TiO2 Photocatalysis in Aromatic "redox Tag"-Guided Intermolecular Formal [2 + 2] Cycloadditions

Article abstract of DOI:10.1021/acs.joc.8b00738

Since the pioneering work by Macmillan, Yoon, and Stephenson, homogeneous photoredox catalysis has occupied a central place in new reaction development in the field of organic chemistry. While heterogeneous semiconductor photocatalysis has also been studied extensively, it has generally been recognized as a redox option in inorganic chemistry where such "photocatalysis" is most often used to catalyze carbon-carbon bond cleavage and not in organic chemistry where bond formation is usually the focal point. Herein, we demonstrate that titanium dioxide photocatalysis is a powerful redox option to construct carbon-carbon bonds by using intermolecular formal [2 + 2] cycloadditions as models. Synergy between excited electrons and holes generated upon irradiation is expected to promote the overall net redox neutral process. Key for the successful application is the use of a lithium perchlorate/nitromethane electrolyte solution, which exhibits remarkable Lewis acidity to facilitate the reactions of carbon-centered radical cations with carbon nucleophiles. The reaction mechanism is reasonably understood based on both intermolecular and intramolecular single electron transfer regulated by an aromatic "redox tag". Most of the reactions were completed in less than 30 min even in aqueous and/or aerobic conditions without the need for sacrificial reducing or oxidizing substrates generally required for homogeneous photoredox catalysis.

Full text of DOI:10.1021/acs.joc.8b00738

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TiO2 Photocatalysis in Aromatic “Redox Tag”-
Guided Intermolecular Formal [2 + 2] Cycloadditions
Yohei Okada, Naoya Maeta, Kaii Nakayama, and Hidehiro Kamiya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00738 • Publication Date (Web): 15 Apr 2018
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TiO Photocatalysis in Aromatic “Redox Tag”-
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Guided Intermolecular Formal [2 + 2] Cycloadditions
Yohei Okada,* Naoya Maeta, Kaii Nakayama, Hidehiro Kamiya
Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16
Naka-cho, Koganei, Tokyo 184-8588, Japan.
ABSTRACT
Since the pioneering work by Macmillan, Yoon, and Stephenson, homogeneous photoredox
catalysis has occupied a central place in new reaction development in the field of organic chemistry.
While heterogeneous semiconductor photocatalysis has also been studied extensively, it has
generally been recognized as a redox option in inorganic chemistry where such “photocatalysis”
is most often used to catalyze carbon-carbon bond cleavage, and not in organic chemistry where
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bond formation is usually the focal point. Herein, we demonstrate that titanium dioxide (TiO )
2
photocatalysis is a powerful redox option to construct carbon-carbon bonds by using
intermolecular formal [2 + 2] cycloadditions as models. Synergy between excited electrons and
holes generated upon irradiation is expected to promote the overall net redox neutral process. Key
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for the successful application is the use of a lithium perchlorate (LiClO
4
)/nitromethane (CH
3
NO )
2
electrolyte solution, which exhibits remarkable Lewis acidity to facilitate the reactions of carbon-
centered radical cations with carbon nucleophiles. The reaction mechanism is reasonably
understood based on both intermolecular and intramolecular single electron transfer (SET)
regulated by an aromatic “redox tag.” Most of the reactions were completed in less than 30 min
even in aqueous and/or aerobic conditions without the need for sacrificial reducing or oxidizing
substrates generally required for homogeneous photoredox catalysis.
INTRODUCTION
Light has the potential to serve as a green and sustainable reagent to catalyze chemical reactions.
1
Stemming from the pioneering work of Honda and Fujishima in 1972, titanium dioxide (TiO
2
)
2
has occupied a central place in the field of semiconductor photocatalysis. The excited
electron/hole pair generated upon irradiation in aqueous aerobic conditions produces reactive
3
oxygen species (ROS) at the surface, which account for subsequent redox transformations. These
species rapidly convert organic compounds into CO
2
and H O via carbon-carbon bond cleavage,
2
therefore, semiconductor photocatalysis has generally been recognized as a redox option in
inorganic chemistry but not in organic chemistry where carbon-carbon bond formation is the focal
point. Nevertheless, the idea that the controlled application of semiconductor photocatalysis would
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be a green and sustainable synthetic procedure in organic chemistry has been proposed and it has
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been demonstrated to catalyze various redox transformations, typically radical-driven reactions
involving a single electron transfer (SET) process.5
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While semiconductor photocatalysis is a heterogeneous process, a homogeneous alternative is
achieved by the use of transition metal complexes, which is now well-known as “photoredox
6
7
8
catalysis.” The early work by MacMillan, Yoon, and Stephenson has triggered explosive growth
9
in new reaction developments in this area. Arguably, heterogeneous semiconductor photocatalysis
has taken a backseat to homogeneous photoredox catalysis in the field of organic chemistry.
However, as clearly pointed out by Kisch,4(a) homogeneous photoredox catalysis generally requires
the presence of sacrificial reducing or oxidizing substrates to quench either excited electrons or
holes, otherwise recombination rapidly takes place. This differs from heterogeneous
semiconductor photocatalysis, in that both reductive and oxidative SETs can potentially be enabled
by excited electrons and holes, which might be advantageous over homogeneous photoredox
catalysis.
1
0
For TiO
2
photocatalysis to be effective in carbon-carbon bond formation, the reactions must be
carried out in dry anaerobic conditions in order not to produce ROS that can damage organic
compounds. However, a striking testament to the utility of TiO photocatalysis in aerobic
2
11
conditions has recently been proposed by Wang, where they described that challenging carbon-
carbon bond formation does occur if the reaction of the carbon-centered radical cation produced
by hole oxidation with a carbon nucleophile is sufficiently more favorable than undesired
oxygenation by ROS.
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We have been developing carbon-carbon bond formation reactions by electrocatalysis in lithium
1
2
perchlorate (LiClO
4
)/nitromethane (CH
3
NO ) electrolyte solution. Our reaction design involves
2
1
3
the aromatic “redox tag” concept, in which an aromatic ring provides both the oxidant and the
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reductant in the overall net redox neutral carbon-carbon bond formation reaction. In most cases,
the use of LiClO
4
/CH
3
NO
2
electrolyte solution is critical, because it exhibits remarkable Lewis
1
4
acidity which facilitates the reactions of carbon-centered radical cations with carbon nucleophiles,
1
5
even unactivated alkenes. Our reaction development is also characterized by the importance of
an intramolecular SET process, which has recently been presented by Melchiorre as an elegant
16
“
electron relay” mechanism. We anticipated that the use of LiClO
4
/CH
3
NO electrolyte solution
2
would pave the way for carbon-carbon bond formation by TiO photocatalysis. It should also be
2
noted that overall net redox neutral processes would benefit from the involvement of both
reductive and oxidative SETs potentially enabled by excited electrons and holes. Described herein
is the aromatic redox tag-guided intermolecular formal [2 + 2] cycloaddition by TiO
photocatalysis.
2
RESULTS AND DISCUSSION
The present work began with the reaction between the enol ether (1) and 1-hexene (2) as a model17,
18
using Aeroxide P25, which is considered to be the “gold standard” for TiO photoctalysis (Table
2
1
). The catalyst consists of roughly 75% anatase and 25% rutile, which exhibit a synergistic effect,
1
9
and is much more active than anatase or rutile alone. Based on the characterization by Brunauer–
Emmett–Teller (BET) theory using adsorption isotherms of nitrogen, the specific surface area was
2
estimated to be 52.3 m /g.
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Table 1. Optimization of the Conditions for the [2 + 2] Cycloaddition.
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The results were much better than expected: the reaction was complete in 3 min to give the desired
cycloadduct (3) (entries 1-3). When the reaction was stopped at 1 min, the yield significantly
dropped off, even though the enol ether (1) was almost completely consumed, suggesting that the
rate-limiting step is nucleophilic attack rather than hole oxidation (entry 4). No desired
cycloadduct (3) was obtained in the absence of TiO under the dark condition (entry 5) and enol
2
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ether (1) was recovered. This was not the case for the reaction carried out in the presence of TiO
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under the dark condition (entry 6), which resulted in inseparable aldehyde mixtures, probably due
to acidic hydrolysis of the enol ether (1). When the reaction was carried out in the absence of TiO
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under irradiation, a trace amount of the cycloadduct (3) was obtained (entry 7). Surprisingly, the
reaction took place smoothly even in aqueous and/or aerobic conditions (entries 8-10), showing
.
+
that the reaction of the radical cation (1 ) produced by hole oxidation with 1-hexene (2) is more
favorable than undesired oxygenation by ROS. It should be noted that no oxygenated products
were observed under our reaction conditions.
While it is not clear if the reaction is “parallel” and/or “anti-parallel,” significant dimerization of
the enol ether (1) occurred in the reaction. The dimer (4) is expected to form via the reaction of
.+
the radical cation (1 ) produced by hole oxidation with the neutral enol ether (1), even in the
presence of 20 eq (1.0 M) of 1-hexene (2). Although it is likely that the neutral enol ether (1) has
higher nucleophilicity than 1-hexene (2) due to its electron density, even so, these observations
seem to be beyond the range of statistical probability. It could be postulated that enol ether (1) was
anchored onto the TiO
If this hypothesis is correct, it is not the large excess of 1-hexene (2) but the loading amount of the
enol ether (1) per unit area of the TiO surface that would be the key to suppressing the
2
surface, creating a local high concentration, which resulted in dimerization.
2
dimerization. Therefore, the selectivity of cycloadduct (3)/dimer (4) was investigated under
modified conditions (Table 2). To our delight, the yield of cycloadduct (3) finally reached 87%
2
yield with a decreased amount of the dimer (4), when 4 mol/m of the enol ether (1) for the TiO
2
surface was used (Table 2, entry 5).
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Table 2. Competition Experiments between the [2 + 2] Cycloaddition and Dimerization.
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This hypothesis was unambiguously confirmed by control experiments using 1-decene (5), enol
ether (6) and alkene (7) (Scheme 1). The reaction between enol ether (1) and 1-decene (5) gave
the desired cycloadduct (8) in good yield by either electrocatalysis or photocatalysis. On the other
hand, based on the oxidation potentials (Figures S3 and S4), the selective oxidation of the enol
ether (6) would be possible even in the presence of the alkene (7), and indeed the reaction gave
the desired cycloadduct (8) by electrocatalysis, whereas only a trace amount of the cycloadduct
(8) was obtained under optimized photocatalysis conditions. Thus it can be concluded that the hole
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oxidation in TiO
2
photocatalysis is guided by the aromatic ring, enabling unique selectivity beyond
the oxidation potentials (Figure 1). Presumably, the reaction began with the fast anchoring of the
enol ether (1) onto the TiO surface, followed by rapid hole oxidation to produce the radical cation
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1.+), which was then trapped by 1-hexene (2) in the rate limiting step to generate transient
cyclobutyl radical cation (3 .+). The aromatic ring then functioned as a redox tag to reduce the
cyclobutyl radical cation to give relatively long-lived aromatic radical cation (3 .+
excited electron was able to reduce the thus formed aromatic radical cation (3 .+
(
c
a
). Since the
a
) simultaneously,
the overall processes were completed to give the desired cycloadduct (3) in a couple of minutes.
Scheme 1. Control Experiments for the [2 + 2] Cycloaddition.
Figure 1. Plausible Reaction Mechanism for the [2 + 2] Cycloaddition.
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With the optimized conditions in hand, the reactions of enol ether (1) with several hexenes (9–14)
were conducted to test the functional group tolerance (Table 3). It should be noted that a pendant
oxygen atom was found to be compatible with the reaction, even without an electron-withdrawing
substituent, since ether (11) and alcohol (12) afforded the desired cycloadducts (17, 18) in good
yields, respectively. These observations are in marked contrast to the previous reports, where a
2
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competitive donation of the oxygen electron(s) into the radical cation seems to occur. This might
stem from the use of the LiClO /CH NO electrolyte solution, which facilitates the nucleophilic
4
3
2
attack of unactivated alkenes to carbon-centered radical cations. On the other hand, the carboxylic
acid (13) gave no desired cycloadduct (19), while the desired cycloadduct (20) was obtained in
good yield from the ester (14). Since a carboxylic acid is a potential anchoring group for the TiO
2
21
surface, competitive anchoring of the carboxylic acid (13) onto the TiO
2
surface would take place,
which inhibits hole oxidation of the enol ether (1). Although this is indeed a negative effect for the
reaction, the surface could also be positively modified with designed ligands as recently pointed
out by Weiss,22 which would be a unique advantage for heterogeneous semiconductor
photocatalysis over homogeneous photoredox catalysis.
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Table 3. Hexene Variation for the [2 + 2] Cycloaddition.a ,b
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To understand the distinctive reactivity unique to the radical cation (1 ), several alkenes (21–25)
were also tested instead of 1-hexene (2) (Table 4). 1,1-Disubstituted alkene (21) was found to be
comparable to 1-hexene (2), while 1,2-disubstituted alkenes (22, 23) were significantly less
effective, affording inseparable diastereomixtures (27). Although tetrasubstituted alkene (25) was
also less effective for the reaction, trisubstituted alkene (24) was unexpectedly found to be
comparable to terminal alkenes (2, 21). This could be explained as a result of the trade-off between
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kinetic and thermodynamic reactivity of the radical cation (1 ), which would be a complementary
intermediate to the radical and/or cation.
1
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Table 4. Alkene Variation for the [2 + 2] Cycloaddition.a ,b
The scope of the aromatic redox tag in the [2 + 2] cycloaddition was investigated next using enol
ethers with variously substituted aromatic rings (30–44) (Table 5). In accordance with our previous
observations, non-substituted phenyl ring (45) was not effective for the reaction, which is
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presumably due to ineffective intramolecular SET to reduce the transient cyclobutyl radical cation
(Scheme 2, SET B). In addition to phenoxy (46) and siloxy (47) groups, a free hydroxy group (48)
was proven to be a productive substituent. The decreased yield is probably due to the acidic proton,
which potentially induces proton-coupled electron transfer under the photocatalysis conditions that
alters the reaction mode. The positioning of the methoxy group was found to be critical, as the
ortho-substitution (49) was comparably effective to the para-variant (1), while meta-substitution
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0
(50) was less effective. Installation of additional methoxy groups was also found to be
disadvantageous for the reaction (51–54), which can be formally understood by an equilibrium
illustrated via an intramolecular SET (Scheme 2, SET A). The radical and/or cation was potentially
localized on either the enol ether moiety or aromatic ring. For effective trapping by 1-hexene (2)
to form the cyclobutyl radical cation, significant reactivity must exist on the enol ether moiety
rather than on the aromatic ring. When additional methoxy groups are installed, the respective
aromatic radical cations are expected to be highly stabilized. In other words, the radical and/or
cation would mainly be localized on the aromatic ring, thus rendering it unable to participate in
further bond formation. On the other hand, weakly electron-donating methyl groups were proven
to be an effective tuning motif for the aromatic redox tag, namely, the yields of the respective
cycloadducts (55–57) were reasonably increased in relation to the number of methyl groups. The
sulfide (58) was also found to be a promising substrate, while the amine (59) was not. These
observations suggest that basicity is also critical for the reaction, since the LiClO
electrolyte solution exhibits Lewis acidity.
4
/CH
3
NO
2
Table 5. Aromatic Redox Tag Variation for the [2 + 2] Cycloaddition.a ,b
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Scheme 2. Plausible Reaction Mechanism for the [2 + 2] Cycloaddition.
Further mechanistic studies were attempted to illustrate the overall picture of the reaction by using
cyclic voltammetry (CV) measurements in conjunction with density functional theory (DFT)
calculations carried out at the B3LYP/6-311G++(2d,2p) level. The shapes of orbitals and spin
densities would be helpful to determine which portions of the substrates were engaged in SET
processes in the reactions. The standard para-methoxy enol ether (1) showed an oxidation peak at
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1
.36 V vs. Ag/AgCl with a negligible reduction wave (Figure 2). The orbital plot for the optimized
structure showed that the HOMO, where oxidative SET is expected to occur, was localized on both
the enol ether moiety and aromatic ring and indeed, spin density was distributed along the HOMO
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.+
in its radical cation form (1 ). Similar results were obtained for the ortho-methoxy enol ether (34)
with an oxidation peak at 1.39 V vs. Ag/AgCl accompanied by a slight reduction wave, suggesting
some reversibility (Figure 3). In contrast, the less effective meta-methoxy enol ether (35) exhibited
a totally different oxidation wave of several peaks, with the lowest one recorded at 0.87 V vs.
Ag/AgCl (Figure 4). The HOMO was dominantly found on the enol ether moiety, where spin
density was overlapping. It should be noted that the ineffective non-substituted enol ether (30) also
possessed a similar HOMO and spin density with an oxidation peak at 1.25 V vs. Ag/AgCl (Figure
5
1
). In light of the fact that para- and ortho-methoxy enol ethers (1, 34) showed oxidation peaks at
.36 and 1.39 V vs. Ag/AgCl, respectively, the values measured for meta-methoxy enol ether (35)
and non-substituted enol ether (30) were unexpectedly low and cannot simply be understood based
on their molecular structures. These results seem to suggest that the enol ether moieties and
aromatic rings were electronically separated in the cases of non-substituted and meta-methoxy
enol ethers (30, 35), even though they were tethered together by ethylene linkers, which might
render these substrates less or ineffective for the reactions. However, both CVs and spin densities
indicated that oxidative SET should be possible even for these unsuccessful enol ethers (30, 35)
and the generated radical cations were expected to have significant reactivity at their enol ether
moieties. Therefore, it is assumed that trapping by 1-hexene (1) would also be possible and the
respective intramolecular SET (SET B in Scheme 2) might be the key to understanding the
unsuccessful reactions. On the other hand, the disadvantageous effect caused by the installation of
additional methoxy groups was supported by both CV measurements and DFT calculations,
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namely, significantly lower oxidation peaks were measured for both 2,4-dimethoxy- and 2,4,6-
trimethoxy enol ethers (36, 37) (Figures 6 and 7). In these cases, two distinct oxidation peaks were
observed, which could be assigned to the aromatic rings and enol ether moieties, suggesting that
they were also electronically separated from each other. It is perhaps fair to say that electron
densities of the aromatic rings and enol ether moieties must be balanced for the electronic
interactions to occur, which is crucial for the successful reactions. Additionally, spin densities of
1
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2
,4-dimethoxy- and 2,4,6-trimethoxy enol ethers (36, 37) were mainly distributed on the aromatic
rings, suggesting that the formal understanding of SET A in Scheme 2 is reasonable.
Figure 2. CV Measurements and DFT Calculations of para-Methoxy Enol Ether (1).
Figure 3. CV Measurements and DFT Calculations of ortho-Methoxy Enol Ether (34).
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Figure 4. CV Measurements and DFT Calculations of meta-Methoxy Enol Ether (35).
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Figure 5. CV Measurements and DFT Calculations of Non-Substituted Enol Ether (30).
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Scheme 3. Spin Densities and HOMOs of Plausible Reaction Mechanism for the [2 + 2]
Cycloaddition. Calculations were carried out with a methyl group instead of the n-butyl group for
simplification.
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Figure 6. CV Measurements and DFT Calculations of 2,4-Dimethoxy Enol Ether (36).
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Figure 7. CV Measurements and DFT Calculations of 2,4,6-Trimethoxy Enol Ether (37).
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To gain mechanistic insights into SET B in Scheme 2, DFT calculations were performed using the
cycloadducts (3, 45) as typical successful and unsuccessful models. In good accordance with our
formal expression of the reaction mechanism, the spin density was selectively found in the
.
+
aromatic rings in the optimized structures of the radical cation (3 ), which seems to be the aromatic
radical cation (3 .+) rather than the cyclobutyl radical cation (3 .+). The orbital plot for the
a
c
optimized structure of the neutral cycloadduct (3) showed that the HOMO nicely overlapped the
.
+
spin density of its radical cation (3 ). The oxidative SET for the neutral cycloadduct (3) is expected
.+
to take place from the HOMO, where the reductive SET to the radical cation (3 ) should also be
involved. On the basis of this hypothesis, both the spin density and HOMO nicely illustrate our
.
+
formal mechanistic understanding. However, in the optimized structures of the radical cation (45 ),
.+) rather
the spin density remained in the cyclobutyl moieties, i.e., the cyclobutyl radical cation (45
c
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than the aromatic radical cation (45
.+). Furthermore, one carbon-carbon bond that constructs the
a
cyclobutyl framework was found to be elongated, indicating incomplete ring formation, which
also supports our formal expression of the reaction mechanism. On the other hand, the HOMO
was mainly distributed on the aromatic ring in the optimized structure of the neutral cycloadduct
0
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(45), where no elongated carbon-carbon bond was observed in the cyclobutyl framework.
.
+
Therefore, reductive SET to the radical cation (45 ) is expected to take place on the aromatic ring,
if the intramolecular SET (SET B in Scheme 2) is possible. Taken together, the overall picture of
the reaction mechanism is rationally illustrated on the basis of dual intramolecular SET processes
(SET A and SET B in Scheme 2), which were regulated by the aromatic redox tag.
CONCLUSION
In conclusion, we have demonstrated that TiO photocatalysis is a powerful redox option to
2
construct carbon-carbon bonds by using intermolecular formal [2 + 2] cycloadditions as models.
Most of the reactions were completed in less than 30 min even in aqueous and/or aerobic conditions,
which was probably attributed to the synergy between the excited electron and hole generated upon
irradiation that promoted the overall net redox neutral process. It should be noted that sacrificial
reducing or oxidizing substrates generally required for homogeneous photoredox catalysis were
not needed for these reactions. The use of LiClO
4
/CH
3
NO electrolyte solution was also key for
2
the successful applications, since it exhibited a remarkable Lewis acidity that facilitated the
reactions of carbon-centered radical cations with carbon nucleophiles. The overall picture of the
reaction mechanism was illustrated on the basis of both intermolecular and intramolecular SET
processes regulated by an aromatic redox tag, which was reasonably supported by CV
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measurements and DFT calculations. We believe that the results described herein will enhance the
application of heterogeneous semiconductor photocatalysis in the field of synthetic organic
chemistry. Further design and development of reactions guided by this redox tag concept in
combination with semiconductor photocatalysis is under investigation in our laboratory.
1
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EXPERIMENTAL SECTION
General Remarks: All reagents and solvents were purchased from commercial sources and used
without further purification. Reactions were monitored by thin-layer chromatography (TLC)
carried out on silica gel plates, with detection by UV absorption (254 nm) and by heating the plates
after dipping them in a solution of 12 M molybdo(VI) phosphoric acid n-hydrate in 95% ethanol.
1
Silica gel (particle size 40−50 μm) was used for column chromatography. H NMR spectra were
collected on a 500 MHz NMR spectrometer using the deuterated solvent as an internal deuterium
reference. Chemical shift data are given in δ units calibrated with residual protic solvent. The
multiplicity of a signal is indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint,
13
1
quintet; m, multiplet. C{ H} NMR spectra were collected at 125 MHz with proton decoupling
using the deuterated solvent as an internal carbon reference. Chemical shift data are given in δ
units calibrated with residual solvent. High-resolution mass spectra (HRMS) were collected on
electrospray ionization (ESI)- or direct analysis in real time (DART)-time-of-flight (TOF)
spectrometers.
Synthesis and Characterization Data.
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General Procedure for the Synthesis of Enol Ethers (from Substituted Phenylpropionic Acids):
The enol ethers were synthesized from the respective substituted phenylpropionic acids (if
available) in 3 steps, including Weinreb amide synthesis, lithium aluminum hydride reduction, and
Wittig reaction. To a solution of the respective substituted phenylpropionic acid (30.0 mmol) and
N,O-dimethylhydroxylamine hydrochloride (4.39 g, 45.0 mmol) in dichloromethane (80 mL)
stirred at room temperature were added N,N'-diisopropylcarbodiimide (6.97 mL, 45.0 mmol), 4-
dimethylaminopyridine (36.7 ng, 0.30 mmol), and N,N-diisopropylethylamine (10.3 mL, 60.0
mmol). The resulting reaction mixture was stirred at room temperature overnight, diluted with
water, and extracted with dichloromethane. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl
acetate = 1/1) gave the respective Weinreb amides in 61−67% yield. To a solution of the respective
Weinreb amide (18.0 mmol) in tetrahydrofuran (80 mL) stirred at 0 °C was added lithium
aluminum hydride (751 mg, 19.8 mmol). The resulting reaction mixture was stirred at 0 °C until
the starting material was consumed (checked by thin layer chromatography), diluted with water,
and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate,
filtered, concentrated in vacuo, and used without further purification. To a solution of
(methoxymethyl)triphenylphosphonium chloride (12.3 g, 36.0 mmol) in tetrahydrofuran (80 mL)
stirred at 0 °C was added potassium tert-butoxide (3.03 g, 27.0 mmol). After the color turned red,
the crude aldehyde was added, stirred at 0 °C until the starting material was consumed (checked
by thin layer chromatography), diluted with water, and extracted with ethyl acetate. The combined
organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel
column chromatography (hexane/ethyl acetate = 20/1) gave the desired enol ethers in 28−31%
yield over 2 steps.
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General Procedure for the Synthesis of Enol Ethers (from the Respective Substituted
Benzaldehydes): The enol ethers were synthesized from the respective substituted benzaldehydes
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(if the corresponding substituted phenylpropionic acids were not available) in 5 steps including
Wittig reaction and acid hydrolysis. To a solution of (methoxymethyl)triphenylphosphonium
chloride (34.3 g, 100.0 mmol) in tetrahydrofuran (160 mL) stirred at 0 °C was added potassium
tert-butoxide (8.42 g, 75.0 mmol). After the color turned red, the respective substituted
benzaldehyde (50.0 mmol) was added, and the reaction was stirred at 0 °C until the starting
material was consumed (checked by thin layer chromatography), diluted with water, and extracted
with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate = 20/1) gave the
respective enol ethers in 87−93% yield. To a solution of the respective enol ether (45.0 mmol) in
acetone (100 mL) stirred at room temperature was added a catalytic amount of concentrated
sulfuric acid. The resulting reaction mixture was stirred at room temperature until the starting
material was consumed (checked by thin layer chromatography), diluted with water, and extracted
with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate = 5/1) gave the
respective substituted benzaldehydes in 35−40% yield. The repetitive Wittig reactions and acid
hydrolysis gave the desired enol ethers in 25−30% yield over 3 steps.
General Procedure for the [2 + 2] Cycloadditions: To a solution of LiClO
4
(1.0 M) in CH
3
NO
2
stirred at room temperature were added the respective enol ethers and alkenes. The resulting
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reaction mixture was stirred at room temperature in front of a 15 W UV lamp (350 nm) until the
starting material was consumed (checked by thin layer chromatography), diluted with water, and
extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered,
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and concentrated in vacuo. Yields were determined by H NMR analysis using benzaldehyde as
an internal standard. Silica gel column chromatography (hexane/ethyl acetate = 50/1) gave the
desired cycloadduct.
1
-Methoxy-4-(4-methoxybut-3-en-1-yl)benzene (1, cis : trans = 1 : 2). Colorless oil.
1
cis: H NMR (CDCl
3
, 500 MHz)  7.12 (2H, d, J = 8.6 Hz), 6.82 (2H, d, J = 8.6 Hz), 5.87 (1H, dt,
J = 6.3, 1.7 Hz), 4.36 (1H, dt, J = 7.3, 6.3 Hz), 3.78 (3H, s), 3.56 (3H, s), 2.60 (2H, t, J = 7.3 Hz),
13
1
2
.35 (2H, dq, J = 7.3, 1.7 Hz); C{ H} NMR (125 MHz, CDCl )  157.8, 146.5, 134.4, 129.4,
3
113.7, 106.1, 59.6, 55.3, 35.1, 25.9.
1
trans: H NMR (CDCl
3
, 500 MHz)  7.09 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 6.29 (1H,
dt, J = 12.6, 1.2 Hz), 4.74 (1H, dt, J = 12.6, 7.3 Hz), 3.79 (3H, s), 3.49 (3H, s), 2.59 (2H, t, J = 7.3
1
3
1
Hz), 2.20 (2H, dq, J = 7.3, 1.2 Hz); C{ H} NMR (125 MHz, CDCl
3
)  157.8, 147.5, 134.2, 129.5,
193.1229, found
+
1
1
13.8, 102.3, 55.9, 55.3, 36.6, 30.1; HRMS [M + H] calculated for C12
H
17
O
2
93.1250.
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1
-(2-(3-Butyl-2-methoxycyclobutyl)ethyl)-4-methoxybenzene (3, all trans). Colorless oil.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H NMR (CDCl
3H, s), 3.11 (1H, t, J = 6.8 Hz), 2.59-2.43 (2H, m), 2.07-1.82 (4H, m), 1.65-1.53 (2H, m), 1.36-
, 500 MHz)  7.08 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 3.78 (3H, s), 3.30
3
(
1
3
1
1
.17 (5H, m), 0.88 (3H, t, J = 7.1 Hz), 0.72 (1H, q, J = 9.1 Hz); C{ H} NMR (125 MHz, CDCl )
3
 157.8, 134.8, 129.4, 113.9, 86.6, 56.6, 55.4, 40.7, 40.2, 37.6, 35.1, 33.0, 29.8, 25.6, 22.9, 14.3;
+
HRMS [M + H] calculated for C18
H
29
2
O 277.2168, found 277.2177.
4
,4'-((3,4-Dimethoxycyclobutane-1,2-diyl)bis(ethane-2,1-diyl))bis(methoxybenzene)
(4).
Colorless oil.
1H NMR (CDCl
, 500 MHz)  7.08 (4H, d, J = 8.6 Hz), 6.82 (4H, d, J = 8.6 Hz), 3.78 (6H, s), 3.30
3
13
1
(6H, s), 3.31-3.26 (2H, m), 2.62-2.45 (4H, m), 1.84-1.78 (4H, m), 1.48-1.43 (2H, m); C{ H}
NMR (125 MHz, CDCl )  157.9, 134.4, 129.3, 113.9, 85.0, 57.0, 55.4, 40.3, 37.1, 33.1; HRMS
3
+
[M + H] calculated for C24
H
33
O
4
385.2380, found 385.2352.
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1
1
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1
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1
1
1
1
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5
5
5
5
5
5
6
1
-Methoxydec-1-ene (6, cis : trans = 1 : 2). Colorless oil.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
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9
0
To a solution of (methoxymethyl)triphenylphosphonium chloride (3.43 g, 10.0 mmol) in
tetrahydrofuran (40 mL) stirred at 0 °C was added potassium tert-butoxide (842 g, 7.50 mmol).
After the color turned red, nonanal (868 L, 5.00 mmol) was added, and the reaction was stirred
at 0 °C until the starting material was consumed (checked by thin layer chromatography), diluted
with water, and extracted with ethyl acetate. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (hexane) gave the
enol ether (6) in 74% yield (630 mg, 3.70 mmol).
1
cis: H NMR (CDCl
3
, 500 MHz)  5.86 (1H, dt, J = 6.3, 1.7 Hz), 4.34 (1H, dt, J = 7.5, 1.2 Hz),
13
1
3
3
.58 (3H, s), 2.05 (2H, dq, J = 6.9, 1.2 Hz); C{ H} NMR (125 MHz, CDCl )  146.0, 107.3, 59.6,
3
1.0, 30.0, 29.7, 29.5, 29.2, 27.9, 24.1, 14.3.
1
trans: H NMR (CDCl
3
, 500 MHz)  6.28 (1H, dt, J = 12.6, 1.2 Hz), 4.73 (1H, dt, J = 12.6, 6.9
13
1
Hz), 3.50 (3H, s), 1.91 (2H, dq, J = 7.5, 1.2 Hz); C{ H} NMR (125 MHz, CDCl )  147.0, 103.3,
3
+
56.0, 32.1, 30.0, 29.7, 29.5, 29.2, 27.9, 22.9, 14.3; HRMS [M + H] calculated for C11
H O
23
1
71.1750, found 171.1723.
1
-(But-3-en-1-yl)-4-methoxybenzene (7). Colorless oil.
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0
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To a solution of 4-methoxybenzyl chloride (2.72 mL, 20.0 mmol) in tetrahydrofuran (60 mL)
o
stirred at 0 C was added allylmagnesium bromide (0.7 mol/L in diethyl ether, 57.2 mL, 40.0
o
mmol). The resulting reaction mixture was stirred at 0 C to room temperature overnight, diluted
with water, and extracted with ethyl acetate. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl
acetate = 30/1) gave the alkene (7) in 62% yield (2.01 g, 12.4 mmol).
1H NMR (CDCl
= 16.6, 10.3, 6.9 Hz), 5.03 (1H, dq, J = 16.6, 1.7 Hz), 4.97 (1H, dd, J = 10.9, 1.7 Hz), 3.79 (3H, s),
, 500 MHz)  7.10 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 5.85 (1H, ddt, J
3
13
1
2
1
.65 (2H, t, J = 7.5 Hz), 2.34 (2H, dt, J = 8.0, 1.2 Hz); C{ H} NMR (125 MHz, CDCl ) d 157.9,
3
+
38.2, 133.9, 129.3, 114.9, 113.7, 55.1, 35.9, 34.5; HRMS [M + H] calculated for C11
15
H O
163.1124, found 163.1147.
1
-Methoxy-4-(2-(2-methoxy-3-octylcyclobutyl)ethyl)benzene (8, alll trans). Colorless oil.
1H NMR (CDCl
, 500 MHz)  7.08 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6 Hz), 3.78 (3H, s), 3.30
3
(3H, s), 3.10 (1H, t, J = 6.9 Hz), 2.57-2.44 (2H, m), 2.06-1.83 (4H, m), 1.65-1.52 (2H, m), 1.40-
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3
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5
5
5
5
5
6
13
1
1
.17 (13H, m), 0.88 (3H, t, J = 6.3 Hz), 0.71 (1H, q, J = 9.7 Hz); C{ H} NMR (125 MHz, CDCl )
3

157.8, 134.8, 129.3, 113.8, 86.6, 56.6, 55.4, 40.7, 40.2, 37.6, 35.5, 32.9, 32.1, 29.9, 29.8, 29.5,
+
27.5, 25.6, 22.9, 14.3; HRMS [M + H] calculated for C22
H
37
2
O 333.2794, found 333.2813.
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
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9
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9
0
Hex-5-en-1-yl benzoate (9). Colorless oil.
To a solution of 5-hexen-1-ol (1.18 mL, 10.0 mmol) and trimethylamine (2.77 mL, 20.0 mmol) in
tetrahydrofuran (30 mL) stirred at room temperature was added benzoyl chloride (1.74 mL, 15.0
mmol). The resulting reaction mixture was stirred at room temperature overnight, diluted with
water, and extracted with ethyl acetate. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl
acetate = 10/1) gave the hexene (9) in 93% yield (1.90 g, 9.30 mmol).
1H NMR (CDCl
, 500 MHz)  8.04 (2H, d, J = 8.5 Hz), 7.55 (1H, t, J = 7.0 Hz), 7.44 (2H, t, J =
.0 Hz), 5.82 (1H, ddt, J = 17.2, 10.3, 6.9 Hz), 5.03 (1H, dq, J = 17.2, 1.7 Hz), 4.97 (1H, dd, J =
0.3, 1.7 Hz), 4.33 (2H, t, J = 6.5 Hz), 2.13 (2H, dt, J = 7.5, 6.9 Hz), 1.79 (2H, quin, J = 7.5 Hz),
3
8
1
1
13
1
.55 (2H, quin, J = 7.0 Hz); C{ H} NMR (125 MHz, CDCl
3
)  166.7, 138.4, 132.9, 130.5, 129.6,
205.1229, found
+
1
28.4,; HRMS [M + H] calculated for C13
H
17
O
2
205.1205.
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6
-Methoxyhex-1-ene (11). Colorless oil.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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5
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5
5
5
5
5
6
0
1
2
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9
0
1
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8
9
0
1
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9
0
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9
0
To a solution of 5-hexen-1-ol (3.54 mL, 30.0 mmol) in diethyl ether (80 mL) stirred at room
temperature was added sodium hydride (60%, dispersion in paraffin liquid, 1.44 g, 36.0 mmol).
After stirring at room temperature for 30 min, methyl iodide (3.74 mL, 60.0 mmol) was added.
The resulting reaction mixture was stirred at room temperature for overnight, diluted with water,
and extracted with pentane. The combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Silica gel column chromatography (pentane) gave the hexene (11) in
42% yield (1.44 g, 12.6 mmol).
1H NMR (CDCl
Hz), 4.95 (1H, d, J = 10.3 Hz), 3.38 (2H, t, J = 6.3 Hz), 3.33 (3H, s), 2.07 (2H, dt, J = 7.5, 6.9 Hz),
, 500 MHz) δ 5.81 (1H, ddt, J = 17.2, 10.3, 6.3 Hz), 5.01 (1H, dq, J = 17.2, 1.7
3
1
3
1
1
.59 (2H, quin, J = 7.5 Hz), 1.45 (2H, quin, J = 7.5 Hz); C{ H} NMR (125 MHz, CDCl ) δ 138.8,
3
+
114.6, 72.8, 58.6, 33.7, 29.2, 25.6; HRMS [M + H] calculated for C
7
H
15O 115.1124, found
1
15.1100.
4
-(2-Methoxy-3-(4-methoxyphenethyl)cyclobutyl)butyl benzoate (15, all trans). Colorless oil.
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