Rearrangement and degradation of 3a,7a-dihydroindole esters

Article abstract of DOI:10.14233/ajchem.2016.19317

The purpose of this paper is to report that pyrroles 1a-c also gave the 1:2 adducts 3a-c when refluxed with dimethyl acetylene dicarboxylate in ether (or ether with AlCl₃) and rearrangement and degradation of 3a,7a-dihydroindole esters 3a-c as

Full text of DOI:10.14233/ajchem.2016.19317

Asian Journal of Chemistry; Vol. 28, No. 1 (2016), 185-188
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19317
Rearrangement and Degradation of 3a,7a-Dihydroindole Esters
DO-HUN LEE
Department of Chemistry, Dong-A University, S11, 37 Nakdong-Daero 550 Bean-gil, Saha-gu, Busan 604-714, Republic of Korea
Corresponding author: Fax: +82 51 2007259; Tel: +82 51 2001053; E-mail: dohlee@dau.ac.kr
Received: 5 May 2015;
Accepted: 26 June 2015;
Published online: 5 October 2015;
AJC-17571
The purpose of this paper is to report that pyrroles 1a-c also gave the 1:2 adducts 3a-c when refluxed with dimethyl acetylene dicarboxylate
in ether (or ether with AlCl3) and rearrangement and degradation of 3a,7a-dihydroindole esters 3a-c as 1:2 molar [4+2] cycloadducts were
investigated. The electrons in compound 3a are assumed to move as in its resonance structure A which should results in the formation of
transition state B. Next, cleavage of the C-C bond between the carbonyl carbon atom and the 3a carbon atom and the 1,3-shift of the
hydrogen atom from 7a position into 2 position will occur easily to form an aromatized stable indole compound 4a.
Keywords: Indole, Indoline, Rearrangement, Degradation, 1,3-Shift, Three-membered cyclic transition state structure.
chromatography (TLC) was performed on glass plates coated
with silicon oxide (silica gel 60F254) and compounds were
visualized using a UV lamp. 1H NMR and 13C NMR spectra
were obtained with Bruker AC 2000 (200 MHz) and Varian
Gemini (200 or 300 MHz) spectrometers. Mass spectra were
measured with HP 5890 GC/Mass (70 eV, EI). The organic
solvents and chemicals were obtained from commercial
products and purified by the appropriate methods before use.
All the starting materials were purchased from Aldrich,
Fluka, Lancaster, or TCI chemical companies and used as
received.
INTRODUCTION
Pyrroles are found in a variety of biological contexts, as
parts of cofactors and natural products. Common naturally
produced molecules containing pyrroles include vitamin B12,
bile pigments like bilirubin and biliverdin and the porphyrins
of heme, chlorophyll, chlorins, bacteriochlorins and porphy-
rinogens [1]. Other pyrrole-containing secondary metabolites
are pyrroloquinoline quinone (PQQ), makaluvamine M, etc.
Moreover, pyrroles are also found in several drugs, viz., atorvas-
tatin, ketorolac and sunitinib. One of the first syntheses of pyrrole-
containing molecules was that of haemin, synthesized by Emil
Fischer in 1929 [2]. The reaction of pyrroles with common
dienophiles seems to follow two different pathway, that is, [4+2]
cycloaddition or a Michael-type addition at the α position of
pyrroles [3]. Pyrroles which have aryl or electron-withdrawing
substituents on the nitrogen gave 1:1 adducts of type 2 with
dimethyl acetylene dicarboxylate (DMAD). With an N-alkyl
group, the 1:1 adduct of type 2 reacted further with dimethyl
acetylene dicarboxylate to give a 1:2 adduct of type 3 [4]. On
the other hand, pyrrole (1a) itself was reported to give a Michael-
type 1:1 adduct 5, though the structure was not thoroughly
established [5].The purpose of this paper is to report that pyrroles
1 also gave the 1:2 adducts 3 when refluxed with dimethyl
acetylene dicarboxylate in ether (or ether with AlCl3) for 4 days
and rearrangement and degradation of 3a,7a-dihydroindole esters
3 as 1:2 molar [4+2] cycloadducts were researched (Scheme-I).
General procedure for the synthesis of 2a-c and 3a-c:
A solution of 1-phenylpyrrole (0.429 g, 3 mmol) and dimethyl
acetylene dicarboxylate (0.825 g, 6 mmol) in ether (20 mL)
was refluxed for 167 h, during which time some white precipi-
tate formed. After 167 h, the reaction mixture was allowed to
stir at room temperature and monitored by TLC to establish
completion of the reaction. The resulting solution was dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel to
afford the desired product. After flash chromatography, 1,2-
dimethylcarboxylate-7-phenyl-7-aza-bicyclo[2,2,1]-1,3-
hexadiene 2b (0.184 g, 21.5 %) and tetramethyl 3a,7a-dihydro-
1-phenylindole-2,3,3a,4-tetracarboxylate 3b (0.310 g, 24.2 %)
were obtained. In case of the reaction in ether withAlCl3 (0.01
g) as an acid catalyst, 2b (0.195 g, 22.8 %) and 3b (0.321 g,
25.1 %) were obtained. 1,2-Dimethyl carboxylate-7-phenyl-
7-aza-bicyclo[2,2,1]-1,3-hexadiene (2b): Rf; 0.42 (TLC eluent;
EXPERIMENTAL
1
hexane:EtOAc = 5:3, v/v) H NMR (CDCl3); δ 3.80 (s, 6H,
Melting points were determined using an electronthermal
capillary melting point apparatus and uncorrected. Thin layer
OCH3), 5.43 (dd, 2H, N-C-H), 6.12 (dd, 2H, =C-H), 7.3-7.8

186 Lee
Asian J. Chem.
R
E
E
E
C
C
E
E
N
E
E
+
N
R
Et2O
(or Et2O+AlCl3)
E
N
R
a, R= -CH3
b, R= -C6H5
3
2
1
c, R= -C6H4Br
Et2O
toluene
(or dioxane)
(or dioxane
or pyridine)
E
E
E
E
E
E
N
R
E
N
R
b, R=
c, R=
b, R=
c, R=
5
4
Br
Br
Scheme-I
(m, 5H, phenyl H); IR (KBr, νmax, cm-1): 2950 (C-H), 1850 s
(C=O), 1600 s (aromatic C=C), 1280 s, 1250 s, 1215 (O-C=O);
UV (EtOH); λmax 223 nm. Tetramethyl 3a,7a-dihydro-1-
phenylindole-2,3,3a,4-tetracarboxylate (3b); Rf; 0.23 (TLC
eluent; hexane:EtOAc = 5:3, v/v) 1H NMR (CDCl3); δ 3.70 (s,
3H), 3.73 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H, all OCH3), 5.40
(d, 1H, C7aH), 6.05 (d, 1H, C5H), 6.95-7.40 (m, 5H, phenyl H);
IR (KBr, νmax, cm-1): 2958 s (C-H), 1750 s, 1730 s, 1700 s (C=O),
1593 (aromatic C=C), 1270 s, 1250 s (O-C=O); UV (EtOH);
The pyridine was distilled off under aspirator pressure and the
residual light brown oil was dissolved in methanol, decolourized
with charcoal and kept in a refrigerator overnight, giving white
prisms. The prisms were collected and recrystallized from
methanol and dichloromethane to give tetramethyl-1-phenyl-
indoline-2,3,3,4-tetracarboxylate (4b) (15.5 %) as white prisms.
In case of Et2O or dioxane as a solvent, 4b (Et2O; 10.5 %,
dioxane; 12.7 %) respectively was obtained. Tetramethyl-1-
phenyl-indoline-2,3,3,4-tetracarboxylate (4b); Rf; 0.35 (TLC
eluent; hexane:EtOAc = 5:3, v/v) 1H NMR (CDCl3); δ 3.75 (s,
3H), 3.84 (s, 3H), 3.92 (s, 3H), 4.02 (s, 3H, all OCH3), 5.04
(d, 1H, C2H), 5.04 (s, 1H, C2H), 7.21-7.73 (m, 8H, phenyl H);
IR (KBr, νmax, cm-1): 3130 s (C-H), 3070 s, 3030 s (aromatic
C-H), 2955 s (C-H), 1755 s, 1740 s, 1735 s, 1725 s (C=O),
1600 s (aromatic C=C), 1295 s, 1245 s, 1220 s (O-C=O); UV
(EtOH); λmax 228 nm. Tetramethyl-1-m-bromophenylindoline-
2,3,3,4-tetracarboxylate (4c); Rf; 0.34 (TLC eluent; hexane:
EtOAc = 5:3, v/v) 1H NMR (CDCl3); δ 3.75 (s, 3H), 3.82 (s,
3H), 3.89 (s, 3H), 3.95 (s, 3H, all OCH3), 5.06 (s, 1H, C2H),
7.11-8.21 (m, 7H, phenyl H); IR (KBr, νmax, cm-1): 3100 s,
3010 s (aromatic C-H), 2960 s, 2940 s (C-H), 1755 s, 1750 s,
1730 s, 1720 s (C=O), 1615 s, 1590 s, 1580 s (aromatic C=C),
1300 s, 1235 s, 1205 s (O-C=O); UV (EtOH); λmax 288.5 nm.
General procedure for chemical degradation of 3:A solu-
tion of tetramethyl 3a,7a-dihydro-1-phenylindole-2,3,3a,4-
tetracarboxylate 3b (0.30 g, 7 × 10-4 mol) in toluene (20 mL)
was refluxed for 150 h. After 150 h, the reaction mixture was
allowed to stir at room temperature and monitored by TLC to
λ
max 235 nm. 1,2-dimethyl carboxylate-7-m-bromophenyl-7-
aza-bicyclo[2,2,1]-1,3-hexadiene (2c); Rf; 0.48 (TLC eluent;
1
hexane:EtOAc = 5:3, v/v) H NMR (CDCl3); δ 3.85 (s, 6H,
OCH3), 5.40 (dd, 2H, N-C-H), 6.34 (dd, 2H, =C-H), 6.8-7.6
(m, 4H, phenyl H); IR (KBr, νmax, cm-1): 2955 s (C-H), 1732 s,
1725 s (C=O), 1595 s (aromatic C=C), 1315 s, 1265 s, 1210 s
(O-C=O); UV (EtOH); λmax 243 nm. Tetramethyl 3a,7a-
dihydro-1-m-bromphenyl-indole-2,3,3a,4-tetracarboxylate
(3c); Rf; 0.22 (TLC eluent; hexane:EtOAc = 5:3, v/v) 1H NMR
(CDCl3); δ 3.60 (s, 3H), 3.70 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H,
all OCH3), 5.41 (d, 1H, C7aH), 5.75 (dd, 1H, C6H), 6.05 (dd,
1H, C7H), 6.2 (d, 1H, C5H), 6.85-7.3 (m, 4H, phenyl H); IR
(KBr, νmax, cm-1): 2970 s (C-H), 1755 s, 1740 s, 1710 s (C=O),
1595 s, 1570 s (aromatic C=C), 1250 s, 1280 s (O-C=O); UV
(EtOH); λmax 280 nm.
General procedure for the rearrangement of 3a,7a-
dihydroindole esters (3): A solution of tetramethyl 3a,7a-
dihydro-1-phenylindole-2,3,3a,4-tetracarboxylate 3b (0.251 g,
5.9 × 10-4 mol) in pyridine (20 mL) was refluxed for 300 h.

Vol. 28, No. 1 (2016)
Rearrangement and Degradation of 3a,7a-Dihydroindole Esters 187
establish completion of the reaction. Toluene was distilled off
under aspirator pressure. The residue was purified by flash
chromatography on silica gel to afford the desired product.
After flash chromatography tetramethyl-1-phenylpyrrole-
2,3,4-tricarboxylate (5b) (0.055 g, 25 %) was obtained. In case
of dioxane on behalf of toluene 5b (22 %) was obtained. Tetra-
methyl-1-phenylpyrrole-2,3,3-tricarboxylate (5b); Rf; 0.4
(TLC eluent; hexane:EtOAc = 5:3, v/v) 1H NMR (CDCl3); δ
3.75 (s, 3H), 3.89 (s, 3H), 4.05 (s, 3H, all OCH3), 7.21-7.65 (m,
5H, phenyl H), 7.15 (s, 1H, pyrrole H); IR (KBr, νmax, cm-1):
3150 s, 3005 s (aromatic C-H), 2960 s (C-H), 1750 s, 1720 s
(C=O), 1600 s (aromatic C=C), 1290 s, 1250 s, 1220 s (O-C=O);
Mass; m/e 77 (105), 288 (100), 317 (44.9) UV (EtOH); λmax
219.5 nm. Tetramethyl-1-m-bromophenylpyrrole-2,3,4-
tricarboxylate (5c); Rf; 0.48 (TLC eluent; hexane:EtOAc =
3:2, v/v) 1H NMR (CDCl3); δ 3.65 (s, 3H), 3.79 (s, 3H), 3.95 (s,
3H, all OCH3), 7.05 (s, 1H, pyrrole H), 7.25-7.80 (m, 4H, phenyl
H); IR (KBr, νmax, cm-1): 3160 s, 3090 s, 3805 s (aromatic C-H),
2950 s (C-H), 1750 s, 1745 s, 1725 s, 1717 s (C=O), 1590 s
(aromatic C=C), 1290 s, 1255 s, 1255 s (O-C=O).
As shown in Table-2, the synthesis of indolines 4b, c in
ether (or dioxane) was tried. Yields of those are very low.
Plausible mechanism from indole 3 to indoline 4 is as follows.
This unequivocally suggests that the transition state for the
rearrangement is highly restricted, that is the degree of freedom
for the structure of the transition state is much less. A first
speclation, the most plausible from for a transition state having
such larger negative entropy, is a cyclic structure [7,8]. It is
well known that a transition state characterized by a larger
negative entropy may possess a three-membered cyclic structure
[9]. However, just the fact that the transition state might possess
a cyclic form, even if unavoidable, is not enough nor adequate
to satisfy all the data mentioned above, Now, the fact that the
first-order rate constant becomes large as the polarity of the
solvent increase requires a charge separation in the transition
state [9,10], no matter what the structure of the transition state
might be. Thus, it can be deduced that the most feasible
transition state for the rearrangement could be some sort of
cyclic form in which charges are separated concomitantly. The
propriety of the above speculation is seen from an examination
of the electron shifts shown in Scheme-II. The electrons in
compound 3a are assumed to move as in its resonance structure
A which should results in the formation of transition state B,
structure B as the transition state has a three-membered cyclic
form and at the same time the charges are well separated as is
required by the foregoing experimental results. Next, cleavage
of the C-C bond between the carbonyl carbon atom and the 3a
carbon atom and the 1,3-shift of the hydrogen atom from 7a
position into 2 position will occur easily to form an aromatized
stable indoline compound 4a. At this state, it can not be deter-
mined whether or not the cleavage and the 1,3-shift occur
simultaneously. But no matter which may happen, it does not
seem to be significant for the mechanism.
RESULTS AND DISCUSSION
Although the adduct 3 began to form in 2 days, the yield
increased to 7 % in 5 days and could be improved to 30 % by
removing the product and refluxing for a longer period of time
(7 days). The yield of 3a was more them 60 % under identical
conditions.
As shown in Table-1 in case of ether with AlCl3 in behalf
of ether 1:1 and 1:2[4+2] cyclo adducts were obtained in high
yield. Compound 3a were reported to isomerize to the indoline
derivate 4a in 4 % yield upon heating at 180 °C for 6 h in the
presence of 5 % palladium-charcoal [6]. The isomerization
could be carried out as efficiently as 74 % by refluxing 3a in
xylene for 24 h.
TABLE-2
PHYSICAL DATA FOR INDOLINE DERIVATIVES
TABLE-1
Reflux
time (h)
840
840
840
Indoline
R
Solvent
Ether
Dioxane
Pyridine
Yield* (%)
PHYSICAL DATA FOR 1:1 AND 1:2 [4+2] CYCLO ADDUCTS
10.5
12.7
16.3
Yield* (%)
Reflux
time (h)
Pyrrole
1a
R
Solvent
Ether
4b
2
3
165
165
a: 23.0 a: 21.6
25.0 32.0
b: 21.5 b: 24.2
24.7 27.3
CH3
Ether
Dioxane
Pyridine
900
900
900
6.2
11.3
15.7
Ether + AlCl3
4c
Ether
167
167
1b
Br
Ether + AlCl3
*Isolated yield
Ether
Ether + AlCl3
158
158
c: 19.7 c: 20.3
1c
23.2
25.6
The conversion of indoles 3b,c to pyrroles 5b,c provides
the definite evidence that pyrrole 5b,c, like 1-substituted pyrroles,
undergoes initial Diels-Alder addition (Table-3). Present results
Br
*Isolated yield
O
C
E
OCH3
E
O
C
E
OCH3
E
O
C
E
E
E
OCH3
E
E
E
E
N
N
E
H
H
N
E
H
N
H
CH3
CH3
CH3
CH3
B
3a
A
4a
Scheme-II

188 Lee
Asian J. Chem.
TABLE-3
REFERENCES
PHYSICAL DATA FOR PYRROLE DERIVATIVES
1. J. Juselius and D. Sundholm, Phys. Chem. Chem. Phys., 2, 2145 (2000).
2. E. Fischer, Sugar and Purine Syntheses, Nobel Prize Lecture (1902).
3. R.A. Jones and G.P. Bean, The Chemistry of Pyrroles, Academic Press,
New York, p. 146 and 256 (1977).
4. R.M. Acheson and J.M. Vernon, J. Chem. Soc., 1148 (1962).
5. R.M. Acheson and J.M. Vernon, J. Chem. Soc., 1008 (1963).
6. T. Ohe, K. Ohe, S. Uemura and N. Sugita, J. Organomet. Chem., 344,
C5 (1988).
Reflux
time (h)
Pyrrole
R
Solvent
Yield* (%)
Toluene
Dioxane
150
150
25.0
22.7
5b
Toluene
Dioxane
150
150
22.5
19.8
5c
Br
7. P. Scheiner, J.H. Schomaker, S. Deming, W.J. Libbey and G.P. Nowack,
J. Am. Chem. Soc., 87, 306 (1965).
*Isolated yield
8. J.H. Hall, F.E. Behr and R.L. Reed, J. Am. Chem. Soc., 94, 4952 (1972).
9. E.M. Kosower, Physical Organic Chemistry, Wiley: New York, Part I
(1968).
10. A.A. Frost and R.G. Pearson, Kinetics and Mechanism, Wiley: New
York, Chp. 7, edn 2 (1961).
are a similar type of pyrroles 5b,c formed from the reaction
raised a suspicion of the structures of them.Although the NMR
spectra and chemical degradation products are well consistent
with pyrrole structure, it seemed to need an unambiguous
proof.
ACKNOWLEDGEMENTS
The work was supported by a grant of Dong-A University
Fund in 2014.