A robust, efficient catalyst system for enolate arylation leading to quaternary 3-aminooxindoles

Article abstract of DOI:10.1016/j.tetlet.2009.02.076

A catalyst screening programme has revealed that a combination of Pd(0) and the N-heterocyclic carbene ligand SIPr forms a particularly robust and efficient catalyst for the formation of important quaternary 3-aminooxindoles via intramolecular enolate ary

Full text of DOI:10.1016/j.tetlet.2009.02.076

Tetrahedron Letters 50 (2009) 3318–3320
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Tetrahedron Letters
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A robust, efficient catalyst system for enolate arylation leading
to quaternary 3-aminooxindoles
b
Emma L. Watson a, Stephen P. Marsden a, , Steven A. Raw
*
a School of Chemistry and Institute of Process Research and Development, University of Leeds, Leeds LS2 9JT, UK
b AstraZeneca Process R&D, Charter Way, Silk Road Business Park, Macclesfield SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst screening programme has revealed that a combination of Pd(0) and the N-heterocyclic carbene
ligand SIPr forms a particularly robust and efficient catalyst for the formation of important quaternary
3-aminooxindoles via intramolecular enolate arylation. Catalyst loadings of 0.1 mol % give complete con-
version in under 4 h.
Received 19 December 2008
Revised 30 January 2009
Accepted 11 February 2009
Available online 14 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Oxindole
Palladium
Enolate
Arylation
N-Heterocyclic carbene
The 3,3-disubstituted oxindole skeleton occurs commonly in
medicinally active compounds of both natural and synthetic origin.
Amongst these structures, compounds bearing heteroatom substit-
uents occur frequently, as in the 3-hydroxyoxindole growth hor-
mone secretagogue SM-130686 (1),1 the 3-aminooxindole
vasopressin VIb receptor antagonist SSR-149415 (2)2 and in the
3-fluorooxindole Maxi-K channel opener BMS-204352 (3, Fig. 1).3
We have recently reported convenient syntheses of quaternary
3-alkoxy4 and 3-aminooxindoles5 by intramolecular palladium-
catalysed arylation6 of ortho-bromoanilides of readily prepared
zinc enolates of amides.12 With respect to the 3-aminooxindoles,
the high catalyst loadings and the necessity for microwave irradia-
tion present economic and practical barriers to the potential scale-
up of these reactions, even within a laboratory setting. We therefore
sought to establish more efficient conditions for the arylation under
standard convection heating conditions, and report herein a robust
catalyst system based upon a palladium(0)/NHC complex capable
of operating at loadings of 0.1 mol %.
In our previous microwave study, we had employed the
Pd(OAc)2/PCy3 catalyst system reported by Hartwig as optimal
for oxindole formation.5 Repeating the reactions using conven-
tional convection heating gave very poor conversion after 24 h
(at best 14% oxindole). Previous poor results with Pd(PPh3)4 had
led us to avoid palladium(0) complexes, but we were encouraged
to rethink this approach by the reported excellent performance
of the pre-formed complex Pd(PtBu3)2 in amide and ester enolate
a-alkoxy and a-amino acid derivatives. In collaboration with the
group of Kündig, highly enantioselective variants of these reactions
were also reported,7 which constitute the first de novo asymmetric
approach to aminooxindole derivatives.
In our initial reports4,5, we found that the conventional reactions
were extremely sluggish and that efficient conversions could most
conveniently be achieved under microwave irradiation using
10 mol % of a catalyst derived from palladium(II) acetate and tricy-
clohexylphosphine. Such high catalyst loadings are common in
oxindole-forming arylation reactions, with 5–10 mol % of the palla-
dium source being used in nearly all reported examples.8,9 This
requirement undoubtedly reflects the highly hindered nature of
the substrates as well as the relatively high pKa of the anilides, since
efficient catalyst systems (1 mol % of palladium or less) have been
reported for the intermolecular arylation of ketones,10 esters11 and
Cl
HO
F3C
OH
O
MeO
N
N
H2NOC
F3C
Cl
CONMe2
O
1
MeO
NEt2
Cl
N
O
S
2
F
O
OMe
O
MeO
N
H
3
* Corresponding author. Tel.: +44 113 343 6425; fax: +44 113 343 6565.
E-mail address: s.p.marsden@leeds.ac.uk (S.P. Marsden).
Figure 1. Representative 3-hetero-substituted oxindoles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.076

E. L. Watson et al. / Tetrahedron Letters 50 (2009) 3318–3320
3319
O
Conversions after 8 h were measured by HPLC and the results are
shown in Figure 2.
From this, we established that tricyclohexylphosphine, Dave-
Phos and SIPr offered good conversions across a range of solvents.
The use of other NHC ligands with Pd2(dba)3 gave poorer results
Br
10% Pd(PtBu3)2
O
O
Et
N
N
NaOtBu, toluene
N
O
100 oC, 8 h
N
Me Et
Me
87%
4
5
Scheme 1. Aminooxindole formation using Pd(PtBu3)2.
Table 1
Substrate scope of low-loading Pd2(dba)3/SIPr-catalysed aminooxindole formation
arylations.11,12 In the event, we were pleased to find that on treat-
ing substrate 45 with 10% Pd(PtBu3)2 under conventional heating at
100 °C for 8 h, an 87% yield of oxindole 5 was obtained (Scheme 1).
By contrast, a reaction employing the same ligand but with
Pd(OAc)2 as the palladium source gave only a 5% yield after heating
at reflux for 24 h (67% recovered starting material).
These results suggested that Pd(0)-based systems may prove to
be superior catalysts for the transformation, and a ligand and sol-
vent screen was therefore carried out using 5 mol % of Pd2(dba)3
(10 mol % palladium) and 10 mol % of a ligand. The ligands chosen
were PCy3, PtBu3 (both added as their air-stable tetrafluoroborate
salts), BINAP, DavePhos and the N-heterocyclic carbene derived
from N,N0-bis(2,6-diisopropylphenyl)-4,5-dihydro-imidazolium
chloride (SIPr), while the solvents selected were toluene, anisole,
dimethoxyethane (DME) and cyclopentyl methyl ether (CPME).
The latter is increasingly popular amongst process chemists owing
to its high boiling point and low propensity for peroxide formation.
R2
NR3R4
O
Br
O
0.5% Pd2(dba)3, 1% SIPrHCl
X
NR3R4
R2
X
3 eq NaOtBu, toluene
N
R1
N
80 oC, 4 h
R1
Entry
1
Product
Yielda (%)
O
Et
N
88 (83b)
O
N
Me
5
6
Et
N
2
3
4
5
6
7
8
9
73
81
65
88
89
81
71
68
69
O
N
Me
Et
N
O
N
Me
7
O
Et
N
F
O
N
Me
8
O
Et
N
O
N
Bn
9
O
Ph
N
O
N
Figure 2. Conversion of compound 4 after 8 h, using 10 mol % catalyst loading and
3 equiv NaOtBu. Reactions in CPME and DME were run at 80 °C, those in toluene and
anisole were run at 100 °C.
Me
10
Ph
N
O
N
Me
11
Ph
N
O
N
Me
Ph
12
O
N
F
O
N
Me
13
Et
N
10
O
N
Me
14
a
Isolated yield.
Yield using 0.05 mol % Pd2(dba)3/0.1 mol % SIPrCl.
b
Figure 3. Conversion of compound 4 using 2.5 and 5 mol % of Pd(0)/ligand.

3320
E. L. Watson et al. / Tetrahedron Letters 50 (2009) 3318–3320
than SIPr,13 while interestingly the preformed Pd(II)-SIPr complex
PEPPSi14 returned the product in a reduced 45% yield. The reaction
tolerates the range of solvents but formation of the oxindole prod-
uct was accompanied by hydrodebrominated starting material (be-
tween 1% and 8%) when using ethereal solvents, and so we elected
to continue our studies with toluene.
We next sought to examine the behaviour of the two most
effective ligands (PCy3 and SIPr) at lower catalyst loadings. The
reaction of 4 was therefore repeated with both ligands at 5% and
2.5% loadings, analysing for conversion by HPLC at hourly intervals.
As can be seen from Figure 3, at these lower loadings the SIPr-de-
rived catalyst demonstrates markedly superior performance, with
full conversion being obtained inside 2 h at 5 mol % and 4 h at
2.5 mol %.
This catalyst system was therefore adopted as optimal, and we
next sought to demonstrate the substrate scope of the process.
Thus, the catalyst was screened at 1 mol % loading against ten sub-
strates and the results are shown in Table 1.15,16 Pleasingly, the
Pd(0)/SIPr system performed well across a broad range of sub-
strates at this lower catalyst loading and temperature. The yields
of the 3-alkyl-substituted oxindoles are comparable to those previ-
ously reported, giving an average yield for compounds 5–7 of 81%,
cf. 83% under the high loading, microwave-mediated conditions.5
Moreover, we were pleased to note that the 3-aryl-substituted
oxindoles performed consistently better under the new conditions,
with the average yield for compounds 10–12 being 10% higher
than the previous values at 80%. This may reflect reduced substrate
and/or enolate decomposition at the lower reaction temperatures.
The novel fluorinated oxindoles 8 and 13 were formed in slightly
lower yields than their non-fluorinated counterparts, suggesting
a negative impact of the electronegative atom upon the reaction.
Finally, we were pleased to note that N-benzyl protecting groups
and 3-indolyl substituents were both tolerated (entries 5 and
10). In particular, no trace of the product of direct C2-arylation of
the indole was seen in the crude NMR of 14, in contrast with the
previously reported conditions.5
References and notes
1. Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.;
Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem.
2001, 44, 4641.
2. Serradeil-Le Gal, C.; Sylvain, D.; Brossard, G.; Manning, M.; Simiand, J.; Gaillard,
R.; Griebel, G.; Guillon, G. Stress 2003, 6, 199.
3. Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.; Weiner, H.; Boissard, C. G.;
Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med.
Chem. 2002, 45, 1487.
4. Hillgren, J. M.; Marsden, S. P. J. Org. Chem. 2008, 73, 6459.
5. Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10, 2905.
6. For a review, see: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
7. Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kündig, E. P. Chem.
Commun. 2008, 4040.
8. (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546;
(b) Freund, R.; Mederski, W. W. K. R. Helv. Chim. Acta 2000, 83, 1247; (c) Lee, S.;
Hartwig, J. F. J. Org. Chem. 2001, 66, 3402; (d) Zhang, T. Y.; Zhang, H. Tetrahedron
Lett. 2002, 43, 1363; (e) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704; (f) Bonnet, L. G.; Douthwaite, R. E.; Hodgson, R.
Organometallics 2003, 22, 4384; (g) Trost, B. M.; Frederiksen, M. U. Angew.
Chem., Int. Ed. 2005, 44, 308; (h) Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini,
M. J.; Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2005, 15, 5022;
(i) Arao, T.; Sato, K.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1576; (j)
Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743; (k) Arao, T.;
Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47, 1417; (l) Kündig, E. P.; Seidel,
T. M.; Jia, Y.-X.; Bernardinelli, G. Angew. Chem., Int. Ed. 2007, 46, 8484; (m)
Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.;
Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087; (n)
Malkov, A. V.; Stewart-Liddon, A. J. P.; Teply, F.; Kobr, L.; Muir, K. W.; Haigh, D.;
Kocovsky, P. Tetrahedron 2008, 64, 4011.
9. (a) For examples below 5 mol % loading, see: (a) Ref. 8c contains two examples at
1–2 mol %.; 3–6 mol %: (b) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193.
10. 1% Pd(0)/Xantphos: (a) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6,
4755; Willis, M. C.; Taylor, D.; Gillmore, A. T. Tetrahedron 2006, 62, 11513;
0.1 mol % Pd-PCP pincer complex: (b) Churruca, F.; SanMartin, R.; Tellitu, I.;
Dominguez, E. Tetrahedron Lett. 2006, 47, 3233; 0.1–2 mol % (DtBPF)PdX2
(X = Cl, Br): (c) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489.
11. 1 mol % Pd(PtBu3)2 (silyl ketene acetals with aryl bromides/chlorides): (a) Hama,
T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 11176; Liu, X.;
Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182; 0.08–1 mol % Pd(PtBu3)2 (aryl
bromides): (b) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545; 0.2–1 mol %
Pd(PtBu3)2 (aryl chlorides): (c) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549.
12. 1% Pd(dba)2/Q-phos: Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 4976.
13. Reactions carried out in toluene at 100 °C for 24 h. 1,3-Bis(2,4,6-
trimethylphenyl)-4,5-dihydroimidazolium tetrafluoroborate gave a 28% yield
of 5; 1,3-bis(tert-butyl)-4,5-dihydroimidazolium chloride gave only a 5% yield..
14. O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.;
Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 4743.
Finally, we elected to study the reaction at still lower loading, to
gauge the robustness of the system. Using a 0.1 mol % palladium/li-
gand loading, we were delighted to find that formation of oxindole
5 was still complete within 4 h (entry 1), giving an isolated yield of
83%. This represents the lowest catalyst loading used to form oxin-
doles to date.
In summary, we have developed an effective and robust new
methodology for the formation of oxindoles using standard con-
vection heating rather than microwave irradiation. Examples rep-
resenting the lowest catalyst loadings used in enolate arylation
reactions to date are found. Given the challenging nature of the
cyclisation substrates under study here, it is expected that this cat-
alyst system will offer improved performance in a range of other
arylation reactions.
15. Standard experimental protocol for arylations: To
(0.0014 mmol), 1,3-bis-(2,6-diisopropylphenyl)-imidazolinium
(0.0028 mmol) and NaOtBu (0.84 mmol) was added toluene (1.2 mL).
a
mixture of Pd2(dba)3
chloride
A
solution of the substrate (0.28 mmol) in toluene (minimum to dissolve the
substrate) was added and the mixture was stirred and heated to 80 °C for 4 h.
The reaction mixture was cooled and concentrated under reduced pressure to
leave a dark brown powdery residue. This was dry loaded onto a silica gel
column and purified by chromatography..
16. All oxindoles have been previously reported in Ref. 5, apart from the following.
Compound 8: m
max/cmꢀ1 (film) 2967, 2855, 1713, 1619; dH (300 MHz, CDCl3)
7.07–6.96 (2H, m, ArH), 6.74 (1H, dd, J 8.4, 4.1, ArH), 3.70–3.59 (4H, m,
O(CH2)2), 3.17 (3H, s, CH3), 2.68–2.58 (4H, m, N(CH2)2), 2.00–1.92 (2H, m, CH2),
1
0.67 (3H, t, J 7.4, CH3); dc (75 MHz, CDCl3) 177.5, 159.8 (d, JCF 239.3), 140.4,
3
2
2
3
131.8 (d, JCF 7.5), 115.3 (d, JCF 23.3), 112.7 (d, JCF 24.8), 108.7 (d, JCF 7.5),
71.3, 67.9, 47.6, 27.6, 26.2, 8.0; HRMS: m/z calculated for C15H20FN2O2 [MH+]:
279.1503; found 279.1496. Compound 13: m
max/cmꢀ1 (film) 2960, 2855, 1712,
1618; dH (300 MHz, CDCl3) 7.53 (2H, m, ArH), 7.37–7.27 (3H, m, ArH), 7.10–
7.00 (2H, m, ArH), 6.78 (1H, dd, J 8.5, 4.1, ArH), 3.80–3.57 (4H, m, O(CH2)2), 3.23
(3H, s, CH3), 2.69–2.45 (4H, m, N(CH2)2); dc (75 MHz, CDCl3) 175.7, 159.6 (d, 1JCF
242.2), 139.9, 138.3, 131.1 (d, 3JCF 7.5), 129.1, 128.7, 127.9, 115.6 (d, 2JCF 23.3),
Acknowledgements
We thank the EPSRC and AstraZeneca for supporting a student-
ship (to ELW).
2
3
114.2 (d, JCF 24.8), 109.2 (d, JCF 8.3), 74.8, 67.9, 48.0, 26.6; HRMS: m/z
calculated for C19H20FN2O2 [MH+]: 327.1503; found 327.1499..