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Synthesis of optically active N-‐C axially chiral tetrahydroquinoline and its response to acid-‐accelerated molecular rotor Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x
a
a
a
b
b
Yuya Suzuki, Masato Kageyama, Ryuichi Morisawa, Yasuo Dobashi, Hiroshi Hasegawa, Satoshi b a Yokojima,* Osamu Kitagawa*
www.rsc.org/
Optically active atropisomeric N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐1,2,3,4-‐ tetrahydroquinoline with an N-‐C chiral axis was prepared via catalytic enantioselective reaction. The addition of methane sulfonic acid to this axially chiral quinoline dramatically lowered the barrier to rotation around the chiral axis. Atropisomeric compounds, owing to rotational restriction around an N-‐C single bond have been receiving increased attention as an 1 interesting class of chiral molecules. Recent noteworthy topics in this field include catalytic enantioselective syntheses. Various N-‐C axially chiral compounds have been prepared with high enantioselectivity through catalytic asymmetric reactions, and used 2,3 as chiral building blocks and chiral ligands. In addition, N-‐C axially chiral compounds have been found useful not only in the field of synthetic organic chemistry but also in molecular devices 4 (molecular rotors). Molecular rotors, whose rate of rotation around a bond can be controlled by external stimuli, are one of the most common classes 5 of molecular devices. Recently, Shimizu et al reported an interesting molecular rotor in which free rotation around an N-‐C bond is significantly accelerated by the addition of a protic acid 4b (Scheme 1). Their molecular rotor is based on a rigid atropisomeric N-‐(quinolin-‐8-‐yl)succinimide framework that is rotationally restricted due to the repulsion between the quinoline nitrogen and imide carbonyl oxygen. At 23 °C, rotation around the ≠ N-‐C bond of imide I is slow (ΔG = 22.2 kcal/mol, t1/2 = 26 min), but upon addition of 3.5 equivalents of MeSO3H the rotation becomes ≠ -‐4 rapid (ΔG = 12.9 kcal/mol, t1/2 = 2.0 x 10 s). Mechanistic considerations show that this acid-‐mediated significant acceleration is due to stabilization of the planar transition state by the formation of an intramolecular hydrogen bond between the protonated quinolone nitrogen and an imide carbonyl oxygen. Shimizu et al. called the acid responsible for such an acceleration of a molecular a.
Department of Applied chemistry, Shibaura Institute of Technology, 3-‐7-‐5 Toyosu, Kohto-‐ku, Tokyo, 135-‐8458, Japan. E-‐mail: kitagawa@shibaura-‐it.ac.jp School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-‐1, Horinouchi, Hachioji, Tokyo, 192-‐0392, Japan. E-‐mail: [email protected] † Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x b.
rotor “proton grease”. H H+ ON ON Me Me N N Me O Me O + H I-H+ I ! = 12.9 kcal/mol) ! = 22.2 kcal/mol) (!G (!G ! H ! O O N Me Me N N N O Me O Me Scheme 1 Acid-‐accelerated molecular rotor (proton grease) reported by Shimizu et al. In this paper, we report the synthesis of optically active N-‐C axially chiral N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐1,2,3,4-‐tetrahydroquinoline (an N-‐C axially chiral cyclic amine) and its response to a new type of acid-‐accelerated molecular rotor (Scheme 2). N H H+ N t-Bu t-Bu quick rotational rotation restriction t-Bu t-Bu Scheme 2 N-‐C Axially chiral cyclic amine and its response to acid-‐ accelerated molecular rotor. As mentioned above, catalytic enantioselective syntheses of various N-‐C axially chiral compounds have been reported 2,3 recently. These compounds have an amide skeleton like anilides, imides, lactams and urea, or a nitrogen-‐containing aromatic heterocyclic framework like indole and 4-‐quinolinone, but there has been no report on the catalytic enantioselctive synthesis of simple N-‐C axially chiral amine. Only three reports have appeared on the preparation of optically active axially chiral amines by optical 6 resolution. In 2005, we succeeded in the highly enantioselective synthesis of N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐3,4-‐dihydroquinolin-‐2-‐one 2 by the
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(R)-‐BINAP-‐Pd(OAc)2 catalyzed intramolecular Buchwald-‐Hartwig 2c amination of NH-‐anilide 1 (Scheme 3). We expected that the reduction of the amide carbonyl group in quinolinone 2 would yield optically active tetrahydroquinoline 3 (N-‐C axially chiral cyclic amine). After a survey of reaction conditions, it was found that the use of Meerwein reagent and NaBH4 gave a good result. That is, tetrahydroquinoline 3 was obtained in 69% yield through NaBH4 reduction of iminium ether 2A prepared by the reaction of 2 with 7 BF4•OMe3 in CH2Cl2 (Scheme 3). However, the ee of the obtained 3 (89%ee) was lower than that of 2 (98%ee). Prolongation of the reaction time for the formation of 3 from iminium ether 2A (NaBH4 reduction) yielded an even lower ee for 3. A shorter reaction time and quick purification gave 3 with a higher ee (up to 92%ee and 81% yield), while the ee of 3 was not changed by the reaction time for the formation of 2A from quinolinone 2. These results indicate that the decrease in the ee of 3 may have been due to the partial racemization of 3, but not of 2A. Indeed, when 3 (89%ee) in CHCl3 was stood for 24 h at rt, the ee decreased to 55%. The rotational barrier around the chiral axis in 3 in CHCl3 was evaluated to be 25.1 kcal/mol at 298 K. Thus, the rotational barrier of 3 was remarkably lower than that of quinolinone 2 (33.1 kcal/mol). In contrast, 3 in the solid state can be stored for several months at rt without any decrease in ee. O 5.0 mol% (R)-BINAP 3.3 mol% Pd(OAc)2 NH N O 1.4 eq. Cs2CO3 t-Bu t-Bu Br toluene 80 °C, 20 h (97%) t-Bu t-Bu 1 2 (98%ee) (!G≠ = 33.1 kcal/mol) BF4•OMe3 N OMe NaBH4 N BF4 t-Bu t-Bu EtOH CH2Cl2 rt, 15 min rt, 23 h t-Bu t-Bu 3 (69%, 89%ee) 2A (!G≠ = 25.1 kcal/mol in CHCl3) 3 (55%ee) CHCl3, rt 24 h Scheme 3 Synthetic route to optically active N-‐C axially chiral cyclic amine 3 and its rotational barrier. As a new structural property of N-‐C axially chiral amine, we found that the rotational barrier in quinoline 3 is decreased by the addition of a protic acid. That is, when 3 (92%ee) in CHCl3 was stood for 10 min or 1 h at 25 °C, the ee remained essentially constant (91%ee, 90%ee, Table 1, entry 1). In contrast, in the presence of 1 equivalent of methanesulfonic acid (MeSO3H, pKa = -‐ 1.8), the ee of 3 decreased to 25% and 7%, respectively after 10 min and 1 h at 25 °C (entry 2). The addition of 2 equivalent of MeSO3H further increased the racemization rate decreasing the ee to 4% after 10 min (entry 3). Although a similar increase in the racemization rate was also observed following the addition of a substoichiometric amount (0.5 or 0.2 eq) of MeSO3H, the
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magnitude of the increase was lower than View that Article from a Online DOI: 10.1039/C5CC03659C stoichiometric quantity of MeSO3H (entries 4 and 5). These results indicate that the rotation rate around an N-‐C chiral axis can be controlled by MeSO3H, and establish the existence of a new type of acid-‐accelerated molecular rotor. The acidity of the protic acid is also important in this molecular rotor. The use of trifluoroacetic acid (pKa = 0.5) increased the racemization rate, but to a lesser degree than MeSO3H (entries 2 and 6). In the presence of acetic acid (pKa = 4.8), no detectable increase in racemization rate was observed (entry 7). Also, no rotational acceleration was observed in dihydroquinolinone 2 following the addition of MeSO3H. In the case of quinolinone (lactam) 2 and the use of a weak acid such as acetic acid, the protonation of the nitrogen atom may not be extensive. Thus, it is + obvious that the formation of a protonated amine 3-‐H is the driving force for the acceleration of the bond rotation, and that increasing the acidity and/or the quantity of the added acid increases the + proportion of 3-‐H , thus facilitating rotation about the N-‐C bond. a, b Table 1. Ee change of 3 in the presence of several protic acids.
H+
N
3
Na2CO3 aq
H
3 (decrease in ee)
t-Bu
(90-92%ee) t-Bu
3-H+
En try
Acid
1 h
2 h
3 h
24 h
%ee
%ee
%ee
%ee
%ee
10 min %ee
0 min
1
none
92
91
90
89
85
54
2
MeSO3H
92
25
7
-‐
-‐
-‐
3
MeSO3H (2 eq)
92
4
-‐
-‐
-‐
-‐
4
MeSO3H (0.5 eq)
90
51
5
-‐
-‐
-‐
5
MeSO3H (0.2 eq)
90
77
46
43
42
13
6
CF3CO2H
92
83
49
24
15
7
7
MeCO2H
92
91
90
88
83
53
a
1 Equivalent of a protic acid was added to 3 (15 mg) in CHCl3 (0.3 mL), and b the mixture was stood at 25 °C. The ee was determined by HPLC analysis + using a chiral OJ-‐H column after neutralization of 3-‐H .
An X-‐ray crystal structure analysis and DFT calculation were undertaken to elucidate the facilitation of rotation about the N-‐C bond by the protonation of the amine. In the crystal structure of 3 8 (Fig 1), it was found that bond N1-‐C8a is notably shorter than bonds N1-‐C1’ and N1-‐C2, and the 2,5-‐di-‐tert-‐butylphenyl group is almost perpendicular to the quinolone ring. This suggests that the
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lone electron pair on the nitrogen atom mainly resonates with the benzene ring of tetrahydroquinoline, and very little with the 2,5-‐di-‐ tert-‐butylphenyl group. Although the X-‐ray crystal structure analysis of protonated amine + 3-‐H was also attempted, unfortunately, no adequate single crystal + was obtained. Therefore, we estimated the structure of 3-‐H by DFT calculation (The structure of hydrochloride of 3 was estimated 9,10 + by DFT method). Most stable conformers of 3-‐H calculated at + the B3LYP/6-‐31G(d) level are shown in Fig 2. In 3-‐H , the three N-‐C bonds were found to be longer than in the un-‐protonated compound 3. Furthermore, although the nitrogen atom of amine 3 2 3 is the hybridization between sp and sp characters (Fig 1, total of + three bond angles around the nitrogen atom = 347.2 °), that of 3-‐H 3 has an almost complete sp character (Fig 2, total of three bond angles around the nitrogen atom = 337.4 °). Such change on hybridization of the nitrogen atom may bring about significant difference in the transition states during the N-‐C bond rotation in 3 + and 3-‐H .
5 6
4
4a
7 8
pseudo equatorial position, and the N-‐C bond rotation proceeds via View Article Online 10.1039/C5CC03659C the rotation of the ortho-‐tert-‐butyl group DOI: toward C2 side but not 9 toward C8 side (Fig 3). In amine 3, the steric repulsion with C8-‐ 11 hydrogen may be stronger than that with C2-‐hydrogen.
5 6 7 8
8a N
1 2 8a N
t-Bu !G≠
= 26.4 kcal/mol at 298 K
5'
4'
3-TS
N1-C2 = 1.479 Å, N1-C1' = 1.419 Å, N1-C8a = 1.437 Å < C2-N1-C1' = 123.7 °, < C2-N1-C8a = 107.2 ° < C8a-N1-C1' = 124.1 ° < C2-N1-C1'-C2' = 28.1 °, < C1'-N1-C8a-C8 = -44.0 °
5 6 7
t-Bu
4
7 8
2
8a N
H
6' 5'
t-Bu
1'
3-H+-TS1 !G≠ = 16.1 kcal/mol at 298 K
N1-C2 = 1.543 Å, N1-C1' = 1.524 Å, N1-C8a = 1.501 Å < C2-N1-C1' = 115.0 ° < C2-N1-C8a = 109.8 ° < C8a-N1-C1' = 113.0 ° < C2-N1-C1'-C2' = -151.6 ° < C1'-N1-C8a-C8 = -98.5 °
Cl
1' t-Bu 2'
3-H+-TS2
≠
3
1 2 8a N
Cl H
6' 5' 4'
t-Bu
3-H+-TS
!G≠ = 16.3 kcal/mol at 298 K
N1-C2 = 1.541 Å, N1-C1' = 1.533 Å, N1-C8a = 1.483 Å < C2-N1-C1' = 111.5 ° < C2-N1-C8a = 103.3 ° < C8a-N1-C1' = 124.7 ° < C2-N1-C1'-C2' = 129.6 ° < C1'-N1-C8a-C8 = -107.0 °
Fig 4. The transition state structure and the rotational barrier of 3-‐ + H calculated at the B3LYP/6-‐31G(d) level.
3'
4'
3-H+
3-H+A
4
3'
3
1
8
4a
2'
4'
Fig 1 X-‐Ray crystal structure of axially chiral quinoline 3.
4a
Fig 3 The transition state structure and the rotational barrier of 3 calculated at the B3LYP/6-‐31G(d) level.
2
N1-C2 = 1.473 Å, N1-C1' = 1.452 Å, N1-C8a = 1.409 Å < C2-N1-C1' = 111.8 °, < C2-N1-C8a = 116.9 ° < C8a-N1-C1' = 118.5 ° < C2-N1-C1'-C2' = -103.4 °, < C1'-N1-C8a-C8 = -26.1 °
5
t-Bu 2' 3'
3
6
≠
3
1'
3'
t-Bu
4
6'
1' t-Bu 2'
6' 5'
4a
3
1
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N1-C2 = 1.535 Å, N1-C1' = 1.506 Å, N1-C8a = 1.498 Å < C2-N1-C1' = 111.6 °, < C2-N1-C8a = 113.3 ° < C8a-N1-C1' = 112.4 ° < C2-N1-C1'-C2' = -93.5 °, < C1'-N1-C8a-C8 = -64.2 ° +
Fig 2 Most stable conformer of 3-‐H calculated at the B3LYP/6-‐ 31G(d) level. +
Indeed, in the transition state structures of 3 and 3-‐H calculated by DFT method (the effect of CHCl3 solvent was taken into account by polarizable continuum model), the significant differences on the orientation of a chiral axis (N1-‐C1’ bond) and the direction of the + bond rotation were found (3-‐TS in Fig 3 and 3-‐H -‐TS in Fig 4). That is, DFT calculation shows that the N1-‐C1’ bond in 3-‐TS occupies
On the other hand, in the N-‐C bond rotation of protonated amine + 3-‐H , two possible transition states were found (Fig 4). In both + + transition state structures 3-‐H -‐TS1 and 3-‐H -‐TS2, the N-‐C1’ bond occupies pseudo axial position. Such pseudo-‐axial orientation of the N-‐C1’ bond should significantly alleviate the steric repulsion between C8-‐hydrogen and tert-‐butyphenyl group to lead to the + remarkable decrease in the rotational barrier of 3-‐H . At the same + time, the N-‐C bond rotation of 3-‐H occurs via the rotation of the 12 ortho-‐tert-‐butyl group toward C8 side but not toward C2 side. Protic acid may promote the axial orientation of the N1-‐C1’bond in the transition state. Also, in comparison with 3, the elongated N-‐C + bonds in 3-‐H should reduce the steric repulsion from C8-‐ and C2-‐ hydrogens (Figures 1-‐4), thus lowering the energetic barrier to + rotation. Indeed, the calculated rotational barrier of 3-‐H at 298 K ≠ (ΔG = 16.1 and 16.3 kcal/mol) was 8.8-‐9.0 kcal/mol lower in ≠ comparison with the experimental value of 3 (ΔG value = 25.1 ≠ 13 kcal/mol, the calculated ΔG = 26.4 kcal/mol).
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We performed the synthesis of an optically active N-‐C axially chiral amine (N-‐C axially chiral tetrahydroquinoline) via catalytic enantioselective reaction and demonstrated its response to a new type of acid-‐accelerated molecular rotor. The protonation of the amine nitrogen by a protic acid facilitated the rotation about the N-‐C chiral bond by elongating the N-‐C bonds and changing the transition state structure.
3 4
Acknowledgement This work was partly supported by a Grant-‐in-‐Aid for Scientific Research (C26460014).
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Notes and references 1
2
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Turner, Tetrahedron Lett., 2009, 50, 3216; (i) N. Ototake, Y. View Article Online Morimoto, A. Mokuya, H. Fukaya, Y. O. Kitagawa, DOI:Shida, 10.1039/C5CC03659C Chem. Eur. J., 2010, 16, 6752; (j) H. Liu, W. Feng, C. W. Kee, D. Leow, W-‐T. Loh, C-‐H. Tan, Adv. Synth. Catal., 2010, 352, 3373; (k) S. Shirakawa, K. Liu, K. Maruoka, K. J. Am. Chem. Soc., 2012, 134, 916; (l) R. Guo, K-‐N. Li, H-‐J. Zhu, Y-‐M. Fan, L-‐ Z. Gong, Chem. Comm., 2014, 50, 5451; (m) N. D. Iorio, P. Righi, A. Mazzanti, M. Mancinelli, A. Ciogli, G. Bencivenni, J. Am. Chem. Soc., 2014, 136, 916; (n) K. Kamikawa, S. Arae, W-‐ Y Wu, C. Nakamura, T. Takahashi, M. Ogasawara, Chem. Eur. J., 2015, 21, 4954. I. Takahashi, Y. Suzuki, O. Kitagawa, Org. Prep. Proc. Int., 2014, 46, 1. (a) B. E. Dial, R. D. Rasberry, B. N. Bullock, M. D. Smith, P. J. Pellechia, S. Profeta, Jr, K. D. Shimizu, Org. Lett., 2011, 13, 244; (b) B. E. Dial, P. J. Pellechia, M. D. Smith, K. D.; Shimizu, J. Am. Chem. Soc., 2012, 134, 3675. (a) T. R. Kelly, H. D. Silva, R. A. Silva, Nature, 1999, 400, 150; (b) P. V. Jog, R. E. Brown, D. K Bates, J. Org. Chem., 2003, 63, 8240; (c) I. Alfonso, M. I. Burguete, S. V. Luis, J. Org. Chem. 2006, 71, 2242; (d) T-‐A. V. Khuong, J. E. Nunez, C. E. Godinez, M. A. Garcia-‐Garibay, Acc. Chem. Res., 2006, 39, 413; (e) D. Zhang, Q. Zhang, J. H. Sua, H. Tian, Chem. Commun., 2009, 1700; (f) M. C. Basheer, Y. Oka, M. Mathews, N. Tamaoki, Chem. Eur. J., 2010, 16, 3489. (a) T. Mino, Y. Tanaka, T. Yabusaki, D. Okumura, M. Sakamoto, T. Fujita, Tetrahedron: Asymmetry, 2003, 14, 2503; (b) T. Mino, H. Yamada, S. Komatsu, M. Kasai, M. Sakamoto, T. Fujita, Eur. J. Org. Chem., 2011, 24, 4540; (c) T. Mino, M. Asakawa, Y. Shima, H. Yamada, F. Yagishita, M. Sakamoto, Tetrahedron, http://dx.doi.org/10.1016/j.tet.2015.01.027. (a) H. Meerwein, P. Borner, O. Fuchs, H. J. Sasse, H. Schrodt, J. Spille, Chem. Ber., 1956, 89, 2060; (b) F. M. F. Chen, N. L. Benoiton, Can. J. Chem., 1977, 5, 1433; (c) Y. Tsuda, T. Sano, H. Watanabe, Synthesis, 1977, 652. CCDC-‐999231 (3) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.com.ac.uk/data_request/cif (see Supporting Information). See Supplementary Material. The most stable conformer of un-‐protonated amine 3 was also evaluated by DFT method. The calculated structure reproduced well the crystal structure shown in Figure 1. See Supporting Information. N. Suzumura, M. Kageyama, D. Kamimura, T. Inagaki, Y. Dobashi, H. Hasegawa, H. Fukaya, O. Kitagawa, Tetrahedron Lett., 2012, 53, 4332. DFT calculation indicates that the rotational barrier (23.7 kcal/mol) via the rotation of ortho-‐tert-‐butyl group toward C2 side is 7.1 kcal/mol higher in comparison with that toward + C8 side. See Supporting Information (3-‐H -‐TS3). We could not evaluate the exact rotational barrier + (experimental value) of the protonated amine 3-‐H because + of the quick racemization of 3-‐H . On the other hand, it is + certain that the rotational barrier of 3-‐H is less than 20 kcal/mol because in the presence of 3 eq of MeSO3H, optically active 3 (87%ee) was almost completely racemized within 1 min at 25 °C.
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Synthesis of optically active N-‐C axially chiral tetrahydroquinoline and its response to acid-‐accelerated molecular rotor Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x
a
a
a
b
b
Yuya Suzuki, Masato Kageyama, Ryuichi Morisawa, Yasuo Dobashi, Hiroshi Hasegawa, Satoshi b a Yokojima,* Osamu Kitagawa*
www.rsc.org/
Optically active atropisomeric N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐1,2,3,4-‐ tetrahydroquinoline with an N-‐C chiral axis was prepared via catalytic enantioselective reaction. The addition of methane sulfonic acid to this axially chiral quinoline dramatically lowered the barrier to rotation around the chiral axis. Atropisomeric compounds, owing to rotational restriction around an N-‐C single bond have been receiving increased attention as an 1 interesting class of chiral molecules. Recent noteworthy topics in this field include catalytic enantioselective syntheses. Various N-‐C axially chiral compounds have been prepared with high enantioselectivity through catalytic asymmetric reactions, and used 2,3 as chiral building blocks and chiral ligands. In addition, N-‐C axially chiral compounds have been found useful not only in the field of synthetic organic chemistry but also in molecular devices 4 (molecular rotors). Molecular rotors, whose rate of rotation around a bond can be controlled by external stimuli, are one of the most common classes 5 of molecular devices. Recently, Shimizu et al reported an interesting molecular rotor in which free rotation around an N-‐C bond is significantly accelerated by the addition of a protic acid 4b (Scheme 1). Their molecular rotor is based on a rigid atropisomeric N-‐(quinolin-‐8-‐yl)succinimide framework that is rotationally restricted due to the repulsion between the quinoline nitrogen and imide carbonyl oxygen. At 23 °C, rotation around the ≠ N-‐C bond of imide I is slow (ΔG = 22.2 kcal/mol, t1/2 = 26 min), but upon addition of 3.5 equivalents of MeSO3H the rotation becomes ≠ -‐4 rapid (ΔG = 12.9 kcal/mol, t1/2 = 2.0 x 10 s). Mechanistic considerations show that this acid-‐mediated significant acceleration is due to stabilization of the planar transition state by the formation of an intramolecular hydrogen bond between the protonated quinolone nitrogen and an imide carbonyl oxygen. Shimizu et al. called the acid responsible for such an acceleration of a molecular a.
Department of Applied chemistry, Shibaura Institute of Technology, 3-‐7-‐5 Toyosu, Kohto-‐ku, Tokyo, 135-‐8458, Japan. E-‐mail: kitagawa@shibaura-‐it.ac.jp School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-‐1, Horinouchi, Hachioji, Tokyo, 192-‐0392, Japan. E-‐mail: [email protected] † Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x b.
rotor “proton grease”. H H+ ON ON Me Me N N Me O Me O + H I-H+ I ! = 12.9 kcal/mol) ! = 22.2 kcal/mol) (!G (!G ! H ! O O N Me Me N N N O Me O Me Scheme 1 Acid-‐accelerated molecular rotor (proton grease) reported by Shimizu et al. In this paper, we report the synthesis of optically active N-‐C axially chiral N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐1,2,3,4-‐tetrahydroquinoline (an N-‐C axially chiral cyclic amine) and its response to a new type of acid-‐accelerated molecular rotor (Scheme 2). N H H+ N t-Bu t-Bu quick rotational rotation restriction t-Bu t-Bu Scheme 2 N-‐C Axially chiral cyclic amine and its response to acid-‐ accelerated molecular rotor. As mentioned above, catalytic enantioselective syntheses of various N-‐C axially chiral compounds have been reported 2,3 recently. These compounds have an amide skeleton like anilides, imides, lactams and urea, or a nitrogen-‐containing aromatic heterocyclic framework like indole and 4-‐quinolinone, but there has been no report on the catalytic enantioselctive synthesis of simple N-‐C axially chiral amine. Only three reports have appeared on the preparation of optically active axially chiral amines by optical 6 resolution. In 2005, we succeeded in the highly enantioselective synthesis of N-‐(2,5-‐di-‐tert-‐butylphenyl)-‐3,4-‐dihydroquinolin-‐2-‐one 2 by the
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(R)-‐BINAP-‐Pd(OAc)2 catalyzed intramolecular Buchwald-‐Hartwig 2c amination of NH-‐anilide 1 (Scheme 3). We expected that the reduction of the amide carbonyl group in quinolinone 2 would yield optically active tetrahydroquinoline 3 (N-‐C axially chiral cyclic amine). After a survey of reaction conditions, it was found that the use of Meerwein reagent and NaBH4 gave a good result. That is, tetrahydroquinoline 3 was obtained in 69% yield through NaBH4 reduction of iminium ether 2A prepared by the reaction of 2 with 7 BF4•OMe3 in CH2Cl2 (Scheme 3). However, the ee of the obtained 3 (89%ee) was lower than that of 2 (98%ee). Prolongation of the reaction time for the formation of 3 from iminium ether 2A (NaBH4 reduction) yielded an even lower ee for 3. A shorter reaction time and quick purification gave 3 with a higher ee (up to 92%ee and 81% yield), while the ee of 3 was not changed by the reaction time for the formation of 2A from quinolinone 2. These results indicate that the decrease in the ee of 3 may have been due to the partial racemization of 3, but not of 2A. Indeed, when 3 (89%ee) in CHCl3 was stood for 24 h at rt, the ee decreased to 55%. The rotational barrier around the chiral axis in 3 in CHCl3 was evaluated to be 25.1 kcal/mol at 298 K. Thus, the rotational barrier of 3 was remarkably lower than that of quinolinone 2 (33.1 kcal/mol). In contrast, 3 in the solid state can be stored for several months at rt without any decrease in ee. O 5.0 mol% (R)-BINAP 3.3 mol% Pd(OAc)2 NH N O 1.4 eq. Cs2CO3 t-Bu t-Bu Br toluene 80 °C, 20 h (97%) t-Bu t-Bu 1 2 (98%ee) (!G≠ = 33.1 kcal/mol) BF4•OMe3 N OMe NaBH4 N BF4 t-Bu t-Bu EtOH CH2Cl2 rt, 15 min rt, 23 h t-Bu t-Bu 3 (69%, 89%ee) 2A (!G≠ = 25.1 kcal/mol in CHCl3) 3 (55%ee) CHCl3, rt 24 h Scheme 3 Synthetic route to optically active N-‐C axially chiral cyclic amine 3 and its rotational barrier. As a new structural property of N-‐C axially chiral amine, we found that the rotational barrier in quinoline 3 is decreased by the addition of a protic acid. That is, when 3 (92%ee) in CHCl3 was stood for 10 min or 1 h at 25 °C, the ee remained essentially constant (91%ee, 90%ee, Table 1, entry 1). In contrast, in the presence of 1 equivalent of methanesulfonic acid (MeSO3H, pKa = -‐ 1.8), the ee of 3 decreased to 25% and 7%, respectively after 10 min and 1 h at 25 °C (entry 2). The addition of 2 equivalent of MeSO3H further increased the racemization rate decreasing the ee to 4% after 10 min (entry 3). Although a similar increase in the racemization rate was also observed following the addition of a substoichiometric amount (0.5 or 0.2 eq) of MeSO3H, the
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magnitude of the increase was lower than View that Article from a Online DOI: 10.1039/C5CC03659C stoichiometric quantity of MeSO3H (entries 4 and 5). These results indicate that the rotation rate around an N-‐C chiral axis can be controlled by MeSO3H, and establish the existence of a new type of acid-‐accelerated molecular rotor. The acidity of the protic acid is also important in this molecular rotor. The use of trifluoroacetic acid (pKa = 0.5) increased the racemization rate, but to a lesser degree than MeSO3H (entries 2 and 6). In the presence of acetic acid (pKa = 4.8), no detectable increase in racemization rate was observed (entry 7). Also, no rotational acceleration was observed in dihydroquinolinone 2 following the addition of MeSO3H. In the case of quinolinone (lactam) 2 and the use of a weak acid such as acetic acid, the protonation of the nitrogen atom may not be extensive. Thus, it is + obvious that the formation of a protonated amine 3-‐H is the driving force for the acceleration of the bond rotation, and that increasing the acidity and/or the quantity of the added acid increases the + proportion of 3-‐H , thus facilitating rotation about the N-‐C bond. a, b Table 1. Ee change of 3 in the presence of several protic acids.
H+
N
3
Na2CO3 aq
H
3 (decrease in ee)
t-Bu
(90-92%ee) t-Bu
3-H+
En try
Acid
1 h
2 h
3 h
24 h
%ee
%ee
%ee
%ee
%ee
10 min %ee
0 min
1
none
92
91
90
89
85
54
2
MeSO3H
92
25
7
-‐
-‐
-‐
3
MeSO3H (2 eq)
92
4
-‐
-‐
-‐
-‐
4
MeSO3H (0.5 eq)
90
51
5
-‐
-‐
-‐
5
MeSO3H (0.2 eq)
90
77
46
43
42
13
6
CF3CO2H
92
83
49
24
15
7
7
MeCO2H
92
91
90
88
83
53
a
1 Equivalent of a protic acid was added to 3 (15 mg) in CHCl3 (0.3 mL), and b the mixture was stood at 25 °C. The ee was determined by HPLC analysis + using a chiral OJ-‐H column after neutralization of 3-‐H .
An X-‐ray crystal structure analysis and DFT calculation were undertaken to elucidate the facilitation of rotation about the N-‐C bond by the protonation of the amine. In the crystal structure of 3 8 (Fig 1), it was found that bond N1-‐C8a is notably shorter than bonds N1-‐C1’ and N1-‐C2, and the 2,5-‐di-‐tert-‐butylphenyl group is almost perpendicular to the quinolone ring. This suggests that the
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lone electron pair on the nitrogen atom mainly resonates with the benzene ring of tetrahydroquinoline, and very little with the 2,5-‐di-‐ tert-‐butylphenyl group. Although the X-‐ray crystal structure analysis of protonated amine + 3-‐H was also attempted, unfortunately, no adequate single crystal + was obtained. Therefore, we estimated the structure of 3-‐H by DFT calculation (The structure of hydrochloride of 3 was estimated 9,10 + by DFT method). Most stable conformers of 3-‐H calculated at + the B3LYP/6-‐31G(d) level are shown in Fig 2. In 3-‐H , the three N-‐C bonds were found to be longer than in the un-‐protonated compound 3. Furthermore, although the nitrogen atom of amine 3 2 3 is the hybridization between sp and sp characters (Fig 1, total of + three bond angles around the nitrogen atom = 347.2 °), that of 3-‐H 3 has an almost complete sp character (Fig 2, total of three bond angles around the nitrogen atom = 337.4 °). Such change on hybridization of the nitrogen atom may bring about significant difference in the transition states during the N-‐C bond rotation in 3 + and 3-‐H .
5 6
4
4a
7 8
pseudo equatorial position, and the N-‐C bond rotation proceeds via View Article Online 10.1039/C5CC03659C the rotation of the ortho-‐tert-‐butyl group DOI: toward C2 side but not 9 toward C8 side (Fig 3). In amine 3, the steric repulsion with C8-‐ 11 hydrogen may be stronger than that with C2-‐hydrogen.
5 6 7 8
8a N
1 2 8a N
t-Bu !G≠
= 26.4 kcal/mol at 298 K
5'
4'
3-TS
N1-C2 = 1.479 Å, N1-C1' = 1.419 Å, N1-C8a = 1.437 Å < C2-N1-C1' = 123.7 °, < C2-N1-C8a = 107.2 ° < C8a-N1-C1' = 124.1 ° < C2-N1-C1'-C2' = 28.1 °, < C1'-N1-C8a-C8 = -44.0 °
5 6 7
t-Bu
4
7 8
2
8a N
H
6' 5'
t-Bu
1'
3-H+-TS1 !G≠ = 16.1 kcal/mol at 298 K
N1-C2 = 1.543 Å, N1-C1' = 1.524 Å, N1-C8a = 1.501 Å < C2-N1-C1' = 115.0 ° < C2-N1-C8a = 109.8 ° < C8a-N1-C1' = 113.0 ° < C2-N1-C1'-C2' = -151.6 ° < C1'-N1-C8a-C8 = -98.5 °
Cl
1' t-Bu 2'
3-H+-TS2
≠
3
1 2 8a N
Cl H
6' 5' 4'
t-Bu
3-H+-TS
!G≠ = 16.3 kcal/mol at 298 K
N1-C2 = 1.541 Å, N1-C1' = 1.533 Å, N1-C8a = 1.483 Å < C2-N1-C1' = 111.5 ° < C2-N1-C8a = 103.3 ° < C8a-N1-C1' = 124.7 ° < C2-N1-C1'-C2' = 129.6 ° < C1'-N1-C8a-C8 = -107.0 °
Fig 4. The transition state structure and the rotational barrier of 3-‐ + H calculated at the B3LYP/6-‐31G(d) level.
3'
4'
3-H+
3-H+A
4
3'
3
1
8
4a
2'
4'
Fig 1 X-‐Ray crystal structure of axially chiral quinoline 3.
4a
Fig 3 The transition state structure and the rotational barrier of 3 calculated at the B3LYP/6-‐31G(d) level.
2
N1-C2 = 1.473 Å, N1-C1' = 1.452 Å, N1-C8a = 1.409 Å < C2-N1-C1' = 111.8 °, < C2-N1-C8a = 116.9 ° < C8a-N1-C1' = 118.5 ° < C2-N1-C1'-C2' = -103.4 °, < C1'-N1-C8a-C8 = -26.1 °
5
t-Bu 2' 3'
3
6
≠
3
1'
3'
t-Bu
4
6'
1' t-Bu 2'
6' 5'
4a
3
1
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N1-C2 = 1.535 Å, N1-C1' = 1.506 Å, N1-C8a = 1.498 Å < C2-N1-C1' = 111.6 °, < C2-N1-C8a = 113.3 ° < C8a-N1-C1' = 112.4 ° < C2-N1-C1'-C2' = -93.5 °, < C1'-N1-C8a-C8 = -64.2 ° +
Fig 2 Most stable conformer of 3-‐H calculated at the B3LYP/6-‐ 31G(d) level. +
Indeed, in the transition state structures of 3 and 3-‐H calculated by DFT method (the effect of CHCl3 solvent was taken into account by polarizable continuum model), the significant differences on the orientation of a chiral axis (N1-‐C1’ bond) and the direction of the + bond rotation were found (3-‐TS in Fig 3 and 3-‐H -‐TS in Fig 4). That is, DFT calculation shows that the N1-‐C1’ bond in 3-‐TS occupies
On the other hand, in the N-‐C bond rotation of protonated amine + 3-‐H , two possible transition states were found (Fig 4). In both + + transition state structures 3-‐H -‐TS1 and 3-‐H -‐TS2, the N-‐C1’ bond occupies pseudo axial position. Such pseudo-‐axial orientation of the N-‐C1’ bond should significantly alleviate the steric repulsion between C8-‐hydrogen and tert-‐butyphenyl group to lead to the + remarkable decrease in the rotational barrier of 3-‐H . At the same + time, the N-‐C bond rotation of 3-‐H occurs via the rotation of the 12 ortho-‐tert-‐butyl group toward C8 side but not toward C2 side. Protic acid may promote the axial orientation of the N1-‐C1’bond in the transition state. Also, in comparison with 3, the elongated N-‐C + bonds in 3-‐H should reduce the steric repulsion from C8-‐ and C2-‐ hydrogens (Figures 1-‐4), thus lowering the energetic barrier to + rotation. Indeed, the calculated rotational barrier of 3-‐H at 298 K ≠ (ΔG = 16.1 and 16.3 kcal/mol) was 8.8-‐9.0 kcal/mol lower in ≠ comparison with the experimental value of 3 (ΔG value = 25.1 ≠ 13 kcal/mol, the calculated ΔG = 26.4 kcal/mol).
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Conclusions
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We performed the synthesis of an optically active N-‐C axially chiral amine (N-‐C axially chiral tetrahydroquinoline) via catalytic enantioselective reaction and demonstrated its response to a new type of acid-‐accelerated molecular rotor. The protonation of the amine nitrogen by a protic acid facilitated the rotation about the N-‐C chiral bond by elongating the N-‐C bonds and changing the transition state structure.
3 4
Acknowledgement This work was partly supported by a Grant-‐in-‐Aid for Scientific Research (C26460014).
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Notes and references 1
2
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Turner, Tetrahedron Lett., 2009, 50, 3216; (i) N. Ototake, Y. View Article Online Morimoto, A. Mokuya, H. Fukaya, Y. O. Kitagawa, DOI:Shida, 10.1039/C5CC03659C Chem. Eur. J., 2010, 16, 6752; (j) H. Liu, W. Feng, C. W. Kee, D. Leow, W-‐T. Loh, C-‐H. Tan, Adv. Synth. Catal., 2010, 352, 3373; (k) S. Shirakawa, K. Liu, K. Maruoka, K. J. Am. Chem. Soc., 2012, 134, 916; (l) R. Guo, K-‐N. Li, H-‐J. Zhu, Y-‐M. Fan, L-‐ Z. Gong, Chem. Comm., 2014, 50, 5451; (m) N. D. Iorio, P. Righi, A. Mazzanti, M. Mancinelli, A. Ciogli, G. Bencivenni, J. Am. Chem. Soc., 2014, 136, 916; (n) K. Kamikawa, S. Arae, W-‐ Y Wu, C. Nakamura, T. Takahashi, M. Ogasawara, Chem. Eur. J., 2015, 21, 4954. I. Takahashi, Y. Suzuki, O. Kitagawa, Org. Prep. Proc. Int., 2014, 46, 1. (a) B. E. Dial, R. D. Rasberry, B. N. Bullock, M. D. Smith, P. J. Pellechia, S. Profeta, Jr, K. D. Shimizu, Org. Lett., 2011, 13, 244; (b) B. E. Dial, P. J. Pellechia, M. D. Smith, K. D.; Shimizu, J. Am. Chem. Soc., 2012, 134, 3675. (a) T. R. Kelly, H. D. Silva, R. A. Silva, Nature, 1999, 400, 150; (b) P. V. Jog, R. E. Brown, D. K Bates, J. Org. Chem., 2003, 63, 8240; (c) I. Alfonso, M. I. Burguete, S. V. Luis, J. Org. Chem. 2006, 71, 2242; (d) T-‐A. V. Khuong, J. E. Nunez, C. E. Godinez, M. A. Garcia-‐Garibay, Acc. Chem. Res., 2006, 39, 413; (e) D. Zhang, Q. Zhang, J. H. Sua, H. Tian, Chem. Commun., 2009, 1700; (f) M. C. Basheer, Y. Oka, M. Mathews, N. Tamaoki, Chem. Eur. J., 2010, 16, 3489. (a) T. Mino, Y. Tanaka, T. Yabusaki, D. Okumura, M. Sakamoto, T. Fujita, Tetrahedron: Asymmetry, 2003, 14, 2503; (b) T. Mino, H. Yamada, S. Komatsu, M. Kasai, M. Sakamoto, T. Fujita, Eur. J. Org. Chem., 2011, 24, 4540; (c) T. Mino, M. Asakawa, Y. Shima, H. Yamada, F. Yagishita, M. Sakamoto, Tetrahedron, http://dx.doi.org/10.1016/j.tet.2015.01.027. (a) H. Meerwein, P. Borner, O. Fuchs, H. J. Sasse, H. Schrodt, J. Spille, Chem. Ber., 1956, 89, 2060; (b) F. M. F. Chen, N. L. Benoiton, Can. J. Chem., 1977, 5, 1433; (c) Y. Tsuda, T. Sano, H. Watanabe, Synthesis, 1977, 652. CCDC-‐999231 (3) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.com.ac.uk/data_request/cif (see Supporting Information). See Supplementary Material. The most stable conformer of un-‐protonated amine 3 was also evaluated by DFT method. The calculated structure reproduced well the crystal structure shown in Figure 1. See Supporting Information. N. Suzumura, M. Kageyama, D. Kamimura, T. Inagaki, Y. Dobashi, H. Hasegawa, H. Fukaya, O. Kitagawa, Tetrahedron Lett., 2012, 53, 4332. DFT calculation indicates that the rotational barrier (23.7 kcal/mol) via the rotation of ortho-‐tert-‐butyl group toward C2 side is 7.1 kcal/mol higher in comparison with that toward + C8 side. See Supporting Information (3-‐H -‐TS3). We could not evaluate the exact rotational barrier + (experimental value) of the protonated amine 3-‐H because + of the quick racemization of 3-‐H . On the other hand, it is + certain that the rotational barrier of 3-‐H is less than 20 kcal/mol because in the presence of 3 eq of MeSO3H, optically active 3 (87%ee) was almost completely racemized within 1 min at 25 °C.
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