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. Author manuscript; available in PMC: 2010 Mar 29.
Published in final edited form as: Angew Chem Int Ed Engl. 2009;48(34):6313–6316. doi: 10.1002/anie.200902328

Enantioselective Allylation, Crotylation and Reverse Prenylation of Substituted Isatins via Iridium Catalyzed C-C Bond Forming Transfer Hydrogenation**

Junji Itoh 1, Soo Bong Han 1, Michael J Krische 1,*
PMCID: PMC2846777  NIHMSID: NIHMS184654  PMID: 19606435

Oxindoles with a Twist

Transfer hydrogenation of substituted isatins in the presence of allyl acetate, α-methyl allyl acetate or 1,1,-dimethylallene employing an ortho-cyclometallated iridium catalyst modified by CTH-(R)-P-PHOS provides products of carbonyl allylation, crotylation and reverse prenylation, respectively, in highly enantiomerically enriched form. These studies represent the first use of activated ketones as electrophilic partners in asymmetric C-C bond forming transfer hydrogenation.

graphic file with name nihms184654f3.jpg

Keywords: Iridium, Allylation, Crotylation, Prenylation, Transfer Hydrogenation, Catalytic, Enantioselective

3-Substituted-3-hydroxy-oxindoles appear as substructures within a fascinating array of natural products, including the convulutamydines,[1a,b] maremycins,[1c,d] donaxaridines,[1e,f] dioxibrassinins,[1g,h,i] celogentin K,[1j] hydroxyglucoisatisins[1k] and TMC-95A–D (Figure 1).[1l] While catalytic asymmetric additions to isatins are known,[2–6] highly enantioselective catalytic allylation, crotylation and reverse prenylation of isatins has remained elusive. In the course developing hydrogen-mediated C-C couplings beyond hydroformylation,[7–15] chiral ortho-cyclometallated iridium C,O-benzoates were found to catalyze highly enantioselective carbonyl allylation,[14a,b] crotylation[14c] and reverse prenylation[12d] under transfer hydrogenation conditions. In contrast to classical allylation procedures that employ stoichiometric organometallic reagents,[16] transfer hydrogenation protocols exploit allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respectively.[12,14a–c] To further evaluate the scope of this emergent methodology, catalytic enantioselective additions to ketones were explored.[17,18] In this account, we report that activated ketones in the form of substituted isatins are subject to highly enantioselective carbonyl allylation, crotylation and reverse prenylation, constituting a convenient synthesis of optically enriched 3-substituted-3-hydroxy-oxindoles.

Figure 1.

Figure 1

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Examples of naturally occurring 3-substituted-3-hydroxy-oxindoles.

Our initial studies focused on the asymmetric allylation of N-benzyl isatin 1a. Using the cyclometallated C,O-benzoate generated in situ from [Ir(cod)Cl]2, BIPHEP and 4-chloro-3-nitrobenzoic acid,[14b] the coupling of allyl acetate (1000 mol%) to 1a at 100 °C in THF (0.2 M) delivered the tertiary homoallyl alcohol 2a in 42% isolated yield. Under otherwise identical conditions, but with a lower loading of allyl acetate (200 mol%) and optimization of reaction temperature, reaction time, and concentration, the isolated yield of homoallyl alcohol 2a was increased to 77%. An assay of chelating chiral phosphine ligands was undertaken, which revealed dramatic enhancement in the level of asymmetric induction at lower reaction temperatures. However, lower temperatures also diminished conversion. This impasse was resolved by increasing the loading of isopropanol from 200 mol% to 400 mol%, which enabled conversion of N-benzyl isatin 1a to homoallyl alcohol 2a in 73% isolated yield and 91% enantiomeric excess using CTH-(R)-P-PHOS as ligand. Notably, under analogous conditions employing our initially disclosed iridium catalyst modified by 3-nitrobenzoic acid,[14a,b] 2a is obtained in 61% isolated yield and 90% enantiomeric excess. These data further illustrate how catalyst performance is enhanced through structural variation of the C,O-benzoate moiety. Data pertaining to the optimization of the catalytic enantioselective allylation of N-benzyl isatin 1a is tabulated in the supporting information.

Optimal conditions identified for the conversion of N-benzyl isatin 1a to the hydroxy-oxindole 2a were applied to substituted isatins 1a–1g (Table 1). To our delight, the products of ketone allylation 2a–2g were produced in moderate to excellent isolated yield (65–92% yield) with uniformly high levels of optical enrichment (91–96% ee). The absolute stereochemical assignment of adducts 2a–2g are based upon that determined for the 5-bromo-dervative 2b via single crystal X-ray diffraction analysis using the anomalous dispersion method.

Table 1.

Catalytic enantioselective allylation N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation.

graphic file with name nihms184654t1.jpg
Entry Isatins 1a–1g Products Yield (%) ee (%)
1 1a, N-benzyl isatin 2a 73 91
2b 1b, 5-bromo-N-benzyl isatin 2b 83 94
3 1c, 5-methyl-N-benzyl isatin 2c 89 92
4 1d, 5-methoxy-N-benzyl isatin 2d 92 94
5 1e, 6-chloro-N-benzyl isatin 2e 73 96
6b 1f, 6-bromo-N-benzyl isatin 2f 80 94
7c 1g, 7-fluoro-N-benzyl isatin 2g 65 93
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a

All reactions were performed in 13 × 100 mm pressure tubes. Cited yields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. See supporting information for further details.

b

10 mol% loading of Cs2CO3 was used and the reaction was conducted for 72 hours.

c

400 mol% loading of allyl acetate was used.

Given these favorable results, the crotylation of substituted isatins 1a–1g was attempted under identical conditions employing α-methyl allyl acetate as the crotyl donor (Table 2). The products of ketone crotylation 3a–3g were produced in moderate to excellent isolated yield (64–87% yield) with moderate to excellent levels of optical enrichment (80–92% ee). In general, crotylation required longer reaction times (Table 2, entries 1, 2, 5–7). Additionally, it was found that lower loadings of Cs2CO3 increased conversion in certain cases. The absolute stereochemical assignment of adducts 3a–3g are based upon that determined for the 5-bromo-dervative 3b via single crystal X-ray diffraction analysis using the anomalous dispersion method.

Table 2.

Catalytic enantioselective crotylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation.

graphic file with name nihms184654t2.jpg
Entry Isatins 1a–1g Products Yield (%) ee (%), dr
1b 1a, N-benzyl isatin 3a 83 80, 13:1
2f 1b, 5-bromo-N-benzyl isatin 3b 72 86, 16:1
3d,e 1c, 5-methyl-N-benzyl isatin 3c 81 89, 18:1
4d,e 1d, 5-methoxy-N-benzyl isatin 3d 87 92, 29:1
5b 1e, 6-chloro-N-benzyl isatin 3e 70 91, 19:1
6f 1f, 6-bromo-N-benzyl isatin 3f 81 89, 15:1
7b,c 1g, 7-fluoro-N-benzyl isatin 3g 64 85, 19:1
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a

As described in Table 2 footnotes.

b

10 mol% loading of Cs2CO3 was used.

c

400 mol% loading of allyl acetate was used.

d

Me-THF was used as solvent.

e

The reaction was run for 40 hours.

f

5 mol% loading of [Ir(cod)Cl]2, 10 mol% loading of CTH-(R)-P-PHOS and 20 mol% loading of 4-CN-3-NO2-BzOH were used.

Finally, the reverse prenylation of substituted isatins 1a–1g was attempted (Table 3). To our delight, adducts 4a–4g were generated in uniformly high isolated yields (70–90% yield) and levels of optical enrichment (90–96 % ee) under mild conditions. Notably, this transformation enables creation of two contiguous quaternary carbon centers. The absolute stereochemical assignment of adducts 4a–4g are based upon that determined for the 5-bromo-dervative 4b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Here, the enantiofacial selectivity of carbonyl addition is opposite to that observed in the case of allylation and crotylation.

Table 3.

Catalytic enantioselective prenylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation.

graphic file with name nihms184654t3.jpg
Entry Isatins 1a–1g Products Yield (%) ee (%)
1 1a, N-benzyl isatin 4a 90 96
2 1b, 5-bromo-N-benzyl isatin 4b 86 90
3 1c, 5-methyl-N-benzyl isatin 4c 79 93
4 1d, 5-methoxy-N-benzyl isatin 4d 81 96
5 1e, 6-chloro-N-benzyl isatin 4e 80 93
6b 1f, 6-bromo-N-benzyl isatin 4f 70 93
7b 1g, 7-fluoro-N-benzyl isatin 4g 79 94
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a

As described in Table 2 footnotes.

b

The reaction was run for 72 hours.

The inversion in absolute stereochemistry observed in isatin reverse prenylation merits further explanation. The catalytic mechanism for carbonyl prenylation employing 1,1-dimethylallene is analogous to that previously reported for corresponding allylations and crotylations (Scheme 1, left).14b,c Assuming isatin crotylation occurs through a chair-like transition structure and an (E)-σ-crotyl iridium intermediate, previously proposed absolute stereochemical models agrees with the observed π-facial selectivity with respect to the crotyl partner.14c The latter observation suggests that isatin crotylation occurs by way of transition structure A, whereas isatin prenylation occurs by way of transition structures B. The basis of this partitioning may arise from non-bonded interactions of the axial methyl group of the σ-prenyl iridium intermediate with the amide π-bond of isatin, which is presumably more destabilizing than non-bonded interactions of the axial methyl group with the electron-deficient rim of the arene (Scheme 1, right).

Scheme 1.

Scheme 1

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A simplified catalytic mechanism depicting isatin prenylation via transfer hydrogenation (left) and a plausible stereochemical model accounting for the observed inversion in absolute stereochemistry in the prenylation of isatins (right).a

aLn = CTH-(R)-P-PHOS (omitted for clarity).

In summary, we report the first enantioselective allylations, crotylations and prenylations of isatin, which are achieved via isopropanol-mediated transfer hydrogenation. Unlike conventional allylation methodologies that employ stoichiometric quantities of allylmetal reagents, the present method exploits allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respetively.[12,14a–c] To our knowledge, these studies represent the first examples of catalytic enantioselective ketone allylation, crotylation and prenylation in the absence of stoichiometric allylmetal reagents. Future studies will focus on the development of related C-C bond forming transfer hydrogenations and synthetic applications of the methods reported herein.

Footnotes

**

Acknowledgment is made to Merck, the Robert A. Welch Foundation, the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable and the NIH (RO1-GM069445) for partial support of this research. Dr. Oliver Briel of Umicore is thanked for the generous donation of [Ir(cod)Cl]2.

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