Substrate-Controlled Regioselective Bromination of 1,2-Disubstituted Cyclobutenes: An Application in the Synthesis of 2,3-Disubstituted Cyclobutenones

Article abstract of DOI:10.1021/acs.joc.1c00261

Easily available disubstituted cyclobutenes were regioselectively halogenated at the allylic position by means of a reaction with bromine. The regioselectivity of bromination is controlled by the presence of a carbocation-stabilizing group. The prepared d

Full text of DOI:10.1021/acs.joc.1c00261

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Article
Substrate-Controlled Regioselective Bromination of 1,2-
Disubstituted Cyclobutenes: An Application in the Synthesis of 2,3-
Disubstituted Cyclobutenones
̌
̌
Tereza Edlová, Hana Dvoráková, Václav Eigner, and Tomás Tobrman*
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ABSTRACT: Easily available disubstituted cyclobutenes were regioselectively halo-
genated at the allylic position by means of a reaction with bromine. The regioselectivity
of bromination is controlled by the presence of a carbocation-stabilizing group. The
prepared disubstituted 3-bromocyclobutenes were converted into the corresponding
disubstituted cyclobutenones. On the basis of the performed experiments, the
mechanism behind the bromination reaction was also proposed.
reduction of cyclobutenones.19 A direct approach to the
preparation of substituted cyclobutenones based on the
modification of the cyclobutene skeleton has not yet been
published. Cyclobutenes are most commonly prepared by 2+2
cycloadditions,21 cyclization of acyclic substrates,22 or ring-
expansion of substituted cyclopropanes.23 However, based on
our previous experience with transition-metal-catalyzed cross-
coupling reactions,24 we proposed the use of the regioselective
bromination of easily available disubstituted cyclobutene 2 as a
novel route to disubstituted cyclobutenone 4 (Scheme 1). It is
important to note here that the preparation of bromocyclo-
butene 3 via the regioselective bromination of cyclobutene 2
has not previously been reported. In fact, the only reported
direct bromination of disubstituted cyclobutene 1a includes
the compound’s reaction with N,N′-dibromodimethylhydan-
toin (DBDMH).25 However, the double-brominated cyclo-
butene 1b does not allow for the direct synthesis of the
substituted cyclobutenone 4. Therefore, we expected that the
brominated cyclobutene 3 would be converted into cyclo-
butenols, the oxidation of which would accomplish the
synthesis of cyclobutanone 4. Cyclobutene 2 is preparable
via the double cross-coupling reaction of the 2-bromocyclo-
INTRODUCTION
■
Cyclobutane is an example of a four-membered cyclic
compound. Many naturally occurring compounds contain
cyclobutane scaffolds,1 including katsumadain C,2 palhinosides
A−H,3 methylcyclobutene,4 and cyclobutene-based sesquiter-
penes.5 Moreover, the derivatives of cyclobutanes serve as
valuable building blocks in relation to organic synthesis.6 The
same is also true in the case of the cyclobutenones. Squaric
acid analogues have been evaluated as compounds that exhibit
antitumor activity,7 and the synthesis of conjugate vaccines
based on squaring acid chemistry has been performed.8
Therefore, significant research effort has been dedicated to
preparing squaric acid derivatives.9 Additionally, disubstituted
cyclobutenones are known to be selective and orally active
COX-2 inhibitors.10 Cyclobutenones have also been used in
the field of organic synthesis to prepare various substances.11
Some synthetic applications of cyclobutenones rely on
asymmetric cycloadditions,12 benzannulations,13 conjugated
additions,14 or ring-expansion for the synthesis of highly
functionalized cyclopentanes.15 The observed reactivity
patterns of the cyclobutenones have been used, for example,
in diazepine synthesis16 as well as in the total synthesis of
( )-naphthacemycin A9.17
Our review of the literature revealed that the vast majority of
disubstituted cyclobutenones can be prepared via the [2+2]
cycloaddition process,18 which affords functionalized cyclo-
butenones that can be further modified by means of the Suzuki
reaction19 or halogen reduction.20 The oxidation of cyclo-
butenyl alcohols en route to the substituted cyclobutenones
can be ruled out, as such alcohols are usually prepared via the
Received: February 2, 2021
Published: April 5, 2021
https://doi.org/10.1021/acs.joc.1c00261
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5820−5831
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Scheme 1. General Scheme Representing Both the Previous
Approach to Dibromocyclobutene 1b and Our Work
Table 1. Condition Screening for the Bromination of the
Cyclobutene 2a
temp
time
(h)
a
entry
Br2 source/solvent
Br2/CCl4
Br2/toluene
Br2/CpOMe
Br2/CHCl3
Br2/DCM
Br2/1,4-dioxane
NBS/CCl4
(°C)
2a:3a:6
b
1
2
3
4
5
6
7
8
9
10
11
12
13
0
0
0
0
0
0
0
80
80
0
0.5
0.5
0.5
0.5
0.5
0.5
24
1.5
1.5
5
0:100(98 ):0
b
0:100(99 ):0
b
0:100(99 ):0
18:79:3
10:80:10
17:67:16
b
0:100(98 ):0
NBS/CCl4
6:88:6
6:87:6
3:93:4
6:87:6
NBS + DBP/CCl4
pyridinium tribromide/CCl4
c
BTMABr3 /CCl4
0
0
0
8
5
2
b
DBDMH/CCl4
Me2BrS(+)Br(−)/CCl4
0:100(97 ):0
b
0:100(99 ):0
butenyl phosphate 5.26 Phosphate 5 is a typical example of a
double electrophilic template containing an activated C−O
bond27 that is easily obtainable from commercial cyclo-
butanone.
a
b
1
The ratio of the 2a, 3a, and 6 was determined by H NMR. Yield
c
(%). Benzyltrimethylammonium tribromide (BTMABr3).
Results and Discussion. Initially, we synthesized a series
of starting 1,2-disubstituted cyclobutenes (Figure 1), and the
symmetrically substituted cyclobutene 2a was used as a model
compound when evaluating the course of the bromination
reaction (Table 1). Our first experiment with bromine in
tetrachloromethane proved successful in terms of yielding the
brominated cyclobutene 3a in an almost quantitative yield
(Table 1, entry 1). Similarly, good results were obtained when
performing the bromination reaction in toluene and cyclo-
pentylmethyl ether (CpOMe), although the other halogenated
solvents and 1,4-dioxane led to a mixture of the desired
product 3a, the starting compound 2a, and the dibrominated
product 6 (Table 1, entries 2−6). N-Bromosuccinimide
(NBS), as an example of a nontoxic source of bromine, also
maintained a quantitative yield of the cyclobutene 3a, albeit
with a reaction time of 24 h (Table 1, entry 7). A significant
reduction in the reaction time was achieved by performing the
bromination at 80 °C, although, in this case, the formation of
the double bromination product 6 was observed (Table 1,
entries 8 and 9). The other tested brominating agents proved
less effective because they either gave a mixture of the two
products 3a and 6 or allowed for the selective formation of the
bromocyclobutene 3a with a significantly longer reaction time
(Table 1, entries 10−13).
The optimized reaction conditions were also tested for other
disubstituted cyclobutenes (Scheme 2). The bromination of
the symmetrically substituted cyclobutenes 2b and 2f followed
the model bromination of the cyclobutene 2a, thereby
affording the brominated cyclobutenes 3b and 3f in high
yields. To our surprise, the bromination of those cyclobutenes
bearing two phenyl rings with different functional groups
proceeded with high regioselectivity, with the corresponding
products being 3c−3e isolated. The bromination of the
cyclobutene 2g under optimized reaction conditions resulted
in the formation of the dibromocyclobutane 7a, of which
approximately 5% comprised the bromocyclobutene 3g (Table
2). However, we quickly found that a mixture of the
dibromocyclobutane 7a and the bromocyclobutene 3g
(7a:3g, 95:5) could be slowly converted into the pure
brominated cyclobutene 3g by means of heating in tetrachloro-
methane (Table 2, entry 1). The use of hydrobromic acid
Figure 1. Structures of starting compounds.
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Scheme 2. Scope of the One-Step Synthesis of 3-Bromo-1,2-
Disubstituted Cyclobutenes
Scheme 3. Scope of the Two-Step Synthesis of 3-Bromo-1,2-
Disubstituted Cyclobutenes
Table 2. Isomerization of Dibromocyclobutane 7a
of compounds whose structure could not be determined was
observed. The discovered bromination reaction is limited to
cyclobutene derivatives, since disubstituted cyclohexene gave a
mixture of products under optimized reaction conditions.
On the basis of the performed experiments, we assume that
the formation of the bromocyclobutene 3 takes place via an
electrophilic addition of bromine to the double bond (Scheme
4). A radical substitution at the allylic position was ruled out in
a
b
entry
conditions
CCl4, 80 °C
time (h)
conversion (%)
c
1
2
3
4
32
96
16
4
100 (100 )
52 (40 )
d
c
HBr, MeCN, 23 °C
HBr, DCM, 23 °C
silica gel, DCM, 23 °C
e
65
c
100 (100 )
a
The starting substance 7a contained 5% of the brominated
b
c
cyclobutene 3g. Determined by means of 1H NMR. Yield.
d
e
Aqueous HBr was used. 5.7 M HBr in acetic acid was used.
Scheme 4. Proposed Mechanism for the Formation of the 3-
Bromocyclobutenes 3
(HBr) proved less efficient in this case (Table 2, entries 2 and
3). A quantitative yield of the brominated cyclobutene 3g and
a significant reduction in the isomerization reaction time were
achieved by stirring the cyclobutene 7a with silica gel in
dichloromethane (Table 2, entry 4).
By further studying the course of the bromination of the
asymmetrically substituted cyclobutenes 2h and 2i, we found
that those cyclobutenes substituted with phenyl-bearing
electron-neutral or electron-withdrawing groups required a
silica gel workup in order to provide the brominated products
3h and 3i in good yields (Scheme 3). The same reactivity was
also observed for the cyclobutene 2j, which gave the
cyclobutene 3j, substituted with a benzoyl group, in a
moderate yield. The synthesis of double electrophilic templates
was successfully accomplished via the bromination of cyclo-
butenes with the diethyl phosphate moiety and bromine atom
(3k and 3l). However, an application of our two-step
procedure for the synthesis of the brominated cyclobutene 3
from the cyclobutene 2 failed in the case of the cyclobutene
2m when the dibromocyclobutane 7b proved resistant to
silica-gel-mediated isomerization. The fact that the course of
bromination of disubstituted cyclobutenes is influenced by
electron effects can be demonstrated by experiments on
bromination of cyclobutene 2s with 3-thienyl and p-tolyl
substituents. In this case, an inseparable mixture of both
regioisomers was formed. It is important to note that 1-(2-
butylcyclobut-1-en-1-yl)-4-methylbenzene did not give bromi-
nated cyclobutene, but the formation of an inseparable mixture
this case because the bromination of the cyclobutene 2a takes
place in the presence of antioxidants, for example, 2,6-di-tert-
butyl-4-methylphenol (BHT) or nitrobenzene. Moreover, the
presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) did
not affect the bromination of the alkene 2a. Thus, the addition
of bromine to the cyclobutene 2 generates two carbocations,
namely, A and B. The formation of the carbocation A is
preferred in this case, as the formed carbocation is stabilized
due to the presence of an aryl substituent with an electron-
donating group (EDG). This finding is consistent with the
ability of an EDG to stabilize carbocations.28 In the next step,
hydrogen bromide is eliminated, which gives the trisubstituted
alkene C. The target product of bromination 3 is subsequently
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formed through the acid-initiated isomerization of the
intermediate C.
As the preparation of substituted cyclobutenones by means
of the modification of the cyclobutene skeleton has not
previously been reported, we decided to extend our study to
examine the conversion of the halogenated cyclobutene 3 into
the cyclobutenone 4 (Table 3). The first step in the proposed
by means of chromatography on silica gel. Our attempts to
characterize the ether 9 using mass spectrometry also proved
unsuccessful, and the molecular peak corresponding to the
substance 9 was not detected. However, we experimentally
verified that the ether 9 can be hydrolyzed into the alcohol 8c
using 1 M H2SO4 in dimethyl sulfoxide. The selective
formation of the alcohols 8a−8c during the silver-mediated
hydrolysis of the bromocyclobutenes 3 contrasts with the
previously published preparation of (E)-2,3-diarylbut-2-ene-
dials via the AgClO4-mediated hydrolysis of 3,4-dibromo-1,2-
diarylcyclobutenes.25
Table 3. Conditions Screening for the Hydrolysis of
Bromocyclobutenes 3
On the basis of the above-mentioned results, we developed a
methodology for the conversion of the cyclobutene 2 into the
cyclobutenone 4 through only the chromatographic separation
of the target compound 4 (Scheme 5). Thus, the starting
Scheme 5. An Application of the Developed Regioselective
Synthesis of the Bromocyclobutenes 3 to the Synthesis of
2,3-Disubstituted Cyclobutenones
a
a
entry
3
solvent
MeCN
MeCN
time (min)
8 (%)
4 (%)
1
2
3
4
5
3a
3a
3c
3g
3g
5
60
120
1080
60
8a, 98
4a, 85
na
b
c
−
MeCN
MeCN
DMSO
8b, 88
8c, 43
4b, 94
4c, 70
de
,
f
g
−
4c, 77
a
b
Yield. Potassium carbonate, potassium hydroxide, triethyl amine,
and sodium acetate were used as the base to facilitate the substitution
c
reaction. The formation of a complex reaction mixture was observed.
d
e
1 equiv of silver nitrate was used as an additive. A mixture of
f
DMSO/H2O in a 6:1 ratio was used. Crudely isolated alcohol 8c was
used for the oxidation. Yield from 3g.
g
transformation covers the hydrolysis of the 3-bromocyclobu-
tene 3 (Table 3). It emerged that the course of the studied
substitution reaction depends on the structure of the utilized
halogen derivative. While the cyclobutene 3a was converted
into the allylic alcohol 8a through the reaction with water
within a few minutes (Table 3, entry 1), the substitution of one
methoxy group with a methyl group extended the reaction time
to 120 min (Table 3, entry 3). The bromocyclobutene 3g with
two biphenyl groups was partially hydrolyzed into the alcohol
8c, which was obtained in a 43% yield (Table 3, entry 4). Our
attempts to perform the substitution reaction of the cyclo-
butene 3a under basic conditions proved unsuccessful, and a
mixture of products was formed in all the tested cases (Table 3,
entry 2). The prepared alcohols 8a−8c were smoothly oxidized
into disubstituted cyclobutenes using TEMPO in the presence
of periodic acid (Table 3, entries 1, 3, and 4). We observed
that the hydrolysis of the cyclobutene 3g with water could be
accelerated through the use of silver nitrate as an additive in
order to give the cyclobutenone 4c in a 77% yield after
oxidation with TEMPO (Table 3, entry 5). It is important to
note that a 1:6 mixture of water and DMSO must be used to
suppress the undesired formation of the ether 9 during the
substitution reaction of the bromocyclobutene 3g. The
formation of the ether 9 as a competitive reaction during the
preparation of the alcohol 8c was confirmed by reacting the
brominated alkene 3g with 0.5 equiv of water to give the ether
9 as the major product. Unfortunately, the ether 9 represents
an unstable compound that decomposed during its separation
cyclobutene 2 was brominated and the bromine substitution
was then performed in the presence of silver nitrate. The
crudely isolated alcohols were subsequently oxidized with
TEMPO, and the prepared cyclobutenenones were obtained
by means of column chromatography. An excellent result was
obtained with the cyclobutene 2a bearing a 4-anisolyl
substituent as an example of an electron-rich aromatic
hydrocarbon. An appropriately selected combination of
carbocation-stabilizing and carbocation-destabilizing substitu-
ents allowed for the preparation of the cyclobutenones 4b−4g
in satisfactory yields. The ability of the substituents to control
the course of the bromination reaction was further emphasized
during the preparation of the 2-(pyren-1-yl)cyclobut-2-en-1-
one 4h, 4i, and 4j, which were prepared in 42−64% yields. The
structures of the prepared substances were determined via two-
dimensional NMR and nuclear Overhauser effect (NOE)
experiments for the substances 3d, 3i, 4b, 4e, 4f, 4h, 4i, and
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(2-Bromocyclobut-1-en-1-yl)benzene (S1b). Prepared according
8b. Moreover, we confirmed the results of the NMR
experiments concerning the substance 4h using X-ray
crystallography.
26
́
to the procedure described by Polak starting from bromobenzene
(3.14 g, 20 mmol) to give (Hexane, Rf = 0.80) 2.8057 g (63%) of the
1
pure product as a light yellow oil. H NMR (300 MHz, CDCl3) δ
7.70−7.57 (m, 2H), 7.43−7.29 (m, 3H), 2.92−2.83 (m, 4H), in
accordance with the literature.29
CONCLUSIONS
■
4-(2-Bromocyclobut-1-en-1-yl)-1,1′-biphenyl (S1c). Prepared ac-
In this study, we have shown that the bromination of
disubstituted cyclobutenes can be performed using bromine
in carbon tetrachloride at 0 °C. The regioselectivity of the
bromination is affected by the position of the carbocation-
stabilizing groups. In some cases, the formation of 3-
bromocyclobutenes can be achieved through the silica-gel-
mediated isomerization of dibromocyclobutanes in dichloro-
methane. The prepared disubstituted 3-bromocyclobutenes
were converted into the corresponding cyclobutenones via a
two-step procedure. First, the 3-bromocyclobutenes were
hydrolyzed by means of the reaction with water in the
presence of silver nitrate, and then the resulting alcohol was
oxidized into the cyclobutenones using TEMPO and periodic
acid.
26
́
cording to the procedure described by Polak starting from 4-
bromobiphenyl (4.66 g, 20 mmol) to give (Hexane, Rf = 0.85) 2.8410
g (50%) of the title compound as a white crystalline solid, Mp 102−
1
103 °C. H NMR (400 MHz, CDCl3) δ 7.73−7.68 (m, 2H), 7.64−
7.58 (m, 4H), 7.48−7.42 (m, 2H), 7.39−7.33 (m, 1H), 2.94−2.87
(m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 140.9, 140.6,
132.0, 128.8, 127.5, 127.0, 126.9, 125.7, 108.3, 34.9, 28.9. HRMS
(APCI) m/z: [M + H]+ Calcd for C16H13Br 285.0274; Found
285.0277.
General Procedure (GP1) for the Preparation of 1,2-
Disubstituted Cyclobutenes from the Diethyl 2-Bromocyclo-
buten-1-yl Phosphate (5). A round-bottom flask was charged with
the diethyl 2-bromocyclobuten-1-yl phosphate (5) (1.0 equiv),
boronic acid (1.3 equiv), Pd(OAc)2 (1 mol %), and RuPhos (2
mol %). The reaction flask was then flushed with argon before toluene
(4 mL/mmol) was added. The reaction mixture was stirred for 1 min
at 23 °C. Next, a 2 M solution of K3PO4 (3.0 equiv) was added and
the reaction mixture was placed in an oil bath at 60 °C and stirred for
18 h. After completion, the reaction mixture was diluted with diethyl
ether and then extracted with water and brine. The organic phase was
dried over MgSO4, and the solvents were evaporated under reduced
pressure. The products were purified using column chromatography
on silica gel. The isolated 2-substituted cyclobuten-yl-phosphate (1
equiv), Pd(OAc)2 (4 mol %), and DPEPhos (4 mol %) or
PdCl2DPEPhos (4 mol %) were sealed with a septum and flushed
with argon. An arylzinc chloride reagent (1.3 equiv, approximately 0.5
M) and AlCl3 (1 equiv, 0.5 M solution in THF) were added via a
syringe. The resulting reaction mixture was placed in an oil bath at 60
°C and stirred for 18 h. After completion, the reaction mixture was
cooled to 23 °C, quenched with a 1 M solution of tartaric acid (2 mL/
mmol), and stirred for 15 min. The organic phase was diluted with
diethyl ether, washed with water and brine, and dried over MgSO4.
The solvents were evaporated under reduced pressure. The products
were then purified using column chromatography on silica gel.
General Procedure (GP2) for the Synthesis of Cyclobutenes
by Means of the Suzuki Reaction. A mixture of aryl or
cyclobutenyl halide (1.0 equiv), either a boronic acid or a boronic
acid neopentyl glycol ester (1.2 equiv), Pd(OAc)2, and ligand was
dissolved in THF (5 mL/mmol). The mixture was then stirred at 23
°C for 2 min, followed by the addition of K3PO4 (3 equiv, 2 M
solution in water). The reaction mixture was placed in an oil bath at
60 °C and stirred for 18 h. Then, the mixture was cooled to ambient
temperature and diluted with diethyl ether (10 mL/mmol) before the
organic phase was washed with water (10 mL/mmol) and brine (10
mL/mmol). The organic layer was dried over MgSO4, and the
solvents were removed under reduced pressure and column
chromatography (silica gel) gave the products.
EXPERIMENTAL SECTION
■
General Information. All TLC analyses were performed on silica
gel plates DC-Alufolien-Kieselgel purchased from Sigma-Aldrich.
Merc Silica Gel 60 (40−63 μm) was used for column chromatog-
raphy. NMR spectra were measured on a Varian Gemini 300 (1H,
300.07 MHz; 13C, 75.46 MHz), Agilent 400MR DD2 (1H, 400 MHz;
13C, 101 MHz), Bruker DRX 500 Avance (1H, 500.13 MHz; 13C, 126
MHz), and a Bruker 600 Avance III (1H, 600.13 MHz, 13C, 150.92
MHz) spectrometer at 298 K. Mass spectra were measured in UCT
Central Laboratories. Anhydrous and degassed THF, toluene, and
DCM were prepared by PureSolv MD7. Tetrachloromethane was
distilled and dried over molecular sieves prior to use. Starting
compounds and reagents were purchased and used without further
purification. The concentration of n-BuLi was determined prior to use
by titration using menthol and 1,10-phenanthroline. Prepared
organozinc reagents were titrated against iodine. The synthesis of
compounds 2c, 2k, 2l was accomplished following a published
procedure.26 The X-ray crystallographic structure of the substance 4h
was deposited into the Cambridge Structural Database under number
CCDC 2043220.
General Procedure for Preparation of Arylzinc Chloride
Reagents. A flame-dried round-bottom flask was charged with aryl
halide (1.0 equiv) before dry THF (0.75 mL/mmol) was added and
the reaction mixture was cooled to −78 °C in an acetone/dry ice
cooling bath. Then, n-BuLi (0.98 equiv) was added dropwise via a
syringe and the reaction mixture was stirred for 30 min at −78 °C if
there were no indications otherwise. Freshly dehydrated ZnCl2 (1.05
equiv before drying) was prepared through heating under reduced
pressure in a pear-shaped flask until melted. When cooled to 23 °C,
the flask was flushed with argon and sealed with a septum. Dry THF
(1 mL/mmol) was added, and the mixture was sonicated until the
ZnCl2 was completely dissolved. The solution was transferred to the
flask containing the aryllithium and then warmed until it reached 23
°C. The concentration of the resulting arylzinc reagent was
determined by means of titration against iodine in THF.
1,2-Bis(4-methoxyphenyl)cyclobut-1-ene (2a). GP1 starting from
diethyl 2-(4-methoxyphenyl)-cyclobuten-1-yl phosphate26 (3.123 g,
10.0 mmol), Pd(OAc)2 (0.0897 g, 0.4 mmol), DPEPhos (0.2154 g,
0.4 mmol), AlCl3 (20 mL, 0.5 M, 10 mmol), and 4-methoxyphe-
nylzinc chloride (28.2 mL, 0.46 M, 13.0 mmol) gave (Hexane/AcOEt
9:1, Rf = 0.40) 2.085 g (80%) of the title compound as a white
crystalline solid, Mp 78−80 °C. 1H NMR (300 MHz, CDCl3) δ
7.48−7.43 (m, 4H), 6.88−6.83 (m, 4H), 3.82 (s, 6H), 2.72 (s, 4H).
13C{1H} NMR (75 MHz, CDCl3) δ 158.7, 136.2, 129.3, 127.2, 113.7,
Preparation of Starting Compounds. 2-(2-([1,1'-Biphenyl]-4-
yl)cyclobut-1-en-1-yl)-5,5-dimethyl-1,3,2-dioxaborinane (S1a). Pre-
pared according to the procedure described by Polak from 4-(2-
26
́
bromocyclobut-1-en-1-yl)-1,1′-biphenyl (2.955 g, 10.4 mmol) to give
(Hexane/AcOEt 20:1, Rf = 0.26) 3.188 g (95%) of the title
compound as a white crystalline solid, Mp 57−58 °C. 1H NMR (400
MHz, CDCl3) δ 7.87−7.82 (m, 2H), 7.66−7.57 (m, 4H), 7.48−7.42
(m, 2H), 7.38−7.33 (m, 1H), 3.75 (s, 4H), 2.94−2.87 (m, 2H),
2.58−2.54 (m, 2H), 1.04 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 158.3, 141.0, 140.5, 135.3, 129.0, 128.8, 127.3, 127.2, 126.9, 126.8,
72.1, 31.7, 29.3, 26.7, 21.9. HRMS (APCI) m/z: [M + H]+ Calcd for
C21H24BO2 319.1864; Found 319.1862.
55.3, 26.6. HRMS (APCI) m/z: [M + H]+ Calcd for C18H18O2
267.1380; Found 267.1381.
1,2-Di-p-tolylcyclobut-1-ene (2b). GP2 starting from 4-bromoto-
luene (0.5130 g, 3 mmol), 2-(2-(4-methylphenyl)cyclobutenyl)-5,5-
dimethyl-1,3,2-dioxaborinane (0.9221 g, 3.6 mmol), Pd(OAc)2
(0.0405 g, 0.18 mmol), PPh3 (0.1680 g, 0.36 mmol), THF (15
mL), and K3PO4 (4.5 mL) gave (Hexane, Rf = 0.55) 0.6304 g (89%)
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1
of the title compound as a white crystalline solid, Mp 54−56 °C. H
NMR (300 MHz, CDCl3) δ 7.44−7.41 (m, 4H), 7.14−7.11 (m, 4H),
2.74 (s, 3H), 2.35 (s, 4H). 13C{1H} NMR (126 MHz, CDCl3) δ
137.8, 137.2, 133.7, 129.0, 126.0, 26.8, 21.4. HRMS (APCI) m/z: [M
+ H]+ Calcd for C18H18235.1481; Found 235.1482.
mmol), Pd(OAc)2 (0.0157 g, 0.07 mmol), RuPhos (0.0709 g, 0.14
mmol), 4-biphenylboronic acid (1.80 g, 9.1 mmol), and toluene (35
mL) gave (Hexane/AcOEt 2:1, Rf = 0.29) 2.28 g (91%) of diethyl 2-
(4-biphenyl)-cyclobuten-1-yl phosphate as a pale brown solid, Mp
50−52 °C. 1H NMR (300 MHz, CDCl3) δ 7.62−7.54 (m, 4H),
7.50−7.40 (m, 4H), 7.37−7.30 (m, 1H), 4.31−4.18 (m, 4H), 3.00−
2.92 (m, 2H), 2.47−2.43 (m, 2H), 1.40 (td, J = 7.1, 1.2 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 140.8, 139.6, 135.4 (d, J = 7.8
4-(2-(4-Methoxyphenyl)cyclobut-1-en-1-yl)benzonitrile (2d).
GP1 starting from diethyl 2-bromocyclobuten-1-yl phosphate (5)
(2.85 g, 10 mmol), Pd(OAc)2 (0.0228 g, 0.1 mmol), RuPhos (0.1014
g, 0.2 mmol), and 4-cyanophenylboronic acid (1.76 g, 13 mmol),
K3PO4(15 mL, 2 M, 30 mmol) in toluene (40 mL). Column
chromatography (Hexane/AcOEt 2:1, Rf = 0.22) gave 2.70 g (88%)
Hz), 131.8, 128.8, 127.3, 127.0, 126.9, 126.5, 120.7 (d, J = 11.0 Hz),
64.6 (d, J = 6.0 Hz), 31.3 (d, J = 2.6 Hz), 20.9, 16.2 (d, J = 6.6 Hz).
HRMS (APCI) m/z: [M + H]+ Calcd for C20H23O4P 359.1407;
Found 359.1403. The isolated diethyl 2-(4-biphenyl)-cyclobuten-1-yl
phosphate (1.7869 g, 5 mmol), Pd(OAc)2 (0.0449 g, 0.2 mmol),
DPEPhos (0.1077 g, 0.2 mmol), AlCl3 (10 mL, 0.5 M, 5 mmol), and
4-biphenylzinc chloride (14.1 mL, 0.46 M, 6.5 mmol) gave (Hexane/
DCM 9:1, Rf = 0.40) 1.14 g (64%) of the title compound as a pale
green crystalline solid, Mp 180−182 °C. 1H NMR (300 MHz,
CDCl3) δ 7.67−7.56 (m, 12 H), 7.48−7.41 (m, 4 H), 7.38−7.31 (m,
2 H), 2.84 (s, 4 H). 13C{1H} NMR (75 MHz, CDCl3) δ 140.7, 140.2,
138.6, 135.2, 128.8, 127.3, 127.0, 126.9, 126.5, 26.9. HRMS (APCI)
m/z: [M + H]+ Calcd for C28H22 359.1794; Found 359.1798.
4-(2-(p-Tolyl)cyclobut-1-en-1-yl)benzonitrile (2h). GP2 starting
from 1-(2-bromocyclobut-1-en-1-yl)-4-methylbenzene26 (0.4460 g, 2
mmol), 4-cyanophenylboronic acid (0.3527 g, 2.4 mmol), Pd(OAc)2
(0.0157 g, 0.07 mmol), RuPhos (0.0652 g, 0.14 mmol), THF (8 mL),
and K3PO4 (3 mL) gave (Hexane/AcOEt 9:1, Rf = 0.44) 0.4618 g
(91%) of the title compound as a yellow crystalline solid, Mp 106−
108 °C. 1H NMR (500 MHz, CDCl3) δ 7.58 (s, 4H), 7.38 (d, J = 8.1
Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 2.79 (dd, J = 14.4, 4.5 Hz, 4H),
2.37 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 143.4, 140.3,
138.4, 135.6, 132.7, 132.1, 129.2, 126.3, 126.2, 119.1, 110.1, 27.5,
26.5, 21.4. HRMS (APCI) m/z: [M + H]+ Calcd for C18H15N
246.1277; Found 246.1281.
1
of the pure product as a yellow oil. H NMR (300 MHz, CDCl3) δ
7.62−7.56 (m, 2H), 7.47−7.43 (m, 2H), 4.30−4.17 (m, 4H), 3.00−
2.94 (m, 2H), 2.46−2.41 (m, 2H), 1.39 (td, J = 7.2, 1.2 Hz, 6 H).
13C{1H} NMR (101 MHz, CDCl3) δ 139.4 (d, J = 7.3 Hz), 136.9,
132.2, 126.3, 119.3 (d, J = 10.9 Hz), 119.1, 109.8, 64.8 (d, J = 6.0
Hz), 31.5 (d, J = 2.6 Hz), 20.8, 16.1 (d, J = 6.6 Hz). HRMS (APCI)
m/z: [M + H]+ Calcd for C15H19NO4P 308.1046; Found 308.1048.
Then the isolated diethyl 2-(4-cyanophenyl)-cyclobuten-1-yl phos-
phate (1.5365 g, 5 mmol), PdCl2DPEPhos (0.0715 g, 0.2 mmol),
AlCl3 (10 mL, 0.5 M, 5 mmol), and 4-methoxyphenylzinc chloride
(14.1 mL, 0.46 M, 6.5 mmol) gave (Hexane/AcOEt 6:1, Rf = 0.32)
1.0834 g (83%) of the title compound as a light yellow crystalline
solid, Mp 106−107 °C. 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 4H),
7.43 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 2.81−
2.73 (m, 4H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.6, 143.0,
140.5, 134.5, 132.2, 128.3, 127.6, 126.2, 119.2, 113.9, 110.0, 55.3,
27.4, 26.3. HRMS (APCI) m/z: [M + H]+ Calcd for C18H15NO
262.1226; Found 262.1227.
1-(2-(4-Methoxyphenyl)cyclobut-1-en-1-yl)-3-(trifluoromethyl)-
benzene (2e). GP1 starting from diethyl 2-(4-methoxyphenyl)-
cyclobuten-1-yl phosphate23 (0.9524 g, 3.05 mmol), Pd(OAc)2
(0.0273 g, 0.12 mmol), DPEPhos (0.0678 g, 0.12 mmol), and 3-
trifluoromethylphenylzinc chloride (9.6 mL, 0.38 M, 3.7 mmol) gave
(Hexane/AcOEt 20:1, Rf = 0.55) 0.7752 g (84%) of the title
4-(2-(4-(Trifluoromethyl)phenyl)cyclobut-1-en-1-yl)-1,1′-biphen-
yl (2i). GP1 starting from diethyl 2-(4-biphenyl)-cyclobuten-1-yl
phosphate (0.3771 g, 1.1 mmol; see the preparation of cyclobutene 2g
for the synthesis of 2-(4-biphenyl)-cyclobuten-1-yl phosphate),
Pd(OAc)2 (0.0094 g, 0.04 mmol), DPEPhos (0.0226 g, 0.04
mmol), AlCl3 (2.2 mL, 0.5 M, 1.1 mmol), and 4-(trifluoromethyl)-
phenylzinc chloride (3.51 mL, 0.38 M, 1.3 mmol) gave (Hexane/
DCM 9:1, Rf = 0.40) 0.0726 g (20%) of the title compound as a white
crystalline solid, Mp 84−85 °C. 1H NMR (400 MHz, CDCl3) δ
7.67−7.56 (m, 10H), 7.48−7.43 (m, 2H), 7.39−7.33 (m, 1H), 2.87−
2.81 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 141.1, 140.7,
140.6, 139.4, 137.3, 134.5, 128.8, 129.0 (q, J = 32.4 Hz), 127.5, 127.1,
126.9, 126.6, 126.2, 125.3 (q, J = 3.8 Hz), 124.2 (q, J = 272.8 Hz),
27.1, 26.8. 19F NMR (282 MHz, CDCl3) δ −62.98. HRMS (APCI)
m/z: [M + H]+ Calcd for C23H17F3 351.1355; Found 351.1359.
Phenyl(2-phenylcyclobut-1-en-1-yl)methanone (2j). n-BuLi (1.35
mL, 2.59 M, 3.5 mmol) was added dropwise to a stirred solution of
(2-bromocyclobut-1-en-1-yl)benzene (0.7245 g, 3.5 mmol) in THF
(15 mL) cooled to −78 °C in a dry ice/acetone bath. The reaction
was stirred for 30 min; then benzaldehyde (0.4409 g, 4.15 mmol) was
added via syringe. The reaction was warmed to 23 °C and stirred for
an additional 1 h, then quenched with MeOH, diluted with ether, and
washed with water and brine. The organic layer was dried over
MgSO4, and the solvent was evaporated. Column chromatography
(Hexane/AcOEt 9:1, Rf = 0.34) afforded 0.6051 g (86%) of pure
product as a light yellow crystalline solid. Phenyl(2-phenylcyclobut-1-
en-1-yl)methanol, TEMPO (0.0468 g, 0.30 mmol), and H5IO6
(0.7522, 3.3 mmol) were stirred in DCM (6 mL) for 4 h at 23 °C.
The reaction mixture was diluted with ether and washed with 1 M
HCl, water, and brine. The organic layer was dried over MgSO4, and
the solvents were evaporated. Column chromatography (Hexane/
AcOEt 20:1, Rf = 0.39) afforded 0.3023 g (86%) of pure product as a
1
compound as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.73−
7.67 (m, 2H), 7.49−7.38 (m, 4H), 6.90−6.84 (m, 2H), 3.83 (s, 3H),
2.77 (s, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 140.6,
137.2, 135.0, 130.8 (q, J = 31.9 Hz), 129.1, 128.9, 128.6, 127.6, 126.9,
124.2 (q, J = 272.1 Hz), 123.7 (q, J = 3.9 Hz), 122.8 (d, J = 3.8 Hz),
114.0, 113.9, 55.5, 27.2, 26.7. 19F NMR (282 MHz, CDCl3) δ −63.19.
HRMS (APCI) m/z: [M + H]+ Calcd for C18H15F3O 305.1145;
Found 305.1148.
1,2-Di(naphthalen-1-yl)cyclobut-1-ene (2f). GP1 starting from
diethyl 2-bromocyclobuten-1-yl phosphate (5) (0.285 g, 1 mmol),
Pd(OAc)2 (0.0024 g, 0.01 mmol), RuPhos (0.0105 g, 0.02 mmol), 1-
naphthylboronic acid (0.2245 g, 1.3 mmol), K3PO4 (1.5 mL, 2 M, 3
mmol), and toluene (4 mL) gave (Hexane/AcOEt 2:1, Rf = 0.28)
0.2930 g (88%) of diethyl (2-(naphthalen-1-yl)cyclobut-1-en-1-yl)
1
phosphate as a lightly brown oil. H NMR (400 MHz, CDCl3) δ
8.39−8.35 (m, 1H), 7.86−7.82 (m, 1H), 7.77−7.73 (m, 1H), 7.57−
7.42 (m, 3H), 4.23−4.10 (m, 4H), 3.05−3.01 (m,2H), 2.73 (dd, J =
6.8, 2.0 Hz, 2H), 1.32 (td, J = 7.1, 1.1 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 135.4 (d, J = 7.3 Hz), 133.8, 130.7, 130.6, 128.4,
127.8, 125.8, 125.8, 125.8, 125.7, 125.3, 120.3 (d, J = 11.0 Hz), 64.6
(d, J = 6.1 Hz), 31.0 (d, J = 2.6 Hz), 24.0, 16.1 (d, J = 6.7 Hz). HRMS
(APCI) m/z: [M + H]+ Calcd for C18H21O4P 333.1250; Found
333.1250. The isolated diethyl 2-(1-naphthyl)-cyclobuten-1-yl
phosphate (0.1837 g, 0.55 mmol), Pd(OAc)2 (0.0049 g, 0.02
mmol), DPEPhos (0.0118 g, 0.02 mmol), and 1-naphthylzinc chloride
(2.16 mL, 0.33 M, 0.72 mmol) gave (Hexane, Rf = 0.23) 0.1472 g
1
(88%) of the title compound as a yellow viscous oil. H NMR (500
MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.5 Hz, 2H),
7.78 (d, J = 8.1 Hz, 2H), 7.49−7.46 (m, 2H), 7.40 (t, J = 7.7 Hz, 4H),
7.21 (t, J = 7.7 Hz, 2H), 3.28 (s, 4H). 13C{1H} NMR (126 MHz,
CDCl3) δ 140.8, 134.3, 133.7, 130.5, 128.2, 127.8, 125.9, 125.8, 125.6,
125.6, 125.3, 30.6. HRMS (APCI) m/z: [M + H]+ Calcd for C24H18
307.1481; Found 307.1484.
1
yellow crystalline solid Mp 40−42. H NMR (400 MHz, CDCl3) δ
7.93−7.89 (m, 2H), 7.78−7.73 (m, 2H), 7.55−7.49 (m, 1H), 7.45−
7.39 (m, 2H), 7.36−7.29 (m, 3H), 3.01−2.97 (m, 2H), 2.93−2.90
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 190.3, 155.5, 138.3,
135.8, 133.6, 132.3, 130.0, 128.8, 128.4, 128.3, 128.2, 28.2, 27.5.
1,2-Di([1,1′-biphenyl]-4-yl)cyclobut-1-ene (2g). GP1 starting
from diethyl 2-bromocyclobuten-1-yl phosphate (5) (1.99 g, 7
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HRMS (APCI) m/z: [M + H]+ Calcd for C17H14O 235.1117; Found
235.1120.
MHz, CDCl3) δ 8.39−8.35 (m, 1H), 7.86−7.82 (m, 4H), 7.77−7.73
(m, 1H), 7.57−7.42 (m, 3H), 4.23−4.10 (m, 4H), 3.05−3.01
(m,2H), 2.73 (dd, J = 6.8, 2.0 Hz, 2H), 1.32 (td, J = 7.1, 1.1 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 136.2 (d, J = 7.4 Hz), 136.1,
131.6, 131.1, 130.6, 128.1, 127.5, 127.5, 127.3, 126.12, 126.08, 125.3,
125.2, 125.1, 125.03, 124.98, 124.9, 121.0 (d, J = 10.7 Hz) 77.5, 77.2,
76.8, 64.8 (d, J = 6.1 Hz), 31.6, 31.6, 24.7, 16.3 (d, J = 6.8 Hz).
HRMS (APCI) m/z: [M + H]+ Calcd for C24H23O4P 407.1407;
Found 407.1409. Then the isolated diethyl (2-(pyren-1-yl)cyclobut-1-
en-1-yl) phosphate (1.219 g, 3 mmol), Pd(OAc)2 (0.0282 g, 0.12
mmol), DPEPhos (0.0678 g, 0.12 mmol), AlCl3 (6 mL, 0.5 M, 3
mmol), and 4-cyanophenylzinc chloride (15.0 mL, 0.26 M, 3.9 mmol)
gave (Hexane/DCM 2:1, Rf = 0.25) 0.642 g (61%) of the title
1,2-Bis(4-cyanophenyl)cyclobut-1-ene (2m). GP1 starting from
diethyl 2-bromocyclobuten-1-yl phosphate (5) (2.85 g, 10 mmol),
Pd(OAc)2 (0.0228 g, 0.1 mmol), RuPhos (0.1014 g, 0.2 mmol), 4-
cyanophenylboronic acid (1.76 g, 13 mmol), K3PO4 (15 mL, 2 M, 30
mmol), and toluene (40 mL) gave (Hexane/AcOEt 2:1, Rf = 0.22)
2.70 g (88%) of diethyl 2-(4-cyanophenyl)-cyclobuten-1-yl phosphate
1
as a yellow oil. H NMR (300 MHz, CDCl3) δ 7.62−7.56 (m, 2H),
7.47−7.43 (m, 2H), 4.30−4.17 (m, 4H), 3.00−2.94 (m, 2H), 2.46−
2.41 (m, 2H), 1.39 (td, J = 7.2, 1.2 Hz, 6 H). 13C{1H} NMR (101
MHz, CDCl3) δ 139.4 (d, J = 7.3 Hz), 136.9, 132.2, 126.3, 119.3 (d, J
= 10.9 Hz), 119.1, 109.8, 64.8 (d, J = 6.0 Hz), 31.5 (d, J = 2.6 Hz),
20.8, 16.1 (d, J = 6.6 Hz). HRMS (APCI) m/z: [M + H]+ Calcd for
C15H18NO4P 308.1046; Found 308.1048. Isolated diethyl 2-(4-
cyanophenyl)-cyclobuten-1-yl phosphate (1.050 g, 3.4 mmol),
Pd(OAc)2 (0.0359 g, 0.14 mmol), DPEPhos (0.0862 g, 0.14
mmol), and 4-cyanophenylzinc chloride gave (Hexane/AcOEt/
CH2Cl2 3:1:1, Rf = 0.22) 0.7945 g (91%) of the title compound as
1
compound as a yellow crystalline solid, Mp 167−168 °C. H NMR
(400 MHz, CDCl3) δ 8.30−7.94 (m, 9H), 7.42−7.38 (m, 2H), 7.24−
7.20 (m, 2H), 3.12 (dt, J = 58.7, 3.3 Hz, 4H). 13C{1H} NMR (101
MHz, CDCl3) δ 143.6, 139.2, 139.1, 131.9, 131.4, 131.3, 131.1, 130.9,
127.9, 127.8, 127.34, 127.28, 126.3, 126.2, 125.50, 125.48, 125.3,
125.2, 124.9, 124.8, 124.8, 119.1, 110.2, 30.8, 26.5. HRMS (APCI)
m/z: [M + H]+ Calcd for C27H17N 356.1434; Found 356.1438.
1-(2-(4-Methoxyphenyl)cyclobut-1-en-1-yl)pyrene (2r). GP1
starting from diethyl 2-(4-methoxyphenyl)cyclobuten-1-yl phos-
phate26 (0.234 g, 0.75 mmol), PdCl2DPEPhos (0.0215 g, 0.03
mmol), AlCl3 (1.5 mL, 0.5 M, 0.75 mmol), and 1-pyrenylzinc chloride
(2.5 mL, 0.39 M, 0.975 mmol) gave (Hexane/AcOEt 20:1, Rf = 0.42)
0.2485 g (92%) of the title compound as a yellow-green crystalline
1
a yellow crystalline solid, Mp 187−189 °C. H NMR (300 MHz,
CDCl3) δ 7.64−7.62 (m, 4H), 7.55−7.53(m, 4H), 2.84 (s, 4H).
13C{1H} NMR (75 MHz, CDCl3) δ 140.7, 139.3, 132.4, 126.6, 118.7,
111.3, 27.1 HRMS (APCI) m/z: [M + H]+ Calcd for C18H12N2
257.1073; Found 257.1074.
4-(2-([1,1′-Biphenyl]-4-yl)cyclobut-1-en-1-yl)benzonitrile (2n).
GP2 starting from 4-(2-bromocyclobut-1-en-1-yl)-1,1′-biphenyl
(0.8550 g, 3.0 mmol), 4-cyanophenylboronic acid (0.5811 g, 3.9
mmol), Pd(OAc)2 (0.0135 g, 0.06 mmol), RuPhos (0.0559 g, 0.12
mmol), THF, and K3PO4 (4.5 mL, 9.0 mmol) gave (Hexane/AcOEt
9:1, Rf = 0.35) 0.8286 g (90%) of the title compound as a yellow solid,
1
solid, Mp 57−58 °C. H NMR (300 MHz, CDCl3) δ 8.32−7.95 (m,
9H), 7.21−7.15 (m, 2H), 6.73−6.67 (m, 2H), 3.74 (s, 3H), 3.18−
3.14 (m, 2H), 3.05−3.02 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3)
δ 159.0, 140.6, 135.9, 132.9, 131.4, 131.1, 130.5, 128.4, 127.5, 127.41,
127.38, 127.3, 127.2, 126.0, 125.9, 125.8, 125.0, 124.93, 124.90, 124.8,
55.1, 30.3, 26.7. HRMS (APCI) m/z: [M + H]+ Calcd for C27H20O
361.1587; Found 361.1586.
1
Mp 140−141 °C. H NMR (400 MHz, CDCl3) δ 7.64−7.54 (m,
10H), 7.48−7.43 (m, 2H), 7.39−7.34 (m, 1H), 2.88−2.79 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 142.9, 141.0, 140.4, 140.2,
136.8, 134.3, 132.2, 128.9, 127.6, 127.2, 126.9, 126.7, 126.4, 119.1,
110.4, 27.4, 26.6. HRMS (APCI) m/z: [M + H]+ Calcd for C23H17N
308.1434; Found 308.1436.
3-(2-(p-Tolyl)cyclobut-1-en-1-yl)thiophene (2s). GP 2 starting
from 1-bromo-2-(4-methylphenyl)cyclobutene26 (0.446 g, 2.0 mmol),
Pd(OAc)2 (0.0045 g, 0.02 mmol), RuPhos (0.0215 g, 0.04 mmol),
and 3-thienylboronic acid (0.3071 g, 2.6 mmol) in THF (8 mL) gave
(Hexane, Rf = 0.5) 0.4250 g (95%) of the title product as a colorless
crystalline solid, Mp 45−47 °C. 1H NMR (500 MHz, CDCl3) δ
7.48−7.46 (m, 2H), 7.38−7.30 (m, 3H), 7.21−7.20 (m, 2H), 2.82−
2.80 (m, 4H), 2.41 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 138.3,
137.3, 137.2, 133.6, 133.0, 129.2, 126.3, 126.1, 125.5, 121.7, 27.3,
27.2, 21.5. HRMS (APCI) m/z: [M + H]+ Calcd for C15H14S:
227.0889; Found 227.0887.
One-Step General Procedure (GP3) for the Halogenation of
1,2-Disubstituted Cyclobutenes. A flame-dried round-bottom
flask was charged with the 1,2-disubstituted cyclobutene 2 (1.0
equiv). Dry solvent was added (12 mL/mmol), and then the reaction
mixture was cooled to 0 °C. A 0.5 M bromine solution in CCl4 was
added dropwise, and the reaction mixture was stirred for 30 min at 0
°C. Then, the reaction mixture was diluted with diethyl ether and
washed with saturated NaHCO3 solution, water, and brine. The
organic phase was dried over MgSO4, and the pure products were
isolated by means of solvent evaporation under reduced pressure.
Two-Step General Procedure (GP4) for the Halogenation of
1,2-Disubstituted Cyclobutenes. A flame-dried round-bottom
flask was charged with the 1,2-disubstituted cyclobutene 2 (1.0
equiv) before dry solvent was added (12 mL/mmol), and the reaction
mixture was cooled to 0 °C. Next, a 0.5 M bromine solution in CCl4
was added dropwise and the reaction mixture was stirred for 30 min at
0 °C. Then, the reaction mixture was diluted with diethyl ether and
washed with saturated NaHCO3 solution, water, and brine. The
organic phase was dried over MgSO4, and the crude products were
isolated by means of solvent evaporation under reduced pressure. The
crude product following the bromination was then diluted with DCM
(4 mL/mmol). Silica gel (2 g/1 g of starting material) was added, and
the mixture was stirred for the indicated period of time. After
completion, the mixture was filtered through Celite and then washed
with DCM and AcOEt. The products were isolated by means of
column chromatography on silica gel.
4-(2-(3-(Trifluoromethyl)phenyl)cyclobut-1-en-1-yl)-1,1′-biphen-
yl (2o). GP2 starting from 4-(2-bromocyclobut-1-en-1-yl)-1,1′-
biphenyl (0.8145 g, 2.9 mmol), Pd(OAc)2 (0.0134 g, 0.06 mmol),
RuPhos (0.0559 g, 0.12 mmol), 3-trifluoromethylphenylboronic acid
(0.7101 g, 3.8 mmol), and K3PO4 (4.5 mL, 2 M, 9 mmol) gave
(Hexane/DCM 9:1, Rf = 0.38) 0.560 g (54%) of the title compound
1
as a yellow solid, Mp 100−101 °C. H NMR (400 MHz, CDCl3) δ
7.78−7.74 (m, 2H), 7.66−7.54 (m, 6H), 7.53−7.42 (m, 4H), 7.39−
7.34 (m, 1H), 2.84 (s, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ
140.7, 140.6, 140.4, 137.2, 136.8, 134.5, 129.1 (q, J = 1.0 Hz), 128.8,
128.8, 127.4, 127.1, 126.9, 126.5, 123.9 (q, J = 3.8 Hz), 122.8 (q, J =
3.8 Hz), 27.0, 26.8. 19F NMR (282 MHz, CDCl3) δ −63.32. HRMS
(APCI) m/z: [M + H]+ Calcd for C23H17F3 351.1355; Found
351.1361.
1-(2-([1,1′-Biphenyl]-4-yl)cyclobut-1-en-1-yl)pyrene (2p). GP2
starting from 2-(2-([1,1′-biphenyl]-4-yl)cyclobut-1-en-1-yl)-5,5-di-
methyl-1,3,2-dioxaborinane (0.7637 g, 2.4 mmol), 1-bromopyrene
(0.5620 g, 2 mmol), Pd(OAc)2 (0.0224 g, 0.1 mmol), PPh3(0.0524 g,
0.2 mmol), K3PO4 (3 mL, 6 mmol), and THF (8 mL) gave (Hexane/
DCM 9:1, Rf = 0.36) 0.6080 g (63%) of the title compound as a
yellow crystalline solid, Mp 106−108 °C. 1H NMR (400 MHz,
CDCl3) δ 8.30−7.98 (m, 9H), 7.56−7.27 (m, 9H), 3.21−3.17 (m,
2H), 3.11−3.07 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.7,
140.0, 139.0, 134.3, 132.7, 131.4, 131.1, 130.7, 128.8, 127.62, 127.55,
127.4, 127.2, 126.9, 126.7, 126.5, 126.0, 125.9, 125.8, 125.2, 125.1,
125.0, 124.9, 124.8, 30.6, 26.8. HRMS (APCI) m/z: [M + H]+ Calcd
for C32H22 407.1794; Found 407.1797.
4-(2-(Pyren-1-yl)cyclobut-1-en-1-yl)benzonitrile (2q). GP1 start-
ing from diethyl 2-bromocyclobuten-1-yl phosphate (5) (2.85 g, 10
mmol), Pd(OAc)2 (0.0224 g, 0.1 mmol), RuPhos (0.0938 g, 0.2
mmol), 1-pyrenylboronic acid (3.69 g, 15 mmol), K3PO4 (15 mL, 2
M, 30 mmol), and toluene (40 mL) gave (Hexane/AcOEt 2:1, Rf =
0.30) 3.471 g (85%) of diethyl (2-(pyren-1-yl)cyclobut-1-en-1-yl)
1
phosphate as a lightly brown solid, Mp 58−59 °C. H NMR (400
5826
https://doi.org/10.1021/acs.joc.1c00261
J. Org. Chem. 2021, 86, 5820−5831

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4,4′-(3-Bromocyclobut-1-ene-1,2-diyl)bis(methoxybenzene)
(3a). GP3 starting from 2a (0.7980 g, 3.0 mmol), bromine (0.5 M in
CCl4, 6.0 mL, 3.0 mmol), and CCl4 (35 mL) gave by the solvent
evaporation 1.025 g (99%) of the title compound as a white
crystalline solid, Mp 57−59 °C. 1H NMR (300 MHz, CDCl3) δ
7.53−7.47 (m, 4H), 6.93−6.86 (m, 4H), 5.31−5.29 (m, 1H), 3.84 (s,
3H), 3.83 (s, 3H), 3.36 (dd, J = 13.4, 4.2 Hz, 1H), 3.20 (dd, J = 13.4,
1.5 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ160.0, 159.5, 137.1,
136.3, 128.2, 128.2, 126.9, 125.6, 114.0, 113.9, 55.3, 55.3, 43.9, 40.5.
HRMS (APCI) m/z: [M + H]+ Calcd for C18H17BrO2 345.0485;
Found 345.0485.
g, 4 h) gave by the solvents evaporation 0.109 g (100%) of the title
compound as a yellow crystalline solid, Mp 127−129 °C. H NMR
1
(300 MHz, CDCl3) δ 7.79−7.55 (m, 12H), 7.52−7.43 (m, 4H),
7.43−7.32 (m, 2H), 5.39 (dd, J = 4.2, 1.5 Hz, 1H), 3.47 (dd, J = 13.7,
4.2 Hz, 1H), 3.31 (dd, J = 13.6, 1.5 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3) δ 141.8, 141.2, 140.5, 140.3, 139.3, 138.4, 132.9, 131.6,
128.9, 128.8, 127.7, 127.5, 127.4, 127.3, 127.2, 127.2, 127.0, 126.9,
42.9, 40.6. HRMS (APCI) m/z: [M + H]+ Calcd for C28H21Br
437.0899; Found 437.0900.
4-(3-Bromo-2-(p-tolyl)cyclobut-1-en-1-yl)benzonitrile (3h). GP4
starting from 2h (0.1016 g, 0.41 mmol), bromine (0.5 M in CCl4,
0.83 mL, 0.41 mmol), CCl4 (10 mL), DCM (4 mL), and silica gel
(0.2050 g, 6 h) gave by the solvents evaporation 0.1227 g (92%) of
the title compound as an orange solid, Mp 78−79 °C. 1H NMR (500
MHz, CDCl3) δ 7.61 (s, 4H), 7.43 (d, J = 8.1 Hz, 2H), 7.27−7.19 (m,
2H), 5.29 (dd, J = 4.3, 1.4 Hz, 1H), 3.40 (dd, J = 13.5, 4.3 Hz, 1H),
3.22 (dd, J = 13.5, 1.4 Hz, 1H), 2.39 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 143.8, 139.6, 138.3, 135.3, 132.4, 129.5, 129.1, 127.1,
127.0, 118.7, 111.9, 41.9, 40.2, 21.1. HRMS (APCI) m/z: [M + H]+
Calcd for C18H14BrN 324.0382; Found 324.0381.
4,4′-(3-Bromocyclobut-1-ene-1,2-diyl)bis(methylbenzene) (3b).
GP3 starting from 2b (0.1140 g, 0.5 mmol), bromine (0.5 M in
CCl4, 1.0 mL, 0.5 mmol), and CCl4 (6 mL) gave (Hexane, Rf = 0.52)
0.1068 g (71%) of the title compound as an off-white solid, Mp 62−
1
63 °C. H NMR (300 MHz, CDCl3) δ 7.50−7.42 (m, 4H), 7.21−
7.13 (m, 4H), 5.37−5.35 (m, 1H), 3.37 (dd, J = 13.5, 4.2 Hz, 1H),
3.22 (dd, J = 13.5, 1.5 Hz, 1H), 2.43 (s, 3H), 2.42 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 139.1, 138.8, 138.4, 137.8, 131.4, 130.0,
129.2, 126.9, 126.8, 43.4, 40.5, 21.5. HRMS (APCI) m/z: [M + H]+
Calcd for C18H17Br 313.0586; Found 313.0587.
4-(4-Bromo-2-(4-(trifluoromethyl)phenyl)cyclobut-1-en-1-yl)-
1,1′-biphenyl (3i). GP4 starting from 2i (0.0406 g, 0.12 mmol),
bromine (0.5 M in CCl4, 0.23 mL, 0.12 mmol), CCl4 (2 mL), DCM
(3 mL), and silica gel (0.0850 g, 6 h) gave (Hexane/DCM 9:1, Rf =
0.56) 0.0338 g (68%) of the title compound as a off-white solid, Mp
1-(3-Bromo-2-(4-methoxyphenyl)cyclobut-1-en-1-yl)-4-methyl-
benzene (3c). GP3 starting from 2c (0.0464 g, 0.19 mmol), bromine
(0.5 M in CCl4, 0.38 mL, 0.19 mmol), and CCl4 (3 mL) gave by the
solvents evaporation 0.058 g (95%) of the title compound as a white
1
solid, Mp 81−83 °C. H NMR (300 MHz, CDCl3) δ 7.54−7.52 (m,
1
134−135 °C. H NMR (400 MHz, CDCl3) δ 7.71−7.59 (m, 10H),
2H), 7.44−7.41 (m, 2H), 7.16−7.14 (m, 2H), 6.93−6.90 (m, 2H),
5.30−5.29 (m, 1H), 3.84 (s, 3H), 3.35 (dd, J = 13.2, 4.5 Hz, 1H),
3.22 (d, J = 13.2 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 159.7, 139.0, 131.5, 129.3, 128.4, 127.6, 126.7, 125.6, 114.0,
55.3, 43.6, 40.5, 21.5. HRMS (APCI) m/z: [M + H]+ Calcd for
C18H17BrO 329.0536; Found 329.0536.
7.51−7.42 (m, 2H), 7.42−7.34 (m, 1H), 5.35 (dd, J = 4.3, 1.4 Hz,
1H), 3.45 (dd, J = 13.6, 4.3 Hz, 1H), 3.29 (dd, J = 13.6, 1.4 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 142.0, 142.0, 140.51, 137.5,
137.1, 131.1, 130.7 (q, J = 32.7 Hz), 129.0, 127.9, 127.6, 127.5, 127.2,
125.8, 125.7, 124.1 (d, J = 272.4 Hz), 121.4, 42.1, 40.7. 19F NMR
(282 MHz, CDCl3) δ −63.23. HRMS (APCI) m/z: [M + H]+ Calcd
for C23H15BrF3 428.0382; Found 428.0380.
4-(3-Bromo-2-(4-methoxyphenyl)cyclobut-1-en-1-yl)benzonitrile
(3d). GP3 starting from 2d (0.0653 g, 0.25 mmol), bromine (0.5 M in
CCl4, 0.50 mL, 0.25 mmol), and CCl4 (3 mL) gave (Hexane/AcOEt
9:1, Rf = 0.11) 0.0742 g (87%) of the title compound as a light yellow
(3-Bromo-2-phenylcyclobut-1-en-1-yl)(phenyl)methanone (3j).
GP4 starting from 2j (0.0404 g, 0.17 mmol), bromine (0.5 M in
CCl4, 0.34 mL, 0.17 mmol), CCl4 (2 mL), DCM (2 mL), and silica
gel (0.0800 g, 16 h) gave (Hexane/AcOEt 20:1, Rf = 0.50) 0.0210 g
1
crystalline solid, Mp 170−172 °C. H NMR (600 MHz, CDCl3) δ
7.63−7.58 (m, 4H), 7.50−7.47 (m, 2H), 6.95−6.92 (m, 2H), 5.27
(dd, J = 4.3, 1.3 Hz, 1H), 3.85 (s, 3H), 3.38 (dd, J = 13.4, 4.3 Hz,
1H), 3.21 (dd, J = 13.3, 1.2 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 160.4, 143.4, 138.4, 134.0, 132.3, 128.6, 127.0, 124.5, 118.7,
114.2, 111.7, 55.4, 42.0, 40.1. HRMS (APCI) m/z: [M + H]+ Calcd
for C18H14BrNO 340.0332; Found 340.0332.
1
(39%) of the title compound as an orange solid, Mp 53−54 °C. H
NMR (300 MHz, CDCl3) δ 7.94−7.86 (m, 2H), 7.72−7.66 (m, 2H),
7.59−7.53 (m, 1H), 7.46−7.40 (m, 2H), 7.38−7.30 (m, 3H), 5.30−
5.25 (m, 1H), 3.62 (dd, J = 14.0, 4.3 Hz, 1H), 3.31 (dd, J = 14.0, 1.4
Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 190.4, 152.2, 137.0,
134.3, 133.2, 130.5, 128.9, 128.8, 128.7, 128.4, 41.8, 40.3. HRMS
(APCI) m/z: [M + H]+ Calcd for C17H13BrO 313.0223; Found
313.0224.
1-(3-Bromo-2-(4-methoxyphenyl)cyclobut-1-en-1-yl)-3-
(trifluoromethyl)benzene(3e). GP3 starting from 2e (0.1435 g, 0.47
mmol), bromine (0.5 M in CCl4, 0.95 mL, 0.47 mmol), and CCl4 (6
mL) gave (Hexane/AcOEt 9:1, Rf = 0.35) 0.1308 g (73%) of the title
3-Bromo-2-(4-methoxyphenyl)cyclobut-1-en-1-yl Diethyl Phos-
phate (3k). GP4 starting from 2k (0.1426 g, 0.46 mmol), bromine
(0.5 M in CCl4, 0.91 mL, 0.46 mmol), CCl4 (4 mL), DCM (4 mL),
and silica gel (0.3021 g, 16 h) gave (Hexane/AcOEt 2:1, Rf = 0.20)
0.1115 g (63%) of the title compound as an orange oil. 1H NMR (400
MHz, CDCl3) δ 7.50−7.45 (m, 2H), 6.93−6.89 (m, 2H), 4.90 (dt, J =
4.1, 1.2 Hz, 1H), 4.29−4.19 (m, 4H), 3.82 (s, 3H), 3.68−3.58 (m,
1H), 3.28−3.20 (m, 1H), 1.39 (tdd, J = 7.2, 2.0, 1.1 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 135.0 (d, J = 7.3 Hz),
127.8, 123.1 (d, J = 11.0 Hz), 122.9 (d, J = 0.7 Hz), 114.0, 65.0 (dd, J
= 6.1, 2.2 Hz), 55.3, 44.9 (d, J = 2.4 Hz), 39.1, 16.1 (dd, J = 6.5, 2.1
Hz). HRMS (APCI) m/z: [M + H]+ Calcd for C15H20BrO5P
391.0305; Found 391.0308.
1-(2,4-Dibromocyclobut-1-en-1-yl)-4-methylbenzene (3l). GP4
starting from 2l (0.0156 g, 0.07 mmol), bromine (0.5 M in CCl4,
0.14 mL, 0.07 mmol), CCl4 (4 mL), DCM (1 mL), and silica gel
(0.049 g, 4.5 h) gave (Hexane, Rf = 0.43) 0.0177 g (85%) of the title
compound as a white crystalline solid, Mp 53−55 °C. 1H NMR (500
MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H),
5.25 (dd, J = 4.2, 1.4 Hz, 1H), 3.56 (dd, J = 13.9, 4.1 Hz, 1H), 3.27
(d, J = 13.8 Hz, 1H), 2.42 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 145.0, 139.4, 129.3, 127.5, 126.1, 110.3, 47.7, 41.5, 21.6.
HRMS (APCI) m/z: [M + H]+ Calcd for C11H10Br2 302.9202; Found
302.9204.
1
compound as a off-white solid, Mp 68−70 °C. H NMR (400 MHz,
CDCl3) δ 7.77−7.68 (m, 2H), 7.60−7.52 (m, 1H), 7.55−7.47 (m,
2H), 7.48−7.43 (m, 1H), 6.97−6.89 (m, 2H), 5.28 (dd, J = 4.3, 1.4
Hz, 1H), 3.85 (s, 3H), 3.41 (dd, J = 13.4, 4.3 Hz, 1H), 3.24 (dd, J =
13.4, 1.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 141.3,
135.0, 134.6, 131.1 (d, J = 32.3 Hz), 129.7, 129.6, 129.0, 128.4, 125.1
(q, J = 3.9 Hz), 124.7, 123.3 (d, J = 3.8 Hz), 114.1, 77.3, 76.7, 55.3,
42.4, 40.3. 19F NMR (282 MHz, CDCl3) δ −63.38. HRMS (APCI)
m/z: [M + H]+ Calcd for C18H14BrF3O 383.0253; Found 383.0256.
1,1′-(3-Bromocyclobut-1-ene-1,2-diyl)dinaphthalene (3f). GP3
starting from 2f (0.0666 g, 0.29 mmol), bromine (0.5 M in CCl4,
0.58 mL, 0.29 mmol) in CCl4 (4 mL) gave by the solvents
evaporation 0.0790 g (94%) of the title compound as a pale orange
solid, Mp 63−64 °C. 1H NMR (300 MHz, CDCl3) δ 7.93−7.76 (m, 6
H), 7.56−7.31 (m, 6 H), 7.22−7.08 (m, 2H), 5.74−5.72 (m, 1H),
3.83 (dd, J = 13.5, 1.7 Hz, 1H), 3.75 (dd, J = 13.6, 3.9 Hz, 1H).
13C{1H} NMR (75 MHz, CDCl3) δ 141.7, 140.7, 133.6, 131.7, 130.7,
130.6, 130.6, 129.5, 129.1, 128.4, 128.3, 127.2, 126.7, 126.2, 126.1,
125.9, 125.2, 125.6, 125.2, 125.1, 45.2, 43.9. HRMS (APCI) m/z: [M
+ H]+ Calcd for C24H17Br 385.0586; Found 385.0583.
4,4″-(3-Bromocyclobut-1-ene-1,2-diyl)di-1,1′-biphenyl (3g). GP4
starting from 2g (0.0896 g, 0.25 mmol), bromine (0.5 M in CCl4, 0.5
mL, 0.25 mmol), CCl4 (10 mL), DCM (4 mL), and silica gel (0.2050
5827
https://doi.org/10.1021/acs.joc.1c00261
J. Org. Chem. 2021, 86, 5820−5831

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
One-Pot Three-Step General Procedure (GP5) for the
Preparation of Cyclobutenones. A flame-dried reaction flask
was charged with the disubstituted cyclobutene 2 (1.0 equiv), and an
inert atmosphere was established. Dry CCl4 (8 mL/mmol) was added,
and the reaction mixture was cooled in an ice bath to 0 °C. Bromine
solution in CCl4 (0.5 M, 1.0 equiv) was added dropwise, and then the
reaction mixture was stirred at 0 °C. After completion (indicated by
the loss of color due to the presence of bromine in the solution), the
reaction was quenched with saturated Na2S2O5, diluted with ether,
and then washed with NaHCO3, water, and brine. The organic phase
was dried over MgSO4 and evaporated, and the crude product was
used without further purification. The crude brominated cyclobutene
was dissolved in DMSO (60 mL/mmol), which was followed by the
addition of AgNO3 (1.0 equiv) and water (10 mL/mmol). The
reaction was stirred at 23 °C for 1 h. The reaction mixture was diluted
with ether and then washed four times with water to remove all the
DMSO. The organic layer was washed with brine, dried over MgSO4,
and evaporated. The crude product was used without further
purification. A flame-dried reaction flask was charged with the crude
product of the substitution reaction, TEMPO (0.20 equiv). An inert
atmosphere was established, and dry DCM (4 mL/mmol) was added.
Then H5IO6 (1.1 equiv) was added by quickly removing the septum,
followed by an argon purge. The reaction was stirred at 23 °C for 4 h
or overnight, as appropriate. The reaction mixture was diluted with
ether and then washed with 1 M HCl, water, and brine. The organic
layer was dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by means of column
chromatography on silica gel.
One-Pot Four-Step General Procedure (GP6) for the
Preparation of Cyclobutenones. A flame-dried reaction flask
was charged with the disubstituted cyclobutene 2 (1.0 equiv), and an
inert atmosphere was established. Dry CCl4 (8 mL/mmol) was added
before the reaction mixture was cooled in an ice bath to 0 °C.
Bromine solution in CCl4 (0.5 M, 1.0 equiv) was added dropwise, and
then the reaction mixture was stirred at 0 °C for the indicated period
of time. After completion (indicated by the loss of color due to the
presence of bromine in the solution), the reaction was quenched with
saturated Na2S2O5, diluted with ether, and then washed with
NaHCO3, water, and brine. The organic phase was dried over
MgSO4 and evaporated, and the crude product was used without
further purification. The crude product following the bromination was
diluted with DCM (4 mL/mmol). Silica gel (approximately 2 g/1 g of
starting material) was added, and the mixture was stirred for the
indicated period of time. After completion, the mixture was filtered
through Celite and then washed with DCM and EtOAc. Next, the
solvent was evaporated and the crude product was used without
further purification. The isolated bromocyclobutene was dissolved in
DMSO (60 mL/mmol), which was followed by the addition of
AgNO3 (1.0 equiv) and water (10 mL/mmol). The reaction was then
stirred at 23 °C for the indicated period of time. The reaction mixture
was diluted with ether and washed four times with water to remove all
the DMSO. The organic layer was washed with brine, dried over
MgSO4, and evaporated. The crude product was used without further
purification. A flame-dried reaction flask was charged with the crude
product of the substitution reaction, TEMPO (0.20 equiv). An inert
atmosphere was established and dry DCM (4 mL/mmol) was added.
Then H5IO6 (1.1 equiv) was added by quickly removing the septum,
followed by an argon purge. The reaction was stirred at 23 °C for 4 h
or overnight, as appropriate. The reaction mixture was diluted with
ether and then washed with 1 M HCl, water, and brine. The organic
layer was dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by means of column
chromatography on silica gel.
was dried over MgSO4, and the solvents were removed under reduced
pressure. Column chromatography (silica gel) afforded the title
compound.
2,3-Bis(4-methoxyphenyl)cyclobut-2-en-1-one (4a). GP5 starting
from 2a (0.0373 g, 0.14 mmol), bromine (0.27 mL, 0.5 M), and CCl4
(2 mL). The substitution reaction was performed using DMSO (3
mL), water (0.5 mL), AgNO3 (0.0240 g, 0.14 mmol), and the
oxidation with TEMPO (0.0022 g, 0.014 mmol), H5IO6 (0.0355 g,
0.156 mmol), and DCM (1 mL) gave (Hexane/AcOEt 6:1, Rf = 0.42)
0.0333 g (83%) of the title compound. Alternatively, the title
compound was prepared according to GP7 starting from 8a (0.0390 g,
0.14 mmol), TEMPO (0.0044 g, 0.028 mmol), and H5IO6 (0.0385 g,
0.17 mmol), DCM (0.5 mL) gave 0.0333 g (85%) of the title
1
compound as a yellow-orange crystalline solid, Mp 89−90 °C. H
NMR (300 MHz, CDCl3) δ 7.73−7.70 (m, 2 H), 7.65−7.62 (m, 2
H), 6.98−6.92 (m, 4 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 3.56 (s, 2 H).
13C{1H} NMR (126 MHz, CDCl3) δ 188.1, 162.1, 159.8, 159.7,
139.2, 130.9, 129.0, 125.5, 122.8, 114.3, 114.1, 55.5, 55.3, 49.3.
HRMS (APCI) m/z: [M + H]+ Calcd for C18H16O3 281.1172; Found
281.1176.
2-(4-Methoxyphenyl)-3-(p-tolyl)cyclobut-2-en-1-one (4b). GP5
starting from 2c (0.1116 g, 0.44 mmol), bromine (0.89 mL, 0.5
M), and CCl4 (4 mL). The substitution reaction was performed using
DMSO (6 mL), water (1 mL), AgNO3 (0.0745 g, 0.44 mmol), and
the oxidation with TEMPO (0.0067 g, 0.04 mmol), H5IO6 (0.0980 g,
0.43 mmol), DCM (2 mL) gave (Hexane/AcOEt 6:1, Rf = 0.44)
0.0948 g (82%) of the title compound. Alternatively, the title
compound was prepared according to GP7 starting from 8b (0.1040
g, 0.39 mmol), TEMPO (0.0122 g, 0.078 mmol), H5IO6 (0.1067 g,
0.47 mmol), DCM (1 mL) to give 0.0940 g (94%) of the title
1
compound as a yellow solid, Mp 88−89 °C. H NMR (500 MHz,
CDCl3) δ 7.71−7.68 (m, 4H), 7.31 (d, J = 7.0 Hz, 2H), 6.97 (d, J =
8.9 Hz, 2H), 3.89 (s, 3H), 3.63 (s, 2H), 2.47 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 188.4, 160.0, 159.8, 142.0, 140.4, 130.0, 129.5,
129.0, 128.8, 122.6, 114.0, 55.3, 49.4, 21.7, in accordance with the
literature.19
2,3-Di([1,1′-biphenyl]-4-yl)cyclobut-2-en-1-one (4c). GP6 starting
from 2g (0.1216 g, 0.34 mmol), bromine (0.68 mL, 0.5 M, 0.34
mmol), CCl4 (4 mL), DCM (2 mL), and silica gel (18 h). The
substitution reaction was performed using DMSO (6 mL), water (1
mL), and AgNO3 (0.1241 g, 0.74 mmol), and the oxidation with
TEMPO (0.0112 g, 0.07 mmol), H5IO6 (0.0930 g, 0.40 mmol), DCM
(2 mL) gave (Hexane/AcOEt 20:1, Rf = 0.39) 0.0975 g (77%) of the
title compound. Alternatively, the title compound was prepared
according to GP7 starting from 3g (0.0248 g, 0.07 mmol), TEMPO
(0.0022 g, 0.014 mmol), H5IO6 (0.0191 g, 0.084 mmol), DCM (0.5
mL) to give (Hexane/AcOEt 20:1, Rf = 0.39) 0.0164 g (70%) of the
title compound as a yellow solid, Mp 161−162 °C, Mp 161−162 °C.
1H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 6.6 Hz, 2H), 7.83 (d, J =
8.2 Hz, 2H), 7.72 (d, J = 6.6 Hz, 2H), 7.69−7.62 (m, 7H), 7.52−7.44
(m, 4H), 7.44−7.35 (m, 3H), 3.71 (s, 2H). 13C{1H} NMR (126
MHz, CDCl3) δ 188.0, 161.1, 144.3, 141.6, 141.2, 140.5, 139.8, 131.4,
129.6, 129.0, 128.9, 128.7, 128.3, 128.1, 127.7, 127.5, 127.4, 127.13,
127.05, 49.8. HRMS (APCI) m/z: [M + H]+ Calcd for C28H20O
373.1587; Found 373.1592.
4-(2-(4-Methoxyphenyl)-3-oxocyclobut-1-en-1-yl)benzonitrile
(4d). GP5 starting from 2d (0.1384 g, 0.53 mmol), bromine (1.06
mL, 0.53 mmol), and CCl4 (4 mL). The substitution reaction was
performed using DMSO (30 mL), water (5 mL), AgNO3 (0.0901 g,
0.53 mmol), and the oxidation with TEMPO (0.0180 g, 0.11 mmol),
H5IO6 (0.1340 g, 0.58 mmol), and DCM (2 mL) gave (Hexane/
AcOEt 6:1, Rf = 0.25) 0.1060 g (74%) of title compound as a yellow
1
solid, Mp 118 °C. H NMR (300 MHz, CDCl3) δ 7.85−7.80 (m,
General Procedure (GP7) for the Oxidation of the Alcohols
8a−8c. Dichloromethane (2 mL/mmol) was added to a mixture of
the alcohols 8a−8c, TEMPO (20 mol %), and periodic acid (1.2
equiv). The resultant mixture was stirred at 23 °C for 3 h. Then, the
crude reaction mixture was diluted with diethyl ether (10 mL/mmol)
before the organic layer was extracted with 1 M HCl (5 mL/mmol),
water (10 mL/mmol), and brine (10 mL/mmol). The organic phase
2H), 7.76−7.71 (m, 2H), 7.66−7.61 (m, 2H), 6.97−6.91 (m, 2H),
3.85 (s, 3 H), 3.65 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ
187.7, 160.6, 156.3, 144.4, 136.8, 132.6, 129.2, 128.9, 121.5, 118.2,
114.4, 114.0, 55.4, 49.8. HRMS (APCI) m/z: [M + H]+ Calcd for
C18H13NO2 276.1019; Found 276.1022.
4-(2-([1,1′-Biphenyl]-4-yl)-3-oxocyclobut-1-en-1-yl)benzonitrile
(4e). GP6 starting from 2n (0.1485 g, 0.48 mmol), bromine (0.97 mL,
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0.48 mmol), CCl4 (4 mL), DCM (4 mL), and silica gel (0.310 g, 18
h). The substitution reaction was performed using DMSO (30 mL),
water (5 mL), AgNO3 (0.0815 g, 0.48 mmol). The substitution
reaction was stirred for 4 h, and the oxidation with TEMPO (0.0144
g, 0.09 mmol), H5IO6 (0.1288 g, 0.54 mmol), DCM (2 mL) gave
(Hexane/AcOEt 6:1, Rf = 0.29) 0.0720 g (46%) of the title
compound as an orange solid, Mp 165−166 °C. 1H NMR (400 MHz,
CDCl3) δ 7.89−7.85 (m, 2 H), 7.79−7.72 (m, 4 H), 7.69−7.60 (m, 4
H), 7.50−7.45 (m, 2H), 7.42−7.36 (m, 1H), 3.72 (s, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ 187.3, 158.3, 144.4, 142.5, 140.1, 136.5,
132.6, 129.1, 128.9, 128.1, 127.9, 127.7, 127.6, 127.0, 118.1, 114.3,
50.0. HRMS (APCI) m/z: [M + H]+ Calcd for C23H15NO 322.1226;
Found 322.1229.
124.9, 124.7, 124.5, 123.3, 118.0, 114.5, 49.5. HRMS (APCI) m/z:
[M + H]+ Calcd for C27H15NO 370.1226; Found 370.1229.
2-(4-Methoxyphenyl)-3-(pyren-1-yl)cyclobut-2-en-1-one (4j).
GP5 starting from 2r (0.0326 g, 0.09 mmol), bromine (0.18 mL,
0.09 mmol), and CCl4 (2 mL). The substitution reaction was
performed using DMSO (6 mL), water (1 mL), AgNO3 (0.0161 g,
0.02 mmol), and the oxidation with TEMPO (0.0031 g, 0.02 mmol),
H5IO6 (0.0230 g, 0.10 mmol), DCM (0.5 mL) gave (Hexane/DCM
1:2, Rf = 0.19) 0.0184 g (54%) of the title compound as an orange
1
solid, Mp 182−183 °C. H NMR (400 MHz, CDCl3) δ 8.29−8.01
(m, 9H), 7.53−7.49 (m, 2H), 6.77−6.73 (m, 2H), 4.01 (s, 2H), 3.77
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 188.6, 160.0, 159.2,
143.0, 132.8, 131.2, 130.7, 129.3, 129.0, 128.6, 128.4, 127.7, 127.3,
126.5, 126.22, 126.18, 126.0, 125.5, 124.9, 124.7, 124.5, 122.7, 113.7,
55.2, 53.1. HRMS (APCI) m/z: [M + H]+ Calcd for C27H18O2
375.1380; Found 375.1389.
2-(4-Methoxyphenyl)-3-(3-(trifluoromethyl)phenyl)cyclobut-2-
en-1-one (4f). GP5 starting from 2e (0.1480 g, 0.49 mmol), bromine
(0.98 mL, 0.49 mmol), and CCl4 (4 mL). The substitution reaction
was performed using DMSO (30 mL), water (5 mL), AgNO3 (0.0833
g, 0.49 mmol), and the oxidation with TEMPO (0.0154 g, 0.1 mmol),
H5IO6 (0.1241 g, 0.54 mmol), DCM (2 mL) gave (Hexane/AcOEt
6:1, Rf = 0.42) 0.0989 g (64%) of the title compound as a yellow solid,
4,4′-(1,2-Dibromocyclobutane-1,2-diyl)dibenzonitrile (7b). GP3
starting from 2m (0.1282 g, 0.5 mmol), bromine (0.5 M in CCl4, 1.0
mL, 0.5 mmol), and CCl4 (10 mL) gave by solvent evaporation 0.204
g (98%) of the title compound as a pale yellow crystalline solid, Mp
1
1
168−169 °C. H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz,
Mp 48−50 °C. H NMR (400 MHz, CDCl3) δ 7.97−7.93 (m, 2H),
4H), 7.69 (d, J = 8.3 Hz, 4H), 3.74−3.64 (m, 2H), 2.83−2.67 (m,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.8, 147.4, 132.6, 132.2,
128.7, 128.4, 118.6, 118.3, 112.8, 112.5, 71.9, 34.3, 34.0. HRMS
(APCI) m/z: [M + H]+ Calcd for C18H12Br2N2 416.9420; Found
416.9419.
7.73−7.69 (m, 1H), 7.67−7.63 (m, 2H), 6.96−6.92 (m, 2 H), 3.84 (s,
3 H), 3.65 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 187.9, 160.4,
157.4, 142.9, 133.5, 131.6, 131.5 (q, J = 2.0 Hz), 131.3, 129.5, 129.1,
127.5 (q, J = 3.0 Hz), 125.3 (q, J = 4.0 Hz), 123.6 (q, J = 273.7 Hz)
121.7, 114.3, 55.3, 49.7. 19F NMR (282 MHz, CDCl3) δ −63.40.
HRMS (APCI) m/z: [M + H]+ Calcd for C18H13F3O2 319.0940;
Found 319.0944.
General Procedure (GP8) for the Synthesis of Alcohols 8a−
8c by Silver Nitrate-Free Hydrolysis. A solution of the
cyclobutenes 3a, 3c, and 3g (1.0 equiv) was dissolved in MeCN (8
mL/mmol) and water (2 mL/mmol), and the resultant mixture was
stirred at 23 °C for the period of time indicated in Table 3. The
solvents were evaporated under reduced pressure, and the products
were isolated by means of column chromatography (silica gel) or
solvent evaporation.
2-([1,1′-Biphenyl]-4-yl)-3-(3-(trifluoromethyl)phenyl)cyclobut-2-
en-1-one (4g). GP6 starting from 2o (0.1712 g, 0.49 mmol), bromine
(0.98 mL, 0.49 mmol), CCl4 (4 mL), DCM (4 mL), and silica gel
(0.3560 g, 18 h). The substitution reaction was performed using
DMSO (30 mL), water (5 mL), AgNO3 (0.0830g, 0.49 mmol), and
the reaction was stirred for 4 h. The oxidation with TEMPO (0.0154
g, 0.1 mmol), H5IO6 (0.1240 g, 0.54 mmol) gave (Hexane/AcOEt
6:1, Rf = 0.38) 0.0630 g (35%) of the title compound as an orange
2,3-Bis(4-methoxyphenyl)cyclobut-2-en-1-ol (8a). GP8 starting
from cyclobutene 3a (0.0488 g, 0.14 mmol), MeCN (2 mL), and
H2O (0.5 mL) gave by the solvents evaporation 0.0387 g (98%) of
1
solid, Mp 87−88 °C. H NMR (300 MHz, CDCl3) δ 8.04−7.98 (m,
1
the title compound as a yellow oil. H NMR (300 MHz, CDCl3) δ
2H), 7.80−7.57 (m, 8H), 7.51−7.43 (m, 2 H), 7.42−7.35 (m, 1H),
3.72 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 187.5, 159.3,
142.9, 142.2, 140.2, 133.3, 131.8, 131.7, 131.7, 131.4, 129.5, 128.9,
128.0, 127.9, 127.8, 127.8, 127.5, 127.1, 125.5 (q, J = 3.7 Hz), 50.0.
19F NMR (282 MHz, CDCl3): δ = −63.48. HRMS (APCI) m/z: [M
+ H]+ Calcd for C23H15F3O 365.1148; Found 365.1153.
7.56−7.48 (m, 4H), 6.91−6.85 (m, 4H), 4.99 (d, J = 4.2 Hz, 1H),
3.83 (d, J = 0.9 Hz, 6H), 3.05 (dd, J = 12.9, 4.2 Hz, 1H), 2.64 (dd, J =
12.9, 1.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 159.6, 159.1,
138.7, 135.8, 128.1, 128.0, 127.8, 126.4, 114.0, 113.8, 67.1, 55.3, 39.7.
HRMS (APCI) m/z: [M + H]+ Calcd for C18H18O3 283.1329; Found
283.1327.
3-([1,1′-Biphenyl]-4-yl)-2-(pyren-1-yl)cyclobut-2-en-1-one (4h).
GP5 starting from 2p (0.2102 g, 0.51 mmol), bromine (1.02 mL,
0.51 mmol), and CCl4 (4 mL). The substitution reaction was
performed using DMSO (30 mL), water (5 mL), AgNO3 (0.0752 g,
0.51 mmol), and the oxidation with TEMPO (0.0140 g, 0.09 mmol),
H5IO6 (0.1204 g, 0.54 mmol), DCM (2 mL) gave (Hexane/DCM
1:1, Rf = 0.20) 0.1320 g (64%, after recrystallization from MeCN/
toluene 20:3) of the title compound as an orange needle crystals, Mp
2-(4-Methoxyphenyl)-3-(p-tolyl)cyclobut-2-en-1-ol (8b). GP8
starting from 3c (0.1116 g, 0.34 mmol), MeCN (4 mL), and H2O
(1 mL) gave (Hexane/AcOEt 6:1, Rf = 0.18) 0.080 g (88%) of the
1
title compound as a yellow solid, Mp 112−115 °C. H NMR (300
MHz, CDCl3) δ 7.57−7.54 (m, 2H), 7.46−7.43 (m, 2H),7.16−7.13
(m, 2H), 6.90−6.88 (m, 2H), 5.00−4.99 (m, 1H), 3.83 (s, 3H), 3.06
(dd, J = 12.9, 3.9 Hz, 1H), 2.65 (dd, J = 12.3, 0.9 Hz, 1H), 2.36 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.2, 140.0, 138.3, 136.2,
132.3, 129.1, 128.1, 126.5, 114.0, 67.1, 55.2, 39.8, 21.4. HRMS
(APCI) m/z: [M + H]+ Calcd for C18H18O2 267.1380; Found
267.1382.
1
216−217 °C. H NMR (400 MHz, CDCl3) δ 8.26−8.10 (m, 5H),
8.06 (s, 2H), 8.05−8.01 (m, 1H), 7.61−7.55 (m, 6H), 7.45−7.40 (m,
2H), 7.39−7.34 (m, 1H), 3.93 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 188.2, 163.6, 144.5, 142.2, 139.7, 131.8, 131.2, 130.9, 130.4,
129.0, 128.3, 128.24, 128.17, 128.15, 127.4, 127.3, 127.1, 126.7, 126.2,
125.7, 125.6, 125.3, 125.0, 124.9, 124.7, 124.5, 49.2. HRMS (APCI)
m/z: [M + H]+ Calcd for C32H20O 421.1587; Found 421.1589.
4-(3-Oxo-2-(pyren-1-yl)cyclobut-1-en-1-yl)benzonitrile (4i). GP5
starting from 2q (0.1720 g, 0.48 mmol), bromine (0.97 mL, 0.48
mmol), and CCl4 (4 mL). The substitution reaction was performed
using DMSO (30 mL), water (5 mL), AgNO3 (0.0820 g, 0.48 mmol),
and the oxidation with TEMPO (0.0174 g, 0.11 mmol), H5IO6
(0.1211 g, 0.53 mmol), DCM (2 mL) gave (Hexane/DCM 1:1, Rf =
0.15) 0.0955 g (54%) of the title compound as an orange solid, Mp
2,3-Di(4-biphenyl)cyclobut-2-en-1-ol (8c). GP8 Starting from 3c.
(0.0851 g, 0.19 mmol), MeCN (1 mL), and H2O (0.25 mL) gave
(Hexane/AcOEt 6:1, Rf = 0.25) 0.0314 g (43%) of the title
1
compound as a yellow crystalline solid, Mp 103−105 °C. H NMR
(300 MHz, CDCl3) δ 7.75−7.59 (m, 12 H), 7.49−7.46 (m, 4 H),
7.39−7.37 (m, 2 H), 5.12−5.11 (m, 1H), 3.16 (dd, J = 13.5, 4.8 Hz,
1H), 2.77 (dd, J = 13.8, 1.2 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 141.3, 141.1, 140.71, 140.69, 140.6, 138.1, 133.8, 132.5,
128.9, 128.8, 127.6, 127.5, 127.4, 127.3, 127.3, 127.1, 127.0, 67.2,
40.0. HRMS (APCI) [M + H]+ calcd for C28H22O: 375.1743; Found
375.1750.
1
220−221 °C. H NMR (500 MHz, CDCl3) δ 8.28−8.03 (m, 8H),
4,4″,4⁗,4‴‴-(Oxybis(cyclobut-1-ene-3,1,2-triyl))tetra-1,1′-bi-
phenyl (9). Prepared by reaction of 3g (0.0868 g, 0.2 mmol), water (1
M in DMSO, 0.10 mL, 0.1 mmol), and AgNO3 (0.0340 g, 0.2 mmol)
in DMSO (3 mL) at 23 °C. After 2 h, the reaction mixture was diluted
7.93−7.89 (m, 1H), 7.60−7.55 (m, 4H), 3.92 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 187.6, 160.9, 145.6, 135.8, 132.4, 132.2, 131.2,
130.8, 129.8, 128.64, 128.59, 128.2, 127.3, 126.4, 126.4, 126.0, 125.9,
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with diethyl ether (30 mL) and the organic phase was washed with
water (4 × 20 mL). The solvent evaporation gave 0.0851 g (100%) of
the title compound as a gray solid in quantitative yield, Mp 82−84 °C.
1H NMR (400 MHz, CDCl3) δ 7.71−7.60 (m, 24H), 7.50−7.44 (t, J
= 7.5 Hz, 8H), 7.41−7.36 (m, 4H), 6.10 (dd, J = 3.9, 1.4 Hz, 2H),
3.36 (dd, J = 13.5, 3.9 Hz, 2H), 3.02 (dd, J = 13.6, 1.4 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ = 142.2, 141.3, 140.5, 140.4,
140.2, 134.0, 132.3, 131.4, 128.9, 128.8, 127.8, 127.6, 127.4, 127.4,
127.24, 127.2, 127.0, 75.9, 36.8. Attempts to confirm the tentative
structure of ether 9 by HRMS (APCI) failed, and the desired
molecular peak was not found.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00261.
■
sı
X-ray crystallography data for compound 4h, NMR
spectra data (PDF)
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Accession Codes
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CCDC 2043220 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
̌
Tomás Tobrman − Department of Organic Chemistry,
University of Chemistry and Technology, Prague 166 28,
Czech Republic; orcid.org/0000-0003-3473-9199;
Email: tomas.tobrman@vscht.cz
Authors
Tereza Edlová − Department of Organic Chemistry, University
of Chemistry and Technology, Prague 166 28, Czech
Republic
̌
Hana Dvoráková − Laboratory of NMR Spectroscopy,
University of Chemistry and Technology, Prague 166 28,
Czech Republic
Václav Eigner − Department of Solid State Chemistry,
University of Chemistry and Technology, Prague 166 28,
Czech Republic
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Harrity, J. P. A. Investigation of Alkyne Regioselectivity in the Ni-
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21, 2701−2704. (b) Lam, T. Y.; Wang, Y.-P.; Danheiser, R. L.
Benzannulation via the Reaction of Ynamides and Vinylketenes.
Application to the Synthesis of Highly Substituted Indoles. J. Org.
Chem. 2013, 78, 9396−9414. (c) Auvinet, A.-L.; Harrity, J. P. A. A
Nickel-Catalyzed Benzannulation Approach to Aromatic Boronic
Esters. Angew. Chem., Int. Ed. 2011, 50, 2769−2772.
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J. W.; Farrell, W.; Helal, C. J.; Reese, M. R.; Sach, N. W.; Lee, J. C.;
Hall, D. G. High-Throughput Ligand Screening Enables the
Enantioselective Conjugate Borylation of Cyclobutenones to Access
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00261
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported from the Grant Agency of the Czech
Republic (Grant No 18-12150S).
■
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