5-chloro substituted 1,5-dihydro-2H-pyrrol-2-ones as intermediates for the efficient synthesis of 5-alkylamino, 5-azido, 5-alkoxyamino, and 5-alkoxy derivatives

Article abstract of DOI:10.1055/s-2001-9757

5-Hydroxy- 1,5-dihydro-2H-pyrrol-2-ones were converted to 5-chloro-1,5-dihydro-2H-pyrrol-2-ones 1a-d. These compounds are shown to be useful intermediates for the preparation of various 5-alkoxy, 5-alkylamino, 5-alkoxyamino, and 5-azido derivatives in high yields.

Full text of DOI:10.1055/s-2001-9757

PAPER
89
5-Chloro Substituted 1,5-Dihydro-2H-pyrrol-2-ones as Intermediates for the
Efficient Synthesis of 5-Alkylamino, 5-Azido, 5-Alkoxyamino, and 5-Alkoxy
Derivatives
Kirill V. Nikitin, Nonna P. Andryukhova*
Department of Chemistry, Moscow State University, 119899, Moscow, Russia
Fax +7(095)9328846; E-mail: newscientist@mtu-net.ru
Received 15 June 2000; revised 2 September
conditions for storage and handling. Their NMR, IR, and
Abstract: 5-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones were convert-
mass spectra fully confirm the monomeric molecular
structure of 1.
ed to 5-chloro-1,5-dihydro-2H-pyrrol-2-ones 1a-d. These com-
pounds are shown to be useful intermediates for the preparation of
various 5-alkoxy, 5-alkylamino, 5-alkoxyamino, and 5-azido deriv-
atives in high yields.
We studied the reactions of 1 with both oxygen and nitro-
gen nucleophilic reagents in order to obtain 5-alkoxy de-
rivatives 3, amines and alkoxyamines 4, as well as azides
Key words: pyrrolones, alkylations, heterocycles, azides
5 (Scheme). The use of nitrogen nucleophiles gives a fac-
ile route to the scarcely known 5-aminosubstituted 1,5-di-
hydro-2H-pyrrol-2-ones.
Substituted 1,5-dihydro-2H-pyrrol-2-ones are widely
used as herbicide components1 and as building blocks for
total syntheses of natural compounds.2 The preparation of
the 5-hydroxy,3 5-alkoxy,4 5-cyano,5 and 5-arylthio6 de-
rivatives of 1,5-dihydro-2H-pyrrol-2-ones is documented
but the use of 5-halo substituted 1,5-dihydro-2H-pyrrol-2-
ones 1 has rarely been employed,1,2 even though some of
these compounds (R2+R2 = fused benzene ring) are
promising7 intermediates to get 3-derivatives of the
3-alkylamino-2-alkyl-3-arylisoindolinone series (Figure).
Some a-chlorinated imides such as N-chlorometh-
ylphthalimide (2) have recently been studied8 in substitu-
tion reactions with several nucleophiles and good
reactivity and selectivity was shown.
O
R2
R2
N
R1
OMe
+PCl5
-POCl3
O
O
R2
R2
R2
+NaN3
+R3OH
-HCl
+R4R5NH
-HCl
N
R1
N R1
1a-d
-NaCl
R2
N3
OR3
3
5
O
R2
R2
O
O
R2
R2
N
R1
N R1
Cl
N
Cl
NR4R5
O
2
4
1
a R1 = Bn, R2+R2 = fused benzene ring
b R1 = Bn, R2 = Me
c R1 = But, R2 = Me
Scheme
d R1 = -CMe2-3,5-Cl2C6H3, R2 = Me
Though alkoxylation of 5-hydroxypyrrolones is rather
fast (using MeOH under acidic conditions) and has been
reported elsewhere,4 we found that some bulky alcohols
or less nucleophilic phenols do not react at all. We used
Figure
The preparation1,2,7 of 1 typically involved substitution of 5-chloropyrrolones 1 to introduce, in high yields, ethoxy,
the 5-hydroxy group using thionyl chloride. We used a tert-butoxy, and phenoxy groups at the 5-position. These
two-step procedure: firstly, methoxylation of 5-hydroxy- reactions were performed in acetonitrile as solvent in the
1,5-dihydro-2H-pyrrol-2-ones4 or 3-hydroxy-1-isoindoli- presence of Et3N as base under mild conditions (20 °C);
none (yields 95-100%) and, secondly PCl5 methoxy the yields and spectral data are reported in Tables 1 and 2.
group cleavage using n-hexane as solvent (yields 99- The substitution of chlorine by alkoxy group proceeds
100%). This method avoids formation of hydrogen chlo- quickly and one hour is sufficient for the reaction to be
ride.
complete (see experimental).
Compounds 1a-d are moisture sensitive, undergoing the The synthesis of 5-alkylaminopyrrolones 4 has not been
hydrolytic chlorine substitution, and require anhydrous reported previously, though 3-alkylaminoisoindolinones
Synthesis 2001, No. 1, 89–92 ISSN 0039-7881 © Thieme Stuttgart · New York

90
K. V. Nikitin, N. P. Andryukhova
PAPER
Table 1 Preparation of Compounds 3−5
Commercially available reagents and solvents were used without
further purification. Mps were measured with a Thomas-Hoover
capillary melting point apparatus and are uncorrected. H NMR
1
Product R1
R2
R3
R4 R5
Yield, %
spectra were recorded on a Varian GEMINI-200 using CDCl3 as
solvent. All chemical shifts (d) are quoted in ppm downfield from
TMS and coupling constants are given in Hz. Mass spectra were re-
corded on a Shimadzu GCMS-OP 1000 mass spectrometer. FT-IR
spectra were recorded on a Mattson Genesis II spectrophotometer.
Chromatographic separations were carried out on a silica gel col-
umn (Merck, 60 microns). Substituted 5-hydroxy and 5-methoxy-
2,5-dihydropyrrol-2-ones were prepared by known procedures.3,4
3a
3b
3c
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
DDB
DDB
DDB
DDB
DDB
DDB
DDB
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
t-Bu
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
94
84
78
88
84
60
69
80
74
73
73
79
Et Et
H
H
H
H
H
H
DDBa
Bn
BnO
ClCH2CH2
BnO
3-Chloro-1-isoindolinones and 5-chloro-1,5-dihydro-2H-pyr-
rol-2-ones 1; General Procedure
Ph
Et Et
To a suspension of substituted 5-methoxy-1,5-dihydro-2H-pyrrol-
2-one (10 mmol) in n-hexane (20 mL) was added phosphorus pen-
tachloride (2.09 g, 10 mmol) and the mixture heated under reflux for
2 h when PCl5 was completely dissolved. The mixture was evapo-
rated at reduced pressure (1 torr) to remove POCl3 and to afford 1
as a glassy solid.
H
H
H
H
H
–
3-FC6H4
3-Cl-4-FC6H3 80
Bn
DDB
BnO
–
61
84
77
78
77
b
4m
5a
5b
-
-
b
Bn
t-Bu
Me
–
–
2-Benzyl-3-chloro-2,3-dihydro-(1H)-isoindol-1-one (1a)
Yield: 100%.
FTIR (KBr): n = 1678 (C=O), 1439, 1065 cm-1
a 1-(3,5-Dichlorophenyl)-1-methylethyl.
b R2 + R2 = Benzene.
1H NMR (CDCl3): d = 4.27 (d, 1H, J = 14.7 Hz), 5.40 (d, 1H,
J = 14.7 Hz), 6.16 (s, 1H), 7.30 -7.40 (m, 5H), 7.50-7.60 (m, 3H),
7.90 (m, 1H).
were prepared7 recently. We applied a two-fold excess of
the reagent (alkylamine, arylamine, or O-benzylhydroxy-
lamine) in acetonitrile in order to absorb the acid, released
in the course of the substitution. A combination of the re-
agent with another base (Et3N) can also be used. The re-
activity of 1 in nucleophilic substitution is high enough
for the reaction to be completed during addition of the re-
agent. Generally, the yields are high to excellent (Table
1); the products 4c, 4d, 4k were obtained in good yields
with benzylamine and O-benzylhydroxylamine.
MS: m/z = 257 (M+).
1-Benzyl-5-chloro-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-one
(1b)
Yield: 98%.
FTIR (KBr): n = 1685 (C=O) cm-1.
1H NMR (CDCl3): d = 1.88 (s, 3H), 1.99 (s, 3H), 4.15 (d, 1H,
J = 14.8 Hz), 5.18 (d, 1H, J = 14.8 Hz), 5.45 (s, 1H), 7.30-7.40 (m,
5H).
MS: m/z = 235 (M+).
1
The H NMR chemical shift difference of the diaste-
1-tert-Butyl-5-chloro-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-
reotopic benzylic methylene protons provides reliable
determination7 of the position of the benzyl moiety in 4b-
e, k, m. In all cases, the position of the benzyl group cor-
responds to that of the initial 5-chloropyrrolone 1 used
and no isomeric products were found. Our findings are in
good accordance with the high substitution selectivity
found in acetonitrile.7
one (1c)
Yield: 98%.
FTIR (KBr): n = 1681 (C=O) cm-1.
1H NMR (CDCl3): d = 1.55 (s, 9H), 1.78 (s, 3H), 1.99 (s, 3H), 5.94
(s, 1H).
MS: m/z = 201 (M+).
5-Chloro-1-[1-(3,5-dichlorophenyl)-1-methylethyl]-3,4-dimeth-
yl-1,5-dihydro-2H-pyrrol-2-one (1d)
Yield: 100%.
FTIR (KBr): n = 1680 (C=O) cm-1.
1H NMR (CDCl3): d = 1.77 (s, 3H), 1.78 (s, 9H), 1.87 (s, 3H), 2.07
(s, 3H), 6.04 (s, 1H), 7.10-7.40 (m, 3H).
The preparation of azides 5 has not been reported to the
best of our knowledge. Starting from 5-chloropyrrolones
1 and sodium azide, azides 5a, b can be readily prepared
in dry acetonitrile at ambient temperature. The presence
of water or alcohols leads to the formation of 5-alkoxy and
5-hydroxypyrrolones, a faster reaction than that leading to
azide formation, and, therefore, must be avoided.
MS: m/z = 333 (M+, 37Cl).
In summary, 5-chloro substituted pyrrolones and 3-chlo-
ro-1-isoindolinones 1 can be easily prepared in excellent
yields and these compounds have been shown to be highly
reactive towards nucleophiles. They serve as key interme-
diates for the facile and convenient preparation of 5-alky-
lamino-, 5-alkoxyamino-, 5-alkoxy, and 5-azido-1,5-
dihydro-2H-pyrrol-2-ones and 1-isoindolinones 3-5 and
may be suitable for parallel syntheses.
1-Benzyl-5-alkoxy-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-ones
3a-c; General Procedure
To a solution of 1 (2.1 mmol) in dry MeCN (2 mL) under N2 at 0 °C,
the dry alcohol (2 mL) or phenol (2.2 mmol) was added followed by
the addition of Et3N (1 mL, 13 mmol), and the reaction mixture was
stirred for 1 h at r.t. The solvent was evaporated under reduced pres-
sure, H2O (10 mL) was added, and the mixture was extracted with
EtOAc (2 ¥ 10 mL). The combined organic layers were dried
(MgSO4), the solvent was evaporated under reduced pressure, and
the residue was purified by column chromatography (n-hexane/
EtOAc) to obtain 3. The characteristics of 3 are reported in Table 2.
Synthesis 2001, No. 1, 89–92 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
5-Chlor Substituted 1,5-Dihydro-2H-pyrrol-2-ones
91
Table 2 Characterization Data of Compounds 3-5
Product
(Formula)
Mp
IR (KBr)
1H NMR (200 MHz, CDCl3/TMS) d, J (Hz)
MS m/z (%)
245 (M+, 21)
(oC)a n (cm−1)
3a
–
1698
(CO)
1.11 (t, 3 H, J = 4), 1.81 (s, 3 H), 1.87 (s, 3 H), 3.00-3.20 (m, 2 H), 4.10
(d, 1 H, J = 15), 4.87 (d, 1 H, J = 15), 4.93 (s, 1 H), 7.20-7.28 (m, 5 H)
(C15H19NO2)
3b
68
––
–
1706
(CO)
1.86 (s, 3 H), 1.89 (s, 3 H), 4.10 (d, 1 H, J = 15), 5.07 (d, 1 H, J = 15), 5.53 294 (MH+, 10)
(s, 1 H), 6.80-7.30 (m, 10 H)
(C19H19NO2)
3c
1680
(CO)
1.23 (s, 9 H, t-Bu), 1.85 (s, 3 H), 1.93 (s, 3 H), 4.27 (d, 1 H, J = 16), 5.06
(d, 1 H, J = 16), 5.12 (s, 1 H), 7.10-7.30 (m, 5 H)
273 (M+, 18)
(C17H23NO2)
4a
1691
(CO)
0.92 (t, 6 H, J = 7.1), 1.82 (s, 6 H), 2.40-2.60 (m, 4H), 4.03 (d, 1 H, J = 15), 272 (M+, 14)
4.41 (s, 1 H), 5.06 (d, 1 H, J = 15), 7.00 (m, 2 H), 7.20-7.30 (m, 3 H)
(C17H24N2O)
4b
–
3317 (NH), 1.40 (s, 3 H), 1.44 (s, 3 H), 1.64 (s, 1 H), 1.70 (s, 3 H), 1.81 (s, 3 H), 4.06 402 (M+, 7).
(C22H24Cl2N2O
1681 (CO) (d, 1 H, J = 16), 4.56 (s, 1 H), 4.96 (d, 1 H, J = 16), 7.00-7.30 (m, 8 H)
4c
58
3345
(NH),
1666 (CO)
1.82 (s, 1 H), 1.87 (s, 6 H), 3.25 (d, 1 H, J = 14), 3.35 (d, 1 H, J = 14), 4.17 306 (M+, 30)
(d, 1 H, J = 15), 4.58 (s, 1 H), 4.97 (d, 1 H, J = 15), 7.10-7.30 (m, 10 H)
(C20H22N2O)
4d
–
3233
(NH),
1671 (CO)
1.84 (s, 6 H), 4.25 (d, 1 H, J = 15), 4.60 (s, 2 H), 4.44 (s, 1 H), 5.04 (d, 1 H, 322 (M+, 22)
J = 15), 5.55 (br s, 1 H), 7.10-7.30 (m, 10 H)
(C20H22N2O2)
4e
90
–
3332
(NH)
1655 (CO)
1.84 (s, 6 H), 2.10 (br s, 1 H), 2.40-2.60 (m, 2 H), 3.50 (t, 2 H, J = 5.6), 4.12 278 (M+, 28)
(d, 1 H, J = 15), 4.51 (s, 1 H), 5.00 (d, 1 H, J = 15), 7.20-7.40 (m, 5 H)
(C15H19ClN2O)
4f
3230
(NH),
1675 (CO)
1.73 (s, 9 H), 1.95 (s, 3 H), 4.57 (d, 1 H, J = 16), 4.63 (d, 1 H, J = 16), 4.85 418 (M+, 10)
(d, 1 H, J = 3), 5.53 (d, 1 H, J = 3), 7.10-7.30 (m, 8 H)
(C22H24Cl2N2O2)
4g
192
3244
(NH),
1.72 (s, 6 H), 1.76 (s, 3 H), 1.87 (s, 3 H), 3.60-3.80 (br s, 1 H), 5.45 (s, 1 H), 388 (M+, 12)
6.55 (d, 2 H, J = 7.7), 6.79 (t, 1 H, J = 7.4), 7.10 (m, 5 H)
(C21H22Cl2N2O)
1675 (CO)
4h
60
1682
(CO)
0.95-1.20 (m, 6 H), 1.68 (s, 3 H), 1.73 (s, 3 H), 1.80 (s, 3 H), 1.91 (s, 3 H), 368 (M+, 12)
2.10-2.50 (m, 2 H), 2.80-3.05 (m, 2 H), 4.80 (s, 1 H), 7.20 (s, 3 H)
(C19H26Cl2N2O)
4i
190
3244
(NH),
1677 (CO)
1.72 (s, 6 H), 1.76 (s, 3 H), 1.87 (s, 3 H), 3.82 (d, 1 H, J = 8.7), 5.40 (d, 1 H, 406 (M+, 9)
J = 8.7), 6.20-6.30 (m, 2 H), 6.40-6.60 (m, 1 H), 7.10-7.30 (m, 4 H)
(C21H21Cl2FN2O)
4j
206
110
182
–
3262
(NH),
1683 (CO) (m, 3 H)
1.72 (s, 6 H), 1.76 (s, 3 H), 1.85 (s, 3 H), 3.72 (d, 1 H, J = 8), 5.29 (d, 1 H, 442 (M+, 37Cl, 10)
J = 8), 6.20-6.40 (m, 1 H), 6.50 (m, 1 H), 6.90-7.00 (m, 1 H), 7.10-7.30
(C21H20Cl3FN2O)
4k
3344
(NH),
1676 (CO)
1.76 (s, 3 H), 1.78 (s, 3 H), 1.86 (s, 3 H), 1.94 (s, 3 H), 3.37 (d, 1 H, J = 13), 402 (M+, 12)
3.62 (d, 1 H, J = 13), 5.10 (s, 1 H), 7.20-7.40 (m, 8 H)
(C22H24Cl2N2O)
4l
3424
(NH),
1676 (CO)
1.43 (s, 3 H), 1.47 (s, 3 H), 1.64 (s, 3 H), 1.73 (s, 3 H), 1.80 (s, 3 H), 1.81 311 (M+-187, 43)
(s, 3 H), 5.04 (s, 1 H), 7.10-7.50 (m, 6 H).
(C24H26Cl4N2O)
4m
3232
(NH),
1698 (CO)
4.37 (d, 1 H, J = 14.9), 4.56 (s, 2 H), 5.18 (br s, 1 H), 5.24 (d, 1 H, J = 14.9), 344 (M+, 38)
5.72 (br s, 1 H), 7.10-7.30 (m, 10 H), 7.40-7.50 (m, 3 H), 7.80 (m, 1 H)
(C22H20N2O2)
5a
–
2102
(N3),
1710 (CO)
4.35 (d, 1 H, J = 15), 5.28 (d, 1 H, J = 15), 5.31 (1 H), 7.30-7.40 (m, 5 H), 222 (M+-42, 42)
7.40-7.50 (m, 3 H), 7.80-7.90 (m, 1 H)
(C15H12N4O)
5b
–
2102
(N3),
1.50 (s, 9 H), 1.80 (s, 3 H), 1.94 (s, 3 H), 4.77 (s, 1 H)
166 (M+-42, 40)
(C10H16N4O)
1696 (CO)
a Mp are not given for liquid and oily products.
Synthesis 2001, No. 1, 89–92 ISSN 0039-7881 © Thieme Stuttgart · New York

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K. V. Nikitin, N. P. Andryukhova
PAPER
5-Alkylamino-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-ones and
5-Benzyloxyamino-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-ones
4; General Procedure
References
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To a solution of 1 (2 mmol) in dry MeCN (2 mL) under N2 at 0 °C,
the amine or O-benzylhydroxylamine (4 mmol) was added. The re-
action mixture was stirred for 1 h at r.t. after which the solvent was
evaporated. H2O (10 mL) was then added, and the mixture was ex-
tracted with EtOAc (3 ¥ 10 mL). The combined organic layers were
dried (MgSO4), the solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography to obtain
4. The characteristics of 4 are reported in Table 2.
5-Azido-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-ones 5a, b;
General Procedure
Farina, F.; Martin, M.; Paredes, M. C.; Ortega, M. C.; Tito, A.
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A solution of 1 (1 mmol) in dry MeCN (3 mL) was added to sodium
azide (5 mmol) under N2. The reaction mixture was stirred for 2 h
at r.t., the solvent was evaporated under reduced pressure, H2O
(10 mL) was added, and the mixture was extracted with EtOAc
(2 ¥ 5 mL). The combined organic layers were dried (MgSO4), the
solvent was evaporated under reduced pressure, and the residue was
purified by column chromatography to obtain 5. The characteristics
of 5 are reported in Table 2.
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Article Identifier:
1437-210X,E;2001,0,01,0089,0092,ftx,en;Z05500SS.pdf
Synthesis 2001, No. 1, 89–92 ISSN 0039-7881 © Thieme Stuttgart · New York