Pd(II)-catalyzed asymmetric fluorination of α-aryl-α- cyanophosphonates with the aid of 2,6-lutidine

Article abstract of DOI:10.1055/s-2007-977437

We describe herein the catalytic asymmetric fluorination of α-cyanophosphonates using chiral Pd(H)-bisphosphine complexes. While metal complexes failed to promote the reaction alone, a reaction system involving Pd(II) and organic base such as 2,6-lutidine

Full text of DOI:10.1055/s-2007-977437

CLUSTER
1139
Pd(II)-Catalyzed Asymmetric Fluorination of a-Aryl-a-cyanophosphonates
with the Aid of 2,6-Lutidine
A
symmetric Fluor
e
ination of
C
n
yanophosph
-
onates ichi Moriya,a Yoshitaka Hamashima,a,b Mikiko Sodeoka*a,b
a
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
b
RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako 351-0198, Japan
Fax +81(48)4624666; E-mail: sodeoka@riken.jp
Received 12 December 2006
O
O
SO2Ph
Abstract: We describe herein the catalytic asymmetric fluorination
of a-cyanophosphonates using chiral Pd(II)–bisphosphine com-
plexes. While metal complexes failed to promote the reaction alone,
a reaction system involving Pd(II) and organic base such as 2,6-lu-
tidine was developed. The Pd(II) complex activates the substrates
through coordination of the nitrile group, and 2,6-lutidine abstracts
an acidic proton, thereby affording the desired fluorinated products
in good yields with up to 78% ee. The products may be useful as
novel physiological phosphate mimics in medicinal chemistry.
Pd cat.
solvent
(EtO)2P
CN
(EtO)2P
CN
+
F
N
∗
SO2Ph
R
F
R
1 (racemate)
2
3
Scheme 1
phates (ca. 6.5), the monofluorinated b-ketophosphonates
are expected to be a better surrogate of phosphates, which
hold promise as effective inhibitors of a series of
phosphatases.8 We planned to examine the reaction of a-
cyanophosphonates, because cyano group is also a useful
functional group, which can be transformed to various
functional groups such as carboxylic acids and primary
amines. Furthermore, in the light of the high affinity of a
nitrile group to late-transition-metal complexes,9 it is
anticipated that a-cyanophosphonates could be activated
by coordination to the cationic Pd complexes, allowing
the reaction with electrophilic fluorinating reagents.
Key words: asymmetric catalysis, fluorine, a-cyanophosphonate,
palladium, medicinal chemistry
It is well known that the incorporation of fluorine atoms
into biologically active compounds sometimes leads to a
significant improvement of physical and chemical proper-
ties of the parent compounds.1 For this reason, fluorinated
organic molecules are often examined in the field of
medicinal chemistry. Considering that such compounds
should have interaction with chiral biological molecules
such as enzymes, it is not surprising that the need for
optically active fluorinated compounds having a fluorine
atom at a stereogenic carbon center is rapidly increasing.2
In the last five years, the catalytic asymmetric fluorination
reaction has witnessed great progress.3 Development of
novel metal as well as organic catalysts allowed the effi-
cient fluorination reactions of b-ketoesters, b-ketophos-
phonates, a-cyanoacetates, oxindoles, and a-unbranched
aldehydes.4,5 However, the number of available chiral
fluorinated compounds is still limited. We believe that
further investigation is necessary to provide a variety of
optically active organofluorine compounds which have
the potential to be used as chiral fluorinated building
blocks in the design of novel drug candidates. As a part of
our continuing program on the synthesis of optically
active fluorinated compounds,6,7 we describe herein the
catalytic asymmetric fluorination of a-cyanophospho-
nates (Scheme 1).
OH2
OH2
P
P
2+
2TfO–
*
Pd
PAr2
PAr2
4
H
O
P
P
P
+
+
2TfO–
*
*
Pd
Pd
P
a: Ar = Ph
b: Ar = 4-MeC6H4
O
H
5
c: Ar = 3,5-Me2C6H3
Figure 1 Chiral palladium–bisphosphine complexes
The starting materials 1 examined in this paper were
prepared according to the reported procedure by coupling
reaction of substituted acetonitriles with diethyl chloro-
phosphate in the presence of LiHMDS or LDA as a strong
base.10 On the basis of our previous results,7 we initially
examined the reaction of 1a with N-fluorobenzenesulfon-
imide (NFSI, 2) under the influence of 4a or 5a (5 mol%
to Pd, Figure 1) using EtOH as a solvent (Table 1). Unlike
b-ketophosphonates, the reaction of 1a failed to proceed
under the conditions previously established (entries 1, 2).
We speculated that 1a might be activated through the co-
ordination of the nitrile group to the cationic Pd com-
plexes. But either Lewis acidity or Brønsted basicity of
these complexes was insufficient to abstract an a-proton
of the substrates which are considered less acidic than b-
ketophosphonates. We envisaged that addition of organic
Previously, we reported a highly enantioselective fluori-
nation reaction of b-ketophosphonates using a catalytic
amount of chiral palladium complexes 4 and 5.6b,d Since
the second pKa values of a-monofluorophosphonic acids
are reported to be similar to those of physiological phos-
SYNLETT 2007, No. 7, pp 1139–1142
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977437; Art ID: Y02006ST
© Georg Thieme Verlag Stuttgart · New York

1140
K.-i. Moriya et al.
CLUSTER
base would be effective to accelerate the abstraction of 1–6, alcoholic solvents were superior among the solvents
the acidic proton. Preferably, the base should be weak in tested. Reactions in aprotic organic solvents such as THF
basicity and nucleophilicity, which would be important to and dichloromethane gave 3a in high yield, but a drop in
suppress uncatalyzed racemic reaction and decomposition enantioselectivity was observed. Interestingly, the reac-
of NFSI as a result of the reaction with amines. Further- tion proceeded even in pure water, and the desired product
more, the base should be bulky to disfavor its coordination was isolated in good yield with enantioselectivity compa-
to the metal complexes. Among several candidates, we rable to that obtained in EtOH. Bulkier chiral bisphos-
found that the addition of 2,6-lutidine (6) was highly phine ligands were also examined, but the enantio-
effective in promoting the fluorination reaction smooth- selectivity was not improved (entries 7, 8). Finally, it was
ly.11,12 Thus, in the presence of 5a as a catalyst and one found that reaction temperature was important for better
equivalent of 6, the fluorination reaction of 1a reached asymmetric induction. As the temperature went down, the
completion at room temperature after only three hours, ee was improved significantly (entries 9, 10). The highest
and the desired product 3a was obtained in 89% yield with enantioselectivity of 66% was observed at –20 °C. Unfor-
48% ee (entry 4). As shown in entries 5 and 6, a stoichio- tunately, however, further improvement of the ee was not
metric amount of 2,6-lutidine was essential for high attained even when the reaction was carried out at –40 °C
chemical yield. Because 2,6-lutidine itself was able to (entry 11).
promote the reaction, although with relatively slow
reaction rate (entry 7), we next examined the use of a
Table 2 Further Optimization of the Reaction Conditions
weaker base such as 2,6-di-tert-butylpyridine (7) (entry
8). While enantioselectivity was slightly enhanced, the
Pd cat. 5
(5 mol% to Pd)
2,6-lutidine (1 equiv)
reaction rate was considerably retarded. Slow addition of
the base was also examined to minimize the undesired
racemic pathway (entry 9). Unfortunately, however,
improvement of the enantioselectivity was not observed,
suggesting that the reaction involving both Pd(II) com-
plexes and the base is much faster than that promoted by
only the base.
+
1a
2
3a
solvent
Entry Solvent
Ligand Temp
Time (h) Yield (%)ee (%)
1
2
MeOH
i-PrOH
THF
a
a
a
a
a
a
b
c
r.t.
3
3
95
90
94
89
35
90
85
85
94
95
96
44
47
33
31
13
41
43
30
58
66
65
r.t.
3
r.t.
3
In the presence of a stoichiometric amount of 2,6-lutidine,
further optimization of the reaction conditions including
solvents, ligands, and temperature was carried out. These
results are summarized in Table 2. As shown in entries
4
CH2Cl2
acetone
H2O
r.t.
3
5
r.t.
12
12
4
6
r.t.
Table 1 Initial Attempts in the Asymmetric Fluorination of 1a
7
EtOH
EtOH
EtOH
EtOH
EtOH
r.t.
Pd cat.
(5 mol% to Pd)
O
O
8
r.t.
4
NFSI (2) (1.5 equiv)
(EtO)2P
CN
(EtO)2P
CN
∗
EtOH, r.t.
9
a
a
a
0 °C
–20 °C
–40 °C
3
Ph
Ph
F
1a
3a
10
11
6
36
Me
N
Me
t-Bu
N
t-Bu
6
7
With these results in hand, we next examined the reactions
using various a-cyanophosphonates (Scheme 2).13 The
concurrent usage of the Pd complex 5a and 2,6-lutidine
was applicable to various a-aryl-a-cyanophosphonates.
The reactions of para- and meta-substituted substrates
(3b–d) proceeded smoothly, affording the desired prod-
ucts in excellent yields with moderate enantioselectivity
(24–44% ee). In the case of 1c and 1d, the reactions were
re-examined at –40 °C. As in the case of entry 11 of
Table 2, the ee was not improved, although the reaction
became slower (6 h; 3c: 92%, 17% ee, 3d: 88%, 37% ee).
In contrast, o-methyl-substituted substrate 1e was less
reactive, probably due to the possible steric interaction.
Thus, the reaction of 1e was slow even when the reaction
was carried out at 0 °C. The product 3e was obtained in
only 36% yield even after 48 hours (38% ee). Like 1a, 2-
naphthyl-substituted cyanophosphonate 1f underwent the
Entry Pd cat.
Base (mol%) Time (h)
Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
4a
5a
4a
5a
5a
5a
–
–
24
24
3
trace
trace
82
–
–
–
6 (100)
6 (100)
6 (50)
6 (25)
6 (100)
7 (100)
6 (100)a
47
48
51
54
–
3
89
24
24
24
4
50
38
62
5a
5a
21
53
45
3
85
a One equivalent of the base was added slowly over 3 h.
Synlett 2007, No. 7, 1139–1142 © Thieme Stuttgart · New York

CLUSTER
Asymmetric Fluorination of Cyanophosphonates
1141
L = solvent or –OH
fluorination reaction smoothly, giving the desired product
3f in 90% yield with 66% ee. In addition, 1-naphthyl-sub-
stituted compound 1g was also subjected to the reaction.
Although the reaction took 40 hours for completion, 1g
was converted into the fluorinated product 3g in excellent
yield with high enantioselectivity of 78%. Unfortunately,
however, this reaction system was not applicable to a-
alkyl-substituted substrates. For example, the reaction of
1h did not afford the corresponding fluorinated compound
even when the reaction was conducted at room tempera-
ture. Although further study is necessary to achieve broad
scope of the substrates and high enantioselectivity, it
should be noted that this is the first example of the
catalytic asymmetric synthesis of a-fluoro-a-cyanophos-
phonates, to our knowledge.14
P
P
L
2+
P
P
L
2+
P(O)(OEt)2
Pd
*
P(O)(OEt)2
*
Pd
NC
Ar
H
NC
2TfO–
TfO–
Ar
8
1
2,6-lutidine, TfOH
base 6
Pd cat.
NFSI
9
P
L
+
TfO–
Pd
*
+
3
P
N(SO2Ph)2
2,6-lutidine, HN(SO2Ph)2
10
11
Scheme 3 Assumed catalytic cycle
ative action to abstract an acidic proton of the substrate
allowed efficient transformation. Although further im-
provement of the enantioselectivity is required for practi-
cal use, this paper demonstrates the first method for the
synthesis of optically active a-fluoro-a-cyanophos-
phonates, which should find applications in medicinal
chemistry. Further investigation to enhance the reaction
efficiency and application to the drug design are under
way in our laboratory.
Pd cat. 5a (2.5 mol%)
2,6-lutidine (1 equiv)
+
1
2
3
EtOH, –20 °C
F
CN
F
CN
∗
∗
P(O)(OEt)2
P(O)(OEt)2
3b
3c
Me
Cl
98%, 44% ee
(3 h)
95%, 24% ee
(1 h)
F
CN
∗
F
CN
∗
P(O)(OEt)2
P(O)(OEt)2
Acknowledgment
3d
3e
Me
This research is financially supported by JSPS for Grant-in Aids for
Young Scientists (B) (YH). We also thank Dr. Takao Saito of
Takasago International Corporation for generous support.
Cl
97%, 41% ee
(1 h)
36% , 38% ee
(0 °C, 48 h)
F
CN
F
CN
∗
∗
P(O)(OEt)2
P(O)(OEt)2
References and Notes
3f
3g
90%, 66% ee
(1 h)
92%, 78% ee
(40 h)
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, 2004.
(b) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.;
Shimizu, M. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000. (c) Biomedical
Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J. R.;
Welch, J. T., Eds.; ACS Symposium Series 639, American
Chemical Society: Washington/DC, 1996.
CN
1h
no reaction (r.t., 12 h)
Ph
P(O)(OEt)2
Scheme 2 Pd(II)–2,6-lutidine-promoted asymmetric fluorination of
various a-cyanophosphonates
(2) (a) Asymmetric Fluoroorganic Chemistry: Synthesis,
Application, and Future Directions; Ramachandran, P. V.,
Ed.; ACS Symposium Series 746, American Chemical
Society: Washington/DC, 2000. (b) Mikami, K.; Itoh, Y.;
Yamanaka, M. Chem. Rev. 2004, 104, 1. (c) Iseki, K.
Tetrahedron 1998, 54, 13887.
(3) (a) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147.
(b) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119.
(c) Pihko, P. M. Angew. Chem. Int. Ed. 2006, 45, 544.
(4) (a) Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 2000,
39, 4359. (b) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545.
(c) Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15,
1007. (d) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.;
Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem. Int.
Ed. 2005, 44, 4204. (e) Kim, H. R.; Kim, D. Y. Tetrahedron
Lett. 2005, 46, 3115. (f) Bernardi, L.; Jørgensen, K. A.
Chem. Commun. 2005, 1324. (g) Kim, S. M.; Kim, H. R.;
Kim, D. Y. Org. Lett. 2005, 7, 2309. (h) Suzuki, S.; Furuno,
H.; Yokoyama, Y.; Inanaga, J. Tetrahedron: Asymmetry
2006, 17, 504.
Although details of the reaction mechanism are now under
investigation, we propose a working model of the catalyt-
ic cycle as shown in Scheme 3. Significant asymmetric in-
duction indicates that a Pd-coordinated carbanion such as
8 is formed as a key intermediate. Both Pd complexes 4
and 5 can provide a vacant orbital for the substrate coor-
dination, and push–pull-type action by the Pd(II) complex
and 2,6-lutidine promotes the proton abstraction of the
substrate (top left). The formed chiral nucleophile 8 reacts
with NFSI to produce the fluorinated product 3. The puta-
tive Pd–sulfonimide 10 undergoes the proton-exchange
reaction with 9, producing 11 as a final proton acceptor,
and thus the catalytic cycle is completed.
In summary, we have developed a novel catalytic asym-
metric fluorination reaction of a-cyanophosphonates. In
these reactions, the combined use of the cationic Pd(II)
complex and 2,6-lutidine was important, and their cooper-
Synlett 2007, No. 7, 1139–1142 © Thieme Stuttgart · New York

1142
K.-i. Moriya et al.
CLUSTER
(5) (a) Enders, D.; Hüttl, M. R. M. Synlett 2005, 991.
(b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard,
A.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 3703.
(c) Steiner, D. D.; Mase, N.; Barbas, C. F. III. Angew. Chem.
Int. Ed. 2005, 44, 3706. (d) Beeson, T. D.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 8826. (e) Huang, Y.;
Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051.
(6) (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.;
Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530.
(b) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.;
Tsuchiya, Y.; Moriya, K.; Goto, T.; Sodeoka, M.
Tetrahedron 2006, 62, 7168. (c) Hamashima, Y.; Takano,
H.; Hotta, D.; Sodeoka, M. Org. Lett. 2003, 5, 3225.
(d) Hamashima, Y.; Suzuki, T.; Shimura, Y.; Shimizu, T.;
Umebayashi, N.; Tamura, T.; Sasamoto, N.; Sodeoka, M.
Tetrahedron Lett. 2005, 46, 1447. (e) Suzuki, T.; Goto, T.;
Hamashima, Y.; Sodeoka, M. J. Org. Chem. 2007, 72, 246.
(f) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164. (g) For
preparation of the Pd complexes, see: Fujii, A.; Hagiwara,
E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
(7) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467.
(8) a-Fluorophosphonates have been used as mimics of a
phosphate moiety. For a general review, see: Berkowitz, D.
B.; Bose, M. J. Fluorine Chem. 2001, 112, 13.
(9) Ru: (a) Murahashi, S.-I.; Naoto, T.; Taki, H.; Mizuno, M.;
Takaya, H.; Komiya, S.; Mizuno, Y.; Oyasato, N.; Hiraoka,
M.; Hirano, M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117,
12436. Rh: (b) Sawamura, M.; Hamashima, H.; Ito, Y.
J. Am. Chem. Soc. 1992, 114, 8295. (c) Kuwano, R.;
Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000, 603, 18.
Pd: (d) Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833;
and references therein.
(11) For detailed discussion on the effect of additional organic
bases, see ref. 6e.
(12) Effective combination of Lewis acids and amines were
previously reported. For examples, see: (a) Itoh, K.;
Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
(b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.;
King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.;
Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem.
Soc. 2002, 124, 13097. (c) Kumagai, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632.
(13) Representative Procedure
To a mixture of a-cyanophosphonate 1a (25.3 mg, 0.1
mmol), NFSI (47.2 mg, 0.15 mmol), and the Pd complex 5a
(4.5 mg, 2.5 mol%) was added EtOH (0.2 mL) at –20 °C. At
this temperature, 2,6-lutidine (12 mL, 0.1 mmol) was added
dropwise, and the reaction mixture was stirred until
complete consumption of the starting material (TLC,
hexane–EtOAc = 2:1). Then, sat. aq NH4Cl was added for
quenching, and the products were extracted with EtOAc.
Usual workup, followed by flash column chromatography
(hexane–EtOAc = 2:1), afforded the fluorinated product 3a
as a colorless oil.
Compound 3a: 1H NMR (400 MHz, CDCl3): d = 1.30 (t,
J = 7.1 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 4.14–4.32 (m, 4
H), 7.46–7.51 (m, 3 H), 7.63–7.68 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 16.1 (d, J = 4.9 Hz), 16.2 (d, J = 5.8 Hz),
65.7 (d, J = 7.4 Hz), 65.9 (d, J = 7.4 Hz), 87.6 (dd, J = 173.5,
195.8 Hz), 114.4 (d, J = 28.0 Hz), 126.0 (t-like, J = 4.9 Hz),
128. 7 (d, J = 1.6 Hz), 130.1 (dd, J = 1.7, 20.7 Hz), 130.5. 19F
NMR (376 MHz, CDCl3, std: TFA): d = –90.95 (d, J = 87.2
Hz). HPLC (DAICEL CHIRALPAK AD-H, n-hexane–
IPA = 99:1, 1.0 mL/min, 254 nm): tR (major) = 43.0 min.,
tR (minor) = 47.0 min.
(14) For preparation of racemic a-fluoro-a-cyanophosphonates
by phosphorylation reaction, see: Yokoyama, Y.; Mochida,
K. Synthesis 1999, 1319.
(10) Iorga, B.; Ricard, L.; Savignac, P. J. Chem. Soc., Perkin
Trans. 1 2000, 3311.
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