Synthesis of chiral P,N-ligands derived from quinoline and their application in asymmetric allylic alkylations

Article abstract of DOI:10.3184/174751911X13082269792294

Chiral P,N-ligands derived from quinoline and with a trans and cis cyclohexane backbone were easily synthesised in four steps from quinoline N-oxide. The enantiopure trans isomer was obtained by the way of chiral resolution of the mixture of trans- and cis-2-(quinolin-2-yl)cyclohexanol with dibenzoyltartaric acid and then subjected to a Mitsunobu reaction and deprotection to give the corresponding cis isomer. The optical pure trans and cis isomer reacted with chlorodiphenylphosphine or PAr₂NEt ₂ to obtain trans and cis P,N-ligands, which were used in asymmetric allylic alkylations with up to 78% ee and 84% ee respectively.

Full text of DOI:10.3184/174751911X13082269792294

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 349
JUNE, 349–351
Synthesis of chiral P,N-ligands derived from quinoline and their
application in asymmetric allylic alkylations
Yan-Hong Shen*, Hui-Chao Lv and Liang Zhao
Department of Chemistry, Anyang Institute ofTechnology, Anyang 455000, P. R. China
Chiral P,N-ligands derived from quinoline and with a trans and cis cyclohexane backbone were easily synthesised in
four steps from quinoline N-oxide. The enantiopure trans isomer was obtained by the way of chiral resolution of the
mixture of trans- and cis-2-(quinolin-2-yl)cyclohexanol with dibenzoyltartaric acid and then subjected to a Mitsunobu
reaction and deprotection to give the corresponding cis isomer. The optical pure trans and cis isomer reacted
with chlorodiphenylphosphine or PAr2NEt2 to obtain trans and cis P,N-ligands, which were used in asymmetric allylic
alkylations with up to 78% ee and 84% ee respectively.
Key words: P,N-ligands, quinoline, chiral resolution, allylic alkylations
Asymmetric transformations in the presence of chiral ligands
have proved to be one of the most efficient methods for the
construction of enantioenriched chiral compounds.1 The devel-
opment of phosphorus- and nitrogen-based chiral ligands
has been extensively investigated in late-transition-metal
catalysis.2–4 Zhou and Pfaltz have successfully used chiral
P,N-ligands with a cyclohexane-backbone and bicyclic P,N-
ligands in the Pd-catalysed allylic alkylations.5,6 However, P,N-
ligands derived from quinoline have been reported in only a
few examples. In the present work, we describe the synthesis
of chiral P,N-ligands derived from quinoline and their applica-
tion in asymmetric allylic alkylations.
enantiopure trans- and cis-pyridyl cyclohexanols with inex-
pensive tartaric acid derivatives.6 Here, we found the di-
benzoyl tartaric acid (DBTA) was an efficient resolving agent.
(D)-DBTA in a mixture of solvents was used to resolve the
racemic trans and cis mixtures. The crude diastereomeric salt
was then recrystallised three times to obtain (1S,2R)-4 in 22%
yield and more than 99%ee. Then, the trans isomer (1S, 2R)-4
was transformed to the cis isomer (1R, 2R)-5 by a Mitsunobu
reaction.6,14 Reaction of trans-4 with BuLi and PPh2Cl in THF
gave trans-ligand 6, and using Pfaltz’s condition, reaction
of cis-5 with PAr2NEt2/4,5-dichloroimidazole/Et3N (1:1:1, 1.5
equiv) under reflux gave the desired cis-ligand 7.5
Finally, we examined the palladium-catalysed asymmetric
allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate
(8) with 3.0 equiv. of dimethyl malonate (DMM) using chiral
P,N-ligand 6 or 7 in CH2Cl2 for 2 h at 25 °C.
For ligand 6, the reaction proceeded in 96% conversion and
enantiomeric excess of up to 78%; for ligand 7, the reaction
proceeded in 95% conversion and enantiomeric excess of up
to 84%.
Following literature precedents,7–10 the reaction of quinoline
N-oxide with the enamine of cyclohexanone in the presence of
an acylating agent gave ketone 3. This was treated with NaHB4
in 95% ethanol for 10 min at room temperature to give a nearly
quantitative yield of a mixture of the trans and cis alcohols 4
and 5. The stereochemistry of the two isomers was established
1
from their H NMR spectra. The chemical shift of the major
isomers (trans OH) was larger than that of the minor isomers
(cis OH), which indicates the presence of an intramolecular
hydrogen bonding in 5.10,11 The ratio of trans and cis isomers
was 71:29. The cis and trans isomers could be easily separated
by column chromatography.
The optical resolution of the isomers was then carried out.
Kita et al. reported kinetic resolution of ( )-trans-2-pyridylcy-
clohexanols using chiral 3β-acetoxyetienic acid, DCC and
DMAP12,13. Zhou reported a convenient method to obtain
Experimental
Solvents and reagents were obtained from commercial sources and
used without further purification. Melting points were determined on
a Mettler FP5 melting point apparatus and are uncorrected. NMR
spectra were recorded on Bruker DRX 400 MHz spectrometer using
DMSO-d6, CDCl3 as solvent, and tetramethylsilane (TMS) as internal
standard. Optical rotations were measured with a JASCO P-1020
* Correspondent. E-mail: yanhong0809@163.com

350 JOURNAL OF CHEMICAL RESEARCH 2011
automatic polarimeter. High resolution mass spectra were recorded on
Applied Biosystems Mariner System 5303. Enantiomeric excess (e.e.)
determination was carried out using HPLC with a Chiralcel AS-H and
AD-H column on an Agilent 1100 Series HPLC instrument.
(1S,2R)-trans-2-(quinolin-2-yl)cyclohexanol (4): M.p. 155°C.
D
[α]27 = –23.7 (c 0.42, CHCl3); >99% ee. (Chiralcel AS-H column,
i-PrOH/hexane 10/90, 1.0 mL min−1, 254nm: t(1S, 2R) = 7.2 min, t(1R, 2S)
=
9.1 min)].
The reduction of ketone: NaBH4 (0.418 g, 11 mmol) was added to
a solution of ketone 3 (2.25 g, 10 mmol) in EtOH (50 mL) at 0 °C, and
the mixture was stirred for 0.5h at room temperature. Then, the sol-
vent was removed under vacuum. Water was added to the residue and
the mixture was extracted with CH2Cl2. The CH2Cl2 solution was dried
over anhydrous Na2SO4 and evaporated in vacuum to give the product
(cis and trans) as a diastereomeric mixture. The cis and trans isomers
could be easily separated by column chromatography and their
(1R,2R)-cis-2-(quinolin-2-yl)cyclohexanol (5):A solution of DEAD
(3.0 mmol) in benzene (20 mL) was slowly added under a N2 atmo-
sphere to the mixture of (1S,2R)-trans-2-(quinolin-2-yl)cyclohexanol
(4) (454mg, 2.0 mmol), p-NO2C6H4COOH (502 mg, 3.0 mmol) and
PPh3 ( 786 mg, 3.0 mmol) in 30 mL benzene at 0 °C. The mixture was
stirred at room temperature for 24h. The solvent was removed under
reduced pressure and the residue was immediately subjected to flash
chromatography to give (1R,2R)-cis-2-(quinolin2-yl)cyclohexyl-
4-nitrobenzoate. The resulting carboxylic esters were dissolved in
MeOH (20 mL) and K2CO3 (1.38 g, 10 mmol) was added. The solu-
tion was stirred under reflux for 3 h. The reaction mixture was concen-
trated in vacuo to dryness and then diluted with water (120 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was
successively washed with KOH (1N), H2O and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo to give the white crystalline
solid (1R,2R)-cis-2-(quinolin-2-yl)cyclohexanol 5 in 91% yield.
M.p.150–152 °C [α]26D = +19.3 (c 0.78, CHCl3).
structure was confirmed by NMR.
( )-trans-2-Quinolin-2ylcyclohexanol (4):
10
M.p. 129–131 °C
(lit.10:129–130 °C). 1H NMR (400 MHz, CDCl3): δ8.10 (d, J = 8.6 Hz,
1H), 8.04 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.68 (td,
J = 7.6, 1.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz,
1H), 4.58 (br, 1H), 4.15 (td, J = 10.0, 4.1 Hz, 1H), 2.86 (td, J = 10.6,
3.0 Hz, 1H), 2.16–2.19 (m, 2H), 1.84–1.86 (m, 2H), 1.44–1.54 (m,
4H).
( )-cis-2-Quinolin-2ylcyclohexanol (5):11 M.p.123–124 °C (lit.11:
126 °C). 1H NMR (400 MHz, CDCl3): δ8.10 (d, J = 8.3 Hz, 1 H), 8.01
(d, J = 8.3 Hz, 1 H), 7.78 (d, J = 7.9 Hz, 1 H), 7.69 (t, J = 8.3 Hz, 1 H),
7.51 (t, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 6.53 (brs, 1 H), 4.45
(s, 1 H), 2.88–2.92 (m, 1 H), 2.03–2.09 (m, 2 H), 1.84–1.87 (m, 2 H),
1.63–1.73 (m, 2 H), 1.45–1.55 (m, 2 H).
[(1S,2R)-trans-2-Quinolin-2ylcyclohexan-1-oxy]diphenyl
phos-
phine (6): n-BuLi (2.5 M in hexane, 0.52 mL) was added to a
Schlenkflaskcontaining(1S,2R)-trans-2-(quinolin-2-yl)cyclohexanol
4 (297 mg, 1.31 mmol) in THF (5 mL) at 0 °C. The reaction mixture
was allowed to warm to room temperature and stirred for 1 h.
The reaction was then cooled to 0 °C and chlorodiphenylphosphine
(0.27 mL, 1.44 mmol) was added using a syringe. The reaction mix-
ture was again allowed to warm to room temperature and stirred for
3 h. The solvent was removed in vacuo, and the reaction was diluted
with 95:5 hexane-AcOEt (1.5 mL). The resulting slurry was loaded
onto a plug of silica and purified by flash chromatography (hexane/
AcOEt = 95:5) to yield 6 as a pale yellow oil.
Resolution of 2-(quinolin-2-yl)cyclohexanol with DBTA: DBTA
(25.6 g, 71.5 mmol) was added to compound 4 (16.2 g, 71.4 mmol) in
a mixed solvent (250 mL ethanol and 250 mL petroleum ether) at
0 °C, and the reaction mixture was heated for several minutes until
it became clear. Then it was allowed to room temperature and kept
stirring overnight. A white solid precipitated and was collected by
filtration and washed with a small amount of petroleum ether (30 mL).
The solid was crystallised a second time by adding 350 mL of ethanol
and 150 mL of petroleum ether and then heating to reflux and cooling
to room temperature. The process was repeated three more times with
280 mL and 200 mL, 180 mL and 100 mL, 130 mL and 100 mL of
ethanol and petroleum ether (all wash with 10 mL of petroleum ether)
respectively. After drying in vacuo for 2h, the final diastereomeric salt
precipitated and filtered as a white solid (3.2 g). It was dissolved in
CH2Cl2 (25ml) and 1M KOH(10 ml). The mixture was stirred for
30 min, and the organic layer was dried over anhydrous MgSO4 and
evaporated in vacuum to give (1S,2R)-4 as white solid.
[(1S,2R)-trans-2-Quinolin-2ylcyclohexan-1-oxy]diphenyl
phos-
phine (6): [α]26D = +26.1 (c 0.10, CHCl3); 1H NMR (400 MHz, DMSO-
d6): δ8.16 (d, J = 8.4 Hz, 1 H), 7.88–7.91 (m, 2 H), 6.70 (m, 1 H), 7.54
(t, J = 7.9 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.29–7.31 (m, 5 H), 6.89
(t, J = 7.9 Hz, 1 H), 6.66 (t, J = 7.7 Hz, 1 H), 6.50 (t, J = 7.5 Hz, 1 H),
4.39–4.44 (m, 1 H), 3.10–3.16 (m, 1 H), 2.16–2.19 (m, 1 H), 1.69–
1.92 (m, 3 H), 1.35–1.52 (m, 4 H); 13C NMR (100 MHz, DMSO-d6):
δ24.4, 25.0, 32.1, 34.3, 53.9 (d, J = 6.2 Hz), 82.5 (d, J = 20.1 Hz),
121.7, 125.6, 126.9, 127.2, 127.3, 127.6, 128.1, 128.2, 128.5, 128.6,
128.8, 129.0, 129.1, 129.4, 129.7, 136.1, 141.7 (d), 143.0 (d, J = 17.1

JOURNAL OF CHEMICAL RESEARCH 2011 351
Hz), 147.4, 163.6; 31P NMR (162 MHz, DMSO-d6): δ105.8; HRMS
Calcd for C27H27NOP (M+1) 412.183. Found: 412.184.
added subsequently. The reaction mixture was stirred at room tem-
perature for 2 h. The solvent was removed under vacuum and the resi-
due was passed through a short silica gel column (EtOAc/hexanes =
1:9) to give an oily product. The enantiomeric excess of the product
was determined by HPLC (Chiralcel AD-H column, i-PrOH/hexane
10/90, 1.0 mL min−1, 254 nm: t(R) = 11.8 min, t(S) = 16.8 min). The
products of the allylic alkylations using ligands 6 and 7 were shown to
have [α]26D = –16.2 (c 0.48, CHCl3) and [α]26D = –17.1 (c 0.50, CHCl3)
respectively.
[(1R,2R)-cis-2-Quinolin-2ylcyclohexan- 1-oxy]diphenyl phosphine
(7): (1R,2R)-cis-2-(quinolin-2-yl)cyclohexanol 5 (68 mg, 0.30 mmol),
4,5-dichloro imidazole (62 mg, 0.45 mmol) were dissolved in CH2Cl2
(4 mL) to give a white suspension. Triethylamine (63 µl, 0.45 mmol)
was added to the reaction mixture to give a clear solution. The mixture
was cooled to 0 °C and N-ethyl-N-(diphenylphosphino)ethanamine
(116 mg, 0.45 mmol) dissolved in CH2Cl2 (2 mL) was added. The
cooling bath was removed and the solution was heated to reflux for
6 h until the reaction was complete (TLC). The mixture was then con-
centrated and directly purified by flash chromatography (hexane/
EtOAc = 10:1–15:1) to yield 7 as a white solid (80 mg, 65%).
Received 12 April 2011; accepted 27 May 2011
Paper 1100653 doi: 10.3184/174751911X13082269792294
Published online: 11 July 2011
[(1R,2R)-cis-2-Quinolin-2ylcyclohexan-1-oxy]diphenyl phosphine
1
(7): M.p. 70–72 °C, [α]25 = –265.5 (c 1.34, CHCl3); H NMR (400
D
MHz, DMSO-d6): δ8.15 (d, J = 8.6 Hz, 1 H), 7.91 (t, J = 8.1 Hz, 2 H),
7.71 (m, 1 H), 7.55 (t, J = 7.0 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 1 H),
7.32–7.40 (m, 5 H), 6.94 (m, 1 H), 6.58–6.68 (m, 4 H), 4.62–4.64
(m, 1 H), 3.20 (m, 1 H), 2.36–2.39 (m, 1 H), 2.04–2.07 (m, 1 H),
1.90–1.98 (m, 2 H), 1.73 (m, 1 H), 1.48–1.53 (m, 3H); 13C NMR (100
MHz, DMSO-d6): δ19.6, 23.8, 25.1, 31.5, 49.2 (d, J = 5.7 Hz), 79.0
(d, J = 19.8 Hz), 120.6, 125.7, 126.7, 127.4, 127.5, 127.6, 127.8,
128.3, 128.4, 128.5, 128.7, 128.9, 129.2, 129.6, 129.8, 130.8, 135.8,
141.9 (d), 143.2 (d), 147.1, 162.9; 31P NMR (162 MHz, DMSO-d6):
δ104.1; HRMS Calcd for C27H27NOP (M+1) 412.18248. Found:
412.18309.
Allylic alkylations with dimethyl malonate: CH2Cl2 (1mL) followed
by [(C3H5)PdCl]2 (2.3 mg, 0.0063 mmol) was added to a Schlenk flask
containing ligand 6 or 7 (5.1mg, 0.0125 mmol). The mixture was
stirred at room temperature for 1 h. Potassium acetate (1.2 mg) and the
allylic acetate (63 mg, 0.25 mmol) dissolved in 1 mL CH2Cl2 was
added to the reaction and the reaction solution was stirred at room
temperature for another 1 h. Dimethyl malonate (86 µL, 0.75 mmol)
and N,O-bis(trimethylsilyl)acetamide (186 µL, 0.75 mmol) were
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