Di-tert-butylneopentylphosphine (DTBNpP): An Efficient Ligand in the Palladium-Catalyzed α-Arylation of Ketones

Article abstract of DOI:10.1002/ejoc.201402474

Di-tert-butylneopentylphosphine (DTBNpP) and palladium(II) acetate provide an efficient catalytic system for the α-arylation of ketones. Aryl bromides were coupled with ketones using 0.25-0.5 mol-% Pd(OAc)₂/DTBNpP in toluene at 50 C, whereas aryl chlorides required a higher catalyst loading (0.5-2.0 mol-%) and a higher temperature (80 C). Coupling of 2-bromophenol with ketones using the Pd/DTBNpP system provides an efficient route for the synthesis of benzofurans.

Full text of DOI:10.1002/ejoc.201402474

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FULL PAPER
DOI: 10.1002/ejoc.201402474
Di-tert-butylneopentylphosphine (DTBNpP): An Efficient Ligand in the
Palladium-Catalyzed α-Arylation of Ketones
Steven M. Raders,[a] Jessica M. Jones,[a] Jeffrey G. Semmes,[a] Steven P. Kelley,[a]
Robin D. Rogers,[a] and Kevin H. Shaughnessy*[a]
Keywords: Synthetic methods / C–C coupling / Palladium / Phosphane ligands / Heterocycles / Ketones
Di-tert-butylneopentylphosphine (DTBNpP) and palladi-
um(II) acetate provide an efficient catalytic system for the α-
arylation of ketones. Aryl bromides were coupled with
ketones using 0.25–0.5 mol-% Pd(OAc)2/DTBNpP in toluene
at 50 °C, whereas aryl chlorides required a higher catalyst
loading (0.5–2.0 mol-%) and a higher temperature (80 °C).
Coupling of 2-bromophenol with ketones using the Pd/
DTBNpP system provides an efficient route for the synthesis
of benzofurans.
group has reported the use of di-tert-butylneopentylphos-
phine (DTBNpP)[12] in palladium-catalyzed C–N and C–C
bond-forming reactions (Figure 1).[13] The neopentyl group
provides a unique set of steric effects compared to that of
tert-butyl groups. Whereas the tert-butyl group provides a
relatively constant steric influence as a function of confor-
mational changes, the neopentyl substituent affords a con-
formationally flexible steric influence. Calculated structures
for Pd(PR3) complexes predict small Pd–P–C–C dihedral
angles for the neopentyl group, leading to a larger steric
influence than is exerted by tert-butyl [solid cone angles:
TTBP (194°) Ͻ DTBNpP (198°) Ͻ TBDNpP (210°) Ͻ
TNpP (227°)].[13a] Similar conformations are seen in X-ray
structures of Pd(PR3)2 complexes of these ligands.[14] Struc-
turally characterized four-coordinate PdII complexes have
larger Pd–P–C–C dihedral angles for the neopentyl substit-
uent than are seen for two-coordinate Pd0 complexes, re-
sulting in a lower steric demand. This diminished steric de-
mand allows Pd-TNpP complexes to be effective catalysts
in the coupling of sterically demanding substrates.[15] We
envisioned that α-arylation of ketones would be an interest-
ing platform in which to explore the steric effects of neo-
pentyl ligands.
Introduction
The palladium-catalyzed α-arylation of carbonyl deriva-
tives originally reported by Buchwald,[1] Hartwig,[2] and
Miura[3] has become a powerful method for synthesis of 2-
aryl carbonyl derivatives.[4] The utility of this methodology
has been demonstrated in the synthesis of complex natural
products and in process-level production of active pharma-
ceutical intermediates.[5] There have been great advances
over the past decade towards the α-arylation of various
carbonyl groups. Sterically demanding, electron rich
mono-[6] and bidentate[7] phosphines and N-heterocyclic
carbenes[8] provide highly active catalysts for the coupling
of aryl halides and pseudohalides with a range of carbonyl
derivatives.
Coupling of aryl halides with silyl enol ethers is an alter-
nate approach to palladium-catalyzed synthesis of α-aryl
carbonyl derivatives. Verkade and Hartwig reported that
Pd(OAc)2/TTBP gave high yields in the presence of a mix-
ture of CsF and Bu3SnF.[9] In 2010, Shreeve, et al. reported
that silicon reagents with bulky substituents increase the
yield of desired α-arylated products.[10] In this methodology,
it was discovered that a fluorine in the α position of the
silyl enol ether improved reaction rates. A drawback of this
method is that it requires an extra synthetic step to generate
the silyl enol ether from a ketone precursor.
Enolate α-arylation is highly sensitive to the steric and
electronic environment at the catalyst center. The ligand
properties affect whether the enolate prefers to be O- or C-
bound as well as the rate of reductive elimination.[11] Our
Figure 1. Neopentylphosphine ligands.
[a] Department of Chemistry, Box 870336, The University of
Alabama,
Our group, in collaboration with Colacot, reported ini-
tial results on the α-arylation of ketones using Pd-DTBNpP
catalysts generated in situ [Pd2(dba)3/DTBNpP] or from
Pd(0, I, or II) precatalysts.[14] The application of Pd(η3-
allyl)(DTBNpP)Cl and Pd(DTBNpP)2 resulted in good
Tuscaloosa, AL 34587-0336, USA
E-mail: kshaughn@ua.edu
http://bama.ua.edu/~kshaughn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402474.
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yields for the coupling of aryl bromides and chlorides with Table 1. Coupling of aryl bromides and ketones.[a,b]
propiophenone, whereas catalysts formed in situ from
Pd2(dba)3 and DTBNpP were less effective. We sought to
identify conditions where the in situ-generated catalyst
could be used effectively. Herein, we report that the catalyst
formed from Pd(OAc)2/DTBNpP is highly effective in the
synthesis of α-arylated compounds from aryl bromides and
chlorides and also in condensations of 2-bromophenol with
ketones to afford benzofurans.
Results and Discussion
Initial optimization of the coupling of 2-bromotoluene
and propiophenone with a variety of inorganic bases (i.e.
NaOtBu, Na2CO3, K3PO4 etc.) and amine bases (Et3N,
iPr2NEt, Cy2NMe, etc.) showed NaOtBu to be the optimal
base. Different polar and non-polar solvents, along with
varying temperatures, were applied to our substrates; tolu-
ene was found to be a suitable solvent producing high prod-
uct yields at 50 °C. Under these conditions, high yields were
obtained using 0.25 mol-% Pd(OAc)2 and 0.25 mol-%
DTBNpP.
With these optimized conditions in hand, a variety of
aryl bromides were coupled with ketones (Table 1). Propio-
phenones were efficiently coupled to a range of aryl brom-
ides with high selectivity for the monoarylation product.
Excellent yields were obtained for aryl bromides with either
no, or one, ortho-substituent (1a–1g). Both electron-de-
ficient and electron-rich aryl bromides gave good yields.
The more hindered 2-bromo-m-xylene gave low conversions
to 1h using DTBNpP. However, the use of the more steri-
cally flexible TNpP ligand provided a 92% yield of 1h. We
have seen similarly improved performance for Pd/TNpP cat-
alysts in the coupling of hindered aryl halides with aryl-
amines.[15] In the case of 1-bromo-2-methoxynaphthalene,
high yields of 1i were achieved using the DTBNpP ligand,
although 1 mol-% of Pd(OAc)2 was necessary. A slightly
improved yield was achieved using Pd2(dba)3 (0.5 mol-%)
[a] Reaction conditions: 2 mmol aryl bromide, 2.4 mmol ketone,
0.25 mol-% Pd(OAc)2, 0.25 mol-% DTBNpP, 3.0 mmol NaOtBu,
50 °C, 24 h (time unoptimized). [b] Isolated yields (average of three
runs). [c] 0.5 mol-% Pd(OAc)2 and 0.25 mol-% DTBNpP. [d] 0.25
mol-% TNpP. [e] 1 mol-% Pd(OAc)2. [f] 0.5 mol-% Pd2(dba)3 and
1 mol-% DTBNpP. [g] 2 equivalents aryl bromide. [h] The tetralone
instead of Pd(OAc)2. The heterocyclic substrate 2-bromo- product underwent air oxidation to naphthol 1q during isolation.
[i] Product obtained as a mixture with 2,2-di(4-biphenyl)-4-methyl-
pyridine was tolerated by the catalyst, although a slightly
3-pentanone (1t, 19%) and 2-(4-biphenyl)-2-methyl-3-pentanone
(1u, 15%). Total yield of arylated product was 92%.
increased catalyst loading [0.5 mol-% Pd(OAc)2] was re-
quired to achieve high yields. The use of 1-(2-thienyl)pro-
panone also led to high yields of mono-α-arylated product
1p in 95% yield. Coupling of 1-bromo-2-isopropylbenzene
and tetralone gave 1-(2-isopropylphenyl)-2-naphthol (1q) in
95% isolated yield. This product was proposed to have
formed upon air oxidation of tetralone 1s during column
chromatography [Equation (1)]. Aromatization was not ob-
served with 1p under similar isolation conditions.
using 1 mol-% catalyst.
The more sterically hindered isobutyrophenone substrate
could be arylated with para- and meta-substituted aryl hal-
ides to afford 1l, 1m, and 1n in 82, 91, and 95% yield,
respectively. However, no conversion was obtained with or-
tho-substituted aryl bromides, even with TNpP as the li-
gand. Notably, monoarylation of methyl ketones is often a
challenge due to competing overarylation.[6e,6f,16] The
DTBNpP/Pd system provides poor monoarylation selectiv-
ity with methyl ketones. Arylation of acetophenone with
1-bromo-4-tert-butylbenzene gave a mixture of mono- and
diarylated products. The application of 2 equivalents of the
aryl bromide gave the diarylated product (1o) in 93% yield.
2-Tetralone was coupled to 5-bromo-m-xylene with com-
plete regioselectivity for the more acidic α-position to give
(1)
2
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A New Ligand for Pd-Catalyzed α-Arylation of Ketones
Arylation of 2-methyl-3-pentanone was achieved with Table 2. Coupling of aryl chlorides and ketones.[a,b]
high yields but only moderate regioselectivity for the less
hindered α-position. Using two equivalents of the ketone, a
mixture of monoarylated product 1r (58%), diarylated
product 1t (19%), and 1u (15%) resulting from arylation of
the more hindered α-position was obtained [Equation (2)].
The regioselectivity for initial arylation of the less-hindered
side of the ketone compared to the more hindered side was
84:16. This selectivity was slightly higher than that achieved
with tri-tert-butylphosphine (76:24).[6a]
(2)
Aryl chlorides could also be efficiently coupled using this
methodology by raising the reaction temperature to 80 °C
and the catalyst loading to 0.5 mol-% (Table 2). Sterically
unhindered, electron-deficient or -rich aryl chlorides were
coupled with propiophenone in good to excellent yields (2a,
[a] Reaction conditions: 2 mmol aryl chloride, 2.4 mmol ketone, 0.5
mol-% Pd(OAc)2, 0.5 mol-% DTBNpP, 3.0 mmol NaOtBu, 80 °C,
24 h (time unoptimized). [b] Isolated yields (average of three runs).
[c] TNpP (0.5 mol-%) used as ligand.
2b). Additionally, an ortho-substituted aryl chloride af-
forded a good yield of coupled product (2d). As was seen
proach involving the alumina-promoted condensation of α-
in the aryl bromide case, low yields were obtained with 2-
bromo ketones with phenols.[18] The reaction is proposed to
chloro-m-xylene using DTBNpP/Pd(OAc)2, but good yields
proceed through alumina-promoted hemiacetal formation
could be achieved by switching to TNpP as the ligand (2e).
followed by electrophilic aromatic substitution to form the
Coupling of isobutyrophenone to 4-chlorotoluene afforded
C–C bond. This methodology generally provided low yields
an 86% yield of 2f. Selective monoarylation of acetophe-
(10–85%) and was limited to the synthesis of electron-rich
none was achieved using 2-chloro-m-xylene and the catalyst
benzofurans.
derived from TNpP and Pd(OAc)2. With the more hindered
aryl substrate, no overarylation was observed. Heteroaryl
chlorides 2-chloro-3-trifluoromethylpyridine and 3-chloro-
pyridine provided good yields of α-arylated products 2h and
2i under the standard conditions. 2-Chloroanisole was re-
gioselectively coupled with 2-methyl-3-pentanone to give 2j
in 82% yield with no diarylation product noted. The more
hindered aryl halide provided selective arylation of the less
hindered α-position in contrast to the mixture of regioiso-
mers obtained with the unhindered 4-bromobiphenyl
Scheme 1. Condensation of 2-bromophenol and acetophenone to
give 2-phenylbenzofuran.
(Table 1).
The 2-arylbenzofurans have wide ranging biological ac-
tivity making them attractive synthetic targets. Recent ef-
We were gratified to find that the Pd(OAc)2/DTBNpP
forts have focused on modular approaches to these struc- (1–2 mol-%) catalyst system effectively promoted the cou-
tures capable of displaying a high degree of structural diver- pling of 2-bromophenols with ketones to give 2-arylbenzo-
sity. Burch reported the condensation of 2-bromophenols furans in generally high yields at 50 °C after acidic workup.
with ketones using a Pd(OAc)2/2-(di-tert-butylphosphanyl)- Notably, these conditions use significantly lower palladium
1,1Ј-binaphthyl catalyst system (5 mol-% Pd) at 80 °C to loadings and lower temperature, while providing higher
give benzofurans in 40–84% yield.[17] The reaction involves yields, than the method reported by Burch. This method is
α-arylation of the ketone, followed by acid-catalyzed hemi- more general than that reported by Cossío. 2-Bromophenol
acetal formation and dehydration to give the benzofuran was coupled with propiophenone (3a), acetophenone (3b),
ring (Scheme 1). Cossío has reported an alternative ap- 2-tetralone (3c), and 1-(2-thienyl)propanone (3d) in high
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yields (Table 3). Product 3c was partially oxidized to aro- portantly, attempts to couple propiophenone with 2-bromo-
matic analog, naphtho[2,1-b]benzofuran, during workup. aniline or protected variants were unsuccessful under our
Additionally, 4-methoxy- and 4-fluoro-functionalized conditions.
bromophenols were coupled with propiophenone in greater
Polyhydroxylated 2-arylbenzofurans are common natural
than 90% yield (3e and 3f); no apparent substituent effects products and possessing a range of biological activities. 4-
were noted for this condensation. The ability to include Bromoresorcinol was coupled with aryl ketones to give 3i
electron-withdrawing substituents on the phenol ring sug- and 3j in 81 and 75% yield, respectively, using 2 mol-%
gests that a wide range of structures will be accessible. catalyst. The additional phenol group was tolerated without
These substrates gave low yields (34–58%) in Burch’s the need for protection. Single crystals of 3i were obtained
method.[17] When 1-bromo-2-naphthol was used as the sub- from slow evaporation of a diethyl ether solution. The so-
strate, only 53% of the desired naphthofuran was obtained lid-state structure is shown in Figure 2, and confirms for-
in the presence of 2 mol-% Pd(OAc)2 and 2 mol-% mation of the benzofuran structure.[21] Benzofuran 3i crys-
¯
DTBNpP (3g). Lower yields were also obtained in the cou- tallizes in space group P1 with four molecules in the asym-
pling of 1-bromo-2-methoxynaphthalene to propiophenone metric unit. The molecules pack with hydrogen bonding be-
(Table 1). Consequently, the lower yield of 3g likely reflects tween the hydroxy groups forming a unidirectional chain
the increased difficulty of the initial coupling reaction. along the a axis (see Supporting Information for crystal
Compound 3k, which can be converted in one step to eupo- packing diagrams). The phenyl rings of adjacent benzo-
matenoid,[17,19] was obtained in a 66% yield by condensa- furan molecules are arranged in a roughly perpendicular
tion of 2-bromo-4-chlorophenol and 4Ј-methoxypropio- way leading to a favorable herringbone motif.
phenone. Palladium-catalyzed condensation of ketones with
2-haloanilines to give indoles[20] has also been reported. Im-
Table 3. Synthesis of benzofurans.[a,b]
Figure 2. Thermal ellipsoid plot (50% probability) of one of the
independent molecular structures in the asymmetric unit of 3i.
Attempts to directly couple 3Ј,5Ј-dihydroxyacetophenone
with 2-bromophenol failed to produce 3k. Efficient conver-
sion to the benzofuran was achieved using a di-TBS-pro-
tected 3Ј,5Ј-dihydroxyacetophenone derivative. After treat-
ment with TFA to effect the ring closure, a mixture of
mono- and di-TBS-protected benzofuran products was ob-
tained. The mixture was fully deprotected with TBAF in
THF to give 3k in 82% isolated yield (Scheme 2).
[a] Reaction conditions: 1 mmol 2-bromophenol, 1.2 mmol ketone,
1.0 mol-% Pd(OAc)2, 1.0 mol-% DTBNpP, 1.5 mmol NaOtBu, Scheme 2. Synthesis of 2-(3,5-dihydroxyphenyl)benzofuran (3k).
50 °C, 24 h (time unoptimized). [b] Isolated yields (average of three
runs). [c] 2.0 mol-% Pd(OAc)2 and 2.0 mol-% DTBNpP used.
[d] 9:1 ratio of 5,6-dihydronaphtho[2,1-b]benzofuran (3c)/naphtho-
[2,1-b]benzofuran obtained. [e] 2.0 mol-% Pd(OAc)2, 2.0 mol-%
DTBNpP and 4.5 mmol NaOtBu used. [f] 3Ј,5Ј-Di(tert-butyldi-
methylsiloxy)acetophenone used as ketone substrate followed by
deprotection with TBAF.
Using the conditions optimized for the DTBNpP/
Pd(OAc)2 catalyst system, the capabilities of DTBNpP-de-
rived precatalysts were explored. The coupling of 4-bromo-
anisole with propiophenone was performed using in
situ
catalyst
[DTBNpP/Pd(OAc)2],
Pd(DTBNpP)2,
4
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A New Ligand for Pd-Catalyzed α-Arylation of Ketones
DTBNpP[12] and TNpP were obtained from FMC, Lithium Divi-
sion and were stored under nitrogen in a glove box. Pd(OAc)2 and
Pd(DTBNpP)2Cl2, and [Pd(DTBNpP)Cl(μ-Cl)]2 (Table 4).
The application of the catalyst derived from Pd(OAc)2 and
DTBNpP enabled almost complete conversion to be
reached (97%) after 4 h. By comparison, the use of
Pd(DTBNpP)2 resulted in a slightly slower rate of conver-
sion (89% after 4 h). The slower rate observed with
Pd(DTBNpP)2 may be due to the higher ligand/Pd ratio.
Interestingly, higher conversion rates were achieved with the
PdII chloride precatalysts. The catalyst derived from
Pd2(dba)3 were provided by Johnson-Matthey. Pd(DTBNpP)2,[22]
[23]
Pd(DTBNpP)2Cl2,[23] and [Pd(DTBNpP)Cl(μ-Cl)]2
were pre-
pared according to literature procedures. Toluene was distilled from
sodium under nitrogen prior to use in coupling reactions. THF
was distilled from sodium/benzophenone under nitrogen. All cross-
coupling reactions were assembled in a nitrogen-filled glovebox.
Reaction temperatures refer to previously equilibrated oil bath tem-
peratures. 1H and 13C NMR spectra are referenced to the NMR
Pd(DTBNpP)2Cl2 nearly reached completion after 2 h solvent peaks or internal TMS. HRMS were obtained on a mag-
netic sector mass spectrometer using EI ionization and operating
in the positive ion mode.
(93%) and was fully converted after 3 h. Dimeric
[Pd(DTBNpP)Cl(μ-Cl)]2 precatalyst with a 1:1 DTBNpP/
Pd ratio gave the highest rate of conversion with 94% con-
version achieved after 1 h. The reason for the higher rate
with chloride-derived catalysts is unclear yet clearly war-
rants further examination. The application of these air-
stable PdII precatalysts will be further explored.
General Procedure for α-Arylation of Ketones: A screw-capped vial
was placed in a glove box where Pd(OAc)2 (0.25–2.0 mol-%),
DTBNpP or TNpP (0.25–2.0 mol-%), and NaOtBu (1.5 equiv.)
were added. The vial was sealed with a septum and taken out of
the glove box. Aryl halide (2 mmol), ketone (4.8 mmol) and toluene
(2 mL) were added and the reaction was placed in an oil bath pre-
heated to 50 or 80 °C. After the reaction had reached completion
as judged by GC, the reaction mixture was dissolved in ethyl acet-
ate and filtered through a plug of silica gel. After drying under
vacuum, the crude reaction mixture was purified by flash
chromatography (2.5–20% EtOAc/hexane) to afford pure product.
Table 4. Comparison of DTBNpP/Pd(OAc)2 and preformed Pd-
DTBNpP complexes.[a]
α-(4-Trifluoromethylphenyl)propiophenone (1a, 2a):[8b] Using the ge-
neral procedure, 4-bromobenzotrifluoride (280 μL, 2 mmol) and
propiophenone (319 μL, 2.4 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
1
% Yield[b]
as a white solid (528 mg, 92%). H NMR (500 MHz, CDCl3): δ =
8.04–7.99 (m, 2 H), 7.59 (d, J = 8.1 Hz, 2 H), 7.53–7.45 (m, 3 H),
7.45–7.39 (m, 2 H), 4.84 (q, J = 6.9 Hz, 1 H), 1.60 (d, J = 7.0 Hz,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 199.5, 145.4 (q, J =
0.9 Hz), 136.0, 133.0, 129.0 (q, J = 32.5 Hz), 128.6, 128.5, 128.1,
125.7 (q, J = 3.8 Hz), 124.1 (q, J = 272.0 Hz), 47.3, 19.2 ppm.
1 h
2 h
3 h
4 h
24 h
Pd(OAc)2/DTBNpP (1:1)
Pd(DTBNpP)2
Pd(DTBNpP)2Cl2
5
20
57
27
33
93
100
83
52
100
97
89
100
100
[Pd(DTBNpP)Cl(μ-Cl)]2 94
[a] Reaction conditions: 1 mmol 4-bromoanisole, 1.2 mmol propio-
phenone, 1.5 mmol NaOtBu, 0.25 mol-% Pd/DTBNpP precatalyst,
2 mL toluene, 50 °C. [b] Yield determined by GC.
Alternatively, 4-chlorobenzotrifluoride (267 μL, 2 mmol) and
propiophenone (319 μL, 2.4 mmol) were coupled using 0.5 mol-
% Pd(OAc)2 and 0.5 mol-% DTBNpP at 80 °C to generate α-(4-
trifluoromethylphenyl)propiophenone (400 mg, 72%).
α-(4-Fluorophenyl)propiophenone (1b):[24] Using the general pro-
cedure, 1-bromo-4-fluorobenzene (220 μL, 2 mmol) and propio-
phenone (319 μL, 2.4 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
Conclusions
In conclusion, we have successfully shown that DTBNpP
is an effective catalyst for the α-arylation of ketones with
aryl bromides and chlorides. The system provides high
yields for a range of substrates with low catalyst loadings
and moderate temperatures for both aryl bromide and
chloride substrates. Sterically hindered starting materials
are effectively coupled using TNpP as the ligand with no
other change in reaction conditions. The Pd/DTBNpP cata-
lyst system provides higher yields and displays a broader
substrate scope in the condensation of 2-bromophenols
with ketones to give benzofuran, while using lower catalyst
loading and temperature, than do previously reported
methods.[17,18] This methodology provides a modular ap-
proach to the synthesis of benzofurans from readily avail-
able bromophenol and ketone precursors.
1
as a yellow oil (397 mg, 87%). H NMR (500 MHz, CDCl3): δ =
7.97 (d, J = 7.0 Hz, 1 H), 7.47 (tt, J = 7.3, 1.2 Hz,1 H), 7.37 (t, J
= 7.6 Hz, 1 H), 7.28 (dd, J = 8.7, 5.3 Hz, 1 H), 6.96 (dd, J = 8.7,
8.7 Hz, 1 H), 4.71 (q, J = 6.9 Hz, 1 H), 1.54 (d, J = 6.9 Hz, 2
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 200.0, 161.6 (d, J =
245.4 Hz), 137.0 (d, J = 3.2 Hz), 136.2, 132.7, 129.2 (d, J = 8.0 Hz),
128.5, 128.4, 115.6 (d, J = 21.4 Hz), 46.7, 19.4 ppm.
α-(2-Methylphenyl)propiophenone (1c, 2d):[6a] Using the general
procedure, 2-bromotoluene (240 μL, 2 mmol) and propiophenone
(319 μL, 2.4 mmol) were coupled using 0.25 mol-% Pd(OAc)2 and
0.25 mol-% DTBNpP at 50 °C to give the product as a clear, color-
1
less crystal (403 mg, 90%). H NMR (500 MHz, CDCl3): δ = 7.88
(d, J = 7.0 Hz, 2 H), 7.47 (t, J = 7.3 Hz, 1 H), 7.38 (t, J = 7.7 Hz,
2 H), 7.24 (d, J = 7.1 Hz, 1 H), 7.17–7.06 (m, 3 H), 4.81 (q, J =
6.8 Hz, 1 H), 2.54 (s, 3 H), 1.53 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 200.8, 140.1, 136.5, 134.4, 132.5,
130.9, 128.4, 126.9, 127.0, 126.9, 44.5, 19.5, 17.9 ppm.
Experimental Section
General Experimental Details: All chemicals were obtained from
commercial sources and used as received, except where noted.
Alternatively, 2-chlorotoluene (234 μL, 2 mmol) and propiophen-
one (319 μL, 2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2
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Date: 09-10-14 16:29:20
Pages: 11
K. H. Shaughnessy et al.
and 0.5 mol-% DTBNpP at 80 °C to generate α-(2-methylphenyl)- Pd2(dba)3 and 1.0 mol-% DTBNpP at 50 °C to give the product as
FULL PAPER
propiophenone (417 mg, 93%).
a yellow oil (423 mg, 73%). 1H NMR (500 MHz, CDCl3): δ = 8.11
(d, J = 8.6 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.78–7.71 (m, 3 H),
7.59 (t, J = 7.1 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.30 (t, J =
7.4 Hz, 1 H), 7.17 (t, J = 7.8 Hz, 2 H), 7.12 (d, J = 9.0 Hz, 1 H),
5.09 (q, J = 6.8 Hz, 1 H), 3.73 (s, 3 H), 1.68 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 202.0, 153.4, 137.0,
131.8, 131.7, 129.6, 129.0, 128.9, 127.8, 127.7, 127.1, 124.3, 123.4,
122.3, 113.5, 55.9, 41.4, 15.5 ppm. HRMS m/z calcd. for C20H18O2
[M]+ 290.1307, found 290.1304.
α-(2-Methyoxyphenyl)propiophenone (1d):[25] Using the general pro-
cedure, 2-bromoanisole (249 μL, 2 mmol) and propiophenone
(319 μL, 2.4 mmol) were coupled using 0.25 mol-% Pd(OAc)2 and
0.25 mol-% DTBNpP at 50 °C to give the product as a clear, color-
1
less crystal (451 mg, 96%). H NMR (500 MHz, CDCl3): δ = 8.03
(d, J = 7.2 Hz, 2 H), 7.48 (tt, J = 7.3, 1.1 Hz, 1 H), 7.38 (t, J =
7.5 Hz, 2 H), 7.23–7.17 (m, 2 H), 6.93–6.87 (m, 2 H), 5.16 (q, J =
6.8 Hz, 1 H), 3.88 (s, 3 H), 1.54 (d, J = 6.9 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 201.1, 155.6, 136.4, 132.3, 130.0,
128.2, 128.2, 128.0, 120.8, 110.7, 55.2, 40.2, 17.4 ppm.
α-(2-Pyridyl)propiophenone (1j):[7b] Using the general procedure, 2-
bromopyridine (191 μL, 2 mmol) and propiophenone (319 μL,
2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and 0.5 mol-%
DTBNpP at 50 °C to give the product as a yellow oil (388 mg,
92%). 1H NMR (500 MHz, CDCl3): δ = 8.50 (ddd, J = 5.0, 1.9,
1.0 Hz, 1 H), 8.03–7.97 (m, 2 H), 7.55 (td, J = 7.7, 1.9 Hz, 1 H),
7.46–7.40 (m, 1 H), 7.34 (t, J = 7.7 Hz, 2 H), 7.22 (dt, J = 7.9,
1.1 Hz, 1 H), 7.06 (ddd, J = 7.6, 4.9, 1.2 Hz, 1 H), 4.93 (q, J =
6.9 Hz, 1 H), 1.57 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 199.4, 160.9, 149.5, 136.8, 136.3, 132.7, 128.8, 128.3,
121.8, 121.7, 50.5, 17.8 ppm.
α-(2-Methyl-4-methoxyphenyl)propiophenone (1e):[7a] Using the ge-
neral procedure, 4-bromo-3-methylanisole (282 μL, 2 mmol) and
propiophenone (319 μL, 2.4 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
as a clear, colorless crystal (492 mg, 97%). 1H NMR (500 MHz,
CDCl3): δ = 7.90 (d, J = 7.3 Hz, 2 H), 7.43 (t, J = 7.3 Hz, 1 H),
7.34 (t, J = 7.6 Hz, 2 H), 7.01 (d, J = 8.5 Hz, 1 H), 6.80 (d, J =
2.8 Hz, 1 H), 6.64 (dd, J = 8.5, 2.8 Hz, 1 H), 4.75 (q, J = 6.8 Hz,
1 H), 3.68 (s, 3 H), 2.49 (s, 3 H), 1.51 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 200.7, 158.0, 136.4, 135.7, 132.2,
132.0, 128.1, 127.7, 116.4, 111.4, 54.6, 43.5, 19.5, 17.9 ppm.
2-(4-Biphenyl)-1-(2-thienyl)-1-propanone (1k): Using the general
procedure, 4-bromobiphenyl (466 mg, 2 mmol) and 1-(2-thienyl)-1-
propanone (299 μL, 2.4 mmol) were coupled using 0.5 mol-%
Pd(OAc)2 and 0.5 mol-% DTBNpP at 50 °C to give the product as
a white solid (531 mg, 91%). 1H NMR (500 MHz, CDCl3): δ =
7.78 (dd, J = 3.8, 1.2 Hz, 1 H), 7.63–7.59 (m, 4 H), 7.57 (dd, J =
5.0, 1.1 Hz, 1 H), 7.50–7.44 (m, 4 H), 7.38 (t, J = 7.4 Hz, 1 H),
7.07 (dd, J = 5.0, 3.8 Hz, 1 H), 4.63 (q, J = 6.9 Hz, 1 H), 1.66 (d,
J = 6.9 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 193.1,
143.6, 140.4, 140.2, 139.8, 133.5, 132.4, 128.6, 128.04, 127.96,
127.5, 127.2, 126.8, 48.8, 19.0 ppm. HRMS m/z calcd. for
C19H16SO [M]+ 292.0922, found 292.0919.
α-[3-Methyl-(4-dimethylamino)phenyl]-4Ј-methoxypropiophenone
(1f): Using the general procedure, 4-bromo-3,N,N-trimethylaniline
(428 mg, 2 mmol) and 4Ј-methoxypropiophenone (421 μL,
2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and 0.5 mol-%
DTBNpP at 50 °C to give the product as a yellow oil (505 mg,
1
85%). H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 8.8 Hz, 2 H),
6.94 (d, J = 8.6 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.62 (d, J =
2.8 Hz, 1 H), 6.50 (dd, J = 8.6, 2.8 Hz, 1 H), 4.66 (q, J = 6.7 Hz,
1 H), 3.78 (s, 3 H), 2.90 (s, 6 H), 2.50 (s, 3 H), 1.47 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 199.8, 162.6, 149.1,
134.8, 130.4, 129.6, 128.4, 127.4, 114.7, 113.3, 110.8, 54.0, 43.2,
40.2, 19.9, 18.0 ppm. HRMS m/z calcd. for C19H23NO2 [M]+
297.1733, found 297.1729.
α-(4-tert-Butylphenyl)-isobutyrophenone (1l):[11] Using the general
procedure, 1-bromo-4-tert-butylbenzene (346 μL, 2 mmol) and iso-
butyrophenone (360 μL, 2.4 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
α-(1-Naphthyl)propiophenone (1g):[8b] Using the general procedure,
1-bromonaphthalene (280 μL, 2 mmol) and propiophenone
(319 μL, 2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and
0.5 mol-% DTBNpP at 50 °C to give the product as a white solid
(499 mg, 96%). 1H NMR (500 MHz, CDCl3): δ = 8.32 (d, J =
8.5 Hz, 1 H), 7.96 (d, J = 7.0 Hz, 2 H), 7.93 (d, J = 8.2 Hz, 1 H),
7.76 (d, J = 8.1 Hz, 1 H), 7.68 (ddd, J = 8.4, 6.8, 1.4 Hz, 1 H), 7.58
(t, J = 7.5 Hz, 1 H), 7.43–7.34 (m, 2 H), 7.33–7.25 (m, 3 H), 5.46
(q, J = 6.8 Hz, 1 H), 1.73 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 200.5, 137.9, 136.2, 134.2, 132.5, 130.5,
129.2, 128.3, 128.3, 127.4, 126.6, 125.7, 125.7, 124.9, 122.4, 43.5,
18.4 ppm.
1
as a white solid (549 mg, 98%). H NMR (500 MHz, CDCl3): δ =
7.56 (dd, J = 8.3, 1.5 Hz, 2 H), 7.43–7.39 (m, 2 H), 7.35 (td, J =
7.3, 1.3 Hz, 1 H), 7.33–7.29 (m, 2 H), 7.22 (t, J = 7.8 Hz, 2 H),
1.64 (s, 6 H), 1.36 (s, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 203.6, 149.4, 141.9, 136.3, 131.4, 129.6, 127.8, 125.7, 125.2, 50.8,
34.2, 31.3, 27.7 ppm.
α-(4-Hydroxyphenyl)isobutyrophenone (1m): Using the general pro-
cedure, 4-bromophenol (346 mg, 2 mmol) and isobutyrophenone
(360 μL, 2.4 mmol) were coupled using 0.25 mol-% Pd(OAc)2 and
0.25 mol-% DTBNpP at 50 °C to give the product as a white solid
(437 mg, 91%). 1H NMR (500 MHz, CDCl3): δ = 7.52 (dd, J =
7.3, 1.2 Hz, 2 H), 7.37 (tt, J = 7.4, 1.1 Hz, 1 H), 7.23 (t, J = 7.7 Hz,
2 H), 7.21–7.18 (m, 2 H), 6.94–6.89 (m, 2 H), 6.70 (s, 1 H), 1.59 (s,
6 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 205.5, 154.8, 136.7,
136.3, 131.7, 129.6, 127.9, 126.9, 116.0, 50.8, 27.8 ppm. HRMS m/z
calcd. for C16H16O2 [M]+ 240.1150, found 240.1159.
α-(2,6-Dimethylphenyl)propiophenone (1h):[7a] Using the general
procedure, 2-bromo-m-xylene (266 μL, 2 mmol) and propiophen-
one (319 μL, 2.4 mmol) were coupled using 0.25 mol-% Pd(OAc)2
and 0.25 mol-% TNpP at 50 °C to give the product as a clear,
1
colorless crystal (438 mg, 92%). H NMR (500 MHz, CDCl3): δ =
7.76 (d, J = 7.0 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.27 (t, J =
7.8 Hz, 2 H), 7.05–6.96 (A2B m, 3 H), 4.56 (q, J = 6.8 Hz, 1 H),
2.32 (br. s, 6 H), 1.55 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 201.8, 139.7, 136.6, 135.3, 132.3, 129.3,
128.02, 128.00, 126.5, 46.0, 20.3, 14.7 ppm.
α-(3-Methoxyphenyl)isobutyrophenone (1n):[6a] Using the general
procedure, 3-bromoanisole (253 μL, 2 mmol) and isobutyro-
phenone (360 μL, 2.4 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
as a light, yellow oil (483 mg, 95%). 1H NMR (500 MHz, CDCl3):
δ = 7.56 (dd, J = 7.2, 1.5 Hz, 2 H), 7.31–7.26 (m, 1 H), 7.23 (t, J
= 8.0 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 2 H), 6.91 (dd, J = 7.1, 1.3 Hz,
2 H), 6.80–6.76 (m, 1 H), 3.69 (s, 3 H), 1.59 (s, 6 H) ppm. 13C
α-(2-Methoxy-1-naphthyl)propiophenone (1i): Using the general
procedure, 1-bromo-2-methoxynaphthalene (474 mg, 2 mmol) and
propiophenone (319 μL, 2.4 mmol) were coupled using 0.5 mol-%
6
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Job/Unit: O42474
/KAP1
Date: 09-10-14 16:29:20
Pages: 11
A New Ligand for Pd-Catalyzed α-Arylation of Ketones
NMR (126 MHz, CDCl3): δ = 202.8, 159.8, 146.6, 135.9, 131.3,
129.7, 129.3, 127.6, 117.8, 111.7, 111.3, 54.7, 51.0, 27.5 ppm.
9.0 Hz, 2 H), 6.78 (d, J = 1.7 Hz, 1 H), 6.76–6.69 (m, 2 H), 5.88
(d, J = 1.4 Hz, 1 H), 5.86 (d, J = 1.4 Hz, 1 H), 4.56 (q, J = 6.8 Hz,
1 H), 3.78 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 198.7, 163.1, 147.9, 146.3, 135.6, 130.9,
129.3, 120.8, 113.6, 108.5, 107.9, 100.9, 55.3, 46.9, 19.5 ppm.
HRMS m/z calcd. for C17H16O4 [M]+ 284.1049, found 284.1055.
2,2-Bis(4-tert-butylphenyl)-1-phenylethanone (1o): Using the general
procedure, 1-bromo-4-tert-butylbenzene (728 μL, 4.2 mmol) and
acetophenone (233 μL, 2.0 mmol) were coupled using 0.25 mol-%
Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
1
α-(4-Methyoxyphenyl)propiophenone (2c):[6a] Using the general pro-
cedure, 4-chloroanisole (245 μL, 2 mmol) and propiophenone
(319 μL, 2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and
0.5 mol-% DTBNpP at 80 °C to give the product as a white solid
(447 mg, 93%). 1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J =
7.3 Hz, 2 H), 7.44 (t, J = 7.88 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 2 H),
7.26 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 2 H), 4.70 (q, J =
6.7 Hz, 1 H), 3.69 (s, 3 H), 1.57 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 200.1, 158.2, 136.2, 133.2, 132.4,
128.5, 128.4, 128.2, 114.1, 54.7, 46.6, 19.2 ppm.
as a white solid (714 mg, 93%). H NMR (500 MHz, CDCl3): δ =
8.07 (d, 7.5 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.7 Hz,
2 H), 7.36 (d, J = 8.3 Hz, 4 H), 7.26 (d, J = 8.4 Hz, 4 H), 6.03 (s,
1 H), 1.32 (s, 18 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 198.5,
149.7, 137.0, 136.1, 132.9, 129.0, 128.7, 128.5, 125.6, 58.5, 34.4,
31.3 ppm. HRMS m/z calcd. for C28H32O [M]+ 384.2453, found
384.2454.
3,4-Dihydro-1-(3,5-dimethylphenyl)-2(1H)-naphthalenone
(1p):
Using the general procedure, 5-bromo-m-xylene (272 μL, 2 mmol)
and 2-tetralone (317 μL, 2.4 mmol) were coupled using 0.25 mol-
% Pd(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give the product
as a light, yellow oil (455 mg, 91%). 1H NMR (500 MHz, CDCl3):
δ = 7.35–7.32 (m, 2 H), 7.31–7.26 (m, 1 H), 7.08 (d, J = 7.4 Hz, 1
H), 6.96 (s, 1 H), 6.79 (s, 2 H), 4.75 (s, 1 H), 3.21 (ddd, J = 15.5,
8.0, 6.2 Hz, 1 H), 3.07 (dt, J = 15.7, 6.5 Hz, 1 H), 2.80 (ddd, J =
16.7, 6.6, 6.3 Hz, 1 H), 2.67–2.59 (m, 1 H), 2.32 (s, 6 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 209.6, 138.0, 137.5, 136.7, 136.6,
129.5, 128.8, 127.7, 127.0, 126.9, 126.3, 59.6, 36.9, 28.2, 21.2 ppm.
HRMS m/z calcd. for C18H18O [M]+ 250.1358, found 250.1352.
α-(2,6-Dimethylphenyl)-4Ј-methoxypropiophenone (2e): Using the
general procedure, 2-chloro-m-xylene (265 μL, 2 mmol) and 4Ј-
methoxypropiophenone (421 μL, 2.4 mmol) were coupled using 0.5
mol-% Pd(OAc)2 and 0.5 mol-% TNpP at 80 °C to give the product
1
as a white solid (488 mg, 91%). H NMR (500 MHz, CDCl3): δ =
7.72 (d, J = 8.9 Hz, 2 H), 7.06–6.96 (m, 3 H), 6.76 (d, J = 8.9 Hz,
2 H), 4.50 (q, J = 6.8 Hz, 1 H), 3.75 (s, 3 H), 2.31 (br. s, 6 H), 1.52
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 200.4,
162.8, 140.2, 135.4, 130.3, 129.7, 129.4, 126.5, 113.3, 55.1, 45.8,
20.4, 14.8 ppm. HRMS m/z calcd. for C18H20O2 [M]+ 268.1463,
found 268.1453.
1-(2-Isopropylphenyl)-2-naphthol (1q):[26] Using the general pro-
cedure, 1-bromo-2-isopropylbenzene (306 μL, 2 mmol) and tet-
ralone (317 μL, 2.4 mmol) were coupled using 0.25 mol-% Pd-
(OAc)2 and 0.25 mol-% DTBNpP at 50 °C. The crude product was
dissolved in a minimum of dichloromethane and evaporated onto
silica gel. Flash chromatography under standard conditions gave
the oxidized naphthol product 1t as a clear, colorless crystal
α-(4-Tolyl)isobutyrophenone (2f):[27] Using the general procedure, 4-
chlorotoluene (237 μL, 2 mmol) and isobutyrophenone (360 μL,
2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and 0.5 mol-%
DTBNpP at 80 °C to give the product as a white solid (410 mg,
1
86%). H NMR (500 MHz, CDCl3): δ = 7.61–7.56 (m, 2 H), 7.40–
1
(498 mg, 95%). H NMR (500 MHz, CDCl3): δ = 7.93–7.87 (m, 2
7.34 (m, 1 H), 7.30–7.24 (m, 4 H), 7.21 (t, J = 8.0 Hz, 2 H), 2.38
(s, 3 H), 1.65 (s, 6 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
203.6, 142.1, 136.2, 136.1, 131.4, 129.54, 129.52, 127.7, 125.4, 50.9,
27.7, 20.8 ppm.
H), 7.65 (dd, J = 7.9, 1.3 Hz, 1 H), 7.57 (td, J = 7.6, 1.5 Hz, 1 H),
7.46–7.36 (m, 4 H), 7.34–7.29 (m, 2 H), 5.10 (s, 1 H), 2.74 (sept, J
= 6.9 Hz, 1 H), 1.22 (d, J = 6.9 Hz, 3 H), 1.13 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 150.4, 149.8, 133.6,
131.8, 131.6, 129.32, 129.30, 128.8, 128.0, 126.7, 126.5, 126.4,
124.6, 123.2, 120.1, 117.2, 30.2, 24.3, 23.8 ppm.
α-(2,6-Dimethylphenyl)acetophenone (2g):[7a] Using the general pro-
cedure, 2-chloro-m-xylene (265 μL, 2 mmol) and acetophenone
(280 μL, 2.4 mmol) were coupled using 0.5 mol-% Pd(OAc)2 and
0.5 mol-% TNpP at 80 °C to give the product as a white solid
(412 mg, 92%). 1H NMR (500 MHz, CDCl3): δ = 8.14 (dd, J =
7.2, 1.1 Hz, 2 H), 7.66 (tt, J = 7.3, 1.5 Hz, 1 H), 7.56 (td, J = 7.6,
1.5 Hz, 2 H), 7.20–7.16 (m, 1 H), 7.13 (br. d, J = 7.5 Hz, 2 H), 4.43
(s, 2 H), 2.28 (s, 6 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
196.8, 137.1, 136.9, 133.1, 132.4, 128.6, 128.0, 127.9, 126.8, 39.6,
20.3 ppm.
2-(4-Biphenyl)-4-methyl-3-pentanone (1r): Using the general pro-
cedure, 4-bromobiphenyl (466 mg, 2 mmol) and 2-methyl-3-penta-
none (494 μL, 4.0 mmol) were coupled using 0.25 mol-% Pd-
(OAc)2 and 0.25 mol-% DTBNpP at 50 °C to give a white solid
(443 mg) that was shown by 1H NMR spectroscopy to be a 76:15:9
mixture of 1r (292 mg, 58%), 2,2-di(4-biphenyl)-4-methyl-3-penta-
none (1t, 75 mg, 19%), and 2-(4-biphenyl)-2-methyl-3-pentanone
(1u, 75 mg, 15%). Masses were determined based on NMR ratios
of the components. Characterization data for 1r. 1H NMR
(500 MHz, CDCl3): δ = 7.73–7.62 (m, 6 H), 7.53–7.46 (m, 3 H),
7.44–7.36 (m, 5 H), 4.05 (q, J = 6.9 Hz, 1 H), 2.81 (sept, J = 6.9 Hz,
1 H), 1.61 (s, 1 H), 1.52 (d, J = 6.9 Hz, 3 H), 1.19 (d, J = 7.0 Hz,
3 H), 1.05 (d, J = 6.8 Hz, 4 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 214.0, 140.2, 139.63, 139.59, 128.6, 128.1, 127.2, 127.1, 126.7,
50.4, 39.0, 18.9, 18.1, 18.0 ppm. HRMS: m/z calcd. for C18H20O
(1r, 1u, M+) 252.1514, found 252.1520; calcd. for C30H28O (1t, M+)
404.2140, found 404.2145.
α-(3-Trifluoromethyl-2-pyridyl)propiophenone (2h): Using the gene-
ral procedure, 2-chloro-3-(trifluoromethyl)pyridine (363 mg,
2 mmol) and propiophenone (319 μL, 2.4 mmol) were coupled
using 2.0 mol-% Pd(OAc)2 and 2.0 mol-% DTBNpP at 80 °C to
give the product as a white solid (447 mg, 80%). 1H NMR
(500 MHz, CDCl3): δ = 8.60 (d, J = 4.4 Hz, 1 H), 7.96 (d, J =
8.0 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 2 H), 7.42 (t, J = 7.3 Hz, 1 H),
7.33 (t, J = 7.7 Hz, 2 H), 7.22 (dd, J = 7.9, 4.9 Hz, 1 H), 5.06 (q,
J = 6.8 Hz, 1 H), 1.62 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 197.9, 159.5, 152.4, 136.5, 134.5 (q, J =
5.5 Hz), 132.4, 128.4, 128.2, 123.8 (q, J = 31.5 Hz), 123.9 (q, J =
273.1 Hz), 121.2, 47.1, 17.4 ppm. HRMS m/z calcd. for
C15H12NOF3 [M]+ 279.0871, found 279.0860.
α-(1,3-Benzodioxol-5-yl)-4Ј-methoxypropiophenone (2b): Using the
general procedure, 5-chloro-1,3-benzodioxole (233 μL, 2 mmol)
and 4Ј-methoxypropiophenone (421 μL, 2.4 mmol) were coupled
using 0.5 mol-% Pd(OAc)2 and 0.5 mol-% DTBNpP at 80 °C to
give the product as a yellow oil (454 mg, 80%). 1H NMR
(500 MHz, CDCl3): δ = 7.95 (d, J = 9.0 Hz, 2 H), 6.85 (d, J =
α-(3-Pyridyl)-4Ј-methoxypropiophenone (2i): Using the general pro-
cedure, 3-chloropyridine (189 μL, 2 mmol) and 4Ј-methoxypropio-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 09-10-14 16:29:20
Pages: 11
K. H. Shaughnessy et al.
FULL PAPER
phenone (421 μL, 2.4 mmol) were coupled using 0.5 mol-%
Pd(OAc)2 and 0.5 mol-% DTBNpP at 80 °C to give the product as
a yellow oil (376 mg, 78%). 1H NMR (500 MHz, CDCl3): δ = 8.55
1
oxidation of 3c. 3c: H NMR (500 MHz, CDCl3): δ = 8.06 (dd, J
= 7.3, J = 1.6 Hz, 1 H), 8.00 (d, J = 8.9 Hz, 0.12 H), 7.90 (dd, J =
7.6, 1.3 Hz, 1 H), 7.67–7.62 (m, 1 H), 7.49–7.39 (m, 3 H), 7.38–
(d, J = 2.3 Hz, 1 H), 8.39 (dd, J = 4.8, 1.6 Hz, 1 H), 7.88 (d, J = 7.34 (m, 1 H), 7.29 (td, J = 7.6, 1.3 Hz, 1 H), 3.24 (t, J = 8.0 Hz,
8.9 Hz, 2 H), 7.55 (dt, J = 8.0, 2.0 Hz, 1 H), 7.13 (ddd, J = 8.1,
2 H), 3.14 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3):
4.8, 0.9 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 2 H), 4.65 (q, J = 6.9 Hz, 1 δ = 156.5, 155.1, 133.4, 131.5, 128.0, 126.8, 125.8, 125.5, 123.3,
H), 3.74 (s, 3 H), 1.47 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR 123.1, 122.6, 119.8, 113.4, 111.3, 29.2, 22.2 ppm. HRMS m/z calcd.
(126 MHz, CDCl3): δ = 197.7, 163.2, 149.1, 147.9, 137.0, 134.7, for C16H12O [M]+ 220.0888, found 220.0889. Naphtho[2,1-b]benzo-
1
130.7, 128.5, 123.4, 113.5, 55.1, 44.1, 19.0 ppm. HRMS m/z calcd.
furan: H NMR (500 MHz, CDCl3): δ = 8.72 (dd, J = 8.2, 1.2 Hz,
1 H), 8.49 (dd, J = 7.8, 1.4 Hz, 1 H), 8.11 (dd, J = 8.2, 1.2 Hz, 1
H), 7.82 (m, 2 H), 7.61–7.55 (m, 2 H), 7.49–7.39 (m, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 155.8, 154.2, 130.4, 129.1, 129.0,
128.5, 127.0, 125.8, 124.9, 124.3, 123.4, 123.1, 121.9, 117.5, 112.6,
111.8 ppm.
3-Methyl-2-(thiophen-2-yl)benzofuran (3d):[17] Using the general
procedure for benzofuran synthesis, 2-bromophenol (116 μL,
1 mmol) and 1-(2-thienyl)-1-propanone (149 μL, 1.2 mmol) were
coupled using 2.0 mol-% Pd(OAc)2 and 2.0 mol-% DTBNpP at
for C15H15NO2 [M]+ 241.1103, found 241.1109.
2-(2-Methoxyphenyl)-4-methyl-3-pentanone (2j): Using the general
procedure, 2-chloroanisole (253 μL, 2 mmol) and 2-methyl-3-
pentanone (494 μL, 4.0 mmol) were coupled using 0.5 mol-%
Pd(OAc)2 and 0.5 mol-% DTBNpP at 80 °C to give the product as
1
a light, yellow oil (338 mg, 82%). H NMR (500 MHz, CDCl3): δ
= 7.23 (ddd, J = 8.1, 7.5, 1.6 Hz, 1 H), 7.11 (dd, J = 7.6, 1.7 Hz,
1 H), 6.92 (td, J = 7.5, 1.1 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 4.31
(q, J = 7.0 Hz, 1 H), 3.83 (s, 3 H), 2.66 (sept, J = 6.8 Hz, 1 H),
1.34 (d, J = 7.0 Hz, 3 H), 1.07 (d, J = 7.1 Hz, 3 H), 0.95 (d, J = 50 °C to give the product as a clear, colorless oil (192 mg, 90%).
6.8 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 215.2, 156.5,
129.4, 128.4, 127.9, 120.8, 110.5, 55.2, 43.7, 38.5, 19.3, 18.1,
16.4 ppm. HRMS m/z calcd. for C13H18O2 [M]+ 206.1307, found
206.1304.
1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 7.0 Hz, 1 H), 7.54–
7.50 (m, 2 H), 7.42 (dd, J = 5.1, 1.2 Hz, 1 H), 7.36–7.28 (m, 2 H),
7.19 (dd, J = 5.0, 3.6 Hz, 1 H), 2.50 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 153.7, 146.8, 133.4, 130.8, 1275, 125.4,
124.7, 124.4, 122.5, 119.1, 110.8, 110.7, 9.1 ppm.
5-Methoxy-3-methyl-2-phenylbenzofuran (3e):[17] Using the general
procedure for benzofuran synthesis, 2-bromo-4-methoxyphenol
(203 mg, 1 mmol) and propiophenone (160 μL, 1.2 mmol) were
General Procedure for Synthesis of Benzofurans: A screw-capped
vial was placed in a glove box where Pd(OAc)2 (1.0–5.0 mol-%),
DTBNpP (1.0–5.0 mol-%), and NaOtBu (3.0 equiv.) were added.
The vial was sealed with a septum and taken out of the glove box.
Aryl halide (1 mmol), ketone (1.2 mmol) and toluene (2 mL) were coupled using 1.0 mol-% Pd(OAc)2 and 1.0 mol-% DTBNpP at
added and the reaction was placed in an oil bath preheated to 50 °C
for 24 h. After the 24 h, TFA/CH2Cl2 (1:1, 2 mL) was added to
reaction mixture and stirred at room temperature for 2 h. The reac-
tion mixture was added to a saturated NH4Cl solution and ex-
tracted with ethyl acetate. The combined ethyl acetate extracts were
dried with MgSO4, filtered, and dried by rotary evaporation. The
crude reaction mixture was purified by flash chromatography (0–
50% EtOAc/hexane) to afford pure product.
50 °C to give the product as a clear, colorless crystal (221 mg, 93%).
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 7.0 Hz, 2 H), 7.51
(t, J = 7.8 Hz, 2 H), 7.44–7.37 (m, 2 H), 7.02 (d, J = 2.5 Hz, 1 H),
6.95 (dd, J = 8.8, 2.6 Hz, 1 H), 3.92 (s, 3 H), 2.49 (s, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 155.8, 151.5, 148.8, 131.7, 131.5,
128.6, 127.8, 126.6, 112.9, 111.3, 101.9, 56.1, 9.7 ppm. Two aro-
matic carbons were coincident.
5-Fluoro-3-methyl-2-phenylbenzofuran (3f):[17] Using the general
3-Methyl-2-phenylbenzofuran (3a):[17] Using the general procedure procedure for benzofuran synthesis, 2-bromo-4-fluorophenol
for benzofuran synthesis, 2-bromophenol (116 μL, 1 mmol) and
propiophenone (160 μL, 1.2 mmol) were coupled using 1.0 mol-%
(191 mg, 1 mmol) and propiophenone (160 μL, 1.2 mmol) were
coupled using 1.0 mol-% Pd(OAc)2 and 1.0 mol-% DTBNpP at
50 °C to give the product as a clear, colorless crystal (217 mg, 96%).
Pd(OAc)2 and 1.0 mol-% DTBNpP at 50 °C to give the product as
1
a clear, colorless oil (189 mg, 91%). H NMR (500 MHz, CDCl3): 1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 7.1 Hz, 2 H), 7.52
δ = 7.97–7.93 (m, 2 H), 7.67–7.57 (m, 4 H), 7.48 (tt, J = 7.4, 1.0 Hz,
1 H), 7.43 (td, J = 7.3, 1.2 Hz, 1 H), 7.38 (td, J = 7.6, 1.0 Hz, 1
(t, J = 7.7 Hz, 2 H), 7.45–7.38 (m, 2 H), 7.20 (dd, J = 8.5, 2.6 Hz,
1 H), 7.03 (td, J = 9.0, 2.7 Hz, 1 H), 2.46 (s, 3 H) ppm. 13C NMR
H), 2.58 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 153.8, (126 MHz, CDCl3): δ = 159.1 (d, J = 238.0 Hz), 152.5, 150.0, 132.0
150.6, 131.4, 131.1, 128.5, 127.8, 126.6, 124.3, 122.3, 119.2, 111.2,
110.9, 9.4 ppm.
(d, J = 10.1 Hz), 131.1, 128.6, 128.2, 126.7, 111.8 (d, J = 26.3 Hz),
111.5 (d, J = 9.5 Hz), 111.4 (d, J = 3.9 Hz), 104.8 (d, J = 24.7 Hz),
9.4 ppm. 19F NMR (339 MHz, CDCl3): δ = –121.2 (td, J = 8.8,
4.0 Hz) ppm.
2-Phenylbenzofuran (3b):[17] Using the general procedure for benzo-
furan synthesis, 2-bromophenol (116 μL, 1 mmol) and acetophen-
one (140 μL, 1.2 mmol) were coupled using 2.0 mol-% Pd(OAc)2 1-Methyl-2-phenylnaphtho[2,1-b]furan (3g):[17] Using the general
and 2.0 mol-% DTBNpP at 50 °C to give the product as a white
solid (184 mg, 95%). H NMR (500 MHz, CDCl3): δ = 7.93 (dd, J 1 mmol) and propiophenone (160 μL, 1.2 mmol) were coupled
procedure for benzofuran synthesis, 1-bromo-2-naphthol (223 mg,
1
= 8.4, 1.3 Hz, 2 H), 7.63 (d, J = 7.3 Hz, 1 H), 7.58 (d, J = 8.1 Hz,
1 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.34 (td,
J = 7.8, 1.2 Hz, 1 H), 7.30 (td, J = 7.4, 1.1 Hz, 1 H), 7.07 (s, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 155.9, 154.9, 130.5,
129.2, 128.8, 128.5, 124.9, 124.2, 122.9, 120.9, 111.2, 101.3 ppm.
using 2.0 mol-% Pd(OAc)2 and 2.0 mol-% DTBNpP at 50 °C to
give the product as a white solid (137 mg, 53%). 1H NMR
(500 MHz, CDCl3): δ = 8.55 (d, J = 8.4 Hz, 1 H), 8.04 (d, J =
8.1 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 2 H), 7.81–7.72 (m, 2 H), 7.67
(ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.62–7.55 (m, 3 H), 7.48 (t, J =
7.3 Hz, 1 H), 2.90 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 151.7, 150.8, 131.2, 130.8, 129.0, 128.5, 127.7, 127.4, 126.0, 125.4,
123.9, 123.7, 123.0, 113.4, 112.2, 12.3 ppm. Two aromatic carbons
were coincident.
5,6-Dihydronaphtho[2,1-b]benzofuran (3c): Using the general pro-
cedure for benzofuran synthesis, 2-bromophenol (116 μL, 1 mmol)
and 2-tetralone (159 μL, 1.2 mmol) were coupled using 1.0 mol-%
Pd(OAc)2 and 1.0 mol-% DTBNpP at 50 °C to give the product as
a clear, colorless oil (202 mg, 92%) that was an inseparable mixture
of 3c (91%) and naphtho[2,1-b]benzofuran (9%) resulting from air
5-Chloro-2-(4-methoxyphenyl)-3-methylbenzofuran (3h):[17] Using
the general procedure for benzofuran synthesis, 2-bromo-4-chloro-
8
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Date: 09-10-14 16:29:20
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A New Ligand for Pd-Catalyzed α-Arylation of Ketones
phenol (207 mg, 1 mmol) and 4Ј-methoxypropiophenone (210 μL,
parameters are very close to that of a monoclinic cell with a as
1.2 mmol) were coupled using 1.0 mol-% Pd(OAc)2 and 1.0 mol-% the unique axis. However, the Rint value for equivalent reflections
DTBNpP at 50 °C to give the product as a clear, colorless oil
corresponding to a monoclinic cell was very high and all attempts
(179 mg, 66%). 1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = to solve the structure in a monoclinic space group met with con-
8.8 Hz, 2 H), 7.46 (d, J = 2.2 Hz, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), siderable difficulty. Ultimately the crystal was solved in the triclinic
¯
7.22 (dd, J = 8.6, 2.2 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 3.88 (s, space group P1 with ZЈ = 4.
3 H), 2.40 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 159.6,
Supporting Information (see footnote on the first page of this arti-
152.3, 151.9, 132.7, 128.1, 127.8, 123.8, 123.6, 118.6, 114.1, 111.6,
109.2, 55.3, 9.2 ppm.
cle): Discussion of the structure refinement and the crystal packing
1
of compound 3i and copies of H and 13C NMR spectra of com-
2-Phenyl-3-methyl-6-benzofuranol (3i): Using the general procedure
for benzofuran synthesis, 4-bromoresorcinol (189 mg, 1 mmol) and
propiophenone (160 μL, 1.2 mmol) were coupled using 2.0 mol-%
Pd(OAc)2 and 2.0 mol-% DTBNpP at 50 °C to give the product as
a white solid (182 mg, 81%). X-ray quality crystals were obtained
pounds from Tables 1, 2, and 3.
Acknowledgments
1
by slow evaporation of a solution of 3h in diethyl ether. H NMR
Financial support of this work by the National Science Foundation
(NSF) (CHE-1058984) is acknowledged. FMC, Lithium Division
is thanked for donation of TNpP, and Johnson-Matthey for do-
nation of palladium compounds.
(500 MHz, CD3CN): δ = 7.75 (dd, J = 8.5, 1.3 Hz, 2 H), 7.47 (t, J
= 7.8 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.34 (t, J = 7.4 Hz, 1 H),
7.10 (br. s, 1 H), 6.95 (d, J = 2.1 Hz, 1 H), 6.81 (dd, J = 8.4, 2.1 Hz,
1 H), 2.40 (s, 3 H) ppm. 13C NMR (126 MHz, CD3CN): δ = 156.5,
155.8, 150.3, 132.5, 129.8, 128.6, 127.1, 125.1, 120.9, 112.8, 112.6,
98.5, 9.8 ppm. HRMS m/z calcd. for C15H12O2 [M]+ 224.0837,
found 224.0830.
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[2] B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119,
2-Phenyl-6-benzofuranol (3j):[28] Using the general procedure for
benzofuran synthesis, 4-bromoresorcinol (189 mg, 1 mmol) and
acetophenone (233 μL, 2.0 mmol) were coupled using 2.0 mol-%
Pd(OAc)2 and 2.0 mol-% DTBNpP at 50 °C to give the product as
a white solid (157 mg, 75%). 1H NMR (500 MHz, CD3CN): δ =
7.81 (dd, J = 8.4, 1.0 Hz, 2 H), 7.45–7.41 (m, 3 H), 7.33 (td, J =
7.4, 0.9 Hz, 1 H), 7.16 (br. s, 1 H), 7.04 (s, 1 H), 7.01 (dd, J = 1.6,
0.3 Hz, 1 H), 6.81 (dd, J = 8.4, 1.1 Hz) ppm. 13C NMR (126 MHz,
CD3CN): δ = 156.9, 156.4, 155.7, 131.6, 130.0, 129.2, 125.3 123.1,
122.4, 113.4, 102.6, 98.8 ppm.
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2-(3,5-Dihydroxyphenyl)benzofuran (3k): Using the general pro-
cedure for benzofuran synthesis, 2-bromophenol (116 μL, 1 mmol)
and
3Ј,5Ј-bis(tert-butyldimethylsiloxy)acetophenone
(183 μL,
1.2 mmol) were coupled using 2.0 mol-% Pd(OAc)2 and 2.0 mol-%
DTBNpP at 50 °C. The crude product was treated with
TBAF·xH2O (784.5 mg, 3 mmol) in THF (10 mL) for several hours
until TLC analysis showed complete deprotection. The resulting
mixture was treated with saturated aqueous NH4Cl and extracted
with diethyl ether. The crude product was flash chromatographed
to give the product as a white solid (185 mg, 82%). 1H NMR
(500 MHz, CD3CN): δ = 7.60 (d, J = 7.3 Hz, 1 H), 7.52 (dd, J =
8.2, 0.9 Hz, 1 H), 7.31 (td, J = 7.8, 1.3 Hz, 1 H), 7.24 (td, J = 7.5,
1.0 Hz, 1 H), 7.17 (s, 2 H), 7.10 (d, J = 1.0 Hz, 1 H), 6.87 (d, J =
2.2 Hz, 2 H), 6.33 (t, J = 2.2 Hz, 1 H) ppm. 13C NMR (126 MHz,
CD3CN): δ = 159.6, 156.7, 155.7, 133.3, 130.2, 125.6, 124.2, 122.2,
112.0, 104.7, 104.2, 102.9 ppm.
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Structure Analysis of 3i: X-ray crystallographic data collection was
performed at 173.0(1) K using a Bruker diffractometer with a Plat-
form 3-circle goniometer and an Apex 2 CCD area detector. Crys-
tals were cooled under a cold nitrogen stream using an N-Helix
cryostat. A hemisphere of data was collected for each crystal using
a strategy of omega scans with 0.5° frame widths. Unit cell determi-
nation, data integration, absorption correction, and scaling were
performed using the Apex2 software suite from Bruker.[29] Space
group determination, structure solution, refinement, and genera-
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3-Methyl-2-phenyl-6-benzofuranol (3i) crystallizes in a lattice with
cell parameters a = 9.7881(5) Å, b = 10.1304(5) Å, c = 22.583(1) Å,
α = 83.697°, β = 89.699(3)°, γ = 89.944(3)° and Z = 8. The cell
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. H. Shaughnessy et al.
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Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42474
/KAP1
Date: 09-10-14 16:29:20
Pages: 11
A New Ligand for Pd-Catalyzed α-Arylation of Ketones
Ketone α-Arylation
phenols with ketones.
S. M. Raders, J. M. Jones, J. G. Semmes,
S. P. Kelley, R. D. Rogers,
K. H. Shaughnessy* ........................ 1–11
D i - t e rt - bu t yl ne op en ty lp ho sp hi ne
(DTBNpP): An Efficient Ligand in the Pal-
ladium-Catalyzed α-Arylation of Ketones
Ketone α-arylation with aryl bromides and
chlorides using di-(tert-butyl)neopentyl-
phosphine (DTBNpP) in combination with
palladium is described. This catalyst system
provides an efficient route to benzofurans
through the condensation of 2-bromo
Keywords: Synthetic methods / C–C cou-
pling / Palladium / Phosphane ligands /
Heterocycles / Ketones
Eur. J. Org. Chem. 0000, 0–0
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