General, Robust, and stereocomplementary preparation of α,β-disubstituted α,β-unsaturated esters

Article abstract of DOI:10.1021/ol9013359

An (E)- and (Z)-stereocomplementary preparative method for α,β-disubstituted α,β-unsaturated esters Is performed via three general and robust reaction sequences: (i) TI-Claisen condensation (formylation) of esters to give α-formyl esters (12 examples, 60-99%), (II) (E)- and (Z)-stereocomplementary enol ρ-toluenesulfonylation (tosylation) using TsCI-N-methylimidazole (NMI)-Et₃N and LiOH (24 examples, 82-99%), and (iii) stereoretentive Suzuki-Miyaura cross-coupling (18 examples, 64-96%).

Full text of DOI:10.1021/ol9013359

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4258-4261
General, Robust, and
Stereocomplementary Preparation of
r,ꢀ-Disubstituted r,ꢀ-Unsaturated
Esters
Hidefumi Nakatsuji, Hiroshi Nishikado, Kanako Ueno, and Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin
UniVersity, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
tanabe@kwansei.ac.jp
Received June 15, 2009
ABSTRACT
An (E)- and (Z)-stereocomplementary preparative method for r,ꢀ-disubstituted r,ꢀ-unsaturated esters is performed via three general and
robust reaction sequences: (i) Ti-Claisen condensation (formylation) of esters to give r-formyl esters (12 examples, 60-99%), (ii) (E)- and
(Z)-stereocomplementary enol p-toluenesulfonylation (tosylation) using TsCl-N-methylimidazole (NMI)-Et3N and LiOH (24 examples, 82-99%),
and (iii) stereoretentive Suzuki-Miyaura cross-coupling (18 examples, 64-96%).
Stereocontrolled preparation of (E)- and (Z)-olefins is a major
topic in organic synthesis. Stereoretentive cross-couplings
have been developed in natural products and pharmaceutical
syntheses due to the wide range of possible substrates and
catalysts, mild reaction conditions, and functional compat-
ibility. Because (E)- and (Z)-R,ꢀ-unsaturated esters are useful
structural scaffolds for various stereodefined olefins, their
stereoselective preparation occupied a synthetically promi-
nent position: Horner-Wadsworth-Emmons reaction,1 de-
hydration of ꢀ-hydroxy esters,2 Michael reaction,3 or
hydrometalation-alkylation4 using R-alkynyl esters are
representative preparative methods. Despite these well-
established methods, a more efficient method with regard to
stereo-, regio-, and chemoselectivities and substrate generality
is in high demand. (E)- and (Z)-stereodefined enol sulfonates
derived from ꢀ-carbonyl esters are promising stereoretentive
cross-coupling partners. We previously reported a practical
stereocomplementary preparation of simple ꢀ-ketoester enol
p-toluenesulfonates (tosylates), followed by stereoretentive
Negishi and Sonogashira cross-couplings to give ꢀ,ꢀ-
disubstituted (E)- and (Z)-R,ꢀ-unsaturated esters.5 This
method, however, cannot be applied for the preparation of
equally important (E)- and (Z)-stereodefined R,ꢀ-disubstituted
(1) (a) Smith, M. B.; March, J. AdVanced Organic Chemistry, 6th ed.;
Wiley: New York, 2007; p 1375. (b) Ku¨rti L.; Czako´, B. Strategic
Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington,
2005; p 212.
(2) Representative examples for the stereoselective preparation: (a)
Zimmerman, H. E.; Ahramjian, L. J. Am. Chem. Soc. 1959, 81, 2086. (b)
Sai, H.; Ohmizu, H. Tetrahedron Lett. 1999, 40, 5019. (c) Feuillet, F. J. P.;
Robinson, D. E. J.; Bull, S. D. Chem. Commun. 2003, 2184. (d) Mani,
N. S.; Mapes, C. M.; Wu, J.; Deng, X.; Jones, T. K. J. Org. Chem. 2006,
71, 5039.
(4) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem.
Soc. 2001, 123, 9918.
(5) (a) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett. 2008,
10, 2131. (b) Recent related stereocomplementary enol trifluoromethane-
sulfonylation: Babinski, D.; Soltani, O.; Frantz, D. E. Org. Lett. 2008, 10,
2901.
(3) Reference,1a p 1501.
10.1021/ol9013359 CCC: $40.75
Published on Web 08/28/2009
 2009 American Chemical Society

isosteres. This objective requires the following reaction
sequences: (a) practical formylation of simple esters, (b)
stereoselective enol p-toluenesulfonylation (tosylation), and
(c) stereoretentive cross-coupling. We disclose here a TiCl4-
mediated R-formylation of a wide variety of esters, followed
by (E)- and (Z)-stereocomplementary enoltosylation and
stereoretentive Suzuki-Miyaura cross-coupling (Scheme 1).3
Table 1. TiCl4-Promoted R-Formylation of Estersa
Scheme 1. Stereocomplementary Preparation of
R,ꢀ-Disubstituted (E)- and (Z)-Stereodefined R,ꢀ-Unsaturated
Esters
R-Formyl esters 1 are fundamental synthons for organic
synthesis. R-Formylation of simple esters with HCO2Me is
a straightforward process, but classical methods using basic
reagents such as NaOMe and NaH produce a highly
unsatisfactory yield and low reaction velocity and require
harsh and rigorous conditions.6
Application of the Ti-Claisen condensation7 was promis-
ing and, to our delight, exhibited a high performance. Table
1 lists the successful results with the following salient
features. (i) All examples produced good to excellent isolated
yield, i.e., substrate generality, except for 1a-1 due to its
unstable and volatile properties (entry 1). (ii) The use of butyl
and allyl analogues in 1a-2 and 1a-3 solved this problem
(entries 2 and 3). (iii) Various aliphatic esters underwent
smooth reaction under mild and practical conditions (0-25
°C, total 2 h) (entries 2-8). (iv) As expected, Ti-Claisen
condensation is also applicable to R-aryl methyl esters
bearing a more acidic methylene group (entries 9-13). (v)
Aliphatic R-formylesters 1a-1, -2, -3, and 1b-f were purified
by simple distillation, whereas R-aryl products 1g-k could
be purified by either distillation or column chromatography
(6) Yields of the traditional basic method range from 0 to 40-50%.
For examples, see: (a) Spengler, J. -P.; Schunack, W. Arch. Pharm.
(Weinheim) 1984, 317, 425. (b) Davies, S. J.; Ayscough, A. P.; Beckett,
R. P.; Bragg, R. A.; Clements, J. M.; Doel, S.; Grew, C.; Launchbury, S. B.;
Perkins, G. M.; Pratt, L. M.; Smith, H. K.; Spavold, Z. M.; Thomas, S. W.;
Todd, R. S.; Whittaker, M. Bioorg. Med. Chem. Lett. 2003, 13, 2709.
Reexamination of NaH-promoted R-formylation using aliphatic simple esters
such as CH3(CH2)4CO2Me in our hands, however, was not reproducible
under the identical conditions. This strongly basic and heterogeneous
condition might be troublesome.
(7) (a) Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917. (b) Yoshida,
Y.; Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett. 1997, 38, 8727.
These papers describe a sole example of R-formylation of PhCH2CH2CO2Me
(∼50%) using TiCl4-Bu3N-catalytic TMSOTf reagent. Compared with
these methods, the present method using more accessible TiCl4-Et3N
remarkably improved the efficiency. (c) Misaki, T.; Nagase, R.; Matsumoto,
K.; Tanabe, Y. J. Am. Chem. Soc. 2005, 127, 2854. (d) Iida, A.; Nakazawa,
S.; Okabayashi, T.; Horii, A.; Misaki, T.; Tanabe, Y. Org. Lett. 2006, 8,
5215.
a General procedure: TiCl4 (8.78 mL, 80 mmol) and Et3N (13.3 mL, 96
mmol) were successively added dropwise to a stirred solution of a methyl
ester (40 mmol) and HCO2Me (7.21 g, 120 mmol) in CH2Cl2 (80 mL) at 0
- 5 °C under an Ar atmosphere, and the mixture was stirred at the same
temperature for 1 h and at 20 - 25 °C for 1 h. Water was added to the
mixture, which was extracted twice with AcOEt. The combined organic
phase was washed with brine, dried (Na2SO4), and concentrated. The
obtained crude oil was purified by distillation or column chromatography
to give the desired R-formyl ester. b Use of toluene solvent.
due to higher stability.8 (vi) Double bonds, ω-chloro, p-Me,
p-MeO, and o- or p-Cl functional groups were tolerated
Org. Lett., Vol. 11, No. 19, 2009
4259

(entries 6, 7, and 10-13). Thus, the present Ti-mediated
formylation has clear advantages over the traditional method.
Next, (E)- and (Z)-stereocomplementary enol tosylation
was investigated. The Merck group disclosed an original
stereocomplementary method for a sole specific γ-amino-
ꢀ-keto ester using Ts2O and Et3N or LDA9 and pointed out
the advantages over the more frequently used enol triflates
with regard to stability and benchtop handling procedures,
etc. Despite the inferior reactivity of enol tosylates to that
of enol triflates, tremendous rapid development of cross-
coupling reactions will allow increasing applications for these
enol tosylate partners.10
Table 3. (E)- and (Z)-Stereocomplementary Enol Tosylation of
R-Formyl Esters 1 Using TsCl-NMI-Basesa
Our longstanding studies on mild, practical, and cost-
effective condensation reactions reveal that N-methylimida-
zole (NMI) is a potential activator for O,N,S-acylations,11
sulfonylation,5 and C-acylation (i.e., crossed Ti-Claisen
condensation).7c,d With this information in hand, we extended
this protocol to stereocomplementary enol tosylations of
R-formyl esters 1 utilizing TsCl-NMI-bases. The initial
trial reaction was conducted using methyl 2-(formyl)hex-
anoate 1b (Table 2). Among several available and inexpen-
Table 2. (E)- and (Z)-Stereocomplementary Enol Tosylation of
Methyl 2-(Formyl)hexanoate 1b Using TsCl-NMI-Bases
entry
base
Et3N
yielda/%
E/Zb
1
2
3
4
5
6
7
8
82
89c
76c
63
74
67
81
92
46c
65
62
49
57
98/2
97/3
97/3
96/4
77/23
99/1
2/98
4/96
4/96
7/93
34/66
47/53
14/86
Bu3N
iPr2NEt
TMEDA
LiOH
9
10
11
14
15
NaOH
KOH
LDA
a General Procedure of Method A. An R-formyl ester (1.00 mmol) in
toluene (1 mL) and TsCl (228 mg, 1.20 mmol) in toluene (1 mL) were
successively added dropwise to a stirred solution of N-methylimidazole
(NMI) (99 mg, 1.20 mmol) and Et3N (121 mg, 1.20 mmol) in toluene (1
mL) at 0-5 °C under an Ar atmosphere, and the mixture was stirred at the
same temperature for 1 h. Water was added to the mixture, which was
extracted twice with AcOEt. The combined organic phase was washed with
brine, dried (Na2SO4), and concentrated. The residue was purified by SiO2
column chromatography (hexane/AcOEt ) 25:1-5:1) to give the desired
(E)-enol tosylates. Method B. An R-formyl ester (1.00 mmol) in toluene
(1 mL), TsCl (228 mg, 1.20 mmol) in toluene (1 mL), and NMI (99 mg,
1.20 mmol) were successively added dropwise to a stirred suspension of
LiOH powder (commercially available, anhydrous; 29 mg, 1.20 mmol) in
toluene (1 mL) at 0-5 °C under an Ar atmosphere, and the mixture was
stirred at the same temperature for 1 h. A workup similar to that of method
LiHMDS
a
1
Determined by H NMR of the crude products using dibutyl oxalate
as an internal standard. b Determined by 1H NMR of the crude products
using dibutyl oxalate as an internal standard. c In the absence of NMI.
sive bases and conditions screened, respective (E)- and (Z)-
selective reactions were performed using Et3N and LiOH:
the best conditions were entry 2 using Et3N base for the (E)-
form and entry 8 using LiOH base for the (Z)-form.
In the absence of NMI, the yield was significantly
decreased (entry 9).
b
1
A gave the desired (Z)-enol tosylates. Determined by H NHR.
Table 3 lists successful examples of the present (E)- and
(Z)-stereocomplementary enol tosylation of various R-formy-
lesters 1. The salient features are as follows. (i) All reactions
examined using 1a-k produced good to excellent yield and
(E)- and (Z)-selectivity under favorable conditions, especially
for process chemistry (toluene, 0-5 °C, 1 h). (ii) These enol
tosylates, 3a,b-12a,b, were stable enough for recrystalli-
zation and/or column chromatographic purification with
4260
Org. Lett., Vol. 11, No. 19, 2009

complete separation of the minor isomers. (iii) Sterically
congested and R-aryl R-formyl esters could also be applied
(entries 13-24).
Next, we focused our attention on the stereoretentive
Suzuki-Miyaura coupling using the (E)- and (Z)-stereofixed
enol tosylates. Table 4 lists the successful results, and the
differed from those of the Merck group’s protocol using
PdCl2(PPh3)2-K2CO3.9 (ii) Almost all (E)- and (Z)-enol
tosylates smoothly underwent the reaction in good to
excellent yield with nearly complete stereoretention. (iii)
Compared with ꢀ-monosubstituted ꢀ-ketoester enol tosy-
lates,5 the present reaction using R,ꢀ-disubstituted substrates
required elevated temperature conditions (reflux in DMF),
probably due to the steric effect of the R-substituents (R1).
This harsh condition might disrupt the E/Z stereochemistry
slightly as in the case of 3b-2 and 11b (entries 2 and 18).
Table 4. (E)- and (Z)-Stereoretentive Suzuki-Miyaura Coupling
of Enol Tosylatesa
In conclusion, we developed a general and robust prepara-
tion of (E)- and (Z)-stereodefined R,ꢀ-disubstituted R,ꢀ-
unsaturated esters utilizing three reaction sequences,
TiCl4-Et3N-mediated R-formylation of simple esters, (E)-
and (Z)-stereocomplementary enol sulfonylation, and ste-
reoretentive Suzuki-Miyaura cross-coupling. The present
protocol provides a new avenue for practical, general, and
stereocomplementary preparation of functionalized olefins.
Acknowledgment. This research was partially supported
by Grant-in-Aids for Scientific Research on Basic Areas (B)
“18350056”, Priority Areas (A) “17035087” and “18037068”,
and Exploratory Research “17655045” from MEXT. We
thank Dr Masaru Mitsuda (Kaneka Corp.) for his helpful
discussion on the Ti-Claisen condensation for process
chemistry.
Supporting Information Available: Experimental pro-
cedure and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9013359
(8) Although the simple distillation is possible, these aliphatic R-formyl
esters are relatively unstable and have to be stored in a refrigerator (ca.
-10 °C) to avoid decomposition. Within ca. 1 week, they should be
transformed to the corresponding stable enol tosylates. Aromatic R-formyl
esters are stable enough for refrigerator storage for some weeks. These
R-formyl esters will be useful for the active methylene precursor.
(9) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org. Lett.
2005, 7, 215.
(10) Representative Suzuki-Miyaura coupling using aryl and vinyl
tosylates: (a) Huffman, M. A.; Yasuda, N. Synlett 1999, 471. (b) Zim, D.;
Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049. (c)
Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.; Sevova,
N.; Boggess, B. Org. Lett. 2002, 4, 1479. (d) Wu, J.; Zhu, Q.; Wang, L.;
Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670. (e) Nguyen, H. N.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (f) Percec, V.;
Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447.
(g) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 7279. (h)
Gøgsig, T. M.; Søbjerg, L. S.; Lindhardt, A. T.; Jensen, K. L.; Skrydstrup,
T. J. Org. Chem. 2008, 73, 3404.
a An (E)- or (Z)-enol tosylate (0.50 mmol) was added to a stirred
suspension of PhB(OH)2 (91 mg, 0.75 mmol), Na2CO3 (159 mg, 1.50 mmol),
Pd(OAc)2 (6 mg, 0.025 mmol), and PCy3 (14 mg, 0.05 mmol) in DMF (3.5
mL) at 20-25 °C under an Ar atmosphere, and the mixture was stirred at
150-155 °C for 2 h. After cooling, water was added to the stirred mixture,
which was extracted twice with AcOEt. The organic phase was washed
with brine, dried (Na2SO4), and concentrated to give the residue, which
was purified by SiO2 column chromatography (hexane/AcOEt ) 50:1-20:
1) to give the desired product. b Use of (E) or (Z) ∼100% pure compounds.
c Reaction temperature was kept at 120-125 °C to avoid the side
dechlorination of the p-Cl group.
(11) (a) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV.
Synth. Catal. 2003, 345, 1209. (b) Nakatsuji, H.; Morita, J.; Misaki, T.;
Tanabe, Y. AdV. Synth. Catal. 2006, 348, 2057. (c) Nakatsuji, H.; Morimoto,
M.; Misaki, T.; Tanabe, Y. Tetrahedron 2007, 50, 12071. We have pointed
out that NMI is superior to DMAP for acylation reactions with regard to
reactivity, cost, and toxicity [NMI (rat LD50, oral, 1130 mg/kg) and DMAP
(56 mg/kg)].
(12) Comparable reactions of 2a (E) using other representative Pd
catalysts were as follows. Pd(PPh3)4, trace; Pd(dppf)2Cl2·CH2Cl2, trace;
Pd(OAc)2-tBu3·HBF4, trace; Pd(PPh3)2Cl2, 29%; Pd(dppe)2Cl2, 50%;
Pd(dppb)2Cl2, 80%.
salient features are as follows. (i) Several condition screen-
ings revealed that the Pd(OAc)2-PCy-K2CO3 catalysis
system12 produced the best yield and stereoretention, which
Org. Lett., Vol. 11, No. 19, 2009
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