ClickFerrophos: New chiral ferrocenyl phosphine ligands synthesized by click chemistry and the use of their metal complexes as catalysts for asymmetric hydrogenation and allylic substitution

Article abstract of DOI:10.1021/ol702519f

The new ferrocenyl P,P- and P,N-ligands 5 and 6 (collectively, "ClickFerrophos") were readily prepared in four steps using Click Chemistry methodology, starting from the commercially available aminoferrocene 1. Rhodium and ruthenium complexes of ClickFerrophos 5 were effective catalysts for the hydrogenation of alkenes and ketones, respectively, producing products with up to 99.7% ee. The analogous palladium complex with 6 worked well for asymmetric allylic alkylation.

Full text of DOI:10.1021/ol702519f

ORGANIC
LETTERS
2
007
Vol. 9, No. 26
557-5560
ClickFerrophos: New Chiral Ferrocenyl
Phosphine Ligands Synthesized by
Click Chemistry and the Use of Their
Metal Complexes as Catalysts for
Asymmetric Hydrogenation and Allylic
Substitution
5
Shin-ichi Fukuzawa,* Hiroshi Oki, Mitsuteru Hosaka, Jun Sugasawa, and
Satoshi Kikuchi
Department of Applied Chemistry, Institute of Science and Engineering, Chuo
UniVersity, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
fukuzawa@chem.chuo-u.ac.jp
Received October 15, 2007
ABSTRACT
The new ferrocenyl P,P- and P,N-ligands 5 and 6 (collectively, “ClickFerrophos”) were readily prepared in four steps using Click Chemistry
methodology, starting from the commercially available aminoferrocene 1. Rhodium and ruthenium complexes of ClickFerrophos 5 were effective
catalysts for the hydrogenation of alkenes and ketones, respectively, producing products with up to 99.7% ee. The analogous palladium
complex with 6 worked well for asymmetric allylic alkylation.
Chiral ferrocenes have been of interest especially in asym-
metric catalysis as chiral ligands. Ferrocenylphosphines are
effective ligands in transition-metal complexes catalyzing
complex catalysts and/or to be used in asymmetric reactions
for which conventional ligands are not effective.
“Click Chemistry” has recently drawn considerable atten-
tion as a powerful and efficient way to synthesize desired
compounds in high yields using a simple and benign
1
asymmetric reactions, often with high enantioselectivity. The
unique structure of ferrocenes allows one to design a variety
of chiral ferrocenyl phosphine ligands, which are useful tools
in metal-catalyzed asymmetric reactions. Although some
useful chiral ferrocenylphosphine ligands have already been
reported, it is still an interesting challenge to create new
ligands of this type in order to devise more effective metal
2
procedure. The Huisgen 1,3-dipolar cycloaddition of azide
and alkynes is the most intensively studied click reaction,
which yields 1,2,3-triazoles in high yields by just mixing
the starting compounds with a Cu(I) catalyst in an aqueous
solvent. The 1,2,3-triazole has recently generated interest as
3
a ligand for metal-catalyzed organic reactions. ClickPhos,
triazole-based monophosphine ligands, have been prepared
by Zhang et al. using Click Chemistry methodology, and
their palladium complexes have been demonstrated to work
(
1) For reviews chiral ferrocenes in asymmetric synthesis, see: (a)
Hayashi, T. Asymmetric Catalysis with Chiral Ferrocenylphosphine Ligands.
In Ferrocenes; Togni, A., Hayashi, T., Eds.; Wiley-VCH: Weinheim, 1995;
pp 105-142. (b) Togni, A. New Chiral Ferrocenyl Ligands for Asymmetric
Catalysis. In Metallocenes; Togni, A., Halterman, R. L., Eds.; Wiley-
VCH: Weinheim, 1998; Vol. 2 pp 689-721. (c) Colacot, T. J. Chem. ReV.
003, 103, 3101-3118. d) Sutcliffe, O. B.; Bryce, M. R. Tetrahedron:
Asymmetry 2003, 14, 2297-2325. (e) Array a´ s, R. G.; Adrio, J.; Carretero,
J. C. Angew. Chem., Int. Ed. 2006, 45, 7674-7715.
3a
effectively in Buchwald and Suzuki coupling reactions. We
2
(2) For reviews of Click Chemistry, see (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004-2021. (b) Gil, M.
V.; Ar e´ valo, M. J.; L o´ pez, OÄ . Synthesis 2007, 1589-1620.
1
0.1021/ol702519f CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

have succeeded in preparing the first new chiral 1,2,3-triazole
ferrocenyl-based P,P- and P,N-ligands (ClickFerrophos) by
this methodology and report their application in asymmetric
Scheme 2. Preparation of the P,N-Ligand 6 and P,P-Ligands
a,b
5
4
hydrogenation and allylic alkylation reactions.
The chiral triazoleferrocenyl-1,5-phosphine 5a was readily
prepared starting from commercially available (S)-ferrocenyl
5
amine (Ugi’s amine) 1 as illustrated in Scheme 1. The
Scheme 1. Preparation of ClickFerrophos 5a
The 1,5-disubstituted 1,2,3-triazole 7 was prepared by the
9
reaction of 3 with magnesium phenylacetylide. The prepara-
stereoselective ortho-lithiation of 1 followed by trapping with
iodine gave the o-iodoferrocenyl amine 2, whose amino
group was replaced by the azide group with retention of
configuration on treatment with methyl iodide and sodium
6
azide. The o-iodoferrocenyl azide 3 was subjected to Click
Chemistry under Sharpless conditions (phenylacetylene,
7
Figure 1. X-ray structure of ClickFerrophos 5a.
CuSO
4
2
/sodium ascorbate in t-BuOH/H O) to give the
corresponding 1,4-disubstituted 1,2,3-triazole 4 in good yield.
The treatment of 4 with 2 molar equiv of n-BuLi in THF at
tion of monophosphine 8 was achieved by the sequence of
lithiation and trapping with Ph PCl. However, the 1,6-
2
diphosphine could not be obtained from 7 or 8 (Scheme 3).
-
2
78 °C followed by trapping with 2 molar equiv of Ph PCl
gave the 1,5-diphosphine 5a in moderate yield (Scheme 1).
The lithiation of the triazole ring was critical and led to the
successful preparation of the 1,5-diphosphine ligand (Tania-
8
phos-type ligand). The monophosphine 6 could be prepared
2
by the reaction of 4 using 1 equiv of n- BuLi and Ph PCl in
Scheme 3. Preparation of the P,N-Ligand 8
diethyl ether (Scheme 2) and led to the diphosphine 5a,b by
stepwise lithiation of the triazole ring in THF and trapping
with R PCl (R ) Ph, Cy). Thus, different phosphinyl groups
2
could be introduced onto the cyclopentadienyl and the
triazole ring with the (S,Rp) configuration. The structure of
5a was confirmed by X-ray crystallography (Figure 1).
(
3) (a) Dai, Q.; Gao, W.; Liu, D.; Kapes, L. M.; Zhang, X. J. Org. Chem.
Thus, new ferrocenyl phosphine ligands containing a
triazole ring were prepared. Their ability to act as ligands in
the asymmetric hydrogenation of alkenes was investigated.10
Some rhodium complexes using 5a as a ligand were first
screened in the hydrogenation of methyl R-acetamidocin-
namate (11a). The reaction was usually performed at room
2
006, 71, 3928-3934. (b) Dets, R. J.; Heras, S. A.; de Gelder, R.; van
Leeuwen, P. W. N. M.; Hiemstra, H.; Reek, J. N. H.; van Maarseveen, J.
H. Org. Lett. 2006, 8, 3227-3230.
(4) Examples of achiral ferrocenyl 1,2,3-triazoles: (a) Casas-Solvas, J.
M.; Vergas-Berenguel, A.; Capit a´ n-Valley, L. F.; Francisco, S.-G. Org. Lett.
004, 6, 3687-3690. (b) Zhao, Y.-B.; Yan, Z.-Y.; Liang, Y.-M. Tetrahedron
Lett. 2006, 47, 1545-1549.
5) The ferrocenyl amine 1 can be prepared on a large scale (20g scale)
by resolution of the racemate. Gokel, G. W.; Ugi, I. K. J. Am. Chem. Soc.
972, 49, 294-296.
6) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J.
Am. Chem. Soc. 1970, 92, 5389-5393.
7) Rostovsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596-2599.
2
(
2 2
temperature for 2 h in MeOH/toluene or MeOH/CH Cl
1
(
(8) Uhlmann, P.; Felding, J.; Vesø, P.; Begtrup, M. J. Org. Chem. 1997,
62, 9177-9181.
(
(9) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237-1240.
5558
Org. Lett., Vol. 9, No. 26, 2007

under atmospheric pressure hydrogen using 1 mol % of
rhodium complex and a ligand. The results are summarized
in Table 1. Any typical cationic rhodium complex examined
Table 2. Asymmetric Hydrogenation of Alkenes Catalyzed by
[
/5 Complexesa
2 4
Rh(nbd) ]BF
Table 1. Asymmetric Hydrogenation of Methyl
R-Acetamidocinnamate Catalyzed by Rhodium/5a Complexesa
b
%, ee (config)c
entry
1
alkene
time (h)
conv (%)
10a
10a
10b
12
13a
13b
14a
14a
14b
15
2
3.5
2
24
24
24
12
2.5
12
24
>99
100
>99
>99
>99
>99
>99
100
>99
58
99 (R)
86 (R)
98 (R)e
84 (R)
99.3 (R)
98 (R)e
91 (S)
d
2
3
4
5
6
7
%, convb
%, eec
entry
Rh complex
1
2
3
4
[Rh(nbd)Cl]2
5
94
88
98
98
99
97
99
99
99
67
[Rh(cod)2]BF4
[Rh(nbd)2]PF6
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
[Rh(nbd)2]BF4
d
8
91 (R)
>99
>99
>99
>99
>99
>99
>99
0
e
9
0
99.7 (S)
f
34 (R)e
1
d
5
a
e
Alkene (1 mmol), [Rh(nbd)2]BF4 (0.010 mol), 5a (0.011 mol), MeOH/
6
b
1
f
toluene (2/2 mL); rt, H2 (1 atm). Determined by H NMR from the crude
7
reaction mixture. c Determined by HPLC (Chiralcel AD-H, OD) or GC
g
8
h
d
(
Chiraldex G-TA, CP-Chirasildex-CB). Data from reference 12c using 9
as a ligand. Conversion and % ee were determined after esterification with
MeOH/SOCl2. The reaction was performed under 5 atm of hydrogen.
e
9
f
i
1
0
a
1
0a (1 mmol), Rh (0.010 mol), 5a (0.011 mol), MeOH/toluene (2/2
b
1
mL); rt, 2 h, H2 (1 atm). Determined by H NMR from the crude reaction
c
d
mixture. Determined by HPLC (Chiralcel AD-H). MeOH/toluene (1/5
mL). MeOH/toluene (0.4/4 mL). f MeOH/CH2Cl2 (0.4/4 mL). g The enan-
tiomer of 5a (R,Sp) was used as a ligand, and the configuration of the product
was S. 5b (0.011 mol) was used as a ligand. i 6 (0.011 mol) was used as
a ligand.
comparison (entries 2 and 8). The reaction with R-acetami-
docinnamic acid (10b) proceeded smoothly to give the
e
h
here worked well to give (R)-N-acetylphenylalanine methyl
ester (12a) in excellent yield with high enantioselectivities
(
up to 99% ee) (entries 2-4). The ratio of MeOH/toluene
(
1/10-1/1) had little effect on yield and enantioselectivity,
2 2
and the reaction in MeOH/CH Cl (1/10) also gave satisfac-
11
tory results (entries 5-7). The use of ent-5a gave the
S-isomer in the reaction with 11a with 99% ee (entry 8).
The use of 5b resulted in lower selectivity that 5a (entry 9).
It must be noted that the reaction with Rh/monophosphine
6
complex did not proceed at all (entry 10), suggesting that
the P,P-chelate complex was the active catalyst, not the P,N-
chelate complex. The P,P-chelate complexation could be
observed in the 31P NMR spectrum; two signals of uncoor-
dinated 5a appearing at -35.1 (d, J ) 32.4 Hz) and -23.8
Figure 2. Taniaphos and examined alkenes.
(
d, J ) 32.4 Hz) ppm shifted +7.4 (dd, J ) 27.8, 153.0 Hz)
and + 15.0 (dd, J ) 27.8, 162.3 Hz), respectively, upon
product quantitatively with an excellent % ee value (entry
coordination to rhodium.1 We chose [Rh(nbd)
2a
2 4
]BF as a
3
) similar to its ester 10a. The hydrogenation with other
catalyst and MeOH/toluene (1/1) as a solvent in the asym-
metric hydrogenation of alkenes, and the reaction was
similarly performed at room temperature under atmospheric
pressure hydrogen for various times. The results are shown
enamides such as 12 and 13a,b proceeded but slowly to give
the corresponding product in good to excellent enantiose-
lectivities (up to 99.3% ee) (entries 4-6). This catalyst was
also applied to the hydrogenation of itaconic acid and its
methyl ester 14a,b, giving high % ee values (up to 99.7%
ee) (entries 7 and 9).
1
2
in Table 2. The results of using a Knochel’s Taniaphos 9
Figure 2) with (R,Rp) stereochemistry and which was
structurally similar to 5a, are also shown in Table 2 for
(
We next applied ClickFerrophos 5a to the ruthenium
complex-catalyzed asymmetric hydrogenation of ketones.13
(10) For reviews of Rh-catalyzed asymmetric hydrogenation, see: (a)
Ohkuma, T.; Kitamura, M.; Noyori, R. Asymmetric Hydrogenation. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; pp 1-110. (b) Chi, Y.; Tang, W.; Zhang, X. Rhodium-Cata-
lyzed Asymmetric Hydrogenation. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 1-31.
(12) (a) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel,
P. Angew. Chem., Int. Ed. 1999, 38, 3212-3214. (b) Ireland, T.; Tappe,
K.; Grossheimann, G.; Knochel, P. Chem. Eur. J. 2002, 8, 843-852. (c)
Tappe, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 91-102. (d)
Chen, W.; Roberts, S. M.; Whittall, J.; Steiner, A. Chem. Comm. 2006,
2916-2918.
(
11) The enantiomer of 5a was prepared from enantiomer of 1 by the
same procedure as shown in Scheme 1.
Org. Lett., Vol. 9, No. 26, 2007
5559

The hydrogenation was carried out using 0.5 mol % of [Ru-
cod)(metallyl) ]/HBr and ligand 5a in EtOH under 10 atm
of hydrogen at 50 °C. The results of the reaction with
representative keto esters (16-19, Figure 3) and dibenzoyl-
(
2
Scheme 4. Asymmetric Reduction of â-Diketone 21
Last, the palladium-catalyzed asymmetric allylic alkylation
of (()-(E)-1,3-diphenyl-2-propenyl acetate 22 with dimethyl
1
4
15
malonate 23 was examined using P,N- ligand 6 and 8.
The reaction was carried out at room temperature for 18 h
Figure 3. Examined keto esters.
3
in CH
(
(
2
Cl
6, 8) in the presence of N,O-bis(trimethylsilyl)acetamide
BSA) and a catalytic amount of potassium acetate as bases.
2
using 5 mol % of [Pd(η -C
3 5 2
H )Cl] and a ligand
methane (20) (a typical 1,3-diketone) are summarized in
Table 3 including results using 9 for comparison (entries 2,
The complex with 6 quantitatively yielded the product 24
with 79% ee, while 8 was not effective for the reaction,
giving the product with poor % ee (Scheme 5).
Table 3. Asymmetric Hydrogenation of Ketones Catalyzed by
[Ru(cod)(metallyl)
2
]/HBr/5a Complexesa
Scheme 5. Asymmetric Allylic Alkylation Catalyzed by Pd/6
and 8 Complexes
b
ee (%) (config)c
entry
1
ketone
time (h)
conv (%)
16
16
17
17
18
18
19
8
13
12
14
24
14
24
>99
100
>99
100
>99
100
>99
93 (R)
80 (R)
98 (S)
88 (S)
84 (R,R)e
86 (R,R)
30 (R)
d
2
3
4
d
In conclusion, ClickFerrophos 5 was successfully used as
a ligand in the rhodium and ruthenium complex-catalyzed
hydrogenation of alkenes and ketones, respectively, produc-
5
6
d
7
1
6
ing products with up to 99.7% ee. The ligand can be
prepared by simple procedure of Click Chemistry which
allows an efficient fine-tuning of the ligand. The variation
of chiral ferrocenyl ligands which have a triazole backbone
would have an potential in asymmetric synthesis.
a
Ketone (2 mmol), [Ru(cod)(metallyl)2]/HBr(0.010 mol), 5a (0.011 mol),
b
1
solvent (4 mL); 50 °C, H2 (10 atm). Determined by H NMR from the
crude reaction mixture. Determined by HPLC (Chiralcel AD-H, OD-H)
or GC (Chiraldex G-TA, CP-Chirasil dex-CB). Data from ref 12c using
as a ligand. Diastereomeric excess (>99%).
c
d
e
9
Acknowledgment. This study was financially supported
by a Grant-in-Aid for Scientific Research from the Japan
Society for the Promotion of Science (JSPS) (No. 16550044).
4
, and 6). In the reaction with ethyl acetoacetate (16) and
ethyl benzoylacetate (17), ruthenium complex with 5a
worked effectively to give high enantioselectivities (entries
1
-4). The reaction with the ketoester 18 gave the product
Supporting Information Available: Full experimental
as almost a single diastereomer with high % ee (entry 5).
The reaction with ethyl benzoylformate (19), a typical
R-ketoester, resulted in poor enantioselectivity giving (R)-
ethyl mandelate in 30% ee (entry 7). High diastereoselectivity
1
13
procedures, characterization data, and H and C NMR
spectra for new chiral ferrocenyl compounds 2-8; crystal-
lographic datafor 5a, 6, and 8 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(>99% de) and enantioselectivity (99% ee) were also
OL702519F
observed in the reaction with the 1,3-diketone 20, the
corresponding diol 21 being obtained as almost a single
diastereomer with 99% ee (Scheme 4). It was noteworthy
that the stereochemical outcomes in the hydrogenations of
(14) For reviews of asymmetric allylic substitution, see: (a) Pfalz, A.;
Lautens, M. Allylic Substitution Reactions; Springer: Berlin, 2000. (b) Guiry,
P. J.; Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497-537.
(15) The chiral pyrazole ferrocenylphosphine ligands, which are similar
10a and ketones 16-18 were the same as the results obtained
to 6 and 8, have been applied to the asymmetric allylic substitutions. (a)
Togni, A.; Burckhart, Urs.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J.
Am. Chem. Soc. 1996, 118, 1031-1047. (b) Burckhart, Urs.; Baumann,
M.; Trabesinger, G.; Gramlich, V.; Togni, A. Organometallics 1997, 16,
with 9, probably due to the structural similarity of these
ligands (the reaction with 14a gave the reverse stereochem-
istry).
5
252-5259.
(16) For recent examples of efficient chiral ferrocenylphosphine ligands
(
13) For reviews of Ru-catalyzed asymmetric hydrogenation, see: (a)
in asymmetric hydrogenations, see: (a) Boaz, N. W.; Mackenzie, E. B.;
Debenham, S. D.; Large, S. E.; Ponasik, J.; James, A. J. Org. Chem. 2005,
70, 1872-1880. (b) Li, X.; Jia, X.; Xu, L.; Kok, S. H. L.; Yip, C. W.;
Chan, A. S. C. AdV. Synth. Catal. 2005, 347, 1904-1908. (c) Hu, X.-P.;
Zheng, Z. Org. Lett. 2004, 6, 3585-3588. (d) Liu, D.; Li, W.; Zhang, X.
Org. Lett. 2002, 4, 4471-4474.
Ohkuma, T.; Noyori, R. Hydrogenation of Carbonyl Groups. In Compre-
hensiVe Asymmetric Synthesis; Jacobsen, E. N., Pfalz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 2000; Vol. 1, pp 199-246. (b) Kitamura, M.; Noyori,
R. Hydrogenation and Transfer Hydrogenation. In Rhuthenium in Organic
Synthesis; Murahashi, S.-i., Ed.; Wiley-VCH: Weinheim, 2004; pp 3-52.
5560
Org. Lett., Vol. 9, No. 26, 2007