Superacid-catalyzed intramolecular cyclization reaction of arylcyanopropionate: Geminal substitution effect on superelectrophilicity

Article abstract of DOI:10.1021/jo800674h

(Chemical Equation Presented) We present superacid-catalyzed intramolecular cyclization reactions of arylcyanopropionates to give cyclized five- and six-membered β-enamino esters in moderate to high yields. Known intramolecular ring-closing reactions of protonated nitrile to aromatic carbon atom are limited to the 6-membered case. Interestingly, a significant synergistic increase of reactivity of the cyano functionality was observed, and the cyano nitrogen atom was converted into an amino group, when an ester group was present in a geminal arrangement. Deuterium exchange experiments excluded the involvement of deprotonation of the α-proton in the cyclization process. The acidity dependence of the cyclization reactions and ¹³C NMR studies of a model compound, methyl cyanoacetate, in various acidic media were consistent with the involvement of the O,N-diprotonated dication of methyl cyanoacetate, a distonic dication, in strong acid, and this is considered to be the de facto electrophile in the present cyclization reaction of arylcyanopropionates.

Full text of DOI:10.1021/jo800674h

Superacid-Catalyzed Intramolecular Cyclization Reaction of
Arylcyanopropionate: Geminal Substitution Effect on
Superelectrophilicity
Satoshi Nakamura,† Hiromichi Sugimoto, and Tomohiko Ohwada*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
ohwada@mol.f.u-tokyo.ac.jp
ReceiVed March 28, 2008
We present superacid-catalyzed intramolecular cyclization reactions of arylcyanopropionates to give
cyclized five- and six-membered ꢀ-enamino esters in moderate to high yields. Known intramolecular
ring-closing reactions of protonated nitrile to aromatic carbon atom are limited to the 6-membered case.
Interestingly, a significant synergistic increase of reactivity of the cyano functionality was observed, and
the cyano nitrogen atom was converted into an amino group, when an ester group was present in a
geminal arrangement. Deuterium exchange experiments excluded the involvement of deprotonation of
the R-proton in the cyclization process. The acidity dependence of the cyclization reactions and 13C
NMR studies of a model compound, methyl cyanoacetate, in various acidic media were consistent with
the involvement of the O,N-diprotonated dication of methyl cyanoacetate, a distonic dication, in strong
acid, and this is considered to be the de facto electrophile in the present cyclization reaction of
arylcyanopropionates.
Introduction
of functional groups afforded novel reactivity, which cannot
be observed with a single functional group. The nature of the
reactivity and the effects of combinations of other functional
groups, however, remained to be investigated.
Active methylene compounds are among the most versatile
and widely used building blocks in organic synthesis because
of both their flexibility as regards combination with electron-
withdrawing groups and the ease of further transformation. The
C-H bond at the R-position of multiple electron-withdrawing
groups is acidic enough that the relevant proton can be easily
removed under basic or acidic conditions to generate a
π-conjugate system, which may exhibit various reactivities. In
addition, it has been reported that geminal functional groups
sometimes show very characteristic reactivities, which are rarely
observed with compounds bearing a single functional group. A
superacid-catalyzed intramolecular cyclization of methyl 3-aryl-
2-nitropropionate to give new heterocyclic compounds, 4H-1,2-
benzoxazines, was recently reported,1 wherein the oxygen atom
of the nitro group was introduced onto the aromatic ring. It
turned out that the geminal ester group significantly facilitated
the reaction. In that work, we showed that certain combinations
In spite of its great versatility in organic synthesis, the cyano
group has been used in only a limited number of acid-catalyzed
aromatic functionalization reactions, such as the Gatterman
reaction and Houben-Hoesch reaction, in which it is finally
transformed into a carbonyl functionality through imine inter-
mediates upon hydrolysis. While intramolecular ring-closing
reactions of protonated nitriles to aromatic carbon atom are
known, it has been recognized that cyclization to five-membered
rings is difficult, and indeed the reported examples are limited
only to six-membered cylizations.2 In this paper, we present a
novel intramolecular cyclization reaction of arylcyanopropi-
onates to give both five- and six-membered ꢀ-enamino esters,
utilizing the methodology we have developed. We observed a
(2) (a) Moustafa, A. H.; Hitzler, M. G.; Lutz, M.; Jochims, J. C. Tetrahedron
1997, 53, 625–640. (b) Colquhoun, H. M.; Lewis, D. F.; Williams, D. J. Org.
Lett. 2001, 3, 2337–2340. (c) Udwary, D. W.; Casillas, L. K.; Townsend, C. A.
J. Am. Chem. Soc. 2002, 124, 5294–5303. (d) Henninger, J.; Polborn, K.; Mayr,
H. J. Org. Chem. 2000, 65, 3569–3570. (e) Urgaonkar, S.; Shaw, J. T. J. Org.
Chem. 2007, 72, 4582–4585.
† Current address: School of Chemistry, University of Edinburgh, Joseph-
Black building, West Mains Road, Edinburgh EH9 3JJ, Scotland, UK.
(1) (a) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2003,
125, 5282–5283. (b) Nakamura, S.; Sugimoto, H.; Ohwada, T. J. Am. Chem.
Soc. 2007, 129, 1724–1732.
10.1021/jo800674h CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4219–4224 4219

Nakamura et al.
TABLE 1. Preliminary Investigation of Superacid-Catalyzed Intramolecular Cyclization
entry
n
R1
R2
R3
temp (°C)
time (h)
product
yield (%)
(82)a
1
2
3
4
5
6
7
8
1
2
3
4
5a
5a
6
7
8
1
1
1
1
1
1
1
1
2
2
2
2
2
3
-CO2Me
-SO2Ph
-CN
-CN
-CN
-CN
-CN
-H
-CN
-H
-CN
-CN
-CN
-CN
-CO2Me
-CO2Me
-COPh
-CN
-CO2Me
-CO2Me
-H
-CO2Me
-H
-CO2Me
-CN
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Me
-H
100
70
0
2
0.5
4
3
5
48
1
48
1
1
1
(81)a b
,
12
30
(64)a b
,
25
50
25
25
25
25
25
25
25
25
25
13a
13a
52
72
(56)a b
,
14
15
15
16
13j
17
100
81
97
9
10
11
12
13
14
9
10
5j
11
5q
44
-CO2Me
-CO2Me
-CO2Me
48
48
48
84c
17
(90)a
a In parentheses, recovery was shown. b Long reaction time resulted in a complex mixture of products. c See also Table 2 (entry 8).
significant synergistic increase of reactivity of the cyano
functionality, and the cyano nitrogen atom is converted to an
amino group (i.e., an sp3-nitrogen atom), when an ester group
is present in the geminal arrangement.3 We also compared the
present reactions with those of the corresponding diester and
dicyano counterparts. In the present reactions, distonic dica-
tions,4 in which the two positive charge centers are separated
by one carbon atom, rather than conjugate cations generated
through loss of an R-proton, are proposed to be involved as
activated electrophiles.
It is noteworthy that the combination of a cyano and an ester
group as geminal electron-withdrawing groups seems to be
important for the present cyclization to give the ꢀ-enamino ester
derivatives. In the case of a keto group, i.e., a benzoyl group
(entry 3) in place of the ester group, the cyclization was also
found to proceed at low temperature, though the yield was
moderate (30%).5 Interestingly, when the cyano group was
replaced by an ester (i.e., a diester derivative, entry 1) or by a
sulfone group (entry 2), efficient cyclization to give indene
derivatives did not occur. Furthermore, the reaction of the
monoester derivative 7 afforded 1-indanone 14 in quantitative
yield (entry 8), and this is in sharp contrast to the reactivity in
the mononitrile case (entry 7). These observations indicated that
under the reaction conditions, the ester group seemed to have
more electrophilicity by itself than a cyano group does, but when
both ester and cyano groups are present in the geminal
arrangement, the ester group enhances the electrophilic reactivity
of the inert cyano group.
Results and Discussion
Superacid-Catalyzed Reactions of Arylcyanopropio-
nates. First, we investigated the reactivities of several active
methylene compounds in an arylalkane system bearing combi-
nations of geminal functional groups in the presence of
trifluoromethanesulfonic acid (TFSA) (Table 1). Unexpectedly,
we found that methyl 2-cyano-3-arylpropionate 5a gave the
cyclized five-membered ꢀ-enamino ester analogue 13a when it
was treated with a large excess of TFSA (100 equiv). In this
reaction, the cyano group was converted to an amino group.
The yield of 13a was increased to 72% when the solution was
stirred at 25 °C for 48 h (entry 6). Reported examples are limited
only to six-membered cylizations,2 and we confirmed this,
because the mononitrile case (6, 56% recovery, entry 7) and
dinitrile case (4, 64% recovery, entry 4) did not provide the
indane product under similar acidic conditions (25 °C, 1-3 h).
While it was difficult to obtain a five-membered-ring product
from 3-phenylpropionitrile 6 (entry 7), a six-membered-ring
cyclization was possible even in the case of the monocyano
substituent: 4-phenylbutyronitrile 8 gave 1-tetralone 15 in 81%
yield (entry 9) in TFSA (25 °C, 1 h), after aqueous workup.
Methyl 4-phenylbutyrate 9 also afforded the same cyclized
product 15, in 97% yield under similar conditions (entry 10).
The cyclization reaction of methyl 2-cyano-4-phenylbutyrate (5j)
gave a six-membered ꢀ-enamino ester (13j) in 84% yield (25
°C, 48 h, entry 12, see also Table 2 (entry 10)). On the other
hand, a seven- or larger-membered ring could not be obtained
(entry 14).
(3) Conversion of a cyano group to an amine functional group occurs in a
few synthetic reactions of heterocyclic compounds, such as the Gewald
aminothiophen synthesis (Li, J. J. Name Reactions in Heterocyclic Chemistry:
John Wiley & Sons: Hoboken, NJ, 2005; Chapter 5). The reactions involve
aromatization of heterocycles, i.e., enamine formation due to the presence of
acidic protons at the R-position of the cyano group.
(4) (a) Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211–220. (b)
Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767–788. (c) Olah, G. A. ;
Klumpp, D. A. Superelectrophiles and Their Chemistry; John Wiley & Sons:
Hoboken, NJ, 2008.
Generality of Cyclization of Arylcyanopropionates. Cyclic
ꢀ-enamino esters are versatile building blocks in organic
synthesis, and efficient methodologies for the synthesis of this
(5) An extended reaction time (48 h) afforded a complex mixture of products.
4220 J. Org. Chem. Vol. 73, No. 11, 2008

Intramolecular Cyclization Reaction of Arylcyanopropionate
TABLE 2. Superacid-Catalyzed Cyclization of Methyl 3-Aryl-2-cyanocarboxylatesa
a Typical procedure (13a): 5a (1 mmol) was dissolved in 7.8 mL of TFSA (100 mmol, 100 equiv) in an ice-water bath, and the solution was allowed
to warm to 25 °C. After 48 h, the solution was poured into ice-water, and the mixture was extracted with CHCl3. The organic phase was washed with
brine, dried over Na2SO4, and evaporated to give a residue, which was column-chromatographed on silica gel (eluent: n-hexane:ethyl acetate ) 10:1).
Removal of the solvent afforded 13a in 72% yield. b Decomposition. c Recovery of the substrate (5e: quantitative yield; 5f: 77%; 5g: 62%). d See also
Table 1 (entry 12).
skelton are in high demand.6 For example, Murakami et al.
SCHEME 1
recently reported a synthetic method for five- and six-membered
ꢀ-enamino esters by means of rhodium-catalyzed nucleophilic
conjugate addition of organoboron species to unsaturated esters.7
A series of ꢀ-enamino esters can also be synthesized with our
protocol and these products are accessible only by the present
reaction (Table 2).8 In the case of aromatic methyl substitution,
the corresponding cyclic products 13b and 13c were obtained
in moderate yields (43% and 48% yield, respectively) (entries
2 and 3), while decomposition of the substrate occurred in the
case of methoxy substitution (entry 4). An aromatic halogen
atom (entries 5 and 6) and an electron-withdrawing group (CF3,
entry 7) inhibited the reaction, while the reaction proceeded
when a combination of halogen atom and methyl groups was
involved (entries 8 and 9). Some six-membered ꢀ-enamino esters
were also obtained in good yields (entries 10-12). It was also
found that tricyclic ꢀ-enamino esters could be obtained when a
naphthalene or indole moiety was used instead of the benzene
(entries 13-16). These substituent effects, i.e., preference for
electron-rich aromatic rings, suggested that the reactions
proceeded through a Friedel-Crafts-type mechanism at the
cyano group.
Reaction Mechanisms Involving Distonic Dications. (a)
Contribution of Deprotonation Process. To investigate the
reaction mechanism, deuterium exchange experiments were
carried out with 5a and related compounds. A solution of 5a in
CF3SO3D (TFSA-d, 100 equiv) was kept at 25 °C for 7 h, and
workup with D2O afforded 13a in 29% yield, together with
recovery of 5a in 32% yield (Scheme 1). In this case, no
deuterium exchange was observed at the R-proton of the
recovered 5a, suggesting that acid-catalyzed deprotonation of
the R-proton of 5a would not be in equilibrium even under
strongly acidic conditions. Similarly, no deuterium exchange
of the R-protons was observed in the cases of the diester 1 and
(6) Fustero, S.; Garc´ıa de la Torre, M.; Jofre´, V.; Carlo´n, R. P.; Navarro, A.;
Fuentes, A. S.; Carrio´, J. S. J. Org. Chem. 1998, 63, 8825–8836.
(7) Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9, 741–743.
(8) The substrates for the cyclization reaction, methyl 3-aryl-2-cyanopro-
pionates, were easily synthesized from the corresponding arylaldehyde and methyl
cyanoacetate, via Knøvenagel condensation and subsequent reduction with
hydrogenation or the triethylamine-formic acid azeotrope. See the Supporting
Information.
J. Org. Chem. Vol. 73, No. 11, 2008 4221

Nakamura et al.
approximately -6.5 and -11, respectively.13 In the case of
cyanopropionates, the electron-withdrawing nature of the sub-
stituents (ester and nitrile) will reduce the basicity of each
individual functionality. When TFSA/TFA ) 1:1, a mixture in
which the acidity (H0) is estimated to be -11.2, was used as
the reaction medium, either the ester carbonyl oxygen atom or
the cyano nitrogen atom of the cyanopropionates should be
protonated, with the former being favored.13 Under these
conditions, however, the cyclization product 13a was not
obtained at all, as described above. Therefore, these results
indicated that cations bearing either the O-protonated ester
carbonyl group or N-protonated cyano group have an insufficient
entraining effect to increase the reactivity of the inert cyano
group in the geminal arrangement.
TABLE 3. Acidity Dependence of the Cyclization Reaction
yield (%)
5a 13a
entry
ratio of the acids (TFSA:TFA)
H0
1
2
3
4
5
100:0
99:1
9:1
1:1
0:100
-14.1
-13.6
-13.0
-11.2
-2.7
0
2
3
62
100
72
64
53
0
0
TABLE 4. 13C NMR Analysis of Methyl Cyanoacetate in Solutions
of Varying Acidity
13C NMR signals
Direct Observation of Distonic Dications. We also carried
out direct spectroscopic observation of cationic species formed
from a model compound, methyl cyanoacetate, in various acidic
media (Table 4). As the acidity of the medium was increased,
the ester carbonyl carbon atom was deshielded, whereas the
cyano carbon atom was shielded in the 13C NMR spectra. After
consideration of the perturbations of the 13C chemical shifts
arising from the solvent effect,14 the observed acidity-dependent
changes of the chemical shifts were consistent with those arising
from protonation of the ester carbonyl oxygen atom and that of
thenitrilenitrogenatom,respectively,asreportedpreviously.11b,12f,15
There are small differences in the 13C chemical shifts of the
species formed in TFSA and in a more acidic medium, i.e.,
TFSA containing 1% (w/w) SbF5 (H0 ≈ -17). All these data
are consistent with the postulate that the O,N-diprotonated
dication (18) of methyl cyanoacetate, a distonic dication, is
formed in the strong acid, and is a de facto electrophile in the
present cyclization reaction of arylcyanopropionates. The ex-
perimentally observed changes of the 13C chemical shifts of the
species formed in TFSA, as compared with the neutral state,
were in good agreement with those of GIAO calculation for
the O,N-diprotonated dication, i.e., low-field shift of the carbonyl
carbon atom upon protonation of the carbonyl group and high-
field shift of the nitrile carbon atom upon protonation of nitrile
nitrogen atom in the 13C NMR spectra (Table 5).16,17 This also
supports the present conclusion concerning the formation of the
O,N-diprotonated dication (18). When toluene was added to a
solvent/acid
H0
CHCl3
TFA
TFA:TFSA (1:1)
TFA:TFSA (1:9)
TFSA
n/a
24.7, 53.7, 113.7, 164.0
23.4, 53.9, 111.4, 166.7
23.9, 55.2, 110.1, 168.5
24.3, 57.1, 109.0, 171.4
24.6, 59.7, 107.6, 175.2
24.6, 60.4, 107.2, 176.2
-2.7
-11
-13
-14
-17
TFSA (1% SbF5)
dicyanide 4 in TFSA-d under similar reaction conditions (see
ref 9). This observation is in sharp contrast to the case of 3-aryl-
2-nitropropionate, in which deprotonation of the R-proton
occurred in TFSA, and this deprotonation process was rate-
determining.1 Furthermore, methyl 2-methyl-2-cyano-4-phenyl-
butyrate, in which the R-proton was replaced with a methyl
group, afforded a cyclized keto ester in a low yield of 17%
when it was treated with TFSA (25 °C, 48 h), followed by
aqueous workup (Table 1, entry 13). This result excluded
involvement of loss of the R-proton in the cyclization process.
(b) Acidity Dependence of Reactions. Reaction of 5a
showed acidity dependence: the reaction rate (in terms of the
product yield after 48 h) increased as the acidity of the reaction
medium was increased by mixing TFSA into TFA (Tables 3
and 4).10–12 The reaction proceeded in a 99:1 (w/w) or 9:1 (w/
w) mixture of TFSA/TFA to afford 13a in slightly lower yield
(64% or 53%, respectively) than in TFSA (72% yield) (entries
1-3), while no cyclized product 13a was obtained and 5a was
recovered in part when TFSA/TFA ) 1:1 (w/w) (entry 4) or
TFA alone (entry 5) was used. The basicity values of ester
carbonyl oxygen atoms and nitrile nitrogen atoms are typically
(13) Arnet, E. M. Prog. Phys. Org. Chem. 1963, 1, 223–403.
(14) These changes of the chemical shifts should be partially due to solvent
effects, i.e., differences in polarity and hydrogen-bonding ability of CDCl3 and
TFA. In these solvents, no protonation of the carbonyl oxygen atom or the cyano
(9) To 100 equiv of TFSA-d was added 300 µmol of the substrate at 0 °C.
The reaction mixture was stirred for 7 h at 25 °C, then poured into 20 mL of
D2O, and extracted with CHCl3. The organic phase was washed with saturated
NaCl, dried over Na2SO4, and evaporated under reduced pressure to give a
residue. The residue was column-chromatographed on silica gel. Removal of
the solvent afforded the substrate 1a in 32% yield and the product 2a in 29%
yield. 1H NMR spectra of the crude product and of the separated recovered
substrate indicated that no proton or deuterium at the methylene position was
exchanged under the reaction conditions.
nitrogen atom occurred, judging from the pKBH values. In TFA, the 13C carbon
+
of the ester carbonyl atom was deshielded (2.7 ppm) and that of the nitrile carbon
atom was shielded (2.3 ppm), as compared with those in CDCl3. On the other
hand, the magnitude of the chemical shift changes observed in going from TFA
to TFSA-SbF5 was larger than in the case of going from CDCl3 to TFA.
(15) (a) Levy, G. C.; Cargioli, J. D.; Racela, W. J. Am. Chem. Soc. 1970,
92, 6238–6246. (b) Olah, G. A.; Westerman, P. W. J. Org. Chem. 1973, 38,
1986–1992.
(10) (a) Hammett, L. P.; Deyrup, A. J. J. Am. Chem. Soc. 1932, 54, 2721–
2739. (b) Paul, M. A.; Long, F. A. Chem. ReV. 1957, 57, 1–45. (c) Jorgenson,
J. J.; Hartter, D. R. J. Am. Chem. Soc. 1963, 85, 878–883. (d) Ryabova, R. S.
Zh. Fiz. Khim. 1966, 40, 339–345.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montogomery, J. A., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M. Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Peterson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross,
J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C. ; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, G.; Dapprich, S.;
Daniels, A. K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford,
S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Gaussian, Inc.: Pittsburgh,
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(11) (a) Saito, S.; Saito, S.; Ohwada, T.; Shudo, K. Chem. Pharm. Bull. 1991,
39, 2718–2720. (b) Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J. Am. Chem.
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(12) For recent representative studies on the acidity dependence of superacid-
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Esteves, P. M.; Etzkorn, M.; Rasul, G.; Prakash, G. K. S. J. Am. Chem. Soc.
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4222 J. Org. Chem. Vol. 73, No. 11, 2008

Intramolecular Cyclization Reaction of Arylcyanopropionate
TABLE 5. 13C NMR GIAO Data Obtained at Several Calculation Levels
SCHEME 2
observed a significant synergistic increase of reactivity of the
cyano functionality, and found that the cyano nitrogen atom
was converted into an amino group when an ester group was
present in a geminal arrangement. We also studied the effect
of ring size and acidity on this reaction. On the basis of
deuterium exchange and spectroscopic studies, we propose the
involvement of distonic O,N-diprotonated dicationic species
(20). Interestingly, we found that changing one of the geminal
groups from nitro to cyano significantly changes the mechanistic
path of the reaction (see Scheme 1).
SCHEME 3. Plausible Cyclization Mechanism
Experimental Section
Synthesis of Methyl 2-Cyano-3-arylpropionates 5 and the
Other Relative Compounds. Method A: Hydrogenation with
Wilkinson’s Catalyst. Typical Procedure: Methyl 2-Cyano-3-
phenylpropionate (5a). To the mixture of benzaldehyde (2.78 g,
26.2 mmol) and methyl cyanoacetate (2.60 g, 26.2 mmol) was added
aluminum oxide 90 (10.9 g), and the mixture was kept for 1 h at
rt, followed by extraction with CHCl3. Evaporation of the solvent
gives the crude condensation product (4.43 g, 23.7 mmol), which
was used in the next reaction without further purification.
The crude product was then dissolved into a mixture of THF
(20 mL) and EtOH (200 mL), and to the solution was added
Rh(PPh3)Cl (1.21 g, 1.31 mmol, 5 mol %). The solution was stirred
for 3 days at rt under H2 atmosphere. Water (300 mL) was added
and the whole was extracted with ether. The organic phase was
washed with brine and dried over Na2SO4, and the solvent was
evaporated under reduced pressure to give a residue that was column
chromatographed on silica gel (eluent n-hexane:AcOEt ) 6:1).
Removal of the solvent afforded 5a as a colorless oil (3.39 g, 17.9
mmol). Total yield 68%. Colorless oil. 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.36-7.25 (m, total 5H), 3.78 (s, 3H), 3.72 (dd, J ) 5.7,
8.5 Hz, 1H), 3.27 (dd, J ) 5.7, 13.8 Hz, 1H), 3.18 (dd, J ) 8.5,
13.8 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ (ppm) 166.0, 135.2,
129.0, 128.9, 127.9, 116.0, 53.6, 39.6, 35.8. ESI-HRMS calcd for
C11H11NNaO2 ([M + Na]+) 212.0687, found 212.0701.
Method B: Reduction with Triethylamine-Formic Acid
Azeotrope. Typical Procedure: Methyl 2-Cyano-3-phenyl-
propionate (5a). To a solution of benzaldehyde (2.00 mL, 19.7
mmol) and methyl cyanoacetate (1.74 mL, 19.7 mmol, 1 equiv) in
CHCl3 (5 mL) was added aluminum oxide 90 (1 g) at 18 °C. Then,
the solution was stirred for 10 min, and the whole was filtered to
remove aluminum oxide. The solution was evaporated under
reduced pressure to give a residue. The crude was recrystallized
solution of methyl cyanoacetate in TFSA, methyl 3-amino-3-
p-tolyl-acrylate 19 was obtained in 30% yield after aqueous
workup. This is also consistent with our proposed reaction
mechanism involving the distonic dication (Scheme 2).
Proposed Reaction Mechanisms. A plausible reaction
mechanism of the intramolecular cyclization is shown in Scheme
3. Generation of the distonic O,N-diprotonated dicationic species
(20) can be attributed to activation of the electrophilic center
of the nitrile carbon atom. The intramolecular cyclization
proceeds to give indane intermediates, followed by deprotona-
tion of the R-proton of the ester to generate the ꢀ-enamino ester.
In the case of the Houben-Hoesch-type reaction, N,N-dipro-
tonated nitriles have been proposed as true electrophiles.11 In
Scheme 3, however, the protonated ester group activates the
electrophilicity of the monoprotonated nitrile group.
In summary, we have developed a new superacid-catalyzed
cyclization reaction that allows us to synthesize both five- and
six-membered cyclic ꢀ-enamino esters from aromatic ring-
containing cyanoacetates. The present reactions provide the first
access to some ꢀ-enamino esters through ring closure of
protonated nitriles by carbon attachment to the aryl ring. We
J. Org. Chem. Vol. 73, No. 11, 2008 4223

Nakamura et al.
from n-hexane/CHCl3 to afford the condensation product as
colorless needles (3.34 g, 12.2 mmol, 91%).
silica gel. Removal of the solvent afforded the substrate 5a in 32%
yield and the product 13a in 29% yield. H NMR spectra of the
crude product and of the separated recovered substrate indicated
that no proton or deuterium at the methylene position was
exchanged under the reaction conditions.
1
To a solution of the condensation product (1.00 g, 5.34 mmol)
in DMF (100 mL) were added formic acid (2.01 mL, 53.4 mmol,
10 equiv) and triethylamine (2.98 mL, 21.4 mmol, 4 equiv) and
the reaction mixture was stirred at 18 °C for 1 week. Then, water
(100 mL) was added, and the whole was extracted with AcOEt.
The organic phase was washed with brine and dried over Na2SO4,
then the solvent was evaporated under reduced pressure to give a
residue, which was column chromatographed on silica gel (eluent:
n-hexane:ethyl acetate ) 10:1) to afford 5a as a colorless oil (515
mg, 2.72 mmol, 51%).
Experiments of Acidity Dependence of Reactions. TFSA and
TFA were mixed in various weight ratios under an Ar atmosphere.
To 5 mL of the combined acid was added 0.5 mmol of 5a at 0 °C.
The whole was stirred at 25 °C for 48 h. Then the mixture was
poured into 50 mL of ice-water and the whole was extracted with
CHCl3. The organic phase was washed with saturated NaCl and
dried over Na2SO4, then the solvent was evaporated under reduced
pressure to give a residue. The residue was column chromato-
graphed on silica gel. Removal of the solvent afforded 5a and 13a.
Low-Temperature 13C NMR Analysis of Methyl Cyano-
acetate. TFSA (0.5 mL) was added to a dried, Ar-filled test tube
(or flask) and cooled to -78 °C. To the solution was added methyl
cyanoacetate (20 mg). With vigorous stirring, the resulting solution
is transferred to a dried, cold NMR tube (precooled to -78 °C). A
coaxial insert containing acetone-d6 is then inserted into the NMR
tube and the NMR spectra were obtained at -15 to -10 °C.
Superacid-Catalyzed Intramolecular Cyclization Reaction
of Methyl 3-Aryl-2-Cyanopropionates and the Related
Compounds. Typical Procedure: Methyl 3-amino-1H-indene-
2-carboxylate (13a). To ice-cooled TFSA (8.9 mL, 100 mmol, 100
equiv) was slowly added 5a (188 mg, 0.99 mmol), and the solution
was stirred at 25 °C for 48 h. To the solution was added CHCl3
(10 mL) and the mixture was poured into ice-water (50 mL), which
was extracted with CHCl3. The organic phase was washed with
brine and dried over Na2SO4, and the solvent was evaporated under
reduced pressure to give a residue, which was column chromato-
graphed on silica gel (eluent n-hexane:AcOEt ) 6:1). Removal of
the solvent afforded 13a as a pale yellow solid (136 mg, 0.72
mmol). Yield 72%. Mp 104.0-105.0 °C (recrystallized from ether,
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. S.N. is also grateful for Research Fellowships for Young
Scientists from the Japan Society for the Promotion of Science.
1
white needles). H NMR (400 MHz, CDCl3) δ (ppm) 7.49-7.34
(m, total 4H), 5.96 (br s, 2H), 3.80 (s, 3H), 3.57 (s, 2H). 13C NMR
(400 MHz, CDCl3) δ (ppm) 168.2, 156.1, 144.2, 138.0, 128.7,
126.3, 124.8, 118.7, 98.1, 50.5, 34.6. Anal. Calcd for C11H11NO2:
C, 69.83; H, 5.86; N, 7.40. Found: C, 69.58; H, 6.02; N, 7.31.
Deuterium Exchange Experiment. To 100 equiv of TFSA-d
was added 300 mmol of the substrate at 0 °C. The reaction mixture
was stirred for 7 h at 25 °C, then poured into 20 mL of D2O, and
extracted with CHCl3. The organic phase was washed with saturated
NaCl, dried over Na2SO4, and evaporated under reduced pressure
to give a residue. The residue was column chromatographed on
Supporting Information Available: Spectroscopic and
analytical data, experimental procedures, Cartesian coordinates,
and energetic values of calculated species. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800674H
4224 J. Org. Chem. Vol. 73, No. 11, 2008