Synthesis of diphenylhexatriene by the Pd-catalyzed dimerization of cinnamyl acetate

Article abstract of DOI:10.1021/jo400032j

A mild and operationally simple method to synthesize diphenylhexatriene (DPH) is reported. The method relies on the Pd-catalyzed dimerization of cinnamyl acetate and provides efficient access to DPH in a single step.

Full text of DOI:10.1021/jo400032j

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Note
Synthesis of Diphenylhexatriene by the Pd-
Catalyzed Dimerization of Cinnamyl Acetate
Tehetena Mesganaw, G.-Yoon Jamie Im, and Neil K. Garg
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400032j • Publication Date (Web): 15 Feb 2013
Downloaded from http://pubs.acs.org on February 16, 2013
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Synthesis of Diphenylhexatriene by the Pd-Catalyzed Dimerization of Cinnamyl Acetate
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Tehetena Mesganaw, G.-Yoon J. Im, and Neil K. Garg*
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University of California, Los Angeles
Department of Chemistry and Biochemistry
Los Angeles, CA 90095
*neilgarg@chem.ucla.edu
Abstract
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Pd(OAc)2
PPh3 resin, Et3N
OAc
EtCN, 105 °C
(73% yield)
diphenylhexatriene
fluorescent probe
gram scale
A mild and operationally-simple method to synthesize diphenylhexatriene (DPH) is reported. The
method relies on the Pd-catalyzed dimerization of cinnamyl acetate and provides efficient access to
DPH in a single step.
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The synthesis of conjugated hydrocarbons that display interesting fluorescence properties remains
an important area of research. For example, compounds such as diphenylhexatriene (DPH, 1),
DiSC3+(5) (2), and CTMPA (3) (Figure 1), play key roles as fluorescent probes in biological studies.1 Of
these, DPH is exceptionally noteworthy as it can be utilized in an array of applications, such as serving
as a lipid membrane fluorescent probe for cancer studies,2 performing as a biological sensor for
detecting fatty acyl chains,2 and monitoring protein aggregation to identify both amorphous and fibrillar
aggregates.1c
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Figure 1. Conjugated Hydrocarbons as Fluorescent Probes.
N
N
diphenylhexatriene (1)
N
N
S
S
N
N
HN
N
N
(Me)3N
N(Me)3
Me
Me
DiSC3+(5)
(2)
CTMPA (3)
Several reported methods for the synthesis of diphenylhexatriene (1) are summarized in Figure
2. Doyle and Yan disclosed a method to arrive at diphenylhexatriene (1) and its isomer 6 in 55% yield
(98:2 mixture of isomers). Their approach first involved conversion of cinnamaldehyde (4) to diazo
compound 5. Subsequent rhodium-catalyzed dimerization of 5 provided DPH (1).3 The Tian group
reported a stereoselective olefination of triphenylphosphonium ylide 8 with N-sulfonyl imine 7 to arrive
at 1 in 87% yield.4 Kasahara and coworkers discovered the palladium-catalyzed coupling of fumaryl
chloride (9) with styrene (10) to provide 1 in 44% yield.5 Two methods to directly convert
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cinnamaldehyde (12) to DPH (1) in good yields have also been reported. A titanium-catalyzed
dimerization furnished DPH (1) in 65% yield, as recently shown by the Barrero group.6 Finally,
Mioskowski and Falck have disclosed a reductive olefination of cinnamaldehyde (12) via a chromium
Brook rearrangement to yield diphenylhexatriene (1) in 83% yield.7
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Figure 2. Various Approaches to Diphenylhexatriene (1).
Rhodium-Catalyzed Coupling of Vinyldiazomethanes (Doyle)
Ph
Rh2(OAc)4
(1 mol%)
1
6
Ph
H2NNH2/EtOH
CHO
CHN2
+
Ph
Ph
then, MnO2, CH2Cl2
CH2Cl2
4
5
(55% yield, 98:2)
Ph
Ph
Olefination of Triphenylphosphonium Ylides and Imines (Tian)
Ph
Ph
1
6
LDA, THF
SO2Me
H
+
PPh3Cl
N
+
–78 ! 23 °C
Ph
Ph
(87% yield, >99:1)
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8
Ph
Ph
Palladium-Catalyzed Coupling of Alkenes with Fumaryl Chloride (Kasahara)
O
Et
N
O
11
Ph
Cl
+
Ph
Cl
Ph
Pd(OAc)2 (4 mol%)
p-xylene, reflux
O
9
10
1
(44% yield)
Titanium-Catalyzed Carbonyl
Coupling Olefination (Barrero)
Reductive Olefination via Chromium Brook
Rearrangement (Mioskowski and Falck)
CrCl2 (3–4 equiv)
CHO
Cp2TiCl2 (1.2 equiv)
TMSCl, THF
CHO
Ph
Ph
1
1
HSiCl3
THF, 65 °C
12
12
(65% yield)
(83% yield)
While investigating unrelated transformations involving π-allyl Pd intermediates, we
unexpectedly found that cinnamyl acetate (13) may be readily converted to diphenylhexatriene (1) using
Pd catalysis. As shown in Table 1, we initially observed that exposure of cinnamyl acetate to Pd(OAc)2,
PPh3, and triethylamine in DMSO gave 1 in 48% yield (entry 1). We also investigated the dimerization
in toluene, 1,2-dichloroethane, and tetrahydrofuran (entries 2–4), but 1 was not observed when these
solvents were employed.8 Gratifyingly, the use of acetonitrile as solvent furnished 1 in 92% yield (entry
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5). After identifying acetonitrile as the optimal solvent, we examined the influence of ligands. Several
phosphorous-based ligands were tested, namely, triphenyl phosphite, tricyclohexylphosphine, and tri-
ortho-tolylphosphine, but DPH (1) formation was not observed (entries 6–8).8 However, dimerization in
the presence of dppf as the ligand yielded 77% of the desired triene 1 (entry 9). We also investigated the
use of Pd/C without ligand additives, but the reaction shut down completely (entry 10). With these
results in hand the conditions described in entry were selected for further optimization studies. In order
to ease the purification process, the use of a triphenylphosphine resin was examined. To our delight,
replacement of PPh3 with a solid-supported variant gave 1 in quantitative yield (entry 11).9 It was also
found that propionitrile could be substituted for acetonitrile to give 1 in comparable yields (entry 12).
The use of propionitrile was beneficial in that it allowed for reactions to be conducted at higher
temperatures and led to more consistent results in larger-scale experiments.
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Table 1. Optimization of Reaction Conditions.a
Pd source
ligand, Et3N
OAc
solvent, 85 °C
13
1
entry
yieldb
Pd source
ligand
solvent
1
2
PPh3
PPh3
48%
0%
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
DMSO
toluene
3
PPh3
1,2-dichloroethane
tetrahydrofuran
acetonitrile
0%
4
0%
PPh3
5
PPh3
92%
0%
6
acetonitrile
P(OPh)3
PCy3
7
0%
acetonitrile
8
acetonitrile
0%
P(o-tolyl)3
dppf
9
acetonitrile
77%
0%
--
10
acetonitrile
11
12
PPh3 resin
PPh3 resin
acetonitrile
propionitrile
100%
96%c
Pd(OAc)2
Pd(OAc)2
a
Conditions unless otherwise stated: Pd source (5 mol%), ligand (15
mol%), cinnamyl acetate 13 (1 equiv), Et3N (3 equiv) in solvent (0.2
b
1
M) at 85 ºC for 24 h. Yield determined by H NMR analysis of the
crude reaction mixture using hexamethylbenzene as an internal
standard. c Reaction performed at 105 ºC.
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With suitable reaction conditions in hand for the efficient synthesis of 1, we tested the scalability
of our procedure (Figure 3). Performing the coupling using >10 mmol of cinnamyl acetate (13) under
our optimized reaction conditions (Pd(OAc)2, PPh3 resin, and triethylamine in propionitrile at 105 ºC)
gave diphenylhexatriene (1) in 73% isolated yield after flash column chromatography.10 This result
underscores the effectiveness of our method for preparing the fluorescent probe DPH (1).
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Figure 3. Synthesis of Diphenylhexatriene (1).
Pd(OAc)2 (5 mol%)
PPh3 resin, Et3N
OAc
EtCN, 105 °C, 2.5 d
(73% yield)
13
1
We also tested the viability of accessing 1 using substrates other than cinnamyl acetate (Figure
4). Initially, we examined the branched isomer of cinnamyl acetate, 14,11 and subjected it to our
coupling conditions. DPH (1) was formed in 96% yield, which is comparable to the results obtained
using cinnamyl acetate (13).12 Other linear derivatives of cinnamyl alcohol were also probed under our
optimized dimerization conditions. Cinnamyl pivalate 1513 underwent smooth coupling to furnish 1 in
88% yield, whereas the corresponding carbonate 1614 yielded only 27% of the desired product. In the
latter case, the remainder of the mass consisted of unreacted starting material and cinnamyl alcohol.
Finally, commercially available cinnamyl chloride 17 was converted to 1 in 70% yield using our
standard conditions.
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Figure 4. Testing Substrate Variation for the Synthesis of Diphenylhexatriene (1).
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8
Pd(OAc)2 (5 mol%)
PPh3 resin, Et3N
9
EtCN, 105 °C, 1 d
1
OAc
(96% yield)
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Pd(OAc)2 (5 mol%)
PPh3 resin, Et3N
X
EtCN, 105 °C, 1 d
1
15; X = OPiv
16; X = OC(O)OMe
17; X = Cl
88% yield, from 15
27% yield, from 16
70% yield, from 17
In summary, we have developed an efficient means to synthesize the important fluorescent probe
diphenylhexatriene. The method relies on the unusual palladium-catalyzed dimerization of cinnamyl
acetate to furnish DPH (1) in good yield. Our method is scalable and provides access to gram quantities
of the desired conjugated triene. The use of alternate electrophilic derivatives, other than cinnamyl
acetate, can also be used to efficiently access 1.
Experimental Section
Representative Procedure for Optimization Studies (Table 1, entry 1 is used as an example).
Diphenylhexatriene (1). A flame-dried 4-mL vial equipped with a magnetic stir bar was charged with
hexamethylbenzene (6.5 mg, 0.04 mmol, 10 mol%), Pd(OAc)2 (4.6 mg, 0.02 mmol, 5 mol%), and PPh3
(15.7 mg, 0.06 mmol, 15 mol%) while purging with N2. Subsequently, DMSO (2.0 mL), Et3N (167 µL,
1.2 mmol, 3 equiv) and cinnamyl acetate (67 µL, 0.4 mmol, 1 equiv) were added to the reaction vial.
The solvent was sparged with N2 for 20 minutes and the vial was capped with a Teflon-lined screw cap.
The reaction was heated at 85 °C for 24 h. The reaction was allowed to cool to room temperature and
was then diluted with benzene:Et2O (1:1, 5 mL). The solution was filtered by passage over a short plug
of silica plug (x 2), and eluted with additional benzene:Et2O (1:1, 5 mL). The yield was determined by
1H NMR analysis with hexamethylbenzene as an internal standard.
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Diphenylhexatriene (1): To a flame-dried pressure tube equipped with a stir bar was added
Pd(OAc)2 (0.129 g, 0.568 mmol) and PPh3 resin (1.42 g, 1.70 mmol), while purging with N2. The vent
needle was removed and EtCN (19 mL), triethylamine (4.74 mL, 34.0 mmol) and cinnamyl acetate
(1.91 mL, 11.4 mmol) were added. The solvent was sparged with N2 and the resulting mixture was
stirred vigorously for 45 min. The pressure tube was capped and the reaction was heated at 105 °C.
After 2.5 d, the reaction mixture was allowed to cool to 23 °C. The mixture was then diluted with
benzene:Et2O (1:1, 20 mL), filtered by passage over silica gel (x 2), and eluted with additional
benzene:Et2O (1:1, 20 mL). The solvent was removed under reduced pressure. Purification by flash
chromatography (95:5 hexanes:EtOAc) afforded diphenylhexatriene (1) as a yellow solid (0.96 g, 73%
yield). Rf 0.4 (95:5 Hexanes:EtOAc); 1H NMR (500 MHz, CDCl3): δ 7.42 (d, J = 7.5, 4H), 7.32 (t, J =
7.5, 4H); 7.24 (t, J = 7.5, 2H), 6.89 (dddd, J = 15.0, 7.5, 7.5, 3.0, 2H), 6.60 (d, J = 15.0, 2H), 6.52 (dd, J
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= 7.5, 3.0, 2H); C NMR (125 MHz, CDCl3): δ 137.4, 133.6, 132.7, 129.1, 128.7, 127.6, 126.4; IR
(film): 3058, 3013, 1594, 1490, 1447, 1178, 1072 cm-1; HRMS-CI (m/z) [M]+ calcd for C18H16,
232.1252; found, 232.1253; m.p. 193–195 °C. Spectral data match those previously reported.4
ACKNOWLEDGMENT. The authors are grateful to Boehringer Ingelheim, DuPont, Eli Lilly, Amgen,
AstraZeneca, NOBCChE/GlaxoSmithKline (T. M.), Bristol–Myers Squibb (T. M.), Roche, the A. P.
Sloan Foundation, the S. T. Li Foundation, the University of California, Los Angeles, and NIH-NIGMS
(R00 GM079922) for financial support. These studies were supported by shared instrumentation grants
from the NSF (CHE-1048804) and the National Center for Research Resources (S10RR025631).
Supporting Information Available: 1H NMR and 13C NMR spectra for compound 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
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8 These experiments predominantly led to the recovery of unreacted starting material.
9 Commercially available PPh3 resin (CAS# 39319-11-4) was employed.
10
Purification of diphenylhexatriene by silica gel chromatography is accompanied by some mass loss,
which is attributed to the compound’s propensity to precipitate out of solution.
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