A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles

Article abstract of DOI:10.1039/C8OB01471J

A straightforward indole synthesis via annulation of C-nitrosoaromatics with conjugated terminal alkynones was realised achieving a simple, highly regioselective, atom- and step economical access to 3-aroylindoles in moderate to good yields. Further functionalizations of indole scaffolds were investigated and an easy way to JWH-018, a synthetic cannabinoid, was achieved.

Full text of DOI:10.1039/C8OB01471J

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L. Ameta, K. M. Nicholas and A. Penoni, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01471J.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles†
Gabriella Ieronimo,a Giovanni Palmisano,a Angelo Maspero,a Alessandro Marzorati,a Luca Scapinello,a
Norberto Masciocchi,a Giancarlo Cravotto,b Alessandro Barge,b Marco Simonetti,c Keshav Lalit Ameta,d
Kenneth M. Nicholase and Andrea Penoni*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
40 therapies and as anti-cancer agents.7 The 1-hydroxyindole nucleus
A straightforward indole synthesis via annulation of C-
was recently found in pigments from flower pot parasol
Leucocoprinus birnbaumii8 and has received ever growing
attention by many research groups for its role in bioactive
molecules.9 The N-hydroxyindole unit, or of an analogue indoline
45 nitrone, is a fundamental fragment of very interesting naturally
occurring compounds such as nocathiacin I,10 coproverdine11 and
nitrosoaromatics with conjugated terminal alkynones was
realised achieving a simple, highly regioselective, atom- and
10 step economical access to 3-aroylindoles in moderate to good
yields. Further functionalizations of indole scaffolds were
investigated and an easy way to JWH-018, a synthetic
cannabinoid, was achieved.
stephacidin B,
a highly complex dimeric prenylated N-
hydroxyindole alkaloid that contains 15 rings and 9 stereogenic
centers and exhibits potent activity against prostate carcinoma;12
50 the corresponding monomeric compound, avrainvillamide was
recently afforded by two different total syntheses by Myers13a and
Baran13b and displayed antibiotic activity towards several Gram
positive cocci.14 Stability of N-hydroxyindoles has been a source
of debate where they are frequently cited as unstable and elusive
55 compounds that can be reduced to indoles or stabilized through
alkylation or acylation to avoid their decomposition or
dimerization.15 Most of the syntheses of N-hydroxy- and N-
alkoxyindoles reported in literature employ an intramolecular
approach to the indole ring closure.16 Previous intramolecular
60 synthetic approaches to N-hydroxyindoles were reported by
different research groups starting from nitrostilbenes17 and a
theoretical study by Davies and Houk discussed the formation of
Indole compounds are deeply studied because of their biological
15 activity and continue to capture the attention of synthetic organic
chemists (Figure 1). A large number of original indole ring
syntheses and applications of known methods to new problems in
indole chemistry have been reported so far.1 Our general interest
in the chemistry of indoles led us to introduce in the last years a
20 synthetic approach to the formation of the indole ring by
cycloaddition of nitro- and nitrosoarenes with alkynes.2 Indoles, N-
hydroxy- and N-alkoxyindoles were regioselectively produced in
moderate to good yields. Ragaini’s research groups reported a very
efficient Pd-based catalyzed reaction with similar regioselectivities
25 and high turn-over parameters using nitroaromatics as starting
materials.3 Recently Srivastava and coworkers developed a gold-4a
and a copper-catalyzed4b analogue annulation affording indoles by
reaction of nitrosoarenes with aromatic alkynes. Naturally
occurring marine alkaloids like meridianins, commonly known as
30 kinase inhibitors, were prepared through the annulation of
nitrosoarenes with substituted ethynylpyrimidines.5 Efficient
synthetic protocols starting from arylhydroxylamines were
introduced by some of us using the in situ generation of
nitrosoaromatics by oxidation with Fe(Pc)(Iron phthalocyanines).6
N-hydroxyheterocycles
during
the
deoxygenation
of
nitroaromatics.18 A recent interesting work by Liu, Zhou et al.
65 reported the synthesis of N-hydroxyindoles by Rh(III)-catalyzed
C-H cyclization of arylnitrones and diazo compounds.19
3-Acylindoles are known to be bioactive compounds and recent
studies highlighted their interesting properties and various
synthetic approaches.20 Some synthetic compounds such as
O
OCH3
70 BPR0L075
(6-methoxy-3-(3’,4’,5’-trimethoxy-benzoyl)-1H-
OCH3
CH3
indole) showing 3-aroylindole unit were discovered to be potent
antitubulin agents.21 3-Aroylindoles were differently prepared by
classic synthetic approaches by acylation of preformed indole
substrates22a-c and very recently by Pd,22d-e Pd-Cu,22f Cu22g and acid
75 catalyzed22h reactions. Not many indolization procedures are
known to afford directly 3-acylindoles starting from easily
available reactants.23
O
OCH3
OCH3
N
N
N
H
H3CO
O
BPR0L075
Pravadoline
35
Figure 1 Synthetic bioactive indole compounds
The ever growing interest in N-hydroxyindole derivatives was
recently illustrated by the biological activities reported for some of
these compounds that became interesting candidates in different
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O
O
toluene
or
dioxane
O2N
Me2SO4
2CO3
X
O
O2N
O
Y
K
X
+
+
toluene
80 °C
N
O
80 °C
5-8 h
N
Y
N
N
R
OR
O
a
a
=
=
1
2
3
4
CH3
H)
=
and
and
=
EDG; R OH, H
X
Y
EWG
(R
(R
)
a-g
a-h
1
2
4-18
45
Table 2 Nitrosoarene-alkynone cycloaddition reactions a
Table 1 Survey for the optimization of the reaction conditionsa
Entry ArNO
X
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-COOH
4-COOH
H
4-COOEt
4-CH3
Y
H
2-Cl
2-Br
R
Prod. Yield (%)
ArC(O)C≡CH
Entry Alkynone/nitrosoarene Alkylative agent / base
molar ratio
R
Prod. Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2g
2h
2b
2f
2a
2a
2a
2a
2a
OH
OH
OH
OH
OH
4
54 b, c
70 b, c
52 b, c
69 b, c
62 c
1
2
3
4
5
6
7
15/1
5/1
15/1
12/1
10/1
5/1
Me2SO4 / K2CO3
Me2SO4 / K2CO3
CH3
CH3
H
H
H
3
3
4
4
4
4
4
tracesb
tracesb
35c
5
6
7
8
9
3-NO2
4-NO2
4-OCH3 OH
4-CHO OH 10
3,4-OCH2O OH 11
2-Cl
4-NO2
H
H
H
none
none
none
none
none
38c
37 b, c
31c
40c
H
H
42c
61 c
1/1
53c
OH 12
OH 13
H
H
H
H
69 c, d, e
67 c, d, e
25 f
a All reactions were carried out using 1a and 2a in toluene for 5h; b product isolated
by chromatography; c product precipitated
14
15
16
17
27 f
20 f
5
Thus stimulated by the intention to apply our convergent indole
synthetic approach to the one-pot preparation of highly
functionalizable compounds and/or biologically active products
having the 3-aroylindole fragment, we used 1-phenyl-prop-2-yne-
1-one 2a as the simplest starting material for a wide survey with
10 nitrosoaromatic derivatives as reaction partners. Previous studies
revealed that C-nitrosoaromatics with electron withdrawing groups
show generally faster reaction times and better product yields. The
study for the optimization of the reaction conditions was carried
out using 4-nitronitrosobenzene 1a and 1-phenyl-2-propyne-1-one
15 2a (Table 1). A general drawback for our previous annulation
reactions between nitrosoarenes and alkynes was the large excess
of alkynes (10-15 fold) that was always used.
Envisioning an instability of the N-hydroxyindoles our first
nitroso-alkyne cycloaddition reactions between 4-nitro-
20 nitrosobenzene 1a and 1-phenyl-prop-2-yn-1-one 2a were run
under alkylating conditions (K2CO3 and Me2SO4 both 6 fold), but
this strategy was not fruitful and led us to isolate the corresponding
N-methoxy-3-aroylindole only in traces. To our delight, working
in the absence of dimethyl sulphate and potassium carbonate, a
25 solid precipitated in the reaction mixture. After spectroscopic
characterization, it was identified as composed only by N-hydroxy-
5-nitro-3-benzoylindole and it was isolated simply by filtration
without any other further purification.
We then determined whether such a large excess of alkyne was
30 strictly necessary to get efficient conversion of nitrosoarenes to
target indoles avoiding the degradation to azoxy-derivatives,
generally the most relevant side products observed in the
cycloaddition of nitrosoarenes with arylacetylenes. Seeking to
optimize the reaction conditions we used different molar ratios
35 nitrosoarene/alkynone, (e.g. 1:5, 1:12, 1:15), but surprisingly, we
found comparable or better yields of indole products by performing
the reactions with a 1:1 nitrosoarene/alkynone molar ratio (Table
1). In contrast to the N-hydroxy-3-arylindoles, N-hydroxy-3-
aroylindoles are generally more stable and do not undergo
40 dimerization to kabutanes15a,24 under the standard reaction
conditions. The procedures were highly functional group tolerant.
Using conjugated alkynones as starting materials the reaction
proceeds with the regioselective formation of N-hydroxy-3-
aroylindoles and/or 3-aroylindoles (Table 2).
4-OCH3
2-COOMe
H
H
30 f
1g
OH 18
33 f
a All reactions were carried out using ArNO (1 mmol) and ArC(=O)C≡CH (1 mmol)
in 12 ml of toluene; b this reaction was carried out even using a large excess of alkyne
c
but no better yields were collected and only faster reaction times were registered;
50 product precipitated; reaction carried out in dioxane; product recrystalyzed;
product isolated by chromatography;
d
e
f
This process shows an excellent atom and step economy. A wide
substrate scope was explored using different substituted
nitrosoarenes and arylalkynones affording indole compounds in
55 moderate to excellent yields (Table 2). Only 3-substituted
regioisomers were isolated. Procedures carried out with electron-
deficient nitrosoaromatics registered better product yields and
shorter reaction times. Electron-rich nitrosoarenes show the
prevalent formation of indoles instead of N-hydroxyindoles. Minor
60 conversions and moderate yields were observed by using
nitrosoaromatics with electron donating groups. With a few
nitrosoarenes, N-H indoles were detected as minor products. A
plausible explanation could be an internal redox process in which
a relevant role is played by the electronic properties of both
65 reagents. The mechanism of an analogous annulation was studied
some years ago using terminal arylacetylenes2e instead of
aroylacetylenes. We reported that the reaction probably occurs
through a stepwise diradical cycloaddition with rate-limiting N-C
bond formation and rapid C-C connection to form the N-
70 hydroxyindole product. Further studies employing electrochemical
methods will be carried out in the near future to investigate other
aspects of the reaction mechanism like the reduction of N-
hydroxyindole compounds to N-H indole products observed in
some cases. Interestingly, running the reaction with pentafluoro-
75 nitrosobenzene, no cycloaddition products were detected, proving
the necessity of an unsubstituted carbon ortho- to the nitroso group.
The electronic properties of substituents on the ring of the aromatic
ynone does not seem to play a dramatic role neither in product
yields nor for reaction times.
80
To confirm the surmised 3-regioselectivity of the reaction, a
single crystal of N-hydroxy-3-(2’-chlorobenzoyl)-5-nitro-1H-
indole (compound 5) was obtained and its X-ray structure§ is
reported in Figure 2. No traces of the 2-substituted regioisomers
were detected in the reaction mixtures.
2
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Organic & Biomolecular Chemistry
O
toluene
or
dioxane
X
O
Ar(Het)
X
+
Ar(Het)
N
O
80 °C
N
R
=
R
OH, H
a-c,
a-l
1
h
20
21-40
g,
50 Table 3 Nitrosoarene-alkyne cycloadditions with other carbonyl-conjugated ynonesa
ArC(O)C≡CH
Figure 2 X-ray derived molecular structure of compound 5, with partial
labelling scheme. Thermal ellipsoids are drawn at the 50% level.
Entry ArNO
X
Ar or Het
R
Prod. Yield (%)
or
The versatility of the indole products was tested in
functionalization procedures using compounds 4 and 5 as starting
materials (Scheme 1).
HetC(O)C≡CH
5
1
2
3
4
5
1a
1b
1h
1c
1a
4-NO2
4-COOH
4-CN
20a
20a
20a
20a
20b
OH
OH
OH
OH
OH
21
22
23
24
25
57 b, c
68 b, d
40 b
X
Cl
(a)
(b)
O
O
O
N
O2N
O2N
H2N
K
2CO3 / Me2SO4
Zn / AcOH
N
N
r.t.
r.t.
MeOH,
96%
MeOH,
70%
N
N
N
H
40 b
=
=
Cl
X
H
X
OH
OCH3
H
or
3
4
5
19
4-NO2
47 b, e
Scheme 1 Functionalization reactions of compound 4 and 5
N
e
M
Compound 4 was methylated by reaction with dimethyl sulphate
6
7
1a
NO2
20c
20c
OH
H
26
27
20 b
30 f
10 in the presence of K2CO3 as base in MeOH affording the
corresponding N-methoxyindole derivative 3 in 96% yield (path
(a)). In a poorly selective reductive reaction compound 5 was
heated with Zn/AcOH and performing contemporarily the
reduction of the nitro group and the N-OH bond to N-H group
15 affording 19 in 70% yield (path (b)).
With the aim to generalize the application of the cycloaddition
between nitrosoarenes and alkynones, ethynyl ketones containing
heterocyclic frameworks or other conjugated units, organometallic
moieties and polycyclic fragments were tested and an extension of
20 the synthetic scope of the reaction was achieved (Table 3). Indole
derivatives 21-24 (Table 2 entries 1-4) showing the benzotriazole
(Bt) unit were prepared by cycloaddition of nitrosoaromatic
N
1g 2-COOMe
e
M
8
9
1a
1a
4-NO2
4-NO2
20d
20e
OH
OH
28
29
65 a, e
50 b
N
e
M
10
11
1a
1a
4-NO2
4-NO2
20f
OH
OH
30
31
51b
O
20g
65 b
12
13
14
1a
1h
1a
4-NO2
4-CN
20h
20h
20i
OH
OH
H
32
33
34
36 b
29 b
49 b
compounds
1 a-c, h with 1-(1H-1,2,3-benzotriazol-1-yl)-2-
N
propyn-1-one 20a.25 Tremendous progress has been achieved in
25 the field of benzotriazole chemistry and different major functions
of benzotriazole in organic transformations were excellently
illustrated very recently by Katritzky and coworkers focusing the
activity of Bt as leaving group, proton activator, cation stabilizer,
anion and radical precursor.26 The use of Bt (benzotriazole) as
30 leaving group is a powerful tool to achieve a wide class of indole
derivatives showing biological activities. Compounds 21-24 are
good candidates to be furtherly functionalized to many different
indole alkaloid products. The potential value of this transformation
is currently in progress and will be deeply investigated in the near
35 future.
H
4-NO2
e
F
15
16
17
18
1a
1h
1c
1c
4-NO2
4-CN
H
20j
20j
20j
20j
OH
OH
OH
H
35
36
37
38
68 b
30 b
38 f
17 f
H
19
20
1h
1a
4-CN
20k
20l
OH
OH
39
40
33 b
NO2
4-NO2
27 b
a
All reactions were carried out using ArNO (1 mmol) and Ar(Het)C(=O)C≡CH (1
mmol) in 12 ml of toluene; b product precipitated; c reaction carried out on gram scale;
reaction carried out in dioxane; this reaction was carried out even using a large
4-Nitronitrosobenzene 1a and 4-nitrosobenzoic acid 1b proved
to be superior reagents with the alkynones through stoichiometric
reaction in toluene or dioxane at 80 °C. N-Hydroxyindoles bearing
a nitro group at C-5 always precipitated from the reaction mixture
40 and were isolated by filtration. The same thing was observed for
N-hydroxyindoles bearing a COOH group at C-5, but because 4-
nitrosobenzoic acid was scarcely soluble in the common solvents,
dioxane was used for cycloadditions. 3-Aroyl-1-hydroxy-1H-
indole-5-carboxylic acids were extremely insoluble and
45 precipitated as yellow solids as the reaction proceeded, together
with azoxybenzene-4,4'-dicarboxylic acid. Removal of this by-
product was sometimes achieved by recrystallization from
dichloromethane or ethyl acetate.
d
e
excess of alkyne but no better yields were collected and only faster reaction times
55 were registered; f product isolated by chromatography.
The product 39 (Entry 19, Table 3) was furtherly investigated
because this very versatile substrate can be used for two different
annulations in the aim to afford biindole scaffolds and quinoline
products (path (a) and (b), Scheme 2). Indolization was achieved
60 in 25% yield, via a cyclization in a Cadogan-Sundberg type
procedure using PPh3 under microwave irradiation. The quinoline
derivative was synthesized by reaction of compound 39 with
indium and ammonium chloride at reflux in methanol/water (24%
yield).
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Page 4 of 6
(a)
(b)
indole compound 14 and traces of azo derivative 44) with large
amount of starting materials. An interesting improvement was
45 observed when the reaction was carried out solventless under
microwave irradiation (62% of 14 and 7% of 44) (Scheme 4). This
last result prompts further studies for the formation of indole
derivatives with unconventional methods.
O
O
NC
NC
NC
PPh3
In / NH4Cl
N
N
H
O2N
MW, 200W, 100 °C
25%
MeOH / H2O reflux
24%
N
H
N
N
H
OH
41
39
42
Scheme 2 Further functionalizations and transformations of 39
As cited before some 3-aroylindoles are known as
antinociceptive drugs and cannabinoid agonists and NSAID (Non
Steroidal Anti-Inflammatory Drugs).27
Conclusions
5
50
The necessity to have an efficient and easily available protocol
for the preparation of N-hydroxyindoles led us to study a direct,
effective and atom economical synthesis. In conclusion we
developed and reported here a direct methodology for the
regioselective preparation of stable N-hydroxy-3-aroylindoles and
O
O
Br
O
toluene
+
N
N
O
80 °C
17%
KOH, CH3CN
20%
N
H
55 3-aroylindoles by cycloaddition of nitrosoarenes with conjugated
alkynones. Terminal ynones were used for the first time in this kind
of reaction and revealed to be privileged reactants for a new
regioselective and atom economical indolization procedure.
Indoles produced by this protocol are interesting scaffolds for the
60 preparation of high valuable compounds generally known as
antinociceptive and NSAID bioactive molecules. Some
preliminary reactions using internal alkynones gave poor yields of
indole products at the moment, however further optimization of the
reaction conditions are under development.
1c
20j
38
43
Scheme 3 Alternative synthesis of JWH-018
Pravadoline is a quite simple and small molecule known as an
analgesic drug.28 Recently a moderate affinity of pravadoline for
10 the cannabinoid receptors was detected. This finding initiated a
search for other Amino Alkyl Indoles (AAIs) with higher potency
and selectivity in antinociceptive activity. The aminoalkylindoles,
naphthalene analogs of pravadoline, have been shown to exhibit
cannabinoid agonist activities such as antinociception in animals,
15 inhibition of adenylate cyclase in brain membranes and have high
affinity for both the cannabinoid CB1 and CB2 receptors in the
brain.29 Huffman’s research group synthesized a huge number of
compounds and JWH-018 43 is only one example that shows a
relevant activity as an analgesic chemical from the
20 naphthoylindole family that acts as a full agonist at both the CB1
and CB2 cannabinoid receptors, with some selectivity for CB2.30
We easily accessed to naphthoylindole scaffolds using different
nitrosoarenes in cycloaddition reactions with 1-(naphthalene-1-
yl)prop-2-yn-1-one 20j (Table 3 entries 15-18). With the synthetic
25 technique presented here in our hands, it was intriguing to develop
an alternative synthesis for the preparation of bioactive 3-
aroylindoles. JWH-018 was synthesized in an interesting shortcut
using an alkylative procedure on compound 37 after the
cyclization.
65
Some of the reactions explored in this research can be easily
used as propitious tests to recognize conjugated alkynones through
the formation of precipitates by reaction with 4-
nitronitrosobenzene. A detailed mechanistic study is in progress.
Future developments trying to understand the formation of N-OH
70 indoles and N-H indoles will be carried out by using some
voltammetry studies and other electrochemistry technique to
disclose the redox step that occurs in some reactions.
Dedication
In Loving Memory of our Friend and Colleague Andrea Dallari
75 Conflict of Interests
There are no conflicts of interest to declare.
Acknowledgements
O
different activation
methods
O
N
+
+
N
N
O
N
H
We thank Dr. Enrica Alberti and Dr. Marta Brucka for NMR
experiments, Francesco Tibiletti, Nicolò Marnoni, Luca Frigerio
80 and Federico Vavassori for experimental assistance.
1c
2a
14
44
thermal conditions in toluene at 80 °C
solventless microwave irradiation
mechanochemical
25%
62%
12%
11%
7%
traces
ball-mill
planetary
30
Scheme 4 Synthesis of compound 14 with different activation methods
Notes and references
In an explorative study we planned to search a more environmental
benign approach to the indolization of nitrosoarenes with
alkynones using even different techniques like ball-milling and
a Dipartimento di Scienza e Alta Tecnologia, Università degli Studi
dell’Insubria, via Valleggio 9, 22100, Como, Italy. Tel: +39 031
2386440; E-mail: andrea.penoni@uninsubria.it
85 b Dipartimento di Scienza e Tenologia del Farmaco, University of Turin,
via Pietro Giuria, 9, 10125, Turin, Italy
35 microwaves in solventless conditions. The product yields were
detected by GC analyses. As a model reaction we used
nitrosobenzene 1c and 1-phenyl-2-propyn-1-one 2a as privileged
substrates. Nitrosobenzene, the substrate of choice because it is
commercially available and more electron rich than compound 1a,
40 gave in standard conditions only moderate yields of indole (25%,
entry 11, Table 2). Poor yields were also achieved using
mechanochemical activation in a planetary ball-mill (12% of
c School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, United Kingdom
d Department of Chemistry, College of Arts, Science and Humanities,
90 Mody University of Science and Technology, Lakshmangarh 332311,
Rajasthan, India.
e Department of Chemistry and Biochemistry, University of Oklahoma,
Stephenson Life Sciences Research Center, 101 Stephenson Parkway,
Norman, OK 73019-5251.
4
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Organic & Biomolecular Chemistry
9
a) M. Somei, Top. Heterocycl. Chem. 2006, 6, 77; b) J. T. Kuethe,
† Electronic Supplementary Information (ESI) available: X-ray crystal 70 Chimia 2006, 60, 543; c) R. M. Acheson, Adv. Heterocycl. Chem. 1990,
structure of 5;details of experimental procedures and spectroscopic data are
51, 105.
available and are reported in ESI. For ESI and crystalographic data in CIF
5 or other electronic format see DOI: 10.1039/b000000x/
‡ Preparative reactions: Alkynols were prepared through the addition of
10 a) K. C. Nicolaou, S. H. Lee, A. A. Estrada and M. Zak, Angew. Chem
Int. Ed. 2005, 44, 3736; b) K. C. Nicolaou, A. A. Estrada, S. H. Lee and G.
C. Freestone Angew. Chem Int. Ed. 2006, 45, 5364; c) K C. Nicolaou, A.
Grignard reagent (ethynylmagnesium bromide ≡-MgBr) or 75 A. Estrada, G. C. Freestone, S. H. Lee and X. Alvarez-Mico, Tetrahedron
ethynyltrimethylsilane (≡-SiMe3) in the presence of BuLi to the
corresponding arylaldehydes. Eventual cleavage of TMS group is operated
10 by TBAF. Ynones were synthesized by oxidation of the alkynols by Dess-
Martin periodinane, MnO2 or Jones reagent. Nitrosoarenes were prepared
by oxidation of the corresponding anilines.
Representative experimental procedure: Nitrosoarene (1 mmol) and
alkynone (1 mmol) were combined in toluene (or 1,4-dioxane) under inert
15 atmosphere and heated at 80 °C untill the complete conversion of the
reactants (monitoring by TLC). Products were isolated by filtration or
chromatography. Detailed procedures are reported in the ESI.
§ Crystallographic data: 5, C15H9ClN2O4, M = 316.69, Monoclinic, a =
12.899(2), b = 7.780(2), c = 13.924(1) Å, β = 94.602(9)°, U = 1392.8(4)
20 Å3, T =298(2) K, space group P21/c , Z = 4, 2529 unique reflections
measured, which were used in all calculations. The final R1 was 0.038
(I>2σ(I)) and wR(F2) was 0.095 (all data). CCDC 834062.
2007, 63, 6088.
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