(1R,5R)-1-(1-dimethylaminoethyl)-2-isopropylidene-5-methylcyclohexanol as a chiral ligand in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1055/s-0029-1219379

An efficient chiral ligand, (1R,5R)-1-(1-dimethylaminoethyl)-2- isopropylidene-5-methylcyclohexanol, has been developed for the enantioselective addition of diethylzinc to some prochiral aldehydes to afford S-alcohols. The overall conversion rate was 80-98% with excellent enantiomeric excess (79-98%). Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1219379

712
LETTER
(1R,5R)-1-(1¢-Dimethylaminoethyl)-2-isopropylidene-5-methylcyclohexanolas
a Chiral Ligand in the Enantioselective Addition of Diethylzinc to Aldehydes
(
1
R
,5
R
)-1-(1
¢
-Dim
s
ethylamin
h
oethyl)-2-iso
o
propylidene
-
k
5-methylcyclohexa
K
nol . Yadav,* Manoj Kumar, Tripti Yadav, Renuka Jain
Department of Chemistry, University of Rajasthan, Jaipur 302055, India
Fax +91(141)2700364; E-mail: drakyada@yahoo.co.in
Received 13 August 2009
compound 1a was obtained first followed by 1b and 1c in
70%, 20% and 8% yield, respectively. The major stereo-
isomer 1a upon treatment with O-methyloxime hydro-
chloride in ethanol and subsequent reduction of oximated
product by lithium aluminium hydride afforded (1R,5R)-
1-(1¢-aminoethyl)-2-isopropylidene-5-methylcyclohexanol
(1d) as the sole product in 90% yield. This compound
upon N-methylation with methyl iodide (2 mol) furnished
the desired chiral ligand, (1R,5R)-1-(1¢-dimethylaminoet-
hyl)-2-isopropylidene-5-methylcyclohexanol (1e)14 in
95% yield (Scheme 2). The chiral ligand obtained, as
above, was purified over a silica gel G column by eluting
with hexane–ethyl acetate (8:2) and characterized, unam-
Abstract: An efficient chiral ligand, (1R,5R)-1-(1¢-dimethylamino-
ethyl)-2-isopropylidene-5-methylcyclohexanol, has been devel-
oped for the enantioselective addition of diethylzinc to some
prochiral aldehydes to afford S-alcohols. The overall conversion
rate was 80–98% with excellent enantiomeric excess (79–98%).
Key words: ionic liquid, intermolecular reductive coupling,
prochiral aldehydes, chiral ligand, enantioselectivity
Asymmetric addition of diethyl-, diphenyl-, and dialky-
nylzinc using a catalytic amount of chiral inductor is one
of the most active and fascinating research areas for enan-
tioselective additions to prochiral aldehydes.1 To achieve
this goal, diverse chiral ligand structures such as b-amino
alcohols,2 aminothiols,3 amines,4 aminonaphthols,5 pyr-
idyl alcohols,6 o-hydroxybenzyl amines,7 BINOL,8 and
ligands derived from natural products have been widely
1
biguously, by elemental analysis, IR, H NMR, and 13C
NMR. It was employed as chiral inductor for the addition
of diethylzinc to a range of prochiral aldehydes.15
been exploited,9 but the enantiomeric excess is some
times disappointing. Metal complexes10 have also been
exploited to achieve this goal.
H
H
Me
Me
H
Me
1. MeONH3Cl
2. LAH
2 mol MeI
NH2
NMe2
O
OH
OH
OH
In our strategy for development of new effective chiral
ligands, we have performed an intermolecular electroduc-
tive coupling11 of (R)-(+)-2-isopropylidene-5-methylcy-
clohexanone [(R)-(+)-pulegone] with acetonitrile in the
ionic liquid 1-butyl-3-methylimidazolium tetrafluorobo-
rate propan-2-ol12 at a smooth copper cathode. A constant
current (0.1 A) was passed corresponding to 1.1 F mol–1
charge transfer; wherein, three products, (1R,5R)-1-(1-hy-
droxy-2-isopropylidene-5-methylcyclohexyl)ethanone (1a),
(1S,5R)-1-(1-hydroxy-2-isopropylidene-5-methylcyclo-
hexyl)ethanone (1b), and 2-isopropylidene-5-methylcy-
clohexanol (1c) were formed (Scheme 1).
95%
1e
90%
1d
1a
Scheme 2
In order to evaluate the optimum concentration of this
new chiral ligand, we have studied the addition of dieth-
ylzinc to benzaldehyde at 3, 5, 8, and 10 mol% concentra-
tion. The product upon hydrolysis gave (S)-phenylpropan-
1-ol (4a) in 85–90% yield with 87%, 93%, 90%, and 89%
enantiomeric excess. These data clearly suggest that 5
mol% concentration of the chiral ligand 1e is best suited
for this reaction (Scheme 3).
The products were separated employing a swollen tri-
acetyl cellulose column prepared by the reported meth-
od.13 The elution was accomplished by ethanol, when
H
Me
H
Me
H
H
Me
Me
+ 1 e–
MeCN
+
+
+
OH
[BMIM]BF4
i-PrOH
O
O
O
OH
H
OH
1a
1c
1b
(R)-(+)-pulegone (1)
Scheme 1
SYNLETT 2010, No. 5, pp 0712–0714
1
6.
3
.2
0
1
0
Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219379; Art ID: D21909ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
(1R,5R)-1-(1′Dimethylaminoethyl)-2-isopropylidene-5-methylcyclohexanol
713
Table 1 Addition of Diethylzinc to Aldehydes Using Ligand 1e (5 mol%)
Entry
Aldehyde 2
Product 4
Conversion (%)
Optical rotation
ee (%)
93a
Config.
1
2
3
4
5
6
7
8
PhCHO
4a
4b
4c
4d
4e
4f
90
82
95
98
92
95
94
80
[a]D25 –42.10 (c 5.3, CHCl3)
[a]D25 –5.80 (c 3.2, CHCl3)
[a]D25 –43.24 (c 3.0, PhCH3)
[a]D25 –16.16 (c 5.1, C6H6)
[a]D25 –9.12 (c 3.7, CHCl3)
[a]D26 +7.79 (c 8.7, EtOH)
[a]D25 +26.26 (c 5.0, EtOH)
[a]D24 –6.32 (neat)
S
S
S
S
S
S
S
S
PhCH=CHCHO
2-MeOC6H4CHO
4-MeOC6H4CHO
n-C6H13CHO
n-C6H17CHO
PhCH2CH2CHO
C6H11CHO
88b
92c
94d
95e
96f
4g
4h
98g
79f
a [a]D –45.45 (c 5.15, CHCl3).16
b [a]D –6.6 (c 3.2, CHCl3).17
c [a]D –47.0 (c 1.2, PhCH3).18
d [a]D –17.2 (c 5.0, benzene).19
e [a]D –9.6 (c 8.3, CHCl3).20
f The e was determined by 1H NMR analysis of the derived acetates using Eu(hfc)3.
g [a]D –26.8 (C, 5.0, EtOH).17
R
H
Acknowledgment
H
HO
1e (5 mol%)
+
Et2Zn
We thank the Head of the Department of Chemistry, University of
Rajasthan, Jaipur for providing laboratory facilities. Analytical data
from CDRI, Lucknow are gratefully acknowledged. We are also
grateful to DST, New Delhi for financial assistance.
O
R
Et
3
4 (S-product)
2
Scheme 3
Eight prochiral aldehydes 4a–h were studied, and the cor-
responding products have been assigned S-configuration
by comparison to the known values in the literature and by
derivatization with Eu(hfc)3 and recording 1H NMR spec-
tra (Table 1). All the products 4a–h have been character-
References and Notes
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1
ized by IR, H NMR, 13C NMR, and elemental analyses.
These data for the representative compounds 4a and 4e
have been presented.21
The observation of the data presented in Table 1 reveals
that, with the new chiral ligand 1e, the overall conversion
rate is 80–98% with excellent ee ranging from 79–98%. o-
Methoxybenzaldehyde afforded lower enantioselectivity
than its para isomer, probably due to the steric effect ex-
erted by the ortho substitutent. Amongst the prochiral al-
dehydes examined, aliphatic aldehydes gave best
enantiomeric excesses with the exception of cyclohexyl
carboxaldehye which exhibited the lowest enantioselec-
tivity.
In conclusion, we have demonstrated that the chiral ligand
1e gave excellent enantiomeric excesses for the addition
for diethylzinc to a range of prochiral aldehydes 4a–h.
The work on the synthesis of new chiral ligands derived
from (+)-dihydrocarvone, (–)-menthone, and (+)-cam-
phor is under investigation and results will be addressed in
future in the form of full paper.
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references cited therein. (c) Yand, X.; Hirose, T.; Zhang, G.
Tetrahedron: Asymmetry 2008, 19, 1670; and references
Synlett 2010, No. 5, 712–714 © Thieme Stuttgart · New York

714
A. K. Yadav et al.
cited therein.
LETTER
Calcd for C12H20O2: C, 73.41; H, 10.27. Found: C, 73.62; H,
10.12.
(12) 1-Butyl-3-methylimidazolium tetrafluoroborate was
synthesized according to the reported method, see: Palimkar,
S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan,
K. V. J. Org. Chem. 2003, 68, 9371.
(6) (a) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed.
Engl. 1990, 29, 205. (b) Cheng, Y. Q.; Zheng, B.; Kang, C.
Q.; Guo, H. Q.; Gao, L. X. Tetrahedron: Asymmetry 2008,
19, 1572.
(7) (a) Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361.
(b) Yang, X. F.; Wang, Z. H.; Koshizawa, T.; Yasutake, M.;
Zhang, G. Y.; Hirose, T. Tetrahedron: Asymmetry 2007, 18,
1257.
(8) (a) Yang, X. W.; Sheng, J. H.; Da C, S.; Wang, H. S.; Su, W.;
Wang, R.; Chan, A. S. C. J. Org. Chem. 2000, 65, 295.
(b) Guo, S.; Judesh, Z. M. A. Tetrahedron Lett. 2009, 50,
281.
(9) (a) Chiral Auxilliaries and Ligands in Asymmetric Synthesis;
Seyden, J. P., Ed.; John Wiley and Sons: New York, 1995.
(b) Blaser, H. U. Chem. Rev. 1992, 92, 935. (c) Dabiri, M.;
Salehi, P.; Kozehgary, G.; Heydari, S.; Heydari, A.;
Esfandyari, M. Tetrahedron: Asymmetry 2008, 19, 1970.
(10) (a) Zhang, F. Y.; Chan, A. S. C. Tetrahedron: Asymmetry
1997, 8, 3651. (b) Hwang, C. D.; Uang, B. J. Tetrahedron:
Asymmetry 1998, 9, 3979. (c) Dean, M. A.; Hitchcock, S. R.
Tetrahedron: Asymmetry 2008, 19, 2563; and references
cited therein.
(13) Hesse, G.; Hagel, R. Chromatographia 1976, 9, 62.
(14) Compound 1a was heated to reflux with O-methyloxime
hydrochloride in the presence of 0.03 M Et3N in EtOH.
Removal of the solvent gave the oximated product which,
upon lithium aluminium hydride reduction, afforded
compound 1d in 90% yield. Compound 1d, when refluxed
with 2 mol of MeI resulted in the desired chiral ligand 1e in
95% yield; bp 150–153 °C (67 mbar); Rf = 0.4 (hexane–
EtOAc, 1:1). IR (neat): n = 3855, 2780, 1645, 886 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.05 (d, 3 H, J = 6.5 Hz, CH3),
1.12 (d, 3 H, J = 7.1 Hz, CH3), 1.30–1.42 (m, 4 H, 2 × CH2),
1.62 (m, 1 H, CH), 1.75 (m, 6 H, 2 × CH3), 1.95 (m, 2 H,
CH2), 2.30 (s, 6 H, 2 × CH3), 2.95 [q, 1 H, J = 7.1 Hz,
CHN(CH3)2], 3.85 (s, 1 H, OH). 13C NMR (75 MHz,
CDCl3): d = 12.10, 19.20, 20.60, 22.40, 26.20, 37.25, 39.50,
44.15, 66.50, 78.30, 125.20, 142.70. Anal. Calcd for
C14H27ON: C, 74.59; H, 12.08; N, 6.21. Found: C, 74.43; H,
11.84; N, 5.96.
(15) Kitamura, M.; Okada, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028.
(16) Picard, R. H.; Kenyon, J. J. Chem. Soc. 1914, 1115.
(17) Sato, T.; Gotoh, Y.; Wakebayashi, Y.; Fugisawe, T.
Tetrahedron Lett. 1983, 24, 4123.
(18) Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52, 135.
(19) Capillon, J.; Guette, J. Tetrahedron 1979, 35, 1817.
(20) Mukaiyama, T.; Hojo, K. Chem. Lett. 1976, 893.
(21) Representative Spectroscopic Data
(11) Typical Experimental Procedure for Preparative-Scale
Electrosynthesis
The electrolysis was carried out in a double-walled cell
(Metrohm, 100 ml) equipped with cover glass inlet and
outlet, thermometer, and magnetic stirrer. This cell was
divided by a medium-porosity glass frit into two separate
compartments. The catholyte was a 10 mL mixture of
[BMIM]BF4–i-PrOH (9:1) containing 0.03 M (R)-(+)-
pulegone and 0.04 M of MeCN. The anolyte was 5 mL of
[BMIM]BF4–i-PrOH (9:1). A smooth copper foil (1 × 1 cm)
was used as a cathode and a platinum foil (1 × 1 cm) was
used as an anode. Nitrogen gas was bubbled for 10 min and
the electroreductive coupling was carried out by passing
current 0.1 A for the time corresponding to charge-transfer
equivalent to 1.1 F/mol.
The catholyte was extracted with EtOAc (3 × 10 mL), the
extract dried over anhyd MgSO4, filtered, and the solvent
was removed by distillation under reduced pressure. The
product so obtained was purified by chromatography on a
swollen triacetyl cellulose(microcrystalline) column, and
elution was performed by EtOH to afford 1a in pure form in
70% yield. Rf = 0.55 (hexane–EtOAc, 10:1). IR (neat): n =
3460, 1700, 1640, 880 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.05 (d, 3 H, J = 6.5 Hz, CH3) 1.28 (m, 2 H, CH2), 1.60
(m, 1 H, CH), 1.65 (m, 2 H, CH2), 1.70 (s, 6 H, 2 × CH3),
1.95 (m, 2 H, CH2), 2.10 (s, 3 H, COCH3), 3.80 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 14.60, 19.20, 20.50, 21.60,
25.60, 38.40, 42.40, 92.50, 125.30, 142.70, 207.10. Anal.
(S)-1-phenylpropan-1-ol (4a)
Bp 94–95 (13.3 mbar); Rf = 0.35 (hexane–EtOAc, 8:2). IR
(neat): n = 3400, 3020, 2990, 1600, 1100 cm–1. 1H NMR
(300 MHz, CDCl3): d = 0.90 (t, J = 6.0 Hz, 3 H, CH3), 1.40–
1.55 (m, 2 H, CH2CH3), 3.60 (br s, 1 H, OH), 4.50 (t, J = 7.0
Hz, 1 H, CHOH), 7.10–7.40 (m, 5 H, ArH). 13C NMR (75
MHz, CDCl3): d = 11.10, 33.10, 78.20, 124.60, 128.40,
128.80, 139.20. Anal. Calcd for C9H12O: C, 79.36; H, 8.88.
Found: C, 79.55; H, 8.70.
(S)-3-Nonanol (4e)
Bp 192–194 °C; Rf = 0.40 (hexane–EtOAc, 8:2). IR (neat):
n = 3600, 2970, 1350, 1100 cm–1. 1H NMR (300 MHz,
CDCl3): d = 0.90 (t, J = 6.0 Hz, 3 H, CH3), 0.95 (t, J = 6.0
Hz, 3 H, CH3), 1.20–1.62 (m, 12 H, 6 × CH2), 2.20 (br s, 1
H, OH), 3.25 (t, J = 7.0 Hz, 1 H, CHOH). 13C NMR (75
MHz, CDCl3): d = 11.00, 15.30, 22.40, 25.20, 29.80, 30.60,
33.10, 38.40, 75.50. Anal. Calcd for C9H20O: C, 74.92; H,
13.98. Found: C, 74.75; H, 13.80.
Synlett 2010, No. 5, 712–714 © Thieme Stuttgart · New York

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