Early amidation approach to 3-[(4-amido)pyrrol-2-yl]-2-indolinones

Article abstract of DOI:10.1021/jo034304q

A new synthesis of 3-[(4-amido)pyrrol-2-yl]-2-indolinones has been developed, where the amide side chain was installed prior to pyrrole formation. This strategy precludes the need to use any coupling reagents to install the amide side chain. This process includes a zinc-free alternative to the Knorr pyrrole synthesis.

Full text of DOI:10.1021/jo034304q

ethyl ester gave the key acid-aldehyde 7.3 This was then
coupled with excess diamine 8 using CDI (carbonyl
diimidazole), leading to the imine-amide intermediate
9. Addition of 5-fluorooxindole 10 to the crude reaction
mixture led to the target molecule.
Ea r ly Am id a tion Ap p r oa ch to
3-[(4-Am id o)p yr r ol-2-yl]-2-in d olin on es†
J erad M. Manley, Monica J . Kalman, Brian G. Conway,
Cynthia C. Ball, J effrey L. Havens, and
Rajappa Vaidyanathan*
The approach described in Scheme 1 relied on a late-
stage coupling of the pivotal pyrrole core 7 with diamine
8 and 5-fluorooxindole 10. An advantage of this strategy
was that it rendered the process amenable to the rapid
synthesis of several analogues. One could imagine treat-
ing pyrrole 7 with a variety of amines and substituted
oxindoles to afford a host of indolinones. However, this
approach had two important limitations from the stand-
point of commercial process development for compound
1. The amidation reaction had to be performed on an
activated carboxylic acid derivative. In such an event, the
presence of the aldehyde moiety led to the formation of
the imine in addition to the desired amide. While the
imine itself did not pose problems in the subsequent aldol
coupling step, its formation necessitated the use of excess
diamine in the amide formation step. This, although
acceptable in the case of inexpensive amines, was an
issue when more expensive amines were involved. Sub-
sequent removal of the excess amine could also prove
problematic. Moreover, of the several known amide
coupling reagents, very few (such as EDC and CDI) gave
satisfactory results. Removal of the byproducts (arising
from the activating agent) from these coupling reactions
could be problematic and should be carefully considered
while developing workup conditions. The use of these
activating agents was also undesirable from an atom
economy standpoint, since no portion of the reagent was
incorporated in the final molecule. These limitations
prompted us to examine alternate approaches to the
target compound.
Chemical Research and Development, Pfizer Inc.,
0200-1500-91-201, 7000 Portage Road,
Kalamazoo, Michigan 49001
rajappa.vaidyanathan@pfizer.com
Received March 7, 2003
Abstr a ct: A new synthesis of 3-[(4-amido)pyrrol-2-yl]-2-
indolinones has been developed, where the amide side chain
was installed prior to pyrrole formation. This strategy
precludes the need to use any coupling reagents to install
the amide side chain. This process includes a zinc-free
alternative to the Knorr pyrrole synthesis.
A number of indolinone derivatives have been known
to exhibit pharmaceutical activity. Specifically, com-
pounds containing an amide group on a heterocyclic ring
condensed with the indolinone have been shown to
modulate protein kinase activity. Such compounds could
possibly be used to treat a variety of conditions such as
various types of cancer, mastocystosis, allergy associated
chronic rhinitis, diabetes, arthritis, angiogenesis, im-
munological and cardiovascular disorders, etc. Of this
class of compounds, 1 is being investigated in phase I/II
clinical trials in cancer.1
We envisioned that the issue of excess diamine could
be resolved if one were to install the aldehyde moiety
after amide bond formation. Our new retrosynthetic
analysis is presented in Scheme 2, whereby the pyrrole
core may be assembled with the amide chain in place.
To synthesize pyrrole 11 via the Knorr reaction, one
would have to start from oxime 3 (derived from tert-butyl
acetoacetate) and â-ketoamide 12. This compound can be
made from diketene 13 and N,N-diethylethylenediamine
8. This approach would circumvent the need to use excess
amine, as well as amide coupling reagents. Our results
are discussed below.
Treatment of diketene with N,N-diethylethylenedi-
amine in tert-butyl methyl ether furnished â-ketoamide
12 in excellent yield (Scheme 3).4 The â-ketoamide was
prone to decomposition and, therefore, had to be either
used immediately or stored at -20 °C. The product was
typically contaminated with polymeric material that
carried over from diketene. However, this did not cause
any problems in the downstream chemistry. Oxime 3,
derived from tert-butyl acetoacetate, was treated with
The first-generation synthesis of this compound uti-
lized the approach depicted in Scheme 1 where the
pyrrole core was assembled via a Knorr pyrrole reaction
between oxime 3 and ethyl acetoacetate (4).2 tert-Butyl
acetoacetate 2 was treated with NaNO2/HOAc to give the
corresponding oxime 3, which was allowed to react with
ethyl acetoacetate 4 in the presence of zinc under the
classical Knorr pyrrole reaction conditions to furnish
pyrrole 5. This compound underwent facile decarboxy-
lation upon treatment with HCl to give the R-free pyrrole
6. Vilsmeier formylation followed by hydrolysis of the
† This paper is dedicated to the memory of Dr. Thomas J . Fleck.
(1) (a) Tang, P. C.; Miller, T.; Li, X.; Sun, L.; Wei, C. C.; Shirazian,
S.; Liang, C.; Vojkovsky, T.; Nematalla, A. S. WO 01/60814. (b) Mendel,
D. B.; Laird, A. D.; Xin, X.; Louie, S. G.; Christensen, J . G.; Li, G.;
Schreck, R. E.; Abrams, T. J .; Ngai, T. J .; Lee, L. B.; Murray, L. J .;
Carver, J .; Chan, E.; Moss, K. G.; Haznedar, J . O.; Sukbuntherng, J .;
Blake, R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon,
G.; Cherrington, J . M. Clin. Cancer Res. 2003, 9, 327.
(3) de Groot, J . A.; Roy, G. M. G-L.; van Koveringe, J . A.;
Lugtenburg, J . Org. Prep. Proced. Int. 1981, 13, 97.
(4) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.; Stille, J .
R. J . Org. Chem. 1997, 62, 1033.
(2) (a) Fischer, H. Organic Syntheses; Wiley: New York, 1943;
Collect. Vol. II, p 202. (b) Treibs, A.; Hintermeier, K. Chem. Ber. 1954,
86, 1167.
10.1021/jo034304q CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/11/2003
J . Org. Chem. 2003, 68, 6447-6450
6447

SCHEME 1
SCHEME 2
SCHEME 3
formed at pH 9 dissolved at pH 13-14. A series of water-
CH2Cl2 extractions led to the isolation of the product in
53% yield. Although this strategy worked well, we still
had to go through pH 9 to reach pH 13! In other words,
there was no way to avoid precipitation of zinc salts,
although they could be dissolved later. We believed that
such gelatinous salts could cause further complications
during scale-up (like binding the agitator) and sought
other alternatives to the zinc chemistry. The environ-
mental concerns associated with the use and disposal of
stoichiometric zinc was another important factor in our
inclination to pursue other options.
One attractive alternative to the zinc chemistry was
to use hydrogenation conditions to form the pyrrole core.
Oxime reduction5 and pyrrole synthesis6 using hydroge-
nation conditions are well-known in the literature;
however, there are very few reports of Knorr synthesis
of pyrroles bearing amide side chains under hydrogena-
tion conditions.7 To our delight, hydrogenation of a
mixture of amide 12 and oxime 3 over 10 wt % Pd/C
catalyst in acetic acid (45 psig, 65-70 °C, 7 h) led to the
amide 12 in the presence of zinc and acetic acid according
to the classic Knorr pyrrole formation conditions, which
led to pyrrole 14. On a small scale, this reaction worked
fairly well (> 60% yield). However, as the reaction scale
was increased, workup proved problematic. Typically, the
products of Knorr reactions (when â-ketoesters are used)
are isolated by a water knock-out.2 In our case, the
presence of an extra amine functionality in 14 rendered
precipitation of the product from an acidic reaction
mixture impossible. The mixture had to be basic for the
product to precipitate out; unfortunately, at pH 9, zinc
salts crashed out of solution, making an extraction or
isolation extremely difficult. Attempts to filter off the zinc
salts before proceeding with the extractive workup proved
disastrous. The workup problem was minimized by
adding CH2Cl2 to the reaction mixture at the end of the
pyrrole formation reaction, followed by basification with
50% NaOH until the pH was 13-14. The zinc salts that
(5) (a) Itoh, K.; Sugihara, H.; Miyake, A.; Tada, N.; Oka, Y. Chem.
Pharm. Bull. 1978, 26, 504. (b) Doyle, T. W.; Belleau, B.; Luh, B.-Y.;
Conway, T. T.; Menard, M.; Douglas, J . L.; Chu, D. T.-W.; Lim, G.;
Morris, L. R.; Rivest, P.; Casey, M. Can. J . Chem. 1977, 55, 484.
(6) (a) Winans, C. F.; Adkins, H. J . Am. Chem. Soc. 1933, 55, 4167.
(b) Ochiai, E.; Tsuda, K.; Ikuma, S. Chem. Ber. 1935, 68, 1710.
(7) Moon, M. W.; Church, A. R.; Steinhards, A. Ger. Offen. DE
2235811, 1973.
6448 J . Org. Chem., Vol. 68, No. 16, 2003

SCHEME 4
nones. This approach relies on the installation of the
amide side chain prior to pyrrole formation. We have
demonstrated that the pyrrole could be assembled with
the amide side chain in place via a hydrogenation
reaction. The hydrogenation strategy helped avoid the
scale-up and environmental issues typically associated
with the use of zinc in the Knorr pyrrole synthesis
reaction. This early amidation route circumvents the
need to use activating agents and excess amine in the
amide formation step.
Exp er im en ta l Section
N-[2-(Dieth ylam in o)eth yl]-3-oxobu tan am ide 12. Diketene
(30.0 g; 357 mmol) was added to a 1000 mL three-neck round-
bottom flask equipped with an addition funnel, N2 inlet, and
overhead stirrer. tert-Butyl methyl ether (500 mL) was trans-
ferred to the flask, and the solution was cooled to 0-5 °C using
an ice-water bath. N,N-Diethylethylenediamine (33.3 g; 287
mmol) was added to the solution dropwise, maintaining the
temperature below 5 °C. The ice-water bath was removed, and
the solution was allowed to stir overnight at room temperature.
Removal of the solvent in vacuo gave 53.1 g (265 mmol) of the
product (93%), which was carried on to the next step without
further purification.
clean formation of pyrrole 14. The reaction workup was
extremely simplesthe catalyst was filtered off, and the
filtrate was basified to pH 11-13 and extracted with CH2-
Cl2 to afford the product in 77% yield. These results
demonstrated that the hydrogenation procedure was a
viable alternative to the zinc protocol, especially for
compounds that cannot be extracted or precipitated under
acidic conditions.
ter t-Bu tyl 4-[[[2-(d ieth yla m in o)eth yl]a m in o]ca r bon yl]-
3,5-d im et h yl-1H -p yr r ole-2-ca r b oxyla t e 14 via t h e Zin c
P r otocol. tert-Butyl acetoacetate (60.0 g; 379 mmol) was added
to a 1000 mL three-neck round-bottom flask equipped with a
stopper, addition funnel, and temperature probe. Acetic acid (120
mL) was added to the flask and the mixture cooled to 5 °C. A
solution of NaNO2 (27.0 g; 391 mmol) in H2O (60 mL) was added
dropwise over 45 min to the three-neck flask, keeping the
temperature below 10 °C. Upon completion of the addition, H2O
(45 mL) was added, and the solution was stirred for an additional
30 min and then allowed to stand at room temperature for 3 h.
TLC (SiO2; 30% ethyl acetate/hexanes) indicated complete
consumption of starting material by this time. A pale yellow
solution of oxime 3 was observed at this stage. The reaction was
assumed to go to completion in quantitative yield (71.0 g; 379
mmol), and the solution was used directly in the next step.
Amide 12 (68.5 g; 342 mmol) was added to a 1000 mL three-
neck round-bottomed flask along with acetic acid (175 mL). The
resulting solution was heated to 65 °C, and Zn (1/8 quantity of
75.2 g; 1150 mmol) was added to the flask. Once at 65 °C, a
solution of oxime 3 (1/8 quantity of 66.9 g; 357 mmol) was added.
This process was continued until all the zinc and oxime were
added. There was a 10-15 °C exotherm between additions;
however, the reaction temperature was brought back to 65 °C
before the next addition. After the last addition, the reaction
mixture was heated to 75 °C and allowed to stir for 1 h. The
reaction vessel was then cooled to room temperature, and the
slurry was filtered through a coarse frit to remove the unreacted
zinc. The filtrate was then transferred to a 2000 mL three-neck
round-bottom flask equipped with an N2 inlet and overhead
stirrer. H2O (300 mL) was added to the flask, and the solution
was basified with 50% NaOH solution. Once the pH of the
reaction solution reached 9.0, zinc salts started to form; excess
NaOH was added until all zinc salts dissolved. The reaction
mixture was then split into two batches, and each batch was
extracted with CH2Cl2 (3 × 250 mL). The organic layers from
both batches were combined and washed with brine (300 mL).
The organics were concentrated and recrystallized from aceto-
nitrile. The product, pyrrole 14, was isolated as off-white crystals
(60.6 g; 181 mmol; 53%). TLC conditions: 86:12:2 CH2Cl2/MeOH/
NH4OH; IR (NaBr) 3333, 3284, 3005, 1687, 1601, 1531, 1502,
Having assembled the pyrrole core, we endeavored to
attach the oxindole side chain and complete the synthe-
sis. We envisioned that the previously noted decarboxy-
lation conditions (HCl/EtOH) used to convert 5 to 6 could
be extrapolated to the current synthesis. However, in this
case, when HCl was used, the decarboxylated product 15
was obtained in good yield, but dimer 17 was also formed.
It was found that this impurity was formed early in the
reaction and increased over time. Several acids were
screened to see if the decarboxylation could be effected
cleanly. We discovered that the use of 1 M H2SO4 in
MeOH (3:1 in H2O) at 65 °C led to clean decarboxylation
without any trace of the undesired byproduct.8 The use
of TFA at lower temperature also gave satisfactory
results. The R-free pyrrole thus obtained (15) was treated
with chloromethylenedimethylammonium chloride in
acetonitrile to form the Vilsmeier adduct 16 in situ.9
Addition of 5-fluorooxindole and KOH to the reaction
mixture at this stage afforded the desired product 1,
which was isolated in 74% yield upon direct filtration of
the reaction mixture (Scheme 4).
1
1434, 1326, 1286 cm-1; H NMR (400 MHz, CDCl3) δ 8.92 (s, 1
In conclusion, we have successfully developed an early
amidation approach to 3-(4-amido)pyrrol-2-yl-2-indoli-
H), 6.43 (s, 1 H), 3.45 (q, J ) 5.4 Hz, 2 H), 2.62 (t, J ) 5.9 Hz,
2 H), 2.55 (q, J ) 7.0 Hz, 4 H), 2.47 (s, 3 H), 2.46 (s, 3 H), 1.55
(s, 9 H), 1.01 (t, J ) 7.1 Hz, 6 H); 13C NMR (100 MHz, CDCl3)
δ 165.7, 161.0, 134.5, 125.7,118.8, 118.3, 80.9, 51.5, 46.5, 36.7,
28.5, 13.4, 11.8, 11.7; HRMS (ES) found m/z 338.2447 (M + H+),
(8) Battersby, A. R.; Dutton, J . C.; Fookes, C. J . R. J . Chem Soc.,
Perkin Trans. 1 1988, 1569.
(9) Hafner, K.; Bernhard, C. Angew. Chem. 1957, 69, 533.
C
18H31N3O3 + H requires 338.2443.
J . Org. Chem, Vol. 68, No. 16, 2003 6449

ter t-Bu tyl 4-[[[2-(Dieth yla m in o)eth yl]a m in o]ca r bon yl]-
3,5-d im eth yl-1H-p yr r ole-2-ca r boxyla te 14 via Hyd r ogen a -
tion . tert-Butyl acetoacetate (30 g; 190 mmol) was added to
three-neck round-bottom flask along with acetic acid (30 mL).
The mixture was cooled to 0-3 °C under N2, and a solution of
NaNO2 (18.3 g; 265 mmol) dissolved in H2O (35 mL) was added
dropwise maintaining the temperature below 10 °C. Once the
addition was complete, the reaction solution was slowly warmed
to room temperature. When the reaction was deemed complete
by TLC (2 h), the mixture was partitioned between aqueous KCl
solution (40 mL) and diethyl ether (50 mL). The aqueous layer
was extracted further with diethyl ether (3 × 25 mL). The
combined organics were washed with H2O (3 × 35 mL), dried
over Na2SO4, and concentrated in vacuo to afford oxime 3 as a
pale yellow oil which was used in the next step without further
purification.
Oxime 3 (20.0 g; 107 mmol) was added to a 500 mL Parr vessel
along with 2.0 g of 5% dry Pd/C. Amide 12 (21.4 g; 107 mmol)
was dissolved in acetic acid (220 mL) and charged to the Parr
bottle. The vessel was purged with N2 and H2 and the mixture
hydrogenated at 45 psig by heating at 65 °C for 7 h. After this
time, the reaction mixture was cooled to room temperature and
filtered to remove Pd, and the cake was washed with acetic acid.
The filtrate was neutralized with 50% aqueous NaOH. CH2Cl2
(500 mL) was added, followed by more 50% aqueous NaOH until
the pH of the aqueous phase was 13. The mixture was trans-
ferred to a separatory funnel, and the layers separated. The
aqueous layer was extracted with CH2Cl2 (3 × 350 mL), and
the combined organics were washed with H2O (2 × 250 mL).
The washes were back-extracted with CH2Cl2 (250 mL), and the
combined organics were concentrated in vacuo. The residue was
dissolved in hot CH3CN, and the resulting solution was filtered
and cooled. The solids that formed were isolated by filtration to
afford 27.7 g (83 mmol; 77%) of pyrrole 14.
with H2O (3 × 300 mL) followed by a brine wash (300 mL). The
organic phases were concentrated to dryness to yield 15 as a
light brown oil (14.2 g; 60 mmol; quantitative yield) which was
used in the next step without further purification: IR (NaBr)
3246, 2969, 1624, 1577, 1529, 1504 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 8.30 (s, 1 H), 6.44 (s, 1 H), 6.33 (s, 1 H) 3.45 (q, J ) 5.8
Hz, 2 H), 2.62 (t, J ) 6.1 Hz, 2 H), 2.56 (q, J ) 7.1 Hz, 4 H), 2.46
(s, 3 H), 2.23 (s, 3 H), 1.01 (t, J ) 7.0 Hz, 6 H); 13C NMR (100
MHz, CDCl3) δ 166.7, 132.6, 117.5, 114.3, 51.6, 46.5, 36.6, 13.5,
12.6, 11.7; HRMS (ES) found m/z 238.1919 (M + H+), C13H23N3O
+ H requires 238.1921.
N-[2-(Diet h yla m in o)et h yl]-5-[(Z)-(5-flu or o-2-oxo-1,2-d i-
h ydr o-3H-in dol-3-yliden e)m eth yl]-2,4-dim eth yl-1H-pyr r ole-
3-ca r boxa m id e 1. Chloromethylenedimethylammonium chlo-
ride (7.8 g; 61 mmol) was added to a 1000 mL three-neck round-
bottom flask equipped with an addition funnel, N2 inlet, and
overhead stirrer. Acetonitrile (84 mL) was added dropwise via
the addition funnel to the flask. Compound 15 (13.7 g; 58 mmol)
was dissolved in acetonitrile (116 mL) and added to the flask
through the addition funnel. The amide chloride gradually
dissolved and the reaction solution turned dark orange. After
15 min, an orange solid precipitated out of solution. The reaction
was complete in 40 min. The 5-fluorooxindole (9.2 g; 61 mmol)
and pulverized KOH (11.9 g; 213 mmol) were added to the
reaction mixture, and stirring was continued. Acetonitrile (10
mL) was used to help transfer over reagents. An orange solid
crashed out immediately. The reaction mixture was stirred at
room temperature for 3.5 h, filtered, and dried to give 1 (16.9 g;
42 mmol) in 74% yield: IR (NaBr) 3298, 3230, 2968, 1676, 1627,
1590, 1544, 1498, 1334 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.75
(dd, J ) 9.4, 2.5 Hz, 1 H), 7.71 (s, 1 H), 7.43 (t, J ) 5.6 Hz, 1 H),
6.92 (td, J ) 9.1, 2.5 Hz, 1 H), 6.84 (dd, J ) 8.5, 4.6 Hz, 1 H),
3.41-3.36 (m, 2 H), 2.65-2.58 (m, 6 H), 2.47 (s, 3 H), 2.43 (s, 3
H), 1.07 (t, J ) 7.1 Hz, 6 H); HRMS (ES) found m/z 399.2204
(M + H+), C22H27FN4O2 + H requires 399.2196.
N-[2-(Diet h yla m in o)et h yl]-2,4-d im et h yl-1H -p yr r ole-3-
ca r boxa m id e 15. Pyrrole 14 (20.0 g; 60 mmol) was added to a
2000 mL three-neck round-bottom flask equipped with an
addition funnel, N2 inlet, and overhead stirrer. A 3:1 mixture of
1 M H2SO4/MeOH and H2O (1200 mL) was added dropwise (over
15 min) to the flask with stirring. Once the addition was
complete, the solution was stirred at 65 °C for 3.5 h. The reaction
mixture was cooled to 0-5 °C in an ice-water bath. H2O (200
mL) was added, and the solution brought to a pH of 12-14 with
50% NaOH. Some salt formation was observed. The salts were
easily filtered off, and the filtrate was transferred to a 2000 mL
separatory funnel. The aqueous mixture was extracted with CH2-
Cl2 (3 × 200 mL). The organic phases were combined and washed
Ack n ow led gm en t. We thank Drs. Peter G. M.
Wuts, Thomas A. Runge, Kevin E. Henegar, and Peter
Giannousis for helpful discussions. Mr. Mark Mowery’s
help in the identification of impurity 17 is gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of compounds 14 and 15. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O034304Q
6450 J . Org. Chem., Vol. 68, No. 16, 2003