Copper-catalyzed asymmetric addition of arylboronates to isatins: A catalytic cycle involving alkoxocopper intermediates

Article abstract of DOI:10.1039/c0cc01635g

A copper-catalyzed addition of arylboronates to isatins has been developed to give 3-aryl-3-hydroxy-2-oxindoles under mild conditions. The catalytic cycle of this process has been examined through a series of stoichiometric reactions and an effective asymmetric variant has also been described by the use of a chiral N-heterocyclic carbene ligand.

Full text of DOI:10.1039/c0cc01635g

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Copper-catalyzed asymmetric addition of arylboronates to
isatins: a catalytic cycle involving alkoxocopper intermediatesw
Ryo Shintani,* Keishi Takatsu and Tamio Hayashi*
Received 28th May 2010, Accepted 8th July 2010
DOI: 10.1039/c0cc01635g
A copper-catalyzed addition of arylboronates to isatins has been
developed to give 3-aryl-3-hydroxy-2-oxindoles under mild
conditions. The catalytic cycle of this process has been examined
through a series of stoichiometric reactions and an effective
asymmetric variant has also been described by the use of a chiral
N-heterocyclic carbene ligand.
(1) A reaction of Cu(Ot-Bu)(IPr) with 2a in dioxane at 30 1C
cleanly produced Cu(4-MeOC6H4)(IPr) (4) in 87% yield
(eqn (2)), as reported by Hou and coworkers.4a (2) Arylcopper
4 thus obtained underwent insertion of isatin 1a in dioxane at
30 1C to give alkoxocopper complex 5 quantitatively (eqn (3)).13
Recrystallization of this complex from n-Bu2O/pentane
afforded crystals suitable for X-ray analysis as shown in Fig. 1.14
(3) Unlike Cu(Ot-Bu)(IPr), alkoxocopper 5 did not undergo
transmetalation with 1.0 equiv. of 2a in dioxane at 30 1C
(eqn (4)). The lack of transmetalation ability of 5 with 2a in
comparison to Cu(Ot-Bu)(IPr) may be attributed to the very
bulky alkyl group in the alkoxy moiety, which is also indicated
by the X-ray crystal structure in Fig. 1.15 (4) In contrast, 82%
of complex 5 was converted to Cu(Ot-Bu)(IPr) in 0.5 h by
treating it with 1.0 equiv. of KOt-Bu in dioxane at 30 1C
(eqn (4)), and the results of eqn (4) can well explain the
necessity of KOt-Bu for the catalytic reaction in eqn (1). (5)
Furthermore, both complexes 4 and 5 effectively catalyzed the
reaction of 1a with 2a.
Copper-catalyzed carbon–carbon bond forming reactions
using organometallic reagents are powerful tools for efficient
construction of organic compounds, and highly reactive
nucleophiles such as Grignard reagents,1 diorganozincs,2 and
triorganoaluminiums2a,b are typically employed. In contrast,
the use of milder nucleophiles such as organosilicon3 and
organoboron4–6 reagents has been much less studied, although
employment of organoboronic acids and their derivatives
would be highly attractive in view of the availability, stability,
and ease of handling of these reagents. Several copper-
catalyzed carbon–carbon bond formations using organoboronic
acid derivatives have been reported,4,5 but those with absolute
stereocontrol in the product formation are quite limited.3d,5 In
this context, here we describe that alkoxocopper complexes
can efficiently catalyze the addition of arylboronic acid
esters to isatins to give 3-aryl-3-hydroxy-2-oxindoles, which
constitute a useful class of compounds that can be found in
various biologically active molecules,7 and that the use of a
chiral N-heterocyclic carbene ligand leads to the development
of an effective asymmetric variant.8,9
Because copper–N-heterocyclic carbene complexes10 are
known to display high catalytic activity for the reactions of
carbonyl compounds,11 including addition of organoboronates
to carbon dioxide,4a we initially employed Cu(Ot-Bu)(IPr)12 as
a catalyst (10 mol%) for the reaction of isatin 1a with
4-methoxyphenylboronate 2a in the presence of 1.0 equiv. of
KOt-Bu in dioxane at 30 1C (eqn (1)). Under these conditions,
the reaction smoothly proceeded to give the desired addition
product (3aa) in 82% yield after aqueous workup. It is worth
noting that the reaction became very sluggish in the absence of
KOt-Bu, giving 3aa only in 22% yield under otherwise the
same conditions.
ð1Þ
ð2Þ
The catalytic cycle for the present reaction was probed by
conducting a series of stoichiometric reactions as follows.4a
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: shintani@kuchem.kyoto-u.ac.jp,
thayashi@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-3988;
Tel: +81-75-753-3983
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 775043 and
775074. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c0cc01635g
Fig. 1 X-Ray crystal structure of 5 (hydrogen atoms are omitted for
clarity). Selected bond lengths (A) and an angle (1): Cu1–C1 1.857(3),
Cu1–O1 1.825(2); C1–Cu1–O1 170.75(11).
c
6822 Chem. Commun., 2010, 46, 6822–6824
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Table 1 Copper-catalyzed asymmetric addition of arylboronate 2a to
isatin 1a: ligand effect
ð3Þ
ð4Þ
Entry
Ligand salt
Yield (%)a
ee (%)b
On the basis of these experiments, a proposed catalytic cycle
for the reaction in eqn (1) is illustrated in Scheme 1. Thus,
Cu(Ot-Bu)(IPr) undergoes transmetalation with arylboronate 2a
to give arylcopper species 4. Insertion of isatin 1a to arylcopper 4
then gives alkoxocopper 5, which reacts with KOt-Bu to
regenerate Cu(Ot-Bu)(IPr) along with primary product 6. Final
product 3aa is obtained from 6 after aqueous workup.
1
2
3
4
5
6
7
8
9c
(R,R)-7
(S)-8a
(S)-8b
(S)-8c
(S)-9
(S)-8d
(S)-8e
(S)-8f
(S)-8c
80
66
67
80
73
67
71
67
71
8
62
83
88
14
31
78
52
88
Because the step from 4 to 5 in Scheme 1 creates a tetra-
substituted carbon stereocenter, we began to develop an
asymmetric variant by employing chiral N-heterocyclic carbene
(NHC) ligands.16,17 Although the reaction of 1a with 2a
smoothly proceeded by the use of C2-symmetric (R,R)-718 as
the ligand precursor, the enantioselectivity of product 3aa was
only 8% ee (Table 1, entry 1). In contrast, C1-symmetric NHC
salt (S)-8a19 having a phenylglycinol-derived tether significantly
improved the enantioselectivity (62% ee; entry 2), and the change
of substituent on the tether from phenyl to isopropyl ((S)-8b,
83% ee; entry 3) or tert-butyl ((S)-8c, 88% ee; entry 4) gave
higher enantioselectivity. The structurally similar NHC salt (S)-9
having a methoxy group instead of a hydroxy group displayed
much lower enantioselectivity (14% ee; entry 5). With regard to
the substituent on the other nitrogen atom of 8, a 2,6-dimethyl-
phenyl group turned out to be optimal. Thus, the decrease
((S)-8d) or increase ((S)-8e and (S)-8f) of the steric bulk of the
2,6-substituents led to erosion of ee (entries 6–8). It is worth
noting that the catalyst loading of Cu–(S)-8c can be lowered to
5 mol%, although a prolonged reaction time is required
(71% yield, 88% ee; entry 9).
a
b
Isolated yield. Determined by chiral HPLC on a Chiralcel OD-H
c
= 90/10. The reaction was
column with hexane/2-propanol
conducted for 36 h in the presence of 5 mol% of CuCl and 5.5 mol%
of (S)-8c.
Table 2 Copper-catalyzed asymmetric addition of arylboronates 2 to
isatins 1: scope
Under the conditions using (S)-8c as the ligand precursor,
not only 1a but also several other isatins (1b–1e) can be
employed in the reaction with 4-methoxyphenylboronate 2a
to give 3 with similar efficiency (67–83% yield, 85–89% ee;
Table 2, entries 1–5). With respect to the nucleophilic component,
various aryl groups including 2-naphthyl and 3-thienyl are
effectively incorporated to isatins 1 with high enantioselectivity
(74–94% yield, 86–92% ee; entries 6–12). The addition of a
2-tolyl or 1-cyclohexenyl group, however, results in moderate
enantioselectivity (72–74% yield, 67–68% ee; entries 13 and 14).
Entry 1 (R)
2 (Ar)
Product Yield (%)a ee (%)b
1
2
3
1a (5-F) 2a (4-MeOC6H4)
1b (5-Me) 2a
1c (6-Br) 2a
3aa
3ba
3ca
3da
3ea
3ab
3cb
3db
3dc
3ad
3ae
3af
3ag
80
67
83
70
76
74
83
87
87
78
85
94
74
72
88
85
89
89
85
91
92
92
4
1d (6-Cl) 2a
5c
6
1e (H)
1a
1c
2a
2b (Ph)
2b
2b
2c (4-MeC6H4)
2d (4-ClC6H4)
2e (2-naphthyl)
2f (3-thienyl)
2g (2-MeC6H4)
7
8
9
1d
1d
92
10
11
12
13
14
1a
1a
1a
1a
86 (R)
86
87
68
67
1a
2h (1-cyclohexenyl) 3ah
a
b
Isolated yield. Determined by chiral HPLC on a Chiralcel OD-H
c
column with hexane/2-propanol. The reaction was conducted for 36 h.
The absolute configuration of product 3ad was determined to
be (R) by X-ray crystallographic analysis.14 The trityl group
on the nitrogen of product 3ab can be readily removed with
retention of the enantiomeric purity. Thus, treatment of 3ab
(91% ee) with CF3CO2H in the presence of triethylsilane
Scheme 1 Proposed catalytic cycle for the copper-catalyzed addition
of 2a to 1a ([Cu] = Cu(IPr), Ar = 4-MeOC6H4).
c
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provides deprotected oxindole 10 in 94% yield with 91% ee
(eqn (5)).20
T. Kawamura, M. Taiji and R. Nagata, Bioorg. Med. Chem. Lett.,
2005, 15, 1789; (d) P. Hewawasam, M. Erway, S. L. Moon,
J. Knipe, H. Weiner, C. G. Boissard, D. J. Post-Munson,
Q. Gao, S. Huang, V. K. Gribkoff and N. A. Meanwell, J. Med.
Chem., 2002, 45, 1487; (e) A. Di Malta, G. Garcia, R. Roux,
B. Schoentjes, C. Serradeil-le Gal, B. Tonnerre and J. Wagnon,
PCT Int. Appl., WO2003008407, 2003.
ð5Þ
8 A copper-catalyzed asymmetric addition of organosilicon reagents
to isatins has been reported, see ref. 3d.
9 For examples of other transition metal-catalyzed arylation of
isatins, see: (a) R. Shintani, M. Inoue and T. Hayashi,
Angew. Chem., Int. Ed., 2006, 45, 3353; (b) P. Y. Toullec, R. B.
C. Jagt, J. G. de Vries, B. L. Feringa and A. J. Minnaard, Org.
Lett., 2006, 8, 2715; (c) H. Lai, Z. Huang, Q. Wu and Y. Qin,
J. Org. Chem., 2009, 74, 283.
In summary, we have developed a copper-catalyzed addition of
arylboronates to isatins to give 3-aryl-3-hydroxy-2-oxindoles
under mild conditions. The catalytic cycle of this process has
been examined through a series of stoichiometric reactions and
an effective asymmetric variant has also been described by the
use of a chiral N-heterocyclic carbene ligand.
10 (a) S. Dı
´
ez-Gonza
´
lez, N. Marion and S. P. Nolan, Chem. Rev.,
ez-Gonzalez and S. P. Nolan,
2009, 109, 3612; (b) S. Dı
´
´
Aldrichimica Acta, 2008, 41, 43; (c) J. C. Y. Lin, R. T.
W. Huang, C. S. Lee, A. Bhattacharyya, W. S. Hwang and I. J.
B. Lin, Chem. Rev., 2009, 109, 3561.
Support has been provided in part by a Grant-in-Aid for
Young Scientists (B), the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and by Mitsubishi
Tanabe Pharma Corporation. K.T. thanks JSPS for a
fellowship.
11 (a) H. Kaur, F. K. Zinn, E. D. Stevens and S. P. Nolan,
Organometallics, 2004, 23, 1157; (b) S. Dı
F. K. Zinn, E. D. Stevens and S. P. Nolan, J. Org. Chem., 2005, 70,
4784; (c) H. Lebel, M. Davi, S. Dıez-Gonzalez and S. P. Nolan,
ez-Gonzalez, H. Kaur,
´ ´
´
´
J. Org. Chem., 2007, 72, 144; (d) D. S. Laitar, E. Y. Tsui and
J. P. Sadighi, J. Am. Chem. Soc., 2006, 128, 11036See also:
(e) V. Jurkauskas, J. P. Sadighi and S. L. Buchwald, Org. Lett.,
Notes and references
2003, 5, 2417; (f) D. S. Laitar, P. Muller and J. P. Sadighi, J. Am.
Chem. Soc., 2005, 127, 17196.
¨
1 For reviews, see: (a) S. R. Harutyunyan, T. den Hartog, K. Geurts,
A. J. Minnaard and B. L. Feringa, Chem. Rev., 2008, 108, 2824;
(b) F. Lopez, A. J. Minnaard and B. L. Feringa, Acc. Chem. Res.,
´
12 N. P. Mankad, D. S. Laitar and J. P. Sadighi, Organometallics,
2004, 23, 3369.
2007, 40, 179; (c) J. Terao and N. Kambe, Acc. Chem. Res., 2008,
41, 1545.
2 For reviews, see: (a) K. Yamada and K. Tomioka, Chem. Rev.,
2008, 108, 2874; (b) A. Alexakis, J. E. Backvall, N. Krause,
¨
O. Pamies and M. Dieguez, Chem. Rev., 2008, 108, 2796;
´
13 Analytical data for compound 5: 1H NMR (C6D6): d 7.50–7.46
(m, 8H), 7.30 (t, J = 7.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.10
(d, J = 8.2 Hz, 2H), 7.03–7.00 (m, 1H), 7.00 (t, J = 7.6 Hz, 6H),
6.94 (t, J = 7.3 Hz, 3H), 6.67 (d, J = 8.8 Hz, 2H), 6.30–6.23
(m, 2H), 6.27 (s, 2H), 3.44 (s, 3H), 2.64–2.56 (m, 4H), 1.31
(c) J. Christoffers, G. Koripelly, A. Rosiak and M. Rossle,
Synthesis, 2007, 1279.
(d, J = 6.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 6H), 1.09
¨
(d, J = 6.9 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H). 13C NMR
(C6D6): d 186.2, 183.6, 159.3 (d, J = 241 Hz), 158.6, 145.9,
143.7, 142.9, 141.6, 138.8, 135.5, 130.5, 129.8, 127.8, 127.6, 126.4,
124.3 (d, J = 7.2 Hz), 122.5, 115.8 (d, J = 6.2 Hz), 113.5, 112.3
(d, J = 23.8 Hz), 111.8 (d, J = 23.8 Hz), 83.0, 74.2, 54.8, 29.0, 24.9,
24.7, 24.1, 24.0. HRMS (ESI-TOF) calcd for C61H62CuFN3O3
(M+H+) 966.4066, found 966.4091.
3 (a) S. Yamasaki, K. Fujii, R. Wada, M. Kanai and M. Shibasaki,
J. Am. Chem. Soc., 2002, 124, 6536; (b) D. Tomita, R. Wada,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 4138;
(c) R. Motoki, D. Tomita, M. Kanai and M. Shibasaki,
Tetrahedron Lett., 2006, 47, 8083; (d) D. Tomita, K. Yamatsugu,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 6946.
4 (a) T. Ohnishi, M. Nishiura and Z. Hou, Angew. Chem., Int. Ed.,
2008, 47, 5792; (b) J. Takaya, S. Tadami, K. Ukai and N. Iwasawa,
Org. Lett., 2008, 10, 2697; (c) Y. Yamamoto, N. Kirai and
Y. Harada, Chem. Commun., 2008, 2010; (d) Y. Yamamoto and
N. Kirai, Org. Lett., 2008, 10, 5513; (e) H. Zheng, Q. Zhang,
J. Chen, M. Liu, S. Cheng, J. Ding, H. Wu and W. Su, J. Org.
Chem., 2009, 74, 943; (f) H. Ohmiya, U. Yokobori, Y. Makida and
M. Sawamura, J. Am. Chem. Soc., 2010, 132, 2895.
5 (a) R. Wada, K. Oisaki, M. Kanai and M. Shibasaki, J. Am. Chem.
Soc., 2004, 126, 8910; (b) R. Wada, T. Shibuguchi, S.
Makino, K. Oisaki, M. Kanai and M. Shibasaki, J. Am. Chem.
Soc., 2006, 128, 7687; (c) D. Tomita, M. Kanai and M. Shibasaki,
Chem.–Asian J., 2006, 1, 161.
6 For examples of the use of diboron reagents, see: (a) H. Ito,
H. Yamanaka, J. Tateiwa and A. Hosomi, Tetrahedron Lett.,
2000, 41, 6821; (b) K. Takahashi, T. Ishiyama and N. Miyaura,
Chem. Lett., 2000, 982; (c) K. Takahashi, T. Ishiyama and
N. Miyaura, J. Organomet. Chem., 2001, 625, 47; (d) H. Ito,
C. Kawakami and M. Sawamura, J. Am. Chem. Soc., 2005, 127,
16034; (e) H. Ito, Y. Sasaki and M. Sawamura, J. Am. Chem. Soc.,
2008, 130, 15774; (f) S. Mun, J.-E. Lee and J. Yun, Org. Lett.,
2006, 8, 4887; (g) J.-E. Lee and J. Yun, Angew. Chem., Int. Ed.,
2008, 47, 145; (h) Y. Lee and A. H. Hoveyda, J. Am. Chem. Soc.,
2009, 131, 3160; (i) I.-H. Chen, L. Yin, W. Itano, M. Kanai and
M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 11664.
14 CCDC 775074 and 775043 contain the supplementary crystallo-
graphic data for this paper, see ESIw.
15 For the crystal structure of Cu(Ot-Bu)(IPr), see ref. 12.
16 For reviews, see: (a) L. H. Gade and S. Bellemin-Laponnaz,
´
Coord. Chem. Rev., 2007, 251, 718; (b) V. Cesar, S. Bellemin-Laponnaz
and L. H. Gade, Chem. Soc. Rev., 2004, 33, 619; (c) M. Perry and
K. Burgess, Tetrahedron: Asymmetry, 2003, 14, 951.
17 For recent progress, see: (a) K. Lee and A. H. Hoveyda, J. Am.
Chem. Soc., 2010, 132, 2898; (b) K. Akiyama, F. Gao and
A. H. Hoveyda, Angew. Chem., Int. Ed., 2010, 49, 419; (c) Y. Lee,
H. Jang and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 18234;
(d) T. L. May, M. K. Brown and A. H. Hoveyda, Angew. Chem.,
Int. Ed., 2008, 47, 7358; (e) R. E. Giudici and A. H. Hoveyda, J. Am.
Chem. Soc., 2007, 129, 3824; (f) K. B. Selim, Y. Matsumoto,
K. Yamada and K. Tomioka, Angew. Chem., Int. Ed., 2009, 48,
´
8733; (g) H. Henon, M. Mauduit and A. Alexakis, Angew. Chem.,
Int. Ed., 2008, 47, 9122; (h) Y.-X. Jia, J. M. Hillgren, E. L. Watson,
S. P. Marsden and E. P. Kundig, Chem. Commun., 2008, 4040;
¨
(i) M. R. Chaulagain, G. J. Sormunen and J. Montgomery, J. Am.
Chem. Soc., 2007, 129, 9568.
18 T. J. Seiders, D. W. Ward and R. H. Grubbs, Org. Lett., 2001, 3,
3225.
19 For precedents of this family of chiral NHC’s, see: (a) H. Clavier,
L. Coutable, J.-C. Guillemin and M. Mauduit, Tetrahedron:
Asymmetry, 2005, 16, 921; (b) H. Clavier, L. Coutable, L. Toupet,
J.-C. Guillemin and M. Mauduit, J. Organomet. Chem., 2005, 690,
5237; (c) D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit
and A. Alexakis, J. Am. Chem. Soc., 2006, 128, 8416See also:
(d) P. L. Arnold, M. Rodden, K. M. Davis, A. C. Scarisbrick,
A. J. Blake and C. Wilson, Chem. Commun., 2004, 1612.
20 A. Volonterio and M. Zanda, J. Org. Chem., 2008, 73, 7486.
7 (a) T. Tokunaga, W. E. Hume, T. Umezome, K. Okazaki, Y. Ueki,
K. Kumagai, S. Hourai, J. Nagamine, H. Seki, M. Taiji,
H. Noguchi and R. Nagata, J. Med. Chem., 2001, 44, 4641;
(b) J. Nagamine, R. Nagata, H. Seki, N. Nomura-Akimaru,
Y. Ueki, K. Kumagai, M. Taiji and H. Noguchi, J. Endocrinol.,
2001, 171, 481; (c) T. Tokunaga, W. E. Hume, J. Nagamine,
c
6824 Chem. Commun., 2010, 46, 6822–6824
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