An effective method to introduce carbon acid functionality: 2,2-bis(trifluoromethanesulfonyl)ethylation reaction of arenes

Article abstract of DOI:10.1002/chem.201102023

Introducing strong acids: The reaction of electron-rich arenes with Tf ₂CHCH₂CHTf₂ (Tf=trifluoromethanesulfonyl; triflyl) smoothly gave 2,2-bis(triflyl)ethylated arenes. This reaction provides a convenient methodology for the introduction of a Tf₂CH group, which is known to be a strongly Bronsted acidic functionality, to organic compounds in a regioselective manner (see scheme). On the basis of this reaction, significantly active and thermally stable carbon acid catalysts were developed.

Full text of DOI:10.1002/chem.201102023

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DOI: 10.1002/chem.201102023
An Effective Method to Introduce Carbon Acid Functionality:
2,2-Bis(trifluoromethanesulfonyl)ethylation Reaction of Arenes
Hikaru Yanai, Hiroshi Ogura, Haruhiko Fukaya, Akira Kotani, Fumiyo Kusu, and
Takeo Taguchi*[a]
Organic Brønsted acids are one of the most important
classes of homogeneous and heterogeneous catalysts.[1] In
particular, trifluoromethanesulfonyl (triflyl; Tf)-derived
acids such as TfOH and Tf2NH and their conjugated bases
are attracting much attention from a wide field of chemical
sciences.[2] Methane derivatives substituted by at least two
Tf groups have been also known to show strong Brønsted
acidity.[3,4] However, the development of Brønsted acid cata-
lysts equipped with a Tf2CH group is very limited due to
some synthetic problems; that is, the strong acidity and the
high polarity of these type of carbon acids causes difficulty
in both preparation and purification steps.
performs as one of the most effective Brønsted acid pre-cat-
À
alysts for C C bond forming reactions using silylated nucle-
ophiles.[8,9] This compound can be prepared by the reaction
of Tf2CH2 with paraformaldehyde on a multi-gram scale
(Scheme 1).[10]
Scheme 1. Preparation of Tf2CHCH2CHTf2 1.
Despite these problems, the Tf2CH group is an attractive
functional group and a key structure of acid catalysts with
high catalyst performance. As shown in Figure 1, the Tf2CH
Toward more refined molecular design of acid catalysts
equipped with a Tf2CH group, the direct introduction of the
Tf2CH group to the molecular architecture of organic com-
pounds with regioselectivity (post synthetic Tf2CH-modifica-
tion) would provide a reasonable and convenient approach
to access the desired Tf2CH-substituted molecules. In this
approach, the number of troublesome purification steps of
Tf2CH-substituted molecules can be minimized in principle.
To realize the post synthetic modification of organic mole-
cules by the carbon acid functionality, we were interested in
the labile nature of Tf2CHCH2CHTf2 1 in polar solvent and/
or at high temperature. That is, the 1,3-diacid 1 partly disso-
ciates to Tf2CH2 2 and Tf2C=CH2 3 by a retro-Michael reac-
tion at solution phase (Scheme 2). Due to the high reactivity
Figure 1. Structure of carbon acid.
region shows notably strong Brønsted acidity and the tetra-
valent carbon center makes it possible to introduce substitu-
ents for additional functionality around the active hydrogen.
As a pioneering work on carbon acid catalysis, Yamamoto
and Ishihara reported Tf2CHC6F5 and its derivatives, namely
“super Brønsted acids”.[5,6] The aryl-substituted derivatives,
which are depicted as Tf2CHAr, may be prepared by a step-
wise procedure through the nucleophilic substitution of re-
active benzylic halides by NaOS(O)CF3 and the following
a-triflylation of the resulting monosulfone compounds by
using tBuLi and Tf2O.[7] We also reported that 1,1,3,3-tetra-
kis(trifluoromethanesulfonyl)propane 1 (Tf2CHCH2CHTf2)
Scheme 2. In situ generation of Tf2C=CH2 3 from Tf2CHCH2CHTf2 1.
[a] Dr. H. Yanai, H. Ogura, H. Fukaya, Dr. A. Kotani, Prof. Dr. F. Kusu,
Prof. Dr. T. Taguchi
of 3, the treatment of neutral nucleophiles with 1 in polar
reaction media would result in the regioselective introduc-
tion of carbon acid functionality through irreversible 1,4-ad-
dition reaction to the in situ generated Tf2C=CH2 3.[11] In
this communication, we describe a simple and useful meth-
odology to introduce carbon acid functionality to the arene
framework through in situ generation of Tf2C=CH2. On the
School of Pharmacy, Tokyo University of Pharmacy
and Life Sciences, 1432-1 Horinouchi, Hachioji
Tokyo, 192-0392 (Japan)
Fax : (+81)42-676-3257
E-mail: taguchi@toyaku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102023.
Chem. Eur. J. 2011, 17, 11747 – 11751
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Table 1. 2,2-BisACTHNUTRGNEUNG
(triflyl)ethylation of electron-rich arenes.[a]
basis of this methodology, we also developed some multiple
carbon acid catalysts.
At first, we examined the reaction of Tf2CHCH2CHTf2 1
with 2,6-xylenol (1.1 equiv) as a nucleophile in several reac-
tion media. Results are shown in Scheme 3. The reaction in
Entry
1
Time
[h]
4
Yield
[%][b]
1
4c
R=H
72[c]
2
3
3
1
4d
4e
R=Me
R=tBu
99
96
4
3
4 f
R=Me
86
5
5
10
24
4g
4h
4i
R=Ph
R=Br
R=CO2Me
88
91
79
6[d]
7[d]
Scheme 3. Survey of efficient reaction media.
8
1
4j
70
low polar 1,2-dichloroethane (DCE) was complete in 2 h at
808C. The H and 19F NMR analysis of this reaction mixture
1
9
5
6
5
4k
4m
4n
R=Me
R=Bn
90
70
88
showed the clean formation of the desired 4a and Tf2CH2.
The following bulb-to-bulb distillation (1908C at 3 mmHg)
using a Kugelrohr oven worked effectively to obtain pure
4a in 92% yield.[12] This reaction also proceeded at 808C
under solvent-free conditions. Furthermore, we found that
the use of acetonitrile as a solvent significantly accelerates
this reaction and the desired product 4a was obtained in
94% yield by stirring for a short reaction time at room tem-
perature (method A).[13] In the reaction of 2,6-diphenylphe-
10[e]
11
12
2
4o
80
[a] Reaction conditions: Tf2CHCH2CHTf2
1
(0.25 mmol), arene
(1.1 equiv), MeCN (0.25 mL). [b] Isolated product yield. [c] A mixture of
para/ortho isomers in a ratio of 2.3:1. [d] Reaction was carried out at
1008C in a sealed tube. [e] Reaction was carried out at 808C.
nol, the 2,2-bisACHTUNGTRENNUNG(triflyl)ethyl product 4b cannot be purified
by bulb-to-bulb distillation due to its high boiling point.
Therefore, acceptably pure 4b was obtained in 97% yield
by the complete consumption of phenolic substrate using 1
(1.1 equiv) and the subsequent removal of Tf2CH2 by a Ku-
gelrohr oven (method B).
substrates. By using 1 (1.1 equiv), 4-methylanisole was con-
verted to the product 4k in 90% yield by the reaction for
5 h at room temperature. In the reaction of 1-(benzyloxy)-4-
According to method A, we examined the 2,2-bis-
methylbenzene, bisACTHNGUTERNN(UG triflyl)ethylation selectively proceeded
A
at the more reactive alkoxyarene ring to give the corre-
sponding product 4m in 70% yield. Likewise, 4n and 4o
were isolated in good yields.
Due to the notably high electrophilicity of intermediate
Tf2C=CH2 3, the multiple introduction of carbon acid func-
tionality was also achieved (method B, Scheme 4). By treat-
The reaction of phenol itself was smoothly completed within
1 h at room temperature to give a 2.3:1 mixture of para-4c
and ortho-4c (Table 1, entry 1) in 72% yield. 4-Substituted
phenols such as p-cresol and 4-tert-butylphenol were con-
verted to the corresponding products 4d and 4e in excellent
yields of the isolated product with the perfect regioselectivi-
ty, respectively (Table 1, entries 2 and 3).[14] The substituent
effects on the reactivity were demonstrated in the reactions
of 2-substituted p-cresol derivatives. That is, 2,4-dimethyl-
phenol and 5-methylbiphenyl-2-ol gave the bis-
ACHTUNGTRENNUNG(triflyl)ethylated products 4 f and 4g in excellent yield by
the reaction at room temperature, respectively (Table 1, en-
tries 4 and 5). Meanwhile, phenolic substrates equipped with
electron-withdrawing groups, such as a bromo group and
ester functionality at the 2-position, required both higher re-
action temperature and a prolonged reaction time to com-
plete the reaction (Table 1, entries 6 and 7). In the reaction
of 2-naphthol, bisACHTUNGTRENNUNG(triflyl)ethylation occurred at the most re-
active 1-position to give 4j in 70% yield (Table 1, entry 8).
We also found that this reaction can be applied to aryl ether
Scheme 4. Preparation of multiple carbon acids.
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An Effective Method to Introduce Carbon Acid Functionality
COMMUNICATION
Table 2. Efficiency in carbon acid-induced VMA reaction.
ing with Tf2CHCH2CHTf2 (3.0 equiv) 1 at 808C, 4-alkylated
phenols such as p-cresol and 4-tert-butylphenol were
smoothly converted to the corresponding double-bis-
ACHTUNGTRENNUNG(triflyl)ethylated products 5d and 5e in 74 and 88% yield,
respectively. In addition, the reaction of benzene-1,3,5-triol
with 1 (3.3 equiv) at room temperature gave the trisubstitut-
ed compound 6 in 64% yield (Scheme 4).
Since the present reaction proceeds under the mild condi-
tions, this procedure could be applied to the direct modifica-
tion of biologically active phenols. For example, the bis-
Entry
Acid catalyst
G
Yield of
[a][%]
7
1[b]
2
3
4
5
1
82
0
0
78
83
4a
4b
5e
6
ACHTUNGTRENNUNG
[a] Combined yield of isolated 7-Si and 7-H. [b] From ref. [8b]. Reaction
was carried out at À248C.
AHCTUNGTRENNUNG
a
(Scheme 5). Furthermore, the reaction of aryl ether (teth-
ered by propanylene linker) with 1 (2.2 equiv) successfully
gave the double-bisACTHNUTRGNE(NUG triflyl)ethylated products 4q in 76%
yield. These examples clearly show that this reaction is a
powerful tool for the post synthetic Tf2CH-modification of
complex arenes.
none smoothly proceeded at room temperature to give the
desired VMA product 7 in 78% yield (Table 2, entry 4). As
shown in Table 2 (entry 5), the reaction in the presence of
triple carbon acid 6 gave essentially the same result.
Multiple carbon acids can be also used as simple Brønsted
acid catalysts. For example, the reaction of (+)-menthol
with benzoic anhydride was nicely catalyzed by the triple
carbon acid 6 (3 mol%) at 708C to give benzoate 8 in 93%
yield (Scheme 6). By using the double carbon acid 5e in-
Scheme 5. Post synthetic Tf2CH modification.
Next, we evaluated the catalyst activity of some prepared
carbon acids in the vinylogous Mukaiyama aldol (VMA) re-
action of cyclohexanone with 2-TBSO-furan. Selected re-
sults are shown in Table 2. Previously, we reported that
Tf2CHCH2CHTf2 1 performs as an external Brønsted acid
catalyst for this reaction and its activity is significantly stron-
ger than those of TfOH and Tf2NH.[8b] That is, 0.5 mol% of
1 was enough to complete this reaction and a mixture of the
VMA product 7-Si and 7-H was obtained in 82% yield by
the reaction at À248C (Table 2, entry 1). On the other hand,
although this VMA reaction was not promoted by 4a and
4d (Table 2, entries 2 and 3), multiple carbon acids such as
5e and 6 showed the excellent activity as external Brønsted
acid catalysts.[15] By using only 0.05 mol% of 5e, which has
a phenolic hydroxy group and two carbon acid functionali-
ties in the molecular structure, the reaction of cyclohexa-
Scheme 6. Reactions catalyzed by multiple carbon acids.
stead of the triple carbon acid 6, the reaction was not com-
plete within the short reaction time. Under the same condi-
tions, the reaction in the absence of any carbon acids gave
benzoate 8 in only 5% yield. Furthermore, it has been re-
ported that benzoylation of sterically hindered menthol with
benzoic anhydride is not catalyzed by strongly acidic per-
fluoroalkane-sulfonic acids such as Nafion.[5a] As shown in
Scheme 6, carbon acid 6 was also effective for the acetal-
forming reaction of aldehyde. Since the acetal-forming reac-
tion of aldehyde with orthoformate is well known to be car-
ried out in the presence of classical acid catalysts such as
TsOH·H2O, this result is important evidence suggesting that
Chem. Eur. J. 2011, 17, 11747 – 11751
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11749

T. Taguchi et al.
multiple carbon acids can act as real “Brønsted acid” cata-
lysts.
such as axis-chiral biaryl frameworks and biaryl ether frame-
works are well used as a scaffold for functional materials.
The present methodology would be applicable to these
structurally more complex arenes. Further studies according
to this concept (the post synthetic Tf2CH-modification of
complex arenes) are under progress in our laboratory.
These results demonstrate that the number of Tf2CH
groups plays an important role to increase in the catalyst ac-
tivity. The pKa values in DMSO measured by the voltam-
metric method[16] clearly showed that the acidities of multi-
ple carbon acids such as 5e (pKa =2.1) and 6 (pKa =2.0) are
stronger than that of 2,4-dimethylphenol-derived carbon
acid 4 f (pKa =2.3).[4] The strong acidity supported by the
statistical (symmetric) effect of multiple carbon acids would
be a crucial factor for their high activity as Brønsted acid
catalysts.[17] In addition, the specific interaction between
Experimental Section
Preparation of Tf2CHCH2CHTf2 1:[10] Paraformaldehyde (90% purity,
122.6 mg, 3.7 mmol) was slowly added to a solution of Tf2CH2 2 (2.0 g,
7.1 mmol) in CH2Cl2 (6.0 mL) at room temperature. After being stirred
at 408C for 6 h, the reaction mixture was dried over anhydrous MgSO4
and concentrated under reduced pressure. The resulting solid was recrys-
talized from chlorobenzene to give Tf2CHCH2CHTf2 1 in 88% yield
(1.8 g, 3.1 mmol). 1H NMR (400 MHz, CDCl3) d=3.46 (2H, t, J=
7.0 Hz), 5.83 ppm (2H, t, J=7.0 Hz); 13C NMR (106 MHz, CDCl3) d=
22.8, 72.5, 119.3 ppm (q, JCÀF =329.6 Hz); 19F NMR (282 MHz, CDCl3)
d=À9.5 (12F, s).
Preparation of 4-(2,2-bis(trifluoromethylsulfonyl)ethyl)-2,6-dimethylphe-
nol 4a: Tf2CHCH2CHTf2 1 (143.2 mg, 0.25 mmol) was added to a solu-
tion of 2,6-xylenol (34.1 mg, 0.28 mmol) in acetonitrile (0.25 mL) at room
temperature. After being stirred at the same temperature for 3 h, the re-
action mixture was concentrated under reduced pressure. The resultant
residue was purified by kugelrohr distillation (180–2008C at 3 mmHg) to
acidic functionalities in 2,6-bisACTHNUTRGENN(UG bisACHTUTGNREN(NUGN triflyl)ethyl) phenol struc-
ture would improve the catalyst activity. In fact, an X-ray
crystallographic analysis of 5e confirmed the intramolecular
hydrogen bonding between the phenolic hydroxy group and
sulfonic oxygen (see, Figure 2 and the Supporting Informa-
tion). In two different conformers of 5e, which form the
unit cell as two pairs, the distances between phenolic oxygen
and sulfonic oxygen were 2.82 and 2.93 ꢁ, respectively. The
À
À
O H···O angles (142.3 and 148.28), C O···O angles (90.4
and 93.98) and O···O=S angles (127.7 and 122.08) also sup-
ported for the intramolecular hydrogen bond. This intramo-
lecular hydrogen bonding would enhance the Brønsted acid-
ity of Tf2CH group. A similar intramolecular hydrogen
bonding was observed in a crystal of triple acid 6. In con-
trast, the 2-naphthol-based derivative 4j did not show this
type of hydrogen bonding in a crystal structure.
give 4a in 94% yield (96.9 mg, 0.234 mmol) with recovery of Tf2CH2
(64.7 mg, 0.231 mmol). Colorless crystals (hexane); M.p. 77.7–79.48C; IR
(KBr): n˜ =3585, 2932, 1492, 1393, 1208, 1109, 694 cmÀ1 1H NMR
2
;
(400 MHz, CDCl3): d=2.23 (6H, s), 3.67 (2H, d, J=5.7 Hz), 4.76 (1H, s,
OH), 5.03 (1H, t, J=5.7 Hz), 6.90 ppm (2H, s); 13C NMR (100 MHz,
CDCl3) d=15.8, 29.8, 80.2, 119.2 (q, JCÀF =330.0 Hz), 123.9, 124.3, 129.2,
152.3 ppm; 19F NMR (282 Hz, CDCl3): d=À9.8 (6F, s); MS (ESI-TOF)
m/z: 437 [M+H]+; HRMS calcd. for C12H12F6O5S2 [M+Na]+, 436.9928;
found, 436.9918. Elemental analysis calcd for C12H12F6O5S2: C, 34.78; H,
2.92. Found: C, 35.18; H, 3.07.
Keywords: acidity
· aldol reaction · Brønsted acids ·
esterification · homogeneous catalysis
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methodology to introduce Tf2CH functionality to arene
frameworks through in situ-generation of Tf2C=CH2. Since
this methodology realizes the extensive molecular design of
a carbon acid equipped with a Tf2CH group, we also suc-
ceeded in the development of highly active Brønsted acid
catalysts (and pre-catalysts) having multiple carbon acid
functionality. It is also noted that arene-based structures
[4] The pKa value of Tf2CH2 in DMSO is 2.1. Tf2CH2 also performs as a
stronger Brønsted acid in solution phase compared with PhOH
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An Effective Method to Introduce Carbon Acid Functionality
COMMUNICATION
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sulted in the formation of a considerable amount (43% yield) of di-
arylmethane as a side product.
[13] The reactions in dibutyl ether or in toluene resulted in the formation
of a complex mixture.
[14] In the reaction of p-cresol with Tf2CHCH2CHTf2 1, Tf2CH2 2 was
recovered in 89% by bulb-to-bulb distillation of crude mixture (see,
the Supporting Information). Recovered Tf2CH2 2 was also used as
a staring material for Tf2CHCH2CHTf2.
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months.
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Received: July 1, 2011
Published online: September 2, 2011
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