Regio- and stereoselective preparation of dienylcarboxylic acids and dienylphosphonic esters using a (Z)-alkenyl sulfone-titanocene(II) system

Article abstract of DOI:10.1016/j.tetlet.2008.03.055

Titanocene(II)-promoted alkenylation of functionalized alkynes with (Z)-alkenyl sulfones proceeded with high regio- and stereoselectivity to produce functionalized dienes. Conjugated dienylcarboxylic acids and dienylphosphonic esters were obtained using a

Full text of DOI:10.1016/j.tetlet.2008.03.055

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3071–3074
Regio- and stereoselective preparation of dienylcarboxylic
acids and dienylphosphonic esters using a (Z)-alkenyl
sulfone–titanocene(II) system
Akitoshi Ogata, Masami Nemoto, Yoshitaka Takano, Akira Tsubouchi, Takeshi Takeda *
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Received 4 February 2008; revised 7 March 2008; accepted 11 March 2008
Available online 14 March 2008
Abstract
Titanocene(II)-promoted alkenylation of functionalized alkynes with (Z)-alkenyl sulfones proceeded with high regio- and stereoselec-
tivity to produce functionalized dienes. Conjugated dienylcarboxylic acids and dienylphosphonic esters were obtained using acetylenic
lithium carboxylates and dialkyl phosphonates as starting materials.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Alkenyl sulfones; Titanocene(II); Alkynes; Dienoic acids; Dienylphosphonic esters
Functionalized conjugated dienes are useful synthetic
intermediates for the synthesis of various natural pro-
ducts.1 A variety of methods for their preparation have
been developed; they often require a multistep procedure.
Recently, we have reported that the alkenylation of car-
bonyl compounds and alkynes proceeded with complete E
stereoselectivity by the treatment with (Z)-alkenyl methyl
sulfones 1 in the presence of the titanocene(II) reagent
Cp2Ti[P(OEt)3]2 2.2 This alkenylation was successfully
applied to the stereoselective preparation of titanium
vinylvinylidene complexes from alkynyl phenyl sulfones,
which involved regioselective coupling of alkynyl and alke-
nyl sulfones.3 These results prompted us to further investi-
gate the stereoselective preparation of functionalized dienes
3, 4 and 5 by the titanocene(II)-promoted reactions of
functionalized alkynes 6, 7 and 8 with (Z)-alkenyl methyl
sulfones 1 (Scheme 1).
butenyl sulfone (1a) with the titanocene(II) reagent 2
followed by the aqueous workup gave the corresponding
2,4-dienoic ester 3a along with a trace amount of its regio-
isomer (Scheme 2). Although the unsaturated ester 3a thus
obtained was a 1:1 mixture of the (2E,4E)- and (2Z,4E)-iso-
mers, the former isomer was produced as a major product
when the reaction was quenched by the addition of benzoic
acid (3 equiv) before the aqueous workup. The similar reac-
tion of the tert-butyl ester 6b with sulfone 1b also gave the
(2E,4E)-dienoate 3b preferentially (74%, 2E,4E:2Z,4E =
85:15).
Various methods for the preparations of 2,4-dienoic
esters have been reported so far. For example, the Wittig
olefination of a,b-unsaturated aldehydes with (triphenyl-
phosphoranylidene)acetic esters,4 the Heck reaction of
FG
Cp2Ti[P(OEt)3]2
R2
R1
2
First, we examined the titanocene(II) 2-promoted reac-
tion of a,b-acetylenic esters 6 with 1. The treatment of ethyl
5-phenyl-2-pentynoate (6a) and methyl (Z)-4-phenyl-1-
+
FG
SO2Me
R1
R2
: FG = COOR3
: FG = COOLi
: FG = PO(OEt)
: FG = COOR3
: FG = COOH
: FG = PO(OEt)
1
6
7
8
3
4
5
2
2
*
Corresponding author. Tel./fax: +81 42 388 7034.
Scheme 1.
E-mail address: takeda-t@cc.tuat.ac.jp (T. Takeda).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.055

3072
A. Ogata et al. / Tetrahedron Letters 49 (2008) 3071–3074
H2O
titanocene(II) 2-(Z)-alkenyl sulfone 1 system. The lithium
Ph
Ph
COOEt
salts 7 were treated with sulfones 1 and 2 to produce the
dienoic acids 4 after acidic aqueous workup (Table 1).11
It is of interest that the reaction of the acetylenic lithium
carboxylates 7 is much more regio- and stereoselective than
that of the corresponding esters 6; the (2E,4E)-dienoic
acids 4 were obtained with >91% stereoselectivity without
the formation of their regioisomers.
The E-selective alkenylation is explained by the forma-
tion of the five-membered titanacycle 9 with retention of
configuration of 1 and subsequent syn-elimination similarly
to the alkenylation of unfunctionalized alkynes.2 Proton-
ation of the dienyltitanium species 10 affords the function-
alized dienes 3 and 4 (Scheme 3). The formation of the
(2Z,4E)-isomers in the reaction of acetylenic esters 6 would
be attributable to the protonation via titanium allenolates
11 produced by the C to O-titanium migration of 10. The
formation of minor stereoisomers of dienoic acids 4 is also
explained by a similar isomerization of the initially formed
dienyltitanium species 10 to 11.
1a
Ph
2
SO2Me
(2 equiv)
3a
(3 equiv)
(72%; 2E,4E:2Z,4E = 50:50)
+
0 ºC, 1 h
Ph
1) PhCO2H
(3 equiv)
3a
6a
COOEt
2) H2O
(72%; 2E,4E:2Z,4E = 79:21)
Ph
1b
H13C6
SO2Me
2
1) PhCO2H
(3 equiv)
(2 equiv)
COOtBu
(3 equiv)
Ph
+
2) H2O
0 ºC, 1 h
3b
H13C6
6b
(74%; 2E,4E:2Z,4E = 85:15)
COOtBu
Scheme 2.
a,b-unsaturated esters,5 the Suzuki coupling between alke-
nyl boranes and b-halo-a,b-unsaturated esters,6 the Stille
coupling between alkenystannanes and b-halo-a,b-unsatu-
rated esters,7 the ruthenium-catalyzed coupling between
alkynes and acrylates8 and the cross-metathesis between
terminal olefins and electron-deficient 1,3-dienes.9
Although the low-valent titanium reagent-mediated alke-
nylation of a certain acetylenic ester with terminal alkynes
has been studied,10 the alkenylation of acetylenic acids has
not been investigated yet. Then we examined the alkenyl-
ation of lithium salts of a,b-acetylenic acids 7 utilizing a
This alkenylation system was found to be versatile for
the preparation of functionalized conjugated dienes; the
simple treatment of diethyl phenylethynylphosphonate
(8a)12 with 1a (1.5 equiv) and 2 (3 equiv) at 0 °C for 1 h fol-
lowed by the aqueous workup gave diethyl (1Z,3E)-2,6-
diphenyl-1,3-hexadienylphosphonate (5a) in 59% yield as
Table 1
Preparation of dienoic acids 4a
Entry
1
Acetylenic lithium carboxylate 7
(Z)-Alkenyl sulfone 1
Dienoic acid 4 (Yield /%; 2E,4E:2Z,4E)b
Ph
Ph
Ph
4a (78, >99:1)
COOH
7a
COOLi
SO2Me
1a
Ph
Ph
Ph
2
3
7a
4b (72, >99:1)
COOH
SO2Me
1b
Ph
Ph
H13C6
7a
4c (85, 95:5)
COOH
SO2Me
1c
H13C6
H13C6
H13C6
4
5
1a
1b
4d (66, 93:7)c
COOH
COOLi
Ph
Ph
7b
H13C6
7b
4e
(86, 96:4)
COOH
H13C6
6
7
7b
1c
1a
4f (69, 91:9)c
4g (68, 92:8)
4h (72, 93:7)
COOH
H13C6
Ph
H3C
H3C
COOH
COOLi
7c
H3C
8
7c
1b
COOH
Ph
a
All the reactions were performed with a similar procedure as described in the text.
Isolated yield based on the carboxylate 7 used.
Contaminated with a small amount of (Z)-2-nonenoic acid. The yield is corrected for the contaminant.
b
c

A. Ogata et al. / Tetrahedron Letters 49 (2008) 3071–3074
3073
Me
O
Cp2
Ti
O
R1
COOR3
R2
R2
S
R1
COOR3
R2
2
R2
TiCp2
H2O
COOR3
R1
+
1
COOR3
COOR3
R1
(PhCO2H)
H
MeO2S
TiCp2SO2Me
H
R2
10
9
t
6
7
(R3 = Et, Bu)
3
4
(R3 = Et, tBu)
(R3 = H)
(R3 = Li)
R2
R1
OR3
OTiCp2SO2Me
11
Scheme 3.
Table 2
Preparation of dienylphosphonic esters 5a
Entry
Acetylenic phosphonic ester 8
(Z)-Alkenyl sulfone 1
Dienylphosphonic ester 5 (Yield /%)b
Ph
Ph
Ph
5b (59)
1
PO(OEt)2
SO2Me
1a
Ph
PO(OEt)2
8a
Ph
Ph
2
3
4
5
8a
8a
5b (60)c
PO(OEt)2
SO2Me
1b
Ph
Ph
H13C6
5c (62)
PO(OEt)2
SO2Me
1c
H13C6
H13C6
H13C6
1a
1b
5d (67)
PO(OEt)2
PO(OEt)2
Ph
8b
H13C6
8b
5e (59)d
PO(OEt)2
Ph
6
1b
5f (63)
PO(OEt)2
Ph
PO(OEt)2
8c
a
All the reactions were performed with a similar procedure for the preparation of dienoic acids 4.
Isolated yield based on the phosphonic ester 8 used.
Contaminated with a small amount of triethyl phosphate. The yield is corrected for the contaminant.
A mixture of stereoisomers (1E,3E:1Z,3E = 93:7).
b
c
d
a sole product. Similarly, various dienylphosphonic esters
useful for the straightforward and regioselective prepara-
tion of acyclic dienylphosphonic esters.
5b–f were obtained by the titanocene(II) 2-promoted cou-
pling of the alkenyl sulfones 1 with acetylenic phosphonic
esters 8 with excellent regio- and stereoselectivity; no
formation of regio- and stereoisomers was observed in all
the reactions examined except for 5e (Table 2). Although
the preparation of dienylphosphonic esters by the zircono-
cene(II)-promoted coupling between terminal alkynes and
acetylenic phosphonic esters was reported, the conjugated
dienes obtained were mixtures of regioisomers.13 As for
the preparation of 1,3-butadienylene-1,4-diphosphonic
esters, the Ti(OiPr)4/iPrMgBr-promoted dimerization of
diethyl 1-hexynylphosphonate was reported.14 The regio-
selective preparation of dienylphosphonic esters by the
palladium-catalyzed Heck-type reaction of diethyl vinyl-
phosphonate with cyclic triflates was also reported.15 The
results listed in Table 2 show that our new procedure is
In conclusion, we have developed regio- and stereoselec-
tive alkenylation of functionalized alkynes utilizing the
titanocene(II) reagent and (Z)-alkenyl sulfones. These
methods are useful for the preparation of various a,b,c,d-
dienoic acids and dienylphosphonic esters with excellent
stereoselectivity.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific
Research (No. 18350018) and Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Trans-
formations of Carbon Resources’ (No. 19020016) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.

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A. Ogata et al. / Tetrahedron Letters 49 (2008) 3071–3074
˚
11. Typical procedure: Finely powdered molecular sieves 4 A (60 mg),
magnesium turnings (16 mg, 0.66 mmol), and Cp2TiCl2 (149 mg,
0.6 mmol) were placed in a flask and dried by heating with a heat gun
in vacuo (2–3 mmHg). After cooling, THF (1.5 mL) and P(OEt)3
(0.21 mL, 1.2 mmol) were added successively with stirring at 25 °C.
After 3 h, the reaction mixture was cooled to 0 °C. A THF (1 mL)
solution of 1a (63 mg, 0.3 mmol) was added dropwise over 5 min to
the mixture and then the mixture was stirred for 30 min. After
powdered 7a (36 mg, 0.2 mmol) was added, stirring was continued at
0 °C for 1 h. The reaction was quenched by the addition of 1 M HCl,
and the insoluble materials were filtered off through Celite and
washed with ether. The layers were separated, and the aqueous layer
was extracted with ether. After the combined organic extracts were
dried (Na2SO4), the solvent was evaporated. Purification of the
residue by silica gel column chromatography (hexane/AcOEt, 3:1)
gave 4a (48 mg, 78%; 2E,4E:2Z,4E = >99:1): 1H NMR d 2.53 (dt,
J = 13.5, 7.2 Hz, 2H), 2.68–2.80 (m, 4H), 2.97–3.08 (m, 2H), 5.74 (s,
1H), 6.09 (d, J = 15.8 Hz, 1H), 6.24 (dt, J = 15.6, 6.8 Hz, 1H), 7.13–
7.35 (m, 10H), 11.1 (bs, 1H); 13C NMR d 30.3, 34.8, 35.4, 35.9, 117.0,
126.0, 126.1, 128.3, 128.4, 128.5, 132.7, 137.2, 141.1, 141.8, 158.9,
172.2; IR (KBr) 3100–2300, 2925, 1671, 1634, 1591, 1417, 1285, 1265,
1248, 1198, 747, 700 cmÀ1. Anal. Calcd for C21H22O2: C, 82.32; H,
7.24. Found: C, 82.28; H, 7.19.
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