Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Chemoselective, Regioselective, and Enantioselective Allylations of NH2OH under Iridium Catalysis Jiteng Chen, Qingchun Liang, and Xiaoming Zhao* School of Chemical Technology and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, People’s Republic of China
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S Supporting Information *
ABSTRACT: The utilization of unprotected NH2OH, which is not only an oxygen nucleophile but also a nitrogen nucleophile, in iridium-catalyzed allylic substitution is realized under mild conditions. The chemoselectivity, stereoselectivity, and multiple allylation are controlled by adjusting the reaction conditions. This method produces the N-(1-allyl)hydroxylamines in good to high yields with high level of chemoselectivities, regioselectivities, and enantioselectivities. The application of allylated hydroxylamine (R)-3a in the synthesis of diallylated hydroxylamine 6 is achieved, along with an excellent diastereomeric ratio.
N
Scheme 1. Hydroxylamines Employed in Ir-Catalyzed Allylic Substitution
itrogen chemistry has been attracting scientists because nitrogen is fundamental to all of life and many industrial processes. The very important nitrogen-containing reagents such as ammonia (NH3), hydrazine (N2H4), and hydroxylamine (NH2OH) are synthesized from the reaction of N2, H2, and O2 by the Haber−Bosch (H-B) process.1 NH2OH is a well-known inorganic reagent; it is inexpensive and abundant in the area of chemistry and chemical industry.2 Iridiumcatalyzed asymmetric allylic substitution has become a powerful tool for the chiral carbon−nitrogen or carbon− oxygen bond formation.3 The application of hydroxylamine derivatives in this type of reaction to form C−N bond or C−O bonds was investigated, in which NH2OH must be protected with Bn or Bz in order to improve the chemoselectivity and to inhibit the multiple allylation (see eq-1 and eq-2 in Scheme 1).4 There are some drawbacks in these methods: (a) the protected groups should be removed from the N- or O-group after the allylation reaction; and (b) the steric demand of Bn or Bz decreases the regioselectivity and enantioselectivity. The use of NH2OH5 in such a reaction, giving the allylated hydroxylamine derivatives, has not been reported until now. The allylated hydroxylamine derivatives are of great importance to [2,3]-sigmatropic rearrangement.6 Compared to NH37 as a nucleophile, NH2OH contains either N or O reactive sites. As shown in Scheme 1, a competition between a nitrogen nucleophile and an oxygen nucleophile on NH2OH will occur; in addition to that, the resulting allylamines,7 which are more reactive than NH2OH, will further undergo the allylation reaction.4 Thus, Ircatalyzed allylation of NH2OH remains a challenge. We envision that (a) NH2OH will occur via Ir-catalyzed allylic substitution and (b) chemoselective allylation will occur (see eq-3 in Scheme 1). In this paper, we described Ir-catalyzed allylic substitutions of NH2OH. To explore the hypothesis, we began with a reaction of (E)cinnamyl methyl carbonate (1a) with NH2OH·HCl (2) in the © XXXX American Chemical Society
presence of an iridacycle8 made from [Ir(COD)Cl]2 and Feringa’s ligand (L1)9,10 (Figure 1). A solvent survey indicated that dimethyl sulfoxide (DMSO) is a suitable solvent (see Table 1, entry 1), while other solvents such as dichloromethane (DCM), acetonitrile, and ethanol gave 3a in poor yields with 3a/3a′ > 20/1 (see Table 1, entries 2, 4, 6, and 7); tetrahydrofuran (THF), dimethyl formamide (DMF), and toluene are not effective for this reaction (Table 1, entries 3, 5, and 6). After screening a range of bases, 1a/2 ratios, and temperatures (see the Supporting Information), when the reaction of 1a (0.1 mmol) with 2 (0.2 mmol) in Et3N and DMSO at room temperature was performed, the formation of Received: April 17, 2019
A
DOI: 10.1021/acs.orglett.9b01357 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
yield than that of L2 (Table 1, entry 1 vs entry 10); L4 gave 80% enantiomeric excess (ee), whereas others such as L3, L5, and L6 were ineffective for this reaction (Table 1, entries 11, 13, and 14). We found that the use of excess 2 decreased the formation of 4a (Table 1, entries 15 and 16). To our delight, the use of 1a/2 in a 1/4 ratio gave 3a (65% yield, 96% ee), along with trace amounts of 4a (Table 1, entry 17). The use of 1a/2 ratios of 1/3 and 1/2 gave rise to the major product 3a, together with the minor product 4a with a high level of ee values (see Table 1, entries 1, 15, and 16). The use of excess 1a increased the formation of 4a, for example, a 1a/2 ratio of 4/1 was used and 4a (80% yield, 96% ee) was achieved (Table 1, entry 17). More interestingly, a treatment of NH2OH (1 equiv) with NaH (1 equiv) followed by Ir-catalyzed allylation under the conditions as entry 10 in Table 1 afforded 3a in a 53% yield with 95% ee, along with a trace amount of 4a (Table 1, entry 12); and no O-allylated hydroxylamines generated from A were observed. These outcomes suggested that this reaction favors B more than its isomer A, which is facilitated by the softness of both B and iridacycle8 (Scheme 2).
Figure 1. Ligands used in this reaction.
N-(1-phenylallyl)hydroxylamine 3a (70% yield, 97% ee) and N,N-bis(1-phenylallyl)hydroxylamine 4a (20% yield, 96% ee) was observed (Table 1, entry 1). The linear allylic product 3a′ was not observed; in contrast with the use of NH(Bz)OBn, the linear allylic product (b/l, 9/1) was obtained.4b Also, O-(1phenylallyl)hydroxylamines were not observed in this case. These results revealed that (a) this type of the reaction favors the N-nucleophile more than the O-nucleophile on NH2OH and (b) the resulting 3a competes with NH2OH 2 for the allylating agent; this further allylation generates 4a. Iridium species such as [Ir(Cp*)Cl2]2 and Ir(COD)(acac) was further examined and proved to be ineffective for this reaction (see Table 1, entries 8 and 9). Generally, the ligand plays a significant role in asymmetric catalysis. Consequently, a series of ligands, such as L1, L2,10 L3,11 L4,12 Carreira’s ligand (L5),13 and PHOX (L6)14 (Figure 1), was explored and both L1 and L2 led to a high level of ee values. L1 gave a higher
Scheme 2. Oxygen Anion of Hydroxylamine 2 and Its Isomer
Next, we examined the scope and generality of allylic substrates 1 under the reaction conditions presented in entry
Table 1. Screening Reaction Conditions for Ir-Catalyzed Allylation of NH2OH (2a)a
entry
Ir catalyst
ligand
solvent
3ab (%)
enantiomeric excess, eec (%)
4ab (%)
enantiomeric excess, eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15e 16f 17g 18h
[Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(Cp*)Cl2]2 Ir(COD)(acac) [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2
L1 L1 L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L6 L1 L1 L1 L1
DMSO DCM THF CH3CN toluene DMF EtOH DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
70 15 trace 10 − trace 35 nrd trace 30 nrd 60 nrd trace 62 65 trace 53
97 95 − − − − 80 − − 93 − 80 − − 97 96 − 95
20 − − trace − − 10 − − trace − trace − − 10 trace 80 trace
96 − − − − − − − − − − − − − 95 − 96 −
a
Reaction conditions: Ir salt (0.004 mmol), ligand (0.008 mmol), 1a (0.1−0.4 mmol), 2 (0.1−0.4 mmol), NEt3 (0.1−0.4 mmol), and solvent (1 mL), 12 h. bIsolated yield. cDetermined by a chiral HPLC. dNot reacted. e2/1a ratio = 3/1. f2/1a ratio = 4/1. g2/1a = 1/4 and 1 mL of solvent. h Tandem NEt3 (0.2 mmol) and NaH (0.2 mmol) was added in this case. B
DOI: 10.1021/acs.orglett.9b01357 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
conditions described in Scheme 4. The allylic substrate 1o (1.08 g, 4.0 mmol) and NH2OH (2) (0.55 g, 8.0 mmol) were
10 of Table 1. The results were summarized as described below: (a) 1a and the substrates 1b−1h bearing an electrondonating substituent (e.g., p-Me, m-Me, p-Ph, m-Ph, mPhO, m-allyl-O, and p-MeO) on the phenyl ring gave 3a−3h in good yields with high regioselectivities and enantioselectivities; (b) the substrates 1i−1l with a bulky fused aryl ring or 3,4di-MeO groups on the phenyl afforded 3i−3l in good yields with a high level of regioselectivities and enantioselectivities; (c) the substrates 1m−1r containing the various electronwithdrawing substituents (e.g., m-F, p-Cl, p-Br, m-CF3, and m-NO2) or 3,4-di-Cl on the phenyl ring produced 3m−3r in moderate yields with high regioselectivities and enantioselectivities; and (d) furanyl-substituted substrate 1s offered 3s in good yield with excellent regioselectivity and enantioselectivity; and aliphatic-substituted substrate 1t gave 3t in a high yield with excellent regioselectivity and enantioselectivity, and this high regioselectivity does not agree with the known Scheme 3. Scope of the Allylic Substrates 1 and 2
Scheme 4. Large-Scale Synthesis of 3o and the Utilization of 3a for the Synthesis of 4a, 5, and 6
utilized and 3o (550 mg, 61% yield, 3o/3o′ > 20/1, and 95% ee) was obtained (Scheme 4). The application of allylated hydroxylamines 3 generated by this method is demonstrated in Scheme 4. The treatment of 3a with zinc powder in acetic acid/H2O (1/1) gave the 1-phenylprop-2-en-1-amine 5 in 95% yield (Scheme 4) and its optical rotation is in agreement with that of the known (R)-5. 15 Therefore, the absolute configuration of 3a was deduced as R. In addition, the reaction of (E)-but-2-en-1-yl methyl carbonate 1u (0.2 mmol) with (R)-3a (95% ee, 0.2 mmol) under the identical conditions afforded the corresponding 6 in a 90% yield with a diastereomeric ratio (dr) of >20/1 (see Scheme 4). Certainly, through the use of 1a instead of 1u in the above-mentioned reaction, 4a was obtained in 80% yield with 96% ee (see Table 1, entry 18, and Scheme 4). In conclusion, we have successfully applied hydroxylamine in Ir-catalyzed allylic substitutions, which gave the allylated hydroxylamines in good to high yields with high levels of chemoselectivities, regioselectivities, and enantioselectivities. This method allows the use of unprotected hydroxylamine, tolerates various functionalized groups, and provides a new way for the transformation of hydroxylamine to chiral allylated hydroxylamines.
a,b,c
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01357. Experimental procedures, characterization data for all new compounds, descriptions of stereochemical assignments, and copies of 1H, 19F, and 13C NMR spectra for all new compounds reported in the text (PDF)
a
Reaction conditions: [Ir(COD)Cl]2 (0.004 mmol), L1 (0.008 mmol), 1 (0.1 mmol), 2a (0.4 mmol), NEt3 (0.4 mmol), and DMSO (1 mL), 12 h. bIsolated yield. cDetermined by a chiral HPLC.
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aminations of aliphatic allylic carbonates3b,7b,c (see Scheme 3).
AUTHOR INFORMATION
Corresponding Author
Note that 3a′−3t′ (3a−3t/3a′−3t′ > 20/1) and 4a−4p were not observed in all cases. The large-scale synthesis of the allylated hydroxylamine derivatives such as 3o was performed under the optimal
*E-mail:
[email protected]. ORCID
Xiaoming Zhao: 0000-0002-1447-128X C
DOI: 10.1021/acs.orglett.9b01357 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
(10) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (11) Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433. (12) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 2001, 1375. (13) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (14) (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769. (15) Bondzić, B. P.; Eilbracht, P. Org. Lett. 2008, 10, 3433.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to the Chinese National Science Foundation (NSF) (Grant No. 21272175) and the Fundamental Research Funds for the Central Universities for financial support of this research.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b01357 Org. Lett. XXXX, XXX, XXX−XXX
