Thermal [2 + 2]-cycloaddition between silylalkynes and allenylphenols followed by the nucleophilic addition of water: Metal-free and economical synthesis of arylcyclobutenals

Article abstract of DOI:10.1039/c9gc04184b

Herein, we report an unprecedented thermal [2 + 2]-cycloaddition between silylalkynes and allenylphenols to form an aromatizing cyclobutachromene intermediate, followed by the nucleophilic addition of water to yield functionalized arylcyclobutenals. This reaction is atom- and pot-economical because all the atoms contained in the starting material are retained in the final product, no other reactants are required, and it proceeds in one-pot.

Full text of DOI:10.1039/c9gc04184b

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Thermal [2 + 2]-cycloaddition between silylalkynes
and allenylphenols followed by the nucleophilic
addition of water: metal-free and economical
synthesis of arylcyclobutenals†
Cite this: DOI: 10.1039/c9gc04184b
Shohei Ohno,‡ Ramon Francisco Avena, ‡ Hiroshi Aoyama,
Hiromichi Fujioka
and Mitsuhiro Arisawa
*
Herein, we report an unprecedented thermal [2 + 2]-cycloaddition between silylalkynes and allenylphe-
nols to form an aromatizing cyclobutachromene intermediate, followed by the nucleophilic addition of
water to yield functionalized arylcyclobutenals. This reaction is atom- and pot-economical because all
the atoms contained in the starting material are retained in the final product, no other reactants are
required, and it proceeds in one-pot.
Received 7th December 2019,
Accepted 9th January 2020
DOI: 10.1039/c9gc04184b
rsc.li/greenchem
hand, intramolecular alkyne–allene [2 + 2] cycloadditions
leading to bi- or tri-cyclic cyclobutenes have been extensively
Introduction
Exploring economical strategies to synthesize the target mole- explored under thermal or transition-metal catalysed con-
cules is one of the most important efforts in both academia ditions (Scheme 2A);9 however, to the best of our knowledge,
and industry, as it can minimize environmental impacts.1 In there was no example in which this reaction was applied other
this context, chemical transformations with aspects of both than the synthesis of bi- or tri-cyclic cyclobutenes until 2017.
atom- and pot-economies are extremely attractive. This is In 2018, Jiang reported [2 + 2] cycloaddition between alkynes
because these strategies maximize the conversion of the start- and allenone-esters followed by addition reaction for the syn-
ing materials into the target molecules, thereby minimizing thesis of polycyclic aromatic hydrocarbons, such as nucleophi-
the use of reactants and solvents, as well as reducing the gene- lic addition of water to intermediate I (Scheme 2B); however,
ration of chemical wastes.2 On the other hand, fine chemicals they did not report unfused monocyclic cyclobutene
and pharmaceuticals frequently face difficulties in removing synthesis.10
heavy-metal catalysts from the final products.3 Therefore, the
Based on this research background, we report an unpre-
combination of metal-free transformations with the atom- and cedented thermal [2 + 2] cycloaddition between silylalkynes
pot-economical concept is generally considered to be green and allenylphenols to form intermediate II, followed by the
and sustainable,4 although it still faces considerable nucleophilic addition of water to yield functionalized arylcyclo-
challenges.
butenals 2 (Scheme 2C). When comparing intermediate I and
Meanwhile, four-membered rings are important structural intermediate II, it becomes clear that intermediate I was
elements of biologically-active compounds,5 and also serve as formed by acid-promoted activation of 2,4-pentadiene-1-one in
versatile synthetic intermediates due to strain-driven chemical the system, and that intermediate II was formed by aromatiza-
reactivities.6 Among them, arylcyclobutenal may serve as a key tion-promoted activation of the cyclobutachromene skeleton.
intermediate for the synthesis of natural products having a This reaction proceeds only by thermal activation energy, no
tetra-substituted cyclobutane structure.7 However, the syn- other reactants are required, and all atoms contained in the
thesis method has only one example and requires two toxic starting material 1 were retained in the final product 2.
metal catalysts: silver and copper (Scheme 1).8 On the other
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6,
Suita, Osaka, 565-0871, Japan. E-mail: arisaw@phs.osaka-u.ac.jp
†Electronic supplementary information (ESI) available. CCDC 1958998. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9gc04184b
‡These authors contributed equally to this work.
Scheme 1 Previously reported synthesis of arylcyclobutenals.
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Fig. 1 X-ray structure of 2a.
based on TLC. However, after purification on silica gel, we
noticed that intermediate II was subjected to subsequent
nucleophilic addition of water. From these data, we concluded
that intermediate II is water-sensitive, and effects of the
solvent are vital to the success of the reaction.
Using the optimum reaction conditions (Table 1, entry 1),
we next examined the substrate scope and limitations of this
reaction and summarized them in Table 2. Having a silyl
group on the alkyne, SiEt3, SiMe2tBu, SiPh2tBu, and SiPh3
derivatives 1b–1e gave the corresponding cyclobutenes 2b–2e
Scheme 2 [2 + 2] Cycloadditions between alkynes and allenes.
Results and discussion
Table 2 Substrate scope and limitations
We prepared substrate 1a and subjected it to several reaction
conditions (Table 1). As a result, when refluxing the toluene
solution of 1a for 2 hours, the desired cyclobutene 2a was
obtained in 92% yield (entry 1) and the structure of 2a was
determined by X-ray structure elucidation (Fig. 1).11
Additionally, using benzene as a solvent, compound 2a was
obtained in a yield of 78%. However, when para-xylene with a
higher boiling point than toluene was used, a longer reaction
time was required, and the yield was decreased (entry 3).
When using methanol or ethanol as a solvent, it gave 59% or
63% after 24 hours (entries 4 and 5). In addition, when DMF
was used, the yield was reduced due to strong conditions, and
many by-products were produced (entry 6). It should also be
noted that in the case of acetonitrile or dioxane (entries 7 and
8), we were able to detect the presence of the intermediate
Table 1 Optimization of the reaction conditions
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Toluene
Benzene
p-Xylene
MeOH
EtOH
DMF
CH3CN
Dioxane
2
92
78
49
59
63
33
89
87
24
24
24
24
3
12
3
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Table 3 Reactions in dry solvent
in 83%, 73%, 99%, and 45% yields, respectively. Also, deriva-
tives with H or alkyl groups on the alkyne, i.e., H derivative 1f,
n-butyl derivative 1g, and tert-butyl derivative 1h, were exam-
ined. As a result, 1h was converted well to 2h in 62% yield, but
1f and 1g were decomposed. Interestingly, in the case of
derivative 1j having a mesityl group on the alkyne, nucleophi-
lic addition of water did not occur after [2 + 2] cycloaddition,
and a stable intermediate 3j was observed. In addition, the
reaction did not proceed with substrate 1k having an iodine on
the alkyne. Finally, when the reaction was examined with sub-
strates 1m–1o having a substituent on the aromatic ring, the
yield was slightly reduced for substrate 1n having a bromo
group, but the others were converted to products with good
yield. Based on the above results, we thought that the bulki-
ness and the electron donating properties of the substituents
on the alkyne played an important role in the efficient nucleo-
philic addition of water after [2 + 2] cycloaddition.
Entry
Solvent
Time (h)
Additive
Yield [3a, 2a]a (%)
1
2
3
4
5
6
7
8
9
Toluene
p-Xylene
Benzene
MeOH
EtOH
CH3CN
1,4-Dioxane
Toluene
Toluene
2
None
None
None
None
None
None
None
H2O (1 eq.)
H2O (2 eq.)
[15%, 5%]
[9%, 3%]
24
24
24
24
12
12
2
[69%, 3%]
[65%, 0%]
[73%, 7%]
[68%, 9%]
[62%, 4%]
[0%, 92%]
[0%, 92%]
2
a Yields were determined by NMR using 1,3,5-trimethoxy-benzene as
an internal standard.
Chemical transformations of 2a were also possible
(Scheme 3). For example, n-Bu4NF was added to 2a in DMF
solution and stirred at 80 °C, and disubstituted cyclobutene 2f
was obtained in 94% yield. Additionally, when the carbonyl of
2a was subjected to the Wittig reaction, vinyl cyclobutene 4
was obtained in 76% yield. Furthermore, the aldehyde on the
cyclobutene of 2a was oxidized to carboxylic acid by Pinnick
oxidation, and intramolecular cyclization occurred sub-
sequently wherein coumarin derivative 5 was obtained in 74%
yield. These results have shown that 2a, efficiently prepared by
our reaction, may serve as a good synthetic intermediate.
In order to investigate the solvent effect and intermediate
of this reaction, the reaction was examined using dry solvents
under a nitrogen atmosphere (Table 3). As a result, almost no
product 2a was obtained in each dry solvent, but instead cyclo-
butachromene intermediate 3a was obtained (entries 1–7).
Among them, intermediate 3a was obtained in good yield in
benzene, methanol, ethanol, acetonitrile and dioxane (entries
3–7), but the yield of intermediate 3a was low in toluene and
xylene (entries 1 and 2). These results show that intermediate
3a is stable in benzene, methanol, ethanol, acetonitrile, and
dioxane and unstable in toluene and xylene. Therefore, in
hydrous toluene solution, an equivalent amount of water was
efficiently added to the unstable intermediate 3a to give
Scheme 4 Scale-up experiment (2 mmol).
product 2a in high yield (entries 8 and 9). From these results,
it was found that this reaction was caused by the formation of
3a by thermal [2 + 2] cycloaddition and subsequent nucleophi-
lic addition of water.
In addition, the possibility of using this reaction in a large-
scale synthesis was examined by using 2 mmol of 1a which
smoothly resulted in the production of 2a in 83% yield
(Scheme 4, conditions A). Furthermore, this reaction can be
performed on a large scale even when water is used as a
solvent, and product 2a was obtained in a yield of 68%
(Scheme 4, conditions B).
Finally, in order to validate the mechanism of this reaction,
we performed D2O labeling experiments (Scheme 5). As a
result, a mixture of deuterium-labeled and non-labeled pro-
ducts was obtained in a 1 : 1 ratio. This supports the proposed
mechanism of this reaction as shown in Scheme 6 wherein 3a
tautomerizes into intermediate II which then undergoes
nucleophilic addition of H2O followed by cleavage of the
resulting hemiacetal to obtain product 2a.
Scheme 3 Chemical transformations.
Scheme 5 D2O labeling experiment.
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(0.5 equiv.). The mixture was stirred under nitrogen at ambient
temperature for 1 h. The mixture was quenched with water and
the organic compounds were then extracted with AcOEt. The
combined organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The obtained residue was
then subjected to column chromatography (neutral flash silica
gel, hexane/AcOEt = 150 : 1) to give compounds 1a–d and 1f–o.
O-Allenyl-2-[(triisopropylsilyl)ethynyl]phenol 1a. Following
general procedures A.1–3, 2-iodophenol (550 mg, 2.50 mmol)
was converted to 1a (586 mg, 3 steps, 75%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d, J = 7.8 Hz), 7.28–7.24
(1H, m), 7.07 (1H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 7.6 Hz,
7.6 Hz), 6.91 (1H, t, J = 6.0 Hz), 5.40 (2H, d, J = 6.0 Hz), 1.13
(21H, s); 13C NMR (100 MHz, CDCl3) δ 202.22, 157.72, 133.65,
129.21, 122.70, 119.04, 116.92, 114.97, 102.04, 95.71, 89.84,
18.47, 11.51; HRMS (MALDI) calcd for C20H29OSi (M + H)+:
313.1982, found: 313.1974.
Scheme 6 Proposed mechanism.
Conclusion
This reaction is the first intramolecular [2 + 2] thermal cyclo-
addition between functionalized allenylphenols and silylalk-
ynes which can further undergo nucleophilic addition of
water. This reaction is atom- and pot-economical because all
atoms contained in starting material 1 were retained in the
final product 2. Additionally, it is a one-pot reaction that
doesn’t require other reactants so there is no need for several
extensive purification processes. Furthermore, chemical trans-
formations of product 2a afforded other useful compounds,
such as vinyl cyclobutene 4 and coumarin derivative 5.
O-Allenyl-2-[(triethylsilyl)ethynyl]phenol
1b.
Following
general procedures A.1–3, 2-iodophenol (550 mg, 2.50 mmol)
was converted to 1b (122 mg, 3 steps, 18%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d, J = 7.3 Hz), 7.29–7.25
(1H, m), 7.07 (1H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 7.3 Hz,
7.3 Hz), 6.89 (1H, t, J = 6.0 Hz), 5.42 (2H, d, J = 6.0 Hz), 1.05
(9H, t, J = 7.8 Hz), 0.68 (6H, q, J = 7.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 202.96, 158.34, 134.41, 129.97, 123.25, 119.33, 117.23,
115.16, 102.07, 97.39, 90.43, 7.96, 4.90; HRMS (MALDI) calcd
for C17H23OSi (M + H)+: 271.1513, found: 271.1508.
Experimental section
O-Allenyl-2-[(tert-butyldimethylsilyl)ethynyl]phenol
1c.
General procedure A for the synthesis of compounds 1a–d and
Following general procedures A.1-3, 2-iodophenol (550 mg,
1f–o
A.1: To a round-bottom flask containing 2-iodophenol (1.0 2.50 mmol) was converted to 1c (360 mg, 3 steps, 53%) as a
equiv.), mono-substituted acetylene (1.15 equiv.), and diiso- colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.44 (1H, dd, J = 7.6,
propylamine (3.0 equiv.) in THF (0.2 M) were added copper(I) 1.6 Hz), 7.29–7.25 (1H, m), 7.07 (1H, d, J = 7.8 Hz), 7.00 (1H,
iodide (2 mol%) and bis(triphenylphosphine) palladium(II) dd, J = 7.8 Hz, 7.8 Hz), 6.88 (1H, t, J = 6.0 Hz), 5.42 (2H, d, J =
dichloride (1 mol%). The mixture was stirred under nitrogen at 6.0 Hz), 1.00 (9H, s), 0.18 (6H, m); 13C NMR (100 MHz, CDCl3)
ambient temperature for 2 h. The mixture was quenched with δ 202.49, 157.88, 133.86, 129.55, 122.79, 118.87, 116.76,
saturated NH4Cl solution and the organic compounds were then 114.62, 100.97, 97.77, 89.99, 26.10, 16.81, −4.64; HRMS
extracted with AcOEt. The combined organic layer was washed (MALDI) calcd for C17H23OSi (M + H)+: 271.1513, found:
with brine, dried over Na2SO4, and concentrated in vacuo. The 271.1502.
obtained residue was then subjected to short column chromato-
graphy (neutral silica gel, hexane/AcOEt = 20 : 1).
O-Allenyl-2-[(tert-butyldiphenylsilyl)ethynyl]phenol
Following general procedures A.1–3, 2-iodophenol (550 mg,
1d.
A.2: To a stirred solution of the obtained 2-substituted-ethy- 2.50 mmol) was converted to 1d (710 mg, 3 steps, 72%) as a
1
nylphenol in DMF (0.5 M) were added propargyl bromide (1.5 colorless oil. H NMR (400 MHz, CDCl3) δ 7.91–7.88 (4H, m),
equiv.) and K2CO3 (2.0 equiv.). The mixture was stirred under 7.56 (1H, d, J = 7.3 Hz), 7.40–7.31 (7H, m), 7.12 (1H, d, J = 8.2
nitrogen at ambient temperature for 6 h. The mixture was Hz), 7.05 (1H, t, J = 7.6 Hz), 6.95 (1H, td, J = 6.0, 0.9 Hz), 5.43
quenched with water and the organic compounds were then (2H, d, J = 6.0 Hz), 1.14 (9H, s); 13C NMR (100 MHz, CDCl3) δ
extracted with AcOEt. The combined organic layer was washed 202.43, 158.28, 135.67, 133.76, 133.35, 129.97, 129.42, 127.67,
with brine, dried over Na2SO4, and concentrated in vacuo. The 122.80, 118.82, 116.63, 114.42, 104.56, 94.48, 90.08, 27.08,
obtained residue was then subjected to short column chrom- 18.77; HRMS (MALDI) calcd for C27H26OSiNa (M + Na)+:
atography (neutral silica gel, hexane/AcOEt = 50 : 1).
417.1645, found: 417.1641.
A.3: To a stirred solution of the obtained O-propargyl-2-
O-Allenyl-2-ethynylphenol 1f. Following general procedures
(substituted-ethynyl)phenol in THF (0.2 M) was added t-BuOK A.1–2, 2-iodophenol (550 mg, 2.50 mmol) was converted to
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O-propargyl-2-((trimethylsilyl)-ethynyl)phenol using trimethyl-
O-Allenyl-4-methoxy-2-[(triisopropylsilyl)ethynyl]phenol 1m.
silylacetylene. Next, following general procedure A.3, the Following general procedures A.1–3, 2-iodo-4-methoxyphe-
obtained crude compound was converted to 1f (160 mg, 3 nol (625 mg, 2.50 mmol) was converted to 1m (608 mg, 3
steps, 41%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.48 steps, 71%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ
(1H, dd, J = 9.5, 2.0 Hz), 7.34–7.29 (1H, m), 7.11 (1H, dd, J = 6.99 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 2.8 Hz), 6.88 (1H, t, J
10.3, 1.2 Hz), 7.02 (1H, ddd, J = 9.5 Hz, 1.2 Hz, 1.2 Hz), 6.86 = 5.7 Hz), 6.81 (1H, dd, J = 9.1, 2.8 Hz), 5.35 (2H, d, J = 5.7
(1H, t, J = 7.4 Hz), 5.46 (2H, d, J = 7.4 Hz), 3.31 (1H, s); Hz), 3.78 (3H, s), 1.13 (21H, s); 13C NMR (125 MHz, CDCl3) δ
13C NMR (100 MHz, CDCl3) δ 203.13, 158.58, 134.62, 130.45, 202.37, 155.57, 152.19, 121.44, 120.22, 118.06, 116.82,
123.12, 118.40, 116.34, 113.31, 90.58, 82.20, 79.74; HRMS 116.00, 102.52, 96.23, 90.87, 56.08, 19.04, 11.72; HRMS
(MALDI) calcd for C11H9O (M
157.0645.
+
H)+: 157.0648, found: (MALDI) calcd for C21H31O2Si (M + H)+: 343.2088, found:
343.2088.
O-Allenyl-2-(tert-butylethynyl)phenol 1h. Following general
O-Allenyl-4-bromo-2-[(triisopropylsilyl)ethynyl]phenol
1n.
procedures A.1–3, 2-iodophenol (550 mg, 2.50 mmol) was con- Following general procedures A.1–3, 4-bromo-2-iodophenol
verted to 1h (277 mg, 3 steps, 53%) as a light yellow oil. 1H (747 mg, 2.50 mmol) was converted to 1n (460 mg, 3 steps,
NMR (400 MHz, CDCl3) δ 7.37 (1H, dd, J = 7.5, 1.6 Hz), 47%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.56 (1H, d, J
7.24–7.19 (1H, m), 7.05 (1H, d, J = 7.8 Hz), 6.98 (1H, dd, J = = 2.3 Hz), 7.36 (1H, dd, J = 8.7, 2.3 Hz), 6.95 (1H, d, J = 8.7 Hz),
7.5 Hz, 7.5 Hz), 6.88 (1H, t, J = 6.0 Hz), 5.42 (2H, d, J = 6.0 Hz), 6.86 (1H, t, J = 6.0 Hz), 5.41 (2H, d, J = 6.0 Hz), 1.12 (21H, s);
1.32 (9H, s); 13C NMR (100 MHz, CDCl3) δ 202.65, 157.42, 13C NMR (100 MHz, CDCl3) δ 202.26, 157.13, 136.21, 132.35,
133.64, 128.64, 123.06, 119.34, 117.23, 115.59, 103.66, 90.04, 119.20, 118.91, 117.33, 115.17, 100.75, 97.86, 90.65, 18.77,
74.61, 31.10, 28.34; HRMS (MALDI) calcd for
(M + H)+: 213.1274, found: 213.1270.
C
15H17O 11.41; HRMS (MALDI) calcd for C20H28OSiBr (M + H)+:
391.1087, found: 391.1090.
O-Allenyl-2-(phenylethynyl)phenol 1i. Following general pro-
O-Allenyl-1-[(triisopropylsilyl)ethynyl]naphthalen-2-ol
1o.
cedures A.1–2 and a modified procedure A.3 wherein the reac- Following general procedures A.1–3, 1-iodonaphthalen-2-ol
tion was performed at 0 °C, 2-iodophenol (550 mg, 2.50 mmol) (675 mg, 2.50 mmol) was converted to 1o (544 mg, 3 steps,
was converted to 1i (294 mg, 3 steps, 51%) as a light yellow oil. 60%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ
1H NMR (400 MHz, CDCl3) δ 7.57–7.51 (3H, m), 7.36–7.28 (4H, 8.33 (1H, d, J = 8.7 Hz), 7.78 (2H, t, J = 9.1 Hz), 7.56 (1H, dd,
m), 7.13 (1H, dd, J = 8.7, 0.9 Hz), 7.05 (1H, ddd, J = 7.6 Hz, J = 8.2, 7.3 Hz), 7.44 (1H, dd, J = 8.2, 6.9 Hz), 7.34–7.26 (1H,
1.4 Hz, 1.4 Hz), 6.91 (1H, t, J = 6.0 Hz), 5.46 (2H, d, J = 6.0 Hz); m), 7.06–7.03 (1H, m), 5.69 (2H, dd, J = 6.0, 0.9 Hz);
13C NMR (100 MHz, CDCl3) δ 202.80, 157.55, 133.69, 131.80, 13C NMR (100 MHz, CDCl3) δ 202.58, 157.24, 134.91,
129.57, 128.75, 128.40, 125.56, 123.01, 118.69, 116.63, 114.53, 130.35, 130.04, 128.54, 127.77, 126.30, 125.62, 118.89,
94.11, 90.20, 85.20; HRMS (MALDI) calcd for
(M + H)+: 233.0961, found: 233.0963.
C
17H13O 120.73, 110.92, 102.13, 100.48, 90.99, 19.22, 11.87; HRMS
(MALDI) calcd for C24H31OSi (M + H)+: 363.2139, found:
O-Allenyl-2-(mesitylethynyl)phenol 1j. Following general pro- 363.2137.
cedures A.1–2 and a modified procedure A.3 wherein the reac-
tion was performed at 0 °C instead of room temperature,
Preparation of 1e from 1f
2-iodophenol (550 mg, 2.50 mmol) was converted to 1j
(466 mg, 3 steps, 68%) as a light yellow oil. 1H NMR (400 MHz,
O-Allenyl-2-[(triphenylsilyl)ethynyl]phenol 1e. To a flame-
CDCl3) δ 7.51 (1H, dd, J = 7.8, 1.4 Hz), 7.28 (1H, td, J = 7.8, 1.4 dried round-bottom flask containing compound 1f (200 mg,
Hz), 7.12 (1H, d, J = 8.2 Hz), 7.06 (1H, dd, J = 7.8, 7.8 Hz), 6.94 1.28 mmol) in THF (0.2 M) at −78 °C was slowly added n-BuLi
(1H, t, J = 5.8 Hz), 6.88 (2H, dd, J = 0.5, 0.5 Hz), 5.43 (2H, d, J = (1 equiv.). The mixture was stirred under nitrogen for
6.0 Hz), 2.49 (6H, s), 2.29 (3H, s); 13C NMR (100 MHz, CDCl3) 15 minutes before adding triphenylsilylchloride (2 equiv.) and
δ 202.51, 157.08, 140.25, 137.74, 132.98, 128.95, 127.51, allowing the mixture to warm to room temperature. After
122.90, 120.15, 118.88, 116.64, 115.41, 92.55, 92.17, 89.97, 3 hours, the mixture was quenched with saturated NH4Cl solu-
21.34, 20.94; HRMS (MALDI) calcd for C20H18O M+: 274.1352, tion and the organic compounds were then extracted with
found: 274.1355.
AcOEt. The combined organic layer was washed with brine,
O-Allenyl-4-methyl-2-[(triisopropylsilyl)ethynyl]phenol 1l. dried over Na2SO4, and concentrated in vacuo. The obtained
Following general procedures A.1–3, 2-iodo-4-methylphenol residue was then subjected to column chromatography
(585 mg, 2.50 mmol) was converted to 1l (530 mg, 3 steps, (neutral silica gel, hexane/AcOEt = 100 : 1) to give compound
1
65%) as a light yellow oil. H NMR (400 MHz, CDCl3) δ 7.06 1e (397 mg, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
(1H, d, J = 2.3 Hz), 7.04 (1H, d, J = 2.3 Hz), 6.95 (1H, d, J = δ 7.75 (6H, dd, J = 7.6, 1.6 Hz), 7.55 (1H, dd, J = 7.6, 1.6 Hz),
8.7 Hz), 6.89 (1H, t, J = 6.0 Hz), 5.38 (2H, d, J = 5.5 Hz), 7.44–7.30 (10H, m), 7.11 (1H, d, J = 7.8 Hz), 7.03 (1H, td, J =
2.28 (3H, s), 1.13 (21H, s); 13C NMR (100 MHz, CDCl3) δ 7.6, 0.9 Hz), 6.92 (1H, t, J = 6.0 Hz), 5.44 (2H, d, J = 6.0 Hz); 13
C
202.70, 156.18, 134.54, 133.04, 130.51, 120.39, 118.05, NMR (100 MHz, CDCl3) δ 202.53, 158.38, 135.66, 133.90,
115.49, 102.88, 95.86, 90.58, 20.90, 19.12, 11.79; HRMS 133.61, 130.20, 129.83, 127.90, 122.72, 118.57, 116.39, 113.99,
(MALDI) calcd for C21H31OSi (M + H)+: 327.2139, found: 105.14, 94.06, 90.05; HRMS (MALDI) calcd for C29H22OSiNa
327.2132.
(M + Na)+: 437.1332, found: 437.1336.
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General procedure B for the synthesis of compounds 2a–e, 2h,
2l–o, and 3j
J = 7.8, 1.7 Hz), 6.95 (1H, dd, J = 8.0, 1.7 Hz), 6.89 (1H, dd, J =
8.6, 1.1 Hz), 6.59 (1H, td, J = 7.4, 1.1 Hz), 3.67 (1H, dd, J = 5.2,
1.7 Hz), 3.12 (1H, dd, J = 13.8, 5.2 Hz), 2.80 (1H, dd, J = 13.8,
1.7 Hz), 1.04 (9H, s); 13C NMR (125 MHz, CDCl3) δ 188.28,
162.97, 155.48, 136.13, 136.04, 133.75, 133.10, 132.72, 132.02,
130.65, 129.42, 129.35, 127.67, 127.40, 122.90, 119.97, 119.01,
32.69, 28.40, 28.29, 19.35; HRMS (MALDI) calcd for
A solution of compound 1a–o (50 mg, 0.16 mmol) in toluene C27H28O2SiNa (M
(commercially available, not dry, 0.03 M) was placed in a test m.p. 112–115 °C (from hexane/ethyl acetate).
tube, purged with nitrogen and sealed. After refluxing for 2 h, 2-(2-Formyl-4-triphenylsilylcyclobut-1-enyl)phenol
+
Na)+: 435.1751, found: 435.1752;
2e.
the solution was cooled to room temperature and concentrated Following general procedure B, compound 1e (66 mg,
in vacuo. The obtained residue was then subjected to column 0.16 mmol) was converted to 2e (31 mg, 45%) as a light yellow
1
chromatography (neutral silica gel, hexane/AcOEt = 10 : 1 to powder. H NMR (400 MHz, CDCl3) δ 9.08 (1H, s), 8.77 (1H, s),
5 : 1).
2-(2-Formyl-4-triisopropylsilylcyclobut-1-enyl)phenol
7.43–7.37 (9H, m), 7.32–7.25 (6H, m), 7.13 (1H, dd, J = 7.8,
2a. 7.8 Hz), 6.91 (1H, d, J = 8.3 Hz), 6.78 (1H, dd, J = 8.0, 1.6 Hz),
Following general procedure B, compound 1a (50 mg, 6.29 (1H, dd, J = 7.6, 7.6 Hz), 3.75 (1H, dd, J = 5.0, 1.8 Hz), 3.21
0.16 mmol) was converted to 2a (49 mg, 92%) as a light yellow (1H, dd, J = 13.3, 5.0 Hz), 2.71 (1H, dd, J = 13.3, 1.8 Hz);
1
prism. H NMR (400 MHz, CDCl3) δ 9.19 (1H, s), 8.88 (1H, s), 13C NMR (100 MHz, CDCl3) δ 189.07, 161.44, 156.37, 135.77,
7.37–7.32 (1H, m), 7.27 (1H, d, J = 1.84 Hz), 7.02 (1H, dd, J = 132.60, 132.45, 131.39, 131.16, 129.88, 127.91, 122.22, 119.61,
8.2, 1.4 Hz), 6.94–6.90 (1H, m), 3.29 (1H, dd, J = 5.0, 1.8 Hz), 119.34, 33.21, 27.71; HRMS (MALDI) calcd for C29H24O2SiNa
3.07 (1H, dd, J = 13.5, 5.0 Hz), 2.85 (1H, dd, J = 13.7, 1.8 Hz), (M + Na)+: 455.1438, found: 455.1430; m.p. 103–107 °C (from
1.07 (18H, s), 0.97 (3H, s); 13C NMR (100 MHz, CDCl3) δ hexane/ethyl acetate).
189.36, 165.07, 156.67, 133.12, 132.37, 130.51, 124.35, 120.46,
120.29, 32.45, 27.84, 19.19, 12.21; HRMS (MALDI) calcd for general procedure B, compound 1h (34 mg, 0.16 mmol) was
C20H29O2Si (M
H)+: 329.1931, found: 329.1930; converted to 2h (23 mg, 62%) as a light brown powder. 1H
2-(2-Formyl-4-tert-butylcyclobut-1-enyl)phenol 2h. Following
−
m.p. 126–128 °C (from hexane/ethyl acetate).
2-(2-Formyl-4-triethylsilylcyclobut-1-enyl)phenol
NMR (500 MHz, CDCl3) δ 9.56 (1H, s), 7.59 (1H, s), 7.31–7.25
2b. (2H, m), 7.00 (1H, d, J = 1.15 Hz), 6.99–6.91 (1H, m), 3.23 (1H,
Following general procedure B, compound 1b (43 mg, dd, J = 4.6, 1.7 Hz), 2.76 (1H, dd, J = 13.75, 4.6 Hz), 2.47 (1H,
0.16 mmol) was converted to 2b (38 mg, 83%) as a light yellow dd, J = 13.75, 1.7 Hz), 0.87 (9H, s); 13C NMR (125 MHz, CDCl3)
oil. 1H NMR (300 MHz, CDCl3) δ 9.18 (1H, s), 9.13 (1H, s), δ 190.44, 161.43, 155.23, 136.17, 131.76, 131.03, 123.16,
7.36–7.31 (1H, m), 7.26–7.22 (1H, m), 7.02 (1H, d, J = 4.1 Hz), 120.36, 118.82, 52.62, 33.24, 27.35, 27.02; HRMS (MALDI)
6.91 (1H, td, J = 7.5, 1.2 Hz), 3.09 (1H, dd, J = 5.0, 1.6 Hz), 3.01 calcd for C15H17O2 (M − H)+: 229.1223, found: 229.1225.
(1H, dd, J = 13.3, 5.0 Hz), 2.65 (1H, dd, J = 13.5, 1.6 Hz), 0.88 M.p. 110–112 °C (from hexane/ethyl acetate).
(9H, t, J = 7.8 Hz), 0.50 (6H, q, J = 8.2 Hz); 13C NMR (100 MHz,
1-Mesityl-2H-cyclobuta[c]chromene 3j. Following general
CDCl3) δ 189.29, 163.89, 156.76, 133.06, 131.10, 130.59, 123.34, procedure B, compound 1j (44 mg, 0.16 mmol) was converted
120.09, 119.92, 32.69, 26.51, 7.52, 2.74; HRMS (MALDI) calcd to 3j (35 mg, 80%) as a colorless oil. 1H NMR (400 MHz,
for C17H23O2Si (M − H)+: 287.1462, found: 287.1463.
CDCl3) δ 7.21–7.17 (1H, m), 7.01 (1H, d, J = 8.2 Hz), 6.95–6.90
2-[2-Formyl-4-(tert-butyldimethylsilyl)cyclobut-1-enyl]phenol (4H, m), 6.47 (1H, s), 3.47 (2H, s), 2.32 (6H, s), 2.30 (3H, s); 13
C
2c. Following general procedure B, compound 1c (43 mg, NMR (100 MHz, CDCl3) δ 153.86, 136.86, 136.77, 134.43,
0.16 mmol) was converted to 2c (37 mg, 73%) as a light yellow 132.41, 129.56, 128.23, 126.18, 126.04, 124.99, 123.03, 122.52,
1
powder. H NMR (400 MHz, CDCl3) δ 9.25 (1H, s), 8.82 (1H, s), 118.46, 117.45, 38.93, 21.03, 20.72; HRMS (MALDI) calcd for
7.35–7.31 (1H, m), 7.22 (1H, dd, J = 7.8, 1.4 Hz), 7.02 (1H, dd, C20H18O M+: 274.1352, found: 274.1356.
J = 8.26, 0.9 Hz), 6.94–6.89 (1H, m), 3.1 (1H, dd, J = 5.0, 1.4
2-(2-Formyl-4-triisopropylsilylcyclobut-1-enyl)-4-methylphenol
Hz), 3.00 (1H, dd, J = 13.76, 5.0 Hz), 2.69 (1H, dd, J = 13.5, 1.6 2l. Following general procedure B, compound 1l (52 mg,
Hz), 0.90 (9H, s), −0.10 (3H, s), −0.25 (3H, s); 13C NMR 0.16 mmol) was converted to 2l (41 mg, 74%) as a light yellow
1
(100 MHz, CDCl3) δ 188.90, 163.56, 156.40, 132.69, 131.70, powder. H NMR (300 MHz, CDCl3) δ 9.17 (1H, s), 8.77 (1H, s),
130.73, 123.22, 120.07, 119.79, 32.92, 27.20, 26.82, 17.77, 7.15 (1H, dd, J = 8.5, 2.31 Hz), 7.07 (1H, d, J = 1.83 Hz), 6.92
−5.61, −8.92; HRMS (MALDI) calcd for C17H23O2Si (M − H)+: (1H, d, J = 8.25 Hz), 3.29 (1H, dd, J = 5.04, 1.35 Hz), 3.06 (1H,
287.1462, found: 287.1461. M.p. 118–121 °C (from hexane/ dd, J = 13.7, 5.04 Hz), 2.84 (1H, dd, J = 13.5, 1.83 Hz), 2.26 (3H,
ethyl acetate).
s), 1.08 (18H, s), 0.98 (3H, s); 13C NMR (100 MHz, CDCl3)
2-[2-Formyl-4-(tert-butyldiphenylsilyl)cyclobut-1-enyl]phenol δ 188.73, 164.55, 153.95, 133.39, 131.32, 130.05, 128.91,
2d. Following general procedure B, compound 1d (63 mg, 123.38, 119.49, 31.72, 27.13, 20.06, 18.58, 11.59; HRMS
0.16 mmol) was converted to 2d (66 mg, 99%) as a light yellow (MALDI) calcd for C21H31O2Si (M − H)+: 343.2088, found:
1
prism. H NMR (500 MHz, CDCl3) δ 9.16 (1H, s), 7.84 (1H, s), 343.2087. M.p. 112–114 °C (from hexane/ethyl acetate).
7.49 (2H, dd, J = 8.0, 1.1 Hz), 7.46 (2H, dd, J = 8.0, 1.7 Hz),
2-(2-Formyl-4-triisopropylsilylcyclobut-1-enyl)-4-methoxyphe-
7.40–7.29 (4H, m), 7.24 (2H, dd, J = 7.5, 7.5 Hz), 7.18 (1H, td, nol 2m. Following general procedure B, compound 1m (55 mg,
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0.16 mmol) was converted to 2m (40 mg, 70%) as a light yellow (2.2 equiv.). The mixture was stirred at room temperature for
1
flake. H NMR (500 MHz, CDCl3) δ 9.21 (1H, s), 8.33 (1H, s), 30 minutes and then it was cooled to 0 °C again before adding
6.98–6.93 (2H, m), 6.73 (1H, d, J = 2.85 Hz), 3.76 (3H, s), 3.27 compound 2a (100 mg, 0.3 mmol). It was then stirred under
(1H, dd, J = 4.87, 1.8 Hz), 3.07 (1H, dd, J = 13.45, 5.0 Hz), 2.85 nitrogen overnight and then quenched with water. The organic
(1H, dd, J = 13.75, 1.7 Hz), 1.08 (18H, s), 0.98 (3H, s); 13C NMR compounds were then extracted with AcOEt. The combined
(125 MHz, CDCl3) δ 188.68, 163.95, 152.91, 150.41, 131.89, organic layer was washed with brine, dried over Na2SO4, and
124.45, 121.32, 119.75, 112.77, 55.61, 31.97, 27.37, 18.38, concentrated in vacuo. The obtained residue was then sub-
11.70; HRMS (MALDI) calcd for
361.2194, found: 361.2195. M.p. 130–132 °C (from hexane/ AcOEt = 20 : 1) to give compound 4 (75 mg, 76%) as a yellow
C21H33O3Si (M +
H)+: jected to column chromatography (neutral silica gel, hexane/
1
ethyl acetate).
oil. H NMR (500 MHz, CDCl3) δ 7.18–7.11 (2H, m), 6.90–6.87
(2H, m), 6.49 (1H, dd, J = 5.15, 10.8 Hz), 5.26 (1H, s), 5.24–5.10
4-Bromo-2-(2-formyl-4-triisopropylsilylcyclobut-1-enyl)
phenol 2n. Following general procedure B, compound 1n (2H, m), 3.06–3.04 (1H, m), 2.82 (1H, dd, J = 13.2, 5.2 Hz), 2.74
(63 mg, 0.16 mmol) was converted to 2n (30 mg, 45%) as an (1H, dd, J = 13.4, 2.0 Hz), 1.00 (21H, s); 13C NMR (125 MHz,
1
orange powder. H NMR (400 MHz, CDCl3) δ 9.27 (1H, s), 9.18 CDCl3) δ 152.37, 140.49, 139.57, 129.86, 129.08, 128.48, 123.12,
(1H, s), 7.41–7.36 (2H, m), 6.91 (1H, d, J = 8.72 Hz), 3.25 (1H, 120.16, 115.55, 114.90, 28.46, 28.44, 18.86, 11.50; HRMS
dd, J = 5.04, 1.84 Hz), 3.07 (1H, dd, J = 13.72, 5.04 Hz), 2.85 (MALDI) calcd for C21H31OSi (M − H)+: 327.2139, found:
(1H, dd, J = 13.72, 1.8 Hz), 1.08 (18H, s), 0.99 (3H, s); 13C NMR 327.2137.
(100 MHz, CDCl3) δ 189.38, 162.76, 155.74, 135.42, 132.59,
1-(Triisopropylsilyl)-1,2-dihydro-3H-cyclobuta[c]chromen-3-
132.20, 125.69, 122.16, 112.22, 32.36, 27.66, 16.67, 11.91; one 5. To a round-bottom flask containing compound 2a
HRMS (MALDI) calcd for C20H28O2SiBr (M − H)+: 407.1036, (100 mg, 0.3 mmol) in tert-butanol (0.05 M) were added
found: 407.1030. M.p. 163–165 °C (from hexane/ethyl acetate).
2-methyl-2-butene (30 equiv.) and an aqueous solution of
1-(2-Formyl-4-triisopropylsilylcyclobut-1-enyl)naphthalene-2- NaClO2 (5 equiv.) and NaH2PO4 (5 equiv.) in 1.0 ml of H2O.
ol 2o. Following general procedure B, compound 1o (58 mg, The mixture was stirred under nitrogen at ambient tempera-
0.16 mmol) was converted to 2o (46 mg, 76%) as an orange ture for 1 h. It was then quenched with water and the organic
flake. 1H NMR (300 MHz, CDCl3) δ 9.39 (1H, s), 7.95 (1H, d, J = compounds were then extracted with AcOEt. The combined
8.25 Hz), 7.67 (2H, d, J = 8.7 Hz), 7.50–7.33 (2H, m), 7.18 (1H, organic layer was washed with brine, dried over Na2SO4, and
d, J = 8.7 Hz), 3.66 (1H, dd, J = 5.0, 1.83 Hz), 3.25 (1H, dd, J = concentrated in vacuo. The obtained residue was then sub-
13.7, 5.0 Hz), 2.97 (1H, dd, J = 13.7, 1.83 Hz), 0.91 (18H, s), jected to column chromatography (neutral silica gel, hexane/
0.76 (3H, s); 13C NMR (125 MHz, CDCl3) δ 187.54, 163.15, AcOEt = 20 : 1) to give compound 5 (73 mg, 74%) as a dark
1
153.25, 138.53, 132.63, 131.90, 129.26, 128.57, 127.12, 124.78, orange prism. H NMR (400 MHz, CDCl3) δ 7.32 (1H, t, J = 7.5
124.14, 119.91, 116.73, 28.70, 18.73, 18.56, 11.38; HRMS Hz), 7.26–7.22 (1H, m), 7.02 (1H, d, J = 8.2 Hz), 6.92 (1H, t, J =
(MALDI) calcd for C24H33O2Si (M + H)+: 381.2244, found: 7.4 Hz), 3.16 (1H, d, J = 5.0 Hz), 2.98 (1H, dd, J = 14.0, 5.0 Hz),
381.2246. M.p. 188–190 °C (from hexane/ethyl acetate).
2.77 (1H, d, J = 14.2 Hz), 1.04 (18H, s), 0.96 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 169.05, 165.97, 154.99, 132.30, 129.61,
123.93, 123.45, 120.24, 120.08, 30.37, 28.20, 18.69, 11.61;
Preparation of 2f from 2a (Scheme 3)
2-(2-Formylcyclobut-1-enyl)phenol 2f. To a round-bottom HRMS (MALDI) calcd for C20H29O2Si (M + H)+: 329.1931,
flask containing compound 2a (150 mg, 0.45 mmol) in DMF found: 329.1930. M.p. 145–147 °C (from hexane/ethyl acetate).
(0.06 M) was added tetrabutylammonium fluoride trihydrate
1-Triisopropylsilyl-2H-cyclobuta[c]chromene 3a. 1H NMR
(3.0 equiv.) and was stirred under nitrogen at 80 °C for 4 h. (400 MHz, CDCl3) δ 7.37 (1H, dd, J = 8.0, 1.6 Hz), 7.23 (1H, dd,
The mixture was then quenched with 0.1 N HCl and the J = 8.0, 1.4 Hz), 7.06–7.02 (2H, m), 6.36 (1H, s), 3.17 (2H, s),
organic compounds were extracted with AcOEt. The combined 1.13 (18H, s), 1.11 (3H, s); 13C NMR (100 MHz, CDCl3) δ
organic layer was washed with NaHCO3 and brine, and then 154.15, 148.78, 129.99, 127.24, 126.25, 125.11, 124.32, 123.52,
dried over Na2SO4, and concentrated in vacuo. The obtained 119.71, 118.40, 38.68, 19.19, 12.40.
residue was then subjected to column chromatography
Procedure for the scale-up synthesis of compound 2a
(Scheme 4)
(neutral silica gel, hexane/AcOEt = 3 : 1) to give compound 2f
(74 mg, 94%) as an orange powder. 1H NMR (500 MHz, CDCl3)
δ 9.42 (1H, s), 9.34 (1H, s), 7.34–7.31 (2H, m), 6.99 (1H, dd, J =
Condition A. To a round-bottom flask containing compound
8.0, 1.15 Hz), 6.92 (1H, td, J = 7.5, 1.15 Hz), 2.93 (2H, t, J = 1a (625 mg, 2 mmol) in dry toluene (0.03 M) was added H2O (2
3.7 Hz), 2.82 (2H, t, J = 3.7 Hz); 13C NMR (125 MHz, CDCl3) equiv.) and the mixture was sonicated for 10 minutes. It was
δ 191.33, 156.86, 156.31, 133.27, 132.33, 130.49, 122.00, then refluxed under nitrogen for 2 hours, cooled to room
120.28, 119.02, 28.99, 23.81; HRMS (MALDI) calcd for temperature and concentrated in vacuo. The obtained residue
C11H11O2 (M
M.p. 160–162 °C (from hexane/ethyl acetate).
2-(4-(Triisopropylsilyl)-2-vinylcyclobut-1-enyl)phenol 4. To a as a light yellow prism.
+
H)+: 175.0754, found: 175.0752. was then subjected to column chromatography (neutral silica
gel, hexane/AcOEt = 5 : 1) to give compound 2a (549 mg, 83%)
round-bottom flask containing methyltriphenylphosphonium
Condition B. A solution of compound 1a (625 mg, 2 mmol)
bromide (2.2 equiv.) in THF (0.2 M) at 0 °C was added t-BuOK in H2O (0.03 M) was sonicated for 10 minutes. It was then
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refluxed under air for 2 hours, cooled to room temperature
and extracted with AcOEt. The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The obtained residue was then subjected to column
chromatography (neutral silica gel, hexane/AcOEt = 5 : 1) to
give compound 2a (450 mg, 68%) as a light yellow prism.
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Procedure for deuterium labeling using D2O (Scheme 5)
A solution of compound 1a (50 mg, 0.16 mmol) in dioxane
(0.03 M) was placed in a flame-dried test tube, purged with
nitrogen and sealed. Using a microsyringe, D2O (2 equiv.) was
added to the solution which was then sonicated for
10 minutes. After refluxing for 2 hours, the solution was
cooled to room temperature and concentrated in vacuo. The
obtained residue was then subjected to column chromato-
graphy (neutral silica gel, hexane/AcOEt = 5 : 1) to give a
1 : 1 mixture of deuterium-labeled 2a and unlabeled 2a.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was partially supported by a Grant-in-Aid from the
JSPS KAKENHI for Precisely Designed Catalysts with
Customized Scaffolding (Grant No. JP 18H04260),
T15K149760, and T15KT00630, by a Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS)) from the AMED under Grant Number
JP18am0101084 and JP19am0101084, and by the Cooperative
Research Program of “Network Joint Research Center for
Materials and Devices” from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT).
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