Organic-base-catalyzed synthesis of phthalides via highly regioselective intramolecular cyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2006.12.015

The organic-base-catalyzed 5-exo intramolecular cyclization reaction of o-alkynylbenzoic acid produces the corresponding phthalide regioselectively in good to excellent yields. The method provides a practical access to the phthalides, an important class o

Full text of DOI:10.1016/j.tetlet.2006.12.015

Tetrahedron Letters 48 (2007) 933–935
Organic-base-catalyzed synthesis of phthalides via highly
regioselective intramolecular cyclization reaction
Chikashi Kanazawa and Masahiro Terada*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 20 November 2006; revised 6 December 2006; accepted 7 December 2006
Abstract—The organic-base-catalyzed 5-exo intramolecular cyclization reaction of o-alkynylbenzoic acid produces the corresponding
phthalide regioselectively in good to excellent yields. The method provides a practical access to the phthalides, an important class of
biologically active molecules.
Ó 2006 Elsevier Ltd. All rights reserved.
Phthalides 2 are an important class of oxygen-containing
heterocycles often seen in naturally occurring and bio-
logically active compounds.1 One of the general routes
for the synthesis of phthalides is the intramolecular cycli-
zation reaction from o-alkynylbenzoic acid and its
analogs (1) (Eq. 1). The drawback of this procedure is,
it gives mixtures of phthalide 2 and isocoumarin 3 via
5-exo and 6-endo cyclization, respectively.2–5 Therefore,
the development of a highly regioselective cyclization
route to phthalides has been paid much attention. Herein
we report an intramolecular cyclization reaction of o-
alkynylbenzoic acid 1 catalyzed by organic bases that
affords phthalides in a highly regioselective manner.6,7
6 h, and desired phthalide 2a was obtained in an excel-
lent yield without the formation of a detectable amount
of isocoumarin 3a. In addition, the geometry of 2a was
found to be (Z)-form exclusively. Among the organic
base catalysts examined, DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene) exhibited the highest catalytic activity
(entry 3). Moreover, 5 mol % DBU was sufficient to
promote completion of the reaction in 6 h even though
the reaction temperature was lowered to 80 °C
(entry 4). Solvent effect was also significant in the
present intramolecular cyclization (entries 4–7). DBU
displayed an excellent performance in highly polar
solvents such as MeCN and DMSO (entries 6 and 7).
R1
R1
R1
O
+
O
R2
R2
R2
CO2H
ð1Þ
O
O
1
2
3
5-exo
6-endo
A
preliminary experiment was conducted using
Although both solvents reduced the reaction time
markedly, MeCN was the best choice from a practical
viewpoint (entry 6), as 2a was isolated in a nearly
quantitative manner (94% yield). It is interesting to note
that a catalytic amount of potassium acetate also
effectively promoted the 5-exo cyclization (entry 8). In
contrast, a dramatic change in regioselectivity was
observed in the presence of a catalytic amount of a
strong acid, H2SO4, giving isocoumarin 3a exclusively
(entry 9).6,8
10 mol % DABCO (1,4-diazabicyclo[2,2,2]octane) as a
catalyst in 1,4-dioxane at 100 °C (Table 1, entry 1). To
our delight, 2-(2-phenylethynyl)benzoic acid 1a (R1 =
Ph, R2 = H, Eq. 1) was consumed completely within
Keywords: Organic-base; Phthalide; Regioselective; Intramolecular
cyclization.
*
Corresponding author. Tel./fax: +81 22 795 6602; e-mail: mterada@
mail.tains.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.015

934
C. Kanazawa, M. Terada / Tetrahedron Letters 48 (2007) 933–935
Table 1. Effects of catalysts and solventsa
Unfortunately, the substitution of an aliphatic group,
Entry Catalyst (mol %) Solvent
Conditionsb
6 h, 100 °C >95:<5
Dioxane 24 h, 100 °C >95:<5
Dioxane
Dioxane
Toluene
MeCN
DMSO
MeCN
Dioxane 12 h, 100 °C
2a/3ac
2-(1-pentyl)benzoic acid 1h, gave ca. 2:1 mixture of
phthalide 2h and isocoumarin 3h (entry 8). However,
the 5-exo selective cyclization was applicable to enyne
1i and terminal alkyne 1j, giving the corresponding
phthalides in good yields without formation of isocoum-
arin derivatives (entries 9 and 10).
1
2
3
4
5
6e
7
8
9
DABCO (10)
DMAPd (10)
DBU (10)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
AcOK (10)
H2SO4 (10)
Dioxane
2 h, 100 °C >95:<5
6 h, 80 °C
6 h, 80 °C
2 h, 80 °C
2 h, 80 °C
6 h, 80 °C
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
<5:>95
The present intramolecular cyclization is most probably
initiated by the generation of a carboxylate anion inter-
mediate via deprotonation of the carboxylic acid by the
organic base catalyst (Fig. 1).2b,6,8 The 5-exo cyclization
of the carboxylate to the triple bond would be assisted
by the conjugate acid of the organic base catalyst. An-
other possibility is that the carboxylic acid of substrate
1 on its own might intermolecularly aid the addition
of the carboxylate anion, because a catalytic amount
of potassium acetate also promotes the reaction effec-
tively. Moreover, the substituent (R2) effect of the back-
bone aromatic ring also suggests that the assistance by
the acids is the key for the intramolecular cyclization
(Table 2, entries 6 and 7). The electron-withdrawing
substituent markedly retards the cyclization presumably
due to the reduced electron density of the triple bond.
The formation of a small amount of isocoumarin 3f
could be ascribed to the enhanced electrophilic nature
at the b-position of the triple bond. In contrast, the
introduction of electron-donating group to the back-
bone aromatic ring diminishes the electrophilic nature
at the b-position of the triple bond and hence 5-exo cyc-
lized product 2g was formed exclusively.
a Unless otherwise noted, the intramolecular cyclization reaction of 1a
(R1 = Ph, R2 = H, 0.3 mmol) was conducted in the indicated solvent
(0.6 mL) in the presence of a catalyst.
b Time required for completion of the reaction.
c Ratio was determined by 1H NMR.
d DMAP = 4-(N,N-dimethylamino)pyridine.
e 2a was isolated in 94% yield.
With the optimal conditions in hand, we next examined
the scope and limitations of the present organic-
base-catalyzed 5-exo cyclization with a series of o-alkyn-
ylbenzoic acids (1) (Table 2). Substrates bearing
electron-donating or electron-withdrawing functional
groups at the para-position of the terminal aromatic ring
(R1) as well as the sterically demanding 1-naphthyl
substituent were tolerated for the reaction and gave
the corresponding phthalides (2b, 2c, and 2e) in good
to excellent yields (entries 2, 3, and 5). In contrast, the
introduction of a substituent at the ortho-position of
the terminal aromatic ring, 1d, diminished the yield of
2d and a considerable amount of isocoumarin 3d was
produced as well (entry 4). Substituents (R2) introduced
to the backbone aromatic ring also affected the mode of
cyclization. The substrate bearing an electron-withdraw-
ing acetyl group yielded isocoumarin 3f although in a
small amount. In contrast, an electron-donating meth-
oxy group facilitated the exclusive formation of desired
phthalide 2g. To expand the applicability of the present
5-exo cyclization, we further examined a couple of
terminal substituents attached to the alkynyl moiety.
A H
R1
β
α
5-exo
O
R2
O
conjugate acid of organic base (ex.
:
)
H
A H
[DBU]
O
or
Table 2. Scope of organic-base-catalyzed intramolecular cyclization
reactionsa
Ar
O H
1
Entry R1
R2
1
Time (h)
2
Yieldb (%)
Figure 1. Plausible mechanism for the organic-base-catalyzed intra-
molecular cyclization.
1
2
3
4
Ph
H
H
H
H
H
Ac
1a
1b
2
4
2a 94
2b 96
2c 80
2d 57c
2e 97
2f 79e
2g 99
2h 58g
2i 65
2j 83
p-MeO–C6H4–
p-CF3–C6H4–
o-MeO–C6H4–
1-Naphthyl
Ph
Ph
nPr
2-Propenyl
H
1c 24
1d 12
1e
In conclusion, we have developed an organic-base-cata-
lyzed intramolecular cyclization reaction of o-alkynyl-
benzoic acid, leading to the 5-exo selective formation
of phthalides in good to excellent yields.9 The method
provides a practical access to the phthalides, an impor-
tant class of biologically active molecules. Further stud-
ies on the synthetic application are under way in our
laboratory.
5
5
6d
7
1f 12
MeO 1g
4
8f
9
H
H
H
1h 12
1i
1j
3
6
10
a Unless otherwise noted, the reaction of 1 (0.3 mmol) was conducted
in MeCN (0.6 mL) in the presence of DBU (15 lmol, 5 mol %) at
80 °C for the indicated time.
b Isolated yield.
Acknowledgments
c Isocoumarin 3d was obtained in 23% yield.
d DMSO was used as solvent.
e Isocoumarin 3f was obtained in 8% yield.
f DBU (10 mol %) was employed.
We acknowledge Research Fellowships from the Japan
Society for the Promotion of Science for Young
Scientists.
g Isocoumarin 3h was obtained in 36% yield.

C. Kanazawa, M. Terada / Tetrahedron Letters 48 (2007) 933–935
935
4. Promoted by iodine complex, see: (a) Biagetti, M.; Bellina,
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5023–5038; (b) Yao, T.; Larock, R. C. J. Org. Chem. 2003,
68, 5936–5942.
References and notes
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6. During the preparation of this manuscript, Uchiyama et al.
reported that the base- and acid-catalyzed alternative
intramolecular cyclization of 1a gave phthalide 2a and
isocoumarin 3a, respectively. See: Uchiyama, M.; Ozawa,
H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya,
K.; Sakamoto, T. Org. Lett. 2006, 8, 5517–5520.
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9. Representative experimental procedure for the organic-base-
catalyzed intramolecular cyclization leading to phthalide 2:
To a MeCN solution (0.6 mL) of 2-(2-phenylethynyl)benz-
oic acid (1a) (66.7 mg, 0.3 mmol) was added DBU (2.2 lL,
15 lmol) under Ar atmosphere. The solution was stirred at
80 °C for 2 h. After the consumption of 1a, the reaction
mixture was cooled to room temperature, filtered through a
short Florisil pad, and concentrated. The residue was
purified by column chromatography (silica gel, n-hexane/
AcOEt 50:1 to 5:1) to afford (Z)-3-(1-benzylidene)phtha-
lide (2a) in 94% yield as a white solid (63 mg). 1H NMR
(400 MHz, CDCl3): r 6.41 (1H, s), 7.32 (1H, tt, J = 7.5,
1.2), 7.40–7.44 (2H, m), 7.53–7.57 (1H, m), 7.71–7.79 (2H,
m), 7.84–7.86 (2H, m), 7.94–7.96 (1H, dt, J = 7.5, 1.0); 13C
NMR (100 MHz, CDCl3): r 106.99, 119.73, 123.35, 125.48,
128.32, 128.67, 129.67, 130.03, 133.01, 134.37, 140.51,
144.47, 166.88. These spectral data are consistent with
previous reports.
´
´
Ruiz, M.; del Olmo, E.; Lopez-Perez, J. L.; Tortoriello, J.;
Feliciano, A. S. Bioorg. Med. Chem. Lett. 2005, 15, 3483–
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Chem. 1995, 60, 3711–3716; (b) Kundu, N. G.; Pal, M.;
Nandi, B. J. Chem. Soc., Perkin Trans. 1 1998, 561–568; (c)
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(d) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.;
Mannina, L. Tetrahedron Lett. 2000, 41, 5281–5286; (e)
Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J.
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Wakamatsu, T. Heterocycles 1995, 41, 2587–2599; (b)
Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron
2000, 56, 2533–2545.