Simultaneous observation of triplet and singlet cyclopentane-1,3-diyl diradicals in the intersystem crossing process

Article abstract of DOI:10.1071/CH15062

Intersystem crossing is an important chemical process. In this study, the rate constant of intersystem crossing, kISC ～3×107s-1, for cyclopentane-1,3-diyl diradicals was unequivocally determined by the simultaneous observation of the decay process of the

Full text of DOI:10.1071/CH15062

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 1700–1706
Full Paper
http://dx.doi.org/10.1071/CH15062
Simultaneous Observation of Triplet and Singlet
Cyclopentane-1,3-diyl Diradicals in the Intersystem
Crossing Process
A
A B D
, ,
C
Takemi Mizuno, Manabu Abe,
and Noriaki Ikeda
A
Department of Chemistry, Graduate School of Science, Hiroshima University,
1-3-1 Kagamiyama, Higashi-hiroshima, Hiroshima 739-8526, Japan.
Japan Science and Technology Agency (JST)-CREST, K’s Gobancho,
7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
B
C
Department of Materials Science and Engineering, Graduate School of Science
and Technology, Kyoto Institute of Technology, Matsugasaki Gosyo Kaidocho,
Sakyo-ku, Kyoto 606-8585, Japan.
D
Corresponding author. Email: mabe@hiroshima-u.ac.jp
Intersystem crossing is an important chemical process. In this study, the rate constant of intersystem crossing,
kISC ,3 ꢀ 107 sꢁ1, for cyclopentane-1,3-diyl diradicals was unequivocally determined by the simultaneous observation
of the decay process of the triplet diradical (lobs ¼ 320 nm) and the growth process of the corresponding singlet diradical
(lobs ¼ 560 nm). The two spin states were directly observed using a long-lived singlet 2,2-dimethoxy-1,3-
diphenylcyclopentane-1,3-diyl diradical.
Manuscript received: 5 February 2015.
Manuscript accepted: 1 March 2015.
Published online: 1 April 2015.
kCP of 3.03 ꢀ 106 sꢁ1, i.e. lifetime ,330 ns, to afford the ring-
closed compound CP2 (Scheme 1c).
Introduction
Diradicals are key intermediates in processes involving
homolytic bond cleavage and bond formation reactions
(Scheme 1a).[1] Intersystem crossing (ISC) between two spin
states – singlet and triplet – is important for understanding the
chemistry of homolytic reactions, although in principle, the
spin-flip process is forbidden. However, spin–orbit coupling
(SOC) permits ISC for diradicals with short two-spin distances
Herein, we report the simultaneous observation of the decay
process of triplet diradical 3DR3 (,320 nm) and the growth of
1
singlet diradical DR3 (,560 nm) in the denitrogenation of
triplet-sensitized azoalkane precursor AZ3 (Scheme 2); in AZ3,
the benzophenone unit (triplet energy (ET) ¼ 69 kcal molꢁ1[6]
(1 kcal molꢁ1 ¼ 4.186 kJ molꢁ1), e355 ¼ 108 L molꢁ1 cmꢁ1 in
acetonitrile) is attached to the meta position of the phenyl
ring for the triplet sensitization of the azo-chromophore
(ET ¼ 62 kcal molꢁ1).[7] We hypothesize that meta-substitution
can prevent the direct growth of 1DR3 by the conjugation of the
corresponding ketyl radical of the singlet excited state. Intra-
molecular sensitization was utilized for the clear observation of
ISC from the triplet to the singlet diradical, because the
intermolecular triplet sensitization of AZ2 with benzophenone
was highly dependent on the AZ2 concentration.
[2]
˚
of ,3 A. For example, the appropriate geometry of two p
orbitals, which accelerate ISC by the SOC mechanism from
triplet to singlet, plays an important role in determining the
stereoselectivity of radical–radical coupling reactions.[3]
Thus far, ISC rate constants (kISC) have been experimentally
determined by the detection of the decay process of long-lived
triplet diradicals, because in general, the lifetime of singlet
diradicals is too short to be observed by conventional spectro-
scopic analysis. For instance, Adam and coworkers determined
the ISC rate constant (kISC ,105 sꢁ1) of a 1,3-diradical DR1
from the decay process of the triplet state (lmax ,320 nm)
(Scheme 1b).[4] As the corresponding singlet state was short-
lived, its growth was not observed. If the growth process of
the singlet state can be simultaneously observed along with the
decay process of the triplet state, kISC thus obtained would be
significantly more reliable. Recently, we succeeded in generat-
ing long-lived singlet diradicals with p-single bond character,
e.g. 1DR2 (lmax ,560 nm), by the photodenitrogenation of the
precursor azoalkane AZ2 (e355 ¼ 68 L molꢁ1 cmꢁ1 in aceto-
nitrile).[5a–d] The singlet diradical decays with a rate constant
Results
Synthesis and Photodenitrogenation of AZ3
The synthesis of precursor azoalkane AZ3 and its photochem-
ical reaction are shown in Scheme 3. The a-dimethoxylation of
3[8] was performed by Tiecco’s method to obtain 4.[9] The
synthesis of pyrazole 5 followed by the Diels–Alder reaction
of 5 with cyclopentadiene afforded azoalkane 6.[10] Benzoyla-
tion using a Weinreb amide[11] produced AZ39, followed by
hydrogenation to yield precursor AZ3. The photo-irradiation of
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

Intersystem Crossing in 1,3-Diradicals
1701
(a)
(b)
Me Me
cleavage
formation
ISC
Ph
Ph
kISC
C
C
C
C
C
C
Singlet
1DR
Triplet
3DR
Diradicals
DR1
(c)
1
∗
OMe
Ph
MeO
Ph
MeO
OMe
Ph
OMe
MeO
MeO
OMe
kCP
hν
Ph
N
Ph
N
N
N
Ph
N2
Ph
Ph
1
1DR2
∗
AZ2
AZ2
CP2
Scheme 1. (a) Intersystem crossing (ISC) in diradicals; (b) structure of DR1; and (c) generation of 1DR2
by the photodenitrogenation of azoalkane precursor AZ2.
MeO
OMe
Ph
MeO
MeO
OMe
Ph
OMe
∗
3
Ph
N
N
N
hν
N
∗
N
N
3
O
ISC
O
O
N2
AZ3
MeO
OMe
Ph
O
O
MeO OMe
Ph
OMe
MeO
Ph
O
ISC
3DR3
1DR3
CP3
Scheme2. Generation of triplet diradical 3DR3 and its ISC (intersystem crossing) to 1DR3 in the photochemical
denitrogenation of AZ3 in this study.
O
O
O
O
a
Br
Br
Ph
MeO
66 %
Ph
1
2
3
OMe
Ph
MeO
O
O
N
N
b
c
Br
Br
d
N
N
Ph
Ph
25 % (2 steps)
85 %
MeO
OMe
MeO OMe
4
5
Br
6
OMe
OMe
MeO
MeO
OMe
Ph
MeO
Ph
N
Ph
N
N
N
g
f
e
O
47 %
quantitatively
O
O
51 %
CP3
AZ3؅
AZ3
Scheme 3. Synthesis of AZ3. Conditions: (a) NaH, THF, 08C; (b) Ph2Se2, (NH4)2S2O8, MeOH; (c) N2H2 H2O, CHCl3; (d) cyclopentadiene,
CF3CO2H, CH2Cl2, 08C; (e) n-BuLi, N-methoxy-N-methylbenzamide, THF, ꢁ788C; (f) H2, Pd/C, EtOAc; (g) high-pressure Hg lamp, benzene.

1702
T. Mizuno, M. Abe, and N. Ikeda
(a)
(a)
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
0.25
0.20
0.15
0.10
0.05
0
0.01 μs
0.3 μs
0.8 μs
0.04 μs
0.1 μs
0.8 μs
Ϫ0.05
Ϫ0.05
300
400
500
600
700
300
400
500
600
700
Wavelength [nm]
Wavelength [nm]
(b) 0.25
0.20
(b)
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
0.30
0.25
0.20
0.15
0.25
0.20
0.15
0.10
0.15
0.10
Ϫ0.05
0.05
0.15
[μs]
0.25
Ϫ0.05
0.05
0.15
[μs]
0.25
3.5
0.05
0
Ϫ0.05
Ϫ0.5
0.5
1.5
Time [
2.5
Ϫ0.05
μ
s]
Ϫ0.5
0.5
1.5
2.5
3.5
Time [μs]
Fig. 1. (a) Transient absorption spectra of AZ2; (b) absorbance change
observed at 560 nm; and (inset) the absorbance change in the range of ꢁ0.05
to 0.30 ms in the laser flash photolysis (LFP) of AZ2 in acetonitrile at 293 K.
(c)
0.25
0.20
0.15
0.10
0.05
0
AZ3 using a high-pressure Hg lamp through a Pyrex filter
(.290 nm) quantitatively formed the denitrogenated compound
CP3 in a deoxygenated benzene solution by bubbling N2
through it for 15 min.[3c]
Transient Absorption Spectroscopy of AZ2 and AZ3
The transient absorption spectrum observed in the photolysis
of AZ2 in acetonitrile at 293 K is shown in Fig. 1. On applying a
4–6-ns pulse from a Nd-YAG laser (lexc 355 nm), planar singlet
diradical 1DR2 was immediately observed at ,560 nm; however,
it decayed with a lifetime (t) of 330 ns (kCP ¼ 3.03 ꢀ 106 sꢁ1) at
293 K (Fig. 1b) to yield the ring-closed product CP2. In the
photolysis of AZ3, the transient absorption of singlet diradical
1DR3 was also observed in the same region with a lmax of
,560 nm (Fig. 2a). In contrast to the flash photolysis of AZ2, the
Ϫ0.05
Ϫ0.5
0.5
1.5
2.5
3.5
Time [μs]
Fig. 2. (a) Transient absorption spectra of AZ3; (b, c) absorbance changes
observed at 560 and 320 nm respectively; and (inset) the absorbance change
in the range of ꢁ0.05 to 0.30 ms in acetonitrile at 293 K. The negative
absorptions in (a) are caused by the emission signal.
1
growth of DR3 was observed until ,100 ns after laser exci-
tation (Fig. 2b). From the double-exponential fit of the data on
the time profile of 1DR3, the decay rate constant (kd) of 1DR3
and the growth rate constant (kg) were determined to be
2.02 ꢀ 106 and 3.24 ꢀ 107 sꢁ1 at 293 K respectively (Table 1,
entry 1).
band is observed at a position typical for the triplet state of
1,3-diphenylpropane-1,3-diyl diradicals,[12] e.g. 3DR1; lmax
,320 nm.[4] Time-dependent density functional theory (DFT)
calculation at the UB3LYP/6–31Gþ(d, p) level of theory
suggests that triplet diradical 3DR3 has an absorption at
354 nm. The residue at 320 nm is due to the formation of
product CP3.
The intramolecular energy transfer from the triplet benzo-
phenone moiety (lT-T ¼ 530 nm)[13] to the azo-chromophore
was visualized by picosecond time-resolved transient absorp-
tion measurements of the photolysis of AZ3 in acetonitrile
(Fig. 3). The kinetic trace at 530 nm indicated a fast decay
process with a rate constant of ,5 ꢀ 1010 sꢁ1. The rapid decay
The decay process corresponds to the formation of the ring-
closed compound CP3, because CP3 is quantitatively isolated
from the photolysis reaction. The growth process was assigned
to the ISC from triplet state 3DR3, generated by the elimination
of molecular nitrogen from the triplet excited state of AZ3.
In fact, a decay species was observed at 320 nm with a rate
constant of 3.44 ꢀ 107 sꢁ1, which is consistent with the growth
1
rate constant of DR3. The species observed at 320 nm was
assigned to triplet diradical 3DR3, because the absorption

Intersystem Crossing in 1,3-Diradicals
1703
Table 1. Time-resolved absorption spectroscopic data for laser flash photolysis (LFP)
experiments of AZ3 and CP3
Entry
Substrate
Temperature [K]
Rate constantA [sꢁ1
]
at 320 nm
kd,320 ꢀ 10ꢁ7
at 560 nm
kg,560 ꢀ 10ꢁ7
kd,560 ꢀ 10ꢁ6
1
2
3
4
AZ3
CP3
AZ3
CP3
293
293
243
243
3.44 ꢂ 0.08
3.49 ꢂ 0.06
3.49 ꢂ 0.10
3.04 ꢂ 0.15
3.24 ꢂ 0.23
3.24 ꢂ 0.17
3.33 ꢂ 0.23
3.04 ꢂ 0.16
2.02 ꢂ 0.01
2.01 ꢂ 0.01
0.086 ꢂ 0.003
0.091 ꢂ 0.005
AMean value and standard error after three measurements under a nitrogen atmosphere.
400
500
600
700
800
900
Ϫ20 ps
(a)
(b)
(c)
0.07
0.05
0.07 μs
0.1 μs
0.5 μs
0 ps
20 ps
0.03
530 nm
0.01
100 ps
560 nm
Ϫ0.01
300
400
500
600
700
500 ps
Wavelength [nm]
0.085
0.065
1 ns
3 ns
0.045
6 ns
0.025
0.005
400
500
600
700
800
900
Wavelength [nm]
Ϫ0.015
Ϫ0.5
0.5
1.5
2.5
3.5
Fig. 3. Transient absorption spectra of AZ3 by picosecond time-resolved
Time [μs]
transient absorption measurements in acetonitrile.
0.055
0.045
process at 530 nm corresponds to the energy transfer from the
triplet-excited benzophenone to the diazene unit, which gener-
ates triplet diradical 3DR3, followed by ISC to singlet diradical
1DR3. In fact, the growth process of the 560-nm species was
observed by time-resolved spectroscopic analysis (Fig. 3).
0.035
0.025
Transient Absorption Spectroscopy of CP3
0.015
To confirm the observation of ISC, i.e. the simultaneous
detection of the decay process of 3DR3 at 320 nm and the growth
process of 1DR3 at 560 nm in the laser flash photolysis (LFP) of
AZ3, the time-resolved transient absorption spectroscopic
analysis of the corresponding ring-closed compound CP3 was
investigated in acetonitrile under similar LFP conditions
(Fig. 4). Similar time profiles of the transients at 320 and 560 nm
were observed in the LFP of CP3 at 293 K. Thus, the growth
process with kg E 3.24 ꢂ 0.7 ꢀ 107 sꢁ1 and the decay process
with kd E 2.01 ꢂ 0.01 ꢀ 106 sꢁ1 were detected at 560 nm
(Fig. 4b); both their rate constants at 560 nm were in good
0.005
Ϫ0.005
Ϫ0.015
Ϫ0.5
0.5
1.5
2.5
3.5
Time [μs]
Fig. 4. (a) Transient absorption spectra of CP3; and (b, c) absorbance
changes observed at 560 and 320 nm respectively in acetonitrile at 293 K.
The negative absorptions in (a) are caused by the emission signal.

1704
T. Mizuno, M. Abe, and N. Ikeda
E
agreement with those observed in the LFP of AZ3 (entries 1 and
2, Table 1). The decay rate constant of the species observed at
320 nm was found to be 3.49 ꢂ 0.06 ꢀ 107 sꢁ1 with single-
exponential fitting, which is also consistent with the value of
kd ¼ 3.44 ꢂ 0.08 ꢀ 107 sꢁ1 observed in the LFP of AZ3 (entries
1 and 2 respectively). Similar transient absorption spectroscopic
behaviour suggested that the decay process at 320 nm corre-
sponds to ISC from 3DR3 to 1DR3 and not to the denitrogenation
of 3AZ3*, which includes the bond-breaking process.
∗
C–C σ
a: Antisymmetric NBMO
s: Symmetric NBMO
∗
OMe
OMe
C–C σ
a
γAB
The assignment of ISC, i.e. the simultaneous detection of the
3
γAB
C–C σ
CH3
CH3
decay process of DR3 (320 nm) and the growth process of
s
1DR3 (560 nm), was confirmed by the temperature effect on the
rate constants. The temperature effect on the spin-flip process, i.
e. ISC, is known to be small, although the rate constants of bond
breaking and bond formation are supposed to be significantly
affected by temperature.[14] In fact, the temperature effect on the
rate constant of the growth at 560 nm (kg,560) and the decay at
320 nm (kd,320) was observed to be marginal in the temperature
range from 293 to 243 K (compare entries 1 and 2 with entries
3 and 4; Table 1), although the decay rate constant (kd,560) of
1DR3, i.e. C–C bond formation process, was significantly
affected by temperature. The small temperature effects on
kd,320 and kg,560 strongly suggested that the time profiles of the
decay at 320 nm and the growth at 560 nm originate from ISC
from the triplet to the singlet in 1,3-diradical DR3.
X ϭ
ϪMe
ϪOMe
C–C σ
Fig. 5. Effect of substituent on the energy gap between the two non-
bonding molecular orbitals (NBMOs) in cyclopentane-1,3-diyl diradicals.
Nanosecond time-resolved transient absorption measurements
by LFP of azoalkane AZ3 permitted the simultaneous detection
of the growth process of singlet diradical 1DR3 (lobs ¼ 560 nm)
and the decay process of triplet diradical 3DR3 (lobs ¼ 320 nm),
because 1DR3 is a long-lived singlet diradical. Kinetic analyses
of the processes revealed that the rate constant of the growth
process (observed at 560 nm) was consistent with that of the
decay process (observed at 320 nm). The observation of a sim-
ilar transient absorption at 320 nm in the photolysis for the
corresponding ring-closed product CP3 indicated that the
Discussion
The ISC rate constant determined in the present study, kISC
,3.24 ꢀ 107 sꢁ1, for 2,2-dimethoxycyclopentane-1,3-diradical
DR3 was significantly higher than that[4] for 2,2-dimethyl-
cyclopentane-1,3-diradical DR1 by two orders of magnitude,
kISC ,3.69 ꢀ 105 sꢁ1. The question arises as to why ISC in DR3
is significantly faster than that in DR1. Adam and coworkers
have discussed the effect of substituents on the ISC rate con-
stants for cyclopentane-1,3-diyl diradicals.[4] A large SOC in
diradicals enhances the rate constant of ISC, because the
transmission factor of SOC, ASOC, is proportional to the square
of Cþ, which represents the coefficient of the wave function of
the singlet diradicals in the ground state,[2,4] as shown in Eqn 1.
3
absorbance originates from triplet diradical DR3. The obser-
vation of ISC was strongly supported by the small temperature
effect on both the decay rate constant at 320 nm (kd,320) and the
growth rate constant at 560 nm (kg,560). This is the first report on
the simultaneous observation of both the triplet and singlet states
in localized diradicals.
Experimental
General Chemical Procedures
ASOC / Cþ2
ð1Þ
All reagents and solvents were purchased from commercial
sources and were used without further purification. Silica gel
(60N, spherical, neutral, 63–210-mm) was purchased from
Kanto Chemical Co., Inc. to use in silica gel column chroma-
tography. 1H and 13C NMR spectra were measured on a Bruker
AscendTM 400 spectrometer. 1H and 13C NMR chemical shifts
are given in parts per million (ppm) relative to internal CDCl3 or
C6D6. IR spectra were recorded on a PerkinElmer Spectrum One
Fourier-transform (FT)-IR spectrometer. UV-vis spectra were
recorded on a Jasco V-630 spectrophotometer. Mass-spectro-
metric data were measured with a mass spectrometric Thermo
Fisher Scientific LTQ Orbitrap XL.
The coefficient Cþ is expressed in0 Eqn 2,[2,4] where gAB
denotes the covalent perturbation, and KAB denotes the coulomb
integral function.
gAB
2KA0 B
C
þ
ꢃ
ð2Þ
gAB corresponds to the energy gap between the two non-
bonding molecular orbitals (NBMOs) that are occupied by the
two electrons for the corresponding 1,3-diradical fragment
(Fig. 5). The low-lying C–O s* orbital is stabilized by hyper-
conjugation with the symmetric NBMO(s) while the C–C s*
orbital is too high-lying to interact (Fig. 5); thus, gAB in
X ¼ OMe becomes larger than that in X ¼ Me, indicating that
ISC in DR3 with the singlet ground state is significantly faster
than that in DR1 with the triplet ground state.
Laser Flash Photolysis Measurements
Spectral grade acetonitrile was purchased from Wako and used
without further purification. All samples were purged with
nitrogen gas or argon gas for 15 min to remove oxygen before
measurement. The concentration of samples was adjusted to
an optical density of 0.1–0.2 at the excitation wavelength
(355 nm). The excitation source for the LFP system was an
Nd-YAG laser that produces a 4–6-ns pulse of up to 7 mJ at
355 nm. Themonitoring system consisted of a 150-W xenon lamp
Conclusions
In summary, we attempted to directly observe ISC by the
simultaneous detection of triplet and singlet diradicals.

Intersystem Crossing in 1,3-Diradicals
1705
as light source, Unisoku-MD200 monochromator and a photo-
multiplier. The temperature was controlled with a CoolSpeck
USP-203 (Unisoku). The excitation source for the picosecond–
nanosecond LFP system was a mode-locked Nd-YAG laser
(Continuum PY61C-10, full-width half-maximum (fwhm) ¼ 17
ps, 10 Hz). The third harmonic (355 nm, 3-mJ pulseꢁ1) was used
to excite a sample in solution contained in a l-cm quartz cell.
Picosecond transient absorption spectra in a delay time range of
ꢁ20–6000 ps were obtained using a picosecond white contin-
uum, which was produced by focussing the fundamental laser
pulse into a flowing H2O/D2O (1 : 1 by volume) solution. The
details of the measurement system have been described else-
where.[5d,15] For picosecond transient absorption measurements,
the absorbance at 355 nm of the sample solutions was adjusted
to ,0.8.
sodium sulfate. After evaporation of the solvent under vacuum,
the residue was purified by silica gel column chromatography
(hexane/EtOAc 4 : 1 v/v) to afford compound 5 (2.09 g,
5.83 mmol, 25 % in two steps) as a yellow solid; mp 126–
1288C. nmax (KBr)/cmꢁ1 3071, 2949, 2931, 2832, 1553, 1443,
1118. dH (400 MHz, CDCl3) 8.42 (s, 1H, ArH), 8.26 (d, J 8.0,
ArH), 8.20 (d, J 8.0, 1H, ArH), 7.69 (d, J 8.0, 1H, ArH), 7.58 (t, J
7.3, 1H, ArH), 7.52 (t, J 7.6, 2H, ArH), 7.39 (t, J 8.0, 1H, ArH),
3.07 (s, 6H, OCH3). dC (100 MHz, CDCl3) 166.98, 165.66,
135.21, 132.61, 130.56, 130.40, 129.53, 129.07, 127.81,
127.46, 126.22, 123.17, 117.18, 52.05. m/z (HRMS-ESI)
359.03983; calc. for C17H16O2N2Br [M þ Hþ] 359. 03897.
(1R,4R,4aS,7aR)-1-(3-Bromophenyl)-8,8-dimethoxy-
4-phenyl-4,4a,5,7a-tetrahydro-1H-1,4-
methanocyclopenta[d]pyridazine 6
Preparation of Azoalkane AZ3 and Ring-Closed
Compound CP3
Cyclopentadiene (7.07 g, 0.11 mol) was added to a solution
of compound 5 (2.09 g, 5.82 mmol) in dry dichloromethane
(50 mL) in a flask covered with aluminium foil under an N2
atmosphere at 08C with stirring. Then a solution of trifluoroa-
cetic acid (0.13 mg, 1.18 mmol) in dichloromethane (10 mL)
was added at the same temperature. The reaction mixture was
allowed to stand for 1 h, and then a saturated aqueous solution of
sodium bicarbonate was added until the solution was neutral-
ized. The organic layer was extracted with dichloromethane
(3 ꢀ 10 mL) and dried over magnesium sulfate. After evapora-
tion of the solvent under vacuum, the residue was purified by
silica gel column chromatography (hexane/EtOAc 8 : 1, v/v) to
afford compound 6 (2.10 g, 4.95 mmol, 85 %) as a white solid.
The product was a mixture of two isomers; mp 154–1568C. nmax
(KBr)/cmꢁ1 3067, 2946, 2920, 2842, 1596, 1563, 1477, 1183,
1102. dH (400 MHz, C6D6) 8.40, 8.26 (s, 1H, ArH), 8.07, 8.01 (d,
J 7.2, 1H, ArH), 7.93, 7.86 (d, J 7.2, 2H, ArH), 7.33–7.26 (m,
3H, ArH), 7.19 (t, J 7.2, 1H, ArH), 6.92–6.90 (m, 1H, ArH),
5.44–5.33 (m, 2H,CH), 3.95–3.82 (m, 1H, CH), 3.39–3.24 (m,
1H, CH), 2.59 (s, 3H, OCH3), 2.43 (s, 3H, OCH2), 2.28–1.97 (m,
2H, CH2). dC (100 MHz, CDCl3) 136.65, 138.48, 135.79,
135.62, 134.57, 134.13, 131.63, 131.07, 130.92, 130.89,
129.90, 129.84, 128.65, 128.35, 128.32, 128.06, 127.89,
127.14, 126.42, 126.12, 122.63, 122.57, 118.12, 94.56, 93.63,
57.34, 56.76, 52.06, 52.05, 51.77, 51.75, 42.46, 41.97, 32.17,
32.06. m/z (HRMS-ESI) 447.06812; calc. for C22H21O2N2BrNa
[M þ Naþ] 447.06786.
(3-Bromophenyl)-3-phenylpropane-1,3-dione 3
Sodium hydride (2.26 g, 60 %, 56.6 mmol) was suspended in
THF (35 mL) at 08C under an N2 atmosphere. A solution of
methyl 3-bromobenzoate 1 (7.43 g, 34.6 mmol) in THF (10 mL)
was added with stirring. After 15 min, a solution of acetophe-
none 2 (4.12 g, 34.3 mmol) in THF (10 mL) was slowly added to
the reaction mixture, and then the mixture was stirred at room
temperature (rt) for 2 h. The reaction mixture was poured into
cracked ice containing 1 M hydrochloric acid (20 mL) with
stirring. The organic layer was extracted with ethyl acetate
(3 ꢀ 10 mL) and dried over sodium sulfate. After evaporation
of the solvent under vacuum, the residue was purified by silica
gel column chromatography (hexane/EtOAc 8 : 1 v/v) and
recrystallization with ethanol afforded compound 3 (6.95 g,
22.9 mmol, 66 %) as a yellow solid; mp 66–688C. nmax (KBr)/
cmꢁ1 1599, 1517, 1456, 1225, 759. dH (400 MHz, CDCl3) 8.11
(s, 1H, ArH), 8.00 (d, J 7.2, 2H, ArH), 7.91 (d, J 8.0, 1H, ArH),
7.68 (d, J 8.0, 1H, ArH), 7.58 (t, J 7.2, 1H, ArH), 7.50 (t, J 7.8,
2H, ArH), 7.37 (t, J 7.8, 1H, ArH), 6.81 (s, 1H, CH). dC
(100 MHz, CDCl3) 186.25, 184.19, 137.73, 135.36, 132.89,
130.39, 130.32, 128.91, 127.40, 125.84, 123.09, 93.43. m/z
(high-resolution electrospray ionization mass spectrometry
(HRMS-ESI)) 324.98361; calc. for C15H11BrO2Na [M þ Naþ]
324.98346.
1-(3-Bromophenyl)-2,2-dimethoxy-3-phenylpropane-
(3-((1R,4R,4aS,7aR)-8,8-Dimethoxy-4-phenyl-
4,4a,5,7a-tetrahydro-1H-1,4-methanocyclopenta[d]
pyridazin-1-yl)phenyl)(phenyl)methanone AZ39
1,3-dione 4
A mixture of compound 3 (6.95 g, 22.9 mmol), diphenyl
diselenide (3.50 g, 11.2 mmol), and ammonium peroxodisulfate
(10.4 g, 45.6 mmol) was refluxed in methanol (100 mL) with
stirring under an N2 atmosphere for 1 h. Then water was added to
the mixture until the ammonium peroxodisulfate had dissolved.
The organic layer was extracted with chloroform (3 ꢀ 10 mL)
and dried over sodium sulfate. Evaporation of the solvent under
vacuum gave the crude product as a red liquid. The crude was
directly used in the next step because compound 4 was not stable
on silica.
A flask was dried by heating under reduced pressure before
compound 6 was introduced into it. Under an N2 atmosphere, a
solution of compound 6 (2.10 g, 4.95 mmol) in dry THF (45 ml)
was cooled to ꢁ788C with acetone/liquid nitrogen. A solution of
n-butyl lithium in hexane (3.7 mL, 5.92 mmol) was added
slowly with stirring, followed by immediate addition of a
solution
of
N-methoxy-N-methylbenzamide
(0.81 g,
4.93 mmol) in THF (5 mL). The reaction mixture was allowed
to stand for 1 h and then water was added to the flask. The
organic layer was extracted with diethyl ether (3 ꢀ 10 mL),
washed with brine and dried over magnesium sulfate. After
evaporation of the solvent under vacuum, the residue was
purified by column chromatography (SiO2, hexane/EtOAc
4 : 1 v/v) to afford AZ39 (1.15 g, 2.55 mmol, 51 %) as a white
solid. The product was a mixture of two isomers; mp 178–
1828C. nmax (KBr)/cmꢁ1 2946, 1654, 1184, 719. dH (400 MHz,
4,4-Dimethoxy-5-phenyl-4H-pyrazole 5
Hydrazine monohydrate (0.83 g, 16.5 mmol) was added to
the solution of compound 4 (,10 g, crude) in chloroform
(70 mL) with stirring under an N2 atmosphere and the mixture
was allowed to stand for 1.5 h. Hydrochloric acid (1 M) was
added and the mixture was stirred for 10 min. The organic layer
was extracted with chloroform (3 ꢀ 10 mL) and dried over

1706
T. Mizuno, M. Abe, and N. Ikeda
C6D6) 8.66, 8.51 (s, 1H, ArH), 8.32–8.00 (m, 3H, ArH), 7.85–
7.78 (m, 3H, ArH), 7.31–7.03 (m, 7H, ArH), 5.49–5.33 (m, 2H,
CH), 3.98–3.91 (m, 1H, CH), 3.45–3.31 (m, 1H, CH), 2.63 (s,
3H, OCH3), 2.48 (s, 3H, OCH3), 2.31–2.26 (m, 1H, CH2), 2.07–
2.03 (m, 1H, CH2). dC (100 MHz, CDCl3) 196.80, 196.78,
137.95, 137.84, 137.69, 136.50, 136.12, 135.94, 134.90,
134.35, 133.27, 132.72, 132.42, 130.53, 130.35, 130.31,
129.98, 129.83, 129.76, 128.70, 128.62, 128.59, 128.47,
128.27, 128.11, 127.95, 126.80, 126.32, 118.47, 94.58, 94.42,
92.89, 92.66, 57.87, 56.66, 52.27, 52.03, 52.01, 42.95, 41.89,
32.42, 32.32. m/z (HRMS-ESI) 473.18341; calc. for
C29H26O3N2Na [M þ Naþ] 473.18356.
(nos. 24109008 and 24109002a) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Reference
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8.59 (s, 1H, ArH), 8.26 (d, J 7.5, 1H, ArH), 8.09 (d, J 7.2, 2H,
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2943, 1662. dH (400 MHz, C6D6) 8.06 (s, 1H, ArH), 7.79 (d, J
7.0, 2H, ArH), 7.69 (d, J 7.9, 1H, ArH), 7.46 (d, J 8.0, 1H, ArH),
7.28 (d, J 7.0, 2H, ArH), 7.13–7.00 (m, 7H, ArH), 3.41 (s, 3H,
OCH3), 2.94–2.84 (m, 2H, CH), 2.76 (s, 3H, OCH3), 1.82–2.80
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197.20, 138.05, 137.52, 135.65, 134.77, 134.36, 132.80, 132.19,
130.51, 130.23, 128.64, 128.29, 128.25, 126.65, 98.59, 54.86,
52.97, 48.17, 47.25, 41.63, 41.48, 28.43, 28.34, 25.26. m/z
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Supplementary Material
1H and 13C NMR spectra of the compounds synthesized in this
study are available on the Journal’s website.
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Acknowledgements
NMR and MS measurements were performed at N-BARD, Hiroshima
University. This study was supported by a Grant-in-Aid for Science
Research on Innovative Areas ‘Stimuli-responsive Chemical Species’
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