The First Formation of (1Z)-1-Alkylidene-1H-isobenzofuranium Amides and 1H-Inden-1-ones: Acid-Promoted 5-exo Cyclization and Hydration/Aldol Condensation Reactions of o-Ethynylbenzophenones

Article abstract of DOI:10.1002/ejoc.201301599

(1Z)-1-(2,2-Dimethylpropylidene)-1H-isobenzofuranium bis(trifluoromethylsulfonyl)amides were synthesized through 5-exo cyclization reactions between sterically encumbered o-alkynylbenzophenones and bis(trifluoromethylsulfonyl)imide (Tf₂NH). It

Full text of DOI:10.1002/ejoc.201301599

FULL PAPER
DOI: 10.1002/ejoc.201301599
The First Formation of (1Z)-1-Alkylidene-1H-isobenzofuranium Amides and
1H-Inden-1-ones: Acid-Promoted 5-exo Cyclization and Hydration/Aldol
Condensation Reactions of o-Ethynylbenzophenones
Noriyoshi Nagahora,*[a] Tatsuya Wasano,[a] Kazuhiro Nozaki,[a] Tamaki Ogawa,[a]
Shuhei Nishijima,[a] Daiki Motomatsu,[a] Kosei Shioji,[a] and Kentaro Okuma*[a]
Keywords: Alkynes / Oxygen heterocycles / Cyclization / Protonation / Hydration
(1Z)-1-(2,2-Dimethylpropylidene)-1H-isobenzofuranium bis-
(trifluoromethylsulfonyl)amides were synthesized through 5-
exo cyclization reactions between sterically encumbered o-
bered o-alkynylbenzophenones with Tf2NH at ambient tem-
perature resulted in acid-promoted hydration and sequential
intramolecular aldol condensation reactions to afford 3-aryl-
alkynylbenzophenones and bis(trifluoromethylsulfonyl)imide 1H-inden-1-one derivatives in good yields. The proposed re-
(Tf2NH). It was confirmed that the five-membered-ring iso-
benzofuranium amide isomerized to give the corresponding
benzopyrylium amide, the six-membered-ring framework
compound, in quantitative yield. Treatment of less encum-
action mechanism was strongly supported by the reaction be-
haviour of 4-chloro- and 5-methoxy-2-ethynylbenzophenone
derivatives as substrates with Tf2NH, leading to the forma-
tion of the corresponding 3-aryl-1H-inden-1-ones.
inden-1-ones through hydration/aldol condensation reac-
tions of o-ethynylbenzophenones.
Introduction
Electrophilic cyclization reactions of o-alkynylphenyl
carbonyl compounds have attracted much attention as
powerful tools for the syntheses of oxygen-containing het-
erocycles.[1] Lewis-acid-induced electrophilic cyclization of
o-alkynyl-substituted benzene derivatives such as benzalde-
hyde,[2] acetophenone,[3] benzamide,[4] benzoic acid,[5]
methyl benzoate,[6] and benzophenone[7] has been investi-
gated,[8] and it was demonstrated that these synthetic meth-
odologies are one of the most useful methods affording
access to heterocycles. Swager’s group demonstrated that 6-
endo-dig cyclization of o-alkynylbenzophenones with the
aid of electrophiles such as TfOH and HBF4 is an effective
strategy for formation of benzo[c]pyrylium salts.[7a] In that
report, however, it was also revealed that the reaction could
not work well in the case of a substrate bearing an n-butyl
group at the alkynyl terminus, with no evidence of forma-
tion of the corresponding benzo[c]pyrylium salt being ob-
tained.[7a] Certain challenges, such as protonation-induced
electrophilic cyclization reactions of ethynylbenzophenones,
therefore still remain. Here we would like to describe the
formation of new (1Z)-1-alkylidene-1H-isobenzofuranium
salts through Brønsted-acid-promoted 5-exo cyclization re-
actions, as well as the unprecedented formation of 1H-
Results and Discussion
The synthetic route to ethynylbenzophenone substrates
4a–d is shown in Scheme 1. Treatment of commercially
available 2-iodobenzoic acid with thionyl chloride at 70 °C
for 5 h, followed by Friedel–Crafts reactions with 1,3,5-tri-
isopropylbenzene, mesitylene, or benzene in the presence of
aluminum chloride, afforded 2-iodo-2Ј,4Ј,6Ј-triisoprop-
ylbenzophenone (1), 2-iodo-2Ј,4Ј,6Ј-trimethylbenzophen-
one (2) or 2-iodobenzophenone (3) in yields of 43%, 64%,
or 78%, respectively.
Sonogashira cross-coupling between 1 and p-tolylacetyl-
ene in the presence of [PdCl2(PPh3)2], copper iodide, and
diisopropylamine gave ethynylbenzophenone 4a in 63%
yield. Similarly, cross-coupling between 1–3 and 3,3-di-
methylbut-1-yne afforded 4b–d in quantitative, 68%, or
51% yields, respectively.
We focused on protonation/intramolecular cyclization re-
actions between ethynylbenzophenones 4a–d and bis(tri-
fluoromethylsulfonyl)imide (Tf2NH) as a Brønsted acid, be-
cause Tf2NH is known to work as a better protonation rea-
gent toward alkynyl species.[9] Intramolecular cyclization
between 4a and Tf2NH in dichloromethane at room tem-
perature afforded the corresponding benzo[c]pyrylium bis-
(trifluoromethylsulfonyl)amide 5a as the sole product, in
58% isolated yield (Table 1, Entry 1). The solid-state struc-
ture of 5a was determined by X-ray crystallographic analy-
sis [Figure 1(a)].[10] The results are similar to other reported
[a] Department of Chemistry, Faculty of Science, Fukuoka
University,
Jonan-ku, Fukuoka 814-0180, Japan
E-mail: nagahora@fukuoka-u.ac.jp
http://www.sc.fukuoka-u.ac.jp/indexe.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301599.
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and in the ratio of 31:69 (Entry 2).[11] To the best of our
knowledge, this result represents the first formation of a
(1Z)-1-alkylideneisobenzofuranium framework. The ratio
of the 6-endo to 5-exo-cyclized products in this reaction did
not dramatically change when the reaction was carried out
at reflux or 0 °C (Entries 3 and 4). Similarly, the reaction
between 4c, bearing a mesityl group, and Tf2NH was car-
ried out under the same conditions as for 4b to give
benzo[c]pyrylium amide 5c and isobenzofuranium amide 6c
in 91% total yield and in a ratio of 29:71 (Entry 5).
1
The H NMR spectra of 5b and 6b in CD3CN showed
characteristic singlet signals at δ = 8.43 and 7.80 ppm,
respectively, attributable in each case to a hydrogen atom
derived from Tf2NH, as judged by integration of the spec-
trum. The former signal is similar to those of protons at
the 4-position in benzo[c]pyrylium derivatives (e.g.,
8.91 ppm for 5a, 8.41 ppm for 5c), and the latter can be
attributed to a proton of the exo-alkene moiety of 6b.
Moreover, by means of NOESY NMR experiment, cross
Scheme 1. Reactions between 4a–d and Tf2NH. Reagents and con-
ditions: (a) SOCl2, 70 °C, 5 h; (b) 1,3,5-(iPr)3C6H3 (for 1), 1,3,5-
Me3C6H3 (for 2), C6H6 (for 3), AlCl3, reflux; (c) p-tolylacetylene peaks between the protons as shown in Figure 2 were vis-
for 4a, 3,3-dimethylbut-1-yne for 4b–d, PdCl2(PPh3)2, CuI, iPr2NH,
ible. These indicate that 6b has the Z configuration in the
THF, reflux; (d) Tf2NH (1.1 equiv.), CH2Cl2.
exo-alkene unit. In its 13C NMR spectrum, 6b exhibited
characteristic peaks at δ = 196.8 and 149.8 ppm, attribut-
able to CC and CD (Figure 2), respectively. These chemical
shifts are not within the range of CA and CB of benzo[c]-
pyrylium derivatives [e.g.; 185.5 (CA) and 164.4 (CB) ppm
for 5a, 186.7 (CA) and 175.6 (CB) ppm for 5b, 185.2 (CA)
and 175.7 (CB) ppm for 5c].
findings,[7] indicating that protonation-induced 6-endo cycli-
zation of 4a occurs to form the 2,6-diarylbenzo[c]pyrylium
derivative.
Table 1. Reactions between 4a–c and Tf2NH in dichloromethane.
Entry Substrate Conditions
Products
Total yield
Ratio
5+6
5/6
1
2
3
4
5
4a
4b
4b
4b
4c
r.t., 1.5 h
r.t., 2.0 h
0 °C, 2.0 h
reflux, 2.0 h
r.t., 2.0 h
5a
88%
77%
66%
73%
91%
–
5b+6b
5b+6b
5b+6b
5c+6c
31:69
38:62
33:67
29:71
Figure 2. Structures of compounds 5a–c and 6b–c. The arrow
shows the observed enhancement in the NOESY spectrum.
The reaction mechanism is considered to be as follows
(Scheme 2). Protonation of the alkyne moiety of ethynyl-
benzophenone 4 might give carbocation intermediates A
and B, followed by nucleophilic attack by the carbonyl oxy-
gen atom at the cationic carbon in a 6-endo fashion (path a
in Scheme 2) to afford 2,6-disubstituted benzo[c]pyrylium
system 5.[7] In contrast, in the case of nucleophilic attack
by the carbonyl oxygen at the proton-activated alkyne moi-
ety in a 5-exo mode (path b in Scheme 2), the cyclization
reaction would result in the formation of the new (1Z)-1-
alkylidene-1H-isobenzofuranium amide 6. In cases in which
Figure 1. Molecular structures of a) 5a, and b) 7d with thermal
ellipsoid plots (30% probability). All hydrogen atoms are omitted
for clarity.
In contrast, treatment of 4b, featuring a tert-butyl group an alkyl group was present at the ethynyl terminus, as in
on the ethynyl unit, with Tf2NH in dichloromethane at compounds 4b or 4c, more stable cations of type B might
room temperature for 2 h gave not only the expected undergo a 5-exo cyclization process to form furanium salts
benzo[c]pyrylium amide 5b, but also the unexpected prod- 6b or 6c as the major products. The stabilities of the inter-
uct (1Z)-1-(2,2-dimethylpropylidene)-1H-isobenzofuranium mediates are thus an important factor determining the reac-
bis(trifluoromethylsulfonyl)amide 6b, in 77% total yield tion outcomes in the presence of a Brønsted acid.
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Electrophilic Cyclization Reactions
suggests two reaction pathways as follows (Scheme 3).
(1) One reaction proceeds by formal addition of a carbonyl–
phenyl bond to an alkynyl moiety and is a unique aryl mi-
gration reaction (path a in Scheme 3), although it has been
reported that transition-metal-catalyzed cyclizations of o-
alkynyl-substituted benzene derivatives proceeded similarly,
with methoxy, benzyl, silyl, and sulfonyl migrations.[14]
(2) The other reaction consists of stereoselective acid-cata-
lyzed hydration of the alkyne unit in 4d, followed by intra-
molecular aldol condensation of the resulting 1,4-diketone
Scheme 2. Plausible mechanism for the formation of 6-endo- and
5-exo-cyclized products.
equivalent
Scheme 3).
G to give 1H-inden-1-one 7d (path b in
We next synthesized compounds 4e (Scheme 4), pos-
sessing an n-butyl group at the ethynyl terminus, and 4f,
containing a perdeuterated phenyl group. It was confirmed
that the reactions of 4e and 4f with Tf2NH also proceeded
smoothly to afford the corresponding 1H-inden-1-ones 7e
and 7f in 74% and 65% yields, respectively. In order to find
out whether the reaction occurs in an intramolecular or
intermolecular fashion, we performed crossover experi-
ment. On treatment of a 1:1 mixture of 4e and 4f with
Tf2NH under the standard conditions, normal products 7e
and 7f were obtained and no crossover products were de-
tected by GC-MS or NMR spectroscopy (Scheme 5). The
reaction should thus proceed in an intramolecular manner.
We next focused on the properties of (1Z)-1-alkylidene-
1H-isobenzofuranium amide 6b. After an acetic acid solu-
tion of a mixture of 5b and 6b had been stirred at room
temperature for 1 h, the 1H NMR spectrum of the reaction
mixture showed exclusive formation of 5b, indicating that
thermal isomerization from 6b to 5b, a thermally stable
structural isomer, readily occurs under the reaction condi-
tions. We consider that the cyclization reactions of 4b–c
with Tf2NH can be said to be under kinetic control and
that 5b, 5c, 6b and 6c are all likely to equilibrate thermally
under these reaction conditions.
We performed theoretical calculations on model mole-
cules 5bЈ and 6bЈ, in which the counter anions in 5b and 6b
are omitted, in order to understand the electronic structures
of 5b and 6b.[12,13] We found that 5bЈ was thermally more
stable than 6bЈ by 10.8 kcalmol–1, which is consistent with
the experimentally observed relative stabilities of 5b and 6b.
On the other hand, the reaction between 4d, containing
a phenyl group, and Tf2NH in dichloromethane at room
temperature unprecedentedly afforded 2-tert-butyl-3-
phenyl-1H-inden-1-one (7d, Scheme 1) together with a
small amount of 6-endo cyclization product 5d. The 7d/5d
ratio was estimated from the 1H NMR spectrum to be 91:9,
Scheme 4. Syntheses of compounds 7e and 7f.
We next examined the reaction behavior of 4-chloro-2-
and compound 7d was isolated in 78% yield. The molecular ethynylbenzophenone (4g, Scheme 6) and 2-ethynyl-5-meth-
structure of 7d was fully characterized by spectroscopic and oxybenzophenone (4h, Scheme 7, below) in the presence of
X-ray crystallographic analysis [Figure 1(b)].[10] The result a Brønsted acid to ascertain the reaction mechanism. Treat-
Scheme 3. Plausible mechanism for the formation of the 1H-inden-1-one derivative.
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N. Nagahora, K. Okuma et al.
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obtained and the molecular structure was confirmed by X-
ray crystallographic analysis (Figure 3),[10] which shows the
methoxy group of 7h located at the 5-position.
Scheme 5. Crossover reaction with compounds 4e and 4f.
Figure 3. Molecular structures of a) 7h, b) 7i, and c) 7k with ther-
mal ellipsoid plots (50% probability). All hydrogen atoms are omit-
ted for clarity.
ment of chlorobenzoic acid 8 with SOCl2 and a subsequent
Friedel–Crafts reaction gave 4-chloro-2-iodobenzophenone
(9) in moderate yield. Compound 9 was treated with 3,3-
dimethylbut-1-yne in the presence of a palladium catalyst
to afford 4g in 75% yield. Treatment of 4g with 1.1 equiv.
of Tf2NH at room temperature afforded 2-tert-butyl-3-
phenylindenone (7g), with a chlorine atom at the 6-position,
in 75% yield (Scheme 6).
These results thus clearly reveal that the formation of 6-
chloro- and 5-methoxy-1H-inden-1-ones 7g and 7h can be
explained in terms of acid-promoted hydration and subse-
quent intramolecular aldol condensation reactions of 4g
and 4h, respectively (path b in Scheme 3). Furthermore, the
reaction mechanism was also supported by previous re-
search into protonation of phenylacetylene to give vinyl cat-
ionic species[15] and into selective Tf2NH-catalyzed
hydration of internal alkynes.[16] Numerous reports on the
acid-catalyzed hydration of internal alkynes have appeared;
most of them require severe reaction conditions, such as
formic acid at 100 °C for 60 h,[17a] PTSA/EtOH at 78 °C for
60 h,[17b] Tf2NH at 100 °C for 40 h,[16] or HCl/EtOH at re-
flux for 8 h.[17c] In contrast, we found that this transforma-
tion of o-ethynylbenzophenones into 1H-inden-1-ones
could be smoothly carried out under mild conditions.
Next, several substituted benzophenone derivatives
bearing electron-donating or -withdrawing groups were
tested; the results are shown in Scheme 8. Introduction of
dimethyl, chloro, and methoxyphenyl groups was also
achieved through Friedel–Crafts reactions with m-xylene,
Scheme 6. Reaction between 4g and Tf2NH. Reagents and condi-
tions: (a) SOCl2, 80 °C, 2 h; (b) C6H6, AlCl3, reflux, 2 h; (c) 3,3-
dimethylbut-1-yne, PdCl2(PPh3)2, CuI, iPr2NH, THF, reflux, 3 h;
(d) Tf2NH (1.1 equiv.), CH2Cl2, room temperature, 2 h.
Moreover,
Scheme 7) was converted into ethynylbenzophenone 4h by pounds 4i–k in good yields (Scheme 8).
way of bromobenzophenone 11 and iodobenzophenone 12. Reactions between 4i–k and Tf2NH were performed un-
2-bromo-5-methoxybenzoic
acid
(10, chlorobenzene, and anisole, respectively, affording com-
1
The reaction between 4h and Tf2NH gave 2-tert-butyl-5- der standard conditions. In the cases of 4i and 4i, the H
methoxy-3-phenylinden-1-one (7h) in 42% yield together and 13C NMR spectra of the reaction mixtures showed the
with the corresponding hydration product – 1,4-diketone corresponding 1H-inden-1-ones 7i and 7j along with the
7Јh – in 49% yield. Fortunately, single crystals of 7h were starting materials. Chromatographic purification afforded
Scheme 7. Reaction between 4h and Tf2NH. Reagents and conditions: (a) SOCl2, 80 °C, 2 h; (b) C6H6, AlCl3, reflux, 1 h; (c) NaI, CuI,
N,NЈ-dimethylethylenediamine, dioxane, in a sealed tube, 110 °C, 22 h; (d) 3,3-dimethylbut-1-yne, PdCl2(PPh3)2, CuI, iPr2NH, THF, re-
flux, 17 h; (e) Tf2NH (1.1 equiv.), CH2Cl2, room temperature, 2 h.
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Electrophilic Cyclization Reactions
preted as follows: the rate-determining step should be the
hydration of the alkyne moiety of 5k, similarly to the case
of hydration of arylacetylenes.[15] The exclusive conversion
of 5k into 1H-inden-1-one 7k, in contrast to the robust na-
tures of benzo[c]pyrylium amides 5b and 5c, is unprece-
dented and unique.
Scheme 9. Transformation of 5k into 7k.
Scheme 8. Syntheses of compounds 7i, 7j, and 7k. Reagents and
conditions: (a) SOCl2, 70–80 °C, 8–24 h; (b) m-xylene (for 13),
chlorobenzene (for 14), anisole (for 15), AlCl3, 70–80 °C, 2–24 h;
(c) 3,3-dimethylbut-1-yne, PdCl2(PPh3)2, CuI, iPr2NH, THF, 70–
80 °C, 4–17 h; (d) Tf2NH (1.1 equiv.), CH2Cl2, room temperature,
2 h.
3-aryl-2-tert-butyl-1H-inden-1-ones 7i and 7j in 94% and
66% yields, respectively. In the case of 4k, 1H-inden-1-one
7k and 6-endo cyclization product 5k were isolated in 40%
and 47% yields, respectively (Scheme 8). The molecular
structures of 7i and 7k were confirmed by X-ray crystallo-
graphic analysis (Figure 3).[10]
We had found that these substituents of 4i–k were able
to tolerate the formation of 7i–k. It may therefore be as-
sumed that the sterically hindered 2,4,6-triisopropylphenyl
and trimethylphenyl groups at R1 in 4b and 4c prevent the
intramolecular aldol condensation from proceeding,
whereas the less bulky groups C6H5, 2,4-Me2C6H3, 4-
ClC6H4, and 4-CH3OC6H4 allow the intramolecular aldol
condensation, leading to the formation of 1H-inden-1-ones
7d–k in good yields.
Figure 4. Top: First-order kinetic plot of the transformation of 5k
in CDCl3 solution (8.70 molL–1) over a range from 293 to 323 K.
The lines are least-squares fits to the data points over three half-
After a CDCl3 solution of benzo[c]pyrylium amide 5k
had been allowed to stand with exclusion of light, gradual lives. Bottom: Eyring plot of the transformation of 5k over a range
from 293 to 323 K.
formation of 1H-inden-1-one 7k as a single product was
detected by NMR spectroscopy; the half-life of 5k
(8.70 molL–1 in a CDCl3 solution) at 20, 30, 40, and 50 °C
In 1999, Swager and co-worker reported that the reaction
was estimated to be 7.89ϫ104, 4.50ϫ104, 2.85ϫ104, and between 4e and TfOH resulted in no formation of the corre-
2.05ϫ104 s, respectively (Scheme 9). Plots of the logarithm sponding six-membered-ring pyrylium trifluoromethane-
of the concentration of 5k against time (Figure 4) show lin- sulfonate 5e, but at least two compounds were detected, al-
ear decay of 5k through Ͼ90% consumption in CDCl3 though characterization of these was not achieved.[7a] With
solution at 20–50 °C, indicating that the transformation is reactivity of o-ethynylbenzophenones toward a Brønsted
first-order with respect to the concentration of the sub- acid now established, a check on the reaction between 4e
strate, with observed rate constants k = 8.78ϫ10–6, and TfOH at room temperature was also made
1.54ϫ10–5, 2.43ϫ10–5, and 3.38ϫ10–5 s–1 at 20, 30, 40, (Scheme 10). NMR spectra of the reaction mixture revealed
and 50 °C, respectively. The active parameters were esti- the formation of the corresponding 5-exo-cyclized product
mated from the Eyring plot shown in Figure 4 to be ΔH‡ = 6e and 1H-inden-1-one 7e in a ratio of 9:91. On separation
+8.4 kcalmol–1, ΔS‡ = –51 calmol–1 K–1, and ΔG‡ (293 K) of the mixture, compound 7e was isolated in 73% yield. We
= +24 kcalmol–1. The estimated ΔG‡ value is similar to have thus confirmed that the reaction of an o-ethynylbenzo-
those reported for acid-catalyzed hydration processes of ar- phenone possessing an alkyl group at the ethynyl terminus
ylacetylenes in the literature.[15a] The characteristic negative afforded not the 6-endo cyclization product but the 5-exo
value of ΔS‡ observed in the reaction of 5k might be inter- cyclization product and the 1H-inden-1-one derivative.
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reaction mixture was heated at reflux for 3 h and then allowed to
cool to room temperature. After the mixture had been poured into
water, it was extracted with dichloromethane. The organic layer was
washed with saturated sodium hydrogen carbonate solution and
brine. The organic layer was dried with anhydrous magnesium sulf-
ate, filtered, and concentrated to afford a yellow solid. Purification
of the crude product by column chromatography on silica gel (elu-
tion with hexane/dichloromethane 1:2) gave compound 1 (1.51 g,
3.47 mmol, 43%) as yellow crystals, m.p. 129.1–129.9 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.11 (dd, J = 8.0, 1.2 Hz, 1 H, ArH), 7.39
(dd, J = 7.6, 1.6 Hz, 1 H, ArH), 7.31 (ddd, J = 7.6, 7.6, 1.2 Hz, 1
H, ArH), 7.10 (ddd, J = 8.0, 7.6, 1.6 Hz, 1 H, ArH), 7.04 (s, 2 H,
ArH), 2.93 (sept, J = 7.2 Hz, 1 H, CH), 2.67 (sept, J = 6.8 Hz, 2
H, CH), 1.28 (d, J = 7.2 Hz, 6 H, CH3), 1.29 (br, 12 H, CH3) ppm.
13C NMR (101 MHz, CDCl3): δ = 200.49, 150.27, 145.46, 142.50,
140.54, 134.89, 132.89, 132.82, 127.75, 127.74, 121.14, 121.13,
93.15, 34.61, 34.49, 31.34, 24.39, 24.25 ppm. MS (EI): m/z = 434
[M]+. C22H27IO: C 60.83, H 6.27; found C 60.78, H 6.21.
Scheme 10. Reaction between 4e and TfOH.
Conclusions
We have succeeded in the first syntheses of (1Z)-1-(2,2-
dimethylpropylidene)-1H-isobenzofuranium bis(trifluoro-
methylsulfonyl)amides 6b–c through protonation-induced
5-exo cyclization reactions between o-alkynylbenzophen-
ones 4b–c and Tf2NH. In reactions between 4d–k and
Tf2NH, however, stereospecific acid-promoted hydration of
the alkyne units in 4d–k and intramolecular aldol conden-
sation gave 1H-inden-1-ones 7d–k in good yields at room
temperature. In particular, the results with substituted eth-
ynylbenzophenones 4g and 4h as substrates provided strong
evidence in support of the proposed reaction mechanism.
The formation of 1H-inden-1-ones is thus noteworthy in
terms not only of the unique acid-catalyzed hydration and
subsequent intramolecular aldol condensation of o-ethynyl-
benzophenones, but also of the development of a new syn-
thetic method for 2,3-disubstituted 1H-inden-1-one deriva-
tives.
Synthesis of 2-Iodobenzophenone (3): The mixture of 2-iodobenzoic
acid (10.0 g, 40.3 mmol) and thionyl chloride (45 mL) was warmed
to 70 °C for 5 h and then allowed to cool to room temperature.
After removal of thionyl chloride, benzene (40 mL, 451 mmol) and
aluminum chloride (3.27 g, 45.3 mmol) were added to the residue.
The reaction mixture was heated at reflux for 4 h and then allowed
to cool to room temperature. After the mixture had been poured
into water, it was extracted with dichloromethane. The organic
layer was washed with saturated sodium hydrogen carbonate solu-
tion and brine. The organic layer was dried with anhydrous magne-
sium sulfate, filtered, and concentrated to afford compound 3
(9.68 g, 31.4 mmol, 78%) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.92 (dd, J = 7.2, 1.2 Hz, 1 H, ArH), 7.81 (dd, J =
7.2, 1.2 Hz, 2 H, ArH), 7.60 (dd, J = 7.4, 2.6 Hz, 1 H, ArH), 7.48–
7.42 (m, 3 H, ArH), 7.29 (dd, J = 7.6, 1.6 Hz, 1 H, ArH), 7.18
(ddd, J = 7.6, 7.6, 1.6 Hz, 1 H, ArH) ppm.
Synthesis of 2-(p-Tolylethynyl)-2Ј,4Ј,6Ј-triisopropylbenzophenone
(4a): Bis(triphenylphosphine)palladium dichloride (163 mg,
0.232 mmol) was added at room temperature to a degassed solution
of compound 1 (2.04 g, 4.70 mmol), p-tolylacetylene (684 mg,
5.89 mmol), and copper iodide (89 mg, 0.47 mmol) in tetra-
hydrofuran (20 mL) and triethylamine (10 mL). The solution was
stirred at reflux for 17 h and then allowed to cool to room tempera-
ture. After saturated ammonium chloride solution had been added,
the reaction mixture was extracted with diethyl ether. The organic
layer was washed with water. The organic layer was dried with an-
hydrous magnesium sulfate, filtered, and concentrated to afford a
yellow oil. Purification of the crude product by column chromatog-
raphy on silica gel (elution with dichloromethane/hexane 3:1) gave
compound 4a (1.25 g, 2.96 mmol, 63%) as a pale yellow solid, m.p.
92.8–94.2 °C. 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 7.6 Hz,
2 H, ArH), 7.48 (dd, J = 7.6, 7.5 Hz, 1 H, ArH), 7.35–7.30 (m, 3
H, ArH), 7.11 (d, J = 7.6 Hz, 2 H, ArH), 7.63 (s, 2 H, ArH), 2.89
[sept, J = 6.9 Hz, 1 H, CH(CH3)2], 2.75 [sept, J = 6.7 Hz, 2 H,
CH(CH3)2], 2.35 (s, 3 H, CH3), 1.25 [d, J = 6.9 Hz, 6 H,
CH(CH3)2], 1.14 [d, J = 6.7 Hz, 12 H, CH(CH3)2] ppm. 13C NMR
(101 MHz, CDCl3): δ = 200.2, 149.7, 145.2, 139.6, 138.5, 136.3,
134.8, 132.0, 131.8, 131.2, 128.9, 127.6, 123.3, 121.1, 120.2, 95.4,
87.8, 34.3, 31.1, 24.2, 23.9, 21.5 ppm. MS (EI): m/z = 422 [M]+.
C31H34O: C 88.10, H 8.11; found C 88.05, H 7.93.
Experimental Section
General: All solvents were purified by standard methods. Prepara-
tive thin-layer chromatography (PTLC) was performed with Merck
1
Kieselgel 60 PF254. H NMR (400 MHz) and 13C NMR (101 Hz)
spectra were measured in CDCl3 or CD3CN with a Varian Mer-
cury 400 plus spectrometer and use either of CHCl3 (δH
7.26 ppm) and CDCl3 (δC = 77.0 ppm) or of CHD2CN (δH
=
=
2.10 ppm) and CD3CN (δC = 1.79 ppm) as internal standards for
1H and 13C NMR spectra, respectively. 19F NMR (376 MHz) spec-
tra were measured in CDCl3 or CD3CN with a Varian Mer-
cury 400 plus spectrometer and use of CFCl3 (δF = 0.00 ppm) as
an external standard. EI and ESI-TOF mass spectroscopic data
were obtained with a JEOL JMS-gcmateII and a JEOL JMS-
T100CS spectrometer, respectively. Infrared spectra were obtained
with a PerkinElmer Spectrum One spectrometer. Elemental analy-
ses were performed with a Yanaco MT-5 CHN-corder. All melting
points were determined with a Yanaco micro melting point appara-
tus or a Mettler Toledo MP90 melting point system and are uncor-
rected. All experiments were performed under argon unless other-
wise noted.
Synthesis of 2-Iodo-2Ј,4Ј,6Ј-triisopropylbenzophenone (1): A mixture
of 2-iodobenzoic acid (2.01 g, 8.06 mmol) and thionyl chloride
(15 mL) was warmed at 70 °C for 5 h and then allowed to cool to
room temperature. After removal of thionyl chloride, acetonitrile
(20 mL), 1,3,5-triisopropylbenzene (4.11 g, 20.2 mmol), and alumi-
num chloride (1.41 g, 19.5 mmol) were added to the residue. The
Synthesis of 2-(3,3-Dimethylbut-1-ynyl)-2Ј,4Ј,6Ј-triisopropylbenzo-
phenone (4b): Bis(triphenylphosphine)palladium dichloride (65 mg,
0.093 mmol) was added at room temperature to a degassed solution
of compound
1 (674 mg, 1.55 mmol), 2,2-dimethylbut-1-yne
1428
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1423–1430

Electrophilic Cyclization Reactions
(140 mg, 1.70 mmol), and copper iodide (50 mg, 0.26 mmol) in
tetrahydrofuran (20 mL) and diisopropylamine (10 mL). The solu-
tion was stirred at reflux for 12 h and then allowed to cool to room
temperature. After saturated ammonium chloride solution had
been added, the reaction mixture was extracted with diethyl ether.
The organic layer was washed with water, dried with anhydrous
magnesium sulfate, filtered, and concentrated to afford a yellow oil.
Purification of the crude product by column chromatography on
silica gel (elution with dichloromethane/hexane 1:1) gave com-
pound 4b (602 mg, 1.55 mmol, quant.) as a colorless oil. 1H NMR
Reaction between Ethynylbenzophenone 4b and Bis(trifluoromethyl-
sulfonyl)imide: solution of bis(trifluoromethylsulfonyl)imide
(126 mg, 0.448 mmol) in dichloromethane (1.5 mL) was added at
room temperature to solution of compound 4b (159 mg,
0.409 mmol) in dichloromethane (5 mL). After the solution had
been stirred at room temperature for 2 h, the solvent was removed
under reduced pressure. Hexane (ca. 10 mL) was added to the resi-
due, and the solution was cooled to 0 °C. The resulting suspension
was filtered and washed with cold hexane to afford a mixture of
benzo[c]pyrylium amide 5b and alkylideneisobenzofuranium amide
A
a
(400 MHz, CDCl3): δ = 7.54 (d, J = 8.0 Hz, 2 H, ArH), 7.40 (dd, 6b (208 mg, 2.97 mmol, 77%, 5b/6b 31:69) as yellow crystals, m.p.
J = 8.0, 8.0 Hz, 1 H, ArH), 7.24 (dd, J = 7.6, 7.6 Hz, 1 H, ArH),
7.03 (s, 2 H, ArH), 2.91 (sept, J = 6.8 Hz, 1 H, CH), 2.75 (sept, J
= 6.8 Hz, 2 H, CH), 1.27 (d, J = 6.8 Hz, 6 H, CH3), 1.23 [s, 9 H,
105–119 °C (5b/6b 31:69). 19F NMR (376 MHz, CD3CN): δ =
–80.6 (s) ppm. MS (ESI): m/z 389 [M
(CF3SO2)2N]+.
C30H37F6NO5S2: C 53.80, H 5.57, N 2.09; found C 53.73, H 5.36,
=
–
C(CH3)3], 1.13 (br, 12 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): N 2.36.
δ = 200.42, 149.64, 145.05, 140.29, 136.51, 134.77, 131.54, 130.70,
Compound 5b: Yellow crystals, m.p. 141.4–143.2 °C. 1H NMR
126.89, 121.09 (2 C), 104.21, 77.99, 34.35 (2 C), 30.92, 30.75, 28.18,
23.99 ppm. MS (EI): m/z = 388 [M]+. C28H36O: C 86.54, H 9.34;
found C 86.32, H 9.34.
(400 MHz, CD3CN): δ = 8.50 (ddd, J = 8.3, 6.2, 1.9 Hz, 1 H, ArH),
8.43 (s, 1 H, ArH), 8.33–8.39 (m, 1 H, ArH), 8.03–7.97 (m, 2 H,
ArH), 7.41 (s, 2 H, ArH), 3.09 (sept, J = 6.9 Hz, 1 H, CH), 2.05
(sept, J = 6.7 Hz, 2 H, CH), 1.54 [s, 9 H, C(CH3)3], 1.34 (d, J =
6.9 Hz, 6 H, CH3), 1.12 (d, J = 6.7 Hz, 6 H, CH3), 1.03 (d, J =
6.7 Hz, 6 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 186.80,
175.66, 154.87, 148.39, 144.65, 143.47, 133.09, 131.48, 129.38,
125.69, 122.65, 122.27, 121.46, 119.86 (quart, JF,C = 321 Hz, CF3),
118.26, 116.50, 37.63, 34.61, 32.46, 30.61, 28.18, 24.74, 23.73,
23.44 ppm.
Synthesis of 2-(3,3-Dimethylbut-1-ynyl)benzophenone (4d): Bis(tri-
phenylphosphine)palladium dichloride (68 mg, 0.097 mmol) was
added at room temperature to a degassed solution of compound 3
(3.02 g, 9.80 mmol), 2,2-dimethylbut-1-yne (884 mg, 10.8 mmol),
and copper iodide (200 mg, 1.05 mmol) in tetrahydrofuran (20 mL)
and diisopropylamine (10 mL). The solution was stirred at reflux
for 15 h and then allowed to cool to room temperature. After satu-
rated ammonium chloride solution had been added, the reaction
mixture was extracted with diethyl ether. The organic layer was
washed with water, dried with anhydrous magnesium sulfate, fil-
tered, and concentrated to afford a yellow oil. Purification of the
crude product by column chromatography on silica gel (elution
with dichloromethane/hexane 1:1) gave compound 4d (1.31 g,
5.00 mmol, 51%) as a pale yellow powder, m.p. 79.8–80.2 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.2 Hz, 2 H, ArH), 7.54
(t, J = 7.6 Hz, 1 H, ArH), 7.38–7.45 (m, 6 H, ArH), 0.90 [s, 9 H,
C(CH3)3] ppm. 13C NMR (101 MHz, CDCl3): δ = 197.43, 141.89,
137.33, 132.84, 132.08, 130.03, 129.89, 128.13, 128.06, 127.47,
122.20, 104.63, 77.24, 30.12, 27.58 ppm. MS (EI): m/z = 262 [M]+.
C19H18O: C 86.99, H 6.92; found C 86.79, H 7.07.
1
Compound 6b: H NMR (400 MHz, CD3CN): δ = 8.33–8.39 (m, 2
H, ArH), 8.05 (br. d, J = 8.2 Hz, 1 H, ArH), 7.93 (ddd, J = 8.2,
6.3, 1.8 Hz, 1 H, ArH), 7.80 [s, 1 H, =CH-C(CH3)3], 7.45 (s, 2 H,
ArH), 3.08 (sept, J = 6.9 Hz. 1 H, CH), 2.54 (sept, J = 6.7 Hz, 2
H, CH), 1.49 [s, 9 H, C(CH3)3], 1.51 (d, J = 6.9 Hz, 6 H, CH3),
1.18 (d, J = 6.7 Hz, 6 H, CH3), 1.16 (d, J = 6.7 Hz, 6 H, CH3) ppm.
2D NOESY NMR (400 MHz, CD3CN): a singlet signal at δ =
7.80 ppm correlates to a multiplet signal between 8.33 to 8.39 ppm.
13C NMR (101 MHz, CDCl3): δ = 196.84, 156.58, 152.04, 151.15,
149.37, 144.37, 144.11, 133.13, 131.48, 127.96, 123.90, 122.79,
119.86 (quart, JF,C = 321 Hz, CF3), 119.26, 115.07, 37.33, 34.76,
32.61, 30.16, 25.15, 23.54 ppm.
Reaction between Ethynylbenzophenone 4d and Bis(trifluoromethyl-
Synthesis of 3-p-Tolyl-1-(2,4,6-triisopropylphenyl)isochromenium
Bis(trifluoromethylsulfonyl)amide (5a): A solution of bis(trifluoro-
methylsulfonyl)imide (481 mg, 1.71 mmol) in dichloromethane
(20 mL) was added at room temperature to a solution of compound
4a (553 mg, 1.31 mmol) in dichloromethane (35 mL). After the
solution had been stirred at room temperature for 1.5 h, the solvent
was removed under reduced pressure. Hexane (10 mL) was added
to the residue, and the solution was cooled to 0 °C. The resulting
suspension was filtered and washed with cold hexane to give com-
pound 5a (809 mg, 1.15 mmol, 88%) as yellow crystals, m.p. 113.2–
sulfonyl)imide:
(765 mg, 2.74 mmol) in dichloromethane (10 mL) was added at
room temperature to solution of compound 4d (625 mg,
A solution of bis(trifluoromethylsulfonyl)imide
a
2.38 mmol) in dichloromethane (40 mL). After the solution had
been stirred at room temperature for 2 h, the solvent was removed
under reduced pressure to afford a mixture of benzo[c]pyrylium
amide 5d and 1H-inden-1-one 7d (5d/7d 9:91) as an orange oil.
Hexane (10 mL) was added to the residue, and the solution was
allowed to stand at room temperature for several minutes. The re-
sulting supernatant was then removed. This process was repeated
five times, and the combined hexane solution was concentrated un-
der reduced pressure to give 1H-inden-1-one 7d as yellow crystals.
The hexane-insoluble orange oil was benzo[c]pyrylium amide 5d.
1
114.2 °C. H NMR (400 MHz, CD3CN): δ = 8.91 (s, 1 H, ArH),
8.44–8.48 (m, 4 H, ArH), 8.36 (d, J = 8.4 Hz, 1 H, ArH), 8.04 (d,
J = 8.4 Hz, 2 H, ArH), 7.98–7.97 (m, 2 H, ArH), 7.51 (d, J =
8.4 Hz, 2 H, ArH), 7.43 (s, 2 H, ArH), 3.10 [sept, J = 6.9 Hz, 1 H,
CH(CH3)2], 2.47 (s, 3 H, CH3), 2.21 [sept, J = 6.7 Hz, 2 H,
CH(CH3)2], 1.36 [d, J = 6.9 Hz, 6 H, CH(CH3)2], 1.12 [d, J =
6.7 Hz, 6 H, CH(CH3)2], 1.07 [d, J = 6.7 Hz, 6 H, CH(CH3)2] ppm.
13C NMR (101 MHz, CD3CN): δ = 185.5, 164.4, 155.9, 149.9,
146.0, 145.5, 145.2, 134.2, 132.6, 131.8, 129.3, 127.8, 127.4, 127.0,
124.0, 123.4, 120.9 (quart, JF,C = 321 Hz, CF3), 117.4, 35.4, 33.0,
25.2, 24.0, 23.5, 21.7 ppm. 19F NMR (376 MHz, CD3CN): δ =
1
Compound 5d: Orange oil. H NMR (400 MHz, CDCl3): δ = 8.72
(d, J = 8.1 Hz, 1 H, ArH), 8.58 (d, J = 8.3 Hz, 2 H, ArH), 8.29 (d,
J = 8.1 Hz, 1 H, ArH), 8.22 (dd, J = 7.8, 8.1 Hz, 1 H, ArH), 8.01–
7.97 (m, 1 H, ArH), 7.96 (dd, J = 7.8, 8.1 Hz, 1 H, ArH), 7.88 (t,
J = 8.3 Hz, 2 H, ArH), 7.38 (s, 1 H, ArH), 1.58 [s, 9 H,
C(CH3)3] ppm. 19F NMR (376 MHz, CD3CN): δ = –80.6 (s) ppm.
MS (ESI): m/z = 263 [M – (CF3SO2)2N]+.
Compound 7d: Yellow crystals, m.p. 111.8–112.9 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.47–7.37 (m, 4 H, ArH), 7.27–7.24 (m, 2
H, ArH), 7.23–7.19 (m, 1 H, ArH), 7.17–7.13 (m, 1 H, ArH), 6.49
–80.6 (s) ppm. MS (EI): m/z
=
423 [M
–
(CF3SO2)2N]+.
C33H35F6NO5S2: C 56.32, H 5.01, N 1.99; found C 56.40, H 5.05,
N 2.30.
Eur. J. Org. Chem. 2014, 1423–1430
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1429

N. Nagahora, K. Okuma et al.
FULL PAPER
(d, J = 7.1 Hz, ArH), 1.16 [s, 9 H, C(CH3)3] ppm. 13C NMR
(101 MHz, CDCl3): δ = 198.41, 153.96, 147.65, 141.46, 135.32,
133.32, 129.86, 128.18, 128.06, 127.89, 127.84, 121.72, 120.36,
33.63, 30.64 ppm. MS (EI): m/z = 262 [M]+. C19H18O: C 86.99, H
6.92; found C 87.08, H 6.99.
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Supporting Information (see footnote on the first page of this arti-
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graphic analyses, theoretical calculations, and copies of 1H and 13
NMR spectra of the reported compounds.
C
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Acknowledgments
This work was partially supported by the Institute for Chemical
Research, Kyoto University (Collaborative Research Program,
grant numbers 2011-69 and 2012-67) and by the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan (Grant-in-Aid
for Young Scientists (B), grant number 23750051). The authors are
grateful to Professor Takahiro Sasamori at Kyoto University for
fruitful discussions.
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Received: October 31, 2013
Published Online: January 8, 2014
1430
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1423–1430