Copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones using a chiral phosphine ligand

Article abstract of DOI:10.1016/j.tetasy.2011.09.003

A series of chiral phosphine PFAM and phosphine oxide POFAM ligands were studied for the copper-catalyzed asymmetric diethylzinc addition to enones. One of these ligands, PFAM2, was an efficient catalyst with a variety of enones to give conjugate addition

Full text of DOI:10.1016/j.tetasy.2011.09.003

Tetrahedron: Asymmetry 22 (2011) 1601–1604
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted
chalcones using a chiral phosphine ligand
Özdemir Dogan a, , Adnan Bulut b, , Savaßs Polat b, M. Ali Tecimer b
⇑
⇑
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b Department of Chemistry, Kırıkkale University, 71450 Kırıkkale, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2011
Accepted 8 September 2011
Available online 18 October 2011
A series of chiral phosphine PFAM and phosphine oxide POFAM ligands were studied for the copper-cat-
alyzed asymmetric diethylzinc addition to enones. One of these ligands, PFAM2, was an efficient catalyst
with a variety of enones to give conjugate addition products in up to 96% yield and 92% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
easily available acryloylferrocene6 by using the Gabriel–Cromwell
reaction.7
Asymmetric catalysis is a useful technique for enantioselective
C–C bond formation reactions.1 This method can provide large
amounts of the desired chiral products by using a small amount
of chiral catalyst. The chiral catalysts developed so far have some
limitations in terms of reaction dependence, substrate dependence,
operational difficulties, and in the synthesis of the chiral ligands.
Therefore, the development of new efficient chiral catalysts is
one of the active research areas in synthetic organic chemistry.
Among the various reactions that can be conducted in a catalytic
asymmetric manner, 1,4-conjugate additions (Michael additions)
have always attracted considerable attention due to their synthetic
utility.2 Many Cu- and Ni-catalyzed enantioselective additions of
Et2Zn to various enones have been reported. It is evident that in
numerous asymmetric conjugate additions, phosphine based chiral
ligands have been applied to advantage.3 In this respect, we have
developed PFAM (phosphino ferrocenyl aziridinyl methanol) li-
gands and their phosphine oxide POFAM ligands (Fig. 1). These
compounds are structurally similar to our previously reported chi-
ral FAM ligands.4 One of these ligands (POFAM6) was found to be
effective for the catalytic asymmetric synthesis of pyrrolidines by
1,3-dipolar cycloaddition reactions of azomethine ylides.5 Herein
we report another application of PFAM ligands, the asymmetric
Cu-catalyzed 1,4-conjugate addition of diethylzinc to various
enones.
In order to test the catalytic activity of these ligands in the
copper-catalyzed asymmetric conjugate addition of diethylzinc to
enones, chalcone 1a was used as the model substrate. Although
the ligand screening experiments revealed that PFAM1, POFAM2,
and PFAM5 (Table 1, entries 1–3) were the most promising ones
for forming the product with (S)-configuration, PFAM2 gave the
product in highest yield and ee with the (R)-configuration (Table 1,
entry 4). Therefore, further optimizations were carried out by using
this ligand. As can be seen from Table 1, different copper sources,
different solvents, different temperatures, and different concentra-
tions of the catalyst (ligand and metal) were tried. From these
experiments the use of 2.5 mol % chiral ligand and 1.5 mol %
Cu(OTf)2 with 1,2-dichloroethane (DCE) as the solvent at ꢀ20 °C
was found to be the optimum conditions.
After determining the optimum conditions, different substrates
were used in order to show the applicability of this catalyst. The re-
sults of these experiments were summarized in Table 2.
In the first series, we investigated the effect of both electron
donating (Table 2, entries 2, 3, and 7) and withdrawing groups
(Table 2, entries 4–6) on the R1 unit of the enone. With the
p-methyl group, product was formed in about the same ee as the
first substrate having no substituent but with a lower yield (entry
2). With a strong electron donor methoxy group, the yield was
about the same as the first substrate but this time the ee was lower
(entry 3). In the case of electron withdrawing groups, strong elec-
tron withdrawing trifluoromethyl group, the product was obtained
in the highest yield with a similar ee to the first substrate (entry 4).
Although a chlorine on the para-position of the substrate showed
no significant effect on the yield and ee (entry 5) of the reaction,
a bromine substituent formed the product in lower yield but
slightly better ee (entry 6) compared to the first substrate.
In the case of more bulky substituents on the R1 unit of the en-
one, ferrocenyl group formed the product in 83% yield with the
2. Results and discussion
Chiral phosphine PFAM and phosphine oxide POFAM ligands
(Fig. 1) were synthesized as reported previously5 starting from
⇑
Corresponding authors.
E-mail address: dogano@metu.edu.tr (Ö. Dogan).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.003

1602
Ö Dogan et al. / Tetrahedron: Asymmetry 22 (2011) 1601–1604
Et
Et
Et
Et
O
Et
Et
O
O
H
H
H
H
OH
H
H
OH
PPh2
PPh2
P
PPh2
R
P
R
P
R
R
R
R
O
O
O
O
Ph2
Ph2
Ph2
N
N
N
N
N
N
R
R
Fc
Fc
Fc
Fc
Fc
Fc
S
R
S
R
R
R
H
H
H
H
H
H
PFAM1
POFAM1
PFAM2
POFAM2
PFAM3
POFAM3
Et
Et
H
Et
H
Et
Et
Et
O
O
O
H
OH
H
OH
H
OH
H
OH
PPh2
PPh2
P
PPh2
P
P
R
R
R
R
R
R
OH
OH
Ph2
Ph2
Ph2
N
N
N
R
N
R
N
N
S
S
S
S
Fc
Fc
Fc
Fc
Fc
Fc
S
S
S
S
R
R
H
H
H
H
H
H
PFAM4
POFAM4
PFAM5
Fc = ferrocenyl
Figure 1. Structures of PFAM and POFAM ligands.
POFAM5
PFAM6
POFAM6
Table 1
Asymmetric ethyl addition to chalcone under different conditions
O
Et
*
O
chiral ligand
+
Et2Zn
Ph
Ph
Cu salt
Ph
Ph
Cu-salt,4h
Entry
Chiral ligand
Ligand (mol %)
Cu salt (mol %)
Temp (°C)
Solvent
Yielda (%)
eeb (%)
Config.c
1
2
3
4
5
6
7
8
PFAM1
POFAM2
PFAM5
PFAM2
PFAM2
PFAM2
PFAM2
PFAM2
PFAM2
PFAM2
PFAM2
12
12
12
12
12
12
12
12
6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl
10
10
10
10
10
10
10
10
5
0
0
0
0
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
66
51
71
75
70
70
70
85
68
69
89
10
14
14
50
18
12
24
60
56
72
88
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
CuCl2
0
0
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
ꢀ20
9
10
11
0
6
2.5
2.5
1.5
ꢀ20
ꢀ20
Toluene/DCE (3:1)
DCE
a
b
c
Isolated yield.
Determined by HPLC using a Chiralcel AD column.
Determined by comparing the literature data.
Table 2
Asymmetric ethyl addition to different enones
O
Et
O
PFAM2 (2.5 mol %)
+
Et2Zn
R1
R2
R1
*
R2
Cu(OTf)2 (1.5 mol %)
DCE, -20 °C, 4h
2a-n
1a-n
Entry
R1
R2
Substrate
Yielda (%)
eeb (%)
Optical rotation sign
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1g
1c
1d
1i
1h
1e
1f
1j
1k
1l
1m
1n
89
79
91
96
88
81
90
83
59
75
91
88
84
80
88
89
72
87
88
91
89
92
90
76
84
71
70
72
ꢀ
ꢀ
ꢀ
+
+
+
+
+
+
+
+
+
+
ꢀ
p-CH3C6H4
p-CH3OC6H4
p-CF3C6H4
p-ClC6H4
p-BrC6H4
m-CH3OC6H4
ferrocenyl
2-Naphthyl
1-Naphthyl
Ph
9
10
11
12
13
14
p-CH3OC6H4
p-ClC6H4
p-BrC6H4
Ph
Ph
Ph
m-CH3OC6H4
a
Isolated yield.
Determined by HPLC using a Chiracel AD column.
b

Ö Dogan et al. / Tetrahedron: Asymmetry 22 (2011) 1601–1604
1603
highest ee (entry 8). The 2-naphthyl substituted enone formed the
product in lowest yield but with a good ee (entry 9). The 1-naph-
thyl substituted enone, on the other hand, formed the product in
moderate yield and ee (entry 10).
(S), tR (–)-2a: 8.5 min for (R). All spectroscopic data are consistent
with those reported in the literature.8a–c
4.1.2. 1-Phenyl-3-p-tolylpentan-1-one 2b
In the second series, we investigated the effect of substituents
on the R2 unit of enone (Table 2, entries 11–14). p-Methoxyphenyl
substituted enone (entry 11) gave the product in the same yield as
the p-methoxyphenyl on R1 group (entry 3) but with a better ee.
For the p-bromo, p-chloro, and m-methoxy cases, the enantioselec-
tivity was around 70% and the yield varied between 80% and 88%.
Cyclohexenone was also tried as the substrate which gave the
product in 90% yield but with low ee (26%).
Using the general procedure, 2b was obtained as a pale yellow
oil (99 mg, 98% yield), ½a D25
¼ ꢀ3:8 (c 2.2, EtOH) for 85% ee; HPLC:
ꢂ
Chiralcel AD column, UV detection at 240 nm, eluent: hexane/2-
propanol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (+)-2b: 6.6 min for
minor enantiomer, tR (ꢀ)-2b: 8.9 min for major enantiomer. All
spectroscopic data are consistent with those reported in the
literature.8b
4.1.3. 3-(4-Methoxyphenyl)-1-phenylpentan-1-one 2c
Using the general procedure, 2c was obtained as a yellow solid
3. Conclusion
(98 mg, 91% yield), mp: 49–50 °C; ½a D25
¼ ꢀ6:4 (c 3.4, EtOH) for 72%
ꢂ
ee; HPLC: Chiralcel AD column, UV detection at 240 nm, eluent:
The application of chiral PFAM and POFAM ligands in Cu-cata-
lyzed diethylzinc additions to enones was investigated. Using
2.5 mol % of PFAM2 ligand with 1.5 mol % Cu(OTf)2), products were
obtained in up to 96% yield and 91% ee. The substituents on the b-
aryl group of the enone, in general, gave the products in good
yields and ee’s except for p-methoxy-substituted system, which
hexane/2-propanol = 95:5, flow 1.0 mL minꢀ1
, 20 °C, tR (+)-2c:
9.1 min for (S), tR (ꢀ)-2c: 13.2 min. for (R). All spectroscopic data
are consistent with those reported in the literature.8b,8c
4.1.4. 3-(4-(Trifluoromethyl)phenyl)-1-phenylpentan 1-one 2d
Using the general procedure, 2d was obtained as a yellow oil
formed the product in moderate ee. Substituents on the
a-aryl
(118 mg, 96% yield), ½a D25
¼ þ7:7 (c 3.6, EtOH) for 87% ee; HPLC:
ꢂ
group of the enone gave the products in good yields but moderate
ee’s except for the p-methoxy case, which formed the product in
good ee. The chiral ligand PFAM2 can be synthesized on a gram
scale and is stable for months with careful handling and storage;
otherwise it is air sensitive and labile to oxidation, slowly convert-
ing to POFAM2. The catalytic effect of these ligands for other asym-
metric reactions is currently under investigation in our laboratory
and will be reported in due course.
Chiralcel AD column, UV detection at 240 nm, eluent: hexane/2-
propanol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (ꢀ)-2d: 6.3 min for
the minor enantiomer, tR (+)-2d: 8.2 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.8a
4.1.5. 3-(4-Chlorophenyl)-1-phenylpentan-1-one 2e
Using the general procedure, 2e was obtained as a colorless oil
(96 mg, 88% yield), ½a D25
¼ þ0:6 (c 3.6, EtOH) for 88% ee; HPLC:
ꢂ
4. Experimental
Chiralcel AD column, UV detection at 240 nm, eluent: hexane/2-
propanol = 98:2, flow 0.5 mL minꢀ1, 20 °C, tR (+)-2e: 26.9 min for
(S), tR (ꢀ)-2e: 28.4 min for (R). All spectroscopic data are consistent
with those reported in the literature.8a
1H and 13C NMR samples were prepared in 1:1 CDCl3–CCl4 and
recorded at 400 MHz and 100 MHz, respectively. 1H NMR data are
reported as chemical shifts (d, ppm) relative to tetramethylsilane (d
0.00). Optical rotations were measured in a 1 dm cell using a
Rudolph Research Analytical Autopol III. The products were puri-
fied by flash column chromatography on Silica Gel 60 (Merck,
4.1.6. 3-(4-Bromophenyl)-1-phenylpentan-1-one 2f
Using the general procedure, 2f was obtained as oil (103 mg,
81% yield), ½a 2D5
¼ þ3:3 (c 1.9, EtOH) for 91% ee; HPLC: Chiralcel
ꢂ
230–400 mesh ASTM). TLC analyses were performed on 250 lm
AD column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (ꢀ)-2f: 23.0 min for the
minor enantiomer, tR (+)-2f: 29.0 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.8d
Silica Gel 60 F254 plates. Enantiomeric excess (ee) was determined
by chiral HPLC. 1,2-Dichloroethane (DCE) was distilled over CaH2
prior to use.
4.1. Representative procedure for enantioselective addition of
diethylzinc to enones
4.1.7. 3-(3-Methoxyphenyl)-1-phenylpentan-1-one 2g
Using the general procedure, 2g was obtained as a pale yellow
waxy oil (96 mg, 90% yield), ½a D25
¼ þ0:8 (c 2.3, EtOH) for 89% ee;
ꢂ
Under N2 atmosphere, chiral ligand PFAM2 (5 mg, 2.5 mol %) and
Cu(OTf)2 (2.17 mg, 1.50 mol %) were charged into DCE (900
After stirring the reaction mixture for 15 minutes, enone 1a
(83.4 mg, 0.40 mmol) in DCE (350 L) was added dropwise. The
reaction mixture was then cooled to ꢀ20 °C followed by the addition
of Et2Zn (500 L, from 1 M solution in toluene). The stirring was con-
lL).
HPLC: Chiralcel AD column, UV detection at 240 nm, eluent: hex-
ane/2-propanol = 95:5, flow 1.0 mL minꢀ1
,
20 °C, tR (+)-2g:
l
17.0 min, tR (ꢀ)-2g: 20.1 min. All spectroscopic data are consistent
with those reported in the literature.4e
l
tinued for 4 h at ꢀ20 °C. The reaction mixture was quenched with
sat. NH4Cl (20 mL) and the mixture was extracted with diethylether
(3 ꢁ 20 mL). The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. Upon purification by flash column
chromatography using silica gel (20:1, hexane/EtOAc), product 2a
was obtained in 89% yield (85 mg, 0.36 mmol).
4.1.8. 3-Ferrocenyl-1-phenylpentan-1-one 2h
Using the general procedure, 2h was obtained as a yellow oil
(115 mg, 83% yield), ½a D25
¼ þ67:0 (c 4.5, EtOH) for 92% ee; HPLC:
ꢂ
Chiralcel OD-H column, UV detection at 240 nm, eluent: hexane/
2-propanol = 98:2, flow 1.0 mL minꢀ1, 20 °C, tR (+)-2h: 13.8 min
for the major enantiomer, tR (ꢀ)-2h: 14.7 min for the minor
enantiomer. All spectroscopic data are consistent with those
reported in the literature.8c
4.1.1. 1,3-Diphenyl-1-pentanone 2a
Using the general procedure, 2a was obtained as a white solid
(87 mg, 92% yield); ½a D25
¼ ꢀ1:7 (c 3.2, EtOH) for 90% ee; HPLC:
ꢂ
4.1.9. 3-(Naphthalen-2-yl)-1-phenylpentan-1-one 2i
Chiralcel AD column, UV detection at 240 nm, eluent: hexane/2-
Using the general procedure, 2i was obtained as a pale yellow
propanol = 95:5, flow 1.0 mL minꢀ1,20 °C, tR (+)-2a: 7.0 min; for
solid (68 mg, 59% yield), ½a D25
¼ þ9:1 (c 2.1, EtOH) for 90% ee;
ꢂ

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Ö Dogan et al. / Tetrahedron: Asymmetry 22 (2011) 1601–1604
HPLC: Chiralcel AD column, UV detection at 240 nm, eluent: hex-
ane/2-propanol = 95:5, flow 1.0 mL minꢀ1
22.9 min for the minor enantiomer, tR (+)-2i: 29.1 min for the ma-
jor enantiomer. All spectroscopic data are consistent with those re-
ported in the literature.4e
Acknowledgments
,
20 °C, tR (ꢀ)-2i:
We thank the Scientific and Technical Research Council of
_
Turkey (TUBITAK, Grant No. TBAG-108T089) and the Middle East
Technical University Research Foundation for the financial
support.
4.1.10. 3-(Naphthalen-1-yl)-1-phenylpentan-1-one 2j
Using the general procedure, 2j was obtained as a solid (86 mg,
References
75% yield), ½a 2D5
¼ þ47:0 (c 2.8, EtOH) for 76% ee; HPLC: Chiralcel
ꢂ
AD column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (–)-2j: 18.5 min for the
minor enantiomer, tR (+)-2j: 20.4 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.8e
1. Reviews: (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994. Chapter 5; (b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.
Comprehensive Asymmetric Catalysis; Springer: New York, 1999; (c) Soai, K.;
Niva, S. Chem. Rev. 1992, 92, 833–856; (d) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101,
757–824; (e) Ojima, I. Catalytic Asymmetric Synthesis II; Wiley-VCH: New York,
2000.
2. For recent reviews on the asymmetric conjugate additions, see: (a)
Harutyunyan, S. R.; Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem.
Rev. 2008, 108, 2824; (b) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.;
Diéguez, M. Chem. Rev. 2008, 108, 2796; (c) Lopez, F.; Minnaard, J. A.; Feringa, B.
L. Acc. Chem. Res. 2007, 40, 179; (d) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
3. For selected phosphine ligands used in conjugate addition, see: (a) Soeta, T.;
Selim, K.; Kuriyama, M.; Tomioka, K. Adv. Synth. Catal. 2007, 349, 629; (b)
Kawamura, K.; Fukuzawa, H.; Hayashi, M. Org. Lett. 2008, 10, 3509; (c) Liu, L.-T.;
Wang, M.-C.; Zhao, W.-X.; Zhau, Y.-L.; Wang, X.-D. Tetrahedron: Asymmetry 2006,
17, 136; (d) Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153; (e)
Mizutani, H.; Degrado, S. J.; Hoveyda, A. M. J. Am. Chem. Soc. 2002, 124, 779; (f)
Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P. Tetrahedron: Asymmetry 1997, 8,
3987; (g) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron 1999, 55, 3843.
4. (a) Dogan, O.; Garner, P. P.; Bulut, A. Turk. J. Chem. 2009, 33, 443; Bulut, A.; Aslan,
A.; Izgü, E.; Dogan, O. Tetrahedron: Asymmetry 2007, 18, 1013; (c) Dogan, O.;
Koyuncu, H.; Garner, P. P.; Bulut, A.; Youngs, W. J.; Panzner, M. Org. Lett. 2006,
21, 4687; (d) Koyuncu, H.; Dogan, O. Org. Lett. 2007, 9, 3477; (e) Isleyen, A.;
Dogan, O. Tetrahedron: Asymmetry 2007, 18, 679; (f) Bulut, A.; Aslan, A.; Dogan,
O. J. Org. Chem. 2008, 73, 7373.
4.1.11. 1-(4-Methoxyphenyl)-1-phenylpentan-1-one 2k
Using the general procedure, 2k was obtained as a solid (97 mg,
91% yield), ½a 2D5
¼ þ5:3 (c 3.1, EtOH) for 84% ee; HPLC: Chiralcel AD
ꢂ
column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (–)-2k: 10.6 min for the
minor enantiomer, tR (+)-2k: 11.9 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.8d
4.1.12. 1-(4-Chlorophenyl)-1-phenylpentan-1-one 2l
Using the general procedure, 2l was obtained as a solid (96 mg,
88% yield), ½a 2D5
ꢂ
= +5.3 (c 3.7, EtOH) for 71% ee; HPLC: Chiralcel AD
column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (ꢀ)-2l: 30.6 min for the
minor enantiomer, tR (+)-2l: 39.0 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.3h
5. Eroksüz, S.; Dogan, O.; Garner, P. Tetrahedron: Asymmetry 2010, 21, 2535.
6. We have improved our initially reported method (Dogan, O.; Senol, V.; Zeytinci,
S.; Koyuncu, H.; Bulut, A. J. Organomet. Chem. 2005, 690, 430) for the synthesis of
this compound: AlCl3 (144 mg, 1.08 mmol) was weighed into a flame dried
10 mL flask. After cooling the flask to 0 °C under nitrogen atmosphere, Al(CH3)3
(540 lL, 1.08 mmol, 2 M heptane solution) was added dropwise. When the
addition is over, CH2Cl2 (2 mL) was added and stirred. In a different flask,
ferrocene (200 mg, 1.08 mmol) was dissolved in CH2Cl2 (10 mL) and then freshly
distilled acryloyl chloride (105 lL, 1.30 mmol) was added. After cooling this
4.1.13. 1-(4-Bromophenyl)-1-phenylpentan-1-one 2m
Using the general procedure, 2m was obtained as solid (107 mg,
84% yield), ½a 2D5
¼ þ4:6 (c 3.9, EtOH) for 70% ee; HPLC: Chiralcel AD
ꢂ
flask to 0 °C under nitrogen, the initially prepared Lewis acid mixture (AlCl3–
AlMe3) was added dropwise (over a period of about 30 min) by a syringe. Some
white solids remained in the Lewis acid reaction flask but this does not affect the
yield. As the Lewis acid was added, the color of the reaction flask became deep
blue. After the addition of the Lewis acid (30 min), TLC analysis showed no
ferrocene. The reaction mixture was hydrolyzed by careful addition of satd
NH4Cl solution (the mixture turns dark yellow). After separating the two layers,
the aqueous layer was extracted with ethyl acetate (10 mL). The combined
organic layers were dried over NaSO4, and concentrated. The crude product was
obtained in 91% yield (236 mg, 0.98 mmol) with respect to ferrocene. The 1H
NMR of crude product showed no impurities or side products therefore no
purification was necessary. This procedure can be applied to up to 10 g of
ferrocene.
column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (ꢀ)-2m: 33.4 min for the
minor enantiomer, tR (+)-2m: 42.6 min for the major enantiomer.
All spectroscopic data are consistent with those reported in the
literature.8d
4.1.14. 1-(3-Methoxyphenyl)-1-phenylpentan-1-one 2n
Using the general procedure, 2n was obtained as solid (86 mg,
80% yield), ½a 2D5
¼ ꢀ4:8 (c 2.2, EtOH) for 72% ee; HPLC: Chiralcel
ꢂ
7. Cromwell, N. H.; Babson, R. D.; Harris, C. E. J. Am. Chem. Soc. 1945, 65, 312.
8. (a) Takahashi, Y.; Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.; Imamoto,
T. J. Org. Chem. 2005, 70, 9009; (b) Wan, H.; Hu, Y.; Liang, Y.; Gao, S.; Wang, J.;
Zheng, Z. J. Org. Chem. 2003, 68, 8277; (c) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4,
3699; (d) Shi, M.; Wang, C.-J.; Zhang, W. Chem. Eur. J. 2004, 10, 5507; (e)
Shadakshari, U.; Nayak, S. K. Tetrahedron 2001, 57, 8185.
AD column, UV detection at 240 nm, eluent: hexane/2-propa-
nol = 95:5, flow 1.0 mL minꢀ1, 20 °C, tR (ꢀ)-2n: 29.3 min for the
minor enantiomer, tR (+)-2n: 32.7 min for the major enantiomer
All spectroscopic data are consistent with those reported in the
literature.8e