J. Zhou et al.
CDCl3): d=221.0, 149.9, 141.7, 139.5, 139.1, 136.4, 128.9, 128.4, 128.2,
127.8, 125.9, 125.3, 114.0, 50.7, 48.1, 44.6, 38.3, 36.0, 31.7, 29.5, 26.7, 25.8,
21.7, 14.0 ppm; GC-MS (EI): calcd for C16H28O [M]: 356.21; found:
356.17.
signals), 126.8, 117.3, 35.36, 35.35, 34.2, 34.1, 32.1, 32.0, 20.1 ppm; MS
(ESI): calcd for C24H27O2 [Mꢀ]: 347.20; found: 347.16.
Stoichiometric study of styrene insertion into [Pd(Ph)(I)
presence of AgOTf: A 4 mL vial containing a magnetic stirring bar was
charged with [Pd(PhI)(dnpf)] (19 mg, 0.020 mmol), dnpf (15.1 mg,
ACHTUNGTREN(NUNG dnpf)] in the
A
ACHTUNGTRENNUNG
Heck reaction of para-cyanophenyl triflate and styrene (gram scale): A
0.020 mmol), and dry DMA (0.5 mL) in an argon-filled glove box. After
stirring at room temperature for 5 min, styrene (5 equiv, 10 mg,
0.10 mmol), 1-dodecane (10 mL), AgOTf (5.2 mg, 0.020 mmol), and uro-
tropine (5.6 mg, 0.040 mmol) were added sequentially. The reaction mix-
ture was covered with aluminum foil and was vigorously stirred at room
temperature. An aliquot was removed at intervals and passed through a
short plug of silica gel. The filtrate was subjected to GC analysis to deter-
mine the yield and selectivity of the Heck products. The calibrated GC
yields of the Heck product after 1, 2, and 12 h were determined to be 63,
68, and 70%, respectively. The selectivity of 1,1-diphenylethene versus
(E)-stilbene was determined to 55:1 and remained constant during the
course of the reaction.
dry 25 mL Schlenk tube containing a magnetic stirring bar was sequen-
tially charged with [PdACHTNUGTRNEUNG(dba)2] (69 mg, 0.12 mmol; 2 mol%), dnpf
(180 mg, 0.24 mmol), and dry THF (15 mL) in an argon-filled glove box.
After stirring at room temperature for 15 min, para-cyanophenyl triflate
(1.51 g, 6 mmol), styrene (1.25 g, 12 mmol), n-dodecane (100 mL, GC
standard), and urotropine (1.68 g, 12 mmol) were added sequentially. The
Schlenk tube was capped tightly and the reaction mixture was heated
with stirring in an oil bath maintained at 808C. An aliquot was taken
after 24 h from the reaction mixture under argon. GC analysis indicated
the full conversion of the aryl triflate and that the selectivity of the Heck
products was 18:1. The mixture was passed through a short pad of silica
gel, washing with Et2O. The filtrate was concentrated and purified by
flash chromatography with Et2O/hexane (1:20) as the eluent to give the
desired Heck product as a colorless oil (1.08 g, 88% yield). The minor
isomer was completely removed by flash chromatography (monitored by
GC analysis). When DMA was used as the solvent, the conversion of the
triflate was very low after 12 h (3%). 1H NMR (400 MHz, CDCl3): d=
7.63 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.38–7.34 (m, 3H), 7.30–
7.28 (m, 2H), 5.60 (s, 1H), 5.55 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=148.8, 146.2, 140.3, 132.2, 128.9, 128.6, 128.4, 128.2, 118.9,
116.8, 111.4 ppm; GC-MS (EI): calcd for C15H11N [M]: 205.09; found:
205.08.
Acknowledgements
We thank Singapore National Research Foundation (NRF-RF2008–10)
and Nanyang Technological University for financial support and John-
son-Matthey for a gift of palladium.
Synthesis of the ethyl ester of bexarotene: [PdACTHNUTRGENUG(N dba)2] (5.7 mg, 0.01 mmol,
Catalyzed Cross-coupling Reactions (Eds.: A. de Meijere, F. Dieder-
ich), Wiley-VCH, Weinheim, 2004, pp. 217; e) G. Zeni, R. C.
Nilsson, K. Olofsson, M. Larhed, “Focus on Regioselectivity and
Product Outcome in Organic Synthesis” in The Mizoroki-Heck Re-
action (Ed.: M. Oestreich), Wiley, New York, 2009, pp. 133.
[4] Examples: a) W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org.
[7] a) Review on decarboxylative and decarbonylative Heck reactions:
L. J. Gooßen, N. Rodrꢃguez, K. Gooßen, Angew. Chem. 2008, 120,
3144; Angew. Chem. Int. Ed. 2008, 47, 3100; b) review on oxidative
Heck reactions: Y. Su, N. Jiao, Curr. Org. Chem. 2011, 15, 3362;
c) review on dehydrogenative Heck reactions: J. Le Bras, J. Muzart,
2 mol%), dnpf (15.1 mg, 0.02 mmol, 4 mol%), and dry THF (1.25 mL)
were sequentially charged into a dry 25 mL reaction tube containing a
stirring bar in an argon-filled glove box. After stirring for 15 min, para-
(ethoxycarbonyl)phenyl triflate (149 mg, 0.50 mmol), 2,5,5,8,8-pentameth-
yl-3-vinyl-5,6,7,8-tetrahydronaphthalene (228 mg, 1.0 mmol), n-dodecane
( 50 mL, GC standard), and urotropine (140 mg, 1.0 mmol) were added
sequentially. The reaction tube was sealed tightly with a screw cap and
the reaction mixture was heated with vigorous stirring in an oil bath at
808C. The reaction was complete after 24 h at 808C (monitored by GC
analysis) and the a/b selectivity of the Heck products in the crude mix-
ture was determined to be 26:1. The resulting mixture was passed
through a short pad of silica gel, washing with diethyl ether. The filtrate
was concentrated and purified by flash chromatography with ethyl ace-
tate/hexane (1:15) as the eluent to give the product as a white solid
(180 mg, 95% yield). 1H NMR (400 MHz, CDCl3): d=7.97(d, J=8.4 Hz,
2H), 7.34 (d, J=8.4 Hz, 2H), 7.13 (s, 1H), 7.08 (s, 1H), 5.81 (d, J=
1.1 Hz, 1H), 5.32 (d, J=1.1 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.95 (s,
3H), 1.70 (pseudosinglet, 4H), 1.39 (t, J=7.1 Hz, 3H), 1.31 (s, 6H),
1.28 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=166.7, 149.4, 145.6,
144.5, 142.5, 138.2, 132.9, 129.7, 129.5, 128.21, 128.17, 126.7, 116.8, 61.0,
35.37, 35.36, 34.1, 34.0, 32.1, 32.0, 20.1, 14.5 ppm; GC-MS (EI): calcd for
C26H32O2 [M]: 376.24; found: 376.19.
Synthesis of bexarotene: Degassed methanol (2.0 mL) and 5 m KOH
(0.2 mL) were added slowly under argon to the ethyl ester of bexarotene
(150 mg, 0.4 mmol) in a 10 mL reaction tube containing a stirring bar.
The reaction mixture was heated to reflux in an oil bath with stirring and
the reaction was completed after 2 h (monitored by TLC analysis). The
reaction mixture was cooled down to room temperature and acidified to
pH 2 by the slow addition of 1 m HCl. Methanol was removed on a
rotary evaporator and the remaining aqueous layer was extracted with
ethyl acetate (10 mL). The organic extract was washed with brine, dried
over anhydrous Na2SO4, and concentrated on a rotary evaporator. The
crude product was purified by flash chromatography with ethyl acetate/
hexane (1:1) as the eluent to give the product as a white solid (110 mg,
89%). 1H NMR (400 MHz, CDCl3): d=11.03 (brs, 1H), 8.04 (d, J=
8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.14 (s, 1H), 7.09 (s, 1H), 5.84 (d,
J=1.1 Hz, 1H), 5.35 (d, J=1.1 Hz, 1H), 1.95 (s, 3H), 1.71 (pseudosinglet,
4H), 1.31 (s, 6H), 1.28 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
172.3, 149.3, 146.6, 144.6, 142.5, 138.1, 132.9, 130.5, 128.2 (3 overlapping
ˇ
[10] A selectivity of 9:1 that favors internal insertion was reported for a
special pair of substrates, but for other substrates the selectivity was
much lower: J. Ruan, J. A. Iggo, N. G. Berry, J. Xiao, J. Am. Chem.
[11] Mechanistic study of the cationic pathway;: C. Amatore, B. Godin,
[12] Computational study on regioselectivity in the Heck reaction: R. J.
3510
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 3504 – 3511