One-pot synthesis of phthalides via regioselective intramolecular cyclization from ortho-alkynylbenzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.09.023

A one-pot synthesis of phthalides via an intramolecular 5-exo-dig cyclization of ortho-alkynylbenzaldehydes under mild NaClO₂ oxidation conditions is described.

Full text of DOI:10.1016/j.tetlet.2010.09.023

Tetrahedron Letters 51 (2010) 5937–5939
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of phthalides via regioselective intramolecular cyclization
from ortho-alkynylbenzaldehydes
⇑
Jim Li , Elbert Chin, Alfred S. Lui, Lijing Chen
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of phthalides via an intramolecular 5-exo-dig cyclization of ortho-alkynylbenzaldehy-
des under mild NaClO2 oxidation conditions is described.
Received 6 August 2010
Revised 2 September 2010
Accepted 7 September 2010
Available online 21 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Phthalides are an interesting class of structures with furan-2-
(5H)-one skeletons which are often found in many natural
products and biologically active compounds.1,2 There has been
considerable focus on their synthesis via intramolecular cyclization
of ortho-alkynylbenzoic acid derivatives (2) in recent years.3–7
Generally, metal complex-catalyzed intramolecular cyclizations
of ortho-alkynylbenzoic acid derivatives (2) provide the desired
furan-2-(5H)-one skeletons 3 and accompany the closely related
isocoumarin 4 since both 5-exo-dig and 6-endo-dig cyclizations
are preferable according to Baldwin’s rule.8 More recently, two
groups reported a regioselective phthalide cyclization promoted
by weak bases.3,4 It is also known that acid-catalyzed cyclization
often favored the isocoumarin formation.9 Herein, we report a
one-pot highly regioselective cyclization of ortho-alkynylbenzalde-
hydes under environmentally friendly sodium chlorite oxidative
conditions that affords phthalides through an intramolecular 5-
exo-dig pathway (Scheme 1).
During our work on converting a series of ortho-alkynylbenzal-
dehydes into their corresponding benzoic acids under very mild
NaClO2 oxidation conditions10, we observed the formation of vari-
ous amounts of phthalide products after the reactions were left for
a period of time. We decided to investigate this transformation fur-
ther and to study its synthetic scope (Scheme 1). The results of
intramolecular phthalide cyclization from a series of ortho-alkynyl-
benzaldehydes (1a–1o)11 are summarized in Table 1. In all cases,
benzaldehydes were rapidly oxidized to the corresponding benzoic
acids in the initial process. The subsequent intramolecular cycliza-
tion often required heating. The typical experimental procedure
was carried out as follows: To
a solution of the aldehyde
(0.4 mmol) in a mixture of t-BuOH/THF/H2O (6 mL, 2:1:3/v:v:v)
at 0 °C were added NaH2PO4 (4.8 mmol), 2-methyl-2-butene
(8 mmol), and followed by NaClO2 (1 mmol). The mixture was al-
lowed to warm to ambient temperature. The reaction mixture
either continued stirring at the same temperature or heated at
50–90 °C over the indicated period of time until of the carboxylic
acid intermediates were consumed.
We first examined the electronic influence of substituents on
the backbone benzaldehyde ring (Table 1, entries 1–5). We were
surprised to find that the corresponding carboxylic acid of unsub-
stituted ortho-benzaldehyde diphenylacetylene 1a showed a sig-
nificant lower reactivity toward the cyclization under the
reaction conditions we attempted. Only 12% of the phthalide 3a
was isolated as the sole product along with 79% of the unreacted
carboxylic acid 2a after the reaction mixture was heated at 90 °C
for 48 h. However, regioselective 5-exo-dig cyclization of substrates
1b–1e bearing both electron-donating and electron-withdrawing
functional groups proceeded well under the given reaction condi-
tions. Substrates with electron-rich moiety were found to be more
O
O
O
O
NaClO2
NaH2PO4
H
O
OH
a
R2
R2
O
R2
R2
+
b
X
X
X
R1
X
α
R1
R1
β
R1
1
3
2
4
Scheme 1. One-pot intramolecular cyclization.
⇑
Corresponding author. Tel.: +1 650 855 6972; fax: +1 650 852 1875.
E-mail address: jli@calithera.com (J. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.023

5938
J. Li et al. / Tetrahedron Letters 51 (2010) 5937–5939
Table 1
One-pot intramolecular cyclization reactionsa
O
O
NaClO2, NaH2PO4
t-BuOH-THF-H2O
O
H
O
R2
X
R2
O
R2
+
X
X
R1
R1
R1
1
3
4
Entry
1
R1
R2
X
Temp (°C)
Time (h)
3
Yield of 3b (%)
1c
2
3
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
Ph
Ph
Ph
Ph
H
C
C
C
C
N
C
C
C
C
C
C
C
C
C
0–90
0–25
0–50
0–50
0–50
0–90
0–90
0–70
0–70
0–90
0–90
0–90
0–90
0–70
48
14
14
14
24
48
28
16
7
16
16
28
48
14
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3l
3m
3n
3o
12d
98
72
5-MeO
4-F
6-F
H
H
H
H
H
H
H
4
85
5
85e
20f
65
6c
7
o-CH3–C6H4–
o-CO2Et–C6H4–
o-Cl–C6H4–
o-CF3–C6H4–
p-MeO–C6H4–
2,4-Di-F–C6H4–
2,4-Di-MeO–C6H4–
t-Bu
H
8
9
53g
94
10
11
12
13
14
84h
72
H
H
H
63i
0j
88
a
All reactions were performed with aldehyde substrates (0.4 mmol), except for 1m (0.15 mmol), NaClO2 (1 mmol), NaH2PO4 (4.8 mmol) and 2-methyl-2-butene (8 mmol)
at the indicated temperature and reaction time.
b
c
d
e
f
Isolation yields.
NaClO2 (5 equiv), NaH2PO4 (24 equiv) and 2-methyl-2-butene (40 equiv) were used.
The corresponding acid 2a was isolated in 79% yield.
Isocoumarin 4e (7%) was observed in the product mixture.
The corresponding carboxylic acid 2f and isocoumarin 4f were isolated in 72% and 4% yields, respectively.
The corresponding carboxylic acid 2g was isolated in 36% yield.
Isocoumarin 4j (14%) was observed in the product mixture.
g
h
i
Isocoumarin 4k (<5%) was observed in the product mixture.
The corresponding carboxylic acid 2n was isolated in 97% yield.
j
reactive toward the cyclization under milder reaction conditions.
Benzaldehyde 1b with a 5-MeO at the para-position to the alkyne
moiety, efficiently led to phthalide 3b as the exclusive product at
25 °C in 14 h.12 Cyclizations of electron-poor substrates 1c–1e
were found to require heating at 50 °C (entries 3–5). Both 4-fluoro
and 6-fluorobenzaldehydes 1c and 1d were able to transform into
their corresponding phthalides 3c and 3d in 72% and 85% yields,
respectively. Conversion of pyridine 1e into phthalide 3e in 85%
isolation yield and accompanied with the corresponding isocoum-
arin 4e in 7% yield, required heating at 50 °C for 24 h (entry 5).
Next, we investigated the substitution effect of R1 group off the
distal b-position of the carbon–carbon triple bond (Table 1, entries
6–14). Interestingly, we found that both ortho- and para-substitu-
tions displayed a range of reactivity for this cyclization. We
observed mostly modest to good yields with excellent regioselec-
tivity for this 5-exo-dig phthalide cyclization which occurred at
provide phthalide 3i in 94% yield at 70 °C in 7 h (entry 9). Substrate
1j bearing a para-MeO on the aromatic ring smoothly cyclized into
phthalide 3j in 84% yield and accompanied with isocoumarin 4j in
14% yield (entry 10). Moreover, cyclizations of both 2,4-di-substi-
tuted substrates (1k and 1l) bearing electron-withdrawing and
electron-donating moieties on the distal aryl rings proceeded to
give the corresponding phthalides 3k and 3l in 72% and 63% yields,
respectively, although formation of 3l with the 2,4-di-MeO substi-
tution required almost twice longer reaction time at 90 °C than 3k
with the 2,4-di-fluoro moiety (entries 11 and 12). However, at-
tempts to cyclize substrate 1m bearing a distal bulky t-Bu group
failed under the several reaction conditions while the correspond-
ing benzoic acid 2m was isolated as the sole product in 91% yield
(entry 13). In the absence of such steric hindrance, cyclization of
1n with a simple terminal alkyne proceeded smoothly to phthalide
3n in 88% yield (entry 14).
the
a
-position of the carbon–carbon triple bond regardless of the
The present intramolecular cyclization is expected to follow the
proposed mechanism reported earlier, which requires an activation
of the carbon–carbon triple bond by a Lewis acid (Scheme 2).3,4 In
all cases, formation of the 5-exo-dig phthalides is always preferen-
tial over the 6-endo-dig isocoumarin (Table 1). We postulate that
both the reactivity and the regioselectivity of this intramolecular
cyclization are influenced by the electronic nature of the carbon–
carbon triple bond. Furthermore, this electronic influence depends
electronic nature of the substituents in R1 group (Table 1).
Both electronic and steric influences of ortho-substituents illus-
trated in the intramolecular cyclizations of a set of substrates
(1f–1i) are summarized in Table 1 (entries 6–9). Cyclization of sub-
strate 1f bearing an electron-donating ortho-Me group was found
to be sluggish which produced the desired phthalide 3f in 20%
yield and accompanied with 72% of the corresponding benzoic acid
2f and 4% of isocoumarin 4f, after the treatment with excess of re-
agents (5 equiv NaClO2, 24 equiv NaH2PO4 and 40 equiv 2-methy-
2-butene) at 90 °C for 48 h (entry 6). On the other hand, substrates
bearing electron-withdrawing moieties at the ortho-position (1g–
1i) underwent cyclization to provide the corresponding phthalides
(3g–3i) in much higher yields at lower reaction temperature and in
a shorter period of time (entries 7–9). To our delight, the 5-exo-dig
cyclization of the most electronic deficient and sterically demand-
ing 1i with an ortho-CF3 group proceeded exceptionally well to
O
O
O
O
a
b
O
R2
R2
O
+
R1
R1
R2
H
A
R1
2'
3
4
Scheme 2. Plausible mechanism for the intramolecular cyclization.

J. Li et al. / Tetrahedron Letters 51 (2010) 5937–5939
5939
on the substitutions on both sides of the carbon–carbon triple
bond, which polarizes the bond as described by the groups of
Gevorgyan and co-workers13 and Larock and co-workers.6b Accord-
ing to Gevorgyan and co-workers,13 the ortho-benzoic acid moiety
in intermediate 20 produces the polarization effect on the carbon–
We also discuss the reactivity and scope of this intramolecular
cyclization influenced by the electronic nature of substituents on
both sides of the carbon–carbon triple bond.
Acknowledgment
carbon triple bond by making the a-position more positive. In the
The authors thank Hans Maag for his helpful discussions and
revision of this manuscript.
case of substrate 1b, the electron-donating para-OMe group in the
backbone benzoic acid ring further enhances the polarization of
the carbon–carbon triple bond in a way that leads to more cationic
References and notes
character at the a-position than the b-position, thus facilitating the
carboxylate nucleophilic attack at the more electrophilic position
leading to the observed 5-exo-dig phthalide cyclization. This addi-
tional polarization effect by the para-OMe group significantly con-
tributes cyclization reactivity and selectivity at a much lower
temperature in comparison to the much less reactive unsubstitut-
ed 1a (12% yield at 90 °C for 48 h).
1. (a) Devon, T. K.; Scott, A. I.. In Handbook of Naturally Occurring Compounds;
Academic Press: New York, 1975; Vol. 1, pp 249–264; (b) Hill, R. A.. In Progress
in the Chemistry of Organic Natural Products; Wien-Springer: New York, 1986;
Vol. 49, (c) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891–900; (d) Xioang, M.
J.; Li, Z. H. Curr. Org. Chem. 2007, 11, 833–844; (e) Zhang, H.; Zhang, S.; Liu, L.;
Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368–374; (f) Holler, U.;
Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2002, 65, 876–882.
2. For recent examples, see: (a) Hall, J. D.; Duncan-Gould, N. W.; Siddiqi, N. A.;
Kelly, J. N.; Hoeferlin, L. A.; Morrison, S. J.; Wyatt, J. K. Bioorg. Med. Chem. 2005,
13, 1409–1413; (b) Zamilpa, A.; Herrera-Ruiz, M.; del Olmo, E.; Lopez-Perez, J.
L.; Tortoriello, J.; Feliciano, A. S. Bioorg. Med. Chem. Lett. 2005, 15, 3483–3486;
(c) Radcliff, F. J.; Fraser, J. D.; Wilson, Z. E.; Heapy, A. M.; Robinson, J. E.; Bryant,
C. J.; Flowers, C. L.; Brimble, M. A. Bioorg. Med. Chem. 2008, 16, 6179–6185.
3. Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.;
Sakamoto, T. Org. Lett. 2006, 8, 5517–5520.
4. (a) Terada, M.; Kanazawa, C. Tetrahedron Lett. 2007, 48, 933–935; (b) Terada,
M.; Kanazawa, C.; Yamanaka, M. Heterocycles 2007, 74, 819–825.
5. (a) Lu, W.-D.; Lin, C.-F.; Wang, C.-J.; Wang, S.-J.; Wu, M.-J. Tetrahedron 2002, 58,
7315–7319; (b) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R.
Tetrahedron 2002, 58, 5023–5038; (c) Marchal, E.; Uriac, P.; Legouin, B.; Toupet,
L.; van de Weghe, P. Tetrahedron 2007, 63, 9979–9990.
6. (a) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432–1437; (b) Mehta, S.; Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141–1147.
7. (a) Zhou, L.; Jiang, H.-F. Tetrahedron Lett. 2007, 48, 8449–8452; (b) Inack-Ngi, S.;
Rahmani, R.; Commeiras, L.; Chouraqui, G.; Thibonnet, J.; Duchene, A.; Abarbri,
M.; Parrain, J.-L. Adv. Synth. Catal. 2009, 35, 779–788.
In contrast, electronic effect of substituents on the distal b-posi-
tion of carbon–carbon triple bond plays a different role in this
intramolecular cyclization (entries 6–14). For the set of ortho-
substituted substrates (entries 1f–1i), it appears that these with
the electron-deficient systems have a favorable effect on the out-
come of this cyclization reaction. Despite having a bulkier ortho-
CF3 in 1i relative to ortho-CH3 in 1f, the rate of cyclization of 1i
(94% yield) is clearly superior than 1f (20% yield) at a lower reac-
tion temperature and a shorter time (entries 6 and 9). According
to Gevorgyan and co-workers,13 electron-withdrawing and elec-
tron-donating substituents in the ortho-position of 1f and 1i induce
different polarizations of the triple bond, as indicated by their
opposite directions of dipole moment vectors. We anticipate that
the dipole moment induced by the ortho-CF3 group is in the same
direction as the one from the carboxylate moiety, so that the over-
all constructive dipole moment further activates the triple bond for
the intramolecular cyclization. On the other hand, electron-donat-
ing ortho-CH3 group induces a dipole moment opposite to the car-
boxylate that leads to a less activated triple bond and the
subsequent slow cyclization of 1f.
8. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736; (b) Johnson, C. D.
Acc. Chem. Res. 1993, 26, 476–482.
9. (a) Tovar, J. D.; Swager, T. M. J. Org. Chem. 1999, 64, 6499–6504; (b) Le Bras, G.;
Hamze, A.; Messaoudi, S.; Provot, O.; Le Calvez, P.-B.; Brion, J.-D.; Alami, M.
Synthesis 2008, 10, 1607–1611.
10. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–890; (b)
Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567–569.
11. Syntheses of 1a–1o were carried out by
a Sonogashira coupling of the
In summary, we report a regioselective one-pot procedure to
synthesize phthalides in good yields from readily available ortho-
alkynylbenzaldehydes under mild NaClO2 oxidation conditions.
corresponding alkynes and aryl halides.
12. This result is in agreement to the observation reported by Terada et. al in Ref. 4a.
13. Rubin, M.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10243–10249.