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Communication | Regular issue | Vol. 81, No. 5, 2010, pp. 1149-1155
Received, 24th February, 2010, Accepted, 9th March, 2010, Published online, 11th March, 2010.
DOI: 10.3987/COM-10-11930
Asymmetric Intermolecular N-H Insertion Reaction of Phenyldiazoacetates with Anilines Catalyzed by Achiral Dirhodium(II) Carboxylates and Cinchona Alkaloids

Hiroaki Saito,* Taketo Uchiyama, Muneharu Miyake, Masahiro Anada, Shunichi Hashimoto, Tohru Takabatake, and Shinichi Miyairi

School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan

Asymmetric N–H insertion of phenyldiazoacetates with anilines catalyzed cooperatively by achiral dirhodium(II) carboxylates and cinchona alkaloids is described. A new catalytic system of dirhodium(II) tetrakis(triphenylacetate), Rh2(TPA)4, and dihydrocinchonine provides phenylglycine derivatives in up to 71% ee.

The transition metal-catalyzed N–H insertion reaction of α-diazocarbonyl compounds, which features C–N bond formation with simultaneous creation of a stereogenic center, offers a potentially powerful strategy for the synthesis of nitrogen-containing compounds.1 Consequently, much effort has been directed towards the development of an enantioselective version of this catalytic process.2 While exceptionally high levels of enantiocontrol in C–H insertions of α-diazocarbonyl compounds have already been achieved by the device of well-defined dirhodium(II) carboxylates and carboxamidates as chiral catalysts,3 it was not until recently that a highly enantioselective N–H insertion process was developed.46 In 2007, Zhou and co-workers demonstrated the first successful examples of intermolecular N–H insertion of α-alkyl-α-diazoacetates with anilines (up to 98% ee) using a chiral copper(I)–spiro bis(oxazoline) catalyst.7 Thereafter, Fu and Lee reported enantioselective N–H insertion reactions of tert-butyl aryldiazoacetates with benzyl or tert-butyl carbamates catalyzed by a planer-chiral copper(I)-bipyridine complex with up to 95% ee.8
In recent years, we have achieved high levels of enantiocontrol in C–H
9 and Si–H10 insertion reactions by developing dirhodium(II) carboxylate catalysts, which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as bridging ligands. As a logical extension of our studies, we addressed the issue of enantiocontrol in Rh(II)-catalyzed N–H insertion reactions.
At the outset of this work, we explored the N–H insertion reaction of methyl phenyldiazoacetate (
1a) with aniline (2a) in dichloromethane using 0.5 mol% of Rh2(S-PTPA)4 (3a). The reaction proceeded smoothly to completion at room temperature within 1 h, giving phenylglycine derivative (4a) in 90% yield (Table 1, Entry 1). The enantioselectivity of this reaction was determined to be 14% ee by HPLC analysis (Daicel Chiralpak AD-H). The preferred absolute stereochemistry of 4a [[α]22D +10.3° (c 2.16, THF) for 14% ee] was established as S by comparing the sign of the optical rotation with the literature value [lit.,11 [α]26D +68.3° (c 0.32, THF) for > 98% ee of (S)-4a]. A survey of solvents revealed that dichloromethane was the optimal solvent for this transformation.12 We next screened other chiral dirhodium(II) carboxylates, Rh2(S-PTA)4 (3b), Rh2(S-PTV)4 (3c), and Rh2(S-PTTL)4 (3d), derived from N-phthaloyl-(S)-alanine, -valine, and -tert-leucine, respectively. Although the reactions with 3b-d afforded 4a in high yields at similar reaction rates as those observed with 3a, these catalysts led to much lower enantioselectivities than Rh2(S-PTPA)4 (Entries 2–4).

In order to further improve the enantioselectivity, our efforts were centered on a double asymmetric induction with the use of a chiral additive.13,14 To this end, we explored the N–H insertion reaction of 1a with 2a in the presence of 1 mol % of 3a as a catalyst and 0.1 mol % of cinchonine (5a) as a chiral additive. To our delight, the reaction proceeded at room temperature smoothly to provide (R)-4a in 86%

yield with 31% ee (Table 2, Entry 1). On the other hand, the use of cinchonidine (5b), a pseudo-enantiomer of 5a, gave (S)-4a in 87% yield with 37% ee (Entry 2). Although the mechanistic profile is not clear at this time, these results suggest that the chirality of cinchona alkaloids rather than that of a dirhodium(II) catalyst dictates the stereochemical course of this process. Thus, we were intrigued by the possibility of the combined use of achiral dirhodium(II) carboxylate catalysts and cinchona alkaoids.15 We were gratified to find that switching the Rh(II) catalyst to Rh2(TPA)4 (3e), a dirhodium(II) carboxylate complex incorporating bulky triphenylacetates as bridging ligands, gave even higher enantioselectivities than those found with Rh2(S-PTPA)4 (55% ee and 53% ee, Entries 3 and 4). A survey of chiral additives revealed that dihydrocinchonine (5e) was the optimal additive for this transformation, giving (R)-4a in 94% yield with 59% ee (Entry 7). Quinine (5c) and quinidine (5d), 6'-methoxy substituted cinchona alkaloids, were not effective (Entries 5 and 6).16 Interestingly, increasing the amount of 5e to 1 mol % had no beneficial effect on enantioselectivity, but the reaction required a significantly longer time to reach completion (Entry 8).17 Using 5e as a chiral additive, we then evaluated the performance of other dirhodium(II) carboxylate catalysts, Rh2(OAc)4 (3f), Rh2(oct)4 (3g), and Rh2(piv)4 (3h). The reactions with the use of these catalysts (3f-h) proceeded to completion much faster than the catalysis with Rh2(TPA)4 (3e), although a considerable drop in enantioselectivity was observed (Entries 9–11). To further enhance the enantioselectivity, we examined the effect of an alkoxy group in the ester moiety on the enantioselectivity. Higher enantioselectivities were obtained by increasing the steric bulk of the ester alkyl group of phenyldiazoacetates (1b-d) with a significant reduction in the reaction rate (62–67% ee, Entries 12–14); however, with the more sterically demanding isopropyl ester (1e), further enhancement of enantioselectivity could not be attained (59% ee, Entry 15).18 Eventually, we assessed the isobutyl ester (1d) as the ester of choice from the standpoint of enantioselectivity.
With optimized conditions in hand, we then investigated the scope of the reaction with respect to the aniline component (Table 3). High yields and good enantioselectivities were consistently observed with electron-withdrawing substituents such as chlorine and bromine at the
para, meta, or ortho position on

the benzene ring (Entries 1–9). It is notable that the enantioselectivity of 71% ee obtained with p-bromoaniline (2e) is the highest reported to date for dirhodium(II) complex-catalyzed N–H insertions (Entry 4).4,5 The reaction with anilines 2k-m bearing a methyl group at the para, meta, or ortho position also afforded the corresponding phenylglycine derivatives (4o-q) in high yields and good enantioselectivities (56–64% ee, Entries 10–12). However, no reaction occurred when p-anisidine (2n) bearing an electron-donating methoxy group was used (Entry 13).
In summary, we have demonstrated that a new catalytic system of Rh
2(TPA)4 and dihydrocinchonine is effective for enantiocontrol in intermolecular N–H insertion reaction of phenyldiazoacetates with anilines. Mechanistic and stereochemical studies on the present N–H insertion reaction are currently in progress.

This research was supported in part by a grant from the "Academic Frontier" Project for Private Universities and a matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology) 2007–2010. We thank Dr. Koichi Metori (Analytical Center, School of Pharmacy, Nihon University) for performing the mass measurement.


1. For reviews, see: (a) T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091; CrossRef (b) M. P. Doyle, M. A. McKervey, and T. Ye, 'Modern Catalytic Methods for Organic Synthesis with Diazo Compounds,' Wiley-Interscience, New York, 1998, pp. 433–486; (c) Z. Zhang and J. Wang, Tetrahedron, 2008, 64, 6577. CrossRef
For a review on asymmetric N–H insertion reactions, see: C. J. Moody, Angew. Chem. Int. Ed., 2007, 46, 9148. CrossRef
For recent reviews on asymmetric C–H insertion reactions, see: (a) M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; CrossRef (b) G. A. Sulikowski, K. L. Cha, and M. M. Sulikowski, Tetrahedron: Asymmetry, 1998, 9, 3145; CrossRef (c) K, M. Lydon and M. A. McKervey, 'Comprehensive Asymmetric Catalysis,' Vol. 2, ed. by E. N. Jacobsen, A. Pfaltz, and H. Yamamoto, Springer, Berlin, 1999, pp. 539–580; (d) M. P. Doyle, 'Catalytic Asymmetric Synthesis,' 2nd ed., ed. by I. Ojima, Wiley-VCH, New York, 2000, pp.191–228; CrossRef (e) H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103, 2861; CrossRef (f) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417. CrossRef
McKervey and co-workers reported the first enantioselective intramolecular N–H insertion of α-alkyl-α-diazoesters (up to 45% ee) using dirhodium(II) tetrakis[(S)-mandelate], see: C. F. Garcia, M. A. McKervey, and T. Ye, Chem. Commun., 1996, 1465. CrossRef
Moody and co-workers reported that intermolecular N–H insertion reactions of methyl phenyldiazoacetate and dimethyl phenyldiazophosphonate with benzyl carbamates catalyzed by chiral dirhodium(II) carboxylates showed enantioselectivities of less than 9% ee, see: R. T. Buck, C. J. Moody, and A. G, Pepper, ARKIVOC, 2002, 8, 16.
Jørgensen and co-workers reported that the enantioselective intermolecular N–H insertion reaction of α-diazoesters with aniline catalyzed by chiral Ag(I)-bis(oxazoline) provided α-amino ester derivatives in up to 48% ee, see: S. Bachmann, D. Fielenbach, and K. A. Jørgensen, Org. Biomol. Chem., 2004, 2, 3044. CrossRef
B. Liu, S.-F. Zhu, W. Zhang, C. Chen, and Q.-L. Zhou, J. Am. Chem. Soc., 2007, 129, 5834. CrossRef
E. C. Lee and G. C. Fu, J. Am. Chem. Soc., 2007, 129, 12066. CrossRef
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The product yields and enantioselectivities obtained with other solvents at 23 °C are as follows: toluene, 84% yield, 7% ee (R); CHCl3, 78% yield, 11% ee (S); chlorobenzene, 69% yield, 10% ee (S); 1,2-dichloroethane, 78% yield, 13% ee (S); THF, 87% yield, 2% ee (R).
Nelson and co-workers reported that the reactivity and selectivity in the Rh(II)-catalyzed O–H insertion reaction of α-diazoketone could be controlled by using coordinating additives such as tetramethylurea or Hünig's base, see: T. D. Nelson, Z. J. Song, A. S. Thompson, M. Zhao, A. DeMarco, R. A. Reamer, M. F. Huntington, E. J. J. Grabowski, and P. J. Reider, Tetrahedron Lett., 2000, 41, 1877. CrossRef
Doyle and co-workers reported that the enantioselective [2+2]-cycloaddition reaction between ethyl glyoxylate and trimethylsilylketene in the presence of 1 mol % of chiral dirhodium(II) carboxamidates and 10 mol % of quinine gave β-lactone derivative in up to 99% ee, see: R. E. Forslund, J. Cain, J. Colyer, and M. P. Doyle, Adv. Synth. Catal., 2005, 347, 87. CrossRef
For examples of enantioselective transformation using achiral dirhodium(II) carboxylates and chiral co-catalysts, see: (a) H. Suga, A. Kakehi, S. Ito, K. Inoue, H. Ishida, and T. Ibata, Org. Lett., 2000, 2, 3145; CrossRef (b) H. Suga, K. Inoue, S. Inoue, and A. Kakehi, J. Am. Chem. Soc., 2002, 124, 14836; CrossRef (c) H. Suga, D. Ishimoto, S. Higuchi, M. Ohtsuka, T. Arikawa, T. Tsuchida, A. Kakehi, and T. Baba, Org. Lett., 2007, 9, 4359; CrossRef (d) W. Hu, X. Xu, J. Zhou, W.-J. Liu, H. Huang, J. Hu, L. Yang, and L.-Z. Gong, J. Am. Chem. Soc., 2008, 130, 7782; CrossRef (e) X. Zhang, H. Huang, X. Guo, X. Guan, L. Yang, and W. Hu, Angew. Chem. Int. Ed., 2008, 47, 6647. CrossRef
The product yields and enantioselectivities obtained with other chiral additives are as follows: (–)-sparteine, 1.5 h, 82% yield, 5% ee (S); brucine, 22 h, 65% yield, 7% (R).
The reaction of 1a with 2a under identical conditions in the absence of Rh2(TPA)4 did not work even after 24 h.
The N–H insertion reaction of tert-butyl phenyldiazoacetate with aniline under the same conditions did not go to completion even after 1 week, and the corresponding phenylglycine derivative was obtained in 58% yield with 57% ee.

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