Enantioselective alkylation of β-keto phosphonates by direct use of diaryl methanols as electrophiles

Article abstract of DOI:10.1039/c2cc35262a

Enantioselective alkylation of β-keto phosphonates with diaryl methanols in the presence of catalytic amounts of copper(ii) trifluoromethanesulfonate and an optically active ligand gives the corresponding alkylated products in good to high yields with a high enantioselectivity.

Full text of DOI:10.1039/c2cc35262a

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COMMUNICATION
Enantioselective alkylation of b-keto phosphonates by direct use of diaryl
methanols as electrophilesw
Masashi Shibata, Masahiro Ikeda, Kazuki Motoyama, Yoshihiro Miyake and
Yoshiaki Nishibayashi*
Received 21st July 2012, Accepted 5th August 2012
DOI: 10.1039/c2cc35262a
Enantioselective alkylation of b-keto phosphonates with diaryl
methanols in the presence of catalytic amounts of copper(II)
trifluoromethanesulfonate and an optically active ligand gives
the corresponding alkylated products in good to high yields with
a high enantioselectivity.
propargylic alcohols may promote the enantioselective alkyl-
ation of simple alcohols with various carbon-centered nucleo-
philes, where copper complex and Brønsted acid cooperatively
activate carbon-centered nucleophiles and alcohols, respec-
tively. In fact, the alkylation of b-keto phosphonates pro-
ceeded enantioselectively. A preliminary result is described
herein.
The development of enantioselective carbon–carbon bond
forming reactions is of great importance in organic chemistry.
Among these reactions, asymmetric direct nucleophilic sub-
stitution reactions of alcohols with carbon-centered nucleo-
philes are expected to provide a useful method for the
construction of carbon–carbon bonds to generate optically
active centers and have attracted much attention from the
environmental and economical points of view because water is
the sole by-product of the transformations.1 Recently, the
enantioselective direct substitution reactions of allylic alcohols
with a variety of carbon-centered nucleophiles have been
extensively studied.2,3 Since our first successful example of
the enantioselective direct substitution reaction of propargylic
alcohols with acetone,4 we have reported asymmetric reactions
of propargylic alcohols with a variety of carbon-centered
nucleophiles.5,6 In sharp contrast, the use of simple alcohols
such as benzylic alcohols for asymmetric direct substitution
reactions has been undeveloped until now. Very recently,
several groups have studied these reactions extensively, but
applicable carbon-centered nucleophiles are limited to alde-
hydes, ketones, enamines and dienamines.7
Treatment of bis(4-methoxyphenyl)methanol (1a) with
3 equivalents of diethyl 2-oxocyclopentylphosphonate (2a)
in the presence of a catalytic amount of copper complex
Cu(OTf)2 with (3aR,3a0R,8aS,8a0S)-2,20-(cyclopropylidene)-
bis{3a,8a-dihydro-8H-indeno[1,2d]-oxazole} (3a) at ꢀ20 1C
for 10 min and then at room temperature for 65 h gave diethyl
1-(bis(4-methoxyphenyl)methyl)-2-oxocyclopentylphosphonate
(4a) in 95% yield with 84% ee (Table 1, Entry 1). This result is
in sharp contrast to the result when ethyl 2-oxocyclopentane-
carboxylate (5) was used as a carbon-centered nucleophile
under the same reaction conditions (87% yield, 46% ee). The
reaction was carried out in other solvents such as dichloro-
methane and tetrahydrofuran (THF), and unsatisfactory
results were observed in both cases (Table 1, Entries 2–3).
Other bis(oxazoline) ligands such as 3b and 3c did not work
effectively (Table 1, Entries 4–5). On the other hand, no
reaction occurred at all when 3d and 3e were used as
bis(oxazoline) ligands (Table 1, Entries 6–7). Only the use of
1.5 equivalents of 2a to 1a was enough to promote the
enantioselective alkylation (Table 1, Entry 8). The use of
5 mol% of Cu(OTf)2 substantially decreased the yield of 4a,
although the addition of 5 mol% of trifluoromethanesulfonic
acid (HOTf) dramatically improved the yield of 4a (Table 1,
Entries 9–10). These results indicate that HOTf plays an
important role in promoting the alkylation effectively.
Recently we have continuously studied the application of
cooperative catalytic reaction systems using distinct catalysts to
enantioselective reactions of propargylic alcohols with carbon-
centered nucleophiles such as aldehydes,8,9 a,b-unsaturated
aldehydes,10 b-keto esters11 and b-keto phosphonates.12
Unfortunately, in our reaction system, only propargylic alcohols
are available as substrates for direct substitution reactions. In
order to develop new cooperative dual catalytic reactions, we
have now envisaged that the use of simple alcohols in place of
Next, alkylation of a variety of diaryl methanols 1 was
carried out by using Cu(OTf)2 with 3a. Typical results are
shown in Table 2. The introduction of alkoxy substituents at
the benzene ring in 1 is necessary to promote the alkylation
smoothly. In all cases, the corresponding alkylated products
were obtained with
a high enantioselectivity (Table 2,
Entries 2–8). The highest enantioselectivity (90% ee) was
observed when 1g was used as a substrate (Table 2, Entry 7).
The use of 6-methoxy-2-naphthyl and thienyl groups as aromatic
moieties in 1 gave slightly lower enantioselectivities (Table 2,
Entries 9–10). An asymmetric diaryl methanol such as 1k reacted
Institute of Engineering Innovation, School of Engineering,
The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-8656, Japan.
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp; Fax: +81-3-5841-1175
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 891211. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc35262a
c
9528 Chem. Commun., 2012, 48, 9528–9530
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Table 1 Enantioselective alkylation of b-keto phosphonate (2a) with
alcohol (1a)a
with 2a under the same reaction conditions to give the corre-
sponding alkylated product (4k) as a mixture of two diastereo-
isomers with a high enantioselectivity (Table 2, Entry 11).
Unfortunately, no reaction occurred at all when bis(4-methy-
phenyl)methanol was used as a substrate. These results
indicate that the use of electron-rich aromatic moieties in 1
is necessary to promote the catalytic reaction.
Alkylation with other b-keto phosphonates also proceeded
smoothly to give the corresponding alkylated products with a
high enantioselectivity. Typical results are shown in Table 3.
When methyl, propyl, and butyl groups were used as ester
moieties in place of the ethyl groups in 2a, a similar high enantio-
selectivity was observed in all cases (Table 3, Entries 2–5). The
reaction of 1g with b-keto phosphonates bearing an indane
skeleton (2f) under the same reaction conditions gave the
corresponding alkylated product in 93% yield with 85% ee
(Table 3, Entry 6). The use of diethyl 2-oxotetrahydrofuran-
3-ylphosphonate and diethyl 3,3-dimethyl-2-oxocyclopentyl-
phosphonate under the same reaction conditions gave 4q and 4r
with a slightly lower enantioselectivities (Table 3, Entries 7–8).
The reaction with diethyl 2-oxocyclohexylphosphonate did
not proceed smoothly although a high enantioselectivity was
Entry
Solvent
Ligand
Yield of 4ab (%)
eec (%)
1
2
3
4
5
6
7
ClCH2CH2Cl
CH2Cl2
THF
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
3a
3a
3a
3b
3c
3d
3e
3a
3a
3a
95
68
29
46
14
0
0
61
9
84
86
74
80
48
—
—
85
87
86
8d
9e
10e,f
57
a
All reactions of 1a (0.15 mmol) with 2a (0.45 mmol) were carried out
in the presence of Cu(OTf)2 (0.015 mmol) and 3 (0.018 mmol) in
b
solvent (3.0 mL). Isolated yield. Determined by HPLC. 1.5 equiv.
c
d
e
of 2a were used. 5 mol% of Cu(OTf)2 and 6 mol% of 3a was used.
f
5 mol% of HOTf was added.
Table 3 Enantioselective alkylation of b-keto phosphonates (2) with
alcohol (1g)a
Entry Phosphonate
Yield of 4b (%) eec (%)
1
R3 = Et (2a) 87 (4g)
90
86
90
88
92
2d
3
R3 = Me (2b) 73 (4l)
n
R3 = Pr (2c) 95 (4m)
n
4
5
R3 = Bu (2d) 89 (4n)
Table 2 Enantioselective alkylation of b-keto phosphonate (2a) with
alcohols (1)a
i
R3 = Pr (2e) 93 (4o)
6e
(2f)
93 (4p)
85
7f
(2g)
(2h)
64 (4q)
78 (4r)
74
66
Entry Alcohol
Yield of 4b (%) eec (%)
1
2
3
4
Ar1 = Ar2 = p-MeOC6H4 (1a)
95 (4a)
82 (4b)
99 (4c)
87 (4d)
95 (4e)
88 (4f)
84
88
87
87
87
83
90
86
77
76
88j
Ar1 = Ar2 = p-EtOC6H4 (1b)
Ar1 = Ar2 = p-nPrOC6H4 (1c)
Ar1 = Ar2 = p-nBuOC6H4 (1d)
Ar1 = Ar2 = p-iPrOC6H4 (1e)
Ar1 = Ar2 = p-BnOC6H4 (1f)
8g
5
6d
7
Ar1 = Ar2 = 4-MeO-3-MeC6H3 (1g) 87 (4g)
Ar1 = Ar2 = 3,4-(MeO)2C6H3 (1h) 93 (4h)
Ar1 = Ar2 = 6-MeO-2-naphthyl (1i) 90 (4i)
9d
(2i)
(2j)
8 (4s)
88
42
8e
9f
10g Ar1 = Ar2 = 2-thienyl (1j)
11h Ar1 = 2-thienyl
85 (4j)
88 (4k)i
10d
59 (4t)
Ar2 = 6-MeO-2-naphthyl (1k)
a
All reactions of 1 (0.15 mmol) with 2a (0.45 mmol) were carried out
in the presence of Cu(OTf)2 (0.015 mmol) and 3a (0.018 mmol) in
a
All reactions of 1g (0.15 mmol) with 2 (0.45 mmol) were carried out
in the presence of Cu(OTf)2 (0.015 mmol) and 3a (0.018 mmol) in
b
ClCH2CH2Cl (3.0 mL). Isolated yield. Determined by HPLC. rt,
c
d
b
ClCH2CH2Cl (3.0 mL). Isolated yield. Determined by HPLC. rt,
c
d
e
f
g
h
i
120 h. 40 1C, 40 h. 50 1C, 100 h. 0 1C, 40 h. rt, 45 h. The ratio
of diastereoisomers is 1.7/1. The ee of the minor isomer is 64%.
e
f
g
j
120 h. rt, 40 h. 50 1C, 65 h. 40 1C, 65 h.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9528–9530 9529

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could not be realized by single catalysts. Further work is
currently in progress to apply this strategy to other reaction
systems.
This work was supported by the Funding Program for Next
Generation World-Leading Researchers (GR025) and
a
Grant-in-Aid for Scientific Research on Innovative Areas
‘‘Advanced Molecular Transformations by Organocatalysts’’
from MEXT, Japan.
Notes and references
1 For recent reviews on achiral direct substitution reactions of
alcohols with various nucleophiles, see: (a) J. Muzart, Tetrahedron,
2005, 61, 4179; (b) Y. Tamaru, Eur. J. Org. Chem., 2005, 2647;
(c) J. Muzart, Eur. J. Org. Chem., 2007, 3077; (d) E. Emer,
R. Sinisi, M. G. Capdevila, D. Petruzziello, F. De Vincentiis and
P. G. Cozzi, Eur. J. Org. Chem., 2011, 647.
Scheme 1 Proposed reaction pathway for the enantioselective alkylation
of b-keto phosphonates with alcohols.
2 For recent reviews on enantioselective substitution reactions of
allylic alcohols. see: (a) B. Sundararaju, M. Achard and
C. Bruneau, Chem. Soc. Rev., 2012, 41, 4467; (b) M. Bandini,
G. Cera and M. Chiarucci, Synthesis, 2012, 504.
3 For selected recent examples, see: (a) C. Garcıa-Yebra,
J. P. Janssen, F. Rominger and G. Helmchen, Organometallics,
2004, 23, 5459; (b) B. M. Trost and J. Quancard, J. Am. Chem.
Soc., 2006, 128, 6314; (c) M. G. Capdevila, F. Benfatti, L. Zoli,
M. Stenta and P. G. Cozzi, Chem.–Eur. J., 2010, 16, 11237;
(d) G. Jiang and B. List, Angew. Chem., Int. Ed., 2011, 50,
9471.
Scheme 2 Asymmetric induction of alkylation between a benzyl
4 Y. Inada, Y. Nishibayashi and S. Uemura, Angew. Chem., Int. Ed.,
2005, 44, 7715.
cation and copper–enolate complex.
5 For recent reviews on catalytic propargylic substitution reac-
tions of propargylic alcohols with various nucleophiles, see:
(a) Y. Miyake, S. Uemura and Y. Nishibayashi, ChemCatChem,
2009, 1, 342; (b) R. J. Detz, H. Hiemstra and J. H. van Maarseveen,
Eur. J. Org. Chem., 2009, 6263; (c) C.-H. Ding and X.-L. Hou,
Chem. Rev., 2011, 111, 1914; (d) Y. Nishibayashi, Synthesis, 2012,
489.
6 (a) H. Matsuzawa, Y. Miyake and Y. Nishibayashi, Angew. Chem.,
Int. Ed., 2007, 46, 6488; (b) H. Matsuzawa, K. Kanao, Y. Miyake
and Y. Nishibayashi, Org. Lett., 2007, 9, 5561; (c) K. Fukamizu,
Y. Miyake and Y. Nishibayashi, J. Am. Chem. Soc., 2008,
130, 10498; (d) K. Kanao, Y. Miyake and Y. Nishibayashi,
Organometallics, 2009, 28, 2920; (e) K. Kanao, Y. Miyake and
Y. Nishibayashi, Organometallics, 2010, 29, 2126.
7 For selected recent examples, see: (a) P. G. Cozzi, F. Benfatti and
L. Zoli, Angew. Chem., Int. Ed., 2009, 48, 1313; (b) Q.-X. Guo,
Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng and L.-Z. Gong, Org.
Lett., 2009, 11, 4620; (c) G. Bergonzini, S. Vera and P. Melchiorre,
Angew. Chem., Int. Ed., 2010, 49, 9685; (d) L. Zhang, L. Cui, X. Li,
J. Li, S. Luo and J.-P. Cheng, Chem.–Eur. J., 2010, 16, 2045;
(e) J. Stiller, E. Marques-Lopez, R. P. Herrera, R. Frohlich,
C. Strohmann and M. Christmann, Org. Lett., 2011, 13, 70;
(f) J. Xiao, K. Zhao and T.-P. Loh, Chem.–Asian. J., 2011,
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1563.
observed (Table 3, Entry 9). Only a moderate enantio-
selectivity was observed when acyclic phosphonates such as
diethyl 3-oxobutan-2-ylphosphonate (2j) were used (Table 3,
Entry 10). These results indicate that the use of b-keto
phosphonates bearing a 2-oxocyclopentyl moiety at the a-position
in 2 is necessary to obtain the corresponding alkylated products in
good to high yields with a high enantioselectivity.
A proposed reaction pathway is shown in Scheme 1. The
initial step is the formation of an enolate (A) generated in situ
from b-keto phosphonate 2 and Cu(OTf)2 bearing 3a. Sub-
sequent attack of A upon a benzyl cation (B), which is formed
from a diaryl methanol and HOTf, results in the formation of
the alkylated product (4).
After the conversion of 4a into the corresponding phosphonic
acid 6 and one recrystallization of 6, the enantiomerically pure 6
was isolated, and its absolute configuration was determined as
S by X-ray analysis.w To account for the enantioselective
formation of (S)-6, we propose transition states between the
benzyl cation and the copper–enolate complex in Scheme 2. In
this reaction system, the square-planar-like copper–enolate
proposed by Jørgensen and co-worker13 attacks the benzyl
cation from the Si-face of the enolate leading to the carbon–
carbon bond formation.
8 (a) M. Ikeda, Y. Miyake and Y. Nishibayashi, Angew. Chem.,
Int. Ed., 2010, 49, 7289; (b) K. Motoyama, M. Ikeda, Y. Miyake
and Y. Nishibayashi, Eur. J. Org. Chem., 2011, 2239.
9 R. Sinisi, M. V. Vita, A. Gualandi, E. Emer and P. G. Cozzi,
Chem.–Eur. J., 2011, 17, 7404.
10 M. Ikeda, Y. Miyake and Y. Nishibayashi, Organometallics, 2012,
31, 3810.
11 M. Ikeda, Y. Miyake and Y. Nishibayashi, Chem.–Eur. J., 2012,
18, 3321.
12 K. Motoyama, M. Ikeda, Y. Miyake and Y. Nishibayashi,
Organometallics, 2012, 31, 3426.
13 A. Kjærsgaard and K. A. Jørgensen, Org. Biomol. Chem., 2005,
3, 804.
In summary, we have found the copper- and Brønsted acid-
catalyzed enantioselective alkylation of b-keto phosphonates
by direct use of diaryl methanols as electrophiles to give the
corresponding alkylated products in excellent yields with high
enantioselectivities (up to 92% ee). We believe that the findings
described herein will open up not only a new type of enantio-
selective direct substitution reaction of simple alcohols
but also a new aspect of cooperative catalytic reactions
using distinct catalysts such as transition metal and Brønsted
acid catalysts to achieve more valuable transformations that
c
9530 Chem. Commun., 2012, 48, 9528–9530
This journal is The Royal Society of Chemistry 2012