Chiral imines and amines based on 2-hydroxypinan-3-one

Article abstract of DOI:10.1007/s10600-011-9783-x

The new chiral derivatives of benzylamine and 2α-hydroxypinan-3-one (1R,2R,5R)-3-[(1S)-α-methylbenzylamino]-2,6,6-trimethylbicyclo[3.1.1] heptan-2-ol (2), (1S,2S,3S,5S)-3-(benzylamino)-2,6,6-trimethylbicyclo[3.1.1] heptan-2-ol (3), and (1R,2R,3R,5R)-3-[(1S)-α-methylbenzylamino]-2,6,6- trimethylbicyclo[3.1.1]heptan-2-ol (4) were synthesized and characterized. It was shown that reduction of the benzylimines by sodium triacetoxyborohydride formed stereoselectively 3β-substituted pinanamines.

Full text of DOI:10.1007/s10600-011-9783-x

Chemistry of Natural Compounds, Vol. 46, No. 6, 2011
CHIRAL IMINES AND AMINES BASED ON 2-HYDROXYPINAN-3-ONE
1*
2
1
Ya. A. Gurꢀeva, O. A. Zalevskaya, L. L. Frolova,
UDC 547.598.33
1
1
I. N. Alekseev, and A. V. Kuchin
The new chiral derivatives of benzylamine and 2ꢁ-hydroxypinan-3-one (1R,2R,5R)-3-[(1S)-ꢁ-
methylbenzylamino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (2), (1S,2S,3S,5S)-3-(benzylamino)-2,6,6-
trimethylbicyclo[3.1.1]heptan-2-ol (3), and (1R,2R,3R,5R)-3-[(1S)-ꢁ-methylbenzylamino]-2,6,6-
trimethylbicyclo[3.1.1]heptan-2-ol (4) were synthesized and characterized. It was shown that reduction of
the benzylimines by sodium triacetoxyborohydride formed stereoselectively 3ꢂ-substituted pinanamines.
Keywords: chiral imines, amines, stereoisomers, stereoselectivity.
Chiral amines and imines are widely used as ligands and chiral promoters of asymmetric synthesis and
catalysis [1, 2]. Amines and imines are key structural elements of many biologically active compounds that are used in
pharmaceuticals and agrochemistry [3, 4]. For example, imines based on ꢁ-methylbenzylamine and isopinocamphone are
used to combat pinewood nematodes [5]. Amines and imines are interesting as ligands for the synthesis of many transition-
metal complexes [6–8].
We used the natural bicyclic monoterpene ꢁ-pinene as starting material for synthesizing chiral imines and amines. It
was selected as the chiral starting material owing to the availability of the natural raw material (ꢁ-pinene occurs in pinewood
resin and is the principal component of turpentine), developed isolation methods ensuring its supply, and the ability to prepare
derivatives based on it that act as ligands. Oxidation of ꢁ-pinene produces 2ꢁ-hydroxypinan-3-one [9]. We used enantiomerically
pure (+)- and (–)-2ꢁ-hydroxypinan-3-one and the primary amines benzylamine and optically pure (–)-(S)-ꢁ-methylbenzylamine
to synthesize the imines.
Imines 1 and 2 were synthesized in 52–60% yields by condensation of the ketone and the corresponding amine in
anhydrous benzene in the presence of a Lewis acid (BF 4Et O) (Scheme 1).
3
2
OH
OH
R
Ph
R
O
N
H
H N CH Ph
2
.
C H , BF Et O
6
6
3
2
1, 2
1: R = H; 2: R = CH
3
Scheme 1
Mixtures of geometric isomers could form during the synthesis of 1 and 2. The PMR spectrum of each of them
showed a single set of resonances that indicated one of the geometric isomers formed. According to the literature [10–12], the
thermally more stable E-isomer formed for their closest analogs.
Reduction of the imines could theoretically produce a mixture of two diastereomeric secondary amines. The reduction
of Schiff bases of 2ꢁ-hydroxypinan-3-one and various alkyl- and arylamines was studied [13]. It was found that reduction by
LiAlH in THF formed 2ꢁ-hydroxy-3ꢁ-[N-alkyl(aryl)]-pinanamines. We managed to achieve exactly the opposite selectivity
4
1) Institute of Chemistry, Komi Scientific Center, Ural Branch, Russian Academy of Sciences, 167982, Syktyvkar,
fax: (8212) 21 84 77, e-mail: gurjeva-ja@chemi.komisc.ru; 2) Syktyvkar State University, 167023, Syktyvkar, Ul.
Petrozavodskaya, 120. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 783–785, November–December, 2010.
Original article submitted May 7, 2010.
©
920
0009-3130/11/4606-0920 2011 Springer Science+Business Media, Inc.

in reducing the benzylimines of 2ꢁ-hydroxypinan-3-one using NaBH(OAc) as the reductant. This is a mild reductant with
3
high stereoselectivity because the three acetoxy groups stabilize the B–H bond and create steric and electron-accepting effects
[14]. Reduction of 1 and 2 by NaBH(OAc) in isopropanol occurred diastereoselectively (Scheme 2) to produce amines 3 and
3
13
4 in yields of 90 and 95%, respectively, as pure diastereomers. This was confirmed by PMR and C spectral data.
15
13
12
10
8
15
16
OH
OH
OH
OH
13
Ph
NH
NH
N
N
Ph
NaBH(OAc)
NaBH(OAc)
3
3
1
7
6
5
3
9
11
12
H
H
1b
2
4
3
Scheme 2
The stereochemistry of the products was determined using PMR spectral data. The 2ꢁ,3ꢁ- and 2ꢁ,3ꢂ-stereoisomers
should have different spin–spin coupling constants (SSCCs) for the H3–H4ꢁ and H3–H4ꢂ protons. These values in 3 were 8.7
and 9.2 Hz, respectively. The dihedral angles H3–C3–C4–H4ꢁ and H3–C3–C4–H4ꢂ were calculated for the 3ꢁ- and
3ꢂ-isomers using molecular mechanics. The values were ꢃ = 25° and 142° for the ꢂ-isomer and 137° and 21° for the ꢁ-isomer.
Based on these values and handbook data [15], the SSCCs for H3–H4ꢁ and H3–H4ꢂ were determined for the ꢂ-isomer (both
J = 9 Hz) and the ꢁ-isomer (J = 11 and J = 7 Hz, respectively). Thus, a comparison of the experimental and calculated data
suggested that the 2ꢁ,3ꢂ-isomer was produced. Analogous calculations were performed for 4 and were consistent with the
3ꢂ-isomer. These results were in agreement with those published [13]. The researchers prepared 2ꢁ-hydroxy-3ꢁ-(N-
butyl)pinanamine, the structure of which was confirmed by an x-ray structure analysis. They reported PMR data, according to
which the SSCCs for the H3–H4ꢁ and H3–H4ꢂ protons were 6.5 and 11.0 Hz, respectively.
EXPERIMENTAL
IR spectra were recorded as thin layers or KBr pellets on an IR Prestige 21 instrument (Shimadzu). PMR and
13
1
C NMR spectra were recorded in CDCl on a Bruker Avance-II-300 instrument at operating frequency 300 MHz ( H) and
3
13
75 MHz ( C) using CDCl resonances (ꢄ 7.27 ppm, ꢄ 77.00 ppm) as internal standards. Resonances were assigned using
3
H
C
13
1
1
1
13
C NMR spectra recorded using J-modulation and 2D H– H (COSY) and H– C (HSQC) correlation spectra. Melting
points were determined using a TP heater. Refractive indices were measured on an IRF-454BM instrument; optical rotation,
on a Kruss automated P3002RS polarimeter (Germany). Elemental analysis was performed on an EA 1110 element analyzer
(CHNSO). The course of reactions was monitored using TLC on Silufol and Sorbfil plates using C H :Et O and
6
14
2
CHCl :MeOH:NH (25%) (100:10:1) as solvents. Compounds on plates were detected using iodine vapor and ninhydrin or
3
3
vanillin solution with subsequent heating to 100–120°C. Column chromatography used silica gel (70–230 mesh, Lancaster).
(S)-ꢁ-methylbenzylamine (ee 99.5%, Lancaster) was used without further purification.
20
(+)-(1R,2R,5R)-2-Hydroxypinan-3-one, [ꢁ] +39° (c 0.9, CHCl ), mp 39–40°C and (–)-(1S,2S,5S)-2-hydroxypinan-
D
3
20
3-one, [ꢁ] –38° (c 1.0, CHCl ), mp 39–40°C were prepared by oxidation of ꢁ-pinene using KMnO and the literature
method [9] ([ꢁ] –42.7° and [ꢁ] +42°, respectively).
D
3
4
20
20
D
D
(1R,2R,5R)-3-(Benzylimino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (1a). A solution of (+)-2ꢁ-hydroxypinan-
3-one (2.9 g, 0.02 mmol) and benzylamine (1.93 g, 0.02 mmol) in anhydrous benzene (60 mL) was refluxed for 21 h in the
°
presence of BF 4Et O (0.9 g, 0.01 mmol) and calcined 4-A molecular sieves (20 g). The mixture was filtered. The molecular
3
2
sieves were rinsed with benzene. Solvent was vacuum distilled. The solid was dissolved in Et O and purified by chromatography
2
[SiO , petroleum ether (PE):EtOAc, 2:1]. Solvent was removed to afford a thick yellow oil that contained according to TLC
2
20
(Sorbfil, PE:EtOAc, 2:1, iodine vapor) a product with R 0.8, yield 2.4 g, 52%, [ꢁ] +11.7° (c 0.7, CHCl ). IR spectrum
(ꢅ, cm ): 3396 (OH), 1651 (C=N).
f
D
3
–1
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.90 (3H, s, CH -9), 1.37 (3H, s, CH -8), 1.57 (3H, s, CH -10),
3
3
3
3
1.62 (1H, d, J
= 10.6, H -7), 2.06–2.16 (2H, m, H-1, H-5), 2.39 (1H, ddd, J
= 1.9, J
= 5.9, J
= 10.6, H -7),
7ꢁ,7ꢂ
ꢁ
7ꢂ,1
7ꢂ,5
7ꢂ,7ꢁ
ꢂ
2.56–2.71 (2H, m, H-4), 4.56 (2H, s, H-11), 7.25–7.39 (5H, m, H
).
arom
921

13
C NMR spectrum (75 MHz, CDCl , ꢄ, ppm): 22.94 (C-9), 27.40 (C-8), 28.23 (C-7), 28.48 (C-10), 33.69 (C-4),
3
38.41 (C-5), 38.53 (C-6), 50.28 (C-1), 54.15 (C-11), 76.63 (C-2), 126.62 (C-15), 127.52 (C-14), 128.41 (C-13), 140.12
(C-12), 176.79 (C-3).
(1S,2S,5S)-3-(Benzylimino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (1b) was prepared from (–)-(1S,2S,5S)-
20
2ꢁ-hydroxypinan-3-one by an analogous method to give a thick yellow oil, yield 60%, [ꢁ] –11.9° (c 0.7, CHCl ).
IR spectrum (ꢅ, cm ): 3421 (OH), 1649 (C=N).
D
3
–1
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.90 (3H, s, CH -9), 1.37 (3H, s, CH -8), 1.57 (3H, s, CH -10),
3
3
3
3
1.62 (1H, d, J
= 10.6, H -7), 2.06–2.15 (2H, m, H-1, H-5), 2.39 (1H, ddd, J
= 1.6, J
= 5.9, J
= 10.6, H -7),
7ꢁ,7ꢂ
ꢁ
7ꢂ,1
7ꢂ,5
7ꢂ,7ꢁ
ꢂ
2.57–2.70 (2H, m, H-4), 4.56 (2H, s, H-11), 7.25–7.39 (5H, m, H
).
arom
13
C NMR spectrum (75 MHz, CDCl , ꢄ, ppm): 22.95 (C-9), 27.39 (C-8), 28.22 (C-7), 28.48 (C-10), 33.70 (C-4),
3
38.39 (C-5), 38.53 (C-6), 50.25 (C-1), 54.15 (C-11), 76.63 (C-2), 126.64 (C-15), 127.52 (C-14), 128.42 (C-13), 140.11
(C-12), 176.83 (C-3).
(1R,2R,5R)-3-[(1S)-ꢁ-Methylbenzylimino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (2). Light-yellow oil, yield
23
23
55%, n 1.5333, [ꢁ] –34.4° (c 0.25, CHCl ). Hydrochloride HL 4HCl, white needle-like crystals, mp 176–177°C.
D
D
3
3
–1
IR spectrum (hydrochloride) (ꢅ, cm ): 3232 (OH), 1662 (C=N). C H NO4HCl.
18 25
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.94 (3H, s, CH -9), 1.36 (3H, s, CH -8), 1.48 (3H, d, J
= 6.5,
3
3
3
12,11
CH -12), 1.51 (1H, d, J
= 10.2, H -7), 1.57 (3H, s, CH -10), 2.04 (1H, ddd, J
= 2.6, J
= 3.0, J = 5.9, H-5), 2.11
3
7ꢁ,7ꢂ
ꢁ
3
5,4ꢂ
5,4ꢁ 5,1
(1H, dd, J = 5.9, J
= 6.0, H-1), 2.32 (1H, ddd, J
= 2.4, J
= 6.0, J
= 10.2, H -7), 2.57 (1H, dd, J
= 3.0,
= 6.5,
= 1.4,
1,5
1,7ꢂ
7ꢂ,4ꢂ
7ꢂ,1
7ꢂ,7ꢁ
ꢂ
4ꢁ,5
11,12
14,16
J
= 17.9, H -4), 2.69 (1H, ddd, J
= 2.4, J
= 2.6, J
= 17.9, H -4), 3.65 (br, OH), 4.73 (1H, q, J
4ꢁ,4ꢂ
ꢁ
4ꢂ,7ꢂ
4ꢂ,5
4ꢂ,4ꢁ ꢂ
H-11), 7.27 (1H, dd, J
= 1.4, J
= 7.1, H-16), 7.35 (2H, dd, J
= 7.1, J
= 7.8, H-15), 7.40 (2H, dd, J
16,14
16,15
15,16
15,14
J
= 7.8, H-14).
14,15
13
C NMR spectrum (75 MHz, CDCl , ꢄ, ppm): 23.00 (C-9), 24.00 (C-12), 27.39 (C-8), 28.06 (C-7), 28.53 (C-10),
3
32.96 (C-4), 38.37 (C-6), 38.42 (C-5), 50.27 (C-1), 58.06 (C-11), 76.53 (C-2), 126.50 (C-15), 126.68 (C-16), 128.42 (C-14),
145.13 (C-13), 174.47 (C-3).
(1S,2S,3S,5S)-3-(Benzylamino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (3). A solution of 1b (2.2 g, 0.009 mol)
in isopropanol (100 mL) was stirred under an Ar atmosphere at room temperature, treated over an hour with NaBH(OAc)
3
(2.8 g, 0.013 mol), stirred for 6 h at room temperature, and treated with stirring with NaOH solution (30 mL, 10%). The
products were separated by extraction with EtOAc (3ꢆ). The organic extract was dried over anhydrous MgSO . Solvent was
4
removed to afford 3 as a bright yellow oil that contained according to TLC (Sorbfil, PE:EtOAc, 1:1, iodine vapor) a single
23
20
–1
product, R 0.2, yield 1.9 g (90%), n 1.5340, [ꢁ] +36.5° (c 0.4, EtOH). IR spectrum (ꢅ, cm ): 3404 (OH).
f
D
D
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.94 (3H, s, CH -9), 1.27 (3H, s, CH -8), 1.43 (3H, s, CH -10),
3
3
3
3
1.51 (1H, dd, J
= 8.7, J
= 5.6, J
= 13.7, H -4), 1.57 (1H, d, J
= 10.3, H -7), 1.88–2.00 (2H, m, H-1, H-5), 2.14 (1H, ddd,
4ꢁ,3
7ꢂ,5
4ꢁ,4ꢂ
ꢁ
7ꢁ,7ꢂ ꢁ
J
J
= 1.4,
J
= 10.3, H -7), 2.34 (1H, ddd, J
= 5.0, J
= 13.3, H -11), 3.94 (1H, d, J
= 9.2, J
= 13.7, H -4), 3.18 (1H, dd,
7ꢂ,1
3,4ꢁ
7ꢂ,7ꢁ
ꢂ
4ꢂ,5
4ꢂ,3
4ꢂ,4ꢁ ꢂ
= 8.7, J
= 9.2, H-3), 3.88 (1H, d, J
= 13.3, H -11), 7.40 (5H, m, H
).
3,4ꢂ
11ꢁ,11ꢂ
ꢁ
11ꢂ,11ꢁ
ꢂ
arom
13
C NMR spectrum (75 MHz, CDCl , ꢄ, ppm): 23.11 (C-9), 24.76 (C-7), 24.81 (C-10), 27.70 (C-8), 33.01 (C-4),
3
39.17 (C-6), 40.34 (C-5), 52.76 (C-11), 55.80 (C-1), 60.20 (C-3), 76.62 (C-2), 126.91 (C-15), 128.12 (C-14), 128.38 (C-13),
140.72 (C-12).
(1R,2R,3R,5R)-3-[(1S)-ꢁ-Methylbenzylamino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol (4). Thick yellow oil that
20
–1
gradually crystallized, yield 95%, [ꢁ] –51.1° (c 0.3, EtOH), mp 67–68°C. IR spectrum (ꢅ, cm ): 3458 (OH), 3340 (NH).
D
C H NO.
18 27
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.93 (3H, s, CH -9), 1.25 (3H, s, CH -8), 1.37 (3H, s, CH -10),
3
3
3
3
1.39 (3H, d, J
= 6.6, CH -12), 1.42 (1H, d, J
= 15.6, H -7), 1.48 (1H, dd, J
= 9.0, J
= 13.2, H -4), 1.88 (1H,
12,11
3
7ꢁ,7ꢂ
ꢁ
4ꢁ,3
4ꢁ,4ꢂ
ꢁ
dd, J = 5.8, J
= 10.6, H-1), 1.94 (1H, ddd, J
= 5.1, J
= 5.1, J = 5.8, H-5), 2.05 (1H, ddd, J
= 5.1, J
= 10.6,
1,5
1,7ꢂ
5,7ꢂ
5,4ꢂ
5,1
7ꢂ,5
7ꢂ,1
J
= 15.6, H -7), 2.30 (1H, ddd, J
= 5.1, J
= 9.0, J
= 13.2, H -4), 2.93 (1H, dd, J
= 9.0, J
= 9.0, H-3),
7ꢂ,7ꢁ
ꢂ
4ꢂ,5
4ꢂ,3
4ꢂ,4ꢁ
ꢂ
3,4ꢁ
3,4ꢂ
3.99 (1H, q, J
= 6.6, H-11), 7.4 (5H, m, H
).
11,12
arom
13
C NMR spectrum (75 MHz, CDCl , ꢄ, ppm): 23.23 (C-9), 24.63 (C-7), 24.95 (C-10), 25.01 (C-12), 27.77 (C-8),
3
32.98 (C-4), 39.11 (C-6), 40.39 (C-5), 55.08 (C-1), 55.23 (C-11), 57.57 (C-3), 77.63 (C-2), 126.66 (C-15), 126.92 (C-16),
128.46 (C-14), 145.79 (C-13).
922

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