Rh2(OAc)4-catalyzed regioselective intermolecular C-H insertion reactions: Novel synthesis of 2-pyrrol-3′-yloxindoles

Article abstract of DOI:10.1055/s-2002-34889

Regioselective synthesis of 2-pyrrol-3′-yloxindoles has been achieved by the reactions of cyclic diazo carbonyl compounds la-e with pyrrole and substituted pyrroles (2a-d) in the presence of rhodium(II) acetate catalyst via intermolecular C-H insertion reaction.

Full text of DOI:10.1055/s-2002-34889

LETTER
1783
Rh (OAc) -Catalyzed Regioselective Intermolecular C–H Insertion Reactions:
2
4
Novel Synthesis of 2-Pyrrol-3 -yloxindoles
N
S
ovel Synthe
s
e
is of 2-Pyrr
n
ol-3 -yloxin
g
Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India
Fax +91(278)567562; E-mail: salt@csir.res.in
Received 27 August 2002
carbonyl compounds, we turned our attention to develop
an efficient general approach to the synthesis of 2-pyrrol-
-yloxindoles using cyclic metallo-carbenoids and herein
Abstract: Regioselective synthesis of 2-pyrrol-3 -yloxindoles has
been achieved by the reactions of cyclic diazo carbonyl compounds
3
1
a–e with pyrrole and substituted pyrroles (2a–d) in the presence of
rhodium(II) acetate catalyst via intermolecular C–H insertion reac- we describe the preliminary results of these reactions.
tion.
10
The required 3-diazooxindole (1a) and substituted
11
Key words: C–H insertion reaction, oxindole, pyrrole, rhodium(II) pyrroles 2 were assembled based on the literature proce-
acetate
dures. The N-substituted-3-diazooxindoles 1b–e were
synthesized by N-alkylation of 3-diazooxindole (1a) us-
ing methyl iodide, benzyl bromide, allyl bromide or prop-
Diazo moiety has become a key component in a number argyl bromide in the presence of sodium hydride/DMF in
of synthetic transformations since from the first recorded 80% to 95% yield. Subsequently, we investigated the
1
synthesis of -diazo carbonyl compound by Curtius in rhodium(II) acetate catalyzed behavior of cyclic diazo
1
883. Diazo carbonyl compounds are extremely versatile carbonyl compounds 1 with pyrroles 2 in an intermolecu-
and have been stupendous in many catalytic carbon- lar fashion. The reaction12 of N-methyl-3-diazooxindole
carbon bond forming reactions. There has been enormous (1a) and N-benzyl pyrrole (2a) with 1 mol% rhodium(II)
interest in the use of rhodium(II) carboxylate catalysts, acetate dimer catalyst in dry dichloromethane was stirred
which are commercially available, air stable and function- at room temperature under an argon atmosphere for 6
al group tolerant for many synthetic transformations of hours. The solvent was concentrated in vacuum and the
2
-
diazo carbonyl compounds. To generate an intermedi- chromatographic purification of the reaction mixture us-
ate rhodium carbenoid, the reaction of -diazo carbonyl ing flash silica gel column chromatography furnished the
compounds in the presence of rhodium(II) carboxylates is products 3a and 4a in 70% and 3% yields, respectively
a well described method, which can undergo an array of (Scheme 1).
reactions such as cyclopropanation, C–H or X–H insertion
3
and ylide formation. The formation of carbon-carbon
bonds using C–H insertion reaction has become a poten-
tial arsenal in synthetic organic chemistry, which can pro-
ceed either by an intermolecular or intramolecular
N2
O
+
N
R2
2
N
2
,4
R1
manner. A number of reports are available in the chem-
ical literature, which describe the intramolecular insertion
of metal-stabilized carbenoids to the C–H bonds for the
construction of five-membered carbocyclic and hetero-
cyclic systems. Until our recent discovery on regiospec-
ific intermolecular insertion reaction, the intermolecular
C–H insertion is believed to be synthetically not useful
because of low selectivity and competitive intramolecular
reactions. A few literature reports are available on the
intermolecular C–H insertion of metallo-carbenoids,
which reveal the formation of a mixture of products with-
out any selectivity. The intermolecular C–H insertion re-
actions of cyclic metallo-carbenoids are not much
developed since these intermediates always have a pro-
1
1
2
1
a; R = CH
2a; R = PhCH
3
2
1
2
1b; R = PhCH
2b; R = 4-CH C H CH
2
3
6
4
2
5
1
2
1c; R = allyl
2c; R = 3,5-(CH )C H CH
3
6
4
2
6
1
2
1d; R = propargyl
2d; R = H
1
1e; R = H
2
,4
Rh (OAc)
2 4
DCM, r.t.
R2
7
11
1
0
12
N
R2
N
9
4
7
8
8
3
3
a
pensity to afford cycloadducts via 1,3-dipolar cycloaddi-
tion reactions. In continuation of our interest in
developing new synthetic strategies employing diazo
5
6
2
O
+
O
9
7a 1N
N
R1
R1
3
4
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1783,1786,ftx,en;D17202ST.pdf.
Scheme 1
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1
784
S. Muthusamy, C. Gunanathan
LETTER
The presence of amide carbonyl group in IR spectrum and yloxindoles 4 (Table 1). These reactions led to facile syn-
a characteristic singlet at = 4.55 ppm for oxindolyl 3- thesis of substituted/unsubstituted 2-pyrrol-3 -yloxin-
1
proton in H NMR spectrum of 3a, confirm the C–H inser- doles as a formal net C–H insertion process. It is very
tion. Further, the presence of a pyrrolyl proton in the interesting to mention here that nearly half of the reac-
down-field region ( = 6.70 ppm) and two pyrrolyl pro- tions, which we carried out are regiospecific. We have not
tons in the up-field region ( = 6.00 ppm) for compound obtained any other products resulting from the potential
1
14
3
a in H NMR spectrum, unequivocally confirm the re- competitive intermolecular N–H insertion reaction
1
2
15
giochemistry of C–H insertion at 2-position of pyrrole (when R , R = H) and cyclopropanation reaction (when
moiety. Similarly, the regiochemistry of product 4a was R = allyl, propargyl) of the rhodium carbenoids. Typical-
1
also confirmed.
ly the quantity of the catalyst was maintained only at 1
mol% for performing the above experiments.
Encouraged by the results obtained in these reactions, we
1
3
were further interested to carry out the reactions of sub- It is relevant to mention here that only one report exists in
stituted and unsubstituted 3-diazooxindoles 1a–e with this line where the reactions of 2-diazo-1,3-cyclohex-
pyrroles 2a–d (Table 1). The N-substituted 3-diazooxin- anedione with pyrrole have been studied by Pirrung and
8a
doles 1a–d reacts faster with N-substituted pyrroles 2a–c co-workers. However, these reactions required inert sol-
compared to the corresponding unsubstituted analog. In vent such as hexaflurobenzene and reflux conditions,
all reactions, the carbenoid insertion took place regiose- which resulted in the mixture of products with low yields
lectively at 2-position of the pyrrole to furnish the corre- without having any selectivity. Even with an excess
sponding 2-pyrrol-3 -yloxindoles 3 as the major product. amount of pyrroles (4 equiv) the cyclic diazo compounds
The crude proton NMR-spectrum of a few reaction mix- are preferably tend to react with solvent such as fluoro-
tures indicated that the presence of the minor regioisomer, benzene than pyrroles. A plausible mechanism for the re-
which could be isolated and characterized as 3-pyrrol-3 - actions of cyclic diazo carbonyl compounds 1 with
Table 1 Reactions of Cyclic Diazoamides 1a–e with Pyrroles 2a–d
Entry
R1
R2
Reaction time (h)
Yield of 3 (%)a
Yield of 4 (%)a
a
b
c
d
e
f
CH3
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
4-CH C H CH
6
6
6
6
9
5
5
5
5
9
5
5
5
5
9
9
9
9
9
70
71
67
65
65
72
75
69
71
58
73
75
70
72
66
67
74
54
64
3
4
–
–
–
5
4
–
–
–
4
3
–
–
–
4
5
–
–
PhCH2
allyl
propargyl
H
CH3
3
6
4
2
2
2
2
2
g
h
i
PhCH2
allyl
4-CH C H CH
3 6 4
4-CH C H CH
3
6
4
propargyl
H
4-CH C H CH
3 6 4
j
4-CH C H CH
3 6 4
k
l
CH3
3,5-(CH ) C H CH
3 2 6 4
2
2
2
2
2
PhCH2
allyl
3,5-(CH ) C H CH
3 2 6 4
m
n
o
p
q
r
s
3,5-(CH ) C H CH
3 2 6 4
propargyl
H
3,5-(CH ) C H CH
3 2 6 4
3,5-(CH ) C H CH
3
2
6
4
CH3
H
H
H
H
PhCH2
allyl
propargyl
a
Yields (unoptimized) refer to isolated and chromatographically pure compounds 3 and 4.
Synlett 2002, No. 11, 1783–1786 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of 2-Pyrrol-3 -yloxindoles
1785
pyrroles 2 in the presence of rhodium(II) acetate may
be proposed as given in Scheme 2. The initially formed
transient rhodium carbenoid 5 underwent insertion to the
nucleophilic 2-position with less extent to 3-position of
pyrrole moiety to produce zwitterions 6 and 7, respective-
ly. The subsequent proton transfer of these zwitterions
furnished products 3 and 4.
(5) (a) Doyle, M. P.; Kalinin, A. V. Tetrahedron Lett. 1996, 37,
371. (b) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.;
1
Zhou, Q. L. J. Org. Chem. 1996, 61, 9146. (c) Taber, D. F.;
Song, Y. J. Org. Chem. 1996, 61, 6706. (d) Wee, A. G. H.;
Liu, B. Tetrahedron Lett. 1996, 37, 145.
(
6) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh, E.;
Dastidar, P. Chem. Commun. 2002, 824.
(7) (a) Maryanoff, B. E. J. Org. Chem. 1982, 47, 3000.
b) Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssie, P.
(
J. Chem. Soc., Chem. Commun. 1981, 688. (c) Maryanoff,
B. E. J. Org. Chem. 1979, 44, 4410. (d) Maryanoff, B. E. J.
Heterocycl. Chem. 1977, 14, 177.
N2
Rh2(OAc)4
O
Rh2(OAc)4
O
-N2
(
8) (a) Pirrung, M. C.; Florian, B. J. Org. Chem. 1999, 64, 3642.
(b) Pirrung, M. C.; Zhang, J.; McPhail, A. T. J. Org. Chem.
N
R1
N
R1
1
5
1
991, 56, 6269.
(9) (a) Muthusamy, S.; Gunanathan, C.; Babu, S. A. Synthesis
002, 471. (b) Muthusamy, S.; Babu, S. A.; Gunanathan, C.;
2
-Rh2(OAc)4
2
R2
N
Jasra, R. V. Synlett 2002, 407. (c) Muthusamy, S.; Babu, S.
A.; Gunanathan, C.; Suresh, E.; Dastidar, P. Bull. Chem. Soc.
Jpn. 2002, 75, 801. (d) Muthusamy, S.; Babu, S. A.;
Gunanathan, C. Tetrahedron Lett. 2002, 43, 3931.
(e) Muthusamy, S.; Babu, S. A.; Gunanathan, C.
N
R2
H
H
+
O
O
N
R1
N
Tetrahedron Lett. 2002, 43, 5981. (f) Muthusamy, S.;
Gunanathan, C.; Babu, S. A. Tetrahedron Lett. 2001, 42,
R1
6
7
5
23.
10) Cava, M. P.; Little, R. L.; Naipier, D. R. J. Am. Chem. Soc.
958, 80, 2257.
(11) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans 1 1973,
99.
(
1
3
4
4
Scheme 2
(
12) General Procedure for the Synthesis of 2-Pyrrol-3 -
yloxindoles: In an oven-dried flask, a solution containing
1
.2 equiv of pyrrole and 1 mol% of rhodium(II) acetate
In conclusion, we have demonstrated the novel and mild
regioselective synthesis of 2-pyrrol-3 -yloxindoles by the
reactions of cyclic rhodium carbenoids generated from the
cyclic diazoamides with substituted and unsubstituted
pyrroles. The scope, mechanistic insights and further ap-
plications of this transformation are currently under active
investigation in our laboratory and will be reported in due
course.
dimer in 10 mL of dry dichloromethane (dried over
phosphorous pentoxide) was degasified under an argon
atmosphere. To this reaction mixture, a solution of 1 equiv
of appropriate cyclic diazoamide in dry dichloromethane
was added dropwise slowly for 1 h period under an argon
atmosphere at r.t. The reaction mixture was allowed to stir
and followed by TLC till the disappearance of the starting
material. The solvent was removed under reduced pressure
and the residue purified by flash silica gel column
chromatography to afford the respective C–H insertion
products.
Acknowledgement
(
13) All new compounds exhibited spectral data consistent with
their structures. Selected spectral data: 3-(1-Benzyl-1H-
pyrrol-2-yl)-1-methyl-1,3-dihydro-indol-2-one (3a):
Colorless solid. Mp 115–117 °C (hexane/EtOAc). IR (KBr):
2932, 1716, 1609, 1490, 1464, 1368, 1345, 1302, 1253,
This research was supported by Young Scientist Scheme, CSIR,
New Delhi. We thank Dr. P. K. Ghosh, Director for his encourage-
ment shown in this work. We thank referees for their valuable com-
ments for the future work. C. G. thanks CSIR, New Delhi for a
Fellowship.
–
1 1
1180, 1085, 714 cm . H NMR (200 MHz, CDCl ): = 3.09
3
(
s, 3 H, N-CH ), 4.55 (s, 1 H), 5.14 (d, 1 H, J = 16.3 Hz),
3
5
.51 (d, 1 H, J = 16.3 Hz), 5.78–5.80 (m, 1 H), 6.09 (t, 1 H,
References
J = 2.5 Hz), 6.69 (t, 1 H, J = 2.5 Hz), 6.79 (d, 1 H, J = 7.7
Hz), 6.97–7.04 (m, 3 H), 7.12–7.33 (m, 5 H). C NMR (50.3
MHz, CDCl3): = 26.9 (N-CH ) 45.1 (CH), 51.7 (N-CH ),
1
3
(
1) (a) Curtius, T. Berichte 1883, 16, 2230. (b) Curtius, T. J.
Prakt. Chem. 1888, 38, 396.
3
2
108.0 (CH), 108.7 (CH), 109.3 (CH), 123.2 (CH), 124.0
(
2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds.
From Cyclopropanes to Ylides; Wiley-Interscience: New
York, 1998.
(
1
CH), 125.7 (CH), 126.1 (quat-C), 127.2 (CH), 127.7 (CH),
28.0 (quat-C), 128.1 (CH), 128.9 (CH), 129.3 (CH), 138.9
(
(
quat-C), 144.9 (quat-C), 175.4 (quat-C). MS: m/z = 302
38.5) [M ], 212 (23.7), 211(100), 168 (14.3), 157 (17.6),
+
(3) (a) Padwa, A. J. Organomet. Chem. 2001, 617–618, 3.
1
7
3
56 (94.5), 154(13), 91(84). Anal. Calcd for C H N O: C,
9.44; H, 6.00; N, 9.26. Found: C, 79.26; H, 5.98; N, 9.23.
-(1-Benzyl-1H-pyrrol-3-yl)-1-methyl-1,3-dihydro-
(
(
b) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.
c) Doyle, M. P.; McKervey, M. A. Chem. Commun. 1997,
20 18 2
983. (d) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96,
223. (e) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51,
10811. (f) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed.
indol-2- one (4a): Colorless solid. Mp 96–98 °C (hexane/
EtOAc). IR (KBr): 2928, 1718, 1627, 1469, 1463, 1368,
–
1 1
1355, 1309, 1263, 1187, 1066, 720 cm . H NMR (200
Engl. 1994, 33, 1797. (g) Doyle, M. P. Chem. Rev. 1986, 86,
19.
4) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
MHz, CDCl3): = 3.18 (s, 3 H, N-CH ), 4.56 (s, 1 H), 4.99
9
3
(s, 2 H, N-CH ), 6.11 (t, 1 H, J = 2.2 Hz), 6.61–6.73 (m, 2
(
2
Synlett 2002, No. 11, 1783–1786 ISSN 0936-5214 © Thieme Stuttgart · New York

1
786
S. Muthusamy, C. Gunanathan
LETTER
3-[1-(3,5-Dimethyl-benzyl)-1H-pyrrol-2-yl]-1-methyl-
H), 6.93 (d, 1 H, J = 7.1 Hz), 7.05–7.36 (m, 8 H). MS:
+
m/z = 212 [M ]. Anal. Calcd for C H N O: C, 79.44; H,
1,3-dihydro-indol-2-one (3k): Gray color solid. Mp 156–
2
0
18
2
6
.00; N, 9.26. Found: C, 79.19; H, 6.02; N, 9.29.
158 °C (hexane/EtOAc). IR (KBr): 2920, 1717, 1609, 1492,
–1 1
1-Methyl-3-[1-(4-methyl-benzyl)-1H-pyrrol-2-yl]-1,3-
1467, 1372, 1343, 1304, 1127, 1086, 843, 750 cm . H
NMR (200 MHz, CDCl ): = 2.25 (s, 6 H, ArCH ), 3.13 (s,
dihydro-indol-2-one (3f): Colorless oil. IR (neat): 2983,
3
3
1
713, 1613, 1493, 1470, 1421, 1372, 1349, 1305, 1265,
3 H, N-CH ), 4.59 (s, 1 H), 5.07 (d, 1 H, J = 16.2 Hz), 5.45
3
–
1 1
1125, 1086, 740 cm . H NMR (200 MHz, CDCl ): = 2.29
(d, 1 H, J = 16.2 Hz), 5.79 (t, 1 H, J = 1.8 Hz), 6.09 (t, 1 H,
J = 2.9 Hz), 6.64 (s, 2 H), 6.69 (t, 1 H, J = 1.8 Hz), 6.75–6.86
(m, 2 H), 7.01 (t, 1 H, J = 7.45 Hz), 7.14 (d, 1 H, J = 7.18
3
(s, 3 H, ArCH ), 3.09 (s, 3 H, N-CH ), 4.55 (s, 1 H), 5.10 (d,
3
3
1
H, J = 16.1 Hz), 5.46 (d, 1 H, J = 16.1 Hz), 5.77 (t, 1 H,
1
3
J = 1.7 Hz), 6.07 (t, 1 H, J = 2.9 Hz), 6.67 (t, 1 H, J = 1.7
Hz), 7.28 (t, 1 H, J = 7.59 Hz). C NMR (50.3 MHz,
Hz), 6.77 (d, 1 H, J = 7.8 Hz), 6.99–7.29 (m, 7 H). 1 C NMR
3
CDCl ): = 21.9 (CH ), 26.9 (CH ,) 45.2 (CH), 51.7 (N-
3
3
3
(
50.3 MHz, CDCl3): = 21.8 (CH ), 27.0 (CH ,) 45.2 (CH),
CH ), 107.8 (CH), 108.6 (CH), 109.2 (CH), 123.1 (CH),
3
3
2
5
1.6 (N-CH ), 107.9 (CH), 108.7 (CH), 109.3 (CH), 123.2
124.0 (CH), 125.1 (CH), 125.6 (CH), 127.2 (quat-C), 127.3
(quat-C), 128.3 (quat-C), 129.0 (CH), 129.7 (CH), 138.7
(quat-C), 138.9 (quat-C), 144.9 (quat-C), 175.5 (quat-C).
2
(
CH), 124.0 (CH), 125.7 (CH), 127.3 (CH), 128.3 (quat-C),
129.0 (CH), 130.0 (CH), 135.8 (quat-C), 137.7 (quat-C),
+
+
145.0 (quat-C), 175.4 (quat-C). MS: m/z = 316 [M ]. Anal.
MS: m/z = 330 [M ]. Anal. Calcd for C H N O: C, 79.97;
2
2
22
2
Calcd for C H N O: C, 79.72; H, 6.37; N, 8.85. Found: C,
H, 6.71; N, 8.48. Found: C, 79.74; H, 6.69; N, 8.51.
(14) (a) Bashford, K. E.; Cooper, A. L.; Kane, P. D.; Moody, C.
J.; Muthusamy, S.; Swann, E. J. Chem. Soc., Perkin Trans. 1
2002, 1672. (b) Bagley, M. C.; Buck, R. T.; Hind, S. L.;
Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1998, 591.
(c) Bagley, M. C.; Moody, C. J. J. Chem. Soc., Perkin Trans.
1 1998, 601.
21
20
2
79.92; H, 6.35; N, 8.82.
1-Methyl-3-[1-(4-methyl-benzyl)-1H-pyrrol-3-yl]-1,3-
dihydro-indol-2-one (4f): Colorless oil. IR (neat): 2965,
1
715, 1612, 1486, 1467, 1451, 1363, 1347, 1320, 1280,
–
1 1
1116, 1085, 735 cm . H NMR (200 MHz, CDCl ): = 2.26
3
(
s, 3 H, ArCH ), 3.19 (s, 3 H, N-CH ), 4.55 (s, 1 H), 4.94 (s,
3
3
2
6
2
7
H, N-CH ), 6.10 (t, 1 H, J = 2.4 Hz), 6.59–6.64 (m, 2 H),
(15) (a) Hu, W.; Timmons, D. J.; Doyle, M. P. Org. Lett. 2002, 4,
901. (b) Davies, H. M. L.; Townsend, R. J. J. Org. Chem.
2001, 66, 6595; and references cited therein.
2
.83 (d, 1 H, J = 7.4Hz), 7.01–7.17 (m, 5 H), 7.26–7.32 (m,
+
H). MS: m/z = 316 [M ]. Anal. Calcd for C H N O: C,
2
1
20
2
9.72; H, 6.37; N, 8.85. Found: C, 79.89; H, 6.39; N, 8.87.
Synlett 2002, No. 11, 1783–1786 ISSN 0936-5214 © Thieme Stuttgart · New York