Synthesis of 3-Benzylphthalide Derivatives by Using a TDAE Strategy

Article abstract of DOI:10.1055/a-1290-8349

A one-pot synthesis of new 3-benzylphthalide derivatives was developed by using a strategy based on tetrakis(dimethylamino)ethylene (TDAE). The reactions in the presence of TDAE of substituted benzyl chlorides with methyl 2-formylbenzoate or of substitute

Full text of DOI:10.1055/a-1290-8349

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–D
letter
A
en
M. Ibrahimi et al.
Letter
Synlett
Synthesis of 3-Benzylphthalide Derivatives by Using a TDAE
Strategy
Maroua Ibrahimia
Omar Khoumerib
Raoudha Abderrahima
Thierry Termeb
Patrice Vanelle*b
O
O
NO2
O
R2
OMe
H
TDAE
X
+
Cl
THF, –20 °C
O2N
R1
X
R2
X = CH, N
O
R1
R1 = H, OMe, Br, Cl, F, Me, Ph, C6H4OMe, C6H4NO2
R2 = Cl, Br, I, CN, CO2Me, Ph, OMe
25 examples, 33–75%
1 mmol scale
a University of Carthage, Faculty of Sciences of Bizerte, Laboratory
of Ressources Matériaux, Valorisation et Écosystème (RME code
LR19ES20), Zarzouna 7021, Bizerte, Tunisia
b Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR,
UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Marseille
13385, France
patrice.vanelle@univ-amu.fr
Corresponding Author
Received: 17.06.2020
Accepted after revision: 15.10.2020
Published online: 15.10.2020
group) and, in 2018, we reported the first example involv-
ing benzonitrile derivatives.6
In continuation of our program directed toward the de-
velopment of original synthetic methods using the TDAE
methodology in medicinal chemistry,7 we report an original
and efficient synthesis of new phthalides based on the
TDAE strategy. This method offers the advantage of avoid-
ing the use of metals, unlike that of Mukherjee and Roy.4
First, the reaction between 4-nitrobenzyl chloride (2a)
and methyl 2-formylbenzoate (1a) in the presence of TDAE
was selected as a model for a preliminary study (Scheme 1).
DOI: 10.1055/a-1290-8349; Art ID: st-2020-k0352-l
Abstract A one-pot synthesis of new 3-benzylphthalide derivatives
was developed by using a strategy based on tetrakis(dimethylami-
no)ethylene (TDAE). The reactions in the presence of TDAE of substitut-
ed benzyl chlorides with methyl 2-formylbenzoate or of substituted
methyl-2-formylbenzoates with 4-nitrobenzyl chloride furnished the
corresponding isobenzofuran-1(3H)-one products in moderate to good
yields.
Key words benzylphthalides, methyl formylbenzoate, nitrobenzyl
chlorides, isobenzofuranones
O
O
TDAE
(1 equiv)
O2N
O
MeO
OHC
+
Cl
Phthalides (isobenzofuranones) are important com-
pounds in organic and medicinal chemistry. Phthalides are
common structural motifs that are often present in natural
products,1 pharmaceuticals, and bioactive molecules.2 They
also act as key building blocks in organic synthesis. Many
methods for synthesizing functionalized phthalides have
been developed, and the usual protocols involve multistep
intra- or intermolecular cyclizations.3 In particular, the re-
action of ortho-formylbenzoates with benzyl chlorides in
the presence of Cp2TiCl and Zn to afford phthalides has
been reported.4
Tetrakis(dimethylamino)ethylene (TDAE) is an organic
reducing agent that reacts with halogenated derivatives to
generate carbanions under mild conditions.5 Since 2003,
the TDAE methodology has been widely explored. Several
reactions between nitrobenzylic substrates and various
electrophiles, such as aromatic aldehydes, ketones, -keto
esters, -keto lactams, diethyl oxomalonate, and sulfoni-
mine derivatives, have been developed. This strategy re-
quires a substrate with an appropriate redox potential to
react with TDAE. Generally, we have used nitrobenzylic de-
rivatives or various heterocycles (with or without a nitro
2a
3a
1a
O2N
Scheme 1 Reaction of 4-nitrobenzyl chloride (2a) with methyl 2-form-
ylbenzoate (1a) in the presence of TDAE
We investigated the influence of such parameters the
solvents (DMF, THF, or MeCN), the amount of methyl 2-
formylbenzoate (1a; 1.5 or 2 equiv), the reaction time, and
the temperature (Table 1). The first tests (Table 1, entries 1–
3) carried out with standard solvents for this method led us
to choose THF as the optimal solvent (entry 3). We then
changed other parameters: the amount of methyl 2-formyl-
benzoate (1a), the reaction time, and the temperature. With
regard to the amount of methyl 2-formylbenzoate (1a), an
excess was necessary to increase the reaction yield, as ob-
served in our previously studies.6 The influence of a tem-
perature of –20 °C (entry 5; yield: 71%) versus 0 °C (entry 7;
56%) confirmed the importance of a low temperature to ini-
tiate the reaction through the formation of a charge-trans-
fer complex between 4-nitrobenzyl chloride (2a) and TDAE.
At 0 °C, some of the starting material was recovered un-
changed (entry 7). The best yield (71%) of 3-(4-nitroben-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Ibrahimi et al.
Letter
Synlett
zyl)isobenzofuran-1(3H)-one (3a) was obtained by using
two equivalents of methyl-2-formylbenzoate (1a) and one
equivalent of 4-nitrobenzyl chloride (2a) in the presence of
one equivalent of TDAE at –20 °C in THF for one hour, fol-
lowed by three hours at room temperature (entry 5). Final-
ly, we examined the corresponding reaction of 4-nitroben-
zyl bromide under the conditions of Table 1, entry 5, but
only 63% of product 3a was recovered. This decrease in yield
was associated with the appearance of the dimeric byprod-
uct 1,2-bis(4-nitrophenyl)ethane. The change of the reac-
tion time at rt (after 1 h at low temperature) does not in-
crease the yield (entry 8 and 9).
formed with the CN group have shown that it requires a dif-
ferent protocol and optimization study.6f Other electron-
withdrawing groups requiring optimization (COR, COOR)
will be the subject of future studies. We therefore extended
this reaction to other nitrobenzyl chlorides 2a–o, which
were either commercially available or were prepared (2k–
m) as shown in Scheme 2. Benzylic chlorides 2k–m were
prepared in three steps from the corresponding bromo-
benzaldehydes by a Suzuki–Miyaura cross-coupling reac-
tion followed by reduction of the aldehyde and chlorination
of the resulting alcohol.
The reaction of methyl 2-formylbenzoate (1a; 2 equiv)
with substituted benzyl chlorides 2a–o in anhydrous THF in
the presence of TDAE at –20 °C for one hour followed by
three hours at room temperature led to the corresponding
derivatives 3a–o in moderate to good yields (33–72%), as
shown in Scheme 3 and Table 2.8 For low yields, no identifi-
able byproducts (dimer, reduction product, etc.) were ob-
tained, only degradation products (tar).
Table 1 Optimization of the Reaction of 4-Nitrobenzyl Chloride (2a)
with Methyl 2-Formylbenzoate (1a) in the Presence of TDAEa
Entry
Solvent
1a (equiv) Temp (°C) Time at rt (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF
MeCN
THF
THF
THF
THF
THF
THF
THF
1.5
1.5
1.5
2
–30
–30
–30
–30
–20
–10
0
3
59
57
64
69
71
68
56
56
66
3
O
3
O
3
O
OMe
H
TDAE
+
2
3
Cl
THF, –20 °C
R1
1a
2a–o
3a–o
O
2
3
R1
2
3
Scheme 3 Generalization of the reaction of methyl 2-formylbenzoate
(1a) with nitrobenzylic chlorides 2a–o by using the TDAE strategy
2
–20
–20
0.5
8
2
a All the reactions were performed by using TDAE (1 equiv).
Table 2 Reaction of Methyl 2-Formylbenzoate (1a) with Nitrobenzylic
Chlorides 2a–o by Using the TDAE Strategya
b Yield of the chromatographically isolated pure product relative to 2a.
Entry
R1
4-NO2
Product
Yieldb (%)
Seeking to establish the scope of this reaction and its
added value, we performed more experiments. No reaction
occurred with nonsubstituted benzyl chloride or with ben-
zyl chlorides substituted with an electron-donating group
in the absence of a nitro group. In the benzylic series, under
the optimized conditions, a nitro group appears to be a pre-
requisite for this reaction. For benzyl chlorides substituted
with other electron-withdrawing groups, no reaction was
observed under the optimized conditions in the case of 4-
(chloromethyl)benzonitrile, but a previous study per-
1
2
3a
3b
3c
3d
3e
3f
71
69
67
69
68
41
68
65
46
60
72
65
47
33
51
2-NO2
3
2-NO2-4,5-(OMe)2
2-NO2-4,5-OCH2O-
2-NO2-5-Br
4
5
6
2-NO2-5-Cl
7
2-NO2-5-Me
2-NO2-5-OMe
3-OMe-4-NO2
3-Me-4-NO2
2-NO2-4-Ph
3g
3h
3i
8
9c
10c
11
12
13c
14
15
X
X
3j
Br
R
Pd(dppf), K2CO3
R
+
3k
3l
1,4-dioxane/H2O (4:1)
80 °C, 12 h
(HO)2B
CHO
CHO
2-NO2-4-(4-MeOC6H4)
4-(4-O2NC6H4)
3-F-4-NO2
X = H, OMe, NO2
R = H, NO2
3m
3n
3o
X
X
X
R
R
R
2-NO2-4-Br
NaBH4
SOCl2, Et3N
Cl
OH
MeOH/HCCl3 (1:1)
rt, 2 h
CH2Cl2, rt, 8 h
a Reaction conditions: methyl 2-formylbenzoate (1; 2 equiv), nitrobenzylic
chloride 2 (1 equiv), TDAE (1 equiv), anhyd THF.
b Yield of the chromatographically isolated pure product relative to the ni-
trobenzylic chloride 2.
CHO
2k X = H, R = NO2
2l X = OMe, R = NO2
2m X = NO2, R = H
c Anhyd DMF as solvent.
Scheme 2 Synthesis of benzylic chlorides 2k–m
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
M. Ibrahimi et al.
Letter
Synlett
It is difficult to correlate certain types of substituent
with the yield because the effect of the substituents occurs
during the two phases of the process (Phase 1: activation of
the substrate and formation of the carbanion; Phase 2: re-
activity of the carbanion during the nucleophile addition on
the aldehyde). However, the low yields of 3f (41%) and 3n
(33%) appear to be due to the electron-withdrawing effect
of fluorine or chlorine which stabilizes the carbanion, mak-
ing it unreactive toward nucleophilic addition.
To extend this reaction to various formylbenzoates, sev-
eral substituted methyl 2-formylbenzoates were prepared
in good yield by the three-step procedure shown in Scheme
4. Radical bromination of substituted isobenzofuran-1-
(3H)-ones with 1.2 equivalents of NBS gave substituted 3-
bromoisobenzofuran-1-(3H)-ones that were converted into
substituted 2-formylbenzoic acids by the action of water.
The substituted 2-formylbenzoic acids reacted with methyl
iodide in acetone for two hours to give the corresponding
substituted methyl 2-formylbenzoates.9
Table 3 Reaction of 4-Nitrobenzyl Chloride 2a with Substituted Meth-
yl 2-Formylbenzoates 1b–k by Using the TDAE Strategy
Entrya
R2
5-Cl
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
4b
4c
4d
4e
4f
46
59
64
75
46
49
50
71
35
5-Br
4-Br
5-I
4-CN
4-CO2Me
4-Ph
4g
4h
4i
5-Ph
4,5-(OMe)2
4j
a All reactions were performed by using the substituted methyl 2-formyl-
benzoate 1b–j (2 equiv), 4-nitrobenzyl chloride 2a (1 equiv), and TDAE (1
equiv) in anhyd THF.
b Yield of chromatographically isolated pure product relative to 4-nitroben-
zyl chloride (2a).
O
O
to the electron-donating effect of the alkoxy groups which
deactivates the formyl group.
NBS, AIBN
CCl4, 4 h
R2
R2
O
O
To extend this reaction to heterocyclic substrates, we
studied the reaction of methyl 2-formylnicotinate (1k) with
4-nitrobenzyl chloride (2a) in the presence of TDAE. This
reaction gave the corresponding phthalide 4k in 34% yield
(Scheme 6).
Br
R2 = Cl, Br, I, CN, CO2Me, Ph
H2O, 100 °C
2 h
O
O
OMe
OH
H
R2
MeI, K2CO3
acetone, 4 h
R2
H
O
O
O
Cl
O
O
Scheme 4 Synthesis of various 2-formylbenzoates
OMe
H
TDAE
N
THF, –20 °C
N
1k
O2N
These new substituted methyl-2-formylbenzoates 1b–j
reacted with 4-nitrobenzyl chloride (2a) under the usual
conditions, i.e., 4-nitrobenzyl chloride (1 equiv) with sub-
stituted methyl-2-formylbenzoates 1b–j (2 equiv) in the
presence of TDAE at –20 °C for one hour in anhydrous THF
followed by three hours at room temperature to give the
corresponding phthalide derivatives 4b–j in moderate to
good yields of 35–75% (Scheme 5 and Table 3).10 For low
yields, no identifiable byproducts (dimer, reduction prod-
uct, etc.) were obtained, only degradation products (tar).
2a
4k 34%
O
NO2
Scheme 6 Reaction of 4-nitrobenzyl chloride (2a) with methyl 2-
formylnicotinate (1k) by using the TDAE strategy
The formation of these phthalide derivatives can be ex-
plained by a nucleophilic addition of a nitrobenzyl carban-
ion, formed by the action of TDAE on 4-nitrobenzyl chlo-
ride, to the carbonyl group of the methyl 2-formylbenzoate,
followed by lactonization through intramolecular transes-
terification (Scheme 7).
O
Cl
O
O
R2
O
OMe
H
TDAE
R2
TDAE
(1 equiv)
O2N
O2N
THF, –20 °C
MeO
Cl
+
1b–j
2a
4b–j
H
O2N
O
CH2
NO2
O
Scheme 5 Generalization of the reaction of 4-nitrobenzyl chloride (2a)
with substituted methyl 2-formylbenzoates 1b–k by using the TDAE
strategy
O
O
MeO
O
O
As shown in the series, no clear correlation was ob-
served between the effect of the electronegativity of the
substituent in the methyl 2-formylbenzoate and the reac-
tion yield. With substrate 1j containing two methoxy
groups (Table 3, entry 9), the yield fell to 35%, probably due
O2N
O2N
Scheme 7 Mechanism of the reaction of 4-nitrobenzyl chloride (2a)
with methyl 2-formylbenzoate (1a) in the presence of TDAE
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
M. Ibrahimi et al.
Letter
Synlett
In conclusion, two new series of highly substituted
phthalide derivatives were obtained through the TDAE
strategy in a one-pot process. This method offers the ad-
vantage of avoiding the use of metals, compared with the
method of Mukherjee and Roy;4 moreover, 3-benzylphtha-
lides are not accessible by other innovative methods based
on dehydrogenative coupling reactions.3c In the presence of
TDAE, the reactions of substituted benzyl chlorides with
methyl 2-formylbenzoate or of substituted methyl-2-form-
ylbenzoates with 4-nitrobenzyl chloride gave the corre-
sponding isobenzofuran-1(3H)-one products in moderate
to good yields.
6173. (f) Khoumeri, O.; Terme, T.; Vanelle, P. Synthesis 2018,
2617. (g) Montana, M.; Terme, T.; Vanelle, P. Lett. Org. Chem.
2010, 7, 453. (h) Roche, M.; Terme, T.; Vanelle, P. Molecules
2013, 18, 1540.
(7) (a) Amiri-Attou, O.; Terme, T.; Vanelle, P. Synlett 2005, 3047.
(b) Khoumeri, O.; Montana, M.; Terme, T.; Vanelle, P. Tetrahe-
dron 2008, 64, 11237. (c) Khoumeri, O.; Terme, T.; Vanelle, P.
Tetrahedron Lett. 2012, 53, 2410. (d) Montana, M.; Terme, T.;
Vanelle, P. Tetrahedron Lett. 2005, 46, 8373. (e) Montana, M.;
Terme, T.; Vanelle, P. Tetrahedron Lett. 2006, 47, 6573. (f) Amiri-
Attou, O.; Terme, T.; Vanelle, P. Molecules 2005, 10, 545.
(8) 3-Benzyl-2-benzofuran-1(3H)-ones 3a–o; General Procedure
The appropriate substituted benzylic chloride 2a–o (1 mmol, 1
equiv) in anhyd THF (15 mL) was added to methyl 2-formylben-
zoate (1a; 328 mg, 2 mmol, 2 equiv) under nitrogen in a two-
necked flask. TDAE (200 mg, 1 equiv) was added dropwise, and
the solution was cooled to –20 °C, maintained at this tempera-
ture for 1 h, and then kept at rt for 3 h. The solution was then
extracted with EtOAc (3 × 20 mL) and the extracts were washed
with brine (3 × 20 mL), dried (MgSO4), and concentrated. The
crude product was purified by chromatography [silica gel,
CH2Cl2–PE (1:1)] and recrystallized from EtOH.
Funding Information
This work was supported by the Centre National de la Recherche Sci-
entifique and Aix-Marseille Université. We thank the Ministry of
Higher Education of Tunisia for financing this work.
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3-(4-Nitrobenzyl)-2-benzofuran-1(3H)-ones (3a)
Supporting Information
White solid; yield: 190.99 mg (71%); mp 169 °C. 1H NMR (250
MHz, DMSO-d6):  = 3.24 (dd, J = 14.3, 7.8 Hz, 1 H, CH2), 3.63
(dd, J = 14.3, 4.1 Hz, 1 H, CH2), 5.99 (dd, J = 7.7, 4.1 Hz, 1 H, CH),
7.54 (d, J = 8.7 Hz, 2 H, ArH), 7.59 (t, J = 7.4 Hz, 3 H, ArH), 7.74 (d,
J = 7.6 Hz, 1 H, ArH), 8.16 (d, J = 8.6 Hz, 2 H, ArH). 13C NMR (62.5
MHz, DMSO-d6):  = 38.9, 80.4, 122.9, 123.2 (2 C), 124.9, 125.4,
129.4, 130.8 (2 C), 134.3, 144.4, 146.4, 149.0, 169.4. HRMS (ESI):
m/z [M + H]+ calcd for C15H12NO4: 270.0761; found: 270.0763.
(9) (a) Dhanasekaran, S.; Bisai, V.; Unhale, R. A.; Suneja, A.; Singh, V.
K. Org. Lett. 2014, 16, 6068. (b) He, Y.; Cheng, C.; Chen, B.; Duan,
K.; Zhuang, Y.; Yuan, B.; Zhang, M.; Zhou, Y.; Zhou, Z.; Su, Y. J.;
Cao, R.; Qiu, L. Org. Lett. 2014, 16, 6366.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1290-8349.
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References and Notes
(1) Suzuki, M.; Ueoka, R.; Takada, K.; Okada, S.; Ohtsuka, S.; Ise, Y.;
Matsunaga, S. J. Nat. Prod. 2012, 75, 1192.
(2) Yoshikawa, M.; Uchida, E.; Chatani, N.; Murakami, N.;
Yamahara, J. Chem. Pharm. Bull. 1992, 40, 3121.
(3) (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213.
(b) Li, Y.; Zhang, J.; Li, D.; Chen, Y. Org. Lett. 2018, 20, 3296.
(c) Renzetti, A.; Fukumoto, K. Molecules 2019, 24, 824. (d) Tang,
Y.; Meador, R. I. L.; Malinchak, C. T.; Harrison, E. E.; McCaskey, K.
A.; Hempel, M. C.; Funk, T. W. J. Org. Chem. 2020, 85, 1823.
(e) Takakura, R.; Ban, K.; Sajiki, H.; Yoshinari Sawama, Y. Synlett
2019, 30, 1919. (f) Nozawa-Kumada, K.; Kurosu, S.; Shigeno, M.;
Kondo, Y. Asian J. Org. Chem. 2019, 8, 1080. (g) Capaldo, L.;
Riccardi, R.; Ravelli, D.; Fagnoni, M. ACS Catal. 2018, 8, 304.
(h) Mahendar, L.; Satyanarayana, G. J. Org. Chem. 2016, 81, 7685.
(4) Mukherjee, S.; Roy, S. C. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2018, 57, 85.
(5) (a) Takechi, N.; Aït-Mohand, S.; Médebielle, M.; Dolbier, W. R. Jr.
Tetrahedron Lett. 2002, 43, 4317. (b) Pooput, C.; Médebielle, M.;
Dolbier, W. R. Jr. Org. Lett. 2004, 6, 301. (c) Pooput, C.;
Médebielle, M.; Dolbier, W. R. Jr. J. Org. Chem. 2006, 71, 3564.
(6) (a) Giuglio-Tonolo, G.; Terme, T.; Médebielle, M.; Vanelle, P. Tet-
rahedron Lett. 2003, 44, 6433. (b) Giuglio-Tonolo, G.; Terme, T.;
Médebielle, M.; Vanelle, P. Tetrahedron Lett. 2004, 45, 5121.
(c) Giuglio-Tonolo, G.; Terme, T.; Vanelle, P. Synlett 2005, 251.
(d) Juspin, T.; Laget, M.; Terme, T.; Azas, N.; Vanelle, P. Eur.
J. Med. Chem. 2010, 45, 840. (e) Khoumeri, O.; Giuglio-Tonolo,
G.; Crozet, M. D.; Terme, T.; Vanelle, P. Tetrahedron 2011, 67,
(10) 3-(4-Nitrobenzyl)-2-benzofuran-1(3H)-ones 4b–j; General
Procedure
A two-necked flask equipped with a N2 inlet was charged with a
solution of 4-nitrobenzyl chloride (2a; 171 mg, 1 mmol,
1 equiv) and the appropriate methyl 2-formylbenzoate 1b–j
(2 mmol, 1.5 equiv) in anhyd DMF (15 mL) at –20 °C under
nitrogen, and then TDAE (200 mg, 1 equiv) was added dropwise.
The solution was maintained at –20 °C for 1 h and then kept at
rt for 2 h at –20 °C. The product workup was as described above
for products 3a–o.
6-Chloro-3-(4-nitrobenzyl)-2-benzofuran-1(3H)-one (4b)
White solid; yield: 139.69 mg (46%); mp 157 °C. 1H NMR (250
MHz, DMSO-d6):  = 3.26 (dd, J = 14.3, 7.8 Hz, 1 H, CH2), 3.63
(dd, J = 14.3, 4.2 Hz, 1 H, CH2), 6.00 (dd, J = 7.7, 4.2 Hz, 1 H, CH),
7.53 (d, J = 8.7 Hz, 2 H, ArH), 7.78 (d, J = 8.1 Hz, 1 H, ArH), 7.84
(d, J = 1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.1, 1.9 Hz, 1 H, ArH), 8.16
(d, J = 8.7 Hz, 2 H, ArH). 13C NMR (62.5 MHz, DMSO-d6):  = 39.8,
80.5, 123.2 (2 C), 124.5, 124.9, 127.5, 130.9 (2 C), 134.2, 134.3,
144.2, 146.4, 147.7, 168.1. HRMS (ESI): m/z [M + NH4]+ calcd for
C15H14ClN2O4: 321.0637; found: 321.0636.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D