Transition-metal-free synthesis of (Z)-3-ylidenephthalides from 2-acyl-benzoic acids

Article abstract of DOI:10.1016/j.tetlet.2014.02.012

We report a highly efficient method for the synthesis of (Z)-3-ylidenephthalides via intramolecular cyclization of readily available 2-acyl-benzoic acids mediated by TSTU at room temperature. Using this method, diversely substituted (Z)-3-ylidenephthalides have been generated in good to excellent yields. The application of the method is highlighted by gram-scale preparation of the antiplatelet drug n-butylphthalide.

Full text of DOI:10.1016/j.tetlet.2014.02.012

Accepted Manuscript
Transition-metal-free synthesis of (Z)-3-ylidenephthalides from 2-acyl-benzoic
acids
Xinhua He, Fengtian Xue
PII:
S0040-4039(14)00233-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.012
TETL 44199
Reference:
Tetrahedron Letters
To appear in:
Received Date:
14 January 2014
Please cite this article as: He, X., Xue, F., Transition-metal-free synthesis of (Z)-3-ylidenephthalides from 2-acyl-
benzoic acids, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.02.012
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Transition-metal-free synthesis of (Z)-3-ylidenephthalides from 2-acyl-benzoic acids
Xinhua Hea and Fengtian Xuea,*
aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street,
Baltimore, Maryland 21201
*Correspondence to Professor Fengtian Xue at the Department of Pharmaceutical Sciences, University of
Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201
Phone: 410-706-8521
Email: fxue@rx.umaryland.edu
Keywords:
(Z)-3-Ylidenephthalides
2-Acyl-benzoic acid
Intramolecular cyclization
Enol
n-Butylphthalide
1

Abstract
We report a highly efficient method for the synthesis of (Z)-3-ylidenephthalides via intramolecular
cyclization of readily available 2-acyl-benzoic acids mediated by TSTU at room temperature. Using this
method, diversely substituted (Z)-3-ylidenephthalides have been generated in good to excellent yields.
The application of the method is highlighted by gram-scale preparation of the antiplatelet drug n-
butylphthalide.
Graphic Abstract
2

(Z)-3-Ylidenephthalides show broad biological activities including inhibitory activity for COX2
as anti-inflammatory agents,1 anti-platelet activity for cardiovascular diseases,2 and modulatory activity
for transient receptor potential channel TRPA1 and TRPM8 as potential treatment of pain.3 Therefore,
the preparation of (Z)-3-ylidenephthalides has attracted significant efforts.
The synthesis of (Z)-3-ylidenephthalides was first reported using the modified Perkin reaction.4
Recently synthesis of (Z)-3-ylidenephthalides has been reported using a variety of catalytic protocols
including Pd-catalyzed cyclocarbonylation of 2-triflyloxyacetophenones,5 Pd-catalyzed cyclization of
alkenoic acids,6 Wittig-Horner reaction of phthalide-3-phosphonates with ketones,7 Ag-catalyzed
heteroannulation of 2-(1-alkynyl)benzoic acids,8 Au (I)-catalyzed cyclization of alkyne acids,9 organo-
base catalyzed intramolecular cyclization,10 Oxidative cyclization of ortho-alkynylbenzaldehydes using
NaClO2,11 NHC-catalyzed oxidative cyclization,12 and Pd/C-mediated coupling-cyclization of o-
bromobenzoic acids.1 Although these available methods have been useful in preparing various (Z)-3-
ylidenephthalides, they usually suffer from limitations such as the involvement of metal catalysts,
generation of significant amount of side products, complex purification procedure, and low isolation
yields.
Since the bloom of peptide synthesis in 1990s, various coupling reagents has been described,13
which, by activating the carboxylic acid group, can assist the formation of a new amide bond or an ester
bond.13 We hypothesize that activation of 2-acyl-benzoic acids (2) by coupling reagents can generate
intermediate 3, which will subsequently undergo an intramolecular cyclization via the enol OH group to
yield (Z)-3-ylidenephthalide 1.
Scheme 1. Synthetic plan to (Z)-3-ylidenephthalides 1 from 2-acyl-benzoic acids 2.
3

To test this idea, a solution of 2-acetyl-benzoic acids (2a) in CH2Cl2 was treated with HBTU in
the presence of TEA (Table 1, entry 1). The reaction went smoothly at room temperature, generating
compound 1a in good yields after 12 h. This encouraging result prompted us to screen other coupling
reagents. Reactions employing carbodiimide-based coupling reagents DIC (Table 1, entry 2) and EDC
(Table 1, entry 3) gave no desired product. When EDC was combined with HOBt, the reaction yielded 3-
((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3-methylisobenzofuran-1(3H)-one (4, Scheme 2) as the only
product in high yields (Table 1, entry 4). Reaction using DPPA as the coupling reagent generated trace
amount of compound 1a (Table 1, entry 5), along with 4-methylene-1H-benzo[d][1,3]oxazin-2(4H)-one 5
as the major product in high yields (Scheme 3).14 Improved yields of compound 1a were observed when
uranium-based coupling reagents HATU (Table 1, entry 6) and TSTU (Table 1, entry 7) were used. For
both reactions, compound 1a was generated in excellent yields. Next, we chose TSTU as the coupling
reagent to screen other organic solvents (Table 1, entries 8-12), and found that the reaction yields dropped
when CH2Cl2 was replaced by other tested solvents including THF, CH3CN, toluene, EtOAc and DMF.
Accordingly, CH2Cl2 was selected as the solvent for further optimization of bases used in the reaction
(Table 1, entries 13-16). We found that DIEA was superior to other tested bases including DMAP,
K2CO3, and NMM. After a short screening of reaction time, we found that the optimal reaction time was
6 h (Table 1, entries 17-18). The decrease of the amount of DIEA will lead to the decrease of yields of
compound 1a (Table 1, entries 19-21).
4

Table 1. Optimization of Reaction Conditions for 1aa
entry
1
reagentb
HBTU
DIC
basec
TEA
solventd
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
T., t
Yield 1a, %e
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 6 h
74
0
2
TEA
3
EDC
TEA
0
4
EDC/HOBt
DPPA
HATU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TSTU
TEA
0f
5
TEA
traceg
91
93
57
88
68
22
61
0
6
TEA
7
TEA
8
TEA
9
TEA
CH3CN
toluene
EtOAc
DMF
10
11
12
13
14
15
16
17
18
19
20
TEA
TEA
TEA
DMAP
K2CO3
NMM
DIEA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
27
70
99
99
83
86
56
DIEA
DIEA
rt, 1 h
DIEA (1.0 equiv)
DIEA (0.5 equiv)
rt, 6 h
rt, 6 h
5

21
TSTU
DIEA (0.1 equiv)
CH2Cl2
rt, 6 h
38
aThe reaction was carried out at room temperature with 1.0 mmol of 2a, 1.0 mmol of coupling
b
reagent and 2.0 mmol of the base in 5.0 mL of solvent. HBTU = O-(benzotriazol-1-yl)-N,N,N′,N′-
tetramethyl uronium hexafluoro phosphate, DIC = N,N′-diisopropylcarbodiimide, EDC = N-(3-
dimethylamino propyl)-N′-ethylcarbodiimide hydrochloride, HOBt = 1-hydroxybenzotriazole hydrate,
DPPA = diphenylphosphoryl azide, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxid hexafluoro-phosphate, TSTU
=
N,N,N′,N′-tetramethyl-O-(N-succinimidyl)
uroniumtetrafluoro borate. cTEA = triethylamine, DMAP = 4-(dimethylamino)pyridine, K2CO3 =
d
potassium carbonate, NMM = 4-methylmorpholine, DIEA = diisopropyl ethylamine. DCM =
dichloromethane, THF = tetrahydrofuran, CH3CN = acetonitrile, EtOAc = ethyl acetate, DMF = N,N-
f
dimethyl formamide. eDetermined by 1H NMR. Compound 4 was isolated in 95% yield, g<5%.
Scheme 2. Formation of compound 4.
Scheme 3. Formation of compound 5.
Next, we explored the substrate scope of this method using the optimized conditions.
A
collection of (Z)-3-ylidenephthalides with diverse R1 and R2 substituents were prepared as shown in Table
2. 2-Propionylbenzoic acid 2b was cyclized well to give the thermodynamic product (Z)-3-methyliene
phthalide 1b in good yields (Table 2, entry 1). The stereochemistry of compound 1b was confirmed by
6

1
comparing its H NMR to published result.2 Similar good yields of (Z)-propylienephthalide 1c were
obtained when 2-pentanoyl benzoic acid 2c was used as the starting material (Table 2, entry 2). When the
phenyl-acetyl substrates (2d, 2e, 2f and 2g) were treated with TSTU, the corresponding (Z)-3-
ylidenephthalides 1d, 1e, 1f and 1g were generated all in high yields (Table 2, entry 3-6). It was noted
that for these reactions, the products were obtained by a simple extraction, which provides a much more
efficient way for the isolation of the (Z)-3-ylidenephthalides.
Table 2. Reactions of Other 2-Acyl-Benzoic Acids a
entry
1
substrate 2
product 1
R1
R2
H
yield, %b
CH3
83
2
3
H
n-Bu
82
98
Ph
H
4
Ph
4-Cl
99
7

5
6
Ph
7-Cl
81
91
p-Cl-Ph
H
a Reaction was carried out at room temperature with 1.0 mmol of 2, 1.0 mmol of TSTU, 2.0
mmol of DIEA in 5.0 mL of DCM. b Isolated yields.
With the ability to access diversely substituted 3-ylidenephthalide core structures in high
efficiency, we next show the transformation of compound 1c into n-butylphthalide (NBP, Scheme 4).
NBP is a widely used antiplatelet drug for the treatment of ischemia15 and stroke.2, 16 Recently NBP has
been reported to be an intriguing neuroprotective agent in the brain,17 as well as a potential therapeutic
agent for the treatment for Alzheimer’s diseases.18 Clinical use of NBP was approved by the State Food
and Drug Administration (SFDA) of China in 2002. As shown in Scheme 4, gram-scale synthesis of NBP
by catalytic hydrogenation of compound 1c using Pd/C gave almost quantitative yields in one step.19
Scheme 4. Synthesis of NBP.
In summary, we described, for the first time, that 2-acyl-benzoic acids can be transformed into
(Z)-3-ylidenephthalides using a TSTU-mediated intramolecular cyclization.20 The value of this method
has been shown in the preparation of various (Z)-3-ylidenephthalides in good to excellent yields. In
particular, the practical gram-scale synthesis of the antiplatelet drug NBP.
8

Acknowledgements
We gratefully acknowledge funding from the Department of Pharmaceutical Sciences, University of
Maryland School of Pharmacy.
Supplementary data
Supplementary data associated with this article can be found in the online version.
9

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Typical procedure for the synthesis of (Z)-3-ylidenephthalide 1a. To a solution of 2-acetyl-
benzoic acid (164 mg, 1.0 mmol) and TSTU (301 mg, 1.0 mmol) in CH2Cl2 (5.0 mL) was added DIEA
(2.0 mmol). The reaction was allowed to stir at room temperature for 6 h. Then, the reaction mixture was
poured into water (10 mL), extracted using EtOAc (3 × 10 mL). The combined organic layers were
washed by brine with water (3 × 10 mL) and NaHCO3 aqueous (3 × 10 mL) and dried over Na2SO4. The
solvent was removed by rotary evaporation to yield (Z)-3-ylidenephthalide 1a as a white solid (144 mg,
0.99 mmol, 99%): 1H NMR (400 MHz, CDCl3) δ 7.88-7.86 (d, J = 8.0 Hz, 1H), 7.71-7.70 (m, 2H), 7.58-
7.53 (m, 1H), 5.21 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 166.8, 151.8, 139.0, 134.5, 130.5, 125.2, 120.6,
91.3. LC-MS (M+Na+) calcd for C9H6NaO2 169, found 169.
11