Synthesis of phosphorylated isoindolinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.02.127

The synthesis of diethyl [2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) ethyl]phosphonates and diethyl [3-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propyl]phosphonates, via metallation (sec-BuLi) of N-substituted isoindolin-1-ones and then the reactio

Full text of DOI:10.1016/j.tetlet.2014.02.127

Tetrahedron Letters 55 (2014) 2420–2422
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Tetrahedron Letters
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Synthesis of phosphorylated isoindolinone derivatives
a,
a,
a
b
⇑
⇑
´
Andrzej Józwiak , Piotr M. Zagórski , Mieczysław W. Płotka , Dariusz Cal
a Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 Lodz, Poland
b Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of diethyl [2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)ethyl]phosphonates and diethyl
[3-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propyl]phosphonates, via metallation (sec-BuLi) of
N-substituted isoindolin-1-ones and then the reaction of the generated lithiated species 4 with diethyl
vinylphosphonate or diethyl 3-bromopropylphosphonate, respectively, is described.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 18 January 2014
Revised 6 February 2014
Accepted 27 February 2014
Available online 6 March 2014
Keywords:
Heterocycles
Lithiation
Phosphorylation
Michael addition
Esters
The isoindolinone core is a key structural element, which is
present in many natural compounds. Several isoindolinone deriva-
tives, such as isoindolin-1-one-3-phosphonates A, have been
reported in the literature. These compounds have attracted atten-
tion due to their potential biologic activity or as structural blocks
for designing bioactive compounds.1–8 The synthesis of 3-oxoisoin-
dolin-1-yl-phosphonates A was carried out either as a three-com-
ponent, one-pot reaction of 2-formylbenzoic acid with primary
amines and dimethyl phosphite,1–3 or by the phosphorylation of
N-acyliminium salts generated from 3-hydroxyisoindolin-1-ones.5
In all cases the phosphonic group was directly bonded to the iso-
indolinone ring. To date, no procedures have been developed for
the preparation of other phosphorylated isoindolinone derivatives,
especially those containing a linker between the isoindolinone core
and the phosphonic moiety, such as B or C.
In this Letter, we report a method for the preparation of diethyl
[2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)ethyl]phosphonates B
and
diethyl
[3-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)pro-
pyl]phosphonates C, using a strategy based on lithiation at position
3 of an N-substituted isoindolin-1-one with sec-BuLi.9 The lithium
derivative was further converted into the target compounds. Our re-
search was based on the reports demonstrating reactions between
diethyl vinylphosphonate10a,b or 3-bromopropylphosphonate,10c
and various lithiated compounds.
Isoindolin-1-ones 3a and 3e were obtained by the reduction of
the appropriate N-substituted phthalimides. Substrates 3b–d were
prepared by the reduction of 3-hydroxy-2-methyl-1H-isoindolin-
1-ones 2b–d (Scheme 1). Compounds 2b–d were synthesized in
good yields by lithiation of N-methylbenzamides using butyllith-
ium (BuLi) in tetrahydrofuran (THF), followed by the reaction of
the generated intermediates with DMF.11 Next, isoindolin-1-ones
2b–d, N-methylphthalimide (1a), and N-benzylphthalimide (1e)
were reduced to give the isoindolin-1-ones 3. Compounds 3 were
deprotonated with sec-butyllithium and the resulting intermedi-
ates 4 were then treated either with diethyl vinylphosphonate
(5) yielding products 7, or with diethyl 3-bromopropylphospho-
nate (6) yielding compounds 8, respectively. Among substrates 3
are compounds containing methoxy electron-releasing or trifluoro-
methyl electron-withdrawing groups. Since the nitro group is
unstable in the presence of carbanions, it was not considered in
this study.12
O
O
O
N R1
N R1
N R1
OR2
OR2
R3
R3
R3
P
OR2
OR2
O
OR2
P
B
A
C
P
O
OR2
O
⇑
Corresponding authors. Tel.: +48 426355794 (A.J.); tel.: +48 426356312
(P.M.Z.).
The use of phosphonate 5 gave compounds 7a–c and 7e in ca.
50% yields. In the case of substrate 3d, the presence of the strong
electron-acceptor trifluoromethyl group may cause an increase in
E-mail addresses: ajozwiak@uni.lodz.pl (A. Józ´wiak), zagorek@op.pl (P.M.
Zagórski).
http://dx.doi.org/10.1016/j.tetlet.2014.02.127
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

´
A. Józwiak et al. / Tetrahedron Letters 55 (2014) 2420–2422
2421
O
O
O
R4
R3
R4
R3
R4
R3
Sn, HCl
Sn, HCl
N R1
N R1
N R1
OH
2b-d
R2
O
R2
R2
1a,e
3a-e
sec-BuLi, THF,
-78 oC, 1 h
O
O
P
Br
O
P
EtO
H2C
OEt
OEt
O
O
EtO
R4
R3
R4
R3
R4
R3
6
5
N R1
N R1
N R1
Li
R2
R2
R2
O
OEt
O
P
P
EtO
EtO
4
OEt
7
8
Product
7a
Yield [%]
R1
R2
H
R3
H
R4
H
Product
8a
Yield [%]
51
48
48
22
54
Me
Me
Me
Me
Bn
91
88
88
62
61
7b
H
OMe
OMe
CF3
H
H
8b
7c
OMe
H
OMe
H
8c
7d
8d
7e
H
H
8e
Scheme 1.
the acidity of the hydrogen atoms at position 3 to such an extent
that the use of the general procedure leads almost exclusively to
the formation of bis-diethoxyphosphoryl derivative 9 in yields of
40%. Diester 7d was obtained in a mixture with compound 9 when
we used one equivalent of diethyl vinylphosphonate (5) and the
reaction was terminated by the addition of methanol after 5 min
at a temperature of À78 °C. Products 7d and 9 were obtained in
yields of 22% and 24%, respectively.
Diethyl 3-bromopropylphosphonate (6) proved to be an
effective reagent for alkylating lithium derivative 4, which allowed
us to obtain products 8 in yields of 61–91%.
Compounds 7 and 8 were difficult to isolate in pure form as well
as to characterize due to the presence of multiple by-products.
Products 7, 8, and 9 were characterized by 1H, 13C, and 31P NMR,
IR and, HRMS spectra. In the 1H NMR spectra of products 7 and
8, the single proton at the newly created stereogenic center at po-
sition 3 gave a characteristic signal around 4.5 ppm, usually as
multiplet (coupling with the CH2 group).
Typical procedure for the synthesis of diethyl phosphonates 7
and 8
To the isoindol-1-one 3 (1 mmol) stirred in THF (15 mL) at
À78 °C under argon was added sec-BuLi (1.25 mmol). The solution
was kept at À78 °C for 1 h and the electrophile was added [diethyl
vinylphosphonate (5, 0.493 g, 3 mmol) or diethyl 3-bro-
mopropylphosphonate (6, 0.780 g, 3 mmol)]. After 0.5 h at
À78 °C, the mixture was warmed to room temperature and stirred
for 12 h. H2O (10 mL) was added, the pH was adjusted to 2 with
HCl (2.0 M solution in H2O) and the organic layer was separated.
The aqueous layer was extracted with CHCl3 (3 Â 20 mL). The com-
bined organic layers were dried over MgSO4 and evaporated. The
residue was purified by chromatography to give the products 7
or 8. In the case of isoindol-1-one 3d, working in accordance with
the procedure was described, we mainly obtained product 9
(0.218 g, 40%) and only a trace amount of 7d. A higher quantity
of diester 7d was formed as a mixture with compound 9 when
1 equiv of diethyl vinylphosphonate (5) was added to lithium
derivative 4d. After 5 min, the reaction was terminated by the
addition of MeOH at À78 °C. Compounds 7d and 9 were separated
by column chromatography.
O
N Me
O
F3C
P
OEt
EtO
Spectral data for representative compounds are given below
EtO
P
EtO
O
Diethyl [2-(2-methyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-iso-
indol-1-yl)ethyl]-phosphonate (7d): yield (0.084 g, 22%); light yel-
low oil; Rf = 0.22 (CH2Cl2/MeOH, 96:4). IR (film): 1698 cm–1
(C@O). 1H NMR (600 MHz, CDCl3): d = 0.95–1.00 (m, 1H, b-H),
9
In summary, we have described a simple synthetic method for the
preparation of diethyl [2-(2-alkyl-3-oxo-2,3-dihydro-1H-isoindol-
1.21–1.31 (m, 7H, b-H and OCH2Me), 2.28–2.35 (m, 2H,
a-H),
1-yl)ethyl]phosphonates
7
and diethyl [3-(2-alkyl-3-oxo-2,
3.07 (s, 3H, NMe), 3.95–4.01 (m, 4H, OCH2Me), 4.62–4.63 (m 1H,
3-H), 7.62–7.63 (m, 1H, 4-H), 7.67–7.69 (m, 1H, 6-H), 7.87 (d,
J = 7.9 Hz, 1H, 7-H). 13C NMR (150.9 MHz, CDCl3): d = 16.3 (two
overlapping d, J = 6.0 Hz), 18.3 (d, J = 144.5 Hz), 23.1 (d,
J = 3.5 Hz), 27.2, 60.7 (d, J = 18.1 Hz), 61.7 (two overlapping d,
J = 6.3 Hz), 119.1 (q, J = 3.9 Hz), 123.7 (q, J = 272.8 Hz), 124.2,
3-dihydro-1H-isoindol-1-yl)propyl]phosphonates 8 using a strategy
based on deprotonation at C-3 of various isoindolin-1-ones. The
newly synthesized compounds constitute an interesting class of
building blocks for further development. They contain a carbonyl
group and acidic CH2 protons adjacent to the phosphorus atom.

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A. Józwiak et al. / Tetrahedron Letters 55 (2014) 2420–2422
2422
125.8 (q, J = 3.6 Hz), 133.7 (q, J = 32.4 Hz), 136.1 (q, J = 1.1 Hz),
143.9, 167.0. 31P NMR (242.9 MHz, CDCl3): d = 30.44. 19F NMR
(565 MHz, CDCl3): d = À62.39. HRMS-EI Calcd for C16H21F3NO4P:
379.11603, found 379.11654.
Diethyl (2-{1-[2-(Diethoxyphosphoryl)ethyl]-2-methyl-3-oxo-6-
trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl}ethyl)phosphonate (9):
yield (0.131 g, 24%); mp 62–63 °C (hexane); Rf = 0.32 (CH2Cl2/
MeOH, 96:4). IR (KBr): 1685 cm–1 (C@O). 1H NMR (600 MHz,
CDCl3): d = 0.75–1.14 (m, 4H, b-H), 1.24–1.26 (m, 12H, OCH2Me),
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
127.
References and notes
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Acknowledgment
The authors thank the University of Lodz for financial support.