Sequential cross-metathesis/phosphorus-based olefination: stereoselective synthesis of 2,4-dienoates

Article abstract of DOI:10.1016/j.tetlet.2007.06.031

A variety of stereodefined 2,4-dienoates have been prepared in a stereoselective manner by sequencing olefin cross-metathesis (CM) with phosphorus-based olefination reactions (Wittig and Horner-Wadsworth-Emmons) in good yield using commercially available reagents.

Full text of DOI:10.1016/j.tetlet.2007.06.031

Tetrahedron Letters 48 (2007) 5367–5370
Sequential cross-metathesis/phosphorus-based
olefination: stereoselective synthesis of 2,4-dienoates
Tapas Paul and Rodrigo B. Andrade*
Temple University, Department of Chemistry, Philadelphia, PA 19122, United States
Received 12 April 2007; revised 5 June 2007; accepted 6 June 2007
Available online 9 June 2007
Abstract—A variety of stereodefined 2,4-dienoates have been prepared in a stereoselective manner by sequencing olefin cross-
metathesis (CM) with phosphorus-based olefination reactions (Wittig and Horner–Wadsworth–Emmons) in good yield using com-
mercially available reagents.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
mercially available Grubbs Second-generation catalyst4
1, terminal and electron-deficient olefins (e.g., crotonal-
dehyde) can be coupled in high yield and with high E:Z
selectivity (>20:1). The reaction is typically clean and
high-yielding, producing an (E)-2-enal, which can be
subsequently treated with an appropriate phosphorus-
based olefinating reagent (e.g., stabilized phosphorane
or phosphonate) in a tandem or one-pot fashion to yield
a stereodefined 2,4-dienoate, depending on the condi-
tions employed. The reaction sequence is summarized
in Scheme 1.
The development of both one-pot and tandem reaction
sequences is driven by the need to streamline linear
synthetic processes.1 This often translates into an increase
in overall product yield resulting from the elimination of
intermediary purification steps, which are both time
consuming and expensive, particularly when chromato-
graphy is required. In order to maximize chemical yield,
all reactions in the tandem sequence should ideally be
clean and efficient with an emphasis on the first. The
identification of reactions that meet these criteria is the
first step towards realizing this goal. Olefin cross
metathesis2 has emerged as a powerful method for the
stereoselective preparation of carbon–carbon double
bonds in high yield, particularly when coupling terminal
and electron-deficient olefins.3 In the presence of com-
Traditional syntheses of 2,4-dienoates generally involve
the iterative olefination of aldehydes using stabilized
Wittig5 or Horner–Wadsworth–Emmons (HWE)6 reac-
tions, which often require reduction–oxidation sequences
to access key enal intermediates between couplings. The
MesN NMes
Cl
Ru
CO2R''
Ph
Cl
Wittig
or
HWE
R
PCy3
R'
Grubbs II 1
CHO
CHO
not isolated
+
or
R
Me
R
R'
CO2R''
R
Scheme 1. Generalized cross-metathesis/phosphorus-based olefination sequence.
Keywords: One-pot; Tandem; Cross-metathesis; Olefination; 2,4-Dienoates.
*
Corresponding author. Tel.: +1 215 204 7155; fax: +1 215 204 9851; e-mail: randrade@temple.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.031

5368
T. Paul, R. B. Andrade / Tetrahedron Letters 48 (2007) 5367–5370
use of vinylogous phosphonates certainly is a more effi-
cient alternative.7 Finally, the chemoselective CM reac-
tion between terminal olefins and 2,4-dienoates8 has
recently been disclosed and applied towards synthesis.9
While good chemoselectivity is achieved with the
(2Z,4E)-dienoate system, which must also be prepared
prior to coupling, (2E,4E)-dienoates display modest
chemoselectivity. Recently, employing 2,4-dienamides
obtained from commercially available sorbic acid has
ameliorated this problem.10 Herein we offer a convenient,
efficient alternative to the aforementioned methods,
which utilizes only commercially available reagents for
the rapid assembly of either (2E,4E)- or (2Z,4E)-dieno-
ates by modifying the second olefination step.11
The reaction mixture was then cooled to 0 ꢁC, treated
with a slight excess of phosphorane 2 and subsequently
warmed to rt. While screening conditions for the second
step, we discovered that equimolar phosphorane
(3.0 equiv) did not result in higher product yields and
that 1.2 equiv of either 2 or 3 would suffice. Our hypoth-
esis that excess crotonaldehyde had decomposed over
the course of the reaction was supported by the fact that
very little methyl sorbate (the byproduct of the Wittig
reaction and crotonaldehyde) was isolated from the
reaction mixture when 3 equiv of 2 were employed.
Yields as high as 77% (see entry 1) were realized with
this procedure, corresponding to an average of 88%
per step. Upon adding phosphorane 2, the solution
was warmed to room temperature and stirred overnight
(12 h). Entry 6 required reflux due to the hindered nat-
ure of phosphorane 3.
2. Results
The one-pot CM/Wittig olefination sequence is summa-
rized in Table 1.12 A variety of terminal olefins were
prepared and subjected to 5 mol % 1 and crotonalde-
hyde in refluxing dichloromethane to effect the first
cross-metathesis step. It was determined that refluxing
the olefin with an excess (3.0 equiv) of crotonaldehyde
for 3 h was the optimal protocol.
All reactions delivered good yields of dienoates 9–14
with entry 6 affording a trisubstituted (2E,4E)-dienoate.
The E/Z geometric isomers were separable by chroma-
tography. While it is known that stabilized phosphor-
anes are stereoselective for the E isomer in the Wittig
reaction, we turned our attention to the Horner–Wads-
worth–Emmons (HWE) reaction in order to (1) increase
Table 1. One-pot CM/Wittig olefination for the stereoselective synthesis of (2E,4E)-dienoates
R1
Ph3P
CO2R2
2: R1=H; R2=Me
Grubbs II 1
CO2R2
3: R1=Me; R2=Et
(5 mol%)
CHO
(3 equiv.)
CHO
+
R
R
Me
R
R1
CH2Cl2
reflux, 3 h
>20/1 E/Z
CH2Cl2
0 ˚C→rt→reflux
not isolated
Entry
1
Olefin
Phosphorane
Product
Yielda,b (ratio: 2E/2Z)c
TBSO
TBSO
CO2Me
2
77% (9:1)
9
4
CO2Me
MeO2C
MeO2C
BzO
2
3
4
2
2
2
57% (9:1)
60% (8:1)
73% (9:1)
5
10
CO2Me
BzO
6
11
CO2Me
7
12
CO2Me
5
6
2
3
48% (11:1)
50% (5:1)
13
8
CO2Et
Me
MeO2C
MeO2C
5
14
a Yields refer to the average of two runs.
b Isolated yield of separable E/Z mixture.
c Ratio determined by 1H NMR.

T. Paul, R. B. Andrade / Tetrahedron Letters 48 (2007) 5367–5370
5369
Table 2. Tandem CM/HWE olefination for the stereoselective synthesis of (2E,4E)-or (2Z,4E)-dienoates
R3
(R5O)2(O)P
CO2R4
15: R3=H; R4=R5=Me
16: R3=Me; R4=R5=Et
17: R3=H;R4=Me;
R5=CH2CF3
CHO
Me
Grubbs II 1
CO2R4
(5 mol%)
CHO
+
or
R
R
R
CH2Cl2
reflux, 3 h
>20/1 E/Z
R2 R3
CHO
THF or diglyme
-78 ˚C→rt
R2
R2=H or Me
not isolated
Me
Entry
1
Olefin
Aldehyde (3 equiv)
Phosphonate
Product
Yielda,b (ratio: 2E/2Z)c
TBSO
TBSO
CO2Et
CHO
Me
16
15
15
17
16
83% (20.1)
18
19
Me
CO2Me
4
TBSO
TBSO
CHO
Me
2
3
4
5
81% (20:1)
55% (18:1)
63% (1:6.5)
69% (5:1)
Me
4
CO2Me
CHO
Me
13
8
CHO
Me
CO2Me
20
8
CO2Et
Me
MeO2C
MeO2C
CHO
Me
5
14
a Yields refer to the average of two runs.
b Isolated yield of separable E/Z mixture.
c Ratio determined by 1H NMR.
the stereoselectivity of the olefination step and (2) access
the Z-enoate by recruiting the Still and Gennari13 phos-
phonate 17 (vide infra). Towards this end, we repeated
the CM sequence with the olefin substrates albeit in a
tandem fashion as HWE reactions are performed in
ethereal solvents (e.g., THF or diglyme).14 The results
are summarized in Table 2.15
prepared via the one-pot CM/Wittig (see Table 1, entry
6) albeit in lower yield (50%).
3. Conclusion
We have developed an efficient olefin cross-metathesis/
phosphorus-based olefination method either in a one-
pot (Wittig) or sequential (HWE) fashion wherein the
latter allows ready access to (2Z,4E)-dienoates in good
yield and with good diastereoselectivity. This process
streamlines traditional reaction sequences to readily ac-
cess useful 2,4-dienoates in a stereoselective fashion. We
are currently investigating other tandem and one-pot se-
quences featuring olefin cross-metathesis and those re-
sults will be reported in due course.
Operationally, the reaction mixtures were concentrated
following the CM step and added to phosphonate
anions corresponding to 15–17 at À78 ꢁC. Yields ranged
from 55% (entry 3) to 83% (entry 1), showing the
synthetic viability of this tandem sequence. The Still–
Gennari olefination with phosphonate 17 delivered
(2Z,4E)-dienoate 20 in 63% yield with a good Z/E ratio
(6.5:1).
In order to expand the scope of this methodology, we
wanted to study what other a,b-unsaturated aldehydes
could be used in the sequence. While (E)-2-methyl-2-
butenal failed to react after 12 h under reflux, recourse
to methacrolein (3 equiv) resulted in a favourable reac-
tion (entry 2). Olefination with trimethyl phosphono-
acetate (16) yielded 81% of dienoate 19 with excellent
2E,2Z selectivity (20:1). Finally, tandem CM/HWE with
phosphonopropionate 16 afforded dienedioate 14 in
69% with good 2E,2Z selectivity (5:1), which was also
4. Experimental
4.1. One-pot CM/Witig sequence (Table 1)
Crotonaldehyde (101 mg, 1.45 mmol) dissolved in deaer-
ated CH2Cl2 (2.2 mL) was added to a solution of olefin
(0.48 mmol) in deaerated CH2Cl2 (1.0 mL). Grubbs sec-
ond-generation catalyst 1 (20 mg, 5 mol %) was added,
and the reaction mixture was heated to 40 ꢁC under an

5370
T. Paul, R. B. Andrade / Tetrahedron Letters 48 (2007) 5367–5370
2. For CM reviews see: Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900, and references cited
therein.
3. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360.
4. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
5. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
6. (a) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73; (b) See
Ref. 5.
Ar atmosphere for 3 h. The reaction mixture was cooled
to 0 ꢁC, and phosphorane 2 (194 mg, 0.58 mmol) was
added. The reaction mixture was stirred at rt for 15 h
(for entries 2 and 6, reaction mixture was refluxed for
1 h), concentrated under reduced pressure and purified
by flash column chromatography eluting with 2–10%
ethyl acetate/hexanes.
4.2. Tandem CM/HWE sequence (Table 2—entries 1, 2
and 5)
7. (a) van den Tempel, P. J.; Huisman, H. O. Tetrahedron
1966, 22, 293; (b) Sato, K.; Mizuno, S.; Hirayama, M. J.
Org. Chem. 1967, 32, 177.
NaH (28 mg, 0.69 mmol) was added to a solution of
phosphonate (0.69 mmol) in THF or diglyme (5.0 mL)
at 0 ꢁC. The reaction mixture was stirred for 30 min.
The crude enal (0.48 mmol) derived from the cross-
metathesis step (see above experimental) was dissolved
in THF or diglyme (3.0 mL) and added to the phospho-
nate solution. The reaction mixture was warmed to rt
and stirred for 15 h. Diethyl ether (10 mL) was added,
and the reaction was quenched with saturated aqueous
NH4Cl (5 mL). The aqueous phase was extracted
with diethyl ether (2 · 20 mL). The combined organic
layers were washed with water (2 · 10 mL), brine (2 ·
10 mL), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash
column chromatography eluting with 2–10% ethyl
acetate/hexanes.
8. (a) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett.
2005, 7, 187; (b) Moura-Letts, G.; Curran, D. P. Org. Lett.
2007, 9, 5.
9. Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733.
10. Ferrie, L.; Amans, D.; Reymond, S.; Bellosta, V.; Capde-
vielle, P.; Cossy, J. J. Organomet. Chem. 2006, 691, 5456.
11. During the review of this manuscript, Snapper published
an article concerning the ruthenium-catalyzed tandem
cross-metathesis/Wittig olefination of terminal olefins for
the synthesis of (2E,4E)-dienoates: Murelli, R. P.; Snap-
per, M. L. Org. Lett. 2007, 9, 1749.
12. Spectral data (1H and 13C NMR) were in agreement for
the following known compounds: Compound 9: Spino, C.;
Rezaei, H.; Dupont-Gaudet, K.; Belanger, F. J. Am.
Chem. Soc. 2004, 126, 9926; Compound 10: Xuan, J. X.;
Fry, A. J. Tetrahedron Lett. 2001, 42, 3275; Compound 11:
Montserrat, C.; de March, P.; Figueredo, M.; Font, J.;
Soria, A. Tetrahedron 1997, 53, 16803; Compound 12:
Horsham, M. A.; Class, T. J.; Johnston, J. J.; Casida, J. E.
J. Agric. Food Chem. 1989, 37, 777; Compound 13: Kim,
D. D.; Lee, S. J.; Beak, P. J. Org. Chem. 2005, 70, 5376,
Compound 14: 1H NMR (400 MHz, CDCl3): d 7.13 (d,
J = 11.2 Hz, 1H), 6.42–6.35 (m, 1H), 6.07–6.00 (m, 1H),
4.19 (q, J = 7.2 Hz, 2H), 3.67 (s, 3H), 2.50 (t, J = 6.4 Hz,
2H), 2.47–2.43 (m, 2H), 1.91 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 173.0, 168.4, 139.7, 137.8, 127.0, 126.2, 60.4,
51.6, 33.3, 28.3, 14.2, 12.5; IR (neat): 2982, 2953, 1739,
1703 cmÀ1; HRMS (FAB) calcd for C12H18O4 + H+,
227.1283; found, 227.1277.
4.3. Tandem CM/HWE sequence (Table 2—entries 3 and
4)
KHMDS (1.06 mL, 0.5 M in toluene, 0.53 mmol) was
added to a solution of phosphonate (0.53 mmol) in
THF (5.0 mL) at À78 ꢁC. The reaction mixture was stir-
red for 30 min. The crude enal (0.48 mmol) derived from
the cross-metathesis step (see above experimental) was
dissolved in THF (3.0 mL) and added to the phospho-
nate solution. The reaction mixture was stirred at
À78 ꢁC for 4 h. Diethyl ether (10 mL) was added, and
the reaction was quenched with saturated aqueous
NH4Cl (5 mL). The aqueous phase was extracted with
diethyl ether (2 · 20 mL). The combined organic layers
were washed with water (2 · 10 mL), brine (2 · 10 mL),
dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chro-
matography eluting with 2–10% ethyl acetate/hexanes.
13. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
14. Attempts at transferring a solution of crude enal in
dichloromethane from the CM step to an ethereal solution
of the appropriate phosphonate anion resulted in lower
product yields.
15. Spectral data (1H and 13C NMR) were in agreement for
the following known compounds: Compound 13: see Ref.
11; Compound 20: Touchard, F. P. Tetrahedron Lett.
2004, 45, 5519, Compound 18: 1H NMR (400 MHz,
CDCl3): d 7.15 (d, J = 11.2 Hz, 1H), 6.38–6.31 (m, 1H),
6.10–6.00 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.61 (t,
J = 6.0 Hz, 2H), 2.25 (q, J = 7.2 Hz, 2H), 1.91 (s, 3H),
1.68–1.61 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.89 (s, 9H),
0.04 (s, 6H); 13C NMR (100 MHz, CDCl3): d 168.6, 142.4,
138.4, 126.3, 125.2, 62.2, 60.4, 32.0, 29.6, 25.9, 18.3, 14.3,
12.5, À5.3. IR (neat): 2953, 2930, 1706 cmÀ1.; HRMS
(FAB) calcd for C17H321O3Si + H+, 313.2199; found,
313.2210. Compound 19: H NMR (400 MHz, CDCl3) d
7.31 (d, J = 15.6 Hz, 1H), 5.89 (t, J = 7.2 Hz, 1H), 5.78 (d,
J = 15.6 Hz, 1H), 3.73 (s, 3H), 3.58 (t, J = 6.8 Hz, 2H),
2.26 (q, J = 8.0 Hz, 2H), 1.76 (s, 3H) 1.65–1.58 (m, 3H),
0.88 (s, 9H), 0.34 (m, 6H). 13C NMR (100 MHz, CDCl3) d
168.0, 149.8, 141.8, 133.1, 115.1, 62.3, 51.4, 32.1, 25.9,
Acknowledgements
Financial support of this work by the Department of
Chemistry at Temple University is gratefully acknowl-
edged. We thank Dr. Yann Schrodi (Materia, Inc.) for
the generous donation of Grubbs II catalyst 1.
References and notes
25.2, 18.3, 12.0, À5.3; IR (neat): 2952, 2930, 1726 cmÀ1
;
HRMS (FAB) calcd for C16H30O3Si + H+, 299.2043;
found, 299.2056.
1. Ho, T.-L. Tandem Organic Reactions; Wiley: New York,
1992.