The stereoselective synthesis of highly functionalized tertiary 3-aminoindoles/anilines or dihydropyrroles from C-(3-indolyl)-N-aryl and C,N-diaryl nitrones

Article abstract of DOI:10.1016/j.tetlet.2010.10.045

We report on the novel properties of nitrones including their transformations via reactions with sodium malonates to give functionalized stereodefined derivatives of tertiary 3-aminoindoles or anilines, as well as fully-substituted dihydropyrroles. The ou

Full text of DOI:10.1016/j.tetlet.2010.10.045

Tetrahedron Letters 51 (2010) 6594–6597
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Tetrahedron Letters
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The stereoselective synthesis of highly functionalized tertiary
3-aminoindoles/anilines or dihydropyrroles from C-(3-indolyl)-N-aryl
and C,N-diaryl nitrones
V. S. Velezheva a, , V. N. Azev a, A. G. Kornienko a, A. S. Peregudov a, I. A. Godovikov a, Yu. L. Sebyakin b
⇑
a A. N. Nesmeyanov Institute of Organoelement compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russia
b M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, 86 Vernadskogo Str., 119571 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2010
Revised 17 September 2010
Accepted 8 October 2010
Available online 14 October 2010
We report on the novel properties of nitrones including their transformations via reactions with sodium
malonates to give functionalized stereodefined derivatives of tertiary 3-aminoindoles or anilines, as well
as fully-substituted dihydropyrroles. The outcome of the reactions is dependent mainly upon the nature
of the starting C-nitrone substituent and solvent used. The formation of a new carbon–nitrogen bond in
the obtained amines occurs via a nucleophilic 1,2-aryl/3-indolyl shift from C to the adjacent nitrogen.
Ó 2010 Elsevier Ltd. All rights reserved.
Among the wide variety of privileged indole scaffold structures,
the novel 3-aminoindole core only appeared recently. 3-Aminon-
dole derivatives, though not easily accessible, have nevertheless
emerged as promising agents with potential application in the de-
sign of drugs against a large number of diseases.1 3-Aminoindole-
based compounds are commonly prepared from the corresponding
3-substituted indoles,1a,b,2 indoxyls,1c,3 and non-indolic precur-
sors.1d–f,4 New, facile, and efficient syntheses of 3-amino-2-pheny-
lindoles were effected by direct cyclization of 2-(disubstituted
amino)benzonitriles in the presence of a base.5 Among other
base-catalyzed methods for the synthesis of 2-substituted 3-al-
kyl/arylaminoindoles, one can mention the interrupted Ugi reac-
tion.6 However, all these methods appear limited in both the
degree and type of functionality at the amino group and the indole
nucleus.
As a part of our continuing interest in the synthesis of bioactive
indole scaffolds, we have developed an efficient method for both
diversification of the 3-aminoindole structure by forming a new
carbon–nitrogen bond and the synthesis of their aromatic analogs.
In previous work, we reported the preparation of functionalized
tertiary 3-aminoindoles tethered to a methylidene malonate acid
fragment as mixtures of Z:E isomers (methylidene malonate series)
in benzene, from easily available indole-3-carbaldehyde based
nitrones and sodium malonate.7 An important application of these
3-aminoindole derivatives with a free position at C-2 was their
conversion into potential antituberculosis d-carbolines.8 A typical
feature of the former reaction is the 1,2-(3-indolyl) shift from
carbon to the nitrogen atom. However, the reported rearrangement
was not general for all nitrones and was relevant to a few
C-(3-indolyl)-N-aryl nitrones only. It is well known that nitrones
generally react with sodium malonates and other C-nucleophiles
affording hydroxylamines,9 3,4-disubstituted isoxazolidin-5-
ones,10 alkenes,11 and aziridines.12 The reaction of C,N-diaryl nitro-
nes with sodium malonates has not been investigated so far. In the
present work, we report that the reaction of other nitrones with
sodium malonates results in the formation of new products, some
of them possessing unexpected fully-substituted dihydropyrrole
structures as well as stereodefined derivatives of tertiary 3-amino-
indoles and anilines.
To further delineate the factors governing the chemoselectivity
of the reactions between nitrones and sodium malonate, we
investigated the reactions of C-(3-indolyl)-N-aryl and C,N-diaryl
nitrones 1a–g and 2a–k of various nucleophilicity. The reactions
of C-(3-indolyl)-N-phenyl and C,N-diphenyl nitrones 1a and 2a
with dimethyl sodium malonate 3a (R4 = Me) in refluxing non-
polar benzene or toluene afforded the corresponding acid from
the methylidene malonate series as a mixture of Z,E-isomers, but
in moderate yield, and as complex non-separable mixtures of com-
pounds. On the other hand, replacing benzene with alcoholic sol-
vents altered the reaction path. Direct conversion of C-(3-indolyl)
nitrone 1a into the sodium salt 4a (88%) was achieved in the
presence of a twofold excess of 3a after a short period of reflux
in methanol (Scheme 1). The 1H and 13C NMR spectra of 4a re-
vealed one set of signals, indicating that one geometric isomer
was obtained. The latter was characterized by 1D and 2D NMR
spectroscopic methods and mass spectrometry as the rearranged
tertiary 3-aminoindole derivative of Z-configuration. In the 1H
NMR spectrum the signal for the N–CH@ proton was observed as
a singlet at 7.81 ppm. The close spatial orientation of the indole
nucleus to the alkoxy ester protons in 4a (pointing to the Z-config-
uration of the double bond) was proved by NOESY experiments.
⇑
Corresponding author. Tel.: +7 499 135 9253; fax: +7 499 135 5085.
E-mail address: vel@ineos.ac.ru (V.S. Velezheva).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.045

V. S. Velezheva et al. / Tetrahedron Letters 51 (2010) 6594–6597
6595
R3
Ph
N
R3
MeOH
R4OH, 65 oC
R3
O
O-
O
º
Na+
N
23 C
Na+
CO2Me
(1a-f)
O
O
R2
2a)
N+
6
OR4
N+
O-
(
N
3
3
O
R3
H
O
4a-g (Z)
4
O
R
N
R2
1) PhH, 23 oC
2) H+
N
R1
R2
R1
2a-g
3, R4OH
OH
1a-g
CO2Me
MeO2C
R2
23 ºC
(2b-h)
N
O
O
(1g)
R4
R4
R1
3 =
O
O
-
7b-h (E)
N
Na+
Tos
3a R4 = Me, 3b R4 = Et
Scheme 2. The synthesis of ISOX salt 6 and diarylamine derivatives 7b–7h from
C,N-diarylnitrones 2b–2g and sodium malonates 3.
5
Scheme 1. The synthesis of 3-aminoindole derivatives 4 and dihydropyrrole 5 from
C-(3-indolyl)-N-aryl nitrones 1 and sodium malonates.
in exactly the same way as its C-aryl-N-methyl analogs under sim-
ilar conditions.10 The spectral characteristics of ISOX salt 6 corre-
spond to those of known similar ISOX salts.10
Besides, a signal due to a strongly shielded ester CH3O group in 4a
was observed upfield at 2.55 ppm, compared to ca. 3.5 ppm as is
commonly observed in methyl esters. Following the successful
preparation of salt 4a, the generality of this procedure was studied
using nitrones with substituents of various nucleophilicity on the
C-(3-indolyl) as well as the C- and N-aryl moieties.
Similarly, reactions of other N-aryl substituted indolyl nitrones
1b–f (even examples containing moderately electron-poor aryl
groups [R3 = F, CO2Et, CN] attached to the nitrogen atom of the nit-
rone functionality) and diethyl sodium malonate 3b took the same
course resulting in salts 4b–g as single isomers in 54–97% yields
(Scheme 1, Table 1). The 1H and 13C NMR spectra of salts 4b–g clo-
sely resembled the spectrum of 4a, thus, all the products have the
Z-configuration. Hence, we have shown that in alcohols the C-to-N
rearrangement occurs with high stereoselectivity to give (Z)-meth-
ylidene malonate salts 4.
Surprisingly, introduction of an electron-withdrawing tosyl
substituent on the indole nitrogen altered dramatically the course
of the reaction. An unexpected compound, dihydropyrrole 5, was
isolated in <10% yield when nitrone 1g was treated with sodium
malonate in methanol. Formally, the unrearranged dihydropyrrole
5 was formed from one and two equivalents of 1g and 3a, respec-
tively, with retention of the bonds of the nitrone functionality
(Scheme 1). In benzene at rt a threefold excess of 3a was required
to increase the yield of 5 to 41%. Compound 5 exhibited character-
istic chemical shifts of the N–CH groups in the 1H and 13C NMR
spectra (4.50 and 5.70 ppm and 58.0 and 70.5 ppm, respectively).
Next, at 23 °C in methanol, the reaction of C,N-diphenyl nitrone
2a with 3a gave highly unstable 5-isoxazolidinone salt 6 (ISOX) in
71% yield (Scheme 2). In this case C,N-diphenyl nitrone 2a behaved
However, nitrones 2b–g with electron-donating C-aryl groups
reacted with sodium malonate 3a with loss of CO2 to afford acry-
lates 7b–g as shown in Scheme 2. In particular, acrylate 7b was ob-
tained in 90% yield under the same conditions, but from virtually
equimolar amounts of starting nitrone 2b (R1 = 4-Me2N, R2 = H)
and 3a. The acrylate 7b was characterized by 1D and 2D NMR spec-
troscopic methods and mass spectrometry as the rearranged ter-
tiary aniline derivative of E-configuration. In the 1H NMR
spectrum the signals of the vinylic N–CH@CH protons were ob-
served as doublets at 8.07 and 4.55 ppm, 3Jtrans ca. 13 Hz. The signal
due to the methoxy group in the E-isomer of 7b occurred down-
field at 3.51 ppm, compared to the Z-isomer of salt 4a. Acrylates
7c–g were obtained in good to high yields under similar mild con-
ditions from nitrones 2c–g with C-electron-donating aromatic
groups only (and various N-aromatic groups, Scheme 2, Table 2).
Similar reaction was then carried out using diethyl sodium malon-
ate 3b in refluxing ethanol to give the corresponding acrylate 7h.
We also discovered that no C-to-N rearrangement occurred in
the reactions of C-aryl nitrones 2a,i–k (R1 = H, Cl, F) in methanol
when the C-aryl group does not contain highly electron-donating
substituents. Dihydropyrroles 8a,i–k, aromatic analogs of the dihy-
dropyrrole 5, were obtained in trace amounts instead of the rear-
ranged products. However, the yields of compounds 8a,i–k were
improved to 30–62% by running the reaction in the presence of a
threefold excess of 3a and with an increased concentration of the
latter (Scheme 3). The best solvent for this multistep reaction
was benzene. Further optimization of the reaction conditions is
in progress. The aliphatic part of the 1H and 13C NMR spectra of
dihydropyrroles 8 closely resemble the spectra of 5. All the other
Table 1
Table 2
Reaction of C-(3-indolyl)-N-aryl nitrones 1a–f with sodium malonates in MeOH and
The reaction of C,N-diarylnitrones 2b–g with sodium malonates in MeOH and EtOHa
EtOHa
Substrate
R1
R2
R3
Productb
Yieldc (%)
Substrateb
R3
Productc
Yieldd (%)
2b
2c
2d
2e
2f
Me2N
Me2N
Me2N
OMe
OH
H
H
H
H
OMe
OMe
H
H
7b
7c
7d
7e
7f
90d
83
80
56
55e
64
82
1a
1a0
1b
1c
1d
1e
1f
H
H
4a
4a0
4b
4c
4d
4e
4f
88
90
87
54
97e
77
78
Br
Me
H
H
H
CO2Et
CN
F
Me
Me
2g
2b
OEt
Me2N
7g
7h
H
a
b
c
Conditions: nitrone (1 mmol), sodium malonate (1.1 equiv), 23 °C, 1.5–3 h.
R4 = Me (7b–g), R4 = Et (7h).
Isolated yield.
a
b
c
Conditions: nitrone (1 mmol), sodium malonate (2 equiv), 2–3 h.
R1 = H (1a–f, 4a–f), R2 = H (1a–1d, 1f, 4a–d, 4f), R2 = F (1e, 4e).
R4 = Me (4a); R4 = Et (4a0–4f).
d
1.5 equiv of methyl sodium malonate were used. Under standard conditions,
d
e
Isolated yield.
the yield was 86% after 8 h.
5% impure by 1H NMR.
Low conversion obtained.
e

6596
V. S. Velezheva et al. / Tetrahedron Letters 51 (2010) 6594–6597
R2
bly, the presence of an N-aryl substituent, compared to an N-
methyl, facilitates cleavage of the relatively weak N–O bond in
the ISOX salt to form N-aryl stabilized zwitterions, such as 10
(Scheme 4). A similar N-substitutent effect on N–O bond cleavage
rates in isoxazolines was observed in the Brandi reaction.15 Hetero-
lytic N–O bond cleavage under mild conditions giving arylnitreni-
um ions with electron-withdrawing groups has been previously
reported.16
Scheme 4 outlines a probable reaction route for the formation of
decarboxylated (E)-N,N-diaryl-substituted enaminoester 7b from
nitrone 2b in polar methanol. It is likely that intermediate ISOX 9
undergoes a secondary reaction generating the open zwitterion
10. The loss of CO2 from 10 assists the aryl shift from the carbon
to the adjacent nitrogen to furnish 7b in a thermodynamically dri-
ven manner. The proton loss from ISOX 9 would lead to the forma-
OH
N
CO2Me
R2
MeO2C
R1
N+
Δ
1) 3a, PhH,
2) H+
O
30-62%
R1
2a,i-k
8a,i-k
2a, 8a (R1 = R2 = H), 2i, 8b (R1 = H, R2 = Me),
2j, 8c (R1 = Cl, R2 = H), 2k, 8d (R1 = F, R2 = H)
Scheme 3. The preparation of 2,5-dihydropyrroles from C,N-diarylnitrones 8a,i–k.
signals in the prepared compounds were in agreement with the as-
signed structures. Finally, dihydropyrrole 8a was oxidized into the
corresponding pyrrole and the structure of the latter was con-
firmed employing X-ray analysis.13
tion of
a non-decarboxylated product of type 4. A similar
isoxazolone rearrangement, under thermal conditions, was ob-
served by Wentrup et al.17 to involve cleavage of the N–O bond fol-
lowed by loss of CO2 and 1,2-migration of the phenyl group in the
putative vinylnitrene.
In conclusion, highly functionalised tertiary 3-aminoindoles/
anilines have been synthesized simply and stereoselectively from
readily available nitrones and sodium malonates in high yields.18,19
This stereoselective transformation is highly useful for further
elaboration of stereodefined 3-aminoindole derivatives and a di-
rect synthesis of functionalized d-carbolines. Although the yields
of the fully-substituted dihydropyrroles obtained are moder-
ate,20,21 it should be noted that the products can be used as novel
scaffolds in the search for pharmacologically interesting pyrroles.
These results revealed that the outcome of the reactions is
dependent mainly upon the nature of the C-nitrone substituent,
and to a certain extent, upon the nature of the solvent used. A
new carbon–nitrogen bond is formed during the preparation of
the corresponding tertiary amine derivatives as (E)-acrylates and
(Z)-methylidene malonates from C-aryl and C-(3-indolyl) nitrones.
The reactions occur in a stereoselective fashion but with different
chemoselectivity. Thus, migration is favored for C-aryl/3-indolyl
groups bearing electron-donating substituents, and this can be
used to enable migration to a nitrogen cationic center as it occurs,
for example, for the Stieglitz rearrangement of tritylamines.14 It is
evident that the formation of a new carbon–nitrogen bond in the
obtained amines occurs via a nucleophilic 1,2-(3-indolyl)/aryl shift
from C to the adjacent nitrogen.
References and notes
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Further evidence for the rearrangement was obtained from a
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ysis of the 1H and 19F NMR and mass spectra of the reaction mix-
ture. The fact that no cross-over products were observed
indicated the intramolecular character of the rearrangement step.
The mechanism of these multistep reactions presumably in-
volves initial formation of 3,4-disubstituted 5-isoxazolidinones,
such as 9 (Scheme 4) and their salts similar to ISOX salt 6. The lat-
ter can serve as key intermediates in the reactions depicted in
Schemes 1–3. This is in line with the fact that the known reactions
of the C-aryl-N-methyl10 and C,N-diphenyl nitrone 2a and sodium
malonates result in the formation of substituted ISOX salts via a
tandem Michael-type addition–intramolecular cyclization. Proba-
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N
3a
N+
O
N
O
MeO2C
O
N
2b
9
9. (a) Grigor’ev, I. A. In Feuer, G., Ed.; Nitrile Oxides, Nitrones, and Nitronates in
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13. Starikova, Z. A.; Velezheva, V. S. Unpublished results.
O
+
OMe
N
N
N
O
- CO2
MeO2C
O
N
7b
10
14. Hoffman, R. V.; Poelker, D. J. J. Org. Chem. 1979, 44, 2364–2369.
Scheme 4. The proposed pathway for the formation of acrylate 7b.

V. S. Velezheva et al. / Tetrahedron Letters 51 (2010) 6594–6597
6597
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J = 13.24 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): 168.5, 147.7, 147.5, 135.2,
130.1, 124.9, 121.3, 118.8, 113.9, 110.5, 93.0, 64.3, 56.1, 50.9, 15.2. mmax(KBr)/
cmꢀ1: 2985, 1692, 1622, 1247. Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N,
4.28. Found: C, 69.57; H, 6.49; N, 4.44.
16. Gassman, P. G.; Granrud, J. E. J. Am. Chem. Soc. 1984, 106, 1498–1499.
17. (a) Wentrup, C.; Falloon, B.; Moloney, D. W. J.; Bibas, H.; Wong, M. W. Pure Appl.
Chem. 1996, 68, 891–894; (b) Kappe, C. O.; Kvaskoff, D.; Moloney, D. W. G.;
Flamming, R.; Wentrup, C. J. Org. Chem. 2001, 66, 1827–1831.
20. Synthesis of dimethyl 3-hydroxy-5-{1-[(4-methylphenyl) sulfonyl]-1H-indol-3-yl}-
1-phenyl-2,5-dihydro-1H-pyrrole-2,4-dicarboxylate 5: benzene (2.5 mL) was
added to NaOMe powder (0.113 g, 2.1 mmol), followed by methyl malonate
(0.24 mL, 2.1 mmol) and the resulting mixture was stirred for 30 min at rt. C-
{1-[(4-Methylphenyl)sulfonyl]-1H-indol-3-yl}-N-phenylnitrone (1g) (0.25 g,
0.7 mmol) was added in one portion and the reaction mixture was stirred for
4 h at rt. TLC analysis (10:1 v/v CHCl3/AcMe) indicated complete consumption
of the starting nitrone. The precipitated product was filtered. C6H6 was
evaporated and Et2O (5 mL) was added to the residue. The precipitate was
filtered and the combined precipitates were washed repeatedly with boiling
iPrOH and then with boiling EtOH. The obtained solid was stirred with 5%
aqueous phosphoric acid and the precipitate was filtered and washed with
H2O. White solid, mp 150–152 °C. (0.155 g, 40%). For the major isomer: 1H
NMR (300 MHz, DMSO-d6): 2.29 (s, 3H), 3.22 (s, 3H), 3.84 (s, 3H), 4.5 (s, 1H),
18. General procedure for the synthesis of sodium (2Z)-3-[(1H-indol-3-
yl)(aryl)amino]-2-(alkoxycarbonyl)acrylates 4a–g. Alkyl malonate (2 mmol)
was added to a freshly prepared sodium alkoxide solution [from 0.048 g
(2 mmol) of Na and 7 mL of the corresponding anhydrous alcohol] and the
mixture was stirred for 5 min at rt. C-[1H-(Indol-3-yl)]-N-aryl nitrone 1a–f
(1 mmol) was added in one portion and the reaction mixture was heated at
65 °C for 2 h. TLC analysis (1:1 v/v CHCl3/AcMe) indicated complete
consumption of the starting nitrone. The solvent was evaporated and Et2O
(10 mL) was added to the oily residue. The precipitate formed was filtered and
recrystallized from aqueous EtOH. Data for sodium (2Z)-3-[N-(1H-indol-3-
yl)(phenyl)amino]-2-(methoxycarbonyl)acrylate (4a): mp 197–200 °C. 1H NMR
(600 MHz, DMSO-d6): 2.54 (s, 3H), 6.86–6.93 (m, 3H), 6.93–6.99 (m, 2H), 7.07
5.l7 (s, 1H), 6.26 (d, J = 8 Hz, 2H), 6.6 (wt, J = 7.9 Hz, 1H), 7.02 (wt, J = 7.9 Hz,
2H), 7.14 (d, J = 7.8 Hz, 2H), 7.25–7.35 (m, 2H), 7.5 (d, J = 7.8 Hz, 2H), 7.8–7.9
(m, 1H), 7.95–8.1 (m, 1H), 8.21 (s, 1H); 13C NMR (75 MHz, DMSO-d6): 174.5,
171.2, 147.2, 146.8, 146.1, 135.7, 134.7, 132.4, 131.0, 129.8, 126.3, 123.1, 122.7,
(wt, J = 7.55 Hz, 1H, IndH-6) (wt is pseudotriplet), 7.20–7.27 (m, 3H), 7.39 (d,
J = 8.24 Hz, 1H, IndH-7), 7.8 (s, 1H), 11.36 (br s, 1H, IndH-1); 13C NMR
(125 MHz, DMSO-d6): 169.37, 168.73, 142.28, 139.67, 135.34, 129.43, 124.13,
124.00, 122.35, 122.22, 121.81, 119.47, 118.57, 118.47, 118.31, 117.54, 112.73,
120.8, 115.3, 112.4, 111.7, 110.1, 90.7, 70.5, 58.0, 55.6, 51.2, 24.6. mmax(KBr)/
cmꢀ1: 1740, 1662; ESI MS: [M+H]+: 547.1536, calcd 547.1533 for C29H27N2O7S.
Anal. Calcd for C29H26N2O7SꢁH2O: C, 61.69; H, 5.00; N, 4.96. Found: C, 61.24; H,
4.67; N, 4.92.
112.27, 49.79.
m :
max(KBr)/cmꢀ1 3383, 1694, 1677, 1614; ESI MS: [M+H]+:
359.1012, calcd 359.1008 for C19H16N2NaO4.
19. General procedure for the synthesis of alkyl (2E)-3-(diarylamino)acrylates 7b–h:
alkyl malonate (1.15 mmol) was added to a freshly prepared sodium alkoxide
solution [from 0.025 g (1.1 mmol) of Na and 3 mL of the corresponding
anhydrous alcohol] and the mixture was stirred for 5 min at rt. C-Aryl-N-aryl
nitrone 2 (0.271 g, 1 mmol) was added in one portion and the reaction mixture
was stirred for the indicated time at rt. TLC analysis (10:1 v/v CHCl3/AcMe)
indicated complete consumption of the starting nitrone. The reaction mixture
was cooled to 0 °C and cold H2O (3 mL) was slowly added. The precipitate
formed was filtered and washed with a mixture of CH3OH and H2O (1:1 v/v).
Data for methyl (2E)-3-[(4-ethoxy-3-methoxyphenyl)(phenyl) amino]acrylate
(7g): mp 121–122 °C. (0.21 g, 64%). 1H NMR (300 MHz, DMSO-d6): 1.33 (t,
J = 6.8 Hz, 3H), 3.55 (s, 3H), 3.71 (s, 3H), 4.04 (q, J = 6.97 Hz, 2H), 4.54 (d,
J = 12.89 Hz, 1H), 6.71 (dd, J = 2.44, 8.71 Hz, 1H), 6.8 (d, J = 2.44 Hz, 1H), 7.0–
21. Synthesis of dimethyl 3-hydroxy-1,5-diphenyl-2,5-dihydro-1H-pyrrole-2,4-
dicarboxylate 8a: benzene (3.4 mL) was added to NaOMe powder (0.384 g,
7.11 mmol), followed by methyl malonate (0.81 mL, 7.11 mmol) and the
mixture was stirred for 30 min at rt. C,N-Diphenylnitrone 2a (0.466 g,
2.37 mmol) was added in one portion and the reaction was refluxed for 0.5 h
at rt. TLC analysis (10:1 v/v CHCl3/AcMe) indicated complete consumption of
the starting nitrone. The reaction mixture was triturated with 15 mL of H2O
and the resulting precipitate was filtered and stirred with 0.25% aqueous HCl
for 3–4 min at 0 °C. The precipitate was filtered and washed with H2O until
neutral pH. White solid, mp 123–125 °C. (0.268 g, 32%). 1H NMR (300 MHz,
DMSO-d6): 3.4 (s, 3H), 3.81 (s, 3H), 4.56 (s, 1H), 5.31 (s, 1H), 6.31 (d, J = 8.2 Hz,
2H), 6.9–7.0 (m, 3H), 7.14–7.21 (m, 3H), 7.84 (d, J = 7.3 Hz, 2H). m
max(KBr)/cmꢀ1
3271, 1740, 1718, 1660. MS (EI) m/z: 353 [M+]. Anal. Calcd for C20H19NO5: C,
7.12 (m, 3H), 7.16 (
w
t, J = 7.32 Hz, 1H), 7.33 (
w
t, J = 7.84 Hz, 2H), 8.04 (d,
67.98; H, 5.42; N, 3.96. Found: C, 67.61; H, 5.60; N, 4.31.