Chiral N-heterocyclic carbene ligands for asymmetric catalytic oxindole synthesis

Article abstract of DOI:10.1039/b810858g

The Pd-catalysed asymmetric intramolecular α-arylation of amide enolates containing heteroatom substituents gives chiral 3-alkoxy or 3-aminooxindoles in high yield and with enantioselectivities up to 97% ee when a new chiral N-heterocyclic carbene ligand is used. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810858g

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COMMUNICATION
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Chiral N-heterocyclic carbene ligands for asymmetric catalytic oxindole
synthesiswz
Yi-Xia Jia,a J. Mikael Hillgren,b Emma L. Watson,b Stephen P. Marsdenb and
E. Peter Ku
¨
ndig*a
Received (in Cambridge, UK) 26th June 2008, Accepted 18th July 2008
First published as an Advance Article on the web 1st August 2008
DOI: 10.1039/b810858g
The Pd-catalysed asymmetric intramolecular a-arylation of
amide enolates containing heteroatom substituents gives chiral
3-alkoxy or 3-aminooxindoles in high yield and with enantio-
selectivities up to 97% ee when a new chiral N-heterocyclic
carbene ligand is used.
Oxindoles containing a quaternary benzylic center constitute a
common structural motif in many natural products and biolo-
gically active compounds.1 Among them, oxindoles with
heteroatoms at the stereogenic center are a useful class of
compounds in the field of medicinal chemistry, including the
potent growth hormone secretagogue SM-130686 (A),2 the
clinical candidate AG-041R (B) as gastrin/CCK-B receptor
antagonist3 and SSR-149415 (C), a drug now in clinical trials
for treatment of anxiety and depression.4 Owing to the signifi-
cance of this structural motif, the development of a catalytic
asymmetric synthetic method for these compounds is highly
valuable. Several examples of transition-metal-catalysed asym-
metric preparation of 3-hydroxyoxindoles have been reported;5
however, to the best of our knowledge, there is no example of
the catalytic asymmetric synthesis of 3-aminooxindoles. More-
over, while the asymmetric palladium-catalysed a-arylation of
amides, pioneered by Hartwig,6 provides an efficient access to
chiral 3-alkyl-3-aryloxindoles, there is no report on the applica-
tion of this process to the synthesis of oxindoles with hetero-
atoms at the stereogenic center.
Scheme 1 The Pd-catalysed asymmetric intramolecular a-arylation
of amides to give chiral 3-alkoxy- or 3-amino-3-aryloxindoles.
(NHC’s) and their successful application in the palladium-
catalysed intramolecular a-arylation of amides, yielding chiral
3-alkyl-3-aryloxindoles with excellent enantiomeric purity (up
to 95% ee).7 Here we report the preliminary results on the
enantioselective synthesis of chiral 3-alkoxyoxindoles and
3-aminooxindoles with high yield and enantioselectivity, using
the new chiral NHC ligand L3 (Scheme 1).8
Initially we carried out the reaction of substrate 1a in the
presence of 5 mol% Pd(dba)2, 5.5 mol% (S,S)-L1 and 1.5 eq.
Table 1 Optimization of the arylation of 1a with (S,S)-L1 as a
liganda
Entry [Pd]
Solvent Base
t/h Yieldb (%) Eec (%)
1
2
3
4
5
6
7
8
Pd(dba)2
DME
THF
tBuONa
24 46
24 Trace
14 97
24 43
24 23
24 43
14 63
24 35
24 16
80
79
76
77
82
77
75
82
82
80
—
—
Pd(dba)2
Pd(dba)2
Pd(dba)2
tBuONa
Toluene tBuONa
Dioxane tBuONa
Recently, two of us (YJ and EPK) have reported the
synthesis of new chiral N-heterocyclic carbene ligands
Pd(C3H5)Cl Toluene tBuONa
Toluene tBuONa
Toluene tBuONa
Toluene tBuOK
Toluene tBuOLi
Toluene NaHMDS 24 31
Toluene NaOTMS 24
Toluene tBuONa
a Department of Organic Chemistry, University of Geneva, 30 Quai
Ernest Ansermet, 1211 Genea 4, Switzerland.
E-mail: Peter.Kundig@.unige.ch
Pd(OAc)2
Pd2(dba)3
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
b School of Chemistry, University of Leeds, Leeds, UK LS2 9JT.
E-mail: S.P.Marsden@leeds.ac.uk
9
10
11
12d
0
0
w This article is dedicated to Prof. Andy Holmes on the occasion of his
65th birthday.
z Electronic supplementary information (ESI) available: Experimental
details for the preparation of the reported compounds. See DOI:
10.1039/b810858g
24
a
b
0.2 mmol substrate, 4 mL solvent. Isolated yield. Determined by
c
d
chiral HPLC. Without ligand.
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Table 2 Screening of ligands for the arylation reaction of 1aa
Table 3 Substrate scope of chiral 3-alkoxy-3-aryloxindoles
Yieldb
(%)
Entry
1
Producta
t/h Yieldb (%)
Eec (%)
Entry
L*
Solvent
t/h
Eec (%)
(+)-2a
(+)-2b
14 99
96 91
92
1
2
3
4
5e
a
(S,S)-L1
(S,S)-L2
(S,S)-L2
(R,R)-L3
(R,R)-L3
Toluene
Toluene
DME
Toluene
Toluene
14
36
24
14
96
97
71
76
82
90
92
97
97d
29
99d
91d
2
16 93
85
b
c
0.2 mmol substrate, 4 mL solvent. Isolated yield. Determined by
d
e
chiral HPLC. (+)-(S)-2a. At 25 1C.
3
4
(+)-2c
(+)-2d
16 94
16 99
79
91
tBuONa at 50 1C in DME, the same conditions which pre-
viously led to good results for synthesis of 3-alkyl-3-aryl-
oxindoles.7 The reaction proceeded smoothly to give oxindole
2a in moderate yield (46%) and good enantioselectivity (80%)
after 24 h (Table 1, entry 1). Among the solvents examined,
toluene gave the highest yield although we noted a small
erosion in asymmetric induction (Table 1, entry 3). Different
palladium sources, such as Pd(C3H5)Cl, Pd(OAc)2 and
Pd2(dba)3, were tested next and Pd(dba)2 was found to be
the most effective (Table 1, entries 5–7). Product yields were
5
(+)-2e
18 89
96
t
t
lower when BuOK, BuOLi or NaHMDS were used in place
of tBuONa (Table 1, entries 8–10). NaOTMS did not promote
this arylation reaction (Table 1, entry 11) and no product was
observed either when the reaction was carried out in the
absence of the NHC ligand (Table 1, entry 12).
6
7
(+)-2f
(+)-2g
36 45
82
91
20 90
While yields were very good, product enantioselectivity did
not reach the level we strove for. We thus turned to other chiral
NHC ligands. The reaction with (S,S)-L2, the best performer
8
(-)-2h
18 99
86
90
9
(+)-2i
16 92
10
(+)-2j
16 95
20 76
93
93
11
(+)-2k
a
0.2 mmol substrate, 4 mL solvent. The absolute configuration shown
(S) is that determined for (+)-2a. Assignment for 2b–2k is made by
b
analogy and is tentative. Isolated yield. Determined by chiral
c
d
HPLC. At 25 1C.
Scheme 2 Synthesis of the new chiral N-heterocyclic carbene ligand
precursor (R,R)-L3. Reagents and conditions: (a) Boc2O, NEt3,
CH2Cl2; (b) NBS, 1 N HCl–acetone, 91% (over 2 steps); (c) 2.5
mol% Pd(dba)2, 5 mol% PtBu3, PhB(OH)2, K2CO3, DME–H2O,
96%; (d) CF3CO2H, H2O, 92%; (e) glyoxal, Na2SO4, CH2Cl2, 71%;
(f) (i) NaBH4, MeOH; (ii) NH4BF4, HC(OEt)3; (iii) NaI, acetone, 88%
(over 3 steps).
in our earlier work,7 proceeded smoothly and the arylation
product was obtained in 71% yield and 82% ee (Table 2, entry
2). The same reaction carried out in DME gave the product in
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Table 4 Substrates scope of arylation to give chiral 3-aminooxindoles
were sluggish (Table 3, entries 6 and 11). Also, although the
yields remained high, oxindoles 2b and 2c, containing the
easily removable benzyl group, were obtained with lower ee
values (Table 3, entries 2 and 3).
Amides containing amino groups could also be arylated to
oxindoles. Since substrates 1l and 1m proved less reactive than
1a–k, a higher temperature (80 1C) was required to achieve full
conversion. This resulted in lower enantioselectivities (Table 4,
entries 1 and 2). Interestingly, reactions of substrates 1n and 1o
can be carried out at 50 1C to give higher ee values (Table 4,
entries 3 and 4), probably because the pyrrolidine and mor-
pholine groups in substrates 1n and 1o are less sterically
hindered than the dialkylamines in substrates 1l and 1n.
It remained to determine the absolute configuration of the
products. This was done for (+)-(S)-2a. Addition of PhMgBr
to isatin afforded rac-2p (Scheme 3).9a,c A highly enantiomeri-
cally enriched sample (496% ee) was obtained by chiral
HPLC (Chiracel OD column (iPrOH–nHex = 10 : 90, 2.0
mL minꢁ1, 254 nm). Its [a]2D5 of +18.4 (c = 1.0, in MeOH)
identified it as the (S)-enantiomer.9b Methylation afforded
(S)-2a with an [a]2D5 of +81.2 (c = 0.5, in acetone).
Entry
1
Producta
T/1C Yieldb (%)
Eec (%)
75
(ꢁ)-2l
80
93
2
3
(ꢁ)-2m
80
94
80
90
(ꢁ)-2n
(ꢁ)-2o
50
50
96
88
In summary, we have developed an asymmetric Pd/NHC-
catalysed intramolecular a-arylation of amide enolates con-
taining heteroatom substituents to furnish optically active
3-alkoxy or 3-aminooxindoles in high yields and enantioselec-
tivities. This protocol will be useful in the synthesis of biolo-
gically active chiral oxindoles.
4
85
a
EPK acknowledges financial support of this research by the
Swiss National Science Foundation (Project 200020_119947)
and SM by the EPSRC (EP/D002818/1), and AstraZeneca
(Dr Steve Raw).
0.2 mmol substrate, 4 mL solvent. The absolute configuration shown
(S) is that determined for (+)-2a. Assignment for 2l–2o is made by
b
c
analogy and is tentative. Isolated yield. Determined by chiral
HPLC.
90% ee but with only 29% yield (Table 2, entry 3). The results
could not be improved in spite of many efforts to optimize the
reaction. Since L1 yielded the product more efficiently than L2
(Table 2, entries 1 and 2), modification of the former was
investigated. Of all modifications carried out we here detail
only the one (L3) that solved our problem in the end. L3 was
obtained from the chiral amine (R)-3 in a high-yielding eight
step procedure (Scheme 2). We were pleased to find that L3 is a
very effective ligand for the arylation reaction, yielding oxin-
dole 2a quantitatively in 92% ee after 14 h (Table 2, entry 4).
Lowering the reaction temperature to 25 1C led to a further
increase of the ee to 97%, albeit that a longer reaction time was
required (Table 2, entry 5).
Notes and references
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Giuseppone, P. Giannakakou and A. O’Brate, J. Am. Chem. Soc.,
2004, 126, 15316; (b) C. Marti and E. M. Carreira, Eur. J. Org.
Chem., 2003, 2209.
2 T. Tokunaga, W. E. Hume, T. Umezome, K. Okazaki, Y. Ueki, K.
Kumagai, S. Hourai, J. Nagamine, H. Seki, M. Taiji, H. Noguchi
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3 M. Ochi, K. Kawasaki, H. Kataoka and Y. Uchio, Biochem.
Biophys. Res. Commun., 2001, 283, 1118.
4 (a) K. Bernard, S. Bogliolo and J. Ehrenfeld, Br. J. Pharmacol., 2005,
144, 1037; (b) G. Gilles and S. L. Claudine, Stress, 2003, 6, 199.
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2006, 45, 3353; (b) T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura,
T. Toru and S. Kanemasa, J. Am. Chem. Soc., 2006, 128, 16488.
6 (a) S. Lee and J. F. Hartwig, J. Org. Chem., 2001, 66, 3402; (b) F.
Glorius, G. Altenhoff, R. Goddard and C. Lehmann, Chem.
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Chem. Pharm. Bull., 2006, 54, 1743; (d) T. Arao, K. Kondo and T.
Aoyama, Tetrahedron Lett., 2006, 47, 1417.
The aforementioned conditions were then applied to other
alkoxy substrates as depicted in Table 3. The chiral oxindoles
were obtained in good yields and with high enantioselectivity.
Exceptions are reactions with substrates containing electron-
withdrawing aryl substituents (1f and 1k), for which reactions
7 E. P. Kundig, T. M. Seidel, Y.-X. Jia and G. Bernardinelli, Angew.
¨
Chem., Int. Ed., 2007, 46, 8484.
8 For the racemic version of this reaction, see: (a) S. P. Marsden, E.
L. Watson and S. A. Raw, Org. Lett., 2008, 10, 2905; (b) J. M.
Hillgren and S. P. Marsden, J. Org. Chem., 2008, 73, doi: 10.1021/
jo8010842.
9 (a) J. M. Bruce and F. K. Sutcliffe, J. Chem. Soc., 1957, 4789; (b) S.
´ ´
Barroso, G. Blay, L. Cardona, I. Fernandez, B. Garcıa and J. R.
Pedro, J. Org. Chem., 2004, 69, 6821; (c) P. Magnus and R.
Turnbull, Org. Lett., 2006, 8, 3497.
Scheme 3 Determination of the absolute configuration of 2b.
4042 | Chem. Commun., 2008, 4040–4042
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