Regioselective nitration of 1-acyl-4-methoxyindolines leads to efficient synthesis of a photolabile L-glutamate precursor

Article abstract of DOI:10.1081/SCC-120004148

Different nitrating reagents give different ratios of 5- and 7-nitro isomers of the title indolines. The best ratio of the 7-nitro isomer was obtained with claycop-acetic anhydride, and these conditions were particularly useful for preparation of a photolabile L-glutamate derivative.

Full text of DOI:10.1081/SCC-120004148

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REGIOSELECTIVE NITRATION OF 1-ACYL-4-
METHOXYINDOLINES LEADS TO EFFICIENT SYNTHESIS OF
A PHOTOLABILE l-GLUTAMATE PRECURSOR
a
b
George Papageorgiou & John E. T. Corrie
a
National Institute for Medical Research , The Ridgeway , Mill Hill, London, NW7 1AA, UK
b
National Institute for Medical Research , The Ridgeway , Mill Hill, London, NW7 1AA, UK
Published online: 12 Dec 2006.
To cite this article: George Papageorgiou & John E. T. Corrie (2002) REGIOSELECTIVE NITRATION OF 1-ACYL-4-
METHOXYINDOLINES LEADS TO EFFICIENT SYNTHESIS OF A PHOTOLABILE l-GLUTAMATE PRECURSOR, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:10, 1571-1577, DOI: 10.1081/
SCC-120004148
To link to this article: http://dx.doi.org/10.1081/SCC-120004148
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SYNTHETIC COMMUNICATIONS, 32(10), 1571–1577 (2002)
REGIOSELECTIVE NITRATION OF
1
-ACYL-4-METHOXYINDOLINES
LEADS TO EFFICIENT SYNTHESIS
OF A PHOTOLABILE L-GLUTAMATE
PRECURSOR
George Papageorgiouand John E. T. Corrie *
National Institute for Medical Research,
The Ridgeway, Mill Hill, London NW7 1AA, UK
ABSTRACT
Different nitrating reagents give different ratios of 5- and
7
7
-nitro isomers of the title indolines. The best ratio of the
-nitro isomer was obtained with claycop–acetic anhydride,
and these conditions were particularly useful for preparation
of a photolabile L-glutamate derivative.
Key Words: Aromatic nitration; Caged l-glutamate; Clay-
pop; Nitroindolines
We have recently described the aqueous solution photochemistry of
-acyl-7-nitroindolines 1, where the products are a carboxylate and a
7
1
1
-nitrosoindole (Scheme 1). Our interest lies in reagents capable of rapid
and efficient near-UV flash photolytic release of carboxylates, notably
L-glutamate, within biological preparations. Recently, we have investigated
*
Corresponding author. Fax: (+44)208 906 4419; E-mail: jcorrie@nimr.mrc.ac.uk
571
1
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1
572
PAPAGEORGIOU AND CORRIE
Scheme 1.
the effect of different substituents on the aromatic ring of the indoline and
found that 4-methoxy substitution, as in 2, has a marked beneficial effect on
2
the photolysis efficiency.
We found that compounds of structure 2 were ꢀ3-fold more photo-
sensitive than the original compounds 1. These quantitative comparisons
of photolysis efficiency were made with the 1-acetyl compounds 1a and 2a
and the advantage was maintained for the corresponding L-glutamate
3
derivative 2b.
Despite the significant improvement in photosensitivity of 2b and
related compounds, the advantage could not readily be exploited because
of the very poor yield for introduction of the nitro group. In this step, the
2
precursor 3b was treated with sodium nitrate in TFA solution and the reac-
tion product was a complex mixture of products, from which the 7-nitro
isomer 2b was isolated by reversed phase HPLC in ꢀ4% yield. The corres-
ponding 5-nitro isomer was obtained in similar yield and the same 1 : 1 ratio
of 5- and 7-nitro isomers was obtained for the 1-acetyl compound 3a, where
isomers 2a and 4 could be easily separated by silica gel chromatography.
Although the detailed photolysis mechanism is not known, oxygen transfer
1
takes place from the 7-nitro group to the adjacent 1-acyl group, so the
5-isomer is not useful. The previous nitration conditions result in concomi-
tant loss of the protecting groups on the amino acid moiety in 3b, so separa-
tion options were limited to methods appropriate to the zwitterion products.
We now report nitration conditions that have the 2-fold advantage of a much
more favourable isomeric ratio of products and leave the protecting groups
intact, so giving additional scope for isomer separation.
DISCUSSION
Exploratory nitrations were carried out on 1-acetyl-4-methoxyindoline
2
a. We showed previously that 3a underwent exclusive Friedel-Crafts
3

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REGIOSELECTIVE NITRATION
1573
acetylation at C-7 and, hence, predicted that nitrosation would also occur at
the desired 7-position. Greater regiospecificity than for nitration was
expected, as the nitrosonium ion is many orders of magnitude less reactive
4
than the nitronium ion. A detailed study of nitrosation reactions of elec-
tron-rich aromatic compounds with nitrosonium tetrafluoroborate has been
5
5
reported. In the event, we were able to reproduce the reported high-yield-
þ
ꢁ
ing nitrosation of anisole with excess NO BF in dry acetonitrile, but simi-
4
lar treatment of 3a gave a mixture that still contained ꢀ50% starting
material, together with the nitrated isomers 2a and 4. The 5-nitro isomer 4
was the more abundant of the two (ratio ꢀ2 : 1). Nitration of other sub-
6
strates under these conditions has been observed when oxygen was present
but the successful control experiment on anisole suggests this was not the
case here. While the result is interesting, we chose instead to examine alter-
native methods for selective 7-nitration.
7
Among the wide range of nitration reagents, the clay-supported
8
lis that effects
copper(II) nitrate (claycop) developed by Laszlo and Corne
´
nitration in the presence of acetic anhydride appeared particularly suitable,
as the reaction proceeds under conditions unlikely to perturb the protecting
groups of 3b. Furthermore, nitration of acetanilide proceeds with extremely
8
b
high ortho-selectivity. We hoped that similar selectivity might be obtained
for our N-acylated substrates 3.
In either CCl or CH Cl as solvent, 3a was consumed in 4 h and
4
2
2
cleanly yielded a mixture of 2a and 4 in a 5 : 1 ratio, i.e., strongly favouring
9
the 7-nitro isomer. In diethyl ether as solvent, the reaction was much more
sluggish: only ꢀ20% of 3a reacted in 4 h and there was no benefit to the
product ratio. Gratifyingly, the same reaction on 3b in CCl overnight gave
4
the nitrated compounds 5a and 6, with the desired isomer as the dominant
product (ꢀ1 : 12 ratio) and the protecting groups intact. In this case, there
was a small quantity of an additional product with TLC mobility intermedi-
ate between that of the starting material and the desired nitrated products.
1
H NMR and high resolution MS (data not shown) indicated this was a
mixture of N-nitroso and N-nitro species on the nitrogen of the protected
amino acid residue. N-Nitrosation and N-nitration of secondary amides and

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574
PAPAGEORGIOU AND CORRIE
carbamates is well known and nitrosation under ostensibly nitrating con-
1
0
ditions has been observed previously. An attempt to suppress these side
reactions by including a 5-fold molar excess of N-methylacetamide in the
nitration mixture resulted in complete recovery of starting material, both for
the N-acetyl compound 3a and the amino acid derivative 3b. It appears that
the formation of the mixture of by-products in small quantity (ꢀ10%) is an
inevitable consequence when the substrate contains a secondary amide
group.
2a and 4 were readily separated by silica gel chromatography, but
isomers 5a and 6 were less easily resolved. However, pure 6 was obtained
by fractional crystallisation of the mixed isomers, and TFA treatment with
simple desalting by preparative HPLC gave 2b. The 5a þ 6 mixture could
also be treated with TFA to remove the protecting groups and 2b isolated
from the resulting mixture by the reversed phase HPLC procedure pre-
2
viously reported. However, the former procedure was more convenient
and the overall yield of 2b from 3b was ꢀ40%.
The claycop nitration provides a satisfactory solution to the problem
but we evaluated homogeneous nitration with copper(II) nitrate–acetic
1
1
anhydride to assess the effect of the clay matrix. Under typical conditions,
a was completely transformed and the nitrated isomers 2a and 4 were
3
obtained in 3 : 2 ratio, i.e., 40% 5-nitro compared to 17% with claycop.
Thus the claycop procedure is more favourable and convenient. These
results greatly facilitate access to 2b and related compounds. Further appli-
cations will be reported elsewhere.
EXPERIMENTAL SECTION
2
General details were as previously described. Claycop was prepared
with a 2 : 3 (w/w) ratio of Cu(NO ) and montmorillonite K10 as
3
2
8
a
1,2
described.
Compounds 1–4 were available from previous work.

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REGIOSELECTIVE NITRATION
1575
Only the experimental data for the successful claycop nitration of 3b and
subsequent isolation of 2b are reported here.
Claycop Nitration of 1-{S-[4-(t-Butoxycarbonyl)-4-
t-butoxycarbonylamino)]butanoyl}-4-methoxyindoline 3b
(
Compound 3b (2.17 g, 5 mmol) was added at room temp. to a
suspension of claycop (3.2 g) in CCl4 (20 ml) and acetic anhydride
(10 ml) and the mixture was stirred overnight. The solid was filtered and
washed with EtOAc and the filtrate was washed with saturated aq.
NaHCO and brine, then dried and evaporated. Flash chromatography
3
[EtOAc–petroleum ether 45 : 55] gave two fractions. The first gave a pale
yellow gum (322 mg) which was discarded (see Discussion section). The
second fraction gave a pale solid (1.61 g) that contained a mixture of 5-
and 7-nitro isomers 5a and 6. Fractional crystallisation (CHCl –petroleum
3
ether) gave 1-{S-[4-(t-butoxycarbonyl)-4-(t-butoxycarbonylamino)]buta-
noyl}-4-methoxy-7-nitroindoline 6 (1.03 g, 43%) as yellow crystals, m.p.
ꢂ
1
5
45–147 C; (Found: C, 57.70; H, 6.98; N, 8.76. C H N O requires C,
2
3
33
3
8
1
7.61; H, 6.94; N, 8.76%); H NMR: (CDCl ) d 7.74 (1H, d, J 8.8 Hz, 6-
3
H), 6.64 (1H, d, 5-H), 5.15 (1H, d, J 7.2 Hz, NH), 4.17–4.25 (3H, m, CH and
-H), 3.91 (3H, s, OMe), 3.04–3.12 (2H, m, 3-H), 2.50–2.56 and 2.58–2.64
2H, 2 ꢃ m, COCH ), 2.25–2.30 and 1.96–2.03 (2H, 2 ꢃ m, CH ), 1.46 (9H,
2
(
2
2
s, CMe ), 1.43 (9H, s, CMe ). The residue in the mother liquor was recrys-
3
3
tallised (EtOAc–petroleum ether) to give 1-{S-[4-(t-butoxycarbonyl)-4-(t-
butoxycarbonyl-amino)]butanoyl}-4-methoxy-5-nitroindoline 5a (57 mg,
ꢂ
2
%) as yellow crystals, m.p. 102–103 C; (Found: C, 57.41; H, 7.12; N,
8
.12. C H N O þ 1/2 EtOAc requires C, 57.35; H, 7.12; N, 8.03%);
2
3
33
3
8
1
H NMR: (CDCl ) d 8.02 (1H, d, J 9.0 Hz, 7-H), 7.86 (1H, d, 6-H), 5.17
3
(
OMe), 3.26 (2H, t, 3-H), 2.46–2.66 (2H, m, COCH ), 2.26–2.34 and
1H, br s, NH), 4.17–4.26 (1H, m, CH), 4.16 (2H, t, J 8.2, 2-H), 3.92 (3H, s,
2
1.96–2.04 (2H, m, CH ), 1.48 (9H, s, CMe ) and 1.42 (9H, s, CMe ).
2 3 3
Signals from the solvent of crystallisation were present at d 4.12, 2.04 and
.26.
1
1
-[S-(4-Amino-4-carboxybutanoyl)]-4-methoxy-7-nitroindoline 2b
A solution of 6 (479 mg, 1 mmol) in TFA (15 ml) was stirred at room
temp. for 1 h and concentrated in vacuo. The residue was dissolved in water
60 ml) and adjusted to pH 7.0 with 1 M aq. NaOH. The solution was
washed with ether and analysed by reversed phase HPLC (mobile
(

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576
PAPAGEORGIOU AND CORRIE
phase 25 mM Na phosphate, pH 6.0 þ 25% MeCN (v/v); 1.5 ml/min),
4.2 min. The solution was lyophilised, redissolved in 25 mM Na phos-
phate, pH 6.0 (60 ml) and pumped onto a preparative reversed phase HPLC
t
R
2
column (details as described ). The column was first washed with water for
2
2
h, then the product was eluted with water þ 20% MeCN (v/v; all flow rates
.5 ml/min). Fractions containing the product were analysed, combined and
quantified (UV spectroscopy) to give a solution of 2b (867 mmol, 87%). The
ꢂ
solution was passed through a 0.2 mm filter, lyophilised and stored at ꢁ20 C
as a pale yellow powder. Fractions from the very end of the eluted peak
contained a trace amount of 5b, tR 5.6 min, and were discarded without
significant loss of 2b.
ACKNOWLEDGMENT
We are grateful to Dr. G. Kelly for recording NMR spectra, to
Dr. K. Welham for mass spectrometric measurements and to the MRC
Biomedical NMR Centre for access to facilities. GP was supported by
NIH Grant HL19242.
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1
. Papageorgiou, G.; Ogden, D.C.; Barth, A.; Corrie, J.E.T. Photorelease
of Carboxylic Acids from 1-Acyl-7-nitroindolines in Aqueous Solution:
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1999, 121, 6503.
2. Papageorgiou, G.; Corrie, J.E.T. Effects of Aromatic Substitution on
the Photocleavage of 1-Acyl-7-nitroindolines. Tetrahedron 2000, 56,
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3. Canepari, M.; Nelson, L.; Papageorgiou, G.; Corrie, J.E.T.; Ogden, D.
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REGIOSELECTIVE NITRATION
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Received in the UKApril 17, 2001

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