Bis-ortho-metalation/silylation of unprotected o-phthalic acids. Straightforward access to new silylated N-hydroxyphthalimide (NHPI) analogs

Article abstract of DOI:10.1016/j.tetlet.2011.10.114

The one pot, in situ ortho-metalation/silylation of unprotected o-phthalic acids using lithium tetramethylpiperidide (LiTMP) and chlorotrimethylsilane is described. This method gives a straightforward access to silylated phthalic anhydrides. These can be

Full text of DOI:10.1016/j.tetlet.2011.10.114

Tetrahedron Letters 53 (2012) 48–50
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Bis-ortho-metalation/silylation of unprotected o-phthalic acids.
Straightforward access to new silylated N-hydroxyphthalimide (NHPI) analogs
⇑
⇑
Jérôme Michaux, Bernard Bessières , Jacques Einhorn
Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, Université Joseph Fourier, 301 Rue de la Chimie, BP 53, 38041 Grenoble Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The one pot, in situ ortho-metalation/silylation of unprotected o-phthalic acids using lithium tetrame-
thylpiperidide (LiTMP) and chlorotrimethylsilane is described. This method gives a straightforward
access to silylated phthalic anhydrides. These can be easily converted into the corresponding silylated
N-hydroxyphthalimide (NHPI) analogs, which are promising new aerobic oxidation catalysts.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 October 2011
Revised 18 October 2011
Accepted 19 October 2011
Available online 25 October 2011
Keywords:
Ortho-metalation
In situ trapping
Silylation
NHPI
Aerobic oxidation
During the recent years, N-hydroxyphthalimide (NHPI) has been
recognized as a powerful organocatalyst, able to promote aerobic
oxidation of a wide range of substrates under mild conditions.1
Our group, as well as others, has been interested in the synthesis
of various NHPI analogs, possessing some new or improved cata-
lytic properties.2 Some highly substituted NHPI analogs were found
to be particularly active catalysts, thus allowing a substantial low-
ering of the catalyst-loading.2b Most of the time, such NHPI analogs
require quite indirect methods for their synthesis.3 In this context,
we became interested in synthetic methods allowing a direct func-
tionalisation of o-phthalic acid itself and of some of its commer-
cially available 4,5-substituted analogs. Direct functionalisation of
o-phthalic acid via electrophilic aromatic substitution reactions
suffers from the strong deactivation of the aromatic ring, thus
requiring forced conditions, as well as from a serious lack of
regioselectivity.
Consequently, we explored the possibility of a direct function-
alisation of unprotected phthalic acids via ortho-metalation
(Scheme 1). Numerous carboxylic acid derivatives are widely used
for directing ortho-metalation.4 Among them, N,N-diethylamide
first utilized by Beak5 has been used extensively because of its
ease of preparation, its efficiency in directing the metalation,
and its robustness toward nucleophilic attack. On the other hand,
the latter advantage is also one major drawback if further func-
tional group transformation is needed. Comins6 and Reitz7 have
E
E
E
E
O
R
R
CO2H
CO2H
R
R
CO2H
CO2H
R
R
1) Base
2) E+
NOH
O
Scheme 1. Synthesis of NHPI analogs via ortho-metalation of o-phthalic acids.
developed tert-amide derivatives that can be cleaved more easily,
although still under rather harsh condition (typically 6 N HCl
hydrolysis). On the other hand, considering that the best protect-
ing group is the one that can be omitted, the group of Mortier has
studied the lithiation of unprotected benzoic acids8 and they have
established the carboxylic acid group to be of intermediate capac-
ity in directing metalation.
We thought that a successful bis-metalation would mean the
formation of rather unlikely tetra anionic specie.9 So we chose to
perform the reaction using the in situ trapping technique, implying
the presence of the electrophile in the reaction media during the
lithiation step. This restricts the choice of electrophiles to reagents,
such as TMSCl,7 that are compatible with the strong base.10
Our first attempt was realized using conditions similar to the
ones developed by Mortier in the metalation of substituted benzoic
acids. We were pleased to observe that the treatment of a THF
solution of phthalic acid 1a and chlorotrimethylsilane (10 equiv)
at À80 °C, with LiTMP (10 equiv) afforded the bis-o-silylated prod-
uct, which was isolated as the corresponding anhydride 2a in a 63%
yield (Table 1, entry 1).11 Further optimization of the stoichiometry
of the rather costly base used showed that its amount could be
⇑
Corresponding authors. Fax: +33 476 635 983.
E-mail addresses: bernard.bessieres@ujf-grenoble.fr (B. Bessières), jacques.
einhorn@ujf-grenoble.fr (J. Einhorn).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.114

J. Michaux et al. / Tetrahedron Letters 53 (2012) 48–50
49
Table 1
Table 2
Lithiation/silylation of o-phthalic acid 1a
Lithiation/silylation of TMS phthalate 3
TMS
TMS
TMS
TMS
TMS
TMS
O
O
O
O
CO2H
CO2TMS
CO2TMS
1) LiTMP
+ Me3SiCl
1) LiTMP
+ Me3SiCl
+
+
O
O
O
O
THF, -80°C to 0°C
2) Dehydratation
CO2H
O
O
2) Dehydratation
O
O
1a
Entry
2a
4a
4a
3
2a
2a, Yielda (%)
4a, Yielda (%)
TMSCl (equiv)
LiTMP (equiv)
2a, Yielda (%)
4a, Yielda (%)
Entry
TMSCl (equiv)
LiTMP (equiv)
1
2
3
10
10
10
10
6
4
63
65
18
—
—
36
1
2
3
4
5
10
10
10
0
2.5
3
3.5
3.5
3.5
38
26
70
—
60
20
30
>98 (70b)
25
80
a
Isolated yield.
1
a
NMR yield.
Isolated yield.
b
decreased to 6 equiv (Table 1, entry 2), while a large excess of
TMSCl (10 equiv) is still needed (Table 1, entry 3).12 Further de-
crease to 4 equiv leads to a mixture of mono- and bis-silylated
compound (Table 1, entry 3).
with the one-pot procedure while studying the substrate scope.
So we looked for commercially available o-phthalic acids unsub-
stituted in position 2 and 6 and submitted them to the metala-
tion/silylation reaction. The results are summarized in Table 3.
4,5-Dichloro-o-phthalic acid gave the bis-silylated anhydride in
a 95% yield (Table 3, entry 1) while the dibromo analog gave a
complex mixture resulting from a halogen dance reaction (Table
3, entry 2).16 2,3-Naphthalenedicarboxylic acid was much less
reactive as only 10% of disilylated anhydride could be obtained
together with 23% of monosubstituted product (Table 3, entry
3). 4-Hydroxy-o-phthalic acid was metalated in a modest 27%
yield, presumably because of steric hindrance generated by the
silylation of the hydroxyl group (Table 3, entry 4). 4-Methyl-o-
phthalic acid gave, in 36% yield, the disilylation product 5 on
which silylation occurred on the 6-position of the aromatic ring
and on the benzylic methyl group (Table 3, entry 5).17 With the
objective of preparing diverse N-hydroxyphthalimides we also
tried to change the silylating agent. Switching from TMS to
TES led to the disilylated product in 60% yield (Table 3, entry
6), but neither TIPSCl nor TBDMSCl afforded any product under
our standard reaction conditions with 1a.
We assumed that the need for such an excess of TMSCl was due to
the in situ formation of the bis-TMS phthalate 3, and then to an inter-
nal transfer of the silyl group from the ester to the adjacent lithiated
position. To test this hypothesis, phthalate 313 was treated with dif-
ferent amounts of base and electrophile. The results are summarized
in Table 2. We first looked for the minimum amount of base needed
while keeping a large excess of electrophile (Table 2, entries 1–3),
and found that 3.5 equiv was optimal. This can be due to the coordi-
nation of 1 equiv of the lithium base between the two ortho carboxyl
functions.14 We next varied the amount of TMSCl in the reaction.
When no extra electrophile is added (Table 2, entry 4), a mixture
of mono- and di-silylated product is nonetheless obtained, which
tends to prove the hypothesis of an internal silyl transfer. The fact
that upon addition of 1 equiv of TMSCl, the yield of 2a increased to
80% (Table 2, entry 5) can be due to the trapping of the carboxylate
formed after the first silyl transfer, thus facilitating the second meta-
lation step. We also tried to exchange LiTMP with simpler LDA, but
no reaction occurred in this case. This result can be ascribed to the
lower basicity of LDA.15
Once having the substituted anhydrides in hand, they were con-
verted into the corresponding NHPI analogs. The anhydrides were
As yields are only slightly better when starting from the sily-
lated phthalate, we chose, for simplicity reasons, to continue
Table 3
Lithiation/silylation of o-phthalic acids 1a–g
SiR3
SiR3
O
O
R1
R2
R1
R2
R1
R2
CO2H
CO2H
1) LiTMP (6 eq)
THF, -80°C
+ R3SiCl
(10 eq)
+
O
O
O
O
2) Dehydratation
SiR3
1
2
4
Entry
1
R1
R2
SiR3
2, Yielda (%)
4, Yielda (%)
1
2
3
4
1b
Cl
Br
Cl
Br
TMS
TMS
TMS
TMS
92
-
1c
1d
1e
NDb
10
NDb
23
—
CH@CH–CH@CH
OH
H
27
TMS
O
O
5
1f
H
H
Me
H
TMS
TES
TMS
O
5
36
60 (2g)
6
1a
—
a
Isolated yields.
b
A complex mixture of silylated products resulting from a halogen dance was obtained.

50
J. Michaux et al. / Tetrahedron Letters 53 (2012) 48–50
Table 4
from the Département de Chimie Moléculaire are gratefully
acknowledged.
Conversion of anhydrides to N-hydroxyphthalimides
SiR3
O
SiR3
SiR3
O
Supplementary data
R1
R1
R2
A: NH2OH, HCl/ EtOH/NEt3
O
N OH
Supplementary data (experimental procedures as well as char-
acterization of new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.114.
or B: NH2OH, HCl/ Pyridine
R2
O
O
SiR3
2a-g, 4d, 5
6a-h
References and notes
Anhydride
R1
R2
SiR3
Cond.
N–OH
Yielda (%)
2a
2b
2d
2e
2g
4d
H
Cl
H
Cl
TMS
TMS
TMS
TMS
TES
Mono TMS
A
A
B
B
B
B
6a
6b
6d
6e
6g
6h
78
24
83
46
38
85
1. (a) Coseri, S. Catal. Rev. 2009, 51, 218–292; (b) Recupero, F.; Punta, C. Chem. Rev.
2007, 107, 3800–3842; (c) Ishii, Y.; Sakaguchi, S. Catal. Today 2006, 117, 105–
113; (d) Sheldon, R. A.; Arends, I. W. C. E. J. Mol. Catal. A: Chemical 2006, 251,
200–214; (e) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2004, 346,
1051–1071; (f) Minisci, F.; Recupero, F.; Pedulli, G. F.; Lucarini, M. J. Mol. Catal.
A: Chemical 2003, 204–205, 63–90; (g) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv.
Synth. Catal. 2001, 343, 393–427.
2. (a) Nechab, M.; Einhorn, C.; Einhorn, J. Chem. Commun. 2004, 1500–1501; (b)
Nechab, M.; Kumar, D. N.; Philouze, C.; Einhorn, C.; Einhorn, J. Angew. Chem., Int.
Ed. 2007, 46, 3080–3083.
3. (a) Einhorn, C.; Einhorn, J.; Marcadal-Abbadi, C.; Pierre, J.-L. J. Org. Chem. 1999,
64, 4542–4546; (b) Alvarez, L. X.; Bessieres, B.; Einhorn, J. Synlett 2008, 1376–
1380; (c) Vanel, R.; Berthiol, F.; Bessieres, B.; Einhorn, C.; Einhorn, J. Synlett
2011, 1293–1295.
4. Reviews: (a) Snieckus, V. Chem. Rev. 1990, 90, 879–933; (b) Schlosser, M.
Angew. Chem., Ind. Ed. 2005, 44, 376–393.
CH@CH–CH@CH
OH
H
H
H
CH@CH–CH@CH
TMS
O
O
5
B
6f
59
TMS
O
5
aIsolated yield.
5. Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823–1824.
6. Comins, D. L.; Brown, J. D. J. Org. Chem. 1986, 51, 3566–3572.
7. Reitz, D. B.; Massey, S. M. J. Org. Chem. 1990, 55, 1375–1379.
8. (a) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030–2033; (b) Gohier, F.;
Castanet, A.-S.; Mortier, J. J. Org. Chem. 2005, 70, 1501–1504; (c) Tolly, D.;
Samanta, S. S.; Castanet, A.-S.; De, A.; Mortier, J. Eur. J. Org. Chem. 2006, 174–
182; (d) Nguyen, T.-H.; Castanet, A.-S.; Mortier, J. Org. Lett. 2006, 8, 765–768;
(e) Chau, N. T. T.; Nguyen, T. H.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J.
Tetrahedron 2008, 64, 10552–10557.
cat (1 mol%)
O
CuCl (5 mol%)
O2 (1 bar)
CH3CN, 35°C, 6 h
cat = NHPI , 62%
9. For a discussion on multiple hydrogen/lithium exchange see: Schlosser, M.;
Guio, L.; Leroux, F. J. Am. Chem. Soc. 2001, 123, 3822–3823.
cat = 6a , 71%
10. (a) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155–6157; (b)
Lipshutz, B. H.; Wood, M. R.; Lindsley, C. W. Tetrahedron Lett. 1995, 36, 4385–
4388.
Scheme 2. Catalytic aerobic oxidation of indane.
11. The crude product is composed of a mixture of the expected diacid and of the
spontaneously dehydrated 2a.
reacted with hydroxylamine hydrochloride using two sets of con-
ditions. Results are summarized in Table 4. Several new NHPI ana-
logs were thus obtained in yields ranging from modest (Table 4, 6b,
24%) to good.
12. Typical procedure: To
a solution of LiTMP (6 mmol) and TMSCl (1.27 mL,
10 mmol) in THF (5 mL) at À78 °C, was added a solution of o-phthalic acid 1a
(166 mg, 1 mmol) in THF. The reaction mixture was stirred at À78 °C under
argon for 1 h before being allowed to warm up to room temperature, and
stirred for another hour at room temperature. After quenching with MeOH
(3 mL), volatiles were removed under vacuum. The crude mixture was then
dissolved in water (10 mL), washed with ethyl acetate (2 Â 20 mL), acidified
with HCl 1 N until pH 1, then extracted with ethyl acetate (2 Â 20 mL). The
organic layer was dried over sodium sulfate, then evaporated to afford the
crude material (ca. 300 mg, off-white solid) as a mixture of o-disilylated
phthalic acid and anhydride. To perform complete dehydration of the acid
product, toluene (10 mL) was added and directly evaporated under vacuum.
This operation was repeated until disappearance of the acid form (monitored
by IR spectroscopy). The product was finally purified by flash chromatography
with a pentane/ethyl acetate 98:2 eluant to give 2a as a white solid (184 mg,
65% yield).
Preliminary assays reveal good behaviors of silylated NHPI ana-
logs as aerobic oxidation organocatalysts. Thus, when 6a was used
as a catalyst in the aerobic oxidation of indane, a 71% of indanone
was obtained after 6 h at 35 °C, using only 1 mol % catalyst loading
and CuCl as a cocatalyst. This compares favorably with NHPI, which
gives indanone in 62% yield under the same conditions (Scheme 2).
Moreover, silylated NHPI analogs have much better solubilities in
solvents of low polarity than the corresponding unsilylated com-
pounds. This opens the way to catalytic aerobic oxidation of neat
hydrocarbons.18
In summary, we have demonstrated that o-phtalic acid and 4,5-
substituted analogs can be easily silylated in both positions ortho
to the carboxylic acid functions, via an in situ trapping reaction
of free phthalic acids or of its silyl esters, with LiTMP and TMSCl
or TESCl. The corresponding disilylated compounds were trans-
formed in a straightforward manner into new NHPI analogs, which
possess promising properties as aerobic oxidation catalysts.
13. Prepared by reaction of 1a in neat HMDS, with saccharin as catalyst. See:
Bruynes, C. A.; Jurriens, T. K. J. Org. Chem. 1982, 47, 3966–3969.
14. A similar effect was observed by Snieckus during the lithiation of ortho-
phthalamides: Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron
Lett. 1985, 26, 1145–1148.
15. A difference of 1.6 pK unit is reported. See: Fraser, R. R.; Mansour, T. S. J. Org.
Chem. 1984, 49, 3442–3443.
16. Reviews: (a) Schnürch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.; Stanetty,
P. Chem. Soc. Rev. 2007, 6, 1046–1057; (b) Schlosser, M. Eur. J. Org. Chem. 2001,
3975–3984.
17. In this case, when the amount of base and electrophile was decreased, the
mono-silylated product obtained was the one resulting from the lithiation/
silylation of the aromatic ring.
18. (a) Guha, S. M.; Obora, Y.; Ishihara, D.; Matsubara, H.; Ryu, I.; Ishii, Y. Adv.
Synth. Catal. 2008, 350, 1323–1330; (b) Sawatari, N.; Yokota, T.; Sakaguchi, S.;
Ishii, Y. J. Org. Chem. 2001, 66, 7889–7891.
Acknowledgments
Financial support from the CNRS and the Université Joseph
Fourier (UMR 5250, FR-2607) and a fellowship award (to J.M.)