Controlling olefin geometry with Pd catalysis: Selective formation of Z-olefins from both E-and Z-allylic carbonates

Article abstract of DOI:10.1021/jo052325+

The palladium-catalyzed formation of Z-olefins from allylic carbonates and a variety of protected dialkyl aminomalonates is reported. The reaction is selective for the Z-isomer, and either acetyl, Boc, or formyl protecting groups are tolerated. The Z-olef

Full text of DOI:10.1021/jo052325+

SCHEME 1
Controlling Olefin Geometry with Pd Catalysis:
Selective Formation of Z-olefins from Both E-
and Z-Allylic Carbonates
Dietrich Steinhuebel,* Michael Palucki, and Ian W. Davies
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
We were particularly interested in using diethyl N-acetami-
domalonate as a glycine surrogate, since it is inexpensive and
readily available and can be converted to an amino ester or
amino acid via straightforward decarboxylation procedure. In
addition, the presence of a robust acetamide protecting group
allows for a high degree of product elaboration without the
concern of unwanted deprotection. A survey of the literature
reveals that most examples of the palladium-catalyzed alkylation
reaction are reported with 1,2-disubstituted olefins. Allylic
substitution reactions with unsymmetrical 1,1-disubstituted
olefins are less common.6 This is perhaps not surprising, given
the reaction’s degree of complexity, since with these substrates
one must control both the regiochemistry of the addition reaction
and the olefin geometry of the product. In this publication, we
report the highly selective palladium-catalyzed allylation of a
variety of 1,1-disubstituted allylic carbonates with substituted
dialkylaminomalonate derivatives to afford the Z-olefin product.
Preparation of allylic alkylation substrate 2-E was ac-
complished in 57% overall yield via DIBAL-H reduction of
the previously reported, readily accessible trisubstituted unsatur-
ated ester, followed by treatment with ethyl chloroformate and
pyridine.7 We were pleased to find that subjecting 2-E to 2.5
mol % [allylPdCl]2, 10 mol % 1,2-bis(diphenylphosphino)ethane
(dppe), diethyl N-acetamidomalonate, and NaH as base in DMF
at 90 °C for 12 h afforded a mixture of the allylation products
3-Z:3-E in a 13:1 ratio. Assay yield of the product was ∼80%,
dietrich_steinhuebel@merck.com
ReceiVed NoVember 9, 2005
The palladium-catalyzed formation of Z-olefins from allylic
carbonates and a variety of protected dialkyl aminomalonates
is reported. The reaction is selective for the Z-isomer, and
either acetyl, Boc, or formyl protecting groups are tolerated.
The Z-olefin product can be formed regardless of whether
the E- or Z-allylic carbonate is used as starting material.
The placement of synthetic amino acids in peptides is one of
the most straightforward techniques to potentially enhance
peptide stability and increase receptor affinity.1 Synthetic amino
acids are frequently used by medicinal chemists as a key
component in establishing and optimizing structure activity
relationships due to their effects on receptor selectivity and
binding. As a consequence, the development of efficient and
cost-effective methods for the selective preparation of substituted
synthetic amino acids continues to attract attention.2
The allylation of glycine derivatives represents one of the
most direct approaches for the preparation of synthetic amino
acids due to the versatility of the products.3 Toward this end,
dialkyl aminomalonates, benzophenone imine, and azalactone
derivatives of glycine have been successfully employed as
nucleophiles in palladium-catalyzed allylic alkylation reac-
tions.4,5 We were recently faced with the challenge of preparing
olefin 1 as a single geometric isomer. The palladium-catalyzed
allylic alkylation of carbonate 2 with a glycine equivalent such
as diethyl N-acetamidomalonate would represent a straight-
forward route to 1 if the regiochemistry and olefin geometry
could be controlled (Scheme 1).
(4) For a general review, see: (a) Trost, B. N.; VanVranken, D. L. Chem.
ReV. 1996, 96, 395-422. (b) Ito, Y.; Kuwano, R. J. Am. Chem. Soc. 1999,
121, 3236-3237. (c) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed.
1999, 38, 1468-1470. (d) Kuwana, R.; Kondo, Y.; Matsuyama, Y. J. Am.
Chem. Soc. 2003, 125, 12104-12105. (e) Kuwana, R.; Kondo, Y. Org.
Lett. 2004, 6, 3545-3547. (f) Yamaguchi, M.; Shima, T.; Yamagishi, T.;
Hida, M. Terahedron Lett. 1990, 31, 5049-5052. (g) Dunkerton, L. V.;
Serino, A. J. J. Org. Chem. 1982, 47, 2814-2816. (h) Bayardon, J.; Sinou,
D. J. Org. Chem. 2004, 69, 3121-3128. (i) For a Ru-catalyzed example,
see: Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem., Int. Ed. 2003,
41, 6.
(5) (a) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett.
2001, 3, 3329-3331. (b) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto,
Y. J. Am. Chem. Soc. 2002,67, 7418-7428. (c) Stolle, A.; Olivier, J.; Piras,
P. P.; Salaun, J.; de Meijere, A. J. Am. Chem. Soc. 1992, 114, 4051-4067.
(d) Genet, J. P.; Juge, S.; Achi, S.; Mallart, S.; Montes, R. J.; Levif, G.
Tetrahedron 1988, 44, 5263-5276. (e) Cazes, B.; Gore, J. J. Chem. Res.
1996, 11, 2768-2792.
(6) (a) Trost, B. M.; Heinemann, C.; Ariza, X.; Weigand, S. J. Am. Chem.
Soc. 1999, 121, 8667-8668. (b) Trost, B. M.; Ariza, X. J. Am. Chem. Soc.
1999, 121, 10727-10737. (c) Hou, X.-E.; Sun, N. Org. Lett. 2004, 6, 4399-
4401. (d) Tamaru, Y.; Horino, Y.; Araki, M.; Tanak, S.; Kimura, M.
Tetrahedron Lett. 2000, 41, 5705-5709. (e) Commandeur C.; Thorimbert,
S.; Malacria, M. J. Org. Chem. 2003, 68, 5588-5592. (f) Gamez, P.;
Ariente, C.; Gore, J.; Cazes, B. Tetrahedron 1998, 54, 14835-14844. (g)
Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22, 2575-
2578. (h) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.;
Masuma, R.; Kuwajima, I.; Omura, S. Org. Lett. 2001, 3, 2289-2291.
(7) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org. Lett.
2005, 7, 215-218. All allylic carbonates utilized in this work are single
isomers by HPLC.
(1) Krohn, K.; Kirst, H.; Maag, H. Antibiotics and AntiViral Compounds;
VCH: Weinheim, 1993. Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi,
S.; Corey, E. J.; Schreiber, S. L. Science 1995, 268, 726-731.
(2) Smith, A. B., III; Guzman, M. C.; Sprengler, P. A.; Keenan, T. P.;
Holcomb, R. C.; Wood, J. L.; Carrol, P. J.; Hirschmann, R. J. Am. Chem.
Soc. 1994, 116, 9947-9962.
(3) (a) Leanna, M. R.; Morton, H. E. Tetrahedron Lett. 1993, 34, 4485-
4488. (b) Kopola, N.; Friess, B.; Cazes, B.; Gore, J. Tetrahedron Lett. 1989,
30, 3963-3966.
10.1021/jo052325+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/22/2006
3282
J. Org. Chem. 2006, 71, 3282-3284

SCHEME 2
SCHEME 3
SCHEME 4
TABLE 1. Screening of Catalysts and Solvents with 2-E
ratios. Interestingly, binap reverses the selectivity in favor of
the E isomer, 2:1.
We next investigated the influence of the electronic charac-
teristics of the aryl ring on the allylation reaction (Scheme 2).
Use of the p-MeO ethyl carbonate 4-E under our optimized
conditions afforded a 12:1 ratio of Z:E olefin products. The pure
6-Z isomer was isolated in 73% yield. The o-F ethyl carbonate
5-E afforded a 16:1 mixture of isomers, and the pure isomer
7-Z was isolated in 58% yield. Both of these results support
the conclusion that electronic factors have minimal influence
on product selectivity.
The scope of the reaction was examined by surveying other
substituted aminomalonate nucleophiles (Scheme 3). Allylic
alkylation of 2-E using diethyl N-Boc aminomalonate gave a
8:1 Z:E product ratio, and the pure 8-Z isomer was isolated in
44% yield, whereas the use of diethyl N-formamidomalonate
gave a 10:1 Z:E product ratio and a 50% isolated yield of 9-Z.
Reaction of the phthalamide-protected diethyl amino-malonate
with carbonate 2-E afforded 8:1 Z:E product selectivity, and a
53% isolated yield of 10-Z was obtained.
entry
Pd sourcea
ligandb
solventc
Z:E ratiod
conv (%)d
1
2
3
4
5
6
7
8
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
Pd2dba3
dppe
dppe
binap
dppp
dppb
binap
Ph3P
dppe
DMF
THF
THF
DMF
DMF
DMF
DMF
DMF
13:1
2:1
1:2
3:1
3:1
1:2
4:1
3:1
98
96
95
99
99
97
96
20
a 2.5 mol% of Pd catalyst. b 10 mol% of bidentate phosphine, 20 mol %
Ph3P. c Reactions in THF were run at 40 °C (entry 2) or 50 °C (entry 3)
for 12 h. Reactions in DMF were run at 90 °C for 12 h, except for entry 6,
which was complete in 3 h. d Z:E ratios and conversion determined by HPLC
and NMR analysis of crude reaction mixture.
A straightforward rationale for the observed selectivity of
these reactions is to invoke chelation of the N-Boc carbonyl
group at the palladium π-allyl intermediate prior to nucleophilic
attack. To probe the effect of the NHBoc group on the
selectivity, both 11-Z and 11-E allylic carbonates were prepared
and subjected to the optimized reaction conditions. Both
reactions afforded the E-product, but the selectivity using 11-E
was 40:1 E:Z whereas 11-Z afforded a 18:1 E:Z ratio (Scheme
4). The high selectivity observed in the absence of the NH-Boc
suggests that coordination of this group to the Pd is not the
governing factor controlling product selectivity. These results
are similar to the selectivity that was observed by Trost et al.
in the allylic alkylation of tertiary allylic acetates with tertiary
azalactone nucleophiles.6
and the major olefin product 3-Z was isolated in 52% yield.
The identity of the E-olefin product was confirmed by inde-
pendent synthesis, and the olefin geometries of both products
were confirmed by NOE experiments.8
A brief survey of reaction parameters was performed to
determine the optimal reaction conditions (Table 1). Use of THF
as solvent, in place of DMF, gave only a 2:1 Z:E product ratio.
Substitution of [allylPdCl]2 with Pd2dba3 resulted in only 20%
conversion. Use of 1,3-bis(diphenylphosphino)propane (dppp),
1,4-bis(diphenylphosphino)butane (dppb), or Ph3P as ligand
resulted in lower selectivity for the Z isomer, 2:1 to 4:1 Z:E
(8) See Supporting Information for the synthesis of all starting material,
products, and all NMR data.
J. Org. Chem, Vol. 71, No. 8, 2006 3283

SCHEME 5
Experimental Procedure
General Procedure for Preparation of Allylic Carbonates.
To a -78 °C solution of the unsaturated ester (31.0 mmol) in 100
mL of CH2Cl2 was added DIBAL-H (71 mmol, 47 mL of 1.5 M in
toluene). After stirring for 1 h at -78 °C, the reaction was complete,
90 mL of a 20 wt % aqueous solution of NaHSO4 was slowly added,
and the solution was warmed to ambient temperature. The solution
was diluted with 90 mL of isopropyl acetate, and the aqueous layer
was cut away. The organic layer was washed with 90 mL of brine
and concentrated. The residue was either purified by chromatog-
raphy with hexane/EtOAc or crystallization from heptane/isopropyl
acetate. The compounds were used directly in the next step. The
allylic alcohol (15.2 mmol) in 40 mL of CH2Cl2 was treated with
pyridine (17.7 mmol, 1.8 mL) and ethyl chloroformate (16.7 mmol,
1.8 mL) at 10 °C. After stirring for 4 h the solution was diluted
with 40 mL of isopropyl acetate, and 20 mL of H2O was added.
After the phase cut, the organic layer was washed with 2 × 30 mL
of 1.0 N HCl and 2 × 30 mL of brine and dried over MgSO4.
Concentration and chromatography on silica gel with hexanes/ethyl
acetate afforded the product.
The effect of the olefin geometry of the starting material on
the Z:E selectivity of the alkylation reaction was also investi-
gated. Subjecting ethyl carbonate 2-Z to the standard reaction
conditions gave a 24:1 Z:E product selectivity. Running this
same reaction in THF at 45 °C improved the 3-Z: 3-E ratio to
40:1. These results are consistent with the solvent screening
results in Table 1, which suggests that the rate of isomerization
of the palladium π-allyl intermediate is slower in THF.
This result along with the results described above can be
rationalized using the mechanistic scheme shown in Scheme 5.
While conversion of 2-Z to 3-Z is mechanistically straightfor-
ward, conversion of 2-E to 3-Z requires isomerization of the
palladium π-allyl complex via an η1-intermediate prior to
alkylation. Furthermore, the slight difference in product ratios
of 3-Z and 3-E from 2-E and 2-Z suggests that the reaction is
not under Curtin-Hammett control. Using 2 equiv of the
nucleophile under the standard reaction conditions decreased
the selectivity to 4:1 Z:E, suggesting that the rate of isomer-
ization is competitive with the rate of alkylation. Further
mechanistic investigations will be required to address these
issues.
General Procedure for Pd-Catalyzed Allylic Substitution
Reaction. A Schlenk flask was charged with the amino malonate
nucleophile (1.8 mmol) and 3 mL of DMF. Under a stream of
nitrogen, NaH (1.8 mmol, 60 wt % suspension) was added, and
the solution aged for 10 min. Under a stream of nitrogen,
1,2-bis(diphenylphosphino)ethane (0.17 mmol), [allylPdCl]2 (0.04
mmol) and the allylic carbonate (1.67 mmol) in 3 mL of DMF
were added in that order. The flask was evacuated and backfilled
with N2 three times. The resulting reaction was stirred overnight
at 90 °C under N2. HPLC of the reaction mixture indicated complete
conversion. The mixture was cooled to room temperature, and 10
mL of isopropyl acetate was added followed by 5 mL of water.
After the phase cut, the aqueous layer was extracted with 2 × 10
mL of isopropyl acetate. The organic layers were washed with 2
× 10 mL of 1.0 N NaOH, 2 × 10 mL of 1.0 N HCl, and 3 × 10
mL of brine. The organic layer was dried over MgSO4, and then
evaporation and chromatography on silica gel with the indicated
solvent system afforded the product.
Acknowledgment. We thank Mr. Robert Reamer for as-
sistance in NMR interpretation, Prof. Barry Trost for useful
discussions, and Ms. Patricia Peart for preparative assistance.
In conclusion, we report a selective and practical method for
the formation of a variety of functionalized Z-allylated glycine
products from E-allylic carbonates. The stereodefined allylic
carbonate starting material can be easily prepared from N-Boc
glycine in five high-yielding steps. Based on these results, we
anticipate more examples of palladium-catalyzed allylation
reactions with unsymmetrical 1,1-disubstituted olefins will be
reported in the future.
Supporting Information Available: Experimental procedures
and characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO052325+
3284 J. Org. Chem., Vol. 71, No. 8, 2006