(P(C6H5)3)CpRu+-catalyzed deprotection of allyl carboxylic esters

Article abstract of DOI:10.1021/jo020281o

A new and efficient catalytic method for deprotection of allyl carboxylic esters using a transition metal complex is reported. The reaction proceeds with a high substrate/catalyst ratio and without use of additional nucleophiles, giving the deprotected carboxylic acid in a quantitative yield. A variety of substrates, including the multifunctional amino acids and peptides, are also usable. The new method is more efficient, safe, and operationally simple in comparison to the conventional palladium-catalyzed method.

Full text of DOI:10.1021/jo020281o

+
(
P (C
6
H
5
)
3
)Cp Ru -Ca ta lyzed Dep r otection of
or other soluble Pd complexes and a stoichiometric
amount of nucleophile such as potasium carboxylate,
alkoxide, morpholine, pyrrolidine, formate, tributyltin
hydride, borohydride, and silane. The use of excess
nucleophile, however, decreases the atom efficiency and
sometimes causes problems during purification of the
products. In this report, we describe a new and efficient
method for the deprotection of allyl carboxylic esters.
The 8-, 9-, and 10-group transition metal complexes
Allyl Ca r boxylic Ester s
Masato Kitamura,* Shinji Tanaka, and
Masahiro Yoshimura
Department of Chemistry and Research Center for Materials
Science, Nagoya University, Chikusa,
Nagoya 464-8602, J apan
6
known to form π-allyl intermediates have been combi-
natorially screened in the deprotection of allyl benzoate
kitamura@os.rcms.nagoya-u.ac.jp
Received April 22, 2002
3
(1a ) under the standard conditions of CH OH as the
solvent, [1a ] ) 100 mM, [catalyst] ) 1 mM, and 25 °C.
The chemical yield of benzoic acid (2a ) was determined
Abstr a ct: A new and efficient catalytic method for depro-
tection of allyl carboxylic esters using a transition metal
complex is reported. The reaction proceeds with a high
substrate/catalyst ratio and without use of additional nu-
cleophiles, giving the deprotected carboxylic acid in a
quantitative yield. A variety of substrates, including the
multifunctional amino acids and peptides, are also usable.
The new method is more efficient, safe, and operationally
simple in comparison to the conventional palladium-
catalyzed method.
1
by H NMR analysis of the signal intensities of allyl and
phenyl moieties (1a , δ 6.01-6.08 (m, 1H, CCHdC); 2a ,
δ 8.13 (d, 2H, J ) 7.33 Hz, aromatic)), after evaporation
of all volatiles.
Considered selection of a protective group is crucial for
success or failure in the synthesis of organic compounds,
1
especially multifunctional molecules. The protective
group must be easily and selectively introduced and
removed, while it must also be stable to the projected
reactions. Among the many useful protective groups so
far developed for this purpose, the allyloxycarbonyl
As shown in Table 1, one cationic complex [CpRu-
7
(
P(C
6
H
5
)
3
)(CH
3
CN)
2
]PF
6
(3), among others, was found to
catalyze the deprotection of 1a to give 2a quantitatively.
After 6 h under standard conditions, benzoic acid (2a )
was isolated in 98% yield. The substrate concentration
can be increased to 1 M without any problems. Use of a
.001 mol amount of 3 completes the reaction within 24
h at 25 °C. With the reaction temperature increased to
2
function has attracted much attention since Tsuji-Trost
3
Pd chemistry was first reported in 1980. The allyl groups
for protecting carboxylic acid are now generally used for
the liquid- or solid-phase synthesis of a wide range of
0
4
natural and unnatural synthetic products. The protec-
tion can be removed in an appropriate aprotic solvent
5
6 5 3 4
containing, typically, a 0.05 mol amount of Pd(P(C H ) )
(
(
5) Tsuji, J .; Minami, I.; Shimizu, I. Synthesis 1986, 623-627.
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Tetrahedron Lett. 1972, 15, 1433-1436. (n) Bricout, H.; Carpentier,
J .-F.; Mortreu, A. J . Chem. Soc., Chem. Commun. 1995, 1863-1864.
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Trost, B. M., Fleming, I., Eds.; Pregamon: Oxford, 1991; Vol. 4, p 585.
(p) Ttsuji, J . In Palladium Reagents and Catalysts; Wiley: New York,
1995; p 290. (q) Harrington, P. J . In Comprehensive Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 12, p 797. (r) Trost, B. M.; Varanken,
D. L. V. Chem. Rev. 1996, 96, 395-422. Pt: (s) Kurosawa, H. J . Chem.
Soc., Dalton Trans. 1979, 939-943. (t) Brown, H.; Carpentier, J .-F.;
Mortreux, A. J . Chem. Soc., Chem. Commun. 1985, 961-970.
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C.; Mereiter, K.; Schmid, R.; Kirchner, K. Organometallics 1999, 18,
3843-3850.
Tetrahedron 1993, 49, 3691-3748. (b) Schelhaas, M.; Waldmann, H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2056-2083. (c) Protecting
Groups in Organic Synthesis, 3rd ed.; Greene, T. W., Wuts, P. G. M.,
Eds.; Wiley: New York, 1999. (d) J arowicki, K.; Kocienski, P. J . Chem.
Soc., Perkin Trans. 1 2000, 2495-2527. (e) Kocienski, P. J . Protecting
Groups; Georg Thieme Verlag, Stuttgart: New York, 1994.
(
2) Reviews: (a) Tsuji, J .; Mandai, T. Synthesis 1996, 1-24. (b)
Guib e´ , F. Tetrahedron 1998, 54, 2967-3042.
3) Reviews: (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393.
b) Tsuji, J . In Organic Synthesis With Palladium Compounds;
Springer-Verlag: New York, 1980; p 125.
4) Rapamycin: (a) Hayward, C. M.; Yohannes, D.; Danishefski, S.
(
(
(
J . J . Am. Chem. Soc. 1993, 115, 9345-9346. Lactacystin: (b) Corey,
E. J .; Reichard, G. A. J . Am. Chem. Soc. 1992, 114, 10677-10678.
Prostaglandin E: (c) Ono, N.; Tsuboi, M.; Okamoto, S.; Tanami, T.;
Sato, F. Chem. Lett. 1992, 2095-2098. (d) Okamoto, S.; Ono, N.; Tani,
K.; Yoshida, Y.; Sato, F. J . Chem. Soc., Chem. Commun. 1994, 279-
2
V
80. Antrimycine D : (e) Schmidt, U.; Riedl, B. J . Chem. Soc., Chem.
Commun. 1992, 1186-1187. Mycinolide-V: (f) Hoffman, R. W.; Ditrich,
K. Liebigs Ann. Chem. 1990, 23-29. â-Lactam antibiotics: (g) J effrey,
P. D.; McCombie, S. W. J . Org. Chem. 1982, 47, 587-590. (h)
Mastalerz, H. J . Org. Chem. 1984, 49, 4094-4095. (i) Ruediger, E. H.;
Solomon, C. J . Org. Chem. 1991, 56, 3183-3187. Peptide: (j) Gun-
narsson, K.; Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1
988, 27, 400-401. (k) Gill, I.; Lopez-Fandino, R.; Vulfuson, E. J . Am.
Chem. Soc. 1995, 117, 6175-6181. Glycopeptide (review): (l) Kunz,
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1
0.1021/jo020281o CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002
J . Org. Chem. 2002, 67, 4975-4977
4975

TABLE 1. Scr een in g Resu lts in th e Ca ta lytic Rem ova l
of th e Allyl Gr ou p of Allyl Ca r boxylic Ester s (1) w ith a
Ca tion ic Com p lex [Cp Ru (P (C6H5)3)(CH3CN)2]P F 6 (3)a
Allyl alkynyl carboxylate 1c was not deprotected under
the standard conditions. The allyl groups of the primary,
secondary, and tertiary alkyl carboxylic esters, 1d -f,
respectively, were also quantitatively removed, but the
rates were reduced by a factor of 2-3. The reactivity of
allyl 4-pentenonate (1g) was very low, but no isomeriza-
tion to the internal olefin occurred. Allyl 5-hexenoate (1h )
was converted to carboxylic acid with ca. 90% isomer-
ization of the terminal olefin to the internal olefin. Other
allyl esters possessing ether, tertiary amine, and halogen
concn,
mM
time,
h
%
convn
entry substrate
1
3
solvent
CH3OH
CH3OH
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
100
1
6
98b
1000
1
24 >99
12
6
6
6
6
6
6
6
c
1000 0.1 CH3OH
98
>99
96
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
C2H5OH
i-C3H7OH
t-C4H9OH
1:1 CH3OH-CH2Cl2
1:1 CH3OH-H2O
1:1 CH3OH-THF
1:1 CH3OH-DMF
1:1 CH3OH-CH3CN
CH3OH
CH3OH
CH3OH
CH3OH
CD3OD
CD3OD
CH3OH
CH3OH
CD3OD
(1i-k , respectively) were also converted to the corre-
99
>99
>99
>99
71
4
99
0
93
97
97
20
93
97
96
97
sponding carboxylic acids in high yields, but the rate of
1j was reduced by ca. 16. The present method was applied
to multifunctional molecules. Each of the tert-butyl,
Fmoc,11 and allyl groups in a protected aspartic acid 4 is
1
1
1
1
1
1
1
1
1
1
2
2
6
6
b
selectively cleaved, without any interference from each
other, by use of CF
P(C )(CH CN) ]PF
standard conditions (CH
3
COOH,12 piperidine, and [CpRu-
6
13
17
17
17
10
48
14
14
100
12
b
(
6
H
5
)
3
3
2
(3), respectively. Under the above
OH, S/C ) 100, 25 °C, 17 h),
b
3
d
d
the only allyl-deprotected 5 was isolated in >99% yield.
Increasing the temperature to 90 °C in ethanol afforded
5 quantitatively after 2 h even with the S/C of 1000. A
protected dipeptide 6, aspargyl-phenylalanine derivative,
could also act as a substrate. In a 1:1 mixture of ethanol
and dichloromethane used to increase the solubility of
1g
1h
1i
1j
1k
b,e
b
d
b
CH3OH
a
Reactions were carried out at 25 °C under an argon atmo-
b
c
sphere unless otherwise specified. Isolated yield. Temperature
50 °C. Reaction was carried out in CD3OD containing mesi-
tylene (100 mM) as an internal standard. Product was obtained
as a 1:9 mixture of 5-hexenoic acid and 4-hexenoic acid.
6
, the allyl group was quantitatively removed to give the
d
)
corresponding acid 7 (S/C ) 100, 25 °C, 17 h or S/C )
e
1
000, 90 °C, 2 h).
5
0 °C, the substrate to catalyst ratio (S/C) can be
increased to 10 000, with which the reaction runs to
completion within 12 h. With an S/C value of 100 000,
5
0% of 1a was converted to 2a at 70 °C in 24 h, the
turnover number and the turnover frequency being
calculated to be 50 000 and 2000/h, respectively. Metha-
nol, ethanol, iso-propyl alcohol, and tert-butyl alcohol are
the solvents of choice. Dichloromethane, water, or THF
can be used as a cosolvent in methanol without signifi-
cant decrease in the reactivity. Methanol containing 50%
DMF is also usable, although the reactivity is reduced
by 71%. The reactivity in 1:1 methanol-acetonitrile was
The allyl cleavage in an allyl carboxylic ester is
assumed to occur via a π-allylruthenium(IV) species,
which reacts with the alcoholic solvent to give the acid
and allyl alkyl ether. Tracing the reaction of allyl
1
4
benzoate (1a , 35 mM) with 3 (3.5 mM) in CD
3
OD at 25
C, by H NMR, we observe complete consumption of 1a
after 18 h to yield 2a together with a 73:27 mixture of
CD OCH CHdCH (δ 3.91 (ddd, 2H, J ) 1.37, 1.83, 5.80
Hz, OCH CdC), 5.16 (ddt, 1H, J ) 1.37, 1.83, 10.5 Hz,
CdCH ), 5.25 (ddt, 1H, J ) 1.37, 1.83, 17.3 Hz, CdCH ),
.84-5.93 (m, 1H, CCHdC)) and (E)-CD OCHdCHCH
δ 1.50-1.53 (m, 3H, CH ), 4.69-4.74 (m, 1H, CdCHC),
very low. A mixed system of [CpRu(CH
3 3 6
CN) ]PF and
1
°
P(C also removes the allyl group, but the catalytic
6
5 3
H )
activity is ca. 10 times lower than that of 3 itself. The
reactivity is halved by the use of a 2 mol amount of
3
2
2
P(C
mol amount of P(C
catalysis. Tricyclohexylphosphine behaves similarly, while
electron-deficient phosphines such as P(C and
P(OCH somewhat reduce the reactivity. CpRuCl-
P(C
6
H
5
)
3
with [CpRu(CH
3 3 6
CN) ]PF , and increasing the
2
5 3
H )
to 3 mol completely inhibits the
2
2
6
5
(
6
3
3
5 3
F )
3
6
.26 (dq, 1H, J ) 1.37, 12.4 Hz, OCHdC)). After 148 h,
3 3
)
8
9
10
allyl methyl-d ether was converted to the (E)-propenyl
(
6
H
5
)
3
)
2
, [Cp*RuCl
2
]
n
, and [Ir(cod)Cl]
2
also showed
3
ether. Neither the methyl ester nor the propanal di-
catalytic activity, the yields of 2a being 99, 48, and 87%,
respectively (S/C ) 100, 70 °C, 12 h). Other Ru com-
methyl ketal is formed. This excludes a mechanism via
the 1,3-hydrogen shift of allyl esters to 1-propenyl esters.
In conclusion, a new efficient catalytic method for the
plexes, including [Ru(p-cymene)Cl
P(C , RuHCl(P(C , and RuH
not effective under the standard conditions.
2
]
2
, [Ru(cod)Cl , RuCl
2
]
n
2
-
(
6
H
5
)
3
)
3
6
H
5
)
3
)
3
2
(P(C H ) ) , were
6 5 3 4
6 5 3
deprotection of allyl carboxylic esters using a P(C H ) -
The allyl ester of alkenyl carboxylic acid 1b can be
converted to 2b with a reactivity similar to that of 1a .
(10) Winkhaus, G.; Singer, H. Chem. Ber. 1966, 99, 3610-3618.
(11) Fmoc ) 9-fluorenylmethoxycarbonyl.
(12) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. Engl.
(
8) Bruce, M. I.; Hameister, C.; Swincer, A. G.; Wallis, R. C. Inorg.
Synth. 1982, 21, 78-84.
9) (a) Tilley, T. D.; Grubbs, R. H.; Bercaw, J . E. Organometallics
984, 3, 274-278. (b) Oshima, N.; Suzuki, H.; Moro-Oka, Y. Chem.
Lett. 1984, 1161-1164.
1996, 35, 2056-2083.
(13) Atherton, E.; Sheppard, R. C. In The Peptides; Udenfriend, S.,
Meienhofer, J ., Eds.; Academic Press: New York, 1987; Vol. 9, p 1.
(14) Nagashima, H.; Mukai, K.; Shiota, Y.; Ara, K.; Itoh, K.; Suzuki,
H.; Oshima, N.; Moro-Oka, Y. Organometallics 1985, 4, 1314-1315.
(
1
4
976 J . Org. Chem., Vol. 67, No. 14, 2002

and Cp-coordinated cationic Ru complex is reported. The
reaction proceeds with high selectivity to give the depro-
tected carboxylic acid in quantitative yield. Use of only
millimol amounts of catalyst is sufficient even for multi-
functional molecules such as amino acids and peptides.
The reaction is clean and operationally simple. Since
ethers are the only side products, the complete evapora-
tion of volatiles from the reaction mixture yields virtually
pure products. Related studies on solid-phase synthesis
of peptides and nucleotides and on the mechanism
involved are being carried out. These results will be
reported in due course.
reaction mixture was concentrated under reduced pressure to
give a crude product. This was chromatographed on silica gel
(
AP350, 50 g; eluent, 1:1 hexanes-ethyl acetate) to give benzoic
1
acid (2a , 780 mg, 6.4 mmol, 98% yield) as a white solid. H and
1
3
C NMR spectra were consistent with the commercially avail-
able authentic sample.
Ack n ow led gm en t. This work was aided by the
Grant-in-Aid for Scientific Research (No. 07CE2004)
from the Ministry of Education, Science, Sports and
Culture, J apan. We are grateful to Professor R. Noyori
for valuable discussions and financial support. We thank
Mr. T. Noda for making the reaction vessels and to Dr.
U. Hackler for his kind technical support in using the
Chemspeed automated screening system.
Exp er im en ta l Section
Gen er a l P r oced u r e for Dep r otection . Compound 1a (1.05
g, 6.5 mmol) and CH
3
OH (65 mL) were placed into a dry argon-
Su p p or t in g In for m a t ion Ava ila b le: Generality of the
deprotection and characterization of all substrates and prod-
ucts obtained by the present method. This material is available
free of charge via the Internet at http://pubs.acs.org.
filled 20 mL Schlenk tube, and the vessel was degassed by three
freeze-thaw cycles. The solution was transferred via a stainless
cannula to another 20 mL Schlenk tube containing [CpRu-
(
P(C
6 5 3 3 2 6
H ) )(CH CN) ]PF (3, 43 mg, 65 µmol) under argon pres-
sure. The pale yellow mixture was stirred at 25 °C for 6 h. The
J O020281O
J . Org. Chem, Vol. 67, No. 14, 2002 4977