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K. P. Schultz et al. / Tetrahedron Letters 57 (2016) 1296–1299
yield.19 Suzuki coupling of bromobenzene provided 1,2-bis(2-
methyl-5-phenylthiophen-3-yl)cyclopent-1-ene (4) in 71% yield.
The next step was to produce the diene using bromine in diethyl
ether.15 In our hands, this reaction never went to completion and
starting material remained by TLC analysis. Attempts to isolate
the diene by column chromatography led to degradation, so the
DA reaction was performed on the crude diene after simple extrac-
tion and workup. Adding 1-hydroxy-3-phenylurea to an acetoni-
trile/dichloromethane solution containing the crude diene and
tetrapropylammonium periodate at 0 °C produced the racemic
cycloadduct 5o in 8% yield. Purification was accomplished via silica
gel chromatography with EtOAc/hexanes (1:9) containing 1% tri-
ethylamine. The product was characterized by 1H, 13C, IR, and
HRMS.
Irradiation of 5o with 312 nm light in acetonitrile produced a
deep red/violet solution with a new band in the visible spectrum
(Fig. 2). Photobleaching is accomplished upon irradiation of the
sample with >395 nm light (Fig. 3). 5 displays moderate fatigue
resistance and degrades 11% after three full cycles. The time
required to achieve ring closing and ring opening was 15 and 100 s,
respectively. 1H NMR spectroscopic studies performed in deuter-
ated DMSO were carried out to observe the ratio of ring closed to
ring opened isomers. Due to the asymmetry in the closed ring form
(Scheme 5), diastereomers are produced. Observation of the four
new bridgehead protons from these diastereomers allowed for
the quantification of the photostationary state. After 210 s of irra-
diation of a 2 ꢀ 10ꢁ3 M DMSO solution the photostationary state
was reached with 90% closed isomer. This is a main advantage of
5 over 3, given that the closed form is the inactive isomer toward
the retro DA reaction and a ‘locked’ system, 5c (Scheme 5), was
produced.
Figure 2. Changes in UV/Vis absorption spectra for 5o (4.5 ꢀ 10ꢁ5 M) in acetonitrile
solution upon irradiation with 312 nm light.
Figure 3. Changes in UV/Vis absorption spectra for 5c (4.5 ꢀ 10ꢁ5 M) in acetonitrile
Our attention now turned to the retro DA reaction on the
‘unlocked’ 5o. Previous studies by Kirby have shown the cyclore-
version to produce cyclopentadiene and an acyl nitroso compound
takes place at 80 °C in several hours in benzene or ethyl acetate.18
1H NMR spectroscopic studies in either deuterated toluene or
DMSO (Fig. S3 and Scheme S1) were used to follow the retro DA
reaction. To a deuterated toluene solution of 5o (1.47 ꢀ 10ꢁ2 M)
was added 1 equiv of N-methylmaleimide. Heating was increased
stepwise from 60 °C to 92 °C at which point a noticeable change
in the NMR spectrum occurred (Fig. 4). After 24 h at 92 °C the mal-
eimide adduct 6o (Scheme 5) was present as shown in Figure 4c.
The bridgehead and bridge protons of 6o become evident at 2.83
and 2.92 ppm (Fig. 4c, up arrow), showing the splitting of the
expected endo isomer.22 Due to the symmetry of 6o, the thiophene
protons produce the singlet at 7.38 ppm (Fig. 4c, up arrow). Finally,
the down arrows in Figure 4a show the disappearance of the
solution upon irradiation with >395 nm light.
dissociation of the cycloadducts was more dependent on steric
rather than electronic factors of the acyl nitroso species.13 We
envisioned that the bulky N-phenyl nitroso and 5,5-dimethylcy-
clopentadiene cycloadduct would facilitate the retro DA due to
steric factors.
The synthesis began with converting commercially available
3,3-dimethylglutaric acid to the acyl chloride using oxalyl chloride
and catalytic DMF in THF at 0 °C in 47% yield.21 Next, Friedel-Crafts
acylation using 2 equiv of 2-chloro-5-methylthiophene with alu-
minum chloride in carbon disulfide produced the (bis)thienyl in
30% yield.19 McMurry coupling using titanium chloride tetrahydro-
furan complex and powdered zinc yielded the cyclopentene in 40%
CH3
O
N
O
O
N
CH3
Ph
O
Ph
Ph
NH
N
NH
N
NH
N
O
O
Ph
Ph
O
S
S
O
O
O
Ph
Visible
UV
S
Ph
S
heat
+
6o
O
Ph
O
Ph
S
Ph
S
S
Ph
Ph
S
NH2
S
Ph
S
Ph
N
N
H
5c
H2O HO
N
H
5o
+ CO2
O
+
HNO
Scheme 5. Demonstration of the photochemical ‘locking’ (5c) and ‘unlocking’ (5o) of the retro DA reaction. Upon release of the acyl nitroso dienophile nitroxyl is likely
generated in aqueous systems. The released cyclopentadiene is trapped with N-methylmaleimide to give cycloadduct 6o.