Fluorous tagged N-hydroxy phthalimide for the parallel synthesis of O-aryloxyamines

Article abstract of DOI:10.1021/cc100098v

The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-catalyzed cross-coupling of aryl boronic acid

Full text of DOI:10.1021/cc100098v

J. Comb. Chem. 2010, 12, 655–658
655
Fluorous Tagged N-Hydroxy Phthalimide for the Parallel Synthesis of
O-Aryloxyamines
Florence S. Gaucher-Wieczorek, Ludovic T. Maillard, Bernard Badet, and
Philippe Durand*
Centre de recherches de Gif, Institut de Chimie des Substances Naturelles, UPR 2301-CNRS,
AVenue de la Terrasse, 91198 Gif-sur-YVette, France
ReceiVed June 4, 2010
The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry
and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-
catalyzed cross-coupling of aryl boronic acids with a fluorous tagged N-hydroxyphthalimide, and (2) a
supported aminolysis was designed and optimized using Taguchi’s method. A library of O-aryloxyamines
was synthesized in high yields with high purity and diversity.
Introduction
The present paper demonstrates a successful application
of fluorous tag technology to the parallel synthesis of
O-aryloxyamines.
The biological1 and pharmacological activities2 of O-
aryloxyamines or their oxime derivatives3 have attracted
much interest in medicinal chemistry.4 In addition, chemose-
lective ligation strategies through oxime bond formation with
oxyamines have received considerable attention in chemical
biology,5 fragment-based drug discovery,6 drug targeting,7
combinatorial,8 dynamic9 and iterative library synthesis.10
Results and Discussion
O-Aryloxyamine syntheses via nucleophilic aromatic
substitution of electrophilic arenes with N-hydroxyl group
donors13 or via nitrogen transfer to an aryloxide14 have been
described, but these methods are limited in scope or use
unstable reagents difficult to prepare. More recently Petrassi
et al15 described the copper-mediated cross-coupling of
phenylboronic acids with N-hydroxyphthalimide followed by
hydrazinolysis to access a larger diversity of O-aryl-
oxyamines. The use of heterogeneous conditions and the
formation of side-products make this two-step strategy of
little practical use for parallel synthesis. Since we previously
reported a supported N-hydroxyphthalimide reagent for the
parallel synthesis of a wide diversity of O-alkyl hydroxyl-
amines from aliphatic alcohols,16a we first attempted to
extend it to arylboronic acids coupling for the parallel
synthesis of O-aryl hydroxylamines. Different reaction
conditions were screened with no success. A similar failure
was observed when the cross-coupling was performed in
solution between arylboronic acids and exo-N-hydroxy-7-
oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide, an N-hy-
droxyimide previously reported for a ROMP-based O-alkyl
hydroxylamine parallel synthesis.17 This suggested that the
use of N-hydroxyphthalimide in solution is mandatory for
an efficient coupling reaction. With the goal of combining
the versatility of solution phase synthesis with the purification
facility of F-SPE, we envisaged a two step process using
cross-coupling of aryl boronic acid with a fluorous-tagged
N-hydroxyphthalimide reagent 1 followed by aminolysis of
the so-formed O-aryl phthalimides 3 (Scheme 1).
Despite their high potential, only a limited number of
O-aryloxyamines are commercially available, and the syn-
thesis of a corresponding library remains a challenge. To
our knowledge, no parallel synthesis of O-aryloxyamines has
been reported to date.
Traditionally, solid phase synthesis is privileged for
parallel syntheses to avoid purification problems associated
with solution-phase synthesis. However, the incompatibility
of polymer-supported reagents with many reaction conditions
as well as the difficulties associated with the characterization
of polymer-bound intermediates and the monitoring of the
reaction progress have limited the scope of its application.
A wide variety of solution-phase approaches that address
these limitations while retaining the purification simplicity
have emerged.11 Among these, “light-fluorous synthesis”12
is based on the addition of perfluoroalkyl groups as “phase
tags” which facilitate purification steps using fluorous solid-
phase extraction (F-SPE). Reactions can be carried out in
homogeneous solution using common organic solvents, and
their progress can be monitored by conventional analytical
methods without tag removal. In addition, since fluorous tags
exhibit high thermal and chemical stabilities the tagged
compounds can be subjected to almost any chemical reaction.
The tagged reagent was obtained on a multigram scale
from commercially available 2-perfluoroalkyl-1-iodoethane
5 and trimellitic anhydride via a five step convergent
synthesis with a 44% overall yield (Scheme 2).
* To whom correspondence should be addressed. E-mail: philippe.durand@
icsn.cnrs-gif.fr.
10.1021/cc100098v  2010 American Chemical Society
Published on Web 07/22/2010

656 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Scheme 1. Parallel Synthesis of O-aryloxyamines
Gaucher-Wieczorek et al.
Table 1. Considered Factors and Their Levels in the Design of
Experiments
levelb
factora
1
2
3
4
A
B
C
D
E
F
catalyst
base
Cu(OAc)2
Pyrc
Air
CH2Cl2
20
48 h
CuCl
Et3N
O2
LutMyc
PNOc
THF
MetImc
TEMPOc
BTFc
oxidant
solvent
T (°C)
DCEc
55
reaction time
96 h
a Independent variable that may influence the response and which is
expressed by the letters A-F. b A distinction within a parameter which
Reaction conditions: (i) Cu(OAc)2, Pyridine, O2, benzotrifluoride (BTF),
rt, 48 h; (ii) F-SPE; (iii) Aminomethylated Polystyrene resin from
Novabiochem, CHCl3/MeOH (9:1), rt, 24 h.
is expressed by
a
number 1-4. c Abbreviations: DCE, 1,2
dichloroethane; LutMyc, lutidine with myristic acid; MetIm, N-methyl
imidazole; PNO, pyridine N-oxide; Pyr, pyridine; TEMPO,
2,2,6,6-tetramethylpiperidine-1-oxide.
Scheme 2. Synthesis of the Fluorous-Tagged
N-Hydroxyphthalimide Reagent 1
mediated cross-coupling of phenylboronic acid 2.{1} with
this tagged reagent under Petrassi’s conditions15 occurred
in moderate yields (40-60% yield) and prompted us to
optimize this step. We suspected solubility problems but
cannot exclude any other factor. To accelerate this approach
we resorted to using Taguchi’s method. This fractional
factorial design optimization technique uses Taguchi-
designed orthogonal arrays (OA), in which only a fraction
of the combination of variables are considered to minimize
the number of experiments while covering a wide range of
operating conditions and maintaining all the information/
data intact.20 Following the selection of the proper OA, a
statistical analysis of the experimental data by the analysis
of variance (ANOVA) determines the influencing parameters,
reveals their interactions, and quantifies their effect.21
On the basis of the literature results on copper-mediated
N-and O-arylations22 we selected catalyst, base, oxidant,
solvent, temperature, and reaction time as factors likely to
affect the yield (A-F Table 1). Each of the studied factors
has up to four levels (Table 1) and five interactions were
considered (AB, AC, AD, AE, AF).
Consequently, a L32(231) OA was chosen and combined
with parameters defined in Table 1 to plan the experimental
conditions (Supporting Information, Table S2). The yield for
each of the 32 reactions was determined by quantitative
HPLC analysis of crude reaction media. From these results
(Supporting Information, Table S2) and their ANOVA
statistical analysis, it was possible to quantify the influence
of each factor as well as their interactions (Supporting
Information, Table S3).21 The catalyst was found to be the
dominant factor (63% contribution) followed by the base
(15%) and the solvent (7%). The catalyst/base interaction
was found to be the only statistically significant one (95%
confidence level) among the 5 tested. Optimum conditions
were obtained by combining levels with the best effect
(Supporting Information, Figure S2) for these main factors.
This simplified Taguchi method led us to perform the
reaction in the presence of Cu(OAc)2 and pyridine in BTF
at 20 °C. BTF has been shown to possess the appropriate
solvent properties for fluorous reagents23 and to exhibit
proper dioxygen solubilization.24 A 4-fold excess of boronic
acid was revealed to be necessary to ensure total consumption
of hydroxyphthalimide 1 but resulted in an increased
formation of diphenyl ether. The presence of this side-product
can be explained by the competitive arylation of water
Reaction conditions: (i) NaN3, DMSO/water (50:1), rt, 90 h; (ii) 55 PSI
H2, Pd/C, Et2O/MeOH (5:2), rt, 24 h; (iii) BnONH2 · HCl, Microwave, neat,
200 °C, 10 min; (iv) SOCl2, DMF, 55 °C, 1 h; (v) 7, DIPEA, rt, 18 h; (vi)
55 PSI H2, Pd/C, Methylethyl ketone, rt, 24 h.
Among the reported conditions tested18 for nucleophilic
substitution of iodide 5 with sodium azide, the best results
were obtained using a mixture of dimethyl sulfoxide
(DMSO)/water as solvent.19 The azide 6 was then reduced
into the amine 7 by palladium catalyzed hydrogenation.
Condensation of trimellitic anhydride 8 with O-benzyl
hydroxylamine hydrochloride under microwave irradiation16a
without any solvent led to the efficient formation of O-
protected phthalimide 9. Coupling of its acid chloride
derivative with the amine 7 followed by palladium-catalyzed
hydrogenolysis gave the fluorous-tagged N-hydroxyphthal-
imide 1. The use of O-allyl protecting group for the
N-hydroxyphthalimide moiety was also evaluated. However,
difficulties encountered in removing the soluble palladium
catalysts used for O-allyl cleavage prompted us to prefer the
benzyl protection (see Supporting Information). Copper-

Parallel Synthesis of O-Aryloxyamines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 657
Table 2. Yields and Purities of N-Aryloxyphthalimides
3{1-31} and O-Aryloxyamines 4{1-31}a
the classical procedure, and with high purity. The reaction
proceeds smoothly with both electron-rich and electron-
deficient arylboronic acids as well as in the presence of a
wide range of functional groups. However, no coupling could
be detected either with heterocyclic boronic acids, such as
pyridine, furan or thiophene, or with phenylboronic acid
bearing electron-withdrawing group (F, CF3 or CN) in the
ortho position (Table 2).
% yieldb
% yielde
R
3
(% purity)c Lit.d
Ortho Substituted
4
(% purity)f
H
3.{1}
3.{2}
3.{3}
3.{4}
3.{5}
99(100)
90(100)
20(43)
30(98)
4(66)
90
60
4.{1}
4.{2}
4.{3}
4.{4}
4.{5}
93(93)
96(96)
0
91(91)
0
Me
CN
CF3
F
0
Aminolysis of N-phenyloxyphthalimide 3.{1} with MeNH2
solution (MeOH or CHCl3/MeOH (80:20)) for 24 h at room
temperature was quantitative. The so-formed O-phenyl-
oxyamine 4.{1} was purified by fluorous SPE and collected
in the fluorophobic fraction (CH3OH/H2O (80:20)). However,
its relative volatility resulted in a loss of material, a behavior
which was noticed with a number of other O-aryloxyamines.
As a result, we considered using a supported aminolysis in
a volatile solvent to recover the O-aryloxyamines via a simple
filtration. Several commercially available aminomethyl27 and
ethylenediamine branched resins28 were tested in three
solvent systems: MeOH, MeOH/CHCl3 (90:10), and CHCl3.
The best results were obtained using the aminomethylated
polystyrene resin from Novabiochem in CHCl3/MeOH for
24 h at room temperature. The O-aryloxyamines 4.{1-31}
were reproducibly obtained in quantitative yield (based on
chemset 3) and high purity (Table 2). The latter was
determined by liquid chromatography/mass spectrometry
(LC/MS) analysis after conversion to their corresponding
acetone oximes (handling of the free oxyamines is difficult
because of their rapid reaction with any trace of carbonyl
compounds).
Para Substituted
Me
OMe
CN
CF3
Cl
Br
I
CHO
CHdCH2
Ph
3.{6}
3.{7}
3.{8}
3.{9}
3.{10}
3.{11}
3.{12}
3.{13}
3.{14}
3.{15}
3.{16}
96(100)
51(55)
76(95)
88(98)
96(95)
94(100)
92(98)
76(86)
89(97)
97(83)
87(97)
4.{6}
4.{7}
4.{8}
4.{9}
4.{10}
4.{11}
4.{12}
4.{13}
4.{14}
4.{15}
4.{16}
93(93)
0
37
66
65
91(91)
92(92)
93(93)
95(95)
92(92)
0h
90(90)
16(40)f
0g
73
57
52
87
2-Thiophene
Meta Substituted
Me
OMe
CF3
3.{17}
3.{18}
3.{19}
3.{20}
3.{21}
3.{22}
3.{23}
3.{24}
3.{25}
3.{26}
95(100)
88(99)
92(98)
93(98)
73(81)
95(99)
87(93)
98(99)
93(96)
92(97)
93(96)
96(97)
4.{17}
4.{18}
4.{19}
4.{20}
4.{21}
4.{22}
4.{23}
4.{24}
4.{25}
4.{26}
4.{27}
4.{28}
98(98)
94(94)
94(94)
96(96)
82(82)
96(96)
95(95)
95(95)
90(90)
91(91)
89(89)
96(96)
57
87
65
F
SMe
OCF3
CO2Me
Ph
OBn
OBn(2-Cl)
OBn(3,5-(OMe)2) 3.{27}
CONEt2
3.{28}
Disubstituted
3,5-F2
3,5-(OMe)2
3.{29}
3.{30}
89(100)
98(99)
72
4.{29}
4.{30}
90(90)
87(87)
Conclusion
Fused
In this study, we have described the first parallel synthesis
of diverse O-aryloxyamines combining the use of a new
fluorous-tagged N-hydroxyphthalimide reagent 1, purification
by reversed-phase fluorous SPE and finally a supported
aminolysis. The Taguchi design of experiments was suc-
cessfully applied for the optimization of the key copper-
mediated reaction. The standardized Taguchi method was
initially used to allow a minimum number of experiments.
However, the interesting results gathered in this research
suggest that this method, besides saving time, gives reliable
results and allows the systematic study of synthesis param-
eters and of their possible interactions.
1-naph
a See chapter
3.{31}
93(100)
4. {31}
0g
6 of Supporting Information for the procedure
used. b Determined by gravimetry and taking into account the purity.
c Determined by UHPLC/MS with UV detection at 220 nm. d Yields
reported by Petrassi et al.15 e Determined by gravimetry and taking into
account the purity determined after derivatization into acetone oxime
(see Supporting Information). f Purity determined by UHPLC/MS with
UV detection at 220 nm after derivatization into acetone oxime
derivatives. g Phenol derivative was the major product. h This product
polymerizes.
released from the phenylboronic acid followed by coupling
of the so-formed phenol with the phenylboronic acid in
excess as previously reported. As the formation of this
impurity could not be prevented despite the use of different
anhydrous conditions,25,26 the F-SPE elution protocol was
adapted to solve this problem. The FluoroFlash SPE car-
tridges were first eluted with three successive fluorophobic
solvent mixtures: (1) DMSO/H2O (90:10) to remove all
nonfluorous material including diphenyl ether; (2) MeOH/
H2O (70/30) to eliminate DMSO, and (3) cyclohexane to
remove all apolar contaminants (e.g., silicon grease from
BTF). The desired product was then eluted in high purity
with acetone as fluorophilic solvent. We explored the scope
and the limitations of the optimized conditions on a range
of structurally diverse arylboronic acids 2{1-31}. In agree-
ment with Taguchi’s predictions, most of the products were
obtained in excellent isolated yields (Table 2), even higher
than those previously described15 on the same substrates with
Acknowledgment. The authors gratefully acknowledge
financial support from ICSN-CNRS (Gif-sur-Yvette, France)
and from the Fondation pour la Recherche Medicale to
F. S. G.-W. We are grateful to P. Vignon, N. Gigant, and
J. He for preliminary experiments, to O. Toison and Franck
Pelissier for their help with the HPLC analysis, and to J.-F.
Gallard for NMR analysis. We thank R. Dodd for critical
reading of the manuscript.
Supporting Information Available. Details of experi-
mental procedures and analytical data were given. It includes
1H NMR, 13C NMR, 19F NMR spectra, IR and MS spectra.
Details for Taguchi’s Design of Experiments are given. This
material is available free of charge via the Internet at http://
pubs.acs.org.

658 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
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CC100098V