CHIRALITY 28:132–135 (2016)
Short Communication Double Asymmetric Induction During the Addition of (RP)-Menthyl Phenyl Phosphine Oxide to Chiral Aldimines ZHONG-YANG ZHOU,† HE ZHANG,† LAN YAO, JING-HONG WEN, SHAO-ZHEN NIE, AND CHANG-QIU ZHAO* College of Chemistry and Chemical Engineering, Liaocheng University, Shandong, China
ABSTRACT P,C-Stereogenic α-amino phosphine oxides were prepared from the addition of (RP)-menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 °C in up to 91:9 drC and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)- or (R)-aldimines, respectively. Chirality 28:132–135, 2016. © 2015 Wiley Periodicals, Inc. KEY WORDS: P,C-stereogenic; double asymmetric induction; addition; α-amino tertiary phosphines oxide; (RP)-menthyl phenyl phosphine oxide The multi P,C-stereogenic compounds attracted great attention due to their wide applications not only as chiral auxiliary and ligands,1 or their precursors, but also as pharmacologically active substances.2–10 However, the two stereogenic centers in the same molecule greatly increased the difficulty to obtain the compounds, and restricted their applications. The preparation of these compounds always involved kinetic resolutions that are tedious and timeconsuming.11–15 Until recent years, the generation of multi P,C-stereogenic centers was realized via asymmetric induction of stereogenic phosphorus.16 For example, Yeung and co-workers reported the addition of P-stereogenic Ph (tBu)POH to unsaturated ketones, affording the γ-keto P, C-stereogenic tertiary phosphine oxides.17 Sieber et al. developed the stereoselective α-modification of cyclic P-stereogenic compounds with electrophilic reagents, affording various P,C-stereogenic phosphine ligands.18 Montchamp’s group obtained P,C-stereogenic α-hydroxyl phosphinates in 94% (de) by means of the asymmetric induction of chiral phosphorus in Wittig rearrangement.19 Recently, Couzijn and we separately reported the addition of the secondary phosphine oxides to aldehydes to afford α-hydroxyl tertiary phosphine oxides in excellent yield and diastereoselectivity.20–22 As important metabolism analogs of α-amino acid in organisms, α-amino phosphoric acid and their derivatives could also be obtained by means of asymmetric induction.23–31 For example, Ordoñez and co-workers reported a one-pot process to afford α-amino phosphonate in 93:7 dr, inducted by (S)-3,3-dimethyl-2-butylamine28,29 (Eq. 1). However, to the best of our knowledge the synthesis of P,C-stereogenic α-amino phosphorus derivatives, which were more potentially applied as (P^N) bidentate ligands in asymmetric catalysis,32–41 has scarcely been studied. Herein we report the asymmetric induction of stereogenic phosphorus during the addition of (RP)-menthyl phenylphosphine oxide 1a to chiral aldimines. Two RP,RC and RP,SC stereomers of tertiary phosphines oxides were obtained via the same reaction. Different from the previous work, the configuration of the α-carbon in adduct was mainly controlled by the stereogenic phosphorus, and (RP)-1a showed matched or © 2015 Wiley Periodicals, Inc.
mismatched induction with (S)- or (R)-aldimines, respectively (Eq. 2). In the matched cases, the highest diastereoselectivity was reached to 91:9 dr. The two stereomers can be separated by preparative thin-layer chromatography (TLC) in most cases.
MATERIALS AND METHODS The typical procedure for preparation of 3aA and 3aB: under nitrogen atmosphere, 1a (dr >99:1, 264 mg, 1 mmol) was heated with (R)-N-1phenylethyl benzaldimine 2a (209 mg, 1 mmol) at 80 °C in a neat state. 31 The reaction was monitored with P-NMR. After 12 h, all 1a was consumed. The resulting solid was dissolved in dichloromethane and purified by preparative TLC on silica gel. The specimen of 3aA was obtained as a white solid (241 mg, 51%, >99:1 drC, hexane/ethyl ace1 tate = 2/1 as eluent, Rf = 0.63). m.p. 40–43 °C; H NMR (400 MHz, CDCl3) δ = 7.33–7.22 (m, 7H), 7.18–7.13 (m, 1H), 7.11–7.01 (m, 7H), 3.84 (d, J = 7.0, 1H), 3.45 (d, J = 6.5, 1H), 2.38–2.30 (m, 1H), 1.99 (dd, J = 29.9, 11.9, 3H), 1.73 (d, J = 8.6, 2H), 1.55 (d, J = 12.4, 1H), 1.30 (t, J = 12.7, 4H), 31 1.00 (dd, J = 17.1, 8.2, 5H), 0.85 (d, J = 6.8, 3H), 0.28 (d, J = 6.8, 3H). P 13 NMR (162 MHz, CDCl3) δ = 43.91 (s). C NMR (100 MHz, CDCl3) δ = 144.24 (s), 137.02 (s), 134.18 (s), 133.31 (s), 130.47 (d, J = 7.88), 130.19 (d, J = 2.56), 129.01 (s),128.96 (s), 128.18 (s), 127.92 (s), 127.81 (s), 127.79 (s),127.38 (s), 127.27 (s), 127.08 (s), 126.92 (d, J = 2.02),
*Correspondence to: C.-Q. Zhao, College of Chemistry and Chemical Engineering, Liaocheng University, Shandong 252059, China. E-mail: [email protected] † The first two authors contributed equally to this work. Received for publication 8 July 2015; Accepted 30 September 2015 DOI: 10.1002/chir.22549 Published online 26 November 2015 in Wiley Online Library (wileyonlinelibrary.com).
ADDITION OF (RP)-MENTHYL PHENYL PHOSPHINE OXIDE TO CHIRAL ALDIMINES
58.83(d, J = 71.80), 55.22 (d, J = 12.30), 43.96 (s), 41.75 (d, J = 62.22), 35.79 (s), 34.37 (s), 33.55 (d, J = 13.1), 28.00 (s), 25.03 (d, J = 7.00), 24.56 (s), 22.47 (s), 21.47 (s), 15.13 (s). Calcd for C31H40NOP: C, 78.61; H, 8.51; N, 2.96. Found: C, 78.45; H, 8.46; N, 2.95. The specimen of 3aB was obtained as white solid (99 mg, 21%, >99:1 drC, hexane/ethyl acetate = 2/1 1 as eluent, Rf =0.41), m.p. 117–120 °C; H NMR (400 MHz, CDCl3) δ = 7.50–7.38 (m, 3H), 7.35–7.16 (m, 10H), 6.81 (d, J = 7.1, 2H), 4.63 (d, J = 18.3, 1H), 3.62 (q, J = 6.2, 1H), 2.56 (s, 1H), 2.40 (d, J = 4.3, 1H), 1.86– 1.62 (m, 5H), 1.56–1.46 (m, 2H), 1.28 (t, J = 7.6, 3H), 1.00 (t, J = 9.5, 4H), 31 0.70 (d, J = 6.7, 3H), 0.34 (d, J = 6.7, 3H). P NMR (162 MHz, CDCl3) 13 δ = 40.14 (s). C NMR (100 MHz, CDCl3) δ = 146.11 (s), 134.98 (s), 132.74 (s), 131.93 (s), 131.30 (d, J = 8.34), 131.12 (d, J = 11.38), 128.75 (s), 128.65 (s), 128.22 (s),128.18 (s), 128.03 (s), 127.64 (s), 127.45 (s), 126.71 (s), 126.60 (s), 57.92(dd, J = 6.20, 8.06), 54.66 (dd, J = 13.30, 5.72), 43.38 (d, J = 3.38), 38.26 (dd, J = 5.20,12.70), 37.60 (dd, J = 5.56, 16.20), 34.67 (s), 34.00 (d, J = 10.26), 33.66 (d, J = 13.08), 28.13 (s), 25.12 (d, J = 11.44), 23.01 (dd, J = 6.98, 6.52), 21.79 (d, J = 5.68), 21.66 (d, J = 5.90), 15.77 (d, J = 2.80). Calcd for C31H40NOP: C, 78.61; H, 8.51; N, 2.96. Found: C, 78.49; H, 8.51; N, 2.97.
RESULTS AND DISCUSSION
When the two starting materials 1a and (R)-2a were heated at 80 °C in the neat state, 1a was nearly entirely consumed after 12 h, which was observed from 31P-NMR spectra. The two peaks of adduct 3a on 31P-NMR spectra were located at 43.91 and 40.14 ppm, in a ratio of 73:27. The reaction proceeded through a P-retained mechanism, and the two stereomers 3aA and 3aB were confirmed to have RP,RC and TABLE 1. Preparation of 3A and 3B by the addition of 1a to 2
a
Entry
Ar
R1
R2
R3
drC
1
Ph
Ph
H
Me
73:27
2
p-MeC6H4
Ph
H
Me
73:27
3
p-iPrC6H4
Ph
H
Me
72:28
4
p-MeOC6H4
Ph
H
Me
71:29
5
p-ClC6H4
Ph
H
Me
72:28
6 7 8
Ph Ph Ph
Me H H
Me Me (CH2)5 nBu, H
77:23 86:14 80:20
9 10
Ph p-iPrC6H4
Ph Ph
Me Me
H H
89:11 90:10
11 12
p-MeOC6H4 p-ClC6H4
Ph Ph
Me Me
H H
91:9 91:9
Isolated yield b (%) 3aA, 51 3aB, 21 3bA, 53 3bB, 23 3cA, 56 3cB, 20 3dA, 58 3dB, 24 3eA, 55 3eB, 22 3fA, 60 3gA, 67 3hA, 58 3hB, 17 3iA, 76 3jA + 3jB, 75 c (91:9) 3kA, 81 3lA + 3lB, 83 c (91:9)
a Typical procedure: 1a (dr >99:1, 1 mmol) was heated with (R)-2a (1 mmol) at 80 °C under neat state for 12 h. The yields were near to quantitative, which 31 and drC (3A:3B) were estimated by P NMR spectra based on 1a. b Unless otherwise specified, single stereomer was isolated. c The drC of the two stereomers are presented in parentheses.
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RP,SC structures, respectively (vide infra). As seen in Table 1, the addition of 1a to various (R)-aldimines 2a-2e gave drC of 3A:3B around 72:28, a moderate diastereoselectivity (entries 1–5). The variously substituted aryl groups in aldimines only showed a slight influence on the drC. Although the selectivities were not quite satisfied, it was interesting that the two stereomers could be simply separated with preparative TLC, affording two kinds of α-amino tertiary phosphine oxides from the same reaction. When nonchiral aldimines 2f-2h were used, the drC around 77:23 to 86:14 were higher than (R)-aldimines 2a-2e (entries 6–8), and varied depending on the alkyl groups of amine moieties. For example, secondary cyclo-hexyl gave better drC than tert-butyl. The drC were further improved to 91:9 for the reactions of (S)-aldimines 2i-2l, which were also scarcely inf luenced by the aryl groups of aldimines (entries 9–12). The better drC for the reaction of nonchiral aldimines 2f-2h than (R)-aldimines 2a-2e showed that the chirality of 3 was induced by the stereogenic phosphorus of 1a, and the asymmetric induction of 1a mismatched to (R)aldimines. The much better drC for the (S)-aldimines exhibited the matched induction of that to 1a. On the basis of the observation, the dominant stereomers of the addition of 1a to 2i-2l were also assigned as RP,RC structure, regardless of the inverted peaks’ location on 31P NMR.* We supposed that the (S)- and (R)-aldimines moieties would supply a different magnetic environment around phosphorus, which resulted in the variation of the peaks’ location. It was obvious that RP-1a was favored to the formation of (R)-configuration on α-carbon of 3. The (R)- and (S)-aldimines could weaken or enhance the induction, respectively. During the reaction of 1a, the remarkable chiral center at phosphorus resulted in the strong induction to form Rα-Cadducts 3A. Meanwhile, the induction from (R)-aldimines, which tended to form Sα-C-adducts,28,29 would partly neutralize the effect of 1a. Therefore, the reaction of (R)-aldimines gave worse drC than (S)- and nonchiral aldimines. The crystallography of 3gA and 3bB unambiguously indicated their RP,RC and RP,SC structure, respectively (Fig. 1). The retained configuration on phosphorus of the addition was thence confirmed. As seen in the cross-conformation structure of 3aA-3eA, which referred to the X-ray diffraction results, the aryl was located between oxygen and phenyl, far to menthyl. Meanwhile, the nitrogen located near the menthyl (Fig. 1A,C). In 3aB-3eB, the positions of aryl and nitrogen were reversed to 3aA-3eA, i.e., the aryl group located near the menthyl (Fig. 1B,D). As we supposed, the interaction a (repulsion between menthyl to aryl groups) mainly controlled the stabilities of the pair of two stereomers. The f lexible configuration of nitrogen, which depended on the chirality of carbon skeleton of (R)- or (S)-phenyl ethylamine, also secondarily inf luenced the structure of α-carbon, due to the repulsion between lone pair electron of nitrogen to α-aryl (interaction b, as seen in Fig. 2).
*
Similar to 3aA, the peaks of major stereomers 3bA–3eA were located 31 downfield on P NMR spectra. (S)-Aldimine 2i–2l afforded major 31 stereomers 3iA–3lA whose peaks on P NMR spectra were located upfield. Chirality DOI 10.1002/chir
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ZHOU ET AL.
Fig. 1. Crystallographic structures for 3gA (A), 3bB (B) and the supposed conformation for 3aA-3eA (C), 3aB-3eB (D).
3fA-3hA, the interaction b was not considered; only the interaction a influence on the ratio of the two stereomers (entries 3–4). The (S)-aldimines showed conflict asymmetric induction to the (R)-ones. For the stabilities of 3i-3l, interaction b took a reversed role to that for 3a-3e. Therefore, both interactions a and b increased the stabilities of 3iA-3lA, and reduced the stabilities of 3iB-3lB (Fig. 2). The induction factors for them were assigned as “a + b” and “-a-b”, respectively (entries 5–6), and the best selectivity was achieved for the reaction.
Fig. 2. The supposed conformation for 3iB-3lB.
CONCLUSION TABLE 2. Supposed induction factors during the addition of 1a to 2 to form 3. Entry 1 2 3 4 5 6
Stereomers
Induction effects
Relative ratio
3aA-3eA 3aB-3eB 3fA-3hA 3fB-3hB 3iA-3lA 3iB-3lB
a-b b-a a -a a+b -a-b
72 28 77 (86) 23 (14) 91 9
The data refer to the drC of Table 1.
The interaction a was significant in 3aB-3eB, leading to their instabilities. Similarly, interaction b resulted in the instabilities of 3aA-3eA. The interactions a and b could be ignored for 3aA-3eA and 3aB-3eB, respectively (Fig. 1C,D). As seen in Table 2, the induction factors were estimated by the relative ratio of the two stereomers. The percentages for 3aA3eA were supposed to depend on the difference between interactions a and b. Thus, their induction factors were assigned as “a-b” (entry 1 of Table 2). Similarly, a and b took reversed roles for the percentages of 3aB-3eB, and the corresponding factors were assigned as “b-a” (entry 2). For Chirality DOI 10.1002/chir
In summary, the addition of 1a to aldimines showed variable diastereoselectivity, which became better with the turn of (R), nonchiral, and (S)-aldimines. On the basis of the results, matched and mismatched induction were speculated between 1a to (S) and (R)-aldimines, respectively. The stereoselectivity was mainly controlled by the interaction between menthyl and α-aryl. The carbon skeleton of (R)-aldimines showed conflicted asymmetric induction to menthyl, probably due to the flexible chirality on their nitrogen. (S)-Aldimines showed the same asymmetric induction to menthyl. In most cases, the two stereomers can be simply separated by preparative TLC, and obtained through the same reaction.
SUPPORTING INFORMATION
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Chirality DOI 10.1002/chir
Short Communication Double Asymmetric Induction During the Addition of (RP)-Menthyl Phenyl Phosphine Oxide to Chiral Aldimines ZHONG-YANG ZHOU,† HE ZHANG,† LAN YAO, JING-HONG WEN, SHAO-ZHEN NIE, AND CHANG-QIU ZHAO* College of Chemistry and Chemical Engineering, Liaocheng University, Shandong, China
ABSTRACT P,C-Stereogenic α-amino phosphine oxides were prepared from the addition of (RP)-menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 °C in up to 91:9 drC and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)- or (R)-aldimines, respectively. Chirality 28:132–135, 2016. © 2015 Wiley Periodicals, Inc. KEY WORDS: P,C-stereogenic; double asymmetric induction; addition; α-amino tertiary phosphines oxide; (RP)-menthyl phenyl phosphine oxide The multi P,C-stereogenic compounds attracted great attention due to their wide applications not only as chiral auxiliary and ligands,1 or their precursors, but also as pharmacologically active substances.2–10 However, the two stereogenic centers in the same molecule greatly increased the difficulty to obtain the compounds, and restricted their applications. The preparation of these compounds always involved kinetic resolutions that are tedious and timeconsuming.11–15 Until recent years, the generation of multi P,C-stereogenic centers was realized via asymmetric induction of stereogenic phosphorus.16 For example, Yeung and co-workers reported the addition of P-stereogenic Ph (tBu)POH to unsaturated ketones, affording the γ-keto P, C-stereogenic tertiary phosphine oxides.17 Sieber et al. developed the stereoselective α-modification of cyclic P-stereogenic compounds with electrophilic reagents, affording various P,C-stereogenic phosphine ligands.18 Montchamp’s group obtained P,C-stereogenic α-hydroxyl phosphinates in 94% (de) by means of the asymmetric induction of chiral phosphorus in Wittig rearrangement.19 Recently, Couzijn and we separately reported the addition of the secondary phosphine oxides to aldehydes to afford α-hydroxyl tertiary phosphine oxides in excellent yield and diastereoselectivity.20–22 As important metabolism analogs of α-amino acid in organisms, α-amino phosphoric acid and their derivatives could also be obtained by means of asymmetric induction.23–31 For example, Ordoñez and co-workers reported a one-pot process to afford α-amino phosphonate in 93:7 dr, inducted by (S)-3,3-dimethyl-2-butylamine28,29 (Eq. 1). However, to the best of our knowledge the synthesis of P,C-stereogenic α-amino phosphorus derivatives, which were more potentially applied as (P^N) bidentate ligands in asymmetric catalysis,32–41 has scarcely been studied. Herein we report the asymmetric induction of stereogenic phosphorus during the addition of (RP)-menthyl phenylphosphine oxide 1a to chiral aldimines. Two RP,RC and RP,SC stereomers of tertiary phosphines oxides were obtained via the same reaction. Different from the previous work, the configuration of the α-carbon in adduct was mainly controlled by the stereogenic phosphorus, and (RP)-1a showed matched or © 2015 Wiley Periodicals, Inc.
mismatched induction with (S)- or (R)-aldimines, respectively (Eq. 2). In the matched cases, the highest diastereoselectivity was reached to 91:9 dr. The two stereomers can be separated by preparative thin-layer chromatography (TLC) in most cases.
MATERIALS AND METHODS The typical procedure for preparation of 3aA and 3aB: under nitrogen atmosphere, 1a (dr >99:1, 264 mg, 1 mmol) was heated with (R)-N-1phenylethyl benzaldimine 2a (209 mg, 1 mmol) at 80 °C in a neat state. 31 The reaction was monitored with P-NMR. After 12 h, all 1a was consumed. The resulting solid was dissolved in dichloromethane and purified by preparative TLC on silica gel. The specimen of 3aA was obtained as a white solid (241 mg, 51%, >99:1 drC, hexane/ethyl ace1 tate = 2/1 as eluent, Rf = 0.63). m.p. 40–43 °C; H NMR (400 MHz, CDCl3) δ = 7.33–7.22 (m, 7H), 7.18–7.13 (m, 1H), 7.11–7.01 (m, 7H), 3.84 (d, J = 7.0, 1H), 3.45 (d, J = 6.5, 1H), 2.38–2.30 (m, 1H), 1.99 (dd, J = 29.9, 11.9, 3H), 1.73 (d, J = 8.6, 2H), 1.55 (d, J = 12.4, 1H), 1.30 (t, J = 12.7, 4H), 31 1.00 (dd, J = 17.1, 8.2, 5H), 0.85 (d, J = 6.8, 3H), 0.28 (d, J = 6.8, 3H). P 13 NMR (162 MHz, CDCl3) δ = 43.91 (s). C NMR (100 MHz, CDCl3) δ = 144.24 (s), 137.02 (s), 134.18 (s), 133.31 (s), 130.47 (d, J = 7.88), 130.19 (d, J = 2.56), 129.01 (s),128.96 (s), 128.18 (s), 127.92 (s), 127.81 (s), 127.79 (s),127.38 (s), 127.27 (s), 127.08 (s), 126.92 (d, J = 2.02),
*Correspondence to: C.-Q. Zhao, College of Chemistry and Chemical Engineering, Liaocheng University, Shandong 252059, China. E-mail: [email protected] † The first two authors contributed equally to this work. Received for publication 8 July 2015; Accepted 30 September 2015 DOI: 10.1002/chir.22549 Published online 26 November 2015 in Wiley Online Library (wileyonlinelibrary.com).
ADDITION OF (RP)-MENTHYL PHENYL PHOSPHINE OXIDE TO CHIRAL ALDIMINES
58.83(d, J = 71.80), 55.22 (d, J = 12.30), 43.96 (s), 41.75 (d, J = 62.22), 35.79 (s), 34.37 (s), 33.55 (d, J = 13.1), 28.00 (s), 25.03 (d, J = 7.00), 24.56 (s), 22.47 (s), 21.47 (s), 15.13 (s). Calcd for C31H40NOP: C, 78.61; H, 8.51; N, 2.96. Found: C, 78.45; H, 8.46; N, 2.95. The specimen of 3aB was obtained as white solid (99 mg, 21%, >99:1 drC, hexane/ethyl acetate = 2/1 1 as eluent, Rf =0.41), m.p. 117–120 °C; H NMR (400 MHz, CDCl3) δ = 7.50–7.38 (m, 3H), 7.35–7.16 (m, 10H), 6.81 (d, J = 7.1, 2H), 4.63 (d, J = 18.3, 1H), 3.62 (q, J = 6.2, 1H), 2.56 (s, 1H), 2.40 (d, J = 4.3, 1H), 1.86– 1.62 (m, 5H), 1.56–1.46 (m, 2H), 1.28 (t, J = 7.6, 3H), 1.00 (t, J = 9.5, 4H), 31 0.70 (d, J = 6.7, 3H), 0.34 (d, J = 6.7, 3H). P NMR (162 MHz, CDCl3) 13 δ = 40.14 (s). C NMR (100 MHz, CDCl3) δ = 146.11 (s), 134.98 (s), 132.74 (s), 131.93 (s), 131.30 (d, J = 8.34), 131.12 (d, J = 11.38), 128.75 (s), 128.65 (s), 128.22 (s),128.18 (s), 128.03 (s), 127.64 (s), 127.45 (s), 126.71 (s), 126.60 (s), 57.92(dd, J = 6.20, 8.06), 54.66 (dd, J = 13.30, 5.72), 43.38 (d, J = 3.38), 38.26 (dd, J = 5.20,12.70), 37.60 (dd, J = 5.56, 16.20), 34.67 (s), 34.00 (d, J = 10.26), 33.66 (d, J = 13.08), 28.13 (s), 25.12 (d, J = 11.44), 23.01 (dd, J = 6.98, 6.52), 21.79 (d, J = 5.68), 21.66 (d, J = 5.90), 15.77 (d, J = 2.80). Calcd for C31H40NOP: C, 78.61; H, 8.51; N, 2.96. Found: C, 78.49; H, 8.51; N, 2.97.
RESULTS AND DISCUSSION
When the two starting materials 1a and (R)-2a were heated at 80 °C in the neat state, 1a was nearly entirely consumed after 12 h, which was observed from 31P-NMR spectra. The two peaks of adduct 3a on 31P-NMR spectra were located at 43.91 and 40.14 ppm, in a ratio of 73:27. The reaction proceeded through a P-retained mechanism, and the two stereomers 3aA and 3aB were confirmed to have RP,RC and TABLE 1. Preparation of 3A and 3B by the addition of 1a to 2
a
Entry
Ar
R1
R2
R3
drC
1
Ph
Ph
H
Me
73:27
2
p-MeC6H4
Ph
H
Me
73:27
3
p-iPrC6H4
Ph
H
Me
72:28
4
p-MeOC6H4
Ph
H
Me
71:29
5
p-ClC6H4
Ph
H
Me
72:28
6 7 8
Ph Ph Ph
Me H H
Me Me (CH2)5 nBu, H
77:23 86:14 80:20
9 10
Ph p-iPrC6H4
Ph Ph
Me Me
H H
89:11 90:10
11 12
p-MeOC6H4 p-ClC6H4
Ph Ph
Me Me
H H
91:9 91:9
Isolated yield b (%) 3aA, 51 3aB, 21 3bA, 53 3bB, 23 3cA, 56 3cB, 20 3dA, 58 3dB, 24 3eA, 55 3eB, 22 3fA, 60 3gA, 67 3hA, 58 3hB, 17 3iA, 76 3jA + 3jB, 75 c (91:9) 3kA, 81 3lA + 3lB, 83 c (91:9)
a Typical procedure: 1a (dr >99:1, 1 mmol) was heated with (R)-2a (1 mmol) at 80 °C under neat state for 12 h. The yields were near to quantitative, which 31 and drC (3A:3B) were estimated by P NMR spectra based on 1a. b Unless otherwise specified, single stereomer was isolated. c The drC of the two stereomers are presented in parentheses.
133
RP,SC structures, respectively (vide infra). As seen in Table 1, the addition of 1a to various (R)-aldimines 2a-2e gave drC of 3A:3B around 72:28, a moderate diastereoselectivity (entries 1–5). The variously substituted aryl groups in aldimines only showed a slight influence on the drC. Although the selectivities were not quite satisfied, it was interesting that the two stereomers could be simply separated with preparative TLC, affording two kinds of α-amino tertiary phosphine oxides from the same reaction. When nonchiral aldimines 2f-2h were used, the drC around 77:23 to 86:14 were higher than (R)-aldimines 2a-2e (entries 6–8), and varied depending on the alkyl groups of amine moieties. For example, secondary cyclo-hexyl gave better drC than tert-butyl. The drC were further improved to 91:9 for the reactions of (S)-aldimines 2i-2l, which were also scarcely inf luenced by the aryl groups of aldimines (entries 9–12). The better drC for the reaction of nonchiral aldimines 2f-2h than (R)-aldimines 2a-2e showed that the chirality of 3 was induced by the stereogenic phosphorus of 1a, and the asymmetric induction of 1a mismatched to (R)aldimines. The much better drC for the (S)-aldimines exhibited the matched induction of that to 1a. On the basis of the observation, the dominant stereomers of the addition of 1a to 2i-2l were also assigned as RP,RC structure, regardless of the inverted peaks’ location on 31P NMR.* We supposed that the (S)- and (R)-aldimines moieties would supply a different magnetic environment around phosphorus, which resulted in the variation of the peaks’ location. It was obvious that RP-1a was favored to the formation of (R)-configuration on α-carbon of 3. The (R)- and (S)-aldimines could weaken or enhance the induction, respectively. During the reaction of 1a, the remarkable chiral center at phosphorus resulted in the strong induction to form Rα-Cadducts 3A. Meanwhile, the induction from (R)-aldimines, which tended to form Sα-C-adducts,28,29 would partly neutralize the effect of 1a. Therefore, the reaction of (R)-aldimines gave worse drC than (S)- and nonchiral aldimines. The crystallography of 3gA and 3bB unambiguously indicated their RP,RC and RP,SC structure, respectively (Fig. 1). The retained configuration on phosphorus of the addition was thence confirmed. As seen in the cross-conformation structure of 3aA-3eA, which referred to the X-ray diffraction results, the aryl was located between oxygen and phenyl, far to menthyl. Meanwhile, the nitrogen located near the menthyl (Fig. 1A,C). In 3aB-3eB, the positions of aryl and nitrogen were reversed to 3aA-3eA, i.e., the aryl group located near the menthyl (Fig. 1B,D). As we supposed, the interaction a (repulsion between menthyl to aryl groups) mainly controlled the stabilities of the pair of two stereomers. The f lexible configuration of nitrogen, which depended on the chirality of carbon skeleton of (R)- or (S)-phenyl ethylamine, also secondarily inf luenced the structure of α-carbon, due to the repulsion between lone pair electron of nitrogen to α-aryl (interaction b, as seen in Fig. 2).
*
Similar to 3aA, the peaks of major stereomers 3bA–3eA were located 31 downfield on P NMR spectra. (S)-Aldimine 2i–2l afforded major 31 stereomers 3iA–3lA whose peaks on P NMR spectra were located upfield. Chirality DOI 10.1002/chir
134
ZHOU ET AL.
Fig. 1. Crystallographic structures for 3gA (A), 3bB (B) and the supposed conformation for 3aA-3eA (C), 3aB-3eB (D).
3fA-3hA, the interaction b was not considered; only the interaction a influence on the ratio of the two stereomers (entries 3–4). The (S)-aldimines showed conflict asymmetric induction to the (R)-ones. For the stabilities of 3i-3l, interaction b took a reversed role to that for 3a-3e. Therefore, both interactions a and b increased the stabilities of 3iA-3lA, and reduced the stabilities of 3iB-3lB (Fig. 2). The induction factors for them were assigned as “a + b” and “-a-b”, respectively (entries 5–6), and the best selectivity was achieved for the reaction.
Fig. 2. The supposed conformation for 3iB-3lB.
CONCLUSION TABLE 2. Supposed induction factors during the addition of 1a to 2 to form 3. Entry 1 2 3 4 5 6
Stereomers
Induction effects
Relative ratio
3aA-3eA 3aB-3eB 3fA-3hA 3fB-3hB 3iA-3lA 3iB-3lB
a-b b-a a -a a+b -a-b
72 28 77 (86) 23 (14) 91 9
The data refer to the drC of Table 1.
The interaction a was significant in 3aB-3eB, leading to their instabilities. Similarly, interaction b resulted in the instabilities of 3aA-3eA. The interactions a and b could be ignored for 3aA-3eA and 3aB-3eB, respectively (Fig. 1C,D). As seen in Table 2, the induction factors were estimated by the relative ratio of the two stereomers. The percentages for 3aA3eA were supposed to depend on the difference between interactions a and b. Thus, their induction factors were assigned as “a-b” (entry 1 of Table 2). Similarly, a and b took reversed roles for the percentages of 3aB-3eB, and the corresponding factors were assigned as “b-a” (entry 2). For Chirality DOI 10.1002/chir
In summary, the addition of 1a to aldimines showed variable diastereoselectivity, which became better with the turn of (R), nonchiral, and (S)-aldimines. On the basis of the results, matched and mismatched induction were speculated between 1a to (S) and (R)-aldimines, respectively. The stereoselectivity was mainly controlled by the interaction between menthyl and α-aryl. The carbon skeleton of (R)-aldimines showed conflicted asymmetric induction to menthyl, probably due to the flexible chirality on their nitrogen. (S)-Aldimines showed the same asymmetric induction to menthyl. In most cases, the two stereomers can be simply separated by preparative TLC, and obtained through the same reaction.
SUPPORTING INFORMATION
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Chirality DOI 10.1002/chir
