Br?nsted acid-controlled [3 + 2] coupling reaction of quinone monoacetals with alkene nucleophiles: A catalytic system of perfluorinated acids and hydrogen bond donor for the construction of benzofurans

Article abstract of DOI:10.1021/jo400613z

We have developed an efficient Br?nsted acid-controlled strategy for the [3 + 2] coupling reaction of quinone monoacetals (QMAs) with nucleophilic alkenes, which is triggered by the particular use of a specific acid promoter, perfluorinated acid, and a solvent, fluoroalcohol. This new coupling reaction smoothly proceeded with high regiospecificity in regard with QMAs for introducing π-nucleophiles to only the carbon α to the carbonyl group, thereby providing diverse dihydrobenzofurans and derivatives with high yields, up to quantitative, under mild conditions in short reaction times. The choice of Br?nsted acid enabled us to avoid hydrolysis of the QMAs, which gives quinones, and the formation of discrete cationic species from the QMAs. Notably, further investigations in this study with regard to the acid have led to the findings that the originally stoichiometrically used acid could be reduced to a catalytic amount of 5 mol % loading or less and that the stoichiometry of the alkenes could be significantly improved down to only 1.2 equiv. The facts that only a minimal loading (5 mol %) of perfluoroterephthalic acid is required, readily available substrates can be used, and the regioselectivity can be controlled by the acid used make this coupling reaction very fascinating from a practical viewpoint.

Full text of DOI:10.1021/jo400613z

Subscriber access provided by Cape Breton University | Library
Article
Brønsted Acid-Controlled [3+2] Coupling Reaction of Quinone Monoacetals
with Alkene Nucleophiles: A Catalytic System of Perfluorinated Acids
and Hydrogen Bond Donor for the Construction of Benzofurans
Yinjun Hu, Tohru Kamitanaka, Yusuke Mishima, Toshifumi Dohi, and Yasuyuki Kita
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 May 2013
Downloaded from http://pubs.acs.org on May 15, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Brønsted Acid-Controlled [3+2] Coupling Reaction of Quinone Monoacetals with Alkene
Nucleophiles: A Catalytic System of Perfluorinated Acids and Hydrogen Bond Donor for
the Construction of Benzofurans
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yinjun Hu, Tohru Kamitanaka, Yusuke Mishima, Toshifumi Dohi, and Yasuyuki Kita*
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga
525-8577 JAPAN
RECEIVED DATE (automatically inserted by publisher);
Corresponding author: kita@ph.ritsumei.ac.jp
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 46
1
2
3
4
5
6
7
8
Abstract
9
We have developed an efficient Brønsted acidꢀcontrolled strategy for the [3+2] coupling reaction of
quinone monoacetals (QMAs) with nucleophilic alkenes, which is triggered by the particular use of a
specific acid promoter, perfluorinated acid, and a solvent, fluoroalcohol. This new coupling reaction
smoothly proceeded with high regiospecificity in regard with QMAs for introducing πꢀnucleophiles to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
only the carbon α to the carbonyl group, thereby providing diverse dihydrobenzofurans and derivatives
with high yields, up to quantitative, under mild conditions in short reaction times. The choice of
Brønsted acid enabled us to avoid hydrolysis of the QMAs which gives quinones and the formation of
discrete cationic species from the QMAs. Notably, further investigations in this study with regard to
the acid have led to the findings that the originally stoichiometrically used acid could be reduced to a
catalytic amount of 5 mol% loading or less and that the stoichiometry of the alkenes could be
significantly improved down to only 1.2 equiv. The facts that only a minimal loading (5 mol%) of
perfluoroterephthalic acid is required, readily available substrates can be used, and the regioselectivity
can be controlled by the acid used make this coupling reaction very fascinating from a practical
viewpoint.
2
ACS Paragon Plus Environment

Page 3 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Introduction
9
Quinones belong to a unique class of molecules in which all of the carbon atoms constituting the ring
structures are electrophilic. Furthermore, they ubiquitously exist in nature and are frequently included
in commercial and industrial chemicals having many broad and attractive applications.1,2 As a result,
these quinoneꢀtype compounds are of importance in organic chemistry as synthetic intermediates and
building blocks.2 Regarding their reactivity, many types of reactions have been developed utilizing the
unsaturated enone structure as a versatile electrophile, especially in cycloaddition reactions with
various nucleophiles and dienes. On the other hand, due to the electrophilic nature of all of the ring
carbons, chemoꢀ and regioꢀselectivity issues arise, sometimes limiting the utility of quinones
themselves in organic synthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As one promising solution to the selectivity issues, quinone monoacetals (QMAs, for example, 1a),
i.e., monoꢀprotected quinones, have been used for differentiating the two carbonyl groups. The
desymmetrized quinones serve as a useful alternative to selective chemical transformations in
controlling the reactivity of quinones, and thus are frequently called ‘‘masked’’ quinones.3 These
compounds can be readily obtained from phenols, quinones, and quinone bisacetals by utilizing any of
the many procedures, among which methods involving chemical oxidations, specifically those using
hypervalent iodine reagents in a suitable alcohol solvent, are straightforward and attractive.4 Due to the
uniqueness of the bifunctional structure of the QMAs based on the α,βꢀunsaturated carbonyl and
allylacetal moieties in one skeleton as well as their easy and efficient preparations, QMAs have been
attracting interest since the 1970s. Regarding the reactivities, both chemoꢀ and regioꢀselective reactions
have been reported (Scheme 1), for instance, additions to the carbonyl carbon (i.e., 1,2ꢀadditions),5
conjugated additions (1,4ꢀadditions, etc.),6 and cyclizations involving these processes.7
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 46
1
2
3
4
5
6
Scheme 1. Reactions of QMAs 1a toward nucleophiles based on the four electrophilic carbons.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In addition to these addition reactions, it seems that QMAs, in principle, can participate in the
chemistry and reactivity of the allylacetal functionalities. However, in sharp contrast to the established
addition chemistry of QMAs regarding the reactivity at the enone moieties, strategies for utilizing the
allylacetals as electrophilic units for substitution reactions were rarely reported,8ꢀ12 except for the
intramolecular reactions13 and wellꢀknown acetal deprotection by hydrolysis. The earliest report of the
substitution for QMAs with the methyl Grignard reagent (MeMgI) was demonstrated more than 30
years ago for introducing the nucleophile to some extent to the carbon α to the carbonyl group of the
QMAs (which also corresponds to the αꢀposition of the carbonyl group).8 The reactions unexpectedly
favored the substitution course instead of the additions by depending on the formation of the stable
magnesium phenoxide. These strategies under basic conditions cannot usually perfectly exclude the
competitive addition processes. Indeed, the SN2’ displacement of the simple QMA dimethyl acetals for
the allylation and propargylation are known to occur only via the 1,2ꢀaddition of the organometallic
species to the carbonyl group followed by rearrangement.9
Considering the addition reactivities promoted under basic conditions, acidic activations of QMAs
4
ACS Paragon Plus Environment

Page 5 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
for substitution chemistry have recently been considered as an alternative strategy, though such
examples are quite limited. The attractive reactivity of QMAs for substitution promoted by diethyl
aluminum chloride (EtAlCl2) was demonstrated by Sartori’s group, who proposed the pseudoꢀ
intramolecular SN2’ process via coordination of the aluminum Lewis acid to the acetal as well as the
phenol nucleophile.10 In addition, the phenoxenium ions, generated from QMAs by treatment with the
appropriate strong acids, were demonstrated by Büchi and other research groups for the [5+2]ꢀtype
cycloadditions resulting from the tandem substitution–annulation sequence.11 On the other hand, only a
few QMAs and activated πꢀnucleophiles were reported for an alternative [3+2] coupling reaction
promoted by Brønsted acids leading to dihydrobenzofurans.12
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Despite their partial success, the limited range of usable nucleophiles under acidic conditions, which
typically have lower nucleophilicities than the basic reagents, significantly restricted the scope of the
attractive strategy. For expanding the utility, new challenges for developing the substitution reactions
of QMAs have thus appeared in recent years by several research groups including us based on the
screening of more suitable activators.14ꢀ17 We recently developed a new method promoted in a specific
solvent, that is, hexafluoroisopropanol (HFIP), for the controlled substitution of QMAs 1 with aromatic
nucleophiles to give biaryl compounds in the presence of a solid acid catalyst.14 Further investigation
of this appealing strategy in the specific solvent system has led to the finding of the controlled [3+2]
coupling reaction of QMAs 1 and alkene nucleophiles 2 (Scheme 2).15 The specific use of the acid
promoter, perfluorobenzoic acid, and the fluoroalcohol solvent concerns the involvement of activated
acid species in situ formed in equilibrium with the aid of the hydrogen bond donor, HFIP.18,19 By the
associating acid, the expeditious and efficient coupling reaction would include the attack of the
nucleophiles 2 at the less hindered carbon site of the QMAs 1 remote from the acetal rather than the
sterically protected acetal carbon; otherwise, the hydrolysis of the acetals by concomitant water usually
occurs. As a result, the new system utilizing the specific Brønsted acid and HFIP has extremely
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 46
1
2
3
4
5
6
7
8
improved the [3+2] coupling strategy for the remarkably extensive QMAs 1 and πꢀnucelophiles 2.
Scheme 2. Brønsted acidꢀcontrolled [3+2] coupling reaction of QMAs by specific acid promoters.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
F
HO2C
F
acid promoter
R'
R'
F
F
O
2
( )
(alkenes)
(CF3)2CHOH (HFIP)
R
O
F
F
O
OMe
3
H O
O
MeO
MeO
C
F
F3C
F3C
(formal [3 + 2] coupling)
R
F
F
F
F
OH
H O
O
F
F
MeO OMe
O
C
F
hydrogen
bond donor
activated acid
species
F3C
F3C
1
( )
OH
H2O
slow
R
R = alkyl, alkoxy,
halogen, etc.
in situ
activation
with acetal carbon blocking
O
quinones
(hydrolysis)
In this paper, we fully summarize our further efforts on the new [3+2] coupling reaction of QMAs 1
and alkenes nucleophiles 2 in the specific reaction systems with special emphasis on the reaction scope,
mechanism, and extension of the stoichiometric strategy to the catalytic coupling reactions. These
further investigations led to the conclusion that the reactions would proceed in a pseudꢀSN2’ interaction
of QMAs 1 and alkenes 2, and stepwise construction of the two carbonꢀcarbon and carbonꢀoxygen
bonds would lead to the thermodynamicallyꢀfavored dihydrobenzofuran products 3.20 The significant
advances based on the further catalyst tuning have now enabled the controlled coupling reactions with
improved stoichiometry of the alkenes 2 (1.2 equiv) under catalysis with the acid promoter at less than
5 mol% loading.
6
ACS Paragon Plus Environment

Page 7 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
Results and Discussion
7
8
9
Optimization of the Reaction Conditions and Acid Promoters for the [3+2] Coupling
Reaction in HFIP. Based on our previous success regarding the controlled coupling reaction of
QMA 1a with aromatic nucleophiles,14 we initially examined the [3+2] coupling reaction of the QMA
1a with allyltrimethylsilane 2a21 in our reported system along with montmorillonite (MT) or a
stoichiometric amount of acetic acid in a mixed solvent with HFIP (Table 1, Eq. 1). These reactions
indeed produced the coupling adduct, dihydrobenzofuran 3aa, to some extent (61% and 19%,
respectively) at room temperature (entries 1 and 2), but the reactions were very slow and required
long times to consume all the starting QMA 1a. For the [3+2] coupling reaction, the MT clay and
acetic acid in ordinary solvents were reported as reaction initiators,12 but these seem to be usable only
for a limited number of extremely activated alkenes, i.e., vinyl sulfide and electronꢀrich chromenes.
Accordingly, we screened a more suitable acid activator to allow more efficient reactions and an
extensive substrate scope. Considering the pKa values, several types of Brønsted acids involving a
series of carboxylic acids (2 equiv relative to the QMA 1a) were systematically evaluated. The results
indicated that only the carboxylic acids with suitable acidic proton strengths22 showed a good
performance in order to develop the coupling reactions (entries 3ꢀ15), among which
pentafluorobenzoic acid (pKa: ca. 1.5ꢀ1.6)22b especially gave the most promising results regarding not
only the product yield, but also the observed production rate and reaction purity (entry 5). Otherwise,
incomplete conversions of the QMA 1a were usually observed for the less acidic activators (entries
2ꢀ4), while the stronger acids, such as trichlorobenzoic and phthalic acids (entries 12 and 13), would
significantly decompose the QMA 1a, resulting in poorer yields of the product 3aa. In particular,
trifluoroacetic acid produced the dihydrobenzofuran 3aa in an acceptable yield (entry 14), but
formation of the quinone as well as some byproducts derived from the background polymerization of
the used alkene 2a was accompanied by the acid and much stronger methanesulfonic acid (entry 15)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 46
1
2
3
4
5
6
7
8
9
and Nafion resin,23 which is recognized as a serious problem for future expansion of the scope of the
QMAs 1 and alkenes 2.24 Lewis acids, such as boron trifluoride and trimethylsilyl triflate, are known
instead to induce the conjugated addition6h and [5+2]ꢀtype cyclization11 for the QMAs 1a and others,
but did not produce the desired [3+2] coupling reaction, as expected (entries 16 and 17).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1 Effects of the reaction promoters for [3+2] coupling reaction of 1a and 2a (Eq. 1).[a]
entry
acid
MKꢀ10[c]
solvent
time
3 days
7 h
yield of 3aa[b]
61%
1
2
3
4
HFIP/DCM
HFIP/DCM
HFIP/DCM
HFIP/DCM
acetic acid
19%
benzoic acid
4ꢀnitrobenzoic acid
2 h
9%
2 h
14%
5
pentafluorobenzoic acid
pentafluorobenzoic acid[e]
pentafluorobenzoic acid[e]
pentafluorobenzoic acid[e]
pentafluorobenzoic acid[e]
pentafluorobenzoic acid[e]
pentafluorobenzoic acid[e]
HFIP/DCM
HFIP/DCM
10 min
10 min
10 min
10 min
1 h
84%
75%
90%
67%
21%
trace
66%
6[d]
7[d,f]
8[dꢀg]
9[d]
HFIP/DCM
HFIP/DCM
TFE/DCM (10/1)
MeCN/DCM (10/1)
HFIP
10[d]
11[d]
1 h
1 h
8
ACS Paragon Plus Environment

Page 9 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
12
13
14
15
16
17
2,4,6ꢀtrichlorobenzoic acid
HFIP/DCM
HFIP/DCM
HFIP/DCM
HFIP/DCM
HFIP/DCM
HFIP/DCM
10 min
10 min
30 min
2 h
59%
58%
72%
n.d.
phthalic acid
trifluoroacetic acid
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
trifluoromethanesulfonic acid
boron trifluoride ꢁ Et2O
trimethylsilyl triflate
1 h
25%
n.d.
2 h
[a] Unless otherwise noted, the screenings were carried out with 2 equiv of acids in HFIP/DCM (10/1
v/v, 0.1 M of QMA 1a) at room temperature. 5 equiv of allyltrimethylsilane 2a was used for the
reactions. [b] Isolated yields after purification. Formation of very small amounts of nonꢀcyclized
allylation product was observed. For the details, see SI. [c] 25 mg relative to 1 mL of the solvent. [d]
Allyltrimethylsilane 2a (2 equiv) in HFIP/DCM (10/1 v/v, 0.2 M of QMA 1a). [e] Pentafluorobenzoic
acid (1 equiv). [f] Performed at 0 oC. [g] 1.2 equiv of allyltrimethylsilane 2a was used.
n.d. = not determined due to low formation of the product 3aa. DCM = dichloromethane.
For the perfluorobenzoic acid affording the good results, we conducted further optimizations of the
[3+2] coupling reaction with respect to the solvent, substrate concentration, temperature, and reagent
and substrate stoichiometries. Regarding the solvent, a considerable decrease in the yield of the
product 3aa was observed upon reducing the HFIP ratio relative to dichloromethane (DCM).
Meanwhile, the reaction at a higher HFIP ratio permitted the reduction of the perfluorobenzoic acid to
1 equiv and allyltrimethylsilane 2a to 2 equiv (entry 6). Lowering the temperature to 0 oC has led to a
further approx. 10% increase in the product yield (entry 7 for 90%). However, the excess use of the
alkene 2a (2 equiv) was still essential, and 1.2 equiv of allytrimethylsilane 2a would cause a
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 46
1
2
3
4
5
6
7
8
considerable decrease in the yield of the product 3aa (entry 8). Finally, the solvent was reꢀexamined
for the reaction. HFIP remained indispensable under the optimized conditions, and the consumption
of the QMA 1a by pentafluorobenzoic acid in other solvents was still very slow; the product 3aa was
not smoothly formed, even in the parent but less polar and weaker hydrogen bond donor, 2,2,2ꢀ
trifluoroethanol (entries 9 and 10). On the other hand, the use of DCM as a coꢀsolvent for HFIP was
plausible for dissolving the reactants to obtain the reproducible results (entry 11). A subtle change in
the concentration of the substrate 1a in the range of 0.1ꢀ0.5 M had only a slight effect on the product
yields. From these observations, we determined the optimized standard conditions for the [3+2]
coupling reaction of the QMAs 1 to be the use of 2 equiv of alkene nucleophiles 2 in the presence of
1 equiv of the acid promoter, perfluorobenzoic acid, in a mixed solvent system of HFIP and DCM. A
Scope of the Reactions. Examination of Extended Series of QMAs 1 and Alkene Nucleophiles
2 for the [3+2] Coupling Reactions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the optimal conditions in hand, we then evaluated the extensive QMAs 1a-i with the diversity
of their ring substituent pattern and functionalities for the reactions toward 2b as the counterpart
(Table 2). Unless otherwise noted, all the experiments were carried out at room temperature in an
open flask. It was confirmed that many types of QMAs 1 were applicable and afforded the
corresponding dihydrobenzofurans 3 in up to quantitative yield at room temperature without
competitive formation of other regioisomers and remarkable byproducts. The cyclizations with
styrene 2b and the QMAs 1b-d having both electronꢀwithdrawing or donating groups smoothly
proceeded, all the reactions of which exclusively occurred at the less hindered positions of the two
carbons α to the carbonyl group of the QMA structures (entries 2ꢀ4). The QMA 1c with a tertꢀbutyl
substituent at the neighboring carbon atom of the acetal moiety seemed to slightly hamper the
substrate reactivity due to its steric hindrance (entry 3). Meanwhile, the less electrophilic methoxy
QMA 1d reacted with the alkene 2b as do the more electrophilic QMAs 1a and 1b, though higher
10
ACS Paragon Plus Environment

Page 11 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
amounts of the acid and a higher concentration of the alkene 2b were needed (entry 4). The
substituents of a tert-butyl and halogen moiety at the neighboring side of the carbonyl group were
intact, and the QMAs 1e and 1f afforded the cyclized coupling products 3eb and 3fb with high
conversions and efficiencies (entries 5 and 6). On the other hand, the disubstituted QMA 1g was not
reactive at all in this [3+2] coupling reaction, probably due to the severe steric requirement of the
transition state (entry 7), which was in accord with the observed perfect regioselectivity for the
QMAs 1b-d during the reactions. To our delight, the formations of the desired cycloadducts 3hb and
3ib were achieved in excellent yields from the naphthalene QMAs 1h and 1i (entries 8 and 9).
Remarkably, all of the reactions except for the QMA 1g were finished within 10 min. at room
temperature with the indicated good efficiencies.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2 Scope of the QMAs 1: Representative examples.[a]
entry
QMA (1)
product (3)
yield[b]
Ph
O
R1
R2
OMe
1
2
R1 = R2 = H (1a)
(3ab)
(3bb)
93%
83%
R1 = H, R2 = Me (1b)
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 46
1
2
3
4
5
6
7
8
9
3
4[c]
5
R1 = H, R2 = tꢀBu (1c)
(3cb)
(3db)
(3eb)
(3fb)
64%
78%
R1 = H, R2 = OMe (1d)
R1 = tꢀBu, R2 = H (1e)
R1 = Cl, R2 = H (1f)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
quant.
86%
6
Ph
7
trace
O
(1g)
OMe
(3gb)
8
9
R3 = H (1h)
(3hb)
(3ib)
quant.
98%
R3 = OAc (1i)
[a] Reactions were conducted using 1 equiv of perfluorobenzoic acid (relative to QMAs 1) in HFIP/
DCM solvent (10/1 v/v, 0.2 M) in the presence of 2 equiv of styrene 2b at room temperature for 10
min. [b] Isolated yields of the products 3 after purification by column chromatography. [c] 2 equiv of
the acid activator and 3 equiv of styrene 2a were used.
In addition to the aboveꢀmentioned QMAs 1 based on the dimethyl acetal, the QMAs 1j and 1k
having mixed acetals would participate in the [3+2] coupling reaction under the standard reaction
conditions, giving only the single products after the selective release of the methoxy group (Scheme
12
ACS Paragon Plus Environment

Page 13 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
3). Specifically, the reaction of the QMA 1j accounted for the high leaving preference for the
methoxy group rather than the larger isopropoxy one (Eq. a). One plausible explanation for the
unique recognitions of the acetals is the facile interaction of the small methoxy group toward the
perfluorinated acid species during their activation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Unique leaving group preferences of the acetal units of QMAs 1j and 1k.
(n.d. = not determined due to lowꢀyield formation.)
Ph
Ph
O
O
O
2b
styrene ( , 2 equiv)
C6F5CO2H (1 equiv)
(a)
HFIP/CH2Cl2
(10/1 v/v)
r.t., 10 min.
n.d.
MeO OiPr
OiPr
OMe
QMA mixed acetal
(3jb), 81%
(1j)
(by selective MeOH elimination)
Ph
O
Ph
O
O
as above
(b)
same conditions
HO
OMe
O
O
OMe
n.d.
1k
(
)
(3kb), 93%
For the QMA derivatives, we found that the valuable indoline compound 3lb was also obtained
from iminoquinone acetals 1l in a similar transformation without optimization (Scheme 4). Such
oxygenated indoline structures are found in natural products showing several interesting biological
activities, such as physostigmine and esermethole.25
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 46
1
2
3
4
5
6
Scheme 4. Construction of indoline skeleton from iminoquinone acetal 1l.
7
8
9
Ph
NTs
TsN
2b
styrene ( , 2 equiv)
C6F5CO2H (1 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HFIP/CH2Cl2
(10/1 v/v)
r.t., 10 min.
MeO OMe
OMe
indoline
3lb
(1l)
(
), 82%
Subsequently, the scope of the reactions regarding the various alkene coupling partners 2 for the
QMAs was investigated by employing QMA 1a as a unified reaction substrate (Table 3). Fortunately,
not only the activated alkene 2a (entry 1), but also many styrene derivatives 2c-g, having either
electron–donating or withdrawing substituents on the aromatic ring (entries 2ꢀ6), smoothly reacted
with the QMA 1a without significant alteration of the reaction efficiencies. Especially, the gemꢀ and
diꢀsubstituted styrenes 2f and 2g were similarly converted to the desired cycloꢀcoupling products, 3af
and 3ag (entries 5 and 6); in the latter, the transꢀisomer of the dihydrobenzofuran was solely obtained
from the transꢀstyrene 2g. The cyclic styrene 2h was also applicable for the construction of the fused
dihydrobenzofuran structure in the product 3ah found in the pterocarpanꢀtype natural products (entry
7), a member of the widely distributed isoflavanoid families showing a broad spectrum of biological
properties including sharp responses to fungal infections, COXꢀ2 inhibition, antitumor,
LDLꢀantioxidant, antiꢀHIV, and anti–snake venom activities.26 These coupling reactions thus
proceeded very fast within 10 min. and provided the expected products 3 in good yields at room
temperature. It should be noted that the use of these alkenes 2 as nucleophiles afforded the
corresponding dihydrobenzofurans 3 only in this strategy, while the reported oxidation methods
starting from phenols were somewhat troublesome in terms of the yields to obtain the same products
3.27
14
ACS Paragon Plus Environment

Page 15 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3 [3+2] coupling reaction of various alkenes 2aꢀh toward QMA 1a.[a]
R'
O
O
R''
alkene (2a-h)
C6F5CO2H (1 equiv.)
HFIP/CH2Cl2
(1/1 v/v)
r.t., 10 min.
MeO OMe
OMe
(3aa-ah)
1a
(
)
entry
1
alkene (2)
product (3)
yield[b]
89%
(2a)
90%[c]
(3aa)
2
3
4
5
6
R’ = Me, R’’1 = R’’2 = H (2c)
R’ = tꢀBu, R’’1 = R’’2 = H (2d)
R’ = Cl, R’’1 = R’’2 = H (2e)
(3ac)
(3ad)
(3ae)
(3af)
83%
92%
94%
81%
93%
R’ = R’’2 = H, R’’1 = Me (2f)
R’ = OMe, R’’1 = H, R’’2 = Me (2g)
(3ag)[d]
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 46
1
2
3
4
5
6
7
7
83%
O
8
9
(2h)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
(3ah)
[a] See the footnote in Table 2 for the reaction conditions. 2 equiv of alkenes 2a-h were used for the
o
reactions. [b] Isolated yields of the products 3 after purification. [c] Performed at 0 C. [d] Only trans
isomer produced.
The alkene nucleophiles having the cationꢀstablizing substituents (βꢀcation by TMS and αꢀcation
by aryl) eventually coupled with the QMAs 1 in the effective manners. Encouraged by the results, we
examined several aliphatic alkenes for the coupling reaction with the QMAs 1. It should be noted that
treating the fiveꢀ and sixꢀmembered exoꢀmethylene compounds 2i and 2j in excess amounts under the
optimized conditions successfully afforded the two types of ringꢀsized spirocyclic
dihydrobenzofurans 3ai and 3aj with comparable results, 78% and 65%, respectively (Scheme 5).
These compounds are known to be potentially useful in consideration of the ubiquitous nature of the
spirocyclic structures in natural products showing interesting biological activities and unique physical
properties, such as for optoelectronics, and as asymmetric ligands for catalytic synthesis, attributed to
their spirocyclic core structures.28 Meanwhile, the monoꢀ and vicinalꢀsubstituted alkenes, i.e., the 1ꢀ
and 2ꢀoctenes, did not smoothly react with the QMAs 1.
16
ACS Paragon Plus Environment

Page 17 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
Scheme 5. Formation of spirocyclic dihydrobenzofurans 3ai and 3aj.
7
8
(3 equiv of alkene was used for each case.)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Due to the mildness of the reaction conditions, dihydrobenzofuran 3ak having a cyclized O,Sꢀ
acetal was obtained in good yield by using the vinyl sulfide 2k as an appropriate π counterpart for the
coupling reaction (Scheme 6). This extended the utility of the [3+2] coupling reaction for production
of the benzofurans 4 from the products 3 as synthetic modules by utilizing the known elimination of
the phenyl sulfide group. Indeed, successive treatments of the formed dihydrobenzofuran product 3ak
with acid and heating or an oxidant,29 such as mꢀchloroperbenzoic acid (mCPBA), were confirmed for
the conversion to the benzofuran 4.
Scheme 6. Formation of cyclized O,Sꢀacetal compound 3ak from vinyl sulfide 2k and successive
conversion of the product to benzofuran 4.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 46
1
2
3
4
5
6
7
8
9
The aboveꢀmentioned results using various QMAs 1 and alkene nucleophiles 2 validated the
extended scope of the [3+2] coupling reaction in the present systems in comparison to the reported
procedures.12 The dramatic improvements in the product yields and the reaction rates now have
promise for the catalysis of perfluorobenzoic acid in HFIP.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mechanistic Considerations. It is known that some QMAs would cause [5+2] cyclizations with
alkenes upon acid treatment.11 For the QMA 1d, the generation of the phenoxenium ion30 was
reported during the reaction to exclusively lead to the [5+2] cyclization by the trapping with styrene
2b, giving rise to the product 5 (Scheme 7).11c On the other hand, our reaction system did not produce
the [5+2] adduct 5 at all with the treatment of the same substrates 1d and 2b, which indicated that our
conditions apparently cannot produce the phenoxeium ions. Because the QMAs 1 were not consumed
in the absence of the alkenes 2 in our reaction systems, it seems that the [3+2] coupling reaction
would instead involve the charged QMA species A associated with the acid species for the activation
and is considered to be initiated by the pseudo concerted attack of the alkenes 2 and elimination of the
methanol.
18
ACS Paragon Plus Environment

Page 19 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
Scheme 7. Alternation of the reaction mechanisms by the acid promoters.
7
8
(HꢀA: perfluorobenzoic acid)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Apparently, the important tolerance toward moisture for our reactions has come from the lack of
involvement of the reactive and unstable phenoxenium ions. The [3+2] coupling reaction of the
QMAs 1 proceeded without the use of the absolutely dehydrated HFIP, and the control experiments
with the extra addition of 1 equiv as well as even 5 equiv of water did not cause a remarkable
decrease in the product yields due to the intermediacy of the more stable charged QMA species A
(Scheme 8), which is the significant merit of the nonꢀdiscrete mechanism (pseudoꢀSN2’ pathway).
However, phenoxenium ions generated under the known conditions underwent competitive quinone
formation by hydrolysis of the acetals in the presence of water (SN1 pathway).
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 46
1
2
3
4
5
6
Scheme 8. Examination of the effect of water.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The plausible mechanism for the [3+2] coupling reaction of the QMAs 1 with alkene nucleophiles
2 is suggested in Scheme 9 for the representative coupling substrates, QMA 1a and alkene 2a. For the
activation of the QMA 1a, the initiation step involves the charged QMA A associated with the
combined acid species of perfluorobenzoic acid and HFIP. Due to the super hydrogen bond donor
ability of the fluoroalcohol solvent, preactivation of the Brønsted acid might first occur by the
coordination of HFIP to the Lewis basic functionality of the acid’s carbonyl group (Brønsted acid
activation by HFIP).19 The charged QMA A can now react with the πꢀnucleophile 2a at the ring
carbon α to the carbonyl group, rather than the sterically encumbered tertiary acetal carbon atom, the
concerted course of which seems to enhance the observed steric trends and regioselectivities for the
reaction of the substituted QMAs 1 discussed in Table 2. The pseudoꢀSN2’ꢀlike introduction of the
nucleophile 2a by the reagent control afforded the ketoꢀtype intermediate B, which simultaneously
cyclized at the carbonyl moiety of the QMA with accompanying aromatization as a driving force. The
stepwise constructions of the carbonꢀcarbon and carbonꢀoxygen bonds between the QMA 1a and
πꢀnucleophile 2a would lead to the formation of the formal [3+2] coupling product,
dihydrobenzofuran 3aa. Apparently, the highly polar fluoroalcohol is a good match for the solvation
of all the charged reaction intermediates.
20
ACS Paragon Plus Environment

Page 21 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Scheme 9. A plausible mechanism for the [3+2] coupling reaction of QMA 1a initiated by
9
perfluorobenzoic acid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMS
C6F5CO2H
O
O
TMS
2a
(
)
formal [3+2] coupling
C6F5CO2H
MeO OMe
OMe
(1a)
H-A (Brønsted acid)
(CF3)2CHOH (HFIP)
3aa
(
)
- H+
+
CF3
TMS
H A
HO
O
CF3
activated
acid species
O
hydrogen
bond donor
+
H
(in situ)
+
+
OMe
H
A
MeO
O
B
Me
HO
CF3
CF3
MeOH
A
TMS
(2a)
To prove the intermediary of the preꢀcyclized ketoꢀtype tautomer B, we presented the following
experiment using the Zꢀtype styrene 2l for the coupling reaction (Scheme 10). In fact, the reaction of
the QMA 1a and cisꢀmethyl styrene 2l produced the corresponding cyclized products 3al as a
regiomixture with an about 30:70 ratio of cisꢀ and transꢀdihydrobenzofurans. After prolonged stirring
of the reaction mixture, epimerization of the two isomeric products was not observed. In addition, no
isomerization of the cisꢀolefin to trans one occurred during the reaction. One can easily accept that
these observations clearly support the involvement of the preꢀcyclized cationic intermediate B’, in
which the free rotation of the CꢀC bonds competitively occurred to the cyclizations to form the more
thermodynamically ꢀfavored trans isomer rather than the cisꢀ3al.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 46
1
2
3
4
5
6
7
8
Scheme 10. Formation of the regiomixture via the stepwise cyclization mechanism.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Extension to the Catalytic Systems. Despite the general success of the aboveꢀmentioned results,
several drawbacks still remained from the practical view regarding the chemical reaction for the [3+2]
coupling reaction of the QMAs 1 and nucleophilic alkenes 2 using perfluorobenzoic acid. The
reactions usually required a stoichiometric amount of the acid, which is considered to be a waste
material after the reactions.31 In addition, the acidꢀinduced background polymerization of the used
alkenes 2 as a problem23 forced their excess use, typically over 2 equiv, for the coupling reactions.
Designing a recyclable alternative to perfluorobenzoic acid by attaching the acid function to an
insoluble polymer partially alleviated these drawbacks,14b but the catalysis of the acid promoter with
improved stoichiometry of the used alkenes 2 in the coupling reactions had not been accomplished by
this approach. Indeed, the use of a semiꢀstoichiometric amount of the alkene 2a (1.2 equiv) with
catalytic use of the acid promoter (20 mol%) under the stated optimized conditions significantly
decreased the yield of the [3+2] product 3aa (Table 4, Eq. 2, entries 1 and 2). Reꢀoptimizing the
solvent ratio for the catalytic conditions somewhat positively affected the reaction efficiency (entry 3),
but the benefit was limited only to a relatively high catalyst loading (entry 4).
22
ACS Paragon Plus Environment

Page 23 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 4 Screening for the catalytic [3+2] coupling reaction of 1a and 2a (Eq. 2).[a]
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
perfluorobenzoic acid [mol%]
2a (equiv)[b]
yield of 3aa[c]
1[d]
2[d]
3
pentafluorobenzoic acid [100]
pentafluorobenzoic acid [20]
pentafluorobenzoic acid [20]
pentafluorobenzoic acid [2]
1.2
1.2
1.2
1.2
67%
56%
72%
48%
4
5
6
2,3,5,6ꢀtetrafluorobenzoic acid a [2]
2,3,4,5ꢀtetrafluorobenzoic acid b [2]
3,4,5ꢀtrifluorobenzoic acid c [2]
2,6ꢀdifluorobenzoic acid d [2]
2,5ꢀdifluorobenzoic acid e [2]
perfluorophthalic acid f [1]
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
45%
24%
15%
27%
18%
41%
61%
72%
78%
72%
7
8
9
10
11
12
13
14
perfluoroisophthalic acid g [1]
perfluoroterephthalic acid h [1]
perfluoroterephthalic acid h [5]
perfluoroterephthalic acid h [5]
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 46
1
2
3
4
5
6
7
8
9
15[e]
16[f]
17[g]
perfluoroterephthalic acid h [5]
1.2
1.2
1.2
69%
65%
84%
perfluoroterephthalic acid h [5]
perfluoroterephthalic acid h [5]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[a] Unless otherwise noted, reactions were examined in HFIP/DCM (1/1 v/v, 0.2 M) at room
temperature for 1 hour. [b] Relative to QMA 1a. [c] Isolated yields after purification. Formation of
very small amounts of nonꢀcyclized allylation product was observed. [d] HFIP/DCM (10/1 v/v, 0.2 M
o
of QMA 1a). [e] HFIP/DCM (2/1 v/v, 0.2 M). [f] HFIP/DCM (1/2 v/v, 0.2 M). [g] Performed at 0 C
for 3 hours.
Aimed at realizing a more practical catalytic reaction, we accordingly had to further attenuate the
reactivity of the acid promoter working with a possible minimal loading. Considering that only the
acids with the suitable pKa values served as the efficient promoters for the [3+2] coupling reaction,
we screened a series of perfluorobenzoic acid derivatives a-h with various pKa values (Figure 1, all
commercially available materials). It is thus possible to systematically attenuate the acidity of the
perfluorobenzoic acids by modifying the functionality at the ring positions. For the catalytic reaction
at a 2 mol% loading, all the partial fluorinated benzoic acids a-e showed lower efficiencies and slow
reaction rates (entries 5ꢀ9), probably due to their weaker acidities in comparison to perfluorobenzoic
acid itself. Meanwhile, a set of more acidic phthalic acids f-h were examined with promising results
under the catalytic conditions (entries 10ꢀ12); among the three isomers, the fluorinated terephthalic
acid h showed the best catalytic performance and was capable of providing the coupling product 3aa
in 72% yield even at a 1 mol% loading (entry 12).
24
ACS Paragon Plus Environment

Page 25 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Screened fluorobenzoic acids as catalysts.
Encouraged by the results with the catalyst h, the general effects regarding the catalyst loading,
reactant ratio, concentration, and temperature were further investigated (entries 13ꢀ17). By employing
the catalyst h at 5 mol%, more promising results were obtained (entry 13), which maintained the
product yield at over 70% even with strict use of the alkene 2a at 1.0 equiv (entry 14). The catalytic
reaction at the temperature of 0 oC has now become comparable to the original stoichiometric one for
the dihydrobenzofuran 3aa production when using the best catalyst h at 5 mol% (entry 17).
With the optimal catalyst h and conditions determined, we confirmed the versatility of the catalytic
system for the described QMAs 1 and nucleophilic alkenes 2 in Tables 2, 3, and Scheme 6. In
comparison, it was found that a series of the dihydrobenzofuran products 3 were successfully
produced by employing the 5 mol% catalyst h with the improved stoichiometry of the alkenes 2 (1.2
equiv). The resultant examples are summarized in Table 5. The excellentꢀtoꢀgood yields (up to 98%
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 46
1
2
3
4
5
6
7
8
for the QMA 1e and alkene 2b) compatible with the stoichiometric reactions (Note: the stoichiometric
reactions in Tables 2 and 3 used 2 equiv of the alkenes 2) while maintaining the regioselectivities
have promised the generality of the catalytic method for the practical [3+2] coupling reactions of the
QMAs 1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5 [3+2] coupling reactions by perfluoroterephthalic acid catalyst h (Eq. 3).[a]
entry
1
QMA (1)
alkene (2)
2b
product (3)
3ab
time
4 h
5 h
5 h
5 h
4 h
5 h
8 h
4 h
4 h
3 h
4 h
yield[b]
82%
76%
67%
98%
85%
90%
94%
85%
84%
78%
80%
1a
1b
1c
1e
1f
2
2b
3bb
3cb
3
2b
4
2b
3eb
5
2b
3fb
6
1h
1i
2b
3hb
3ib
7
2b
8
1j
2b
3jb
9
1k
1a
1a
2b
3kb
3ac
10
11
2c
2d
3ad
26
ACS Paragon Plus Environment

Page 27 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
5 h
5 h
4 h
5 h
4 h
7 h
4 h
88%
79%
84%
90%
74%
81%
88%
1a
1a
1a
1a
1a
1a
1a
2e
2f
3ae
3af
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ag[c]
3ah
3ai
2g
2h
2i[d]
2j[d]
2k
3aj
3ak
[a] Reactions were performed using 1.2 equiv of alkenes 2 in the presence of 5 mol% of the acid
catalyst h in HFIP/DCM=1/1 (0.2 M) at room temperature. [b] Isolated yields after purification. [c]
Only trans isomer was obtained. [d] 3 equiv of alkene 2i and 2j was used.
Nonetheless, the much stronger acids, e.g., toluenesulfonic acid, trifluoroacetic and methane
sulfonic acids, on behalf of the catalyst h would provide quite sluggish reaction outcomes, showing
much poorer yields of the desired product 3aa; as already described, such acids were harmful to the
QMA 1a and the alkene 2a (vide supra). Therefore, the appropriate acidity is an important factor
required for the catalyst, while interestingly, aliphatic carboxylic acids having pKa values similar to
that of the catalyst h, that is, the trichloroꢀ and dichloroacetic acids, showed somewhat lower
efficiencies as the catalysts (below 65% yields of the product 3aa at 2 mol% loading). Although the
origin of the higher catalytic activity of the catalyst h is still unclear, one significant difference in the
perfluorobenzoic acids relative to the others is the presence of the intramolecular Hꢀbonding in the
orthoꢀfluorobenzoic acid structure,32 which makes the acidic site of the molecule quite bulky.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 46
1
2
3
4
5
6
7
8
Compared with the less effective catalysts f and g, the best catalyst h has much opportunity for the
HꢀF bondings. It seems that this conformation favorably affected the desired protection of the acetal
carbon in the assumed transition state A (see the mechanism in Scheme 9) from the nucleophilic
attack and thus might exclude the quinone formation by the addition of concomitant water as well as
other side reactions. In our previous studies, steric blocking of the electrophilic acetal carbon by a
bulky activator was very important for suppressing quinone formation.14 Hence, the perfluorinated
benzoic acids would have a superior effect on controlling the coupling reactions in the catalytic cycle
compared to the acids having similar pKas.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Conformation of the perfluoroterephthalic acids.
Conclusions
In summary, we have demonstrated in this study that the quinone monoacetals (QMAs), which have
recently emerged as useful quinone alternatives for controlling the addition and substitution
chemistries due to their unique bifunctional structures based on both the α,βꢀunsaturated carbonyl and
allylacetal moieties in one skeleton, are versatile electrophiles for the efficient [3+2] coupling reaction
with nucleophilic alkenes under specific acidic conditions. The rare success of the substitutionꢀtype
chemistry of QMAs should appear due to the appealing Brønsted acidꢀcontrolled strategy consisting of
the combined system of a specific acid promoter and solvent, that is, perfluorobenzoic acid and
28
ACS Paragon Plus Environment

Page 29 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
fluoroalcohol. This new and expeditious [3+2] coupling reaction smoothly proceeded with a high
regiospecificity for the QMAs by introducing the πꢀnucleophiles toward only the carbons α to the
carbonyl group, providing diverse dihydrobenzofuran products and their derivatives with yields up to
quantitative in short reaction times at room temperature. This investigative report details the estimated
reaction scope and mechanism for their deep understandings and the extension of the preliminary study
(2 equiv of alkenes, 100 mol% acid promoter)15 to develop the coupling reactions at minimal catalyst
loadings with improved stoichiometry of the substrates. Interestingly, the mechanism was rationalized
to proceed via the concerted addition manner including the charged QMA species in the transition state
by coordination of the specific acid promoter, which is activated by the hydrogenꢀbond donor
fluoroalcohol, rather than the discrete phenoxenium ions. In addition, the observation of the
thermodynamicallyꢀfavored dihydrobenzofurans accounts for the stepwise construction of the
carbonꢀcarbon and carbonꢀoxygen bonds of the products via the resulting precyclized ketoꢀ
intermediate (Scheme 9, intermediate B). As the reaction promoter, the perfluorinated benzoic acids
with the intramolecular Hꢀbonding seem to be plausibly effective for controlling the coupling reactions
in the desired substitution manner. Hence, the potent reactivities for additions to the conjugated enone
moiety and quinone formation from QMAs can be excluded by the reagent control. Ongoing studies
with respect to the diversity of the nucleophiles might be expected as the advanced work on this
Brønsted acidꢀcontrolled [3+2] coupling reaction and the basis of the inherent ambident reactivities of
the QMAs.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
1
General. Melting point (mp) was measured by melting point apparatus. H NMR (and 13C NMR)
spectra were recorded by spectrometers operating at 400 or 300 MHz (100 or 75 MHz for 13C NMR) at
29
ACS Paragon Plus Environment