Transformations of 2,2-dimethyl-2,4-dihydro-3H-pyrrol-3-on-1-oxide derivatives in the Vilsmeier-Haack reaction conditions

Article abstract of DOI:10.1016/j.tet.2008.07.070

Enhydroxylaminones-2,2-dimethyl-2,4-dihydro-3H-pyrrol-3-on-1-oxides were shown to give various chlorinated products in the Vilsmeier-Haack reaction. The general sequence of the reaction steps is determined and the extent of the reaction was shown to be st

Full text of DOI:10.1016/j.tet.2008.07.070

Tetrahedron 64 (2008) 9191–9196
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Transformations of 2,2-dimethyl-2,4-dihydro-3H-pyrrol-3-on-1-oxide
derivatives in the Vilsmeier–Haack reaction conditions
,
b
,
b
b
b
a,b
Christina Becker a , Galina Roshchupkina , Tatyana Rybalova , Yuri Gatilov , Vladimir Reznikov
*
a Novosibirsk State University, Pirogova Street 2, 630090 Novosibirsk, Russian Federation
b N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, akad. Lavrent’eva ave. 9, 630090 Novosibirsk, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Enhydroxylaminonesd2,2-dimethyl-2,4-dihydro-3H-pyrrol-3-on-1-oxides were shown to give various
chlorinated products in the Vilsmeier–Haack reaction. The general sequence of the reaction steps is
determined and the extent of the reaction was shown to be strongly dependent on the substrate
structure.
Received 30 June 2008
Accepted 17 July 2008
Available online 23 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
Rearrangement
1-Hydroxy-1,2-dihydro-3H-pyrrol-3-one
Vilsmeier–Haack reaction
1. Introduction
2. Results and discussion
b
-Oxonitrones (enhydroxylaminones), in contrast to
b
-dike-
Pyrrolin-3-on-1-oxide derivatives 1 undergo a series of suc-
cessive transformations in the reaction with the Vilsmeier reagent,
which lead primarily to the 4-chloro-substituted enaminones 2 and
then to the dichloro-substituted 2H-pyrrole derivatives 3. The re-
action of 5-methyl-substituted pyrrolin-oxide 1c proceeds further
to give enamide 4; increasing the amount of the Vilsmeier reagent
results in the formation of enaminoimine 5 as a main product and
enaminoaldehyde 6das a by-product (Scheme 1).
The fact that enaminones 2 are the intermediates in the for-
mation of dichloroderivatives 3 is confirmed by the reaction of
2a with the Vilsmeier reagent, producing the corresponding
dichloroderivative 3a in a good yield.
The reaction progress of 1 depends on the character of the
substituent at the fifth position of the pyrroline cycle. Thus, in the
case of phenyl- and trifluoromethyl-substituted derivatives 1a,b,
the reaction could be stopped at the formation of enaminones 2,
while in the case of tert-butyl-substituted pyrroline 1d, the only
isolated product was dichloro-substituted compound 3d. The
corresponding enaminone 2d was not obtained (Scheme 1).
Pyrroline 1c transforms into enamide 4 under Vilsmeier–Haack
reaction conditions, which exists in solution as an equilibrium
mixture of two conformers (Scheme 2). 1H NMR spectrum in
DMSO-d6 (30 ꢀC) reveals the signals of methylene protons of con-
former A at 5.84 and 4.80 ppm and of conformer B at 5.11 and
4.55 ppm; the signals of the aldehyde proton are at 8.94 and
8.79 ppm for A and B, respectively (molar ratio of conformers: A/
B¼1.2:1). An exchange between the protons at 5.84 and 5.11 ppm,
tones and their nitrogen analogues– -ketoimines or enaminones
b
(in general, this tautomeric form is predominant), are on in-
sufficiently explored class of organic compounds. There are a few
reports concerning enhydroxylaminones where their reactions
with some nucleophilic and electrophilic reagents were described.
An electrophilic attack in these compounds is usually directed to
the enamine carbon or oxygen of the hydroxyl group.1 The behavior
of enhydroxylaminones in the Vilsmeier–Haack reaction has not
been previously studied. The derivatives of the isoxazolin-5-one
that could be considered as topological endo-cyclic analogues of
enhydroxylaminones are the most studied objects, and even for
these compounds some of the reactions with electrophiles are
ambiguous, and are the matter of a discussion among researchers. It
was shown, in particular, that the direction of the reaction of iso-
xazoline-5-ones with the Vilsmeier reagent,2–6 and the composi-
tion of the products depends noticeably on the structure of the
substrate and on the reagents ratio. In contrast to the isoxazolin-
5-one derivatives, the enhydroxylaminones derived from 2,2-di-
methyl-2,4-dihydro-3H-pyrrol-3-on-1-oxide possesses an hydroxyl
groupdone more potential reaction center. In the present work,
the behavior of these enhydroxylaminones in the Vilsmeier–
Haack reaction has been studied.
* Corresponding author. Tel.: þ7 383 3307 387; fax: þ7 383 3309 752.
E-mail address: bchs@nioch.nsc.ru (C. Becker).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.070

9192
C. Becker et al. / Tetrahedron 64 (2008) 9191–9196
POCl3
further electrophilic attack of the Vilsmeier reagent at nitrogen
OPOCl2
Cl
E
DMF
Cl
N
atom accompanied by the removal of a proton from methyl
group gives an intermediate 7. Its further hydrolysis affords the
N-formylsubstituted product 4 (cf. Ref. 7) (Scheme 1).
The alternative route of the transformation of compounds 1 to
2 could be an electrophilic attack of the Vilsmeier reagent on the
oxygen atom of N-hydoxylamino group followed by chloride ion
attack on the carbon atom at the position 4 of heterocycle and
simultaneous removal of a good leaving group from nitrogen
atom to form product 2 (Scheme 3). An indirect argument against
this way is the fact that the reaction of N-benzoyloxy-substituted
O
R
OH
R
R
OE
N
O
N
O
N
E
H
OE
Cl
E
Cl
O
E
1
E
R
R
R
NH
NH
N
E
Cl
Cl
Cl
Cl
HOE
OE
Cl
O
O
2
compounds
8 either with ammonium chloride or with tri-
N
O
N
ethylbenzylammonium chloride in DMF yielding compounds 2
does occur, but proceeds very slowly (several weeks at room
temperature).
R
N
N
OH
H2O
E
Cl
Cl
Cl
HOPOCl2
(R = CH3)
Cl
3
Cl
Cl
4
7
O
O
E
R
R
O
O
Ph
N
N
Ph
N
N
OPOCl2
Cl
N
N
N
2
N
N
H
Cl
OBz
N
N
O
O
8
O
OH
Cl
Cl
HOPOCl2
Cl
Scheme 3.
Cl
Cl
Cl
Of note is that the reaction of exo-cyclic enhydroxylaminone 9
with the Vilsmeier reagent proceeds in the same manner and leads
to chloro-substituted compound 10 (Scheme 4). In other words,
such a behavior in the Vilsmeier–Haack reaction seems to be quite
general for enhydroxylaminones, at least at the first stages of the
process.
DMF
H
1: R = Ph (a), CF3 (b), Me (c), t-Bu (d)
2: R = Ph (a), CF3 (b)
3: R = Ph (a), t-Bu (d)
N
O
NH
N
Cl
Cl
Cl
6
Cl
5
Scheme 1.
O
O
N
POCl3
DMF
OH
1.
2.
OH
Cl
4.80 and 4.55 ppm, 8.94 and 8.79 ppm were observed when the
temperature was increased to 80 ꢀC. Decreasing the temperature
back to 30 ꢀC restores the initial spectrum.
NH
N
N
9
10
Scheme 4.
H
H
H
O
a
a
O
H
H
H
b
b
One could suppose that the Vilsmeier–Haack reaction with
pyrrolines 1 proceeds in this way due to the possibility of electro-
philic attack of the Vilsmeier reagent at the oxygen atom of the
hydroxylamino group. In order to suppress this route, N-benzoy-
loxy-substituted pyrroline derivatives 8 were involved into the
reaction. Compounds 8 were synthesized by the acylation of
compounds 1 with benzoyl chloride.1
N
N
Cl
Cl
Cl
A
Cl
B
4
Scheme 2.
It was found that the reaction of pyrrolines 8a,d with the
Vilsmeier reagent leads to the formation of 4-benzoyloxy-
substituted 2H-pyrrole derivatives 11a,d, dichloro-substituted de-
rivatives 3a,d, and iminoketones 12a,d, respectively (Scheme 5).
The structure of compound 11a was proved by X-ray diffraction
analysis (Fig. 1).
The reaction of 1c with a larger excess of POCl3 (see details in
Section 4) gives enaminoimine 5 along with enaminoaldehyde 6.
Enaminoimine 5 was probably formed as the result of the elec-
trophilic attack of one more equivalent of the Vilsmeier reagent at
the methylene group in intermediate 7 (Scheme 1). Similar trans-
formations were observed earlier for the Vilsmeier–Haack reaction
of 3-oxyl-2,2,4,4-tetramethyl-5-methyleneimidazolidine-1-carbal-
dehyde derivatives.7
The probable scheme of the transformation of pyrrolines 1 into
the products 2–4 includes initial nucleophilic attack of the chloride
ion at the carbon of the carbonyl group facilitated by electrophilic
catalysis by the Vilsmeier reagent. Further migration of the chlo-
rine atom to position 4 of the heterocycle (intra- or inter-
molecular) accompanied by the removal of a good leaving group
gives rise to enaminone 2. At the next step, a nucleophilic attack of
the chloride ion at the carbonyl carbon occurs for the second time,
and subsequent elimination leads to the dichloro-substituted
compound 3. In the case of the methyl-substituted pyrroline,
E
[2]
3
PhCOO
O
O
N
Ph
R
R
R
N
N
POCl3
DMF
OH H O
/
PhCOO
2
8
O
O
HOE
O
O
13
E
Cl
12
Cl
Cl
Ph
11
(a),
R = Ph
t-Bu(d)
Scheme 5.

C. Becker et al. / Tetrahedron 64 (2008) 9191–9196
9193
conjugated electron-withdrawing carbonyl group hampers this
process.
Thus, in the course of the Vilsmeier–Haack reaction, the acyloxy
group is removed from the nitrogen atom and migrates to the po-
sition 4 of heterocycle; the migration can proceed intermolecularly.
Taking into account lower stability of the alkoxide anion in
comparison to the acetate anion, the preservation of N-alkoxy
group in N-alkoxyenaminone molecules 16 and 17 in the course of
the Vilsmeier–Haack reaction could be expected. In fact, the re-
action of compound 16, derived according to Scheme 7, with the
Vilsmeier reagent resulted in the formation of 12a along with
dichloro-substituted 2H-pyrrole 3a and benzyl chloride. The for-
mation of benzyl chloride probably occurs as a result of SN2-type
substitution with simultaneous formation of pyrroline 1a, which
can react further, as described above, to give dichloroderivative 3a
(Scheme 1). The formation of ketone 12a seems to be a result of the
sequence of transformations similar to those described above
(Schemes 1 and 5) including the migration of benzyloxy group to
the position 4 of heterocycle and hydrolysis of the migration
productdthe vinyl ether (Scheme 8).
Figure 1. X-ray structure of 11a.
The formation of these products is in line with the reaction
scheme proposed above (Scheme 1). The first step of the trans-
formation seems to be the formation of intermediate 13. Then, ei-
ther migration of chlorine atom with simultaneous removal of
benzoyloxy group finally gives compound 3, or migration of ben-
zoyloxy group leading to ester 11 occurs. Hydrolysis of the latter
gives product 12 on treatment of the reaction mixture. Isolation of
individual compound 12 failed because it is chromatographically
inseparable from compound 3, but according to 1H, 13C NMR, and
GC–MS data for the mixture of these products, compound 12 has
the suggested structure.
Ph
OBn
N
Ph
O
1. NaH
DMF
2. BnCl
O
N
N
1. LDA
2.RCO2Et
CH3OH
H3O+
16
NH
N
N
N
Ph
OBn
OBn
OH
N
OBn
NH
A similar rearrangement was observed earlier while studying
the acylation reaction of nitrones bearing at least one hydrogen
19
Scheme 7.
atom at the b
-carbon of the nitrone group.8–12 The authors con-
cluded that the rearrangement proceeds intramolecularly either as
a sigmatropic shift (like Hetero-Oxy-Cope rearrangement) or via
the ion-pair mechanism. The possibility of intermolecular rear-
rangement either was rejected on the base of kinetic study or
wasn’t considered at all. The realization of a cyclic planar transition
state in the case of the intermediate 13 is impossible, which makes
the probability of the rearrangement as a concerted process
doubtful. The Vilsmeier–Haack reaction with an equimolar mixture
of compounds 8a and 14d gives products 15a and 11d, as follows
from GC–MS data. Obviously, these products can be formed ex-
clusively as the result of intermolecular rearrangement (Scheme 6,
the molar ratio of products is given in parentheses).
R
Ph
O
O
N
Ph
Ph
1. POCl3
DMF
Ph
N
N
3a
O
2. OH
H2O
Cl
OE
Cl
O
Ph
(R = CH2Ph)
16, 17
POCl3
OH
H2O
DMF
12a
(R = CH3)
16 (R = CH2Ph),
17 (R = CH3)
Ph
O
N
OH
H2O
3a
Cl
OE
Ph
Ph
Ph
O
N
N
O
Scheme 8.
Ph
O
O
N
12a
3a
O
O
Cl
11a
O
O
Cl
15a
The reaction of N-methoxy-substituted compound 17 with the
Vilsmeier reagent also leads to the formation of dichloro-
substituted compound 3a. Considerable amounts of the starting
substrate were isolated along with 3a, although the former has
been completely consumed according to the TLC data of the
reaction mixture (Scheme 8).
Trifluoromethyl-substituted derivative 8b reacts differently to
the other N-benzoyloxy-analogues. The N-substituent is retained
and the main product of the reaction is compound 18 along with
some amount (w35%) of the starting material, although it was not
detected in the reaction mixture by TLC before its treatment. The
probable scheme of the reaction includes the intermediate for-
mation of 13b and its further transformation either into 18, or
into initial compound 8b on treating the reaction mixture
(Scheme 9).
(3.6)
(4.2)
Ph
POCl3
DMF
(10.1)
N
O
(3.6)
8a
t-Bu
t-Bu
O
N
O
t-Bu
12d
O
O
3d
N
(10.1)
(11.5)
Cl
Cl
15d
11d
O
14d
(1.0)
(1.8)
Scheme 6.
The migration of benzoyloxy group in compound 8 does not
proceed even at heating up to 100 ꢀC. This suggests that nitrogen–
oxygen bond cleavage proceeds by heterolytic mechanism and

9194
C. Becker et al. / Tetrahedron 64 (2008) 9191–9196
4.2.2. 1-(Benzoyloxy)-5-tert-butyl-2,2-dimethyl-1,2-dihydro-
3H-pyrrol-3-one 8d
O
O
Ph
OH
Ph
OH
N
Ph
F3C
O
Compound 8d was synthesized by the method above, but the
reaction time was 4 h. The precipitate of 8d was filtered off, washed
with 2 mL of cold water, dried, and purified by preparative TLC on
silica gel (CHCl3/CH3OH (40:1)), yield: 0.13 g (41%). Mp 117–118.5 ꢀC
(hexane). Rf (3% MeOH/CHCl3) 0.73. [Found C 71.23, H 7.41, N 4.88.
O
F3C
F3C
POCl3
DMF
O
O
N
N
OH
H2O
[13b]
H2O
O
Cl
O
8b
Cl
18
C
17H21NO3 requires: C 71.08, H 7.32, N 4.88%.] dH (200 MHz, CDCl3)
Scheme 9.
1.28 (9H, s, C–(CH3)3), 1.29 (3H, s), 1.35 (3H, s, C2–(CH3)2), 5.46 (1H,
s, C4H), 7.4–7.7 (3H, m), 8.0–8.1 (2H, m, Ph). dC (100 MHz, CDCl3)
23.9, 27.3 (C2–(CH3)2), 28.7 (C–(CH3)3), 34.4 (C–(CH3)3), 73.7 (C2),
104.9 (C4H), 127.3 (i-Ph), 128.9, 129.7 (o,m-Ph), 134.0 (p-Ph), 164.2
(C5), 186.7 (O–C]O), 202.1 (C3]O). nmax (KBr) 1751 (O–C]O), 1702
3. Conclusion
It was shown that the Vilsmeier–Haack reaction with enhy-
droxylaminonesdthe derivatives of 2,2-dimethyl-2,4-dihydro-3H-
pyrrol-3-on-1-oxidedproceeds via the loss of N-substituent and
leads to the chloro-substituted enaminones and then to the
dichloro-substituted 2H-pyrrole derivatives. 4-Formyl-substituted
products are not formed in all cases. The rearrangement of
N-benzoyloxy-derivatives was observed and it was shown to
proceed intermolecularly.
(C]O), 1649, 1565 (C]C) cmꢂ1. UV (ethanol): lmax (lg
(4.11), 283 nm (3.92).
3)¼232
4.2.3. 1-(Acetyloxy)-5-tert-butyl-2,2-dimethyl-1,2-dihydro-
3H-pyrrol-3-one 14d
A solution of pyrroline 1d (0.3 g, 1.64 mmol) and acetic anhy-
dride (0.16 mL, 1.64 mmol) in CHCl3 (3 mL) was kept for 5 days at
room temperature then washed with aqueous solution of Na2CO3
(3 mL), dried (MgSO4), and evaporated. Compound 14d was iso-
lated by silica gel column chromatography (CHCl3). Yield: 0.22 g
(82%), mp 79–81 ꢀC (lit.1 mp 78–80 ꢀC). Rf (CHCl3) 0.42.
4. Experimental
4.1. General
4.2.4. 1-(Benzyloxy)-2,2-dimethyl-5-phenyl-1,2-dihydro-
IR spectra were recorded with Bruker IFS 66 spectrometer as KBr
pellets (concentration 0.25%, thickness of a pellet 1 mm) or as so-
lutions in CCl4 (concentration 2%). UV spectra were measured with
Specord M-40 spectrophotometer in EtOH. NMR spectra were
recorded with Bruker WP 200 SY, Bruker AC 200, Bruker AV 300,
and Bruker AM 400 spectrometers on 5% solutions in CDCl3 or
(CD3)2CO with solvent as an internal standard at 25 ꢀC. The com-
position of the reaction mixtures was found from GC–MS data using
quadrupole MS (Hewlett–Packard MSD 5971) coupled to HP
G1800A GC fitted with HP-5 fused silica gel column, injector and
detector (MSD) temperatures were 280 and 170 ꢀC, respectively,
MSD was operated at 70 eV. High-resolution mass spectra were
recorded with Finnigan MAT 8200 mass spectrometer with a direct
sample injection and resolution of 10,000. Melting points were
measured using ‘Boetius’ plate and are uncorrected. TLC monitoring
was carried out on Silufol-254 or Alufol-254 plates. In all cases
solvent evaporation was carried out under reduced pressure.
Compounds 2a, 14d were identified by comparing with ones
synthesized previously.1 Compounds 8a,c, 17,1 1a–d,13 and 914 were
synthesized as described.
3H-pyrrol-3-one 16
2,2,4,5,5-Pentamethyl-2,5-dihydro-1H-imidazol-1-ol
(2.0 g,
12.82 mmol) was added to a stirred suspension of NaH (0.6 g,
25.63 mmol) in N,N-dimethylformamide (10 mL) under argon. The
mixture was stirred for 15 min and then benzyl chloride (1.77 mL,
15.38 mmol) was added dropwise. The stirring was continued for
4.5 h, then the reaction mixture was poured into brine (100 mL)
and extracted with hexane (2ꢁ20 mL). The combined extract was
washed with portion of water (10 mL) and then with brine (10 mL),
dried (MgSO4), and evaporated. 1-(Benzyloxy)-2,2,4,5,5-pentam-
ethyl-2,5-dihydro-1H-imidazole was purified on an Al2O3 column
(hexane, hexane/diethyl ether (1:1)). Yield: 2.3 g (75%), colorless
oil. Rf (50% diethyl ether/hexane) 0.45. HRMS (EI): Mþ, found:
246.1736. C15H22N2O requires: 246.1732. dH (300 MHz, CDCl3) 1.19
(6H, s, C5–(CH3)2), 1.33 (6H, s, C2–(CH3)2), 1.88 (3H, s, C4–(CH3)), 4.74
(2H, s, OCH2), 7.30–7.39 (5H, m, Ph). dC (62 MHz, CDCl3) 16.2 (CH3),
21.0, 23.8, 27.9, 31.1 (C5–(CH3)2, C2–(CH3)2), 72.4 (C5), 78.6 (CH2),
90.1 (C2), 128.0 (p-Ph), 128.4, 129.0 (o,m-Ph), 138.1 (i-Ph), 174.9 (C4).
nmax (CCl4) 1651 (C]N) cmꢂ1
.
A solution of 1-(benzyloxy)-2,2,4,5,5-pentamethyl-2,5-dihydro-
1H-imidazole (1.3 g, 5.28 mmol) in diethyl ether (10 mL) was added
dropwise to a well stirred ice-cold solution of LDA (prepared from
lithium (0.15 g, 21.14 mmol), bromobenzene (1.22 mL, 11.62 mmol)
and N,N-diisopropylamine (1.46 mL, 10.56 mmol) in anhydrous
diethyl ether (20 mL)) under argon. The stirring was continued for
45 min and then the ethyl benzoate (1.13 mL, 7.93 mmol) was
added to an ice-cold reaction mixture in two portions. The mixture
was stirred for 1 h, then water (15 mL) was added. The ether layer
was separated, the aqueous one extracted with CHCl3 (15 mL).
Combined organic extract was dried (MgSO4) and evaporated.
2-(1-(Benzyloxy)-2,2,5,5-tetramethylimidazolidin-4-ylidene)-1-phe-
nylethanone was purified on a silica gel column (CHCl3/CH3OH
(30:1)). Yield: 1.6 g (90%), mp 59.5–60.5 ꢀC (hexane). Rf (CHCl3)
0.19. HRMS (EI): Mþ, found: 350.1990. C22H26N2O2 requires:
350.1994. dH (400 MHz, CDCl3) 1.43 (12H, s, C2–(CH3)2, C5–(CH3)2),
4.82 (2H, s, CH2), 5.62 (1H, s, ]CH), 7.3–7.5 (8H, m), 7.8–7.9 (2H, m,
Ph), 10.32 (1H, br s, NH). dC (100 MHz, CDCl3) 23.3, 24.7, 28.9, 30.9
(C5–(CH3)2, C2–(CH3)2), 68.6 (C5), 79.0 (C2), 80.6 (CH2), 83.3 (CH),
126.8, 128.0, 128.2, 128.6 (o,m-Ph), 127.9, 130.5 (p-Ph), 137.2, 140.1
(i-Ph), 169.3 (C4), 189.4 (C]O). nmax (CCl4) 1623, 1622, 1600, 1583,
4.2. Syntheses
4.2.1. 1-(Benzoyloxy)-2,2-dimethyl-5-(trifluoromethyl)-
1,2-dihydro-3H-pyrrol-3-one 8b
Benzoyl chloride (0.45 mL, 3.84 mmol) was added dropwise to
a well stirred solution of pyrroline 1b (0.50 g, 2.56 mmol) and
NaOH (0.26 g, 6.40 mmol) in water (15 mL) under argon. The re-
action mixture was stirred for 30 min, then extracted with CHCl3
(3ꢁ25 mL); combined extract was dried by MgSO4 and then
evaporated. The crude product 8b was purified on a silica gel col-
umn (chloroform). Yield: 60%, mp 36–37 ꢀC. Rf (3% MeOH/CHCl3)
0.68. [Found: C 55.91, H 3.86, N 4.92. C14H12F3NO3 requires: C 56.19,
H 4.01, N 4.68%.] dH (200 MHz, (CD3)2CO) 1.44 (6H, s, C2–(CH3)2),
6.35 (1H, s, C5]C4–H), 7.5–7.8 (3H, m), 8.0–8.1 (2H, m, Ph). dC
(50 MHz, (CD3)2CO) 22.3 (C2–(CH3)2), 75.5 (C2), 111.9 (C4), 120.7 (q, J
303 Hz, CF3), 127.7, 129.9, 130.6, 135.2 (Ph), 162.2 (q, J 37 Hz, C5),
164.3 (O–C]O), 201.2 (C]O). nmax (KBr) 1768 (O–C]O), 1724
(C]O), 1179, 1149 (CF3) cmꢂ1. UV (ethanol): lmax (lg
283 nm (4.04).
3)¼232 (4.10),

C. Becker et al. / Tetrahedron 64 (2008) 9191–9196
9195
1539 (O]C–C]C–N) cmꢂ1. UV (ethanol): lmax (lg
331 nm (4.28).
3
)¼242 (3.90),
(CHCl3) 0.36. HRMS (EI): Mþ, found: 239.0272. C12H11Cl2N requires:
239.0269. dH (200 MHz, CDCl3) 1.42 (6H, s, C2–(CH3)2), 7.4–7.5 (3H,
m), 7.85–7.95 (2H, m, Ph). dC (50 MHz, CDCl3) 23.0 (C2–(CH3)2), 75.9
(C2), 122.4 (C4), 128.3, 128.6, 130.5, 132.5 (Ph), 157.8 (C3), 166.7 (C5).
nmax (CCl4) 1605, 1580, 1533 (C]C, C]N) cmꢂ1. UV (ethanol): lmax
A solution of 2-(1-(benzyloxy)-2,2,5,5-tetramethylimidazolidin-4-
ylidene)-1-phenylethanone (0.5 g) in a mixture methanol–20% HCl
(1:1) was heated at 52 ꢀC for 24 h, then it was evaporated nearly to
half of the volume, neutralized by 5% NaOH, and extracted with
CHCl3 (3ꢁ15 mL). Combined extract was dried by MgSO4 and
evaporated. 1-(Benzyloxy)-2,2-dimethyl-5-phenyl-1,2-dihydro-3H-
pyrrol-3-one 16 and 1-(benzyloxy)-2,2-dimethyl-5-phenyl-1,2-dihy-
dro-3H-pyrrol-3-imine 19 were separated on a silica gel column
(CHCl3, CHCl3/CH3OH (15:1)). Yields of products 16 and 19 are 0.2 g
(50%) and 0.1 g (25%), respectively.
(lg
3)¼251 nm (4.12).
4.2.5.4. 5-tert-Butyl-3,4-dichloro-2,2-dimethyl-2H-pyrrole 3d. Com-
pound 3d was extracted with ether (3ꢁ15 mL) and purified on
a silica gel column (mixtures of hexane/diethyl ether from 10:0 to
10:1), yield: 11%, mp 22–23 ꢀC. Rf (50% diethyl ether/hexane) 0.58.
HRMS (EI): Mþ, found: 219.0582. C10H15Cl2N requires: 219.0582. dH
(400 MHz, CDCl3) 1.26 (6H, s, C2–(CH3)2), 1.32 (9H, s,
t-Bu). dC (100 MHz, CDCl3) 23.0 (C2–(CH3)2), 27.2 (C–(CH3)3), 35.9
(C–(CH3)3), 74.3 (C2), 122.4 (C4), 157.6 (C3), 175.2 (C5). nmax (KBr)
Compound 16: mp 61–63 ꢀC. Rf (CHCl3) 0.53. HRMS (EI): Mþ,
found: 293.1412. C19H19NO2 requires: 293.1416. dH (300 MHz,
CDCl3) 1.50 (6H, s, C–(CH3)2), 5.06 (2H, s, CH2), 5.56 (1H, s, CH), 7.12–
7.22 (2H, m), 7.26–7.31 (3H, m), 7.40–7.50 (3H, m), 7.56–7.60 (2H, m,
Ph). dC (75 MHz, CDCl3) 23.4 (C–(CH3)2), 72.8 (C–(CH3)2), 79.0 (CH2),
104.9 (C4), 128.4, 128.6, 128.7, 128.8, 129.0, 131.1, 131.3, 135.1 (Ph),
177.6 (C5), 202.3 (C3]O). nmax (KBr) 1694 (O]C–C]C) cmꢂ1. UV
1601, 1539 (C]C, C]N) cmꢂ1. UV (ethanol): lmax (lg
(3.61).
3
)¼244 nm
4.2.5.5. 3,4-Dichloro-2,2-dimethyl-5-methylene-2,5-dihydro-1H-pyr-
role-1-carbaldehyde 4. Compound 4 was isolated by extraction
with CHCl3 (3ꢁ15 mL) and purified on a silica gel column (hexane/
diethyl ether (10:1)). Yield of the isomers mixture: 53%, colorless
oil. Rf (CHCl3) 0.24. HRMS (EI): Mþ, found: 205.0061. C8H9Cl2NO
requires: 205.0061. dH (300 MHz, CDCl3, 25 ꢀC) 1.54 (6H, s, C2–
(CH3)2, A), 1.59 (6H, s, C2–(CH3)2, B), 4.57 (1H, d, J 3.3 Hz, HbCHa, B),
4.67 (1H, d, J 3.3 Hz, HaCHb, B), 4.91 (1H, d, J 1.0 Hz, HbCHa, A), 5.95
(1H, d, J 1.0 Hz, HaCHb, A), 8.56 (1H, s, HC]O, A), 8.75 (1H, s, HC]O,
B). dC (75 MHz, CDCl3,) 22.9 (q, J 130.7 Hz, C2–(CH3)2, B), 26.6 (q, J
129.2 Hz, C2–(CH3)2, A), 67.8 (C2–(CH3)2, A), 69.3 (C2–(CH3)2, B),
83.7 (dd, J 166.1, 162.1 Hz, CH2, B), 94.3 (dd, J 170.6, 160.5 Hz, CH2,
A), 122.5 (C4, B), 124.1 (C4, A), 135.4 (C3, A), 139.3 (C3, B), 140.5 (C5,
A), 142.5 (C5, B), 156.9 (d, J 212.4 Hz, HC]O, B), 158.7 (d, J 196.2 Hz,
HC]O, A). nmax (CCl4) 1755 (H–C]O), 1694, 1617 (C]C,
C]N) cmꢂ1. The molar ratio of isomers is A/B¼1:1.7.
(ethanol): lmax (lg
3
)¼256 (4.04), 301 nm (3.97).
Compound 19: mp 166–169 ꢀC. Rf (7% MeOH/CHCl3) 0.07. HRMS
(EI): Mþ, found: 292.1574. C19H20N2O requires: 292.1576. dH
(300 MHz, CDCl3) 1.81 (6H, s, C–(CH3)2), 5.03 (2H, s, CH2), 6.10 (1H,
s, C4H), 7.18–7.23 (2H, m), 7.28–7.35 (3H, m), 7.44–7.52 (2H, m),
7.54–7.62 (1H, m), 7.68–7.72 (2H, m, Ph), 10.27 (1H, br s, NH). dC
(75 MHz, CDCl3) 24.3 (C–(CH3)2), 74.3 (C–(CH3)2), 80.6 (CH2), 95.0
(C4), 128.0, 129.0, 129.1, 129.3 (2 signals), 129.5, 133.1, 133.4 (Ph),
174.8 (C5), 183.2 (C3). nmax (KBr) 2877 (N–H), 1682,1600, 1581
(C]C–C]N) cmꢂ1. UV (ethanol): lmax (lg
(4.02).
3
)¼272 (4.01), 350 nm
4.2.5. Reaction with the Vilsmeier reagent (general method)
POCl3 (0.19 mL, 2.00 mmol) was added dropwise to ice-cold
N,N-dimethylformamide (2 mL). The solution was stirred for
10 min, compounds 1, 2a, 8, 9, 14d, 16, or 17 (1.00 mmol) were
added and the stirring was continued for 3 h at 20 ꢀC. The reaction
mixture was poured into the saturated ice-cold solution of Na2CO3
(7 mL), the resulting mixture was kept at 20 ꢀC for 30 min and then
extracted either with diethyl ether or CHCl3. Combined extract was
thoroughly washed with water, dried by MgSO4, and evaporated.
The crude product was purified as described below.
4.2.5.6. N-[2-(3,4-Dichloro-2,2-dimethyl-2H-pyrrol-5-yl)vinyl]-N,N-
dimethylamine 5 and (3,4-dichloro-5,5-dimethyl-1,5-dihydro-2H-
pyrrol-2-ylidene)acetaldehyde 6. Compounds 5 and 6 were syn-
thesized according to a general method using 3 mmol of POCl3
(instead of 2 mmol). A mixture of products was extracted with
CHCl3 (3ꢁ15 mL) and the products were separated on an Al2O3
column (CHCl3). Yields of compounds 5 and 6 are 11% and 3%,
respectively.
Compound 5: mp 70–73 ꢀC (hexane). Rf (CHCl3) 0.04. HRMS (EI):
Mþ, found: 232.0531. C10H14Cl2N2 requires: 232.0534. dH (300 MHz,
CDCl3) 1.30 (6H, s, C(CH3)2), 2.92 (6H, s, N(CH3)2), 4.95 (1H, d, J
13.2 Hz, CH), 7.60 (1H, d, J 13.2 Hz, HC–NMe2). dC (75 MHz, CDCl3)
24.1 (s, N(CH3)2, C(CH3)2), 74.2 (C(CH3)2), 84.9 (N1]C5–C]C–N),
123.4 (C4), 147.0 (N1]C5–C]C–N), 153.9 (C3), 165.2 (C5). nmax (KBr)
4.2.5.1. 4-Chloro-2,2-dimethyl-5-phenyl-1,2-dihydro-3H-pyrrol-3-one
2a. Compound 2a was extracted with ether (3ꢁ15 mL). The residue
after evaporation was triturated with a small amount of diethyl
ether, the resultant precipitate 2a was filtered off and recrystallized
from a mixture of hexane/EtOAc, yield: 33%, mp 190–191 ꢀC (lit.1
mp 190–191 ꢀC). dC (50 MHz, CDCl3) 24.2, 24.3 (C2–(CH3)2), 63.9
(C2), 101.1 (C4), 127.9, 128.8, 129.5, 132.3 (Ph), 167.8 (C5), 198.3
(C]O).
1641, 1602 (N]C–C]C–N) cmꢂ1. UV (ethanol): lmax (lg
3)¼253
(4.11), 350 nm (4.19).
4.2.5.2. 4-Chloro-2,2-dimethyl-5-(trifluoromethyl)-1,2-dihydro-3H-
pyrrol-3-one 2b. Compound 2b was purified by sublimation at
2 mmHg and 40–50 ꢀC. Yield: 25 %, mp 138–139 ꢀC (hexane/EtOAc).
[Found: C 40.10, H 3.30, N 6.63, Cl 16.56. C7H7NOF3Cl requires: C
39.34, H 3.28, N 6.56, Cl 16.63%.] HRMS (EI): Mþ, found: 213.0167.
C7H7ClF3NO requires: 213.0168. dH (200 MHz, CDCl3) 1.37 (6H, s,
C2–(CH3)2), 6.28 (1H, br s, NH). dC (50 MHz, CDCl3) 22.3, 23.6 (C2–
(CH3)2), 64.9 (C2),103.2 (C4),118.8 (q, J 275 Hz, CF3),156.2 (q, J 37 Hz,
C5), 199.0 (C]O). nmax (KBr) 3181 (N–H), 1668 (C]O), 1569 (C]C),
Compound 6: mp 101–104 ꢀC. Rf (CHCl3) 0.38. HRMS (EI): Mþ,
found: 205.0057. C8H9Cl2NO requires: 205.0061. dH (300 MHz,
CDCl3) 1.43 (6H, s, C(CH3)2), 5.39 (1H, d, J 2.1 Hz, CH), 9.26 (1H, d, J
2.1 Hz, HC]O), 9.50 (1H, br s, NH). nmax (KBr) 3313 (NH),1639,1592,
1562 (O]C–C]C–N) cmꢂ1
.
4.2.5.7. 2-Chloro-2-(1,2,2,5,5-pentamethylimidazolidin-4-ylidene)-
1-phenylethanone 10. Compound 10 was extracted with CHCl3
(3ꢁ15 mL) and purified on a silica gel column (CHCl3), yield: 40%,
mp 168.5–169 ꢀC (hexane/EtOAc). Rf (CHCl3) 0.68. [Found: C 65.46,
H 7.28, N 9.58, Cl 12.11. C16H21ClN2O requires: C 65.64, H 7.18, N 9.57,
Cl 12.14%.] dH (200 MHz, CDCl3) 1.39 (6H, s, C5–(CH3)2), 1.51 (6H, s,
C2–(CH3)2), 2.33 (3H, s, N–CH3), 7.24 (3H, m), 7.36 (2H, m, Ph), 11.33
(1H, br s, NH). dC (75 MHz, CDCl3) 22.8 (C5–(CH3)2), 26.0 (N–CH3),
27.1 (C2–(CH3)2), 67.7 (C5), 78.6 (C2), 93.8 (C–Cl), 127.4, 127.6
1227, 1192, 1171, 1138 (CF3) cmꢂ1. UV (ethanol): lmax (lg
(3.89).
3
)¼335 nm
4.2.5.3. 3,4-Dichloro-2,2-dimethyl-5-phenyl-2H-pyrrole 3a. Com-
pound 3a was extracted with ether (3ꢁ15 mL) and isolated on
a silica gel column (diethyl ether), yield: 50%, mp 25.5–27 ꢀC. Rf

9196
C. Becker et al. / Tetrahedron 64 (2008) 9191–9196
(o,m-Ph), 129.2 (p-Ph), 140.7 (i-Ph), 167.2 (C4), 191.4 (C]O). nmax
(KBr) 3223 (NH), 1595, 1538 (O]C–C]C–N), 1278 (C–N) cmꢂ1. UV
C–(CH3)3, C5–(CH3)), 1.44 (3H, s, C5–(CH3)), 3.95 (1H, s, C4H). dC
(100 MHz, CDCl3) 26.4, 27.9 (C5–(CH3)2), 27.0 (C–(CH3)3), 34.9
(C–(CH3)3), 66.0 (C4), 67.0 (C5), 175.3 (C2), 196.0 (C3).
(ethanol): lmax (lg
3)¼241 (3.59), 342 nm (4.03).
4.2.5.8. 3-Chloro-2,2-dimethyl-5-phenyl-2H-pyrrol-4-yl
benzoate
4.2.5.10. A reaction of a mixture of compounds 8a and 14d with the
Vilsmeier reagent. The reaction was carried out according to the
general method. The ratio of starting compounds 8a/14d was 1:1.
The reaction mixture was extracted with CHCl3 (3ꢁ15 mL) and the
resulting mixture was purified by filtration through silica gel layer
using chloroform as solvent. Then the mixture was analyzed with
11a and 4-chloro-5,5-dimethyl-2-phenyl-4,5-dihydro-3H-pyrrol-3-
one 12a. A mixture of products 11a, 3a, and 12a was extracted with
ether (3ꢁ15 mL) and purified on a silica gel column (diethyl ether).
The products were separated on a silica gel column (CHCl3, CHCl3/
CH3OH (100:1)). Yield of 11ad30%, yield of a mixture of 3a and
12ad22%. Compound 12a was not isolated in individual form
because of its low stability upon chromatography.
GC–MS: found m/z¼239:
C
12H11Cl2N (4.2), 3a; m/z¼219:
C
C
10H15Cl2N (11.5), 3d; m/z¼221: C12H12ClNO (3.6), 12a; m/z¼201:
Compound 11a: mp 65–66.5 ꢀC (hexane). Rf (3% MeOH/CHCl3)
0.18. HRMS (EI): Mþ, found: 325.0870. C19H16ClNO2 requires:
325.0870. dH (400 MHz, CDCl3) 1.50 (6H, s, C2–(CH3)2), 7.3–7.4 (3H,
m), 7.45–7.55 (2H, m), 7.6–7.7 (1H, m), 8.1–8.2 (2H, m), 8.8–8.9 (2H,
m, 2 Ph). dC (100 MHz, CDCl3) 23.1 (C2–(CH3)2), 73.4 (C2), 132.5 (C3),
127.2, 128.0, 128.5, 128.7, 130.2, 130.5, 134.0, 139.3 (2Ph), 148.0 (C4),
162.4 (C5), 165.8 (O–C]O). nmax (KBr) 1757 (O–C]O), 1644 (C]C–
10H16ClNO (10.1), 12d; m/z¼325: C19H16ClNO2 (10.1), 11a; m/z¼
243: C12H18ClNO2 (1.0), 15d; m/z¼263: C14H14ClNO2 (3.6), 15a;
m/z¼305: C17H20ClNO2 (1.8), 11d, the molar ratio of products is
given in parentheses.
4.2.5.11. A reaction of compound 16 with the Vilsmeier reagent. The
reaction was carried out according to the general method. The re-
action mixture was extracted with CHCl3 (3ꢁ15 mL) and the
products were separated on a silica gel column (hexane, mixtures
hexane/diethyl ether with ratio from 10:1 to 1:2). Yields of benzyl
chloride, compound 3a, and compound 12a are 14%, 22% and 50%,
respectively.
C]N) cmꢂ1. UV (methanol): lmax (lg
3
)¼238 nm (4.40).
X-ray crystallography experiment. Data for compound 11a
(2
q
<50ꢀ) were measured on a Bruker P4 single crystal diffrac-
tometer, with graphite monochromated Mo-Ka radiation. A cor-
rection for absorption was made by integration method
(transmission 0.8166–0.9485). The structure was solved by the
direct method using the SHELXS-97 program and refined in the
full-matrix anisotropic (isotropic for H atoms) approximation by
the SHELXL-97 program. The hydrogen atom positions were located
geometrically. Crystallographic data (excluding structure factors)
for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation no. CCDC-623496. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
X-ray structuredata for 11a: C19H16ClNO2, M¼325.78, monoclinic,
4.2.5.12. A reaction of compound 17 with the Vilsmeier reagent. The
reaction was carried out according to the general method. The re-
action mixture was extracted with CHCl3 (3ꢁ15 mL) and the
products 17 and 3a were separated on a silica gel column (CHCl3). A
conversion was 63%, yield of 3ad21%.
4.2.5.13. 1-(Benzoyloxy)-4-chloro-5,5-dimethyl-2-(trifluoromethyl)-
2,5-dihydro-1H-pyrrol-2-ol 18. Compound 18 was extracted with
ether (3ꢁ15 mL) and isolated on a silica gel column (hexane/
diethyl ether (10:1)). A conversion was 65%, yield of 18d40%, mp
128–129 ꢀC (hexane/EtOAc). Rf (20% diethyl ether/hexane) 0.44.
[Found: C 49.94, H 3.86, N 4.12, Cl 10.48. C14H13ClF3NO3 requires: C
50.07, H 3.87, N 4.17, Cl 10.58%.] dH (400 MHz, (CD3)2CO) 1.38 (3H,
s), 1.50 (3H, s, C2–(CH3)2), 6.10 (1H, s, C4H), 6.6–6.7 (1H, br s, OH),
7.5–7.6 (2H, m), 7.65–7.69 (1H, m), 8.08–8.16 (2H, m, Ph). dC
(100 MHz, (CD3)2CO) 23.2, 25.1 (C2–(CH3)2), 73.1 (C2), 93.4 (q, J
33 Hz, C5), 120.0 (C4), 123.7 (q, J 284 Hz, CF3), 129.5, 129.6, 130.5,
134.4 (Ph), 146.2 (C3), 165.2 (O–C]O). nmax (KBr) 3379 (OH), 1736
a¼9.3024(12), b¼34.622(4), c¼10.3003(10) Å,
b
¼90.315(10)ꢀ,
V¼3317.4(7) Å3, space group P21/c, Z¼8, dc¼1.305 g cmꢂ3
, m(Mo-
Ka)¼0.239 mmꢂ1, F(000)¼1360. The final indexes are S¼1.024,
R1¼0.0512, wR2¼0.1155 for all 5818 independent reflections and
R1¼0.0402, wR2¼0.1076 for 4720 F0>4
s.
Compound 12a: Rf (CHCl3) 0.49. HRMS (EI): Mþ, found:
221.0605. C12H12ClNO requires: 221.0607. dH (400 MHz, CDCl3) 1.39
(3H, s), 1.57 (3H, s, C5–(CH3)2), 4.19 (1H, s, C4H), 7.40–7.52 (3H, m),
8.15–8.20 (2H, m, Ph). dC (100 MHz, CDCl3) 26.5, 27.9 (C5–(CH3)2),
66.1 (C4), 67.9 (C5), 128.4, 128.8, 132.1, 132.5 (Ph), 163.6 (C2),
196.2 (C3).
(O–C]O), 1188 (CF3) cmꢂ1. UV (ethanol): lmax (lg
275 (3.06), 282 (3.06), 316 nm (3.35).
3
)¼229 (4.00),
References and notes
4.2.5.9. 5-tert-Butyl-3-chloro-2,2-dimethyl-2H-pyrrol-4-yl benzoate
11d and 2-tert-butyl-4-chloro-5,5-dimethyl-4,5-dihydro-3H-pyrrol-
3-one 12d. The reaction mixture was extracted with CHCl3
(3ꢁ15 mL), a mixture of products was separated by preparative TLC
on an Al2O3 (hexane). Yield of 11dd6%, yield of chromatographi-
cally homogenous mixture of 3d and 12dd15%.
1. Reznikov, V. A.; Vishnivetskaya, L. A.; Volodarskii, L. B. Bull. Acad. Sci. USSR Div.
Chem. Sci. (Engl. Transl.) 1990, 39, 335–340.
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3. Ashok, K.; Sridevi, G.; Umadevi, Y. Synthesis 1993, 623–626.
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6. Beccalli, E. M.; Marchesini, A.; Molinari, H. Tetrahedron Lett. 1986, 27,
627–630.
7. Reznikov, V. A.; Vishnivetskaya, L. A.; Volodarskii, L. B. Chem. Heterocycl. Compd.
(Engl. Transl.) 1988, 504–508.
8. Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070–2076.
9. Demeunynck, M.; Tohme, N.; Lhomme, M.-F.; Mellor, J. M.; Lhomme, J. J. Am.
Chem. Soc. 1986, 108, 3539–3541.
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13. Reznikov, V. A.; Volodarskii, L. B. Chem. Heterocycl. Compd. (Engl. Transl.) 1990, 7,
767–772.
Compound 11d: mp 123–124.5 ꢀC (hexane). Rf (50% diethyl
ether/hexane) 0.45. HRMS (EI): Mþ, found: 305.1180. C17H20ClNO2
requires: 305.1183. dH (400 MHz, CDCl3) 1.29 (9H, s, t-Bu), 1.46 (6H,
s, C2–(CH3)2), 7.50–7.58 (2H, m, m-Ph), 7.63–7.69 (1H, m, p-Ph),
8.12–8.15 (2H, m, o-Ph). dC (100 MHz, CDCl3) 23.1 (C2–(CH3)2), 27.4
(C–(CH3)3), 35.8 (C–(CH3)3), 72.5 (C2), 128.1 (s, C3, i-Ph), 129.1, 130.5,
134.5 (m,o,p-Ph), 139.4 (C4), 161.9 (s, C5, O–C]O). nmax (KBr) 1754
(O–C]O), 1645 (C]C–C]N) cmꢂ1
(lg
)¼233 nm (4.26).
Compound 12d: Rf (50% diethyl ether/hexane) 0.58. GC–MS:
found m/z¼201: C10H16ClNO. dH (400 MHz, CDCl3) 1.25 (12H, s,
.
UV (ethanol): lmax
3
14. Martin, V. V.; Volodarskii, L. B. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.)
1980, 29, 956–962.