
General Procedure F: Thermal Diyl Trapping Reac-
tion and ATC in the Absence of Lewis Acid. A 1-L round-
bottom flask was charged with toluene (500 mL) and degassed
with argon for 1 h. A reflux condenser was then attached to
the round-bottom flask. To the top of the reflux condenser was
attached a syringe pump and the system was purged again
with argon. The solution of diazene aldehyde (2.43 mmol) in
previously degassed toluene (20 mL) was slowly added via
syringe pump through the condenser into the refluxing toluene
over 3 h; refluxing was continued for another 2 h. The solution
was then cooled to room temperature, and the solvent was
removed in vacuo. The crude oil was purified by chromatog-
raphy on silica gel.
General Procedure G: Thermal Diyl Trapping Reac-
tion in the Presence of a Lewis Acid. A solution of diazene
aldehyde (1.0 mmol) and ZnCl2 (2.5 mmol) in THF (100 mL)
was placed in a 500-mL round-bottomed flask equipped with
a reflux condenser and degassed by bubbling N2 and Ar
through the solution for 1 h. The solution was then refluxed
for 3 h under N2 and cooled to room temperature. The solvent
was reduced to 50 mL in vacuo. The reaction mixture was
quenched with water (20 mL) and the aqueous layer was
extracted with ethyl acetate. The organic phase was washed
with brine and dried over Na2SO4. Solvents were removed
under reduced pressure and the colorless oil was purified by
chromatography on silica gel.
J ) 4.0 Hz, 2H, Cp H), 6.53-6.42 (m, 2H, Cp H), 6.21 (dt, J )
5.2, 1.6 Hz, 1H, CdCH), 3.68 (t, J ) 6.4 Hz, 2H, CH2OTBS),
2.59 (q, J ) 7.6 Hz, 2H, CdCHCH2), 1.76 (m, 2H, CH2CH2-
OTBS), 0.92 (s, 9H, SiC(CH3)3), 0.069 (s, 3H, SiCH3), 0.062 (s,
3H, SiCH3); 13C NMR (CDCl3, 100 MHz) δ 146.3, 142.8, 133.1,
130.9, 125.7, 119.3, 62.4, 32.7, 27.7, 26.1, 18.4, -5.1; LRCI-
MS m/z 193 (M+ - C4H9), 163, 117, 101, 92, 75, 59; HRMS
calcd for (C15H26OSi - C4H9) 193.104869, found 193.104036.
Diethyl 7-[4-(tert-Butyldimethylsiloxy)butylidene]-2,3-
diazabicyclo[2.2.1]heptane-2,3-dicarboxylate (Scheme 2,
Series 1, Step d). Fulvene 16 (6.0 g, 24.0 mmol) was
transformed into 8.4 g of pure carbamate according to the
general procedure B in 84% yield. TLC Rf 0.35 (SiO2, 20%
ether/pentane), vanillin; IR (neat) 2932, 2860, 1742, 1704,
1462, 1371, 1309, 1250, 1186, 1096, 834, 796, 770 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 5.41-5.29 (br m, 1H, CdCH), 4.92-
4.90 (m, 1H, NCHCH2), 4.1-4.08 (br m, 5H, NCHCH2, 2 ×
CH2CH3), 3.57-3.50 (m, 2H, CH2OTBS), 2.14-2.02 (m, 2H,
CdCHCH2), 1.86-1.46 (m, 6H, CH2CH2OTBS, NCHCH2CH2-
CHN), 1.28-1.21 (m, 6H, 2 × CH2CH3), 0.87-0.86 (br s, 9H,
C(CH3)3), 0.026-0.019 (br s, 6H, Si(CH3)2). Due to the exist-
ence of a dynamic equilibrium between isomers at room
temperature, the peaks are broad and few low-intensity peaks
(equilibrating isomers) are also observed: 13C NMR (CDCl3,
100 MHz) δ 159.0, 157.1, 144.4, 117.1, 108.6, 62.6, 62.2, 60.4,
32.6, 26.0, 25.8, 25.0, 21.1, 18.3, 14.6, 14.3, -5.17, -5.19; LRCI-
MS m/z 369 (M+ - C4H9), 325, 251, 233, 221, 209, 193, 167,
149, 119, 103, 92, 75, 59; HRMS calcd for (C21H38N2O5Si -
C4H9) 369.184576, found 369.183585.
Diethyl 7-(4-Hydroxybutylidene)-2,3-diazabicyclo[2.2.1]-
heptane-2,3-dicarboxylate (19a; Scheme 2, Series 1, Step
e). TBS protected carbamate (8.0 g, 18.8 mmol) was depro-
tected to give carbamate alcohol 19a (5.2 g, 90%) as a colorless
foam following general procedure C. TLC Rf 0.25 (SiO2, 50%
EtOAc/hexane), vanillin; IR (neat) 3500, 2935, 2859, 1709,
1465, 1400, 1374, 1311, 1187, 1149, 1104, 1059, 868, 837, 768
1
cm-1; H NMR (CDCl3, 400 MHz) δ 5.26 (br m, 1H, CdCH),
4.99-4.80 (m, 1H, NCHCH2), 4.13-4.0 (br m, 5H, NCHCH2,
2 × CH2CH3), 3.49-3.39 (m, 2H, CH2OH), 2.61-2.37 (br s 1H,
OH), 2.18-1.96 (m, 2H, CdCHCH2), 1.96-1.46 (m, 6H, CH2-
CH2OH, NCHCH2CH2CHN), 1.27-1.18 (m, 6H, 2 × CH2CH3).
Due to the existence of a dynamic equilibrium between isomers
at room temperature, the peaks are broad and few low-
intensity peaks (equilibrating isomers) are also observed: 13C
NMR (CDCl3, 100 MHz) δ 159.1, 157.5, 144.5, 138.7, 125.4,
116.9, 108.3, 62.6, 62.2, 60.8, 53.5, 31.9, 30.2, 29.6, 25.4, 24.8,
14.45, 14.42; ESI+/TOF m/z 335 (M+ + Na); HRMS calcd for
(C15H24N2O5 + Na) 335.15774, found 335.15771.
4-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)-1-bu-
tanol (19b; Scheme 2, Series 1, Step f). Carbamate alcohol
19a (5.0 g, 16.0 mmol) afforded 1.9 g of pure diazene alcohol
as a colorless oil following general procedure D in 75% yield.
TLC Rf 0.35 (SiO2, 100% ether), vanillin; IR (neat) 3403, 2946,
1723, 1480, 1285, 1113, 1058, 908, 847, 808, 783, 772, 764,
General Procedure H: Photochemical Diyl Trapping
Reaction. A mixture of diazene aldehyde (0.22 mmol) in
acetonitrile (200 mL) was placed in a Pyrex round-bottomed
flask, positioned 2-3 cm from the lamp, and degassed with
argon for 30 min. A stirred solution of the sample was
irradiated with a 450 W Hanovia lamp (water-cooled) for 2 h
under a nitrogen atmosphere at room temperature. The solvent
was removed in vacuo to obtain crude product, which was
purified by chromatography on silica gel when needed.
1
757, 727 cm-1; H NMR (CDCl3, 400 MHz) δ 5.38 (app s with
very small coupling, 1H, J ) 2.0, NCHCH2), 5.0 (overlapping
t and d, J ) 7.0, 2.8 Hz, 2H, CdCH, NCHCH2), 3.52 (t, J )
6.4 Hz, 2H, CH2OH), 2.23-2.19 (br m, 1H, OH), 2.08-1.98
(m, 2H, CdCHCH2), 1.65-1.61 (m, 2H, exo hydrogen on
ethano bridge), 1.60-1.50 (m, 2H, CH2CH2OH), 1.06 (app d,
2H, J ) 8.4 Hz, endo hydrogen on ethano bridge); 13C NMR
(CDCl3, 100 MHz) δ 145.2, 116.9, 76.9, 72.7, 61.6, 32.1, 25.3,
21.5, 21.1; ESI+/TOF m/z 355 (2M+ + Na), 189 (M+ + Na),
174, 167, 101; HRMS calcd for (C9H14N2O + Na) 189.09983,
found 189.0998.
5-[4-(tert-Butyldimethylsiloxy)butylidene]-1,3-cyclo-
pentadiene (16; Scheme 2, Series 1, Step c). 4-tert-
Butyldimethylsilyloxybutanal12 (6.0 g, 29.7 mmol) was trans-
formed into the fulvene 16 (6.5 g, 88%) as described in general
procedure A. TLC Rf 0.6 (SiO2, 20% ether/pentane), UV,
vanillin; IR (neat) 2954, 2857, 1649, 1479, 1380, 1251, 1100,
4-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)butanal (5;
Scheme 2, Series 1, Step b). Diazene alcohol 19b (1.0 g, 6.0
mmol) gave 0.86 g of pure diazene aldehyde 5 as a colorless
oil according to general procedure E in 87% yield. TLC Rf 0.52
(SiO2, 100% ether), vanillin; IR (neat) 2947, 2868, 2730, 1720,
1479, 1439 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.69 (t, J ) 1.2
Hz, 1H, CHO), 5.22 (app s with very small coupling, J ) 1.1
1
842, 765, 727 cm-1; H NMR (CDCl3, 400 MHz) δ 6.55 (br d,
(12) Choy, N.; Shin, Y.; Nguyen, P. Q.; Curran, D. P.; Balachandran,
R.; Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46 (14), 2846.
J. Org. Chem, Vol. 69, No. 25, 2004 8579

Maiti et al.
Hz, 1H, NCHCH2), 5.05 (app t, J ) 2.0 Hz, 1H, NCHCH2),
5.04 (t, J ) 7.8 Hz, 1H, CdCH), 2.45 (dt, J ) 1.6, 7.8 Hz, 2H,
CH2CHO), 2.24 (m, 2H, CdCHCH2), 1.62-1.58 (m, 2H, exo
hydrogen on ethano bridge), 0.95 (app dt, J ) 3.2, 7.6 Hz, 2H,
endo hydrogen on ethano bridge); 13C NMR (100 MHz) δ 201.1,
146.3, 115.2, 76.8, 72.6, 43.3, 21.7, 21.4, 20.9; LRCI-MS m/z
165 (M + 1), 153, 137, 119, 109, 93, 86, 80, 67, 55; HRMS calcd
for (C9H12N2O + H) 165.102788, found 165.103129.
61.9, 61.5, 61.2, 56.9, 53.2, 31.2, 28.5, 27.8, 25.8, 25.1, 13.8;
ESI+/TOF m/z 675 (2M+ + Na), 349 (M+ + Na); HRMS calcd
for (C16H26N2O5 + Na) 349.17339, found 349.1724.
5-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)-1-pen-
tanol (20b; Scheme 2, Series 1, Step f). Carbamate alcohol
20a (4.0 g, 12.3 mmol) was transformed into the diazene
alcohol 20b (1.87 g, 86%), obtained as yellow oil following
general procedure D. TLC Rf 0.37 (SiO2, 100% ether), vanillin;
IR (neat) 3409, 2939, 2861, 1719, 1571, 1479, 1439, 1284, 1114,
Bicyclo[4.3.0]nona-4,6-dien-2-ol (31; Scheme 4). Diazene
aldehyde 5 (0.2 g, 1.2 mmol) afforded 0.12 g (73%) of pure
alcohol 31 as a colorless oil following general procedure G. TLC
Rf 0.56 (SiO2, 20% EtOAc/hexane), vanillin; IR (neat) 3390,
3032, 2924, 1666, 1434, 1325, 1211, 1140, 1084, 1022, 991, 903,
1
1058, 929, 842, 738 cm-1; H NMR (CDCl3, 400 MHz) δ 5.27
(app d, J ) 2.0 Hz, 1H, NCHCH2), 5.0 (overlapping t and d, J
) 7.6, 2.1 Hz, 2H, CdCH, NCHCH2), 3.52 (t, J ) 6.4 Hz, 2H,
CH2OH), 1.91-1.84 (m, 2H, CdCHCH2), 1.55-1.51 (m, 2H,
exo hydrogen on ethano bridge), 1.39-1.30 (m, 2H, CH2CH2-
OH), 1.29-1.24 (m, 2H, CH2CH2CH2OH), 0.97 (app d, J ) 8.8
Hz, 2H, endo hydrogen on ethano bridge); 13C NMR (CDCl3,
100 MHz) δ 144.1, 117.3, 76.9, 72.7, 62.7, 32.1, 28.9, 25.7, 21.6,
21.2; ESI+/TOF m/z 383 (2M+ + Na), 203 (M+ + Na), 181 (M+
+ 1); HRMS calcd for (C10H16N2O + H) 181.13408, found
181.1334.
1
862, 834, 722 cm-1; H NMR (CDCl3, 400 MHz) δ 6.35 (dd, J
) 2.9, 6.7 Hz, 1H, CHdCCHdCH), 5.68 (d, J ) 2.3 Hz, 1H,
CHdCCHdCH), 5.61 (m, 1H, CHdCCHdCH), 4.01 (td, J )
2.1, 5.2 Hz, 1H, CHOH), 2.87 (m, 1H, CHCHOH), 2.53-2.29
(m, 4H), 2.00-1.80 (m, 2H); 13C NMR (100 MHz) δ 137.0, 127.6,
125.1, 123.8, 66.1, 48.1, 34.7, 31.4, 24.7; LREI-MS m/z 136
(M+), 117, 91, 79, 65, 41; HRMS calcd for C9H12O 136.088815,
found 136.089002.
5-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)penta-
nal (6; Scheme 2, Series 1, Step b). Doering oxidation of
diazene alcohol (1.0 g, 5.5 mmol) to make diazene aldehyde 6
(0.89 g, 90%) was performed according to general procedure
E. TLC Rf 0.47 (SiO2, 100% ether), vanillin; IR (neat) 2942,
5-[5-(tert-Butyldimethylsiloxy)pentylidene]-1,3-cyclo-
pentadiene (17; Scheme 2, Series 1, Step c). 5-tert-
Butyldimethylsilyloxypentanal13 (5.0 g, 23.1 mmol) was trans-
formed into fulvene 17 (5.42 g, 89%) as a yellow oil following
general procedure A. TLC Rf 0.65 (SiO2, 20% EtOAc/hexane),
vanillin; IR (neat) 2928, 2857, 1648, 1471, 1380, 1255, 1095,
834, 764, 731 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.57 (br d, J
) 1.6 Hz, 2H, Cp H), 6.57-6.41 (m, 2H, Cp H), 6.22 (dt, J )
5.2, 1.6 Hz, 1H, CdCH), 3.68 (m, 2H, CH2OTBS), 2.59 (q, J )
8.0 Hz, 2H, CdCHCH2), 2.55-1.61 (2 m, 4H, CH2CH2CH2-
OTBS), 0.94 (s, 9H, SiC(CH3)3), 0.09 (s, 6H, Si(CH3)2); 13C NMR
(CDCl3, 100 MHz) δ 146.2, 143.0, 133.1, 130.8, 125.7, 119.2,
62.8, 32.5, 30.9, 26.1, 25.9, 18.5, -5.11, -5.13; LRCI-MS m/z
207 (M+ - C4H9), 183, 147, 133, 115, 104, 91, 75, 59; HRMS
calcd for (C15H26OSi - C4H9) 207.120519, found 207.120198.
2865, 2722, 1721, 1479 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
9.58 (t, J ) 1.6 Hz, 1H, CHO), 5.22 (app d, J ) 2.0 Hz, 1H,
NCHCH2), 4.96 (app d, J ) 2.0 Hz, 1H, NCHCH2), 4.94 (t, J
) 7.6 Hz, 1H, CdCH), 2.24 (dt, J ) 1.6, 7.6 Hz, 2H, CH2CHO),
1.88 (m, 2H, CdCHCH2), 1.54-1.47 (m, 4H, CH2CH2CHO, and
exo hydrogen on ethano bridge), 0.95 (app dt, J ) 2.0, 11.0,
2H, endo hydrogen on ethano bridge); 13C NMR (100 MHz) δ
201.8, 145.7, 116.0, 76.5, 72.3, 42.6, 27.9, 21.4, 21.2, 20.8;
LRCI-MS m/z 179 (M+ + H), 151, 144, 133, 121, 107, 91, 83,
67, 57, 49; ESI-TOF m/z 201 (M+ + Na), 193, 186, 179 (M+
+
H); HRMS calcd for C10H14N2ONa 201.09983, found 201.0996.
1,2,3,3a,4a,5,6,7b-Octahydrodicyclopenta[b,d]furan (32;
Scheme 5). Diazene aldehyde 6 was subjected to deazetation
under each of the three different diyl trapping reaction
conditions described earlier as general procedures F, G, and
H. The major product isolated by column chromatography from
all three methods has identical spectral properties. Yield:
general procedure F, 65%; General procedure G, 70%; general
procedure H, 77-78%. TLC Rf 0.6 (SiO2, 10% EtOAc/hexane),
vanillin; IR (neat) 2931, 2853, 1445, 1329, 1148, 1057, 1045,
972, 953, 889, 853, 796, 761 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 5.50 (m, 1H, CdCH), 4.93 (m, 1H, HCdCCH), 4.85 (m, 1H,
OCHCHCdC), 2.99 (ddd, J ) 5.6, 8.0, 9.2 Hz, 1H, OCHCHCd
C), 2.26-2.41 (m, 2H), 2.25 (m, 1H), 1.89-1.51 (m, 7H); 13C
NMR (100 MHz) δ 152.5, 120.7, 90.5, 88.4, 41.8, 35.9, 53.8,
34.2, 32.0, 26.3; LREI-MS m/z 150 (M+), 135, 131, 121, 117,
106, 93, 91, 83, 79, 67, 53, 43; HRMS calcd for C10H14O
150.104465, found 150.104334.
5-[6-(tert-Butyldiphenylsiloxy)hexylidene]-1,3-cyclo-
pentadiene (18; Scheme 2, Series 1, Step c). 6-(tert-
Butyldiphenylsilyloxy)hexanal14 (6.0 g, 16.9 mmol) was trans-
formed into fulvene 18 (6.1 g, 90%), obtained as a yellow oil
following general procedure A. TLC Rf 0.68 (SiO2, 20% EtOAc/
hexane), UV, vanillin; IR (neat) 2930, 2857, 1649, 1476, 1380,
1252, 1109, 838, 765, 728 cm-1; 1H NMR (CDCl3, 400 MHz) δ
7.70-7.68 (m, 4H, ArH), 7.46-7.38 (m, 6H, ArH), 6.55-6.39
(m, 4H, Cp H), 6.22 (dt, J ) 5.2, 1.7 Hz, 1H, CdCH), 3.67 (t,
J ) 6.3 Hz, 2H, CH2OTBDPS), 2.53 (q, J ) 7.2 Hz, 2H, Cd
CHCH2), 1.65-1.42 (m, 6H, CH2CH2CH2CH2OTBDPS), 1.03
(s, 6H, Si(CH3)2); 13C NMR (CDCl3, 100 MHz) δ 146.1, 135.7,
134.2, 133.1, 130.8, 129.7, 127.7, 125.7, 119.3, 63.9, 32.5, 31.1,
29.3, 27.0, 25.7, 19.4.
Diethyl 7-[5-(tert-Butyldimethylsiloxy)pentylidene]-
2,3-diazabicyclo[2.2.1]heptane-2,3-dicarboxylate (Scheme
2, Series 1, Step d). Carbamate (6.8 g, 82%) was prepared
from fulvene 17 (5.0 g, 18.9 mmol) following general procedure
B. TLC Rf 0.35 (SiO2, 20% EtOAc/hexane), vanillin; IR (neat)
2934, 2857, 1749, 1705, 1463, 1372, 1310, 1248, 1186, 1104,
836, 773 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.25-5.23 (br m,
1H, CdCH), 4.84-4.82 (m, 1H, NCHCH2), 4.23-4.0 (br m, 5H,
NCHCH2, 2 × CH2CH3), 3.50-3.49 (m, 2H, CH2OTBS), 2.07-
1.88 (m, 2H, CdCHCH2), 1.87-1.11 (m, 12H, CH2CH2OTBS,
NCHCH2CH2CHN, 2 × CH2CH3), 0.86-0.76 (br s, 9H, C(CH3)3),
0.08-0.01 (br s, 6H, Si(CH3)2). Due to the existence of a
dynamic equilibrium between isomers at room temperature,
the peaks are broad and few low intensity peaks (equilibrating
isomers) are also observed; 13C NMR (CDCl3, 100 MHz) δ
158.9, 157.0, 144.1, 138.3, 129.0, 128.2, 125.3, 118.1, 108.1,
62.8, 62.6, 32.2, 28.5, 26.0, 18.3, 14.5, 14.2, -5.25; LRCI-MS
m/z 383 (M+ - C4H9), 339, 267, 233, 207, 189, 163, 147, 133,
117, 105, 91, 75, 61, 49; HRMS calcd for (C22H40N2O5Si - C4H9)
383.200226, found 383.199726.
Diethyl 7-(5-Hydroxypentylidene)-2,3-diazabicyclo-
[2.2.1]heptane-2,3-dicarboxylate (20a; Scheme 2, Series
1, Step e). TBS-protected carbamate (6.5 g, 14.7 mmol) was
deprotected by using tetrabutylammonium fluoride to give
carbamate alcohol 20a (4.4 g, 92%) according to general
procedure C. TLC Rf 0.25 (SiO2, 50% EtOAc/hexane), vanillin;
IR (neat) 3487, 2937, 2861, 1706, 1464, 1402, 1373, 1319, 1186,
1
1148, 1104, 1057, 870, 766 cm-1; H NMR (CDCl3, 400 MHz)
δ 5.11-4.99 (br m, 1H, CdCH), 4.67-4.57 (m, 1H, NCHCH2),
4.01-3.75 (br m, 5H, NCHCH2, 2 × CH2CH3), 3.33-3.18 (m,
2H, CH2OH), 1.88-1.76 (m, 2H, CdCHCH2), 1.76-0.89 (m,
14H, CH2CH2CH2OH, NCHCH2CH2CHN, 2 × CH2CH3). Due
to the existence of a dynamic equilibrium between isomers at
room temperature, the peaks are broad and few low-intensity
peaks (equilibrating isomers) are also observed; 13C NMR
(CDCl3, 100 MHz) δ 158.3, 156.5, 143.5, 137.6, 116.9, 107.1,
(13) Nakamura, H.; Aoyagi, K.; Shim, J.-G.; Yamamoto, Y. J. Am.
Chem. Soc. 2001, 123 (3), 372.
(14) Sono, M.; Nakashiba, Y.; Nakashima, K.; Tori, M. J. Org. Chem.
2000, 65 (10), 3099.
8580 J. Org. Chem., Vol. 69, No. 25, 2004

Cyclopentatrimethylenemethane Diradicals
Diethyl 7-[6-(tert-Butyldiphenylsiloxy)hexylidene]-2,3-
diazabicyclo[2.2.1]heptane-2,3-dicarboxylate (Scheme 2,
Series 1, Step d). Carbamate (6.8 g, 79%) was prepared from
fulvene 18 (6.0 g, 14.9 mmol) according to general procedure
B. TLC Rf 0.21 (SiO2, 20% EtOAc/hexane), vanillin; IR (neat)
2933, 2857, 1746, 1703, 1462, 1428, 1372, 1312, 1186, 1109,
Bicyclo[5.3.0]dec-7-ene-2-carbaldehyde
(40)
and
3,3a,4a,5,6,7,8,8aOctahydro-2H-benzo[b]cyclopenta[d]fu-
ran (41; Scheme 7). Under the conditions described in general
procedure F, aldehyde 8 produced both 40 and 41 in a 9:1 ratio
in a total yield of 72-73%. With use of general procedure G,
aldehyde 8 produced only 41 in 74-75% yield. 40: TLC Rf
(SiO2, 10% EtOAc/hexane), vanillin; IR (neat) 2924, 2851, 2706,
1725, 1445, 1002, 795, 684, 653 cm-1 1H NMR (CDCl3, 400
0.60
867, 771 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.68-7.64 (m,
;
;
4H, ArH), 7.45-7.35 (m, 6H, ArH), 5.30-5.29 (br m, 1H, Cd
CH), 4.91-4.87 (m, 1H, NCHCH2), 4.25-4.17 (br m, 5H,
NCHCH2, 2 × CH2CH3), 3.66-3.61 (m, 2H, CH2OTBDPS),
2.08-2.02 (m, 2H, CdCHCH2), 2.01-1.18 (m, 16H, CH2CH2-
CH2CH2OTBDPS, NCHCH2CH2CHN, 2 × CH2CH3), 1.06-
1.03 (br s, 9H, C(CH3)3). Due to the existence of a dynamic
equilibrium between isomers at room temperature, the peaks
are broad and few low-intensity peaks (equilibrating isomers)
are also observed: 13C NMR (CDCl3, 100 MHz) δ 159.2, 144.0,
138.2, 135.7, 134.2, 129.7, 127.7, 63.9, 62.8, 62.7, 53.6, 32.5,
29.5, 28.9, 27.0, 25.5, 25.4, 19.3, 14.6; ESI+/TOF m/z 601 (M+
+ Na); HRMS calcd for (C33H46N2O5Si + Na) 601.30682, found
601.3063.
MHz) δ 9.73 (d, J ) 0.8 Hz, 1H, CHO), 5.46 (m, 1H, CdCH),
3.25 (m, 1H, CdCCH), 2.96-2.83 (m, 1H, CHCHO), 2.67-1.21
(m, 12H); 13C NMR (100 MHz) δ 204.8, 148.1, 126.3 (126.1),
56.7 (55.32), 47.2 (47.0), 31.7 (31.4), 31.2 (30.9), 30.15 (30.10),
28.8 (28.9), 27.6 (27.5), 23.5; LREI-MS m/z 164 (M+), 146, 133,
122, 117, 105, 91, 79, 67, 53, 41; HRMS calcd for C11H16O
164.120115, found 164.120600. 41: TLC Rf 0.59 (SiO2, 10%
EtOAc/hexane), vanillin; IR (neat) 2929, 1695, 1047, 919, 877,
1
848, 798, 737, 722, 711, 691, 666 cm-1; H NMR (CDCl3, 400
MHz) δ 5.53 (dd, J ) 1.6, 3.2 Hz, 1H, CdCH), 5.08 (m, 1H,
CdCCH), 4.08 (m, 1H, OCHCHCdC), 2.52-2.35 (m, 3H,
allylic), 2.33-2.26 (m, 1H), 2.04-1.97 (m, 1H), 1.72-1.65 (m,
2H), 1.64-1.60 (m, 1H), 1.59-1.42 (m, 3H), 1.32-1.09 (m, 2H);
13C NMR (100 MHz) δ 153.3, 120.7, 86.59, 80.0, 39.0, 35.6,
33.8, 29.0, 26.0, 24.0, 20.1; LREI-MS m/z 164 (M+), 146, 136,
131, 121, 107, 93, 83, 77, 67, 53, 41; HRMS calcd for C11H16O
164.120115, found 164.120164.
Diethyl 7-(6-Hydroxyhexylidene)-2,3-diazabicyclo[2.2.1]-
heptane-2,3-dicarboxylate (21a; Scheme 2, Series 1, Step
e). TBDPS protected carbamate (6.5 g, 11.2 mmol) was
deprotected to give carbamate alcohol 21a (3.5 g, 94%) accord-
ing to general procedure C. TLC Rf 0.23 (SiO2, 50% EtOAc/
hexane), vanillin; IR (neat) 3472, 2935, 2858, 1710, 1464, 1400,
1-(2,4-Cyclopentadienyliden)-3-[2-(4-methoxyphenyl)-
(4R)-1,3-dioxolan-4-yl]propane (23; Scheme 2, Series 2,
Step a). Fulvene 23 (5.45 g, 91%) was prepared from aldehyde
2215 (5.0 g, 21.1 mmol) according to general procedure A. TLC
1374, 1316, 1245, 1188, 1148, 1106, 1057, 864, 770, 699 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 5.28-5.20 (br m, 1H, CdCH),
4.85-4.79 (m, 1H, NCHCH2), 4.20-4.00 (br m, 5H, NCHCH2,
2 × CH2CH3), 3.54-3.47 (m, 2H, CH2OH), 2.36-2.27 (m, 3H,
CdCHCH2, OH), 2.03-1.89 (m, 16H, CH2CH2CH2CH2OH,
NCHCH2CH2CHN, 2 × CH2CH3). Due to the existence of a
dynamic equilibrium between isomers at room temperature,
the peaks are broad and few low-intensity peaks (equilibrating
isomers) are also observed; 13C NMR (CDCl3, 100 MHz) δ
158.9, 157.5, 144.0, 138.2, 117.4, 109.4, 62.4, 62.1, 60.4, 58.9,
32.4, 29.3, 28.6, 25.17, 25.10, 14.4, 14.1; ESI+/TOF m/z 363
(M+ + Na); HRMS calcd for (C17H28N2O5 + Na) 363.18904,
found 363.1885.
1
Rf 0.51 (SiO2, 20% EtOAc/hexane), vanillin; H NMR (CDCl3,
400 MHz) δ 7.44-7.35 (m, 2H, ArH), 6.93-6.87 (m, 2H, ArH),
6.59-6.38 (m, 4H, CpH), 6.20 (dt, J ) 5.0, 1.6 Hz, 1H, Cd
CH), 5.76 (s, 1H, OCHO), 4.32-4.21 (m, 2H, OCHHCHO), 3.82
(s, 3H, OCH3), 3.66-3.60 (m, 1H, OCHHCHO), 2.79-2.61 (m,
2H, CdCHCH2), 2.02-1.72 (m, 2H, CH2CH2CO); 13C NMR
(100 MHz) δ 160.7, 141.3, 133.6, 131.1, 128.2, 128.0, 125.7,
119.2, 113.96, 113.94, 104.2, 76.3, 70.0, 55.5, 33.6, 27.6; LREI-
MS m/z 284 (M+), 179, 153, 135, 132, 117, 105, 92, 77, 65, 51,
43; HRMS calcd for C18H20O3 284.14124, found 284.14114.
Diethyl 7-3-[2-(4-Methoxyphenyl)-(4R)-1,3-dioxolan-4-
yl]propylidene-2,3-diazabicyclo[2.2.1]heptane-2,3-dicar-
boxylate (Scheme 2, Series 2, Step b). Fulvene 23 (5.4 g,
19.0 mmol) was transformed into the carbamate (7.25 g, yellow
foam, 83%) as described in general procedure B. TLC Rf 0.25
(SiO2, 25% EtOAc/hexane), vanillin; IR (neat) 2980, 2938, 1742,
1702, 1615, 1588, 1516, 1373, 1306, 1247, 1187, 1105, 1030,
6-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)-1-hex-
anol (21b; Scheme 2, Series 1, Step f). Carbamate alcohol
21a (3.4 g, 10.0 mmol) was transformed into diazene alcohol
21b (1.67 g, 86%) following general procedure D. TLC Rf 0.20
(SiO2, 100% ether), vanillin; IR (neat) 3398, 2933, 2857, 1643,
1480, 1439, 1282, 1114, 1052, 894, 854, 845, 740 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 5.39 (app d, J ) 2.0 Hz, 1H, NCHCH2),
5.11 (overlapping t and d, J ) 7.6, 2.1 Hz, 2H, CdCH,
NCHCH2), 3.63 (dt, J ) 2.0, 6.5 Hz, 2H, CH2OH), 2.01 (br s,
1H, OH), 2.01-1.88 (m, 2H, CdCHCH2), 1.68-1.51 (m, 2H,
exo hydrogen on ethano bridge), 1.58-1.21 (m, 6H, CH2CH2CH2-
CH2OH), 1.06 (app d, J ) 8.8 Hz, 2H, endo hydrogen on ethano
bridge); 13C NMR (100 MHz) δ 146.9, 117.5, 72.8, 62.9, 55.2,
834, 773 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.41-7.34 (m,
;
2H, ArH), 6.92-6.86 (m, 2H, ArH), 5.73 (s, 1H, OCHO), 5.24
(br m, 1H, CdCH), 4.92 (m, 1H, NCHCH2), 4.25-4.12 (m, 7H,
NCHCH2, CH2(O), 2 X CH2CH3), 3.80 (s. 3H, OCH3), 3.60 (m,
1H, CH2CH(O)), 2.33-2.11 (m, 2H, CdCHCH2), 1.97-1.48 (m,
6H, CdCHCH2CH2, NCHCH2CH2CHN) ,1.33-1.20 (m, 6H, 2
× CH2CH3). Due to the existence of a dynamic equilibrium
between isomers at room temperature, the peaks are broad
and few low-intensity peaks (equilibrating isomers) are also
observed: ESI+/TOF m/z 943 (2M+ + Na), 483 (M+ + Na),
461 (M+ + H), 325, 306, 270, 198; HRMS calcd for (C24H32N2O7
+ Na) 483.2117, found 483.21107.
32.6, 29.3, 29.1, 25.3, 21.7, 21.2; ESI+/TOF m/z 411 (2M+
+
Na), 389 (2M+ + H), 217 (M+ + Na), 195 (M+ + H), 167, 144;
HRMS calcd for (C11H18N2O + Na) 217.13113, found 217.1313.
6-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)hexanal (8;
Scheme 2, Series 1, Step b). Doering oxidation of diazene
alcohol 21b (1.0 g, 5.1 mmol) to make diazene aldehyde 8
(0.89 g, 90%) was performed according to general procedure
E. TLC Rf 0.45 (SiO2, 100% ether), vanillin; IR (neat) 2940,
2860, 2722, 1719, 1479, 1441, 1390, 1284, 1113, 1085, 1041,
893, 847, 675 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.70 (t, J )
0.8 Hz, 1H, CHO), 5.33 (app d, J ) 1.2 Hz, 1H, NCHCH2),
5.07-5.03 (m, 2H, NCHCH2, and CdCH), 2.38 (dt, J ) 0.8,
7.2 Hz, 2H, CH2CHO), 1.96 (m, 2H, CdCHCH2), 1.61-1.49
(m, 4H, CH2CH2CHO, and exo hydrogen on ethano bridge),
1.35-1.27 (m, 2H, CH2CH2CH2CHO), 0.95 (app d, J ) 10.8
Hz, 2H, endo hydrogen on ethano bridge); 13C NMR (100 MHz)
δ 202.4, 145.3, 116.8, 76.9, 72.6, 43.6, 28.9, 28.8, 21.5, 21.4,
21.1; LRCI-MS m/z 193 (M+ + H), 165, 147, 135, 125, 120,
109, 97, 81, 67; HRMS calcd for (C11H16N2O + H) 193.134088,
found 193.134184.
7-3-[2-(4-Methoxyphenyl)-(4R)-1,3-dioxolan-4-yl]prop-
ylidene-2,3-diazabicyclo[2.2.1]hept-2-ene (Scheme 2, Se-
ries 2, Step c). Carbamate (7.1 g, 15.4 mmol) prepared as
described above was transformed into the diazene (3.92 g,
yellow oil, 81%) following general procedure D. TLC Rf 0.54
(SiO2, 100% ether), vanillin; IR (neat) 2941, 2887, 1614, 1517,
1303, 1248, 1170, 1079, 1034, 892, 830, 768, 735, 702 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.40-7.30 (m, 2H, ArH), 6.91-
6.82 (m, 2H, ArH), 5.65 (s, 1H, OCHO), 5.36 (app d, J ) 3.0
Hz, 1H, NCHCH2), 5.01 (br m, 2H, CdCH, NCHCH2), 4.11-
3.94 (m, 2H, CHCH2O), 3.74 (s, 3H, OCH3), 3.60 (m, 1H,
(15) (a) Brimble, M. A.; Park, J. H.; Taylor, C. M. Tetrahedron 2003,
59 (31), 5861. (b) Shimizu, A.; Nishiyama, S. Synlett 1998, 11, 1209.
J. Org. Chem, Vol. 69, No. 25, 2004 8581

Maiti et al.
CH2CHO), 2.18-2.04 (m, 2H, CdCHCH2), 1.72-1.51 (m, 4H,
exo hydrogen on ethano bridge, CdCHCH2CH2), 1.03 (app d,
2H, J ) 8.7 Hz, endo hydrogen on ethano bridge); 13C NMR
(100 MHz) δ 160.2 (160.1), 145.5 (145.4), 129.7 (130.2), 127.8
(127.7), 116.0, 113.5, 103.8 (102.8), 76.6, 75.8 (75.7), 72.4, 70.3
(69.73), 55.1, 33.1 (32.7), 25.4, 25.29 (25.25), 21.3 (20.8); ESI+/
TOF m/z 337 (M+ + Na), 309, 223; HRMS calcd for (C18H22N2O3
+ Na) 337.1528, found 337.1521.
2H, NCHCH2, and CdCH), 4.59-4.42 (m, 2H, CH2OPMB),
3.79 (s, 3H, OCH3), 3.68-3.60 (m, 1H, CHCHO), 2.16-1.95
(m, 2H, CdCHCH2), 1.70-1.53 (m, 4H, exo hydrogen on
ethano bridge, CdCHCH2CH2), 1.10-1.04 (app d, J ) 8.2 Hz,
2H, endo hydrogen on ethano bridge); 13C NMR (100 MHz) δ
203.9, 159.7, 146.1, 146.5, 129.8, 116.2, 114.1, 82.4, 76.9, 72.7,
55.4, 29.8, 22.8, 21.5, 21.1; ESI+/TOF m/z 629 (2M+ + H), 315
(M+ + H), 287, 189, 121; HRMS calcd for (C18H22N2O3 + H)
315.17031, found 315.1692.
5-(4-Methoxybenzyloxy)-(2R,5S,6R,8R)-tricyclo[6.3.0.02,6]-
undec-1(11)-ene (33; Scheme 5). Diazene aldehyde 7 (350
mg, 1.1 mmol) was subjected to deazetation as described in
general procedure F to afford the tricyclic heterocycle 33 (230
mg, 72%) as a colorless oil. TLC Rf 0.55 (SiO2, 20% EtOAc/
hexane), vanillin; IR (neat) 2936, 2854, 1698, 1612, 1512, 1462,
1301, 1247, 1172, 1071, 1039, 956, 817 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.27 (d, J ) 8.0 Hz, 2H, aromatic), 6.87 (d, J )
8.0 Hz, 2H, ArH), 5.50 (m, 1H, CdCH), 4.89 (ddd, J ) 0.8,
2.0, 8.0 Hz, 1H, HCdCCH), 4.74 (dd, J ) 1.6, 6.4 Hz, 1H,
OCHCHCdC), 4.51 (2d, J ) 11.6 Hz, 2H, CH2Ar), 3.93 (ddd,
J ) 2.4, 5.0, 8.0 Hz, 1H, CHOCH2Ar), 3.79 (s, 3H, OCH3), 3.17
(ddd, J ) 4.0, 8.0, 12.0 Hz, 1H, OCHCHCdC), 2.56 (m, 2H,
CHCdCHCH2), 2.27 (m, 1H, OCHCHHCH2), 2.08 (m, 1H,
ArCH2OCHCH2CHH), 1.84 (m, 1H, ArCH2OCHCHH), 1.77 (m,
1H, ArCH2OCHCHH), 1.65 (m, 1H, OCHCHHCH2), 1.50 (m,
ArCH2OCHCH2CHH); 13C NMR (100 MHz) δ 159.2, 151.3,
130.7, 129.4, 121.5, 113.9, 93.7, 88.2, 85.5, 70.9, 55.4, 40.4, 36.0,
33.9, 31.6, 28.9; LREI-MS m/z 286 (M+), 165, 137, 121, 91, 77,
51; HRMS calcd for C18H22O3 286.157895, found 286.158011.
5-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)-2-(4-meth-
oxybenzyloxy)-(2R)-pentan-1-ol (Scheme 2, Series 2, Step
d). To a stirred solution of the diazene (1.0 g, 3.18 mmol),
whose preparation was just described, in CH2Cl2 (15 mL) was
added Dibal-H (4.8 mL, 1.0 M solution in hexane, 4.8 mmol)
at -78 °C. After 1 h, the reaction mixture was quenched with
a dropwise addition of Rochelle’s salt (20 mL), warmed to room
temperature, and stirred for another 30 min. Then the mixture
was extracted with CH2Cl2, and the organic phase was
concentrated under reduced pressure and purified by silica gel
column chromatography to give diazene alcohol (0.74 g, 74%)
as a colorless oil. TLC Rf 0.35 (SiO2, 100% ether), vanillin; IR
(neat) 3425, 2942, 2865, 1612, 1586, 1513, 1455, 1348, 1301,
1248, 1176, 1033, 826, 752, 713 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 7.26-7.19 (m, 2H, ArH), 6.87-6.82 (m, 2H, ArH), 5.32
(app s, 1H, NCHCH2), 5.06-4.99 (br m, 2H, CdCH, NCHCH2),
4.43, (q, J ) 11.3 Hz, 2H, CH2Ar), 3.75 (s, 3H, OCH3), 3.63-
3.31 (m, 3H, CH2CHOPMB, CH2OH), 2.57 (br s, 1H, OH),
2.08-1.89 (m, 2H, CdCHCH2), 1.64-1.39 (m, 4H, exo hydro-
gen on ethano bridge, CdCHCH2CH2), 1.03 (app d, J ) 8.2
Hz, 2H, endo hydrogen on ethano bridge); 13C NMR (100 MHz)
δ 159.8, 145.5, 130.3, 129.3, 116.9, 113.8, 78.5, 76.7, 72.5, 71.1,
63.7, 55.2, 30.8, 24.9, 21.4, 20.9; ESI+/TOF m/z 339 (M+
+
Acknowledgment. We thank the National Science
Foundation (Grant No. CHE-0200855) for its support
of this research and Procter & Gamble Pharmaceuticals,
who provided funding to support the research contribu-
tions of Dr. Maiti.
Na), 311, 146; HRMS calcd for (C18H24N2O3 + Na) 339.1685,
found 339.1678.
5-(2,3-Diazabicyclo[2.2.1]hept-2-en-7-yliden)-2-(4-meth-
oxybenzyloxy)-(2R)-pentanal (7; Scheme 2, Series 2, Step
e). Doering oxidation of diazene alcohol (1.0 g, 5.5 mmol) to
make diazene aldehyde 7 (0.89 g, 90%) was performed accord-
ing to general procedure E. TLC Rf 0.5 (SiO2, 100% ether),
vanillin; IR (neat) 2944, 2863, 1729, 1612, 1512, 1455, 1302,
Supporting Information Available: 1H and 13C NMR
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1247, 1175, 1111, 1031, 823, 731 cm-1; H NMR (CDCl3, 400
MHz) δ 9.56 (d, J ) 0.4 Hz, 1H, CHO), 7.25 (m, 2H, ArH),
6.90 (m, 2H, ArH), 5.34 (app s, 1H, NCHCH2), 5.10-4.98 (m,
JO048717I
8582 J. Org. Chem., Vol. 69, No. 25, 2004