Asymmetric synthesis, characterization and stereoselectivity of novel 1-{2-[(1R,2S)-2-(Chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene via boronate complex

Article abstract of DOI:10.14233/ajchem.2014.16244

Novel 1-[2-{(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene was synthesized by cyclopropanation reaction through a novel route. Carbamate was reacted with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to form boronic ester which was further treated with 1-bromo-3,5-bis(trifluoromethyl)benzene in the presence of n-BuLi and nucleophilic boronate complex was synthesized. 1-[2- {(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene was then prepared by reacting boronate complex with different electrophiles like trichloroisocyanuric acid (TCCA) and N-chlorosuccinimide (NCS). Yields and diastereomeric ratios (d.r) were studied by using various aryl lithiums and electrophiles at different temperatures. Best yield, diastereomeric ratio (d.r), enantiomeric ratio (e.r), enantiomeric excess (e.e), enantiospecificity and [a]D were 67 %, 2.1:1, 68.6:28.9, 39.7, 0.41 and +3.84, respectively.

Full text of DOI:10.14233/ajchem.2014.16244

Asian Journal of Chemistry; Vol. 26, No. 8 (2014), 2437-2442
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16244
Asymmetric Synthesis, Characterization and Stereoselectivity of Novel
1-{2-[(1R,2S)-2-(Chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene via Boronate Complex
*
HABIB HUSSAIN , SYEDA RUBINA GILANI, ZULFIQAR ALI and IMDAD HUSSAIN
Department of Chemistry, University of Engineering and Technology, Lahore, Pakistan
*Corresponding author: Tel: +92 321 4618681; E-mail: hbubak@gmail.com
Received: 26 August 2013;
Accepted: 23 September 2013;
Published online: 15 April 2014;
AJC-15044
Novel 1-[2-{(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene was synthesized by cyclopropanation reaction through a
novel route. Carbamate was reacted with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to form boronic ester which was further treated
with 1-bromo-3,5-bis(trifluoromethyl)benzene in the presence of n-BuLi and nucleophilic boronate complex was synthesized. 1-[2-
{(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene was then prepared by reacting boronate complex with different
electrophiles like trichloroisocyanuric acid (TCCA) and N-chlorosuccinimide (NCS). Yields and diastereomeric ratios (d.r) were studied
by using various aryl lithiums and electrophiles at different temperatures. Best yield, diastereomeric ratio (d.r), enantiomeric ratio (e.r),
enantiomeric excess (e.e), enantiospecificity and [α]D were 67 %, 2.1:1, 68.6:28.9, 39.7, 0.41 and +3.84, respectively.
Keywords: Boronic ester, Boronate complex, Aryllithium, Electrophiles, Cyclopropanation, Stereoselectivity.
et al.11 prepared many alcohols and amines from alkyl boronates
INTRODUCTION
in good yields.
In the past decade, there has been great interest in the
In recent study, we developed a novel route for the syn-
development of catalytic enantioselective methods for the
preparation of chiral, optically enriched organoboronates as
precursors of enantio-enriched compounds. There is a wide
thesis of novel 1-[2-{(1R,2S)-2-(chloromethyl)cyclopropyl]-
ethyl}-4-methoxybenzene (9) by using boronate complexes
as nucleophiles. Boronic esters were converted into reactive
use of organometallic nucleophiles in organic synthesis but
nucleophilic boronate complexes by reacting with some aryl
there are a few chiral examples of these useful reagents. Organic
litium and after combining with certain electrophiles desired
synthesis usually involves combination of many nucleophiles
product was obtained. Reaction was investigated at different
with electrophiles. Boronate complexes containing stereogenic
temperatures using various aryllithiums and electrophiles to
boron act as nucleophiles1 and were synthesized by reacting
get the best yields and stereoselectvity. High yields and d.r
trivalent borons with different nucleophiles2,3. Kaiser et al.4
were obtained by tuning the temperature with different aryl
lithium and electrophiles like trichloroisocyanuric acid
(TCCA) and N-chlorosuccinimide (NCS).
prepared boronate complex (99 % e.e) without racemization
at boron through chirality transfer from a carbon. Chang et al.5
synthesized chiral alkylboronates in high yields and 98 % e.e
by reacting Grignard reagent with unsaturated esters and
EXPERIMENTAL
thioesters. Gauthier et al.1 converted boronic esters into reactive
nucleophiles and resulting boronate complexes were reacted
with a number of electrophiles with inversion of stereochemi-
stry. Lou et al.6, Chong et al.7 and Goodman and Pellegrinet8
synthesized reactive boronate species by replacing alkoxy
groups with biphenols. Vedejs et al.9 converted many amino
acids into asymmetric boronate complexes. Boronate complexes
had been used as reaction intermediates for the synthesis of
many useful asymmetric products. Lessard et al.10 reacted
chiral allylic boronate to various aldehydes and synthesized
useful α-hydroxyalkyl derivatives in high stereoselectivity. Hall
N,N-Diisopropylcarbamoyl chloride, 3-(4-methoxy-
phenyl)-1-propanol, n-butyl lithium (n-BuLi), sec-butyl
lithium solution (s-BuLi) (1.6 M), allylboronic acid pinacol
ester, (-) sparteine, N,N,N,N-tetramethyl-ethylenediamine
(TMEDA), 1,3-bis(trifluoromethyl)-5-bromobenzene, 1-bromo-
naphthalene, N-chlorosuccinimide (NCS) and trichloroiso-
cyanuric acid (TCCA) were purchased form Sigma Aldrich
while triethylamine was purchased from Fischer.All chemicals
were used as such as received. Anhydrous dichloromethane
(DCM), diethyl ether, acetonitrile and tetrahydrofuran (THF)
were obtained after distillation with sodium benzophenone

2438 Hussain et al.
Asian J. Chem.
ketyl under nitrogen and stored in Young's flasks over 4 Å
molecular sieves. N,N,N,N-tetramethylethylene-diamine
(TMEDA) was distilled over CaH2. Being air and water sensi-
tive, all reactions were carried out in flame-dried glass-ware
under nitrogen atmosphere using standard Schlenk lines.
Synthesis of 3-(4-methoxyphenyl)propyl-N,N-diisopro-
pylcarbamate (4): Triethylamine (Et3N) (5 mL, 36.1 mmol,
1.2 eq) (3) was added to a solution of N,N-diisopropylcar-
bamoyl chloride (5.43 g, 33.1 mmol, 1.1 eq.) (1) and 3-(4-
methoxyphenyl)-1-propanol (5 g, 30.1 mmol, 1.0 eq.) (2) in
CH2Cl2 (30 mL) at room temperature. The resulting mixture
was refluxed for 16 h, allowed to cool to room temperature
and quenched with 1 N NaOH (50 mL). The layers were
separated and the aqueous phase was extracted with CH2Cl2.
The combined organic layers were washed with 1 N HCl, water
and brine, dried (MgSO4), concentrated and purified by column
chromatography (SiO2, 90:10 petrol/EtOAc) to obtain the
desired 3-(4-methoxyphenyl)propyl-N,N-diisopropyl-
carbamate (4) (8.69 g, 99 %) as white solid (Fig. 1.)
(1.88 mL, 8.18 mmol, 1.2 eq.) (5a) in Et2O (34 mL) at -78 °C
was added sec-BuLi (1.6 M in 92:8 cyclohexane/hexane, 5.8
mL, 7.50 mmol, 1.1 eq.) dropwise. The resulting mixture was
stirred for 5 h at -78 °C before allylboronic acid pinacol ester
(1.53 mL, 8.18 mmol, 1.2 eq.) (5) was dropwise added. The
reaction mixture was further stirred at -78 °C for 1 h, allowed
to warm to room temperature. A solution of MgBr2·OEt2 in
Et2O, made as follows, was added to the reaction mixture at
this point: [1,2-dibromoethane (1.19 mL, 13.77 mmol, 1.0 eq)
was added to a suspension of magnesium (0.33 g, 13.77 mmol,
1.0 eq.) in Et2O (17.2 mL) at room temperature. The reaction
flask was then placed into a water bath in order to control the
moderate exotherm and was further stirred for 2 h. Both layers
of the biphasic mixture thus obtained were transferred to the
former mixture via syringe. The mixture was refluxed for 16 h.
The reaction mixture was allowed to cool down to room
temperature and was carefully quenched with water. Diethyl
ether was added, the layers were separated and the aqueous
phase was extracted with Et2O. The combined organic layers
were washed with 1N HCl, 1N NaOH, water and brine, dried
MgSO4, concentrated and purified by column chromatography
(SiO2) to obtain the pure (R)-2-(1-(4-methoxyphenyl)hex-5-
en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6) (1.67 g,
77.6 %) as colorless oil (Fig. 2).
1
Carbamate (4) was characterized through H NMR, 13C
NMR and functional groups were confirmed through IR. This
crude product (4) was used for the synthesis of (R)-2-(1-(4-
methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (6) and 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7).
1
Complete characterization was done by H NMR, 13C
1H NMR (400 MHz, CDCl3) δ ppm 7.10 (2H, d, J = 8.80
Hz, 2 × ArH) 6.83 (2H, d, J = 8.80 Hz, 2 × ArH) 4.10 (2H, t,
J = 6.5 Hz, OCH2) 3.96 (2H, br s, 2 × -CH(CH3)2) 3.78 (3H, s,
OCH3) 2.62-2.69 (2H, m, CH2CH2CH2O) 1.90-1.98 (2H, m,
CH2CH2CH2O) 1.22 (12H, d, J = 6.85 Hz, 4 × CH3) 13C NMR
(100 MHz, CDCl3) δ ppm 157.8 (1C, NCOO), 155.8 (1C,ArC),
133.6 (1C,ArC), 129.3 (2C, 2 ×ArCH), 113.8 (2C, 2 ×ArCH),
64.0 (1C, CH2CH2CH2O), 55.2 (1C,OCH3), 45.8 (2C, br, 2 ×
CH(CH3)2), 31.6 (1C,CH2CH2CH2O), 31.1 (1C,CH2CH2CH2O),
21.0 (4C, br, 4 × CH3). IR (film): ν(cm-1) 3026 (sp2 C-H
Stretch), 2967, 2868 (sp3 C-H stretch), 1685 (C=O stretch),
1512, 1435 (sp2 C=C stretch), 1288, 1244 (sp3 C-O stretch),
832, 771 (sp2 C-H oop bending). m.p = 36-38 °C
NMR and IR. Fine peaks confirmed the purity of the secondary
boronic ester (6) and it was used as starting material for reaction
(Fig. 4). 1H NMR (400 MHz, CDCl3) δ ppm 7.09 (2H, d, J =
8.80 Hz, 2 × ArH) 6.81 (2H, d, J = 8.80 Hz, 2 × ArH) 5.86-
5.75 (1H, m, CH=CH2) 5.04 (1H, d, J = 2.20 Hz, CH=CHH)
4.94 (1H, d, J = 10.27 Hz, CH=CHH) 3.78 (3H, s, OCH3)
2.63-2.48 (2H, m, ArCH2CH2CHBCH2) 2.27-2.11 (2H, m,
ArCH2CH2CHBCH2) 1.78-1.58 (2H, m, ArCH2CH2CHB
CH2) 1.25 (12H, s, 4 × CH3) 1.08-1.18 (1H, m,ArCH2CH2CHB
CH2) 13C NMR (100 MHz, CDCl3) δ ppm 157.6 (1C, -OCH3),
138.4 (2C, 2 ×ArCH), 135.0 (2C, 2 ×ArCH), 129.2 (1C,ArC-
O), 114.9 (1C, -CH2CH=CH2), 113.6 (1C, -CH=CH2), 83.0 (2C,
2 × C(CH3)2), 55.2 (1C, ArCCH2), 35.3 (1C, -CH2CH2CHB),
34.5 (1C, -CH2CHB), 33.1 (1C, -CHBCH2CH), 24.9 (1C,
-CH2CH2CHB), 24.8 (4C, 2 × (CH3)2C).11B NMR (96.23 MHz,
None) δ ppm 33.24. IR (film): ν(cm-1) 3026 (sp2 C-H Stretch),
Synthesis of (R)-2-(1-(4-methoxyphenyl)hex-5-en-3-
yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6): To a solution
of primary carbamate (2 g, 6.82 mmol, 1.0 eq) (4) and (-) sparteine
O
O
OH
CH2Cl2
O
N
+
N
+
Et3N
O
O
(3)
(4)
(2)
(1)
Fig. 1. 3-(4-Methoxyphenyl propyl-N,N-disopropylcarbamate
O
O
O
B
s-BuLi
O
(5a)
O
N
(-) Sparteine
+
B
O
Et2O
O
O
(6)
(4)
(5)
Fig. 2. Synthesis of (R)-2-(1-(4-methoxyphenyl)hex-5-ene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Vol. 26, No. 8 (2014) Asymmetric Synthesis and Stereoselectivity of 1-{2-[(1R,2S)-2-(Chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene 2439
2977, 2924, 2852 (sp3 C-H stretch), 1511, 1456 (sp2 C=C
stretch), 1243, 1175, 1142 (sp3 C-O stretch), 846, 822, 670
(sp2 C-H oop bending).
Synthesis of 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7): Racemic 2-(1-
(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (7) was prepared by substituting (-)sparteine
by N,N,N,N-tetramethylethylenediamine (TMEDA) (1.22 mL,
8.18 mmol, 1.2 eq.) (5b) (Fig. 3).
added at -40 °C and the reaction mixture was allowed to warm
to room temperature (Fig. 4). EtOAc was dded and the layers
were separated. The aqueous phase was extracted with EtOAc,
the organic layers were combined, washed with brine, dried
(MgSO4), concentrated. The crude mixture was finally purified
by column chromatography (SiO2, 99:1 Pentane/EtOAc) to
give desired 1-(2-((1R,2S)-2-(chloromethyl)cyclopropyl)-
ethyl)-4-methoxybenzene (9) as colorless oil (0.025 g, 49 %).
1H NMR (400 MHz, CDCl3) δ ppm 7.12 (2H, d, J = 8.31 Hz,
2 × ArH) 6.83 (2H, d, J = 8.80 Hz, 2 × ArH) 3.79 (3H, s,
OCH3) 3.69 (0.7H, dd, J = 11.25, 7.09 Hz, major CHHCl)
3.49-3.34 (0.3 H, minor CHHCl, 1H, m, CHHCl) 2.71 (1H, t,
J = 7.83 Hz, ArCHHCH2CH) 2.66 (1H, t, J = 7.70 Hz,
ArCHHCH2CH) 1.81-1.71 (0.7 H, m, major ArCH2CHHCH)
1.65-1.43 (0.3H, minor ArCH2CHHCH, 1H, m, ArCH2CH-
HCH) 1.33-1.22 (0.7H, m, major CH(CH2)CHCH2Cl) 1.06-
0.95 (0.3H, minor CH(CH2)CHCH2Cl, 0.7H, m, CH(CH2)CH-
CH2Cl) 0.88-0.81 (0.3H, m, CH(CHH)CHCH2Cl) 0.79-0.70
(0.3H, m, CH(CH2)CHCH2Cl) 0.54-0.46 (1H, m, CH(CHH)-
CHCH2Cl) 0.06 (0.7H, q, J = 5.54 Hz, CH(CHH)CHCH2Cl).
13C NMR (100 MHz, CDCl3) δ ppm 157.77 (1C, major, ArC),
157.71 (1C, minor,ArC), 134.25 (1C, major,ArC), 134.21 (1C,
minor,ArC), 129.32 (1C, major,ArC), 113.72 (1C, minor,ArC),
113.69 (1C, major,ArC), 55.26 (1C, major, OCH3), 55.24 (1C,
minor, OCH3), 50.22 (1C, minor, CH2Cl), 46.65 (1C, major,
CH2Cl), 35.63 (1C, minor, CH2CH2CH(CH2)CH-CH2Cl),
35.26 (1C, major, CH2CH2CH(CH2)CHCH2Cl), 34.69
(1C, minor, CH2CH2CH(CH2)CHCH2Cl), 30.54 (1C, major,
CH2CH2CH(CH2)CHCH2Cl), 21.34 (1C, minor, CH2CH2CH-
(CH2)CHCH2Cl), 19.83 (1C, minor, CH2CH2CH(CH2)CH-
CH2Cl), 18.54 (1C, major, CH2CH2CH(CH2)CHCH2Cl), 17.72
(1C, major, CH2CH2CH(CH2)CHCH2Cl), 12.93 (1C, minor,
CH2CH2CH(CH2)CHCH2Cl), 12.11 (1C, major, CH2CH2CH
(CH2)CHCH2Cl). IR (film): ν (cm-1) 3026 (sp2 C-H stretch),
2977, 2930, 2855, 2835 (sp3 C-H stretch), 1510, 1455 (sp2
C=C stretch), 1242, 1176, 1035 (sp3 C-O stretch), 822, 696,
575 (sp3 C-Cl stretch). HRMS (ESI) calcd. for C13H17OCl
[M+H]+ 225.1039, found 225.1039. [α]D +3.84 (c 0.52, CDCl3)
SFC separation conditions: Chiralpak IA column with
guard, 5 % iPrOH in hexane, flow rate: 2 mL/min, 39.9 °C; tR
Pure sec-boronic ester (7) was collected as colorless oil
(1.62g, 75.3 %). 1H NMR (400 MHz, CDCl3) δ ppm 7.09 (2H,
d, J = 8.80 Hz, 2 × ArH) 6.81 (2H, d, J = 8.80 Hz, 2 × ArH)
5.86-5.75 (1H, m, CH=CH2) 5.04 (1H, d, J = 2.20 Hz,
CH=CHH) 4.94 (1H, d, J = 10.27 Hz, CH=CHH) 3.78 (3H, s,
OCH3) 2.63-2.48 (2H, m, ArCH2CH2CHBCH2) 2.27-2.11 (2H,
m, ArCH2CH2CHBCH2) 1.78-1.58 (2H, m, ArCH2CH2CHB-
CH2) 1.25 (12H, s, 4 × CH3) 1.08-1.18 (1H, m,ArCH2CH2CH-
BCH2) 13C NMR (100 MHz, CDCl3) δ ppm 157.6 (1C, -OCH3),
138.4 (2C, 2 ×ArCH), 135.0 (2C, 2 ×ArCH), 129.2 (1C,ArC-
O), 114.9 (1C, -CH2CH=CH2), 113.6 (1C, -CH=CH2), 83.0
(2C, 2 × C(CH3)2), 55.2 (1C, ArCCH2), 35.3 (1C, -CH2CH2-
CHB), 34.5 (1C, -CH2CHB), 33.1 (1C, -CHBCH2CH), 24.9
(1C, -CH2CH2CHB), 24.8 (4C, 2 × (CH3)2C). 11B NMR (96.23
MHz, None) δ ppm 33.24. IR (film): ν(cm-1) 3390 (O-H
stretch), 3001 (sp2 C-H stretch), 2931, 2835 (sp3 C-H stretch),
1511, 1441 (sp2 C=C stretch), 1244, 1177, 1036 (sp3 C-O
stretch), 915, 822 (sp2 C-H oop bending).
Synthesis of 1-(2-((1R,2S)-2-(chloromethyl)cyclopropyl)-
ethyl)-4-methoxybenzene (9): To a solution of 1,3-bis(trifluoro-
methyl)-5-bromobenzene (0.08 g, 0.274 mmol, 1.2 eq) (6a)
in THF (2.4 mL) at -78 °C was added n-BuLi (1.6 M in hexane,
0.17 mL, 0.274 mmol, 1.2 eq.) dropwise. The mixture was
stirred 1 h at -78 °C before a solution of boronic ester (0.072 g,
0.228 mmol, 1.0 eq.) (6) in THF (1.2 mL) was added dropwise.
The reaction mixture was stirred for 0.5 h at -78 °C and 0.5 h
at room temperature to give the boronate complex solution
(8). The reaction mixture was cooled to -40 °C, a solution of
TCCA (0.064 g, 0.274 mmol, 1.2 eq.) (8a) in MeCN (1.2 mL)
was then added dropwise over 1min and the reaction mixture
was stirred for 5 min at -40 °C. 20 % Na2S2O3 (3 mL) was
O
O
O
B
s-BuLi
(5b)
O
B
TMEDA
O
N
+
O
Et2O
O
(7)
O
(5)
Fig. 3. Synthesis of 2-(1-(4-methoxyphenyl)hex-5-ene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(4)
CF3
F3C
n-BuLi
O
B
O
O
O
(6a)
3,5-(CF3)2C6H3Br
B
Cl
TCCA (8a)
Li
THF, -78oC
MeCN, -40oC, 5min
(9)
O
O
(6)
(8)
O
Fig. 4. Synthesis of 1-(2-((1R,2S)-2(chloromethyl)cyclopropyl)ethyl)-4-methoxybenzene

2440 Hussain et al.
Asian J. Chem.
CF3
O
O
F3C
B
n-BuLi
O
B O
(6a)
3,5-(CF3)2C6H3Br
Cl
(8a)
TCCA
Li
(7)
THF, -78oC
MeCN, -40oC, 5min
O
(11)
O
(10)
O
Fig. 5. Synthesis of 1-(2-((1R)-2(chloromethyl)cyclopropyl)ethyl)-4-methoxybenzene
16.5 min for (R)-enantiomer (minor) and tR 23.0 min for (S)-
enantiomer (major). e.r. = 68.6:28.9.
mmol) in THF/Et2O (1:1 v/v, 1mL) at 0 °C under vigorous
stirring. The reaction mixture was allowed to warm to room
temperature and further stirred for 2 h. Et2O and water was
added and phases were separated. The aqueous phase was
extracted with Et2O; the combined organic layers were washed
with brine, dried (MgSO4), concentrated and purified by
column chromatography (SiO2) to obtain the pure (R)-1-(4-
methoxyphenyl)hex-5-en-3-ol (12) as colourless oil (0.022 g,
73.3 %) (Fig. 6).
Synthesis of 1-(2-((1R)-2-(chloromethyl)cyclopropyl)-
ethyl)-4-methoxybenzene (11): Product 1-(2-((1R)-2-(chloro-
methyl)cycloprpyl)ethyl)-4-methoxybenzene (11) was synthe-
sized by substituting starting material (6) with racemic boronic
ester (7) (Fig. 5).
Pure product (11) was obtained as colorless oil (0.024,
48.6 %). 1H NMR (400 MHz, CDCl3) δ ppm 7.12 (2H, d, J =
8.31 Hz, 2 × ArH) 6.83 (2H, d, J = 8.80 Hz, 2 × ArH) 3.79
(3H, s, OCH3) 3.69 (0.7H, dd, J = 11.25, 7.09 Hz, major
CHHCl) 3.49-3.34 (0.3H, minor CHHCl, 1H, m, CHHCl) 2.71
(1H, t, J = 7.83 Hz, ArCHHCH2CH) 2.66 (1H, t, J = 7.70 Hz,
ArCHHCH2CH) 1.81-1.71 (0.7H, m, major ArCH2CHHCH)
1.65-1.43 (0.3H, minor ArCH2CHHCH, 1H, m, ArCH2CH-
HCH) 1.33-1.22 (0.7H, m, major CH(CH2)CHCH2Cl) 1.06-
0.95 (0.3H, minor CH(CH2)CHCH2Cl, 0.7H, m, CH(CH2)CH-
CH2Cl) 0.88-0.81 (0.3H, m, CH(CHH)CHCH2Cl) 0.79-0.70
(0.3H, m, CH(CH2)CHCH2Cl) 0.54-0.46 (1H, m, CH(CHH)-
CHCH2Cl) 0.06 (0.7H, q, J = 5.54 Hz, CH(CHH)CHCH2Cl).
13C NMR (100 MHz, CDCl3) δ ppm 157.77 (1C, major,
ArC), 157.71 (1C, minor,ArC), 134.25 (1C, major,ArC), 134.21
(1C, minor,ArC), 129.32 (1C, major,ArC), 113.72 (1C, minor,
ArC), 113.69 (1C, major,ArC), 55.26 (1C, major, OCH3), 55.24
(1C, minor, OCH3), 50.22 (1C, minor, CH2Cl), 46.65 (1C,
major, CH2Cl), 35.63 (1C, minor, CH2CH2CH(CH2)CHCH2Cl),
35.26 (1C, major, CH2CH2CH(CH2)CHCH2Cl), 34.69
(1C, minor, CH2CH2CH(CH2)CHCH2Cl), 30.54 (1C, major,
CH2CH2CH(CH2)CHCH2Cl), 21.34 (1C, minor, CH2CH2-
CH(CH2)CHCH2Cl), 19.83 (1C, minor, CH2CH2CH(CH2)CH-
CH2Cl), 18.54 (1C, major, CH2CH2CH(CH2)CHCH2Cl), 17.72
(1C, major, CH2CH2CH(CH2)CHCH2Cl), 12.93 (1C, minor,
CH2CH2CH(CH2)CHCH2Cl), 12.11 (1C, major, CH2CH2CH-
(CH2)CHCH2Cl). IR (film): ν(cm-1) 3026 (sp2 C-H stretch),
2977, 2930, 2855, 2835 (sp3 C-H stretch), 1510, 1455 (sp2
C=C stretch), 1242, 1176, 1035 (sp3 C-O stretch), 822, 696,
575 (sp3 C-Cl stretch). HRMS (ESI) calcd. for C13H17OCl
[M+H]+ 225.1039, found 225.1039.
O
O
OH
B
NaOH/H2O2
THF, Et2O
O
(12)
O
(6)
Fig. 6. Synthesis of (R)-1-(4-methoxyphenyl)hex-5-en-3-ol
1H NMR (400 MHz, CDCl3) δ ppm 7.12 (2H, d, J = 8.80
Hz, 2 × ArH) 6.83 (2H, d, J = 8.56 Hz, 2 × ArH) 5.82 (1H,
dddd, J = 17.64, 9.63, 7.95, 6.60 Hz, CH=CH2) 5.17-5.14 (1H,
m, CH=CHH) 5.14-5.11 (1H, m, CH=CHH) 3.79 (3H, s,
OCH3) 3.66 (1H, br s, -OH) 2.80-2.70 (1H, m,
ArCHHCH2CHBCH2) 2.68-2.59 (1H, m, ArCHHCH2CHB-
CH2) 2.36-2.27 (1H, m,ArCH2CH2CHBCHH) 2.23-2.12 (1H,
m, ArCH2CH2CHBCHH) 1.79-1.72 (2H, m, ArCH2CH2CH-
BCH2) 1.60 (1H, br s, ArCH2CH2CHBCH2) 13C NMR (100
MHz, CDCl3) δ ppm 157.7 (1C, -OCH3), 134.6 (2C, 2 ×ArCH),
134.0 (2C, 2 ×ArCH), 129.2 (1C,ArC-O), 118.2 (1C, -CH2CH
=CH2), 113.8 (1C, -CH=CH2), 69.8 (1C, -CH2CHB), 55.2 (1C,
ArCCH2), 42.0 (1C, -CHBCH2CH, 38.6 (1C, -CH2CH2CHB),
31.0 (1C, -CH2CH2CHB). IR (film): ν (cm-1) 3026 (sp2 C-H
stretch), 2977, 2924, 2852 (sp3 C-H stretch), 1511, 1456 (sp2
C=C stretch), 1243, 1175, 1142 (sp3 C-O stretch), 846, 822,
670 (sp2 C-H oop bending).
SFC separation conditions: Chiralpak IA column with
guard, 5 % iPrOH in hexane, flow rate: 2 mL/min, 39.9 °C; tR
11.4 min for (S)-enantiomer (minor) and tR 13.2 min for (R)-
enantiomer (major). [α]D 20 + 0.20 (c 1.0, CHCl3), e.r. = 99.0:1.0
The proposed mechanism are shown in Fig. 7.
SFC separation conditions: Chiralpak IA column with
guard, 5% iPrOH in hexane, flow rate: 2 mL/min, 39.9 °C; tR
16.5 min for (R)-enantiomer (minor) and tR 23.0 min for (S)-
enantiomer (major).
RESULTS AND DISCUSSION
3-(4-Methoxyphenyl)propyl-N,N-diisopropylcarbamate
(4) (Table-1, entry 1) was synthesized in excellent yields by
reacting N,N-diisopropylacetamide (1) and 3-(4-methoxy-
phenyl)propan-1-ol (2) at mentioned conditions. Both chiral
(6) and racemic (7) secondary boronic esters were prepared
by lithiation-borylation reaction in good yields. (R)-2-(1-(4-
methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (6) (Table-1, entry 2) was formed by reacting
Synthesis of (R)-1-(4-methoxyphenyl)hex-5-en-3-ol (12)
Oxidation of (R)-2-(1-(4-methoxyphenyl)hex-5-en-3-
yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6): A solution
of 3M NaOH/30 % H2O2 (2:1 v/v, 1 mL) was added dropwise
to a solution of ((R)-2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6) (0.03 g, 0.115

Vol. 26, No. 8 (2014) Asymmetric Synthesis and Stereoselectivity of 1-{2-[(1R,2S)-2-(Chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene 2441
F C
3
CF
3
F C
3
CF
3
n-BuLi
(i)
Lithium-halogen
Exchange
Li
Br
CF
3
CF
3
O
B
F C
3
F C
3
O
O
O
F C
3
CF
3
(ii)
Cl
ration
1,3-Mig
Cl+
O
O
B
+
B
Li
Cl
+
Li
O
O
Li
O
O
Fig. 7
3-(4-methoxyphenyl)propyl-N,N-diisopropylcarbamate (4)
with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5) in the
presence of sec-BuLi and (-) sparteine (5a) in Et2O while in
the synthesis of 2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7) (Table-1, entry 3),
TMDA (5b) was used instead of (-) sparteine (5a). These
boronic esters (6, 7) were used in cyclopropanation reaction
as starting materials.
Boronate complex (8) was then synthesized after reacting
(R)-2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (6) with 1,3-bis(trifluoro-
methyl)-5-bromobenzene (6a). Boron-ate (8) acted as nucleo-
phile and was then combined with some electrophiles like
TCCA and NCS, after 1,3-migration it resulted in 1-[2-{(1R,2S)-
2-(chloromethyl)cyclopropyl]ethyl}-4-methoxybenzene (9).
In the same way, boronic ester (7) was used to prepare 1-(2-
((1R)-2-(chloromethyl)cyclopropyl)ethyl)-4-methoxybenzene
(11) through boronate complex (10). Both chiral and racemic
cyclopropanation products (9, 11) were synthesized and tuned
the reaction for best yields and stereoselectivity.
In order to get best yields and stereoselectivity, reaction
(Figs. 4 and 5) was investigated at different temperatures using
a number of aryllithiums and electrophiles like TCCA and NCS.
Effect of temperature on the reaction was studied first by
reacting boronate complex at different temperatures using
TCCA as the electrophilic chlorine source. It was found that
at higher temperature (room temperature), both yields and d.r.
was worse and favoured the other diastereomer (Table-2, entry
1). So reaction was attempted at lower temperatures -40 °C
and -78 °C respectively and found that d.r. was only slightly
better.At -40 °C, improvement was seen both in yields and d.r
(Table-2, entry 2) so reaction was carried out at further low
temperature -78 °C but results were discouraging (Table-2,
entry 3).
TABLE-1
PHYSICAL CHARACTERISTIC OF STARTING MATERIALS
Entry
Starting Material
3-(4-Methoxyphenyl)propyl-N,N-diisopropylcarbamate
(R)-2-(1-(4-methoxyphenyl) hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
2-(1-(4-methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Colour
Yield (%)
99.0
77.6
1
2
3
White solid
Colorless oil
Colorless oil
75.3
TABLE-2
EFFECT OF TEMPERATURE ON STEREOSELECTIVITY
Entry
1
Boronic Ester
Aryllithium
Electrophile
TCCA
Temp. (°C)
R.T
Product
Yield (%)
d.r (%)
1.18:1
O
Cl
Cl
Cl
3,5-
(CF3)2C6H3Br
O
O
O
B
13
49
22
O
O
O
O
O
O
O
B
3,5-
(CF3)2C6H3Br
2
3
TCCA
TCCA
-40
-78
2:1
O
B
3,5-
(CF3)2C6H3Br
2.1:1
TABLE-3
EFFECT OF ARYL LITHIUMS ON STEREOSELECTIVITY
Entry
1
Boronic Ester
Aryllithium
Electrophile
Temp. (°C)
Product
Yield (%)
49
d.r (%)
2:1
O
Cl
Cl
O
B
3,5-(CF3)2C6H3Br
TCCA
-40
O
O
O
O
O
B
1-
O
2
TCCA
-40
67
1.8:1
Bromonaphthalene

2442 Hussain et al.
Asian J. Chem.
TABLE-4
EFFECT OF ELECTROPHILES ON STEREOSELECTIVITY
Entry
1
Boronic Ester
Aryllithium
Electrophile
TCCA
Temp. (°C)
-40
Product
Yield (%)
49
d.r (%)
12:1
O
Cl
Cl
3,5-
(CF3)2C6H3Br
O
B
O
O
O
O
O
B
3,5-
(CF3)2C6H3Br
O
2
NCS
-40
18
1.8:1
TABLE-5
DATA SHOWING STEREOSELECTIVITY AND [α]D
e.s
Entry
1
Products
d.r
e.r
e.e
[α]D
Cl
0.41
2.1:1
68.6:28.9
39.7
+3.84
O
OH
----
2
----
99.0:1.0
98.0
+0.20
O
Then, we investigated if steric bulk of aryl lithium had
some affect on stereoselectivity so 3,5-(CF3)2C6H3Br was
replaced by 1-bromonaphthalene at -40 °C. However, the use
of 1-bromonaphthalene actually resulted in slightly lower d.r.,
although yield was slightly improved (Table-3, entry 2).
Similarly, reaction was also tried by changing the electro-
philes to see how this would affect the stereoselectivity. In the
light of above observations, 3,5-(CF3)2C6H3Br was used as aryl
lithium and temperature was kept -40 °C and reaction was
tuned by changing electrophile. Use of NCS instead of TCCA
resulted in slightly lower yield and lower diastereoselectivity
(Table-4, entry 2).
entry 2). The best diastereoselectivity obtained was 2.1:1, using
1,3-bis(trifluoromethyl)-5-bromobenzene at -78 °C (Table-2,
entry 3). Enantiomeric ratio (e.r), enantiomeric excess (e.e),
enantiospecificity (e.s) and [α]D for 1-[2-{(1R,2S)-2-(chloro-
methyl)cyclopropyl]ethyl}-4-methoxybenzene (9) were
68.6:28.9, 39.7, 0.41 and +3.84 respectively (Table-5, entry 1).
ACKNOWLEDGEMENTS
The authors are thankful to Higher Education Commission
of Pakistan for providing research funds. The authors also
acknowledged the Department of Chemistry, University of
Engineering and Technology, Lahore, Pakistan and Superior
University, Raiwand Road, Lahore, Pakistan for guidance,
research and laboratory facilities.
1
As analyzed from H NMR, cyclopropanation product
1-[2-{(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-4-
methoxybenzene (9) was a mixture of 70:30 (major/minor)
diastereomers. For the determination of e.r, (R)-2-(1-(4-
methoxyphenyl)hex-5-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (6) was oxidized into (R)-1-(4-methoxy-
phenyl)hex-5-en-3-ol (0.022g, 73.3 %) (12). Enantiomeric
ratio determined by supercritical fluid chromatography (SFC)
was 68.6:28.9 while enantiomeric excess (e.e), enanatio-
specificity (e.s) and [α]D calculated were 39.7, 0.41 and +3.84,
respectively (Table-5, entry 1).
REFERENCES
1. R. Larouche-Gauthier, T.G. Elford and V.K. Aggarwal, J. Am. Chem. Soc.,
133, 16794 (2011).
2. H.C. Brown and A.K. Gupta, J., Organomet. Chem., 341, 73 (1988).
3. S. Toyota and M. Oki, Bull. Chem. Soc. Jpn, 65, 1832 (1992).
4. P.F. Kaiser, J.M. White and C.A. Hutton, J. Am. Chem. Soc., 130, 49,
16450 (2008).
5. J.C.H. Lee and D.G. Hall, J. Am. Chem. Soc., 132, 5544 ( 2010).
6. S. Lou, P.N. Moquist and S.E. Schaus, J. Am. Chem. Soc. 128, 12660
(2006).
7. D. Chong, A. Nafady, P.J. Costa, M.J. Calhorda and W.E. Geiger, J.
Am. Chem. Soc., 127, 15676 (2005).
8. S.C. Pellegrinet and J.M. Goodman, J. Am. Chem. Soc., 128, 3116 (2005).
9. E. Vedejs, S.C. Fields, S. Lin and M.R. Schrimpf, J. Org. Chem., 60,
3028 (1995).
10. S. Lessard, F. Peng and D.G. Hall, J. Am. Chem. Soc., 131, 9612 (2009).
11. G.D. Hall, J.C.H. Lee and J.Y. Ding, Pure Appl. Chem., 84, 2263 (2012).
Conclusion
Novel 1-[2-{(1R,2S)-2-(chloromethyl)cyclopropyl]ethyl}-
4-methoxybenzene (9) was synthesized in good yields (Table-
3, entry 2), diastereometric ratios (d.r) and enantiomeric ratios
(e.r) (Table-5, entry 1). Temperature had dominant effect on
stereoselectivity (Table-2, entry 2). Best yield for this cyclo-
propanation reaction was 67 % using 1-bromonaphthlene as
aryllithium and performing the reaction at -40 °C (Table-3,