N-(phenylselenomethyl)phthalimide as new reagent for mild protection of alcohols as Pim-ethers

Article abstract of DOI:10.1016/j.tetlet.2012.03.070

A mild activation of N-(phenylselenomethyl)phthalimide by iodonium ion in the presence of alcohols to give the corresponding O-phthalimidomethyl derivatives (Pim-ethers) is provided. Simple cleavage of the phthalimido group with ethylenediamine is also reported thus making this approach a new and efficient method of protecting alcohols.

Full text of DOI:10.1016/j.tetlet.2012.03.070

Tetrahedron Letters 53 (2012) 2709–2711
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Tetrahedron Letters
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N-(Phenylselenomethyl)phthalimide as new reagent for mild protection
of alcohols as Pim-ethers
Andrea Temperini a, , Lucio Minuti b
⇑
a Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, via del Liceo 1, 06123 Perugia, Italy
b Dipartimento di Chimica, Università di Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild activation of N-(phenylselenomethyl)phthalimide by iodonium ion in the presence of alcohols to
give the corresponding O-phthalimidomethyl derivatives (Pim-ethers) is provided. Simple cleavage of the
phthalimido group with ethylenediamine is also reported thus making this approach a new and efficient
method of protecting alcohols.
Received 9 February 2012
Revised 14 March 2012
Accepted 20 March 2012
Available online 29 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Marco Tingoli in the
occasion of his retirement
Keywords:
N,Se Acetals
Protecting groups
Selenium
Alcohols
Phthalimide
Nowadays organoselenium reagents are widely employed in
many synthetic transformations due to their wide availability, to
the numerous chemical manipulations which can be effected by
the selenium moiety before or during its removal, and to the mild
reaction conditions required in various steps.1 Despite many types
of organoselenium compounds available, mixed N,Se acetals have
been scarcely employed as intermediates.2
iodide and the succinimide intermediates. Then the imidocarbeni-
um ion reacts with the oxygen atom of the alcohol to give the cor-
responding N,O acetal while phenylselenyl iodide is converted into
diphenyl diselenide and iodine
To our knowledge there are only two procedures to perform the
phthalimidomethylation of alcohols which use N-bromomethylph-
thalimide6 or O-phthalimidomethyl trichloroacetimidate.7 The
known4 and stable N,Se acetal 5 can be easily prepared in excellent
yield from N-chloromethylphthalimide.8 Initially, a variety of
selenophilic activators such as copper(II) chloride, silver triflate,
N-bromosuccinimide, and N-iodosuccinimide in different solvents
For example, mixed N,Se acetals 1 were used as good
a-amid-
oalkyl radical precursors for the stereoselective preparation of deu-
terated and allylated products 2 (Scheme 1).3 More recently, there
has been a report of the treatment of functionalized N,Se acetal 3
with triflic acid to generate N-acyliminium ion which after tandem
intramolecular isomerization/cyclization produced new fused
N,Se-heterocyclic system 4 (Scheme 1).4
TIPSO CO2Et
TIPSO CO2Et
Herein, we report the heterolytic cleavage of the C–Se bond on
the mixed N,Se acetal 5 by the action of iodonium ion. In the pres-
ence of an alcohol 6 in the reaction medium, the corresponding N,O
acetal 7 can be obtained thus performing the protection of the hy-
droxyl group as phthalimidomethyl (Pim) ether derivative (Scheme
2). As in the case of the activation of MOM- and MEM-phenyl
selenides5 the reaction probably proceeds by the attack of iodoni-
um ion, generated from N-iodosuccinimide, to the selenium atom
N
SePh
N
R
R
Z
2
1
O
Se
O
N
N
Se
OH
3
4
to give the a-imidocarbenium ion together with the phenylselenyl
R= Alkyl
Z= D or CH2=C(CO2Me)CH2-
⇑
Corresponding author.
E-mail address: tempa@unipg.it (A. Temperini).
Scheme 1. Use of N,Se acetals 1 and 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.070

2710
A. Temperini, L. Minuti / Tetrahedron Letters 53 (2012) 2709–2711
O
N-I
O
O
O
O
PhSeSePh
I2
N
ROH
N
NH
SePh
OR
CH2Cl2/ -15 °C
O
5
O
O
cat TMSOTf
6
7
Scheme 2. Reaction of alcohols 6 with phthalimidomethyl phenyl selenide 5.
have been used to evaluate their ability to promote the phthalymi-
domethylation of alcohol 6a under a standard set of reaction con-
ditions (0.1 M, RT, 1.2 equiv of 5 and 1.2 equiv of activator). We
found that N-iodosuccinimide (NIS) was the most effective pro-
moter in dichloromethane solution and in the presence of TMSOTf
as catalyst. Consistent results were obtained with 1.4 equiv of NIS,
1.4 equiv of 5, and 0.07 equiv of TMSOTf in dichloromethane at
ꢀ15 °C with reaction times ranging from 1 to 2 h.9 The reaction
of 5 with primary, secondary, and tertiary alcohols, such as 6a–i,
in the presence of TMSOTf as catalyst, gave the corresponding
phthalimidomethyl derivatives 7a–i (Table 1). The NMR spectral
analysis of the products agreed with the assigned structures.
The results reported in Table 1 clearly demonstrated that the
protection reactions proceeded smoothly to afford the correspond-
ing Pim-ethers 7a–i in good to excellent yields (68–92%). The var-
ious functionalities present in the substrates (e.g., carbon–carbon
triple bond, tosylamino, ether, ester, acetal, nitro, and carbonyl
groups) were compatible with the mild reaction conditions em-
ployed. The yields of compounds 7d and 7e were comparable with
those obtained by using O-phthalimidomethyl trichloroacetimi-
for the hydroxy group protection has been scarcely employed10
although the Pim-derivatives of thiol and carboxylic acid are well
documented.11 However the phthalimidomethyl group is compat-
ible with and orthogonal to all important hydroxy protecting
groups.7 It offers selective removal with nucleophiles particularly
in the carbohydrate chemistry thus complementing the repertoire
of the available hydroxy protecting groups which are sensitive to
acids, bases, or hydrogenolysis. In this context we found that the
phthalimidomethyl group could be smoothly removed in a one-
pot reaction without the use of carcinogenic hydrazine hydrate.11
The simple treatment of compounds 7a, 7b, 7d, 7h, and 7i with
an excess of ethylenediamine (5 equiv) in methyl alcohol at room
temperature gave the starting alcohols 6a, 6b, 6d, 6h, and 6i,
respectively in excellent yields (Table 2). The reaction performed
Table 2
Phthaloyl group cleavage of some representative Pim-ethers
ethylenediamine in methanol at RT
7
with 5 equiv of
Yieldb (%)
Entry
Pim-ether 7
Time (h)
Alcohola
6
date.7 The hydroxy group of
a-hydroxyketone 6f as well as of the
1
2
3
4
5
7a
7b
7d
7h
7i
10
8
8
9
8
6a
6b
6d
6h
6i
82
77
b-hydroxy nitro compound 6c were successfully protected as
Pim-derivatives 7f and 7c in excellent yields (86% and 83%, respec-
tively). It should be noted that tertiary alcohols 6h and 6i, that
might be subjected to dehydration reaction,6 gave the correspond-
ing Pim-ethers 7h and 7i in good yields (83% and 74%, respectively)
establishing the first examples of the protection of tertiary alcohols
as Pim-ether derivatives. The use of the phthalimidomethyl moiety
84
90c
88c
a
b
c
All products were characterized by 1H and 13C NMR.
Yields of isolated products; P97% pure material by 1H NMR.
Yield estimated on the crude mixture by 1H NMR relative to internal standard.
Table 1
Phthalimidomethylationa of alcohols 6 with phthalimidomethyl phenyl selenide 5 promoted by NIS and catalytic TMSOTf
Entry
Alcohol 6b
OH
CF3
OH
Product 7 Pim = phthalimidomethyl
Yieldc (%)
80
OPim
CF3
1
6a
7a
OPim
NHTs
2
3
6b
6c
7b
7c
68
86
NHTs
O2N
O2N
OPim
OH
OH
OPim
O
O
BnO
BnO
4
6d
7d
81d
BnO
BnO
BnO
BnO
OMe
OMe
OH
OPim
5
6
6e
6f
7e
7f
92d
83
OH
Ph
OH
Ph
Ph
Ph
O
O
OH
OPim
7
6g
7g
82
Cl
CO2Et
Cl
CO2Et
8
9
6h
6i
7h
83
74
OH
OH
OPim
3m
OPim
a
b
c
Reaction times ranging from 1 to 2 h.
All products were characterized by 1H and 13C NMR and mass spectroscopy.
Yields of isolated products; P97% pure material by 1H NMR.
d
A similar yield was obtained with O-phthalimidomethyl trichloroacetimidate.7

A. Temperini, L. Minuti / Tetrahedron Letters 53 (2012) 2709–2711
2711
in isopropyl alcohol12 or in ethanol at reflux13 did not give better
yields.
The easy and efficient removal of phthalimidomethyl group to
give the starting alcohols makes this approach a new and efficient
method of protecting alcohols.
In conclusion a general and mild procedure for the activation of
phthalimidomethyl phenyl selenide 5 with iodonium ion and sub-
sequent reaction with alcohols to give the corresponding Pim-
ether derivatives 7 has been described. Phthalimidomethyl phenyl
selenide 5 can be stored at +4 °C for a long period of time without
any detectable decomposition. Furthermore, the selenium atom
can be recovered at the end of the procedure as diphenyl diselenide
and then reused for the synthesis of compound 5. Reported limita-
tions on the use of the phthalimidomethyl protecting group have
also been overcome by introducing a new cleavage procedure.
heated at 110 °C for 1 h and then cooled to room temperature. Solid N-
chloromethylphthalimide (0.78 g, 4 mmol) was added to the orange solution.
After stirring at room temperature for 12 h, 2 N aqueous hydrochloric acid
(10 mL) was added carefully to the white suspension. The entire product
mixture was poured into 50 mL of water and 40 mL of diethyl ether, mixed, and
separated. The aqueous phase was extracted with 20 mL of diethyl ether and
the combined organic phases were washed with H2O (4 ꢁ 10 mL), 10 mL of
brine, dried over sodium sulfate and concentrated. The solid residue was
washed with light petroleum (2 ꢁ 10 mL) and dried over P2O5 to afford 5 in 82%
yield and with spectral data in good agreement with those reported in the
literature.4
9. General procedure for the protection of alcohols 6 as Pim-derivatives: A mixture of
alcohol 6 (1 mmol), N,Se acetal 5 (1.4 mmol) and activated 3-Å molecular sieves
(0.40 g) in dry dichloromethane (16 mL) was stirred for 0.5 h under argon
atmosphere at room temperature. Solid N-iodosuccinimide (1.4 mmol) was
added and then the mixture cooled to ꢀ15 °C. After the addition of TMSOTf
(12 lL, 0.07 mmol) the reaction mixture was stirred and monitored by TLC.
Reaction times ranged from 1 to 2 h. The brown colored reaction mixture was
then filtered through a celite path and the filtrate washed with 20 mL of 10%
aqueous sodium thiosulfate pentahydrate solution. The aqueous phase was
extracted with 10 mL of dichloromethane and the combined organic phases
were washed with 10 mL of brine, dried over sodium sulfate, and then
evaporated under vacuum. Purification by silica gel column chromatography
afforded the phthalimidomethyl-ether derivative 7. Physical and spectral data
of some selected compounds are reported. 2-[(2-Nitroethoxy)methyl]-1H-
isoindole-1,3(2H)-dione (7c): Yield 86%; mp 108–110 °C; 1H NMR (200 MHz,
CDCl3): d = 8.04–7.88 (m, 2H), 7.86–7.71 (m, 2H), 5.22 (s, 2H), 4.55 (t, 2H,
J = 5.10 Hz), 4.20 (t, 2H, J = 5.10 Hz). 13C NMR (50 MHz, CDCl3): d = 167.8 (2C),
Acknowledgments
Financial support from the MIUR, National Projects PRIN 2007,
Fondazione Cassa Risparmio Perugia, and the University of Perugia
is gratefully acknowledged.
134.6 (2C), 131.7 (2C), 123.19 (2C), 74.5, 67.3, 65.3. m
max/cmꢀ1 2955, 1777,
1726, 1559, 1354, 1330, 1112, 977, 733. 2-[(2-Oxo-1,2-diphenylethoxy)methyl]-
1H-isoindole-1,3(2H)-dione (7f): Yield 83%; mp 262–264 °C; 1H NMR (200 MHz,
CDCl3): d = 8.04–7.66 (m, 6H), 7.60–7.15 (m, 8H), 6.08 (s, 1H), 5.34 (AB system,
2H). 13C NMR (50 MHz, CDCl3): d = 196.1, 167.6 (2C), 135.6, 134.9, 134.3 (2C),
133.1, 131.7 (2C), 129.0 (2C), 128.7 (2C), 128.6, 128.4 (2C), 127.8 (2C), 123.7
References and notes
1. (a) Paulmier, C. Selenium Reagents and Intermediates in Organic Synthesis;
Oxford: Pergamon, 1986; (b)Organoselenium Chemistry; Liotta, D., Ed.; John
Wiley
& Sons: New York, 1987; (c)Organoselenium Chemistry – A Pratical
(2C), 83.9, 66.5. m
max/cmꢀ1 3073, 2968, 1773, 1717, 1679, 1357, 1231, 1104,
Approach; Back, T. G., Ed.; Oxford: New York, 2000; (d)Topics in Current
Chemistry: Organoselenium Chemistry: Modern Developments in Organic
Synthesis; Wirth, T., Ed.; Springer: Berlin, 2000.
943, 735. GC–MS (EI): m/z (%) = 355 (6) [Mꢀ16]+, 281 (27), 207 (100), 160 (19),
147 (17), 128 (60), 105 (17), 77 (13). Ethyl 4-chloro-3-[(1,3-dioxo-1,3-dihydro-
2H-isoindol-2-yl)methoxy]butanoate (7g): Yield 82%; Oil; ½ ꢂ 10.9 (c 0.92,
a 2D4
2. (a) Pollak, I. E.; Grillot, G. F. J. Org. Chem. 1966, 31, 3514–3516; (b) Bachi, M. D.;
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8. Synthesis of the N,Se acetal 5: The N,Se acetal 5 was prepared by a slight and
safer modification of the original procedure4 where, the required phenylselenol
intermediate was replaced by sodium phenylselenolate. In a 50 mL three-neck
flask equipped with a reflux condenser were placed diphenyl diselenide (0.63 g,
2 mmol) and 16 mL of dry DMF. The solution was heated at 60 °C and stirred
rapidly under nitrogen while NaBH4 (0.15 g, 4 mmol) was added portionwise.
Hydrogen was evolved and the reaction mixture turned colorless and
homogeneous upon complete reduction of the selenide. The reaction was
CHCl3); 1H NMR (200 MHz, CDCl3): d = 7.96–7.85 (m, 2H), 7.84–7.70 (m, 2H),
5.25 (s, 2H), 4.38–4.20 (m, 1H), 4.01 (q, 2H, J = 7.15 Hz), 3.62 (d, 2H, J = 5.30 Hz),
2.67–2.55 (m, 2H), 1.18 (t, 3H, J = 7.15 Hz). 13C NMR (50 MHz, CDCl3): d = 170.2,
167.7 (2C), 134.3 (2C), 131.7 (2C), 123.6 (2C), 74.7, 66.2, 60.6, 45.2, 37.8, 13.9.
m
max/cmꢀ1 2982, 1778, 1723, 1351, 1203, 1077, 983, 855, 729. GC–MS (EI): m/z
(%) = 276 (4) [Mꢀ49]+, 176 (25), 160 (100), 133 (15), 104 (19), 77 (18). 2-{[(1,1-
Dimethylprop-2-yn-1-yl)oxy]methyl}-1H-isoindole-1,3(2H)-dione (7i): Yield 74%;
mp 88–90 °C; 1H NMR (200 MHz, CDCl3): d = 7.92–7.81 (m, 2H), 7.80–7.68 (m,
2H), 5.29 (s, 2H), 2.48 (s, 1H), 1.54 (s, 6H). d = 167.4 (2C), 134.2 (2C), 131.9 (2C),
123.5 (2C), 84.5, 72.7, 69.9, 62.6, 28.7 (2C). m
max/cmꢀ1 3263, 2987, 2105, 1778,
1726, 1387, 1154, 1061, 737. GC–MS (EI): m/z (%) = 228 (10) [Mꢀ15]+, 213 (10),
160 (100), 148 (15), 130 (22), 104 (21), 77 (18).
10. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261–2265.
11. Wuts, P. G. M.; Green, T. W. Protective Groups in Organic Chemistry, 4th ed.; John
Wiley & Sons: New York, 2007.
12. Temperini, A.; Terlizzi, R.; Testaferri, L.; Tiecco, M. Chem. Eur. J. 2009, 15, 7883–
7895.
13. Kanie, O.; Crawley, S. C.; Palcic, M. M.; Hindsgual, O. Carbohydr. Res. 1993, 243,
139–164.