Cyclization of arylacetoacetates to indene and dihydronaphthalene derivatives in strong acids. Evidence for involvement of further protonation of O,O-diprotonated β-ketoester, leading to enhancement of cyclization

Article abstract of DOI:10.1021/ja908749u

The chemical features, such as substrate stability, product distribution, and substrate generality, and the reaction mechanism of Bronsted superacid-catalyzed cyclization reactions of aromatic ring-containing acetoacetates (β-ketoesters) were examined in detail. While two types of carbonyl cyclization are possible, i.e., keto cyclization and ester cyclization, the former was found to take place exclusively. The reaction constitutes an efficient method to synthesize indene and 3,4-dihydronapthalene derivatives. Acid-base titration monitored with ¹³C NMR spectroscopy showed that the acetoacetates are fully O¹,O³-diprotonated at H ₀) -11. While the five-membered ring cyclization of the arylacetoacetates proceeded slowly at H₀) -11, a linear increase in the rate of the cyclization was found with increasing acidity in the high acidity region of H₀) -11.8 to -13.3. Therefore, the O ¹,O³-diprotonated acetoacetates exhibited some cyclizing reactivity, but they are not the reactive intermediates responsible for the acceleration of the cyclization in the high acidity region. The reactive cationic species might be formed by further protonation (or protosolvation) of the O¹,O³-diprotonated acetoacetates; i.e., they may be tricationic species. Thermochemical data on the acid-catalyzed cyclization of the arylacetoacetates showed that the activation energy is decreased significantly as compared with that of the related acid-catalyzed cyclization reaction of a compound bearing a single functional group, such as a ketone. These findings indicate that intervention of the trication contributes to the activation of the cyclization of arylacetoacetates in strong acid, and the electron-withdrawing nature of the O-protonated ester functionality significantly increases the electrophilicity of the ketone moiety.

Full text of DOI:10.1021/ja908749u

Published on Web 12/17/2009
Cyclization of Arylacetoacetates to Indene and
Dihydronaphthalene Derivatives in Strong Acids. Evidence for
Involvement of Further Protonation of O,O-Diprotonated
ꢀ-Ketoester, Leading to Enhancement of Cyclization
Hiroaki Kurouchi, Hiromichi Sugimoto, Yuko Otani, and Tomohiko Ohwada*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received October 14, 2009; E-mail: ohwada@mol.f.u-tokyo.ac.jp
Abstract: The chemical features, such as substrate stability, product distribution, and substrate generality,
and the reaction mechanism of Brønsted superacid-catalyzed cyclization reactions of aromatic ring-containing
acetoacetates (ꢀ-ketoesters) were examined in detail. While two types of carbonyl cyclization are possible,
i.e., keto cyclization and ester cyclization, the former was found to take place exclusively. The reaction
constitutes an efficient method to synthesize indene and 3,4-dihydronapthalene derivatives. Acid-base
titration monitored with 13C NMR spectroscopy showed that the acetoacetates are fully O1,O3-diprotonated
at H0 ) -11. While the five-membered ring cyclization of the arylacetoacetates proceeded slowly at H0 )
-11, a linear increase in the rate of the cyclization was found with increasing acidity in the high acidity
region of H0 ) -11.8 to -13.3. Therefore, the O1,O3-diprotonated acetoacetates exhibited some cyclizing
reactivity, but they are not the reactive intermediates responsible for the acceleration of the cyclization in
the high acidity region. The reactive cationic species might be formed by further protonation (or
protosolvation) of the O1,O3-diprotonated acetoacetates; i.e., they may be tricationic species. Thermo-
chemical data on the acid-catalyzed cyclization of the arylacetoacetates showed that the activation energy
is decreased significantly as compared with that of the related acid-catalyzed cyclization reaction of a
compound bearing a single functional group, such as a ketone. These findings indicate that intervention of
the trication contributes to the activation of the cyclization of arylacetoacetates in strong acid, and the
electron-withdrawing nature of the O-protonated ester functionality significantly increases the electrophilicity
of the ketone moiety.
Scheme 1. Chemoselective Cyclization
Introduction
Since sulfuric acid-catalyzed cyclization of 2-aceto-4-phe-
nylbutyrate (ꢀ-phenethylacetoacetates) to afford six-membered
3,4-dihydronapthalene derivatives was reported in 1925 (Scheme
1, n ) 2),1,2 there have been several studies of related reactions,
such as the transformation of 2-aceto-3-arylpropionates to five-
membered indene derivatives (Scheme 1, n ) 1),3 which was
recently applied to the synthesis of bioactive indenone deriva-
tives.4 However, especially in the case of the five-membered
ring cyclization to afford indene derivatives, the previous studies
have been limited to substrates containing aromatic rings bearing
(1) Auwers, K. v.; Mo¨ller, K. J. Prakt. Chem. (Leipzig) 1925, 104, 124–
152.
a strong electron-donating group, such as a hydroxyl or an
alkyloxy group.3
(2) (a) Bardhan, J. C.; Adhya, R. N.; Bhattacharyya, K. C. J. Chem. Soc.
1956, 1346–1349. (b) Nasipuri, D. J. Chem. Soc. 1958, 2618–2621.
(c) Nasipuri, D.; Roy, D. N. J. Chem. Soc. 1961, 3361–3366. (d)
Griffin, R. W.; Gass, J. D.; Berwich, M. A.; Shulman, R. S. J. Org.
Chem. 1964, 29, 2109–2116. (e) Wenkert, E.; Greenfield, S. A. Chem.
Ind. (London) 1967, 1252.
On the other hand, in the six-membered ring cyclization to
afford 3,4-dihydronapthalene derivatives, a halogen substituent
on the aromatic ring was reported to allow the cyclization.2d
Although the previous studies have uncovered the substituent
effects at least in part, the scope of these cyclization reactions
is still unknown and the mechanisms are poorly understood.
Mechanistically, either keto cyclization (a) or ester cyclization
(b) appears to be possible (Scheme 1), but in fact, the keto
cyclization exclusively takes place. The acetoacetate functional-
ity (generally ꢀ-ketoester) (A, Scheme 2) is expected to undergo
(3) (a) Koo, J. J. Am. Chem. Soc. 1953, 75, 1891–1895. (b) Koo, J.
Organic Syntheses; John Wiley & Sons: New York, 1973; Collect.
Vol. V, pp 550-551. (c) Guy, A.; Guette´, J.-P. Synthesis 1980, 222–
223. (d) Ghoshal, P. N.; Pathak, B. J. Indian Chem. Soc. 1976, 53,
1126–1130.
(4) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee,
S. D.; Jung, W. H.; Yang, S. D.; Kim, S. J.; Woo, J. R.; Lee, J. H.;
Cheon, H. G.; Kim, S. S. J. Med. Chem. 2006, 49, 4781–4784.
9
10.1021/ja908749u  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 807–815 807

A R T I C L E S
Kurouchi et al.
Scheme 2. Protonation of 1,3-Dicarbonyl Compounds
Scheme 3
multiple protonations in strong Brønsted acids. Indeed, proto-
nations of 1,3-dicarbonyl compounds, such as 1,3-diketones,
ꢀ-ketoesters, and ꢀ-ketoacids, in superacids have been inten-
activated tricationic electrophiles. These highly reactive trica-
tionic species enhance the keto cyclization reaction in strong
acid.12
sively studied by Brouwer,5 Olah,6 Larsen,7 and others.8
A
number of reports have noted that 1,3-dicarbonyl compounds
can be diprotonated: O1,O3-diprotonated dicarbonyl species (D)
have been obtained from ꢀ-ketoesters (R2 ) OR),5–7 as well as
ꢀ-ketoacids (R2 ) OH)6 and ꢀ-ketoamides (R2 ) NRR′),9 in
superacid solutions. The two important resonance structures for
the dication are the bisoxonium structure (D-1) and the
biscarbenium structure (D-2).
Results and Discussion
Chemical Features of the Cyclization Reactions. Reaction
Conditions. We optimized the reaction conditions (acid, amount
of acid, cosolvent, reaction temperature, reaction time, etc.) by
using the parent unsubstituted substrate methyl 2-aceto-3-
phenylpropionate (1a) as a prototype (Scheme 3 and Table 1).
Sulfuric acid, which has frequently been employed,1,2 was found
to promote the five-membered ring cyclization reaction of 1a
to afford indenes, i.e., a mixture of 2-(methoxycarbonyl)-3-
methylindene (2a) and 3-methylindene-2-carboxylic acid (3a)
(Table 1 and Scheme 3). However, the yield of the cyclized
products was only moderate (49% yield) (Table 1, entry 1).
Therefore, we studied the cyclization of 1a catalyzed by
trifluoromethanesulfonic acid (TFSA): In the presence of TFSA,
1a underwent the cyclization reaction to give a mixture of
indenes, 2a and 3a, in high yield (Table 1, entries 2-5).
In the presence of various amounts of TFSA (10-50 equiv),
the reactions of 1a were consistently efficient and clean (entries
2-5). In the case of 5 equiv of TFSA, the reaction of 1a was
rather slow (entry 6). On the other hand, in the case of 1b
(entries 11-13), which contains an electron-rich aromatic
system, naphthalene, and 5 equiv of TFSA, rather than 10 equiv,
together with the use of dichloromethane (DCM) as a cosolvent
(entries 11-12) was most efficient (minimizing the formation
of some undefined subsidiary reaction products). When 50 equiv
of TFSA was used, the combined yield of 2b and 3b signifi-
cantly decreased (entry 13). Therefore, for synthetic practicality,
we chose to use 5 or 10 equiv of TFSA together with DCM as
a cosolvent, throughout our study of the substrate generality of
the reaction.
The former structure is called a distonic (i.e., distant) dication,
and the latter is called a gitonic (i.e., close) dication, according
to Olah.10 Both dicationic resonance structures (D-1 and D-2)
of O1,O3-diprotonated dicarbonyl compounds bear cationic
centers that are unconjugated and separated at least by one
carbon atom. Thus, these cationic centers are assumed to interact
with each other through an inductive effect. Diprotonated ethyl
acetoacetate (D, R1 ) H, R2 ) OEt) was observed by low-
5
temperature NMR under stable ionic conditions (in HF-SbF5
6
and FSO3H-SbF5 ). These dications (D) have been proposed
to act as superelectrophiles in some Friedel-Crafts-type
reactions.9,11 In this paper we will disclose the reaction features,
substrate generality, and reaction mechanism of the acid-
catalyzed cylization reaction of arylacetoacetates 1 to afford
indenes and 3,4-dihydronapththalene derivatives in Brønsted
superacids. This is the first time that these variations of product
distribution, or even the basic reaction features, have been
reported. While related O1,O3-diprotonated arylacetoacetates (D,
R1 ) -(CH2)nAr, R2 ) OMe) show some cyclizing reactivity,
the present study provides evidence supporting the inVolVement
of further protonation (or protosolVation) of O1,O3-diprotonated
arylacetoacetates in the high acidity region, generating highly
Reaction Features. As shown in Table 1 and Scheme 3, the
acid-catalyzed cyclization reaction of 1a/b afforded a mixture
of ester (2a/b) and carboxylic acid (3a/b) products. The
formation of 3 was rather unexpected, because previous studies
have indicated that esters are generally stable in TFSA (this is
also the case for the ester products 2q-2s in Table 2).13,14 We
speculated that indenecarboxylic acid 3a was formed by aqueous
quenching of the acylium ion 5a, which would be formed in
the acid medium through acid-catalyzed ester cleavage of the
(5) Brouwer, D. M. Recl. TraV. Chim. Pays-Bas 1968, 87, 225–237.
(6) Olah, G. A.; Ku, A. T.; Sommer, J. J. Org. Chem. 1970, 35, 2159–
2164.
(7) Larsen, J. W.; Bouis, P. J. Am. Chem. Soc. 1975, 97, 6094–6102.
(8) Bruck, D.; Dagan, A.; Rabinovitz, M. Tetrahedron Lett. 1978, 19,
1791–1794.
(9) (a) Klumpp, D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A.
Org. Lett. 2004, 6, 1789–1792. (b) Kumar, K.; Sai, S.; Gilbert, T. M.;
Klumpp, D. A. J. Org. Chem. 2007, 72, 9761–9764.
(10) Review:Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767–
788.
(12) Mayr, H.; Ofial, A. R. Angew. Chem., Int. Ed. 2006, 45, 1844–1854.
(13) With poly(phosphoric acid) (PPA) catalyst, the ester functionality
remained in the indene products from the reaction of arylacetoacetates
(see ref 3).
(14) Nakamura, S.; Sugimoto, H.; Ohwada, T. J. Org. Chem. 2008, 73,
4219–4224.
(11) (a) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their
Chemistry; John Wiley & Sons: New York, 2008. (b) Olah, G. A.;
Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211–220. (c) Lammertsma,
K.; Schleyer, P. v. R.; Schwarz, H. Angew. Chem., Int. Ed. Engl. 1989,
101, 1313–35.
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808 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Cyclization of Arylacetoacetates
A R T I C L E S
Table 1. Reaction and Workup Conditions
entry
substrate
acid//workup
cosolventa
temp (°C)
time (h)
yield (%) (2:3)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
4a
H2SO4 (20 equiv)
TFSA (50 equiv)
TFSA (20 equiv)
TFSA (10 equiv)
none
none
none
DCM
DCM
DCM
none
DCM
DCM
none
DCM
DCM
none
DCM
20
0
0
0
19
0
0-24
25//25
25
0//15
0
5
5
5
49 (12:88)
97 (38:62)
90 (69:31)
76 (62:38)c
87 (67:33)
24 (63:37)d
92 (11:89)
85 (0:100)
87 (100:0)
91 (86:7)
20
10
30
7.5
15//8
15
5//22
1.5
2.0
0.5
7
TFSA (10 equiv)
TFSA (5 equiv)
TFSA (20 equiv) + CF3CO2Na (2 equiv)e
TFSA (10 equiv)//TFA (12 equiv)f
g
TFSA (10 equiv)//(TMS)CHN2
TFSA (50 equiv)//Na2CO3/MeOH
TFSA (10 equiv)
TFSA (5 equiv)
TFSA (50 equiv)
TFSA (10 equiv)
h
83 (77:23)
93 (74:26)
44 (40:60)
70 (0:100)
0
0
0-25
a DCM ) dichloromethane. Typical reaction procedure: To a solution of 1 (1 mmol) in 5 mL of DCM was added a specified amount of the acid at 0
°C. After the specified reaction time at the specified temperature, water was added to the reaction mixture. The whole was extracted with DCM, and the
crude products were purified by column chromatography (silica gel). b Combined yield of the product ester 2 (R ) Me) and carboxylic acid 3 (R ) H)
based on the isolation yield. The ratio of the ester 2 and the carboxylic acid 3 is shown in parentheses. c Recovery 22%. d Recovery 73%. e Sodium
trifluoroacetate (2 equiv) was added to the TFSA solution in the initial stage. f After the completion of the cyclization reaction in TFSA, TFA (12 equiv)
was added to the TFSA solution. The mixture was stirred at 25 °C for 8 h. g The crude product was esterified with TMS-diazomethane (1 equiv) in 3
mL of DCM, followed by isolation with column chromatography. h After the completion of the cyclization reaction in TFSA (0 °C, 5 h), the whole was
added to a mixture of Na2CO3 (50 equiv) and 20 mL of dry methanol, cooled at -78 °C. The whole was stirred at 15 °C for 22 h.
conjugate ester 2a or its protonated form (2a-H) (Scheme 4).15
To clarify the features of this reaction, the acid solution of 1a
in TFSA (10 equiv) was monitored in situ by 1H NMR
carboxylation at room temperature to give the ketone 4-phe-
nylbutan-2-one (6a) (e.g., neat 4a under an argon atmosphere
at rt was completely decarboxylated to 6a within 30 h). Thus,
4a is of limited practical value as a starting material of the
relevant cyclization reaction (Scheme 3), although when it was
used immediately after synthesis, it underwent cyclization to
afford only 3a in 70% yield in TFSA (Table 1, entry 14). In
this context, the use of the acetoacetates 1 as the starting
material, even though they produce a mixture of the ester 2
and the carboxylic acid 3, seems the best practical option.
spectroscopy at -16 °C (Figure 1).16 The integral of the H
1
NMR signal was normalized in terms of the initial concentration
of 1a.17 In TFSA solution, protonated 1a was observed at the
initial stage of the cyclization reaction (Figure 1).17 As the
cyclization reaction proceeded (i.e., as 1a decreased), 2a-H
(protonated 2a) appeared. Compound 5a was detected following
the accumulation of 2a, but it was not present in the initial stage
of the cyclization reaction (the structure of ion 5a was
experimentally confirmed; see Supporting Information Figure
S1).18 Finally, most of 1a was consumed, leaving 2a-H and 5a
in the solution. Cyclized product 2a-H gave neutral 2a, and
the ion 5a gave carboxylic acid 3a in the aqueous workup
process.16
Because we obtained a mixture of indene ester and inden-
ecarboxylic acid in the reaction of 1a, it may be reasonable to
use benzylacetoacetic acid (4a) (Scheme 3), instead of 1a, as a
starting material. However, 4a was too unstable to be stored
under conventional conditions: it undergoes spontaneous de-
Isolation. When the crude mixture of products (the ester 2a
and acid 3a), obtained after completion of the cyclization
reaction of 1a in TFSA, was subjected to esterification with
TMS-diazomethane, only the indene methyl ester 2a was
obtained in 87% yield (Table 1, entry 9). When the cyclization
reaction of 1a in TFSA (50 equiv) at 0 °C was quenched with
cold MeOH/Na2CO3, the ester product 2a was much favored
over the acid product 3a (Table 1, entry 10). Furthermore, when
the cyclization reaction of 1a was accomplished in TFSA
containing sodium trifluoroacetate (2 equiv) at 24 °C for 7.5 h,
where the acidity of the acid medium was lower, a more biased
reaction occurred in favor of the indenecarboxylic acid 3a (2a:
3a ) 11:89, Table 1, entry 7). Instead of the salt, addition of
TFA to the acid reaction mixture, obtained after completion of
the cyclization of 1a in TFSA, resulted in complete conversion
of the cyclized products to the carboxylic acid 3a (85% yield)
after 8 h at 25 °C (Table 1, entry 8). In a weaker acid, ester
cleavage of 2a was enhanced to afford 3a (see Scheme 4). These
results are consistent with the present and previous observations
that the formation of 3 was favored (3a in Table 1, entry 1) or
exclusive (in the literature1,2) in sulfuric acid (H0 ≈ -10), a
weaker acid than TFSA.
(15) Olah, G. A.; Hartz, N.; Rasul, G.; Burrichter, A.; Prakash, G. K. S.
J. Am. Chem. Soc. 1995, 117, 6421–6427.
(16) This experiment used an amount of TFSA similar to that in the cases
of entries 3-6 in Table 1. The ratios of 2a-H and 5a (they correspond
to 2a and 3a after aqueous workup) in Figure 1 are consistent with
those of 2a and 3a observed in entries 3-6 in Table 1.
(17) In TFSA, 1a formed protonated keto (1a-H) and enol (1a′-H) forms.
Similar enol formation in the acid was also observed in the case of
1d (see Scheme 5). In Figure 1, we show the summation of 1a-H and
1a′-H as the amount of 1a for the sake of simplicity.
Substrate Generality. We studied the substrate generality of
the cyclization reaction of arylacetoacetates (Table 2). Ethyl
esters, such as 1c, showed reactivity similar to that of methyl
ester 1a. In the case of the five-membered ring cyclization to
afford indene derivatives, the compounds bearing alkyl (1e-1h)
and phenyl (1i) substituents on the benzene ring underwent
efficient cyclization reaction in a similar manner to that of the
naphthalene substrate 1b, affording the cyclized products
(18) Methyl cinnamate afforded cinnamic acid (9% yield) in TFSA (10
equiv) with DCM as a cosolvent at 25 °C for 15 h, followed by
aqueous workup (86% recovery, based on 1H NMR integration).
Similarly, in TFSA (50 equiv), methyl cinnamate afforded the
carboxylic acid in 31% yield (recovery 54%, isolation yield) after 40 h.
The saturated methyl ester 16a did not yield the corresponding
carboxylic acid in TFSA at-6 °C.
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A R T I C L E S
Kurouchi et al.
Table 2. Substrate Generality of the Cyclization Reaction of 1a-1s
a Isolation yield. Reaction conditions: 1 (1 mmol), TFSA (10 equiv), and DCM (5 mL). The ratio of the ester 2 (R ) Me or Et) and the carboxylic
acid 3 (R ) H) is shown in parentheses. b TFSA (50 equiv), 0 °C, 5 h (without DCM). c A 5 equiv amount of TFSA was used. d The carboxylic acid
e
product 3c is the same as 3a. The ratios of the products were determined by the integration of H NMR signals after column chromatography. f When
10 equiv of TFSA was used, the product ester 2i (55%) and carboxylic acid 3i (20%) were obtained after 3 h at 22 °C. g TFSA (50%)-TFA (50%) (10
equiv), DCM, 0 °C, 1 h.
1
with those of a previous study using sulfuric acid.2d Therefore,
Scheme 4
the six-membered ring cyclization proceeds more readily than
the five-membered ring cyclization under similar conditions.
This is probably because a 6-exo-trigonal cyclization transition
state is more favorable than a 5-exo-trigonal one, having less
conformational strain.14,19
The effects of variation of the acyl group of 1 on the reaction
were also studied: 1j (n-propyl group) and 1p (ethyl group)
underwent the cyclization reaction efficiently to afford the
corresponding cyclized products (2j/3j and 2p/3p) in high yields.
However, an isopropyl substituent in the acetyl moiety of 1k
resulted in the formation of a complex mixture (data not shown).
Furthermore, the arylacetoacetates 1q, 1r, and 1s (Table 2),
in which the R-proton was replaced with a methyl group,
afforded the keto-cyclized products in TFSA: the reaction of
(84-91% yield, Table 2). On the other hand, a bromo substituent
on the benzene ring (1d) hampered the cyclization under typical
reaction conditions. As for six-membered ring cyclization,
methyl 2-aceto-4-phenylbutyrate (1k) underwent the cyclization
reaction in TFSA to afford 1-methyl-2-carbomethoxy-3,4-
dihydronaphthalene (2k) and 1-methyl-3,4-dihydronaphthalene-
2-carboxylic acid (3k) in high yield (87% combined yield). In
the case of the six-membered ring cyclization, the substrates
bearing halogen substituents (1l and 1m) also underwent
efficient cyclization reaction (80% and 82% yield, respectively)
in a manner similar to that of substrates bearing an alkyl
substituent (1n and 1o). The results for 1l and 1m are consistent
(19) (a) Nakamura, E.; Sakata, G.; Kubota, K. Tetrahedron Lett. 1998, 39,
2157–2158. (b) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476–482.
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810 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Cyclization of Arylacetoacetates
A R T I C L E S
Figure 1. 1H NMR-monitored reaction profile of cyclization of 1a in TFSA
(at -16 °C).
Figure 2. Acid titration curves of 1d (at -15 °C).
1q afforded the ester 2q (as a single product) in 80% yield in
TFSA, the yield being comparable to that of the reaction of
nonmethylated 1k. In the five-membered ring cyclization, the
yields of the cyclized products 2r and 2s were lower, but similar
keto cyclization proceeded. These facts exclude the possibility
that an enolizable R-proton is a prerequisite for the reaction
and the resultant enol forms of the acetoacetate 1 participated
in the cyclization reaction (vide post; see also ref 22).
Acidity Dependence of the Cyclization. The reaction showed
apparent acidity dependence (Table 3). As the acidity of the
acid medium increased,20 the indene cyclization of 1a started,
and the yield of the cyclized products (combined yield of ester
2a and acid 3a) increased. We studied the acidity dependence
of the reaction of 1a in the absence (Table 3) and in the presence
of DCM as a cosolvent (Supporting Information Table S1).21
The cyclization reaction of 1a proceeded, but only slightly (6%
yield of 3a), in a weaker acid, e.g., at H0 ) -9.7, at 0 °C for
5 h (Table 3, entry 3), and a large amount of the starting 1a
was recovered (recovery 83%). At -11.8 (H0) (entry 4), the
yield of the cyclized products was increased (35%). As judged
from the yield of the cyclized products (under the present
reaction conditions: 0 °C, 5 h), the cyclization of 1a to afford
indenes 2a and 3a was complete in the acidity range of -13 to
-14.1 (H0). The kinetics of 1a were studied in the acidity range
of -11 to -13 (vide post).
Furthermore, in the case of the cyclization to dihydronaph-
thalene, the cyclization of 1k is also promoted as the acidity of
the medium is increased (Table 3, entries 7-12). In the case of
the reaction of 1k, the cosolvent DCM was used. The reaction
of 1k started even at H0 ) -7.8 (6% yield of the cyclized
products) (entry 8), and a 58% yield of the cyclized products
(10% yield of ester 2k and 48% yield of the acid 3k) was
obtained at H0 ) -9.7 (entry 9), together with recovery of the
acetoacetate 1k (38%). The cyclization of 1k to afford dihy-
dronaphthalenes 2k and 3k was complete at acidity between
H0 ) -11.8 and H0 ) -14.1 under the present reaction
conditions (0 °C, 1 h). The cyclization of 1k to afford 2k/3k
was too rapid to allow precise study of the kinetics.
Acid-Base Titration of Arylacetoacetates. We carried out
titration of arylacetoacetate with the present acid system,
TFSA-TFA, at various levels of acidity. Methyl 2-aceto-3-(p-
bromophenyl)propionate (1d) was used as a base substrate
1
because of its inertness to cyclization (see Table 2). In the H
and 13C NMR spectra obtained at -15 °C (in the absence of
DCM), we could detect the carbonyl form and the enol form of
1d (Scheme 5).17,22 For the carbonyl form, by plotting the 13C
chemical shift variation of the carbonyl carbon atoms of the
acetyl and carbomethoxy groups of 1d against the acidity of
the acid medium, we obtained two acid-base titration curves
(Figure 2 and Supporting Information Table S2).23 Because the
O-monoprotonated species 7d and 7d′ are in equilibrium
(20) Saito, S.; Saito, S.; Ohwada, T.; Shudo, K. Chem. Pharm. Bull. 1991,
39, 2718–2720.
(21) The trends of the acidity dependence in the presence of DCM were
consistent with those in the absence of DCM (see Table 3 and Table
S1 in the Supporting Information).
(22) The enol structures of 1d started to appear in the 1H NMR spectra in
the acid region stronger than H0 ) -8 (Scheme 5 and Table S2 in the
Supporting Information). As shown in Figure S3 (Supporting Informa-
tion), the 13C NMR chemical shifts of the two carbonyl groups were
almost constant in the range of acidity from H0 ) -8 to H0 ) -14.
The reported pKBH+ values of the carbonyl oxygen atoms of conjugate
ketones (e.g., benzalacetophenone, -4.3 to -5.7) and conjugate esters
(e.g., trans-cinnamic acid, -6.2) (see ref 25a and (a) Ho¨gfeldt, E.;
Bigeleisen, J. J. Am. Chem. Soc. 1960, 82, 15–20. (b) Noyce, D. S.;
King, P. A.; Kirby, F. B.; Reed, W. L. J. Am. Chem. Soc. 1962, 84,
1632-1635) are estimated to be as large as -6. Furthermore, in the
enol forms of the arylacetoacetate 9d or 9d′ (Scheme 5), the olefin
was substituted with an electron-donating hydroxyl group. Thus, the
carbonyl oxygen atoms of 9d and 9d′ were more basic than those of
typical compounds. Therefore, in the acid range of H0 ) -8 to -14,
practically complete O-protonation of the enol carbonyl group oc-
curred, resulting in the generation of the monocation 10d (Scheme
5), which is resonance-stabilized. R-Methylated acetoacetates 1q, 1r,
and 1s afforded the cyclized product in the acid (Table 2), though
enolization is impossible. Therefore, we concluded that the enol form
or its O-protonated form (such as 10d) of the acetoacetates 1 is in
equilibrium with the (O-protonated) keto form (Scheme 5).
(Scheme 5),5–8 it is difficult to determine the pKBH values of
+
the acetoacetate 1d as a ketone base or an ester base. However,
the pKBH+ values for the acetyl group and the methoxycarbonyl
group of related compounds bearing a single carbonyl group
(i.e., ketone (6a) and ester (16a), respectively; see Figure 4 and
Supporting Information Figure S5) are similar in magnitude,24
+
so we can estimate the pKBH values of the acetoacetate 1d to
be H0 ) -9.0 (for the acetyl group, 1d f 7d′) and H0 ) -9.2
(23) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids; John Wiley
& Sons: New York, 1985.
+
(24) The pKBH values of the ketone 6a and ester 16a were estimated to
be -8.5 and -8.5, respectively, in an acid-base titration experiment
(see Figure 4 and Supporting Information Figure S5).
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 811

A R T I C L E S
Kurouchi et al.
Table 3. Acidity Dependence of Cyclization Reactionsa
entry
substrate
acid system
acidity (-H0)
yield of 2 (%)
yield of 3 (%)
yield of 2 + 3 (%)
recovery of 1 (%)
1
2
3
4
5
6
7
8
9
1ab
1ab
1ab
1ab
1aa
1ab
1kc
1kc
1kc
1kc
1kc
1kc
100% TFA
2.7
7.8
9.7
11.8
13.0
14.1
2.7
7.8
9.7
11.8
13.0
14.1
0 (2a)
0 (2a)
0 (2a)
0 (3a)
0 (3a)
6 (3a)
30 (3a)
71 (3a)
60 (3a)
0 (3k)
0
0
6
35
96
97
0
97
97
83
55
0
1% TFSA-99% TFA
10% TFSA-90% TFA
50% TFSA-50% TFA
90% TFSA-10% TFA
100% TFSA
5 (2a)
25 (2a)
37 (2a)
0 (2k)
0
100% TFA
94
89
38
0
0
0
1% TFSA-99% TFA
10% TFSA-90% TFA
50% TFSA-50% TFA
90% TFSA-10% TFA
100% TFSA
3 (2k)
3 (3k)
6
10 (2k)
15 (2k)
29 (2k)
30 (2k)
48 (3k)
78 (3k)
60 (3k)
59 (3k)
58
93
89
89
10
11
12
a Isolation yield. b Reaction conditions: 1 (1 mmol), acid (50 equiv), 0 °C, 5 h (without DCM). c Reaction conditions: 1k (1 mmol), acid (10 equiv),
DCM, 0 °C, 1 h.
Scheme 5
(for the methoxycarbonyl group, 1d f 7d). The magnitudes of
deshielding shifts in the 13C NMR of the ketone and ester
carbonyl carbon atoms of 1d upon O-protonation are comparable
to those observed in reference compounds bearing a single
ketone (6a, Figure 4) and an ester (16a, Figure S5) group,
respectively.25,26
In the acid region stronger than H0 ) -11.8, simultaneous
O1,O3-diprotonation of the acetoacetate 1d was practically
complete to yield the dication 8d.27 A similar acid-base titration
curve was obtained in the case of methyl acetoacetate, the
simplest model substance (at -20 °C, Supporting Information
Figure S2), indicating an insignificant effect of the phenylethyl
moiety on the basicity of the acetoacetate. These observations
were consistent with previous studies on the formation of O1,O3-
diprotonated ꢀ-ketoesters in superacids.5–8
Acidity-Rate Relationship of Cyclization. To further clarify
the reaction mechanism, we measured the rate constants of the
cyclization reaction of 1a, 1c, and 1e in solutions with defined
acidity. The reaction was conducted in NMR tubes at -6 °C,
and the concentration of 1a (or 1c or 1e) was followed by means
1
of H NMR spectroscopy in the presence of 50 equiv of acid
(25) (a) Amett, E. M. Prog. Phys. Org. Chem. 1963, 1, 223–403. (b)
Campbell, H. J.; Edward, J. T. Can. J. Chem. 1960, 38, 2109–2116.
(c) Edward, J. T.; Wang, I. C. Can. J. Chem. 1962, 40, 966–975.
(26) The reported basicity of aliphatic ketones lies at around H0 ) -7.2
and that of esters at H0 ) -6.8 (see ref 25). Thus, the estimated
basicity values of the ketone and ester carbonyl groups of 1d seem to
be rather decreased. This is probably because the two carbonyl groups
of the acetoacetate 1d mutually interact through the insulating carbon
atom and attenuate the electron density through their electron-
withdrawing inductive effects. This electron-withdrawing effect would
be increased upon O-protonation of individual carbonyl oxygen atoms.
(27) The chemical shifts of 1d observed in CF3SO3H-1% (w/w) SbF5 (H0
) -16.8) indicated the chemical shift data change very little with
increasing acidity and the dication formation is practically complete
at H0 - 11.8 (Supporting Information Table S2).
(without the use of DCM). The results are shown in Table 4.
All the reactions followed good first-order kinetics (r > 0.99).
The order of the rate constants was 1e > 1a ≈ 1c. At H0 )
-11.8, where the O1,O3-diprotonation of 1 was complete (see
Figure 2), 1a, 1c, and 1e underwent five-membered ring
cyclization, but slowly (Table 4). This observation demonstrated
that the O1,O3-diprotonated acetoacetates 8a, 8c, and 8e show
reduced cyclization reactivity (Scheme 6).28 On the other hand,
(28) The preference of the keto cyclization of 8 is consistent with the lower
lying π* orbital of the ketone moiety as compared with the π* orbital
of the ester moiety (see Figure 6).
9
812 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Cyclization of Arylacetoacetates
A R T I C L E S
Scheme 6. Intervention of Further Protonation (Protosolvation)
Table 4. Rate Constants for Cyclization of 1a, 1c, and 1e at
-6 °Ca b
,
1a
1c
1e
H0
104k (s-1
)
H0
104k (s-1
)
H0
104k (s-1
)
-11.8
-12.2
-12.5
-13.0
-13.3
-13.5
-14.1
0.185
0.282
0.736
3.09
3.12
3.63
-11.8
-12.2
-12.5
-13.0
-13.3
-13.5
-14.1
0.113
0.277
0.792
2.05
3.85
3.43
-11.8
-12.2
-12.5
-13.0
-13.3
0.817
1.78
4.15
14.9
27.4
4.38
4.82
a Acidity function values; see refs 20 and 28. b Errors of rates (2%.
Scheme 7. Acid-Catalyzed Cyclization of Ketone 6a
intervention of the trication 11a, should be involved (Scheme
6; see also the Supporting Information).30c,31
Acceleration of Keto Cylization by the Ester Group. To
evaluate the effect of the coexisting ester group of arylacetoac-
etates 1, we studied the acid-catalyzed cyclization reaction of a
compound bearing a single functional group, such as a ketone,
i.e., 4-phenyl-2-butanone (6a) (Scheme 7). We first carried out
the acid-base titration of 6a in acids with defined acidity. When
the 13C chemical shift variation of the carbonyl carbon atom of
6a (measured at -6 °C) was plotted against the acidity of the
acid medium, we observed a typical acid-base titration curve
(Figure 4 and Supporting Information Table S3),22 and the
pKBH+ value of 6a was estimated to be about -8.5. This value
is close to those (around -6.2 to -7.5) reported for aliphatic
ketones.25
Figure 3. Acidity-rate profiles of the cyclization of arylacetoacetates 1a,
1c, and 1e (-6 °C).
as shown in Figure 3, the reaction rates for la, 1c, and 1e are
proportional to the acidity of the medium. Acceleration of the
reaction was significant: the slopes in the acidity-rate profiles
were 0.93 for la, 1.03 for lc, and 1.05 for 1e, which are close
to unity. According to the Zucker-Hammett hypothesis,29 when
a low concentration of cationic species formed by protonation
is the reactive species and is involved in the rate-determining
step of the reaction, linear dependency of the rate on the acidity
should be observed. Several applications of this hypothesis have
been reported among reactions involving monocations30a,b and
superelectrophiles generated by multiprotonation (protosolva-
tion).30c-h It has been shown that the substrate 1 is already fully
diprotonated at acidity stronger than H0 ) -11. Therefore, the
diprotonated 1 (i.e., dication 8) is not the reactive intermediate
responsible for the linear increase of the rate in this region of
high acidity (H0 ) -11.8 to -13.3). Thus, further protonation
(or protosolvation) of the diprotonated ketoester 8a, i.e., the
We carried out the cyclization reaction of 6a in TFSA at 32
°C, but obtained a complex mixture after aqueous workup. This
is in sharp contrast to the previous study of the acid-catalyzed
cyclization of 1,3-diphenyl-1-propanone, in which 3-phenyl-
1H-indene was obtained in high yield after aqueous workup.30c
Unexpectedly, however, when we monitored the acid solution
of 6a in TFSA (at 32 °C), the ion 12a formed by cyclization
was clearly observed (Scheme 7). The ion 12a was identical,
1
in terms of chemical shifts in the H and 13C NMR spectra,
with the ion formed from 1-methyl-2,3-dihydro-1H-inden-1-ol
(15a) in TFSA at -6 °C (Scheme 7 and Supporting Information
Figure S4).
We thus studied the acidity-rate profile of the reaction of
6a to afford the ionized product 12a. The cyclization reaction
did not proceed in acid weaker than H0 ) -12. The reaction
(29) Zucker, L.; Hammett, L. P. J. Am. Chem. Soc. 1939, 61, 2791–2798.
(30) For monocations: (a) Lucchini, V.; Modena, G.; Scorrano, G.; Tonel-
lato, U. J. Am. Chem. Soc. 1977, 99, 3387–3392. (b) Baigrie, L. M.;
Cox, R. A.; Slebocka-Tilk, H.; Tencer, M.; Tidwell, T. T. J. Am. Chem.
Soc. 1985, 107, 3640–3645. For dications: (c) Satio, S.; Sato, Y.;
Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1994, 116, 2312–2317. (d)
Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem.
Soc. 1995, 117, 3037–3043. (e) Suzuki, T.; Ohwada, T.; Shudo, K.
J. Am. Chem. Soc. 1997, 119, 6774–6780. (f) Ohwada, T.; Suzuki,
T.; Shudo, K. J. Am. Chem. Soc. 1998, 120, 4629–4637. (g)
Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611–
617. (h) Olah, G. A.; Mathew, T.; Marinez, E. R.; Esteves, P. M.;
Etzkorn, M.; Rasul, G.; Prakash, G. K. S. J. Am. Chem. Soc. 2001,
125, 11556–11561.
(31) In the case of six-membered ring cyclization reaction, the O1,O3-
diprotonated dication 8k contributed significantly to the cyclization,
because the cyclization reaction proceeded at H0 ) -9.7 (Table 3,
entry 9), where the O1,O3-diprotonated dication 8k would be in
equilibrium with monoprotonated cations 7k and 7k′ (Scheme 5). In
the high acidity region (stronger than H0 ) -11.8), a similar
intervention of the corresponding tricationic species 11k can also be
considered because the basicity of the acetoacetate of 1k is similar to
that of 1a (see Figure 2). Therefore, in the six-membered ring
cyclization reaction, the dication 8k would participate significantly in
the cyclization, while the tricationic species 11k is postulated to
accelerate the cyclization in the strong acid region.
(32) Ammann, C.; Meier, P.; Merbach, A. E. J. Magn. Reson. 1982, 46,
319–321.
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 813

A R T I C L E S
Kurouchi et al.
Figure 4. Acid titration curve of ketone 6a (at -6 °C).
Figure 6. LUMO levels and orbital distributions.
TFSA were also evaluated (see Table 5 and Supporting
Information Figure S5).30d,33 The reaction of 16a in TFSA
(25 °C, 48 h) afforded 1-indanone 17a in quantitative yield.14
The reaction of 16a also followed good first-order kinetics
(r > 0.99) (see Table S5, Supporting Information). The obtained
thermodynamic parameters of 16a were as follows: Ea ) 113.0
kJ mol-1 (27.0 kcal mol-1), ∆Hq ) 110.4 kJ mol-1 (26.4 kcal
mol-1), and ∆Gq ) 95.0 kJ mol-1 (22.7 kcal mol-1) (0 °C)
(Table 5).
Figure 5. Acidity-rate profiles of the cyclization of ketone 6a (at 32 °C).
showed good first-order kinetics (r > 0.99) in the acidity region
of H0 ) -12.2 to -13.3 (Table S4, Supporting Information).
As shown in Figure 5, the logarithm of the rate constant
increased proportionally to the acidity, and the slope was 0.47
(r >0.99). In the acidity region H0 ) -12.2 to -13.3, the ketone
6a is fully monoprotonated to generate 13a (Figure 4). This
result is consistent with the postulation that the reactive species
should be a further protonated (or protosolvated) form of 13a,
that is, the O,O-diprotonated ketone 14a. A similar dication has
been proposed in the related acid-catalyzed cyclization reaction
of 1,3-diphenyl-1-propanone.30c Intervention of this kind of
dication was also demonstrated in an acid-catalyzed aldehyde-
ketone isomerization reaction.30h
The ester cyclization (16a) has activation energies (Ea and
∆Hq) similar in magnitude to those of the keto cyclization (6a).
As compared with the keto cyclization of 6a and ester
cyclization of 16a, the cyclization of 1a (for the keto cyclization)
is energetically much more favorable. Therefore, it is reasonable
to assume that the observed acid-catalyzed keto cyclization of
1a can be attributed to the intervention of the tricationic 11a
(which bears a substructure similar to that of the dication 14a),
and the electron-withdrawing nature of the O-protonated ester
functionality present in 11a significantly enhanced the electro-
philicity of the ketone moiety (Schemes 6 and 7).9,11
Such activation of the electrophilicity, favoring the cycliza-
tion, can be seen in a comparison of the calculated orbital levels
and orbital distributions of the LUMO/LUMO + 1 of model
cations, O1,O3-diprotonated (19) and triprotonated (20) methyl
acetoacetate (energy minima obtained by full geometry opti-
mization with B3LYP/6-311G**)34 (Figure 6). In the case of
O1,O3-diprotonated methyl acetoacetate (19), the LUMO and
LUMO + 1 (natural bond orbital analysis)35 are assigned to
the carbonyl π* orbitals of the keto and ester moieties,
respectively,28 and they are relatively close in energy. On the
other hand, in the case of triprotonated methyl acetoacetate (20),
The reaction rates of la and 6a in TFSA were obtained at
three different temperatures to calculate the thermochemical
parameters for the acid-catalyzed cyclization (Table 5):31 for
1a, Ea ) 54.2 kJ mol-1 (13.0 kcal mol-1), ∆Hq ) 51.9 kJ mol-1
(12.4 kcal mol-1), and ∆Gq ) 84.2 kJ mol-1 (20.1 kcal mol-1
)
(0 °C) and, for 6a, Ea ) 114.0 kJ mol-1 (27.2 kcal mol-1), ∆Hq
) 97.1 kJ mol-1 (23.2 kcal mol-1), and ∆Gq ) 96.1 kJ mol-1
(23.0 kcal mol-1) (0 °C). For comparison, thermochemical
parameters for acid-catalyzed cyclization of a compound bearing
a single ester group, i.e., methyl 3-phenylpropionate (16a), in
(33) (a) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. A. J. Am. Chem.
Soc. 1975, 97, 2928–2929. (b) Hwang, J. P.; Prakash, G. K. S.; Olah,
G. A. Tetrahedron 2000, 56, 7199–7203. (c) Hulin, B.; Koreeda, M.
J. Org. Chem. 1984, 49, 207–209.
(34) Frisch, M. J.; et al. Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(35) (a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
899. (b) NBO version 3.
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814 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Cyclization of Arylacetoacetates
A R T I C L E S
Table 5. Observed Rate Constants for the Cyclization Reactions in TFSA and Calculated Activation Parameters
c
e
tempa (°C)
104k (s-1
)
log k
Eab (kJ mol-1
)
∆Hq (kJ mol-1
)
∆Gq(0 °C)d (kJ mol-1
)
∆Sq (J K-1 mol-1
)
1a f 2a/3a
-15
-3
9
1.23
3.79
9.66
-3.91
-3.42
-3.01
54.2
51.9
97.1
84.2
-118
6a f 12a
20
33
45
0.535
2.31
10.6
-4.27
-3.64
-2.97
114.0
96.1
95.0
3.85
56.6
16a f 17a
20
33
45
1.29
7.24
38.0
-3.89
-3.14
-2.42
113.0
110.4
b
a The temperature was corrected (see ref 32). Errors (0.2 °C. Errors (2.0 kJ mol-1
.
c Errors (2.0 kJ mol-1
.
d Errors (3.7 kJ mol-1
.
e Errors (6.5
eu at 273.15 K (0 °C).
both the LUMO and LUMO + 1 have decreased energy, and
the significantly lower lying LUMO indicates activation of 20
as an electrophile. Furthermore, the LUMO is comprised of the
keto carbonyl π* orbital. Thus, these orbital diagrams are
consistent with the enhanced cyclization reactivity of the
tricationic species (such as 11).
acetoacetates; i.e., the tricationic species 11 intervene. Ther-
mochemical data for the acid-catalyzed cyclization of the
arylacetoacetates indicated that the activation energy is decreased
significantly as compared with that of the related acid-catalyzed
cyclization reaction of a compound bearing a single functional
group, such as a ketone and an ester. Therefore, it is reasonable
to assume that the intervention of the trication contributes to
the activation of the cyclization of the arylacetoacetates in strong
acid, and the electron-withdrawing nature of the O-protonated
ester functionality embedded in 11 significantly increases the
electrophilicity of the ketone moiety. Thus, the present study
offers a new concept to explain the activation of electrophilicity
of the cations in these, and probably also other, reactions.11,14
Conclusion
Herein, we have uncovered the chemical features, such as
substrate stability, product distribution control, and substrate
generality, and the reaction mechanism of Brønsted superacid-
catalyzed cyclization reactions of aromatic ring-containing
acetoacetates (arylacetoacetates). While two types of carbonyl
cyclization are possible, i.e., keto cyclization and ester cycliza-
tion, the former exclusively takes place. The reactions constitute
an efficient method to synthesize indene and 3,4-dihydronaptha-
lene derivatives. Acid-base titration using 13C NMR spectra
showed that the acetoacetates are fully O1,O3-diprotonated at
acidity stronger than H0 ) -11. While the five-membered ring
cyclization of 1 (e.g., 1a) proceeded slowly at H0 ) -11, a
linear increase in the rate of the cyclization was found in the
acidity region of H0 ) -11.8 to -13.3. Therefore, the O1,O3-
diprotonated acetoacetates (e.g., 8a) exhibited some cyclizing
reactivity, but they are not the reactive intermediate responsible
for the acceleration of the cyclization in the high acidity region.
The reactive cationic species can be deduced to be further
protonated (or protosolvated) forms of the O1,O3-diprotonated
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. Some
of the calculations were carried out at the Computer Center, Institute
for Molecular Science. We thank the computational facility for
generous allotments of computer time.
Supporting Information Available: Additional tables and
figures, Experimental Section, additional computation and
experiments, and complete ref 34. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA908749U
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J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 815