Organic Syntheses, Vol. 81, p.63 (2005).
. (E)-2-Methyl-3-phenylacrylic acid butyl ester (1)
. An oven-dried, 250-mL, three-necked, round-bottomed flask
equipped with a reflux condenser
(fitted with an argon inlet adapter
), rubber septum
, glass stopper
, and a teflon-coated magnetic stir bar
is cooled to room temperature under a flow of argon. The flask is charged with bis(tri-tert-butylphosphine)palladium (Pd(P(t-Bu)3)2) (0.482 g, 0.943 mmol, 3.0 mol% Pd)
) and again purged with argon
. Toluene (32 mL)
) is added, and the mixture is stirred at room temperature, resulting in a homogeneous brown-orange solution. Chlorobenzene (3.20 mL, 31.5 mmol) (Note 11)
, N-methyldicyclohexylamine (Cy2NMe) (7.50 mL, 35.0 mmol) (Note 12)
, and butyl methacrylate (5.50 mL, 34.6 mmol) (Note 12)
are then added successively via syringe
. The resulting mixture is allowed to stir at room temperature for 5 min, resulting in a homogeneous light-orange solution. The rubber septum is then replaced with a glass stopper, and the flask is heated in a 100°C oil bath
under a positive pressure of argon for 22 hr (Note 13)
. Upon heating, the solution becomes bright canary-yellow in color, and within 10-15 min the formation of a white precipitate (the amine hydrochloride salt) is observed. Upon completion of the reaction, shiny deposits of palladium metal form on the sides of the flask, and a large quantity of white precipitate is present. The reaction mixture is allowed to cool to room temperature and then diluted with 100 mL of diethyl ether
. The resulting solution is washed with 100 mL of H2
O, and the aqueous layer is extracted with three 50-mL portions of diethyl ether
. The combined organic phases are washed with 100 mL of brine
and then concentrated by rotary evaporation. Any residual solvent is removed at 0.5 mm. The crude product, a dark-brown oil, is then purified by flash column chromatography (Note 14)
to afford 6.67 - 6.72 g
) of 1
as a pale red-orange liquid. This liquid appears to be pure by 1
H and 13
C NMR spectroscopy; however, if desired, the discoloration can be removed by filtering the product through a small column of silica gel (3 cm diameter × 10 cm height), which furnishes 6.49-6.62 g
) of 1
as a clear, colorless liquid (Notes 15
was prepared according to the following procedure. In a nitrogen-filled Vacuum Atmospheres glovebox
, a 100-mL, one-neck, round-bottomed flask
equipped with a teflon-coated magnetic stir bar
is charged with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (2.98 g, 3.25 mmol) (Note 3)
. A solution of tri-tert-butylphosphine (P(t-Bu)3) (2.88 g, 14.2 mmol) (Note 4)
in 43 mL of N,N-dimethylformamide (DMF) (Note 5)
is then added to the reaction flask via a glass pipette
, and the resulting dark green-brown solution is stirred at room temperature for 23 hr. The reaction mixture is then filtered through a 30-mL medium-porosity glass frit to collect the unpurified product, Pd(P(t-Bu)3)2
, as a gray solid. The reaction flask is rinsed with three 6-mL portions of DMF
and 5 mL of methanol (Note 6)
, which are passed through the glass frit (the final rinses should be colorless). The reaction product is then dissolved in 100 mL of toluene (Note 7)
, and the resulting solution is filtered through a 3-cm diameter 0.45 µm Gelman acrodisc (to remove some insoluble black material) into a 250-mL Schlenk tube
, affording a homogeneous orange-yellow solution. The Schlenk tube is removed from the glovebox, and the toluene
solution is concentrated under high vacuum (0.5mm) to a volume of approximately 25 mL, at which point a white crystalline solid begins to precipitate. The Schlenk tube is taken into the glovebox, and the toluene
solution and crystalline solid are transferred to a 250-mL Erlenmeyer flask
via a glass pipette. MeOH (100 mL)
is then added slowly via pipette over 10 min, resulting in the precipitation of additional white crystalline solid. The solution is allowed to stand for one hour, and then the mother liquor is separated from the solid via pipette. The solid is washed with two 10-mL portions of MeOH
, transferred to a tared 20-mL glass vial
, and dried under high vacuum, affording 2.41 g
) of Pd(P(t-Bu)3)2
as a white, crystalline solid (Note 8)
. The Pd(P(t-Bu)3)2
can be stored indefinitely under nitrogen
in a Vacuum Atmospheres glovebox. Although Pd[P(t-Bu)3]2
has been reported to be "stable in air in the solid state,"2
if a glovebox is not available, it is recommended that Pd[P(t-Bu)3]2
be stored in a tightly capped vial in a desiccator
, preferably under argon
Alternatively, Pd[P(t-Bu)3]2 may be purchased from Strem Chemicals
Pd2(dba)3 was purchased from the Aldrich Chemical Company
and used as received.
P(t-Bu)3 (99%) was purchased from Strem Chemicals
and used as received.
DMF (anhydrous, DriSolv) was purchased from EM Science
and degassed under high vacuum for 10-15 min prior to use.
Methanol (certified A.C.S., purchased from Fisher Scientific)
was distilled from Mg(OMe)2
and was degassed by three freeze-pump-thaw cycles prior to use.
Toluene (J. T. Baker; CYCLE-TRAINER solvent delivery kegs)
was vigorously purged with argon
for 2 hr and then passed through two packed columns of neutral alumina and copper(II) oxide
H} NMR (C6
, 202 MHz): δ 85.3; 1
H NMR pdf
, 500 MHz): δ 1.51 (t, J
= 5.4 Hz). The NMR sample must be prepared under inert atmosphere to avoid aerobic oxidation of the catalyst as evidenced by free P(t
at δ 1.27 ppm in the 1
H NMR spectrum. Even with these precautions, ca. 1% of P(t
Toluene (anhydrous, 99.8%, Sure/SealTM bottle) was purchased from the Aldrich Chemical Company
and used as received.
is an equally suitable solvent for these Heck couplings (and is the solvent used in the published procedures); however, due to the lower cost and the lower toxicity of toluene
, it was chosen as the solvent for these reactions.
Chlorobenzene (anhydrous, 99.8%, Sure/SealTM bottle) was purchased from the Aldrich Chemical Company
and used as received.
The progress of the reaction was monitored by GC.
Flash column chromatography was performed using silica gel (6 cm diameter × 35 cm height), eluting with 19/1 hexane/diethyl ether
has the following properties: bp 111°C (1 mm) 1
H NMR pdf
, 500 MHz) δ: 0.98 (t, J
= 7.5, 3H), 1.45 (sext, J
= 1.0, 2H), 1.71 (qn, J
= 1.0, 2H), 2.12 (d, J
= 1.5, 3H), 4.22 (t, J
= 6.6, 2H), 7.33 (m, 1H), 7.39 (m, 4H), 7.68 (apparent d, J
= 1.5, 1H); 13
C NMR (CDCl3
126 MHz): δ 13.7, 14.0, 19.3, 30.7, 64.8, 128.2, 128.4, 128.7, 129.6, 136.0, 138.8, 168.8; IR (neat, cm−1
): 3059, 3026, 2960, 2933, 2873, 1709, 1635, 1492, 1448, 1388, 1356, 1254, 1201, 1115, 1074, 1003, 931, 766, 704; Anal. Calcd for C14
: C, 77.03; H, 8.31. Found: C, 77.02; H, 8.30.
The checkers found that the product could be further purified by distillation (110°C/1 mm).
To allow more efficient stirring, it was beneficial to run this reaction at half of the concentration (2 mL solvent per mmol of aryl chloride) of the original published procedure (1 mL solvent per mmol of aryl chloride).
Styrene (99+%) was purchased from Aldrich Chemical Company
and gently sparged with argon for 5-10 min prior to use.
Flash column chromatography was performed using silica gel (10 cm diameter × 27 cm height), eluting with 4/1 toluene/hexane
. A small amount of aryl chloride that remained unreacted after 72 hr was recovered mixed with a small quantity (<5%
) of the desired product.
has the following properties: mp (corr.) 115-117°C
(lit.4 mp 115 °C
H NMR pdf
, 500 MHz): δ 7.09 (d, J
= 16.5, 1H), 7.22 (d, J
= 16.5, 1H), 7.33 (d, J
= 7.1, 1H), 7.40 (t, J
= 7.1, 2H), 7.54 (d, J
= 7.5, 2H), 7.59 (d, J
= 8.3, 2H), 7.64 (d, J =
8.4, 2H); 13
C NMR (CDCl3
, 126 MHz): δ 110.8, 119.3, 126.9, 127.0, 127.1, 128.9, 129.1, 132.6, 132.7, 136.5, 142.1; IR (neat, cm−1
): 3029, 2964, 2225, 1648, 1604, 1531, 1450, 1278, 1226, 1174, 1095, 966, 821, 769; Anal. Calcd for C15
N: C, 87.78; H, 5.40; N, 6.82. Found: C, 87.43; H, 5.26; N, 6.86.
The checkers found that the product could be further purified by sublimation (127°C/0.5 mm).
The submitters obtained the product in 89%
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
Since its discovery in the early 1970's, the palladium
-catalyzed arylation of olefins (Heck reaction; eq 1 and Figure 1)5,6
has been applied to a diverse array of fields, ranging from natural products synthesis7,8
to materials science9
to bioorganic chemistry.10
This powerful carbon-carbon bond-forming process has been practiced on an industrial scale for the production of compounds such as naproxen11
and octyl methoxycinnamate
The Heck reaction is typically performed in the presence of a palladium/tertiary phosphine
catalyst and a stoichiometric amount of an inorganic or organic base. High functional-group tolerance and the ready availability and low cost of simple olefins contribute to the exceptional utility of the Heck arylation.
Until recently, one important unsolved problem for the Heck reaction was the poor reactivity of aryl chlorides, which are arguably the most attractive class of aryl halides, due to their lower price and greater availability as compared with the corresponding bromides and iodides.13,14
For the few catalyst systems that have displayed activity for Heck couplings of aryl chlorides (e.g., those of Milstein (bulky, electron-rich chelating bisphosphines),15
Herrmann (palladacycles, N
Reetz (tetraphenylphosphonium salts),17
and Beller (phosphites),18,19,20
the scope of the reactions has been quite narrow and the reaction temperatures have been rather high (≥120 °C). This need for elevated temperatures can be problematic for a variety of reasons, including decomposition of thermally unstable substrates and decreased regio- and stereoselectivities.
, in the presence of Cy2NMe
, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21,22,23
Example A, the coupling of chlorobenzene
with butyl methacrylate
, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin; α-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24
) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26
). Example B, the coupling of 4-chlorobenzonitrile
, demonstrates that Pd/P(t-Bu)3
can catalyze the Heck reaction of activated aryl chlorides at room temperature
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