Palladium-catalyzed selective carboelimination and cross-coupling reactions of benzocyclobutenols with aryl bromides

Article abstract of DOI:10.1021/jo201632c

The palladium-catalyzed selective β-carboelimination and cross-coupling chemistry of benzocyclobutenols is described. In contrast to the base-mediated ring-opening reactions of benzocyclobutenols, this variant proceeds with exclusive cleavage of the proximal bond.

Full text of DOI:10.1021/jo201632c

Note
pubs.acs.org/joc
Palladium-Catalyzed Selective Carboelimination and Cross-Coupling
Reactions of Benzocyclobutenols with Aryl Bromides
Andrei Chtchemelinine, David Rosa, and Arturo Orellana*
Department of Chemistry, York University, 440 Chemistry Building, 4700 Keele Street, Toronto, ON, Canada M3J 1P3
S
* Supporting Information
ABSTRACT: The palladium-catalyzed selective β-carboelimination and
cross-coupling chemistry of benzocyclobutenols is described. In contrast to
the base-mediated ring-opening reactions of benzocyclobutenols, this
variant proceeds with exclusive cleavage of the proximal bond.
he strain inherent in small ring organic molecules bestows
upon them reactivity not observed in the less-strained
recently, the palladium-catalyzed28−30 and rhodium-cata-
lyzed31−33 desymmetrization of tert-cyclobutanols has been
developed into a useful synthetic method. In contrast, the
palladium-catalyzed chemistry of benzocyclobutenols has not
been explored. Our interest in developing synthetic methods
based on the palladium-catalyzed chemistry of cyclic34,35 and
acyclic36 tertiary alcohols37 and the lack of studies on the
transition metal-catalyzed ring opening of benzocyclobutenols
prompted us to explore this class of compounds. In particular,
we were interested in developing a carbon−carbon bond
forming reaction proceeding through a selective palladium-
catalyzed proximal bond cleavage of a tert-benzocyclobutenol.38
We envisioned a mechanistic scenario wherein an
arylpalladium(II) intermediate (I), resulting from oxidative
addition of an aryl halide to Pd(0)Ln, would undergo ligand
exchange with the benzocyclobutenol (Scheme 1, I to II). We
surmised that it should be possible to selectively deprotonate
the palladium-bound benzocyclobutenol (II to III) without
deprotonating the free benzocyclobutenol because of their
expected pKa difference, and that this should prevent
uncontrolled, base-catalyzed ring-opening reactions. Given the
relative bond strengths of Pd−C(sp2) and Pd−C(sp3)
bonds,39 and the ample precedent for selective β-carboelimi-
nation leading to alkyl- and arylpalladium(II) intermediates
from tertiary alcohols,22−24,33,40−47 we expected that inter-
mediate III would lead selectively to intermediate IV, which
could be reductively eliminated to generate the desired product.
Initial experiments using an electron-neutral aryl bromide
and a simple catalyst system showed formation of the desired
cross-coupled product in moderate yield and a significant
amount of the ring-opened product (Table 1, entry 1). In
addition, the long reaction time required for consumption of
most of the starting material proved impractical. After some
optimization,44 it was found that the use of DavePhos as the
T
higher homologues. As a result, strain-releasing reactions of
these compounds can be an integral design feature in multistep
synthesis. Cyclopropanol and cyclobutanol derivatives have
been exploited in the context of synthetic organic chemistry;
however, the use of benzocyclobutenols is less common.
Nevertheless, the preparation1−6 and use of benzocyclobutenols
have received some attention, and they have proven to be
useful intermediates in complex molecule synthesis.7,8
Furthermore, benzocyclobutenols or the corresponding alk-
oxides have been postulated as reaction intermediates.9 By and
large, the synthetic use of benzocyclobutenols is dominated by
cleavage of the distal bond via thermal cycloreversion to
generate α-hydroxyquinonedimethanes10 that subsequently
participate in cycloaddition11−13 or electrocyclization14−19
reactions. In 1960, Cava and Muth demonstrated20 that
benzocyclobutenones suffer carbon−carbon bond cleavage at
the proximal and distal bonds under basic conditions,
presumably through the intermediacy of the corresponding
oxyanion (eq 1). This reaction has found significantly less use,
likely because of difficulties in controlling the position of
carbon−carbon bond cleavage. Although it has been shown that
a number of substitutents on the aryl ring favor cleavage of the
proximal bond under basic conditions, attempts to intercept the
presumed aryl anion intermediate with carbon-based electro-
philes have failed, even under anhydrous conditions.21
Palladium-catalyzed ring-opening reactions of protected22−24
and unprotected25,26 cyclopropanol derivatives have received
significant attention since Kuwajima’s seminal report.27 More
Received: August 9, 2011
Published: September 23, 2011
© 2011 American Chemical Society
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corresponding aryl triflate. Surprisingly, however, this substrate
gave mostly the undesired ring-opened product (entry 6).
Exploration of the substrate scope for this reaction
demonstrates that a variety of oxidative addition partners are
tolerated (Table 2). Electron-poor (entries 3, 4, 15, 17, and
Scheme 1. Envisioned Catalytic Cycle for the Cross
Coupling of Aryl Halides with Benzocyclobutenols
Table 2. Scope of the Palladium-Catalyzed Cross Coupling
of Benzocyclobutenols with Aryl Bromides
Table 1. Summary of Reaction Optimization
ligand and Pd2dba3 as the palladium source in combination with
Ag2CO3 provided the cross-coupled product in excellent yield
and in a short reaction time (entry 2). Cs2CO3 also proved to
be a competent base in the process but required a longer
reaction time (entry 3). The cross-coupling reaction failed with
the corresponding aryl chloride, likely because of a difficult
oxidative addition step (entry 4), while the use of the
corresponding aryl iodide gave the cross-coupled product
along with a significant amount of the ring-opened product
(entry 5). It is well-established that silver(I) can promote the
generation of cationic palladium intermediates by abstraction of
a halide ion. It is reasonable to expect that such cationic
palladium complexes may readily coordinate with an alcohol to
generate a protonated palladium alkoxide (i.e., intermediate II
in Scheme 1), especially in nonpolar solvents. To test if this
effect is operative, we conducted the reaction with the
21), electron-neutral (entries 1, 2, 6, 11, 14, 18, and 20), and
electron-rich (entries 5, 7, 12, 13, 19, and 22) aryl bromides
give the cross-coupled product in good to excellent yield. The
diminished yield observed with a substrate bearing a primary
alkyl chloride (entry 13) may be due in part to reaction with
the electron-rich phosphine ligand. In addition, this reaction
tolerates the use of heteroaryl bromides (entries 9, 10, and 16).
Furthermore, the use of ortho-substituted aryl bromides (entries
6 and 7) does not have a noticeable effect on the reaction;
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however, the use of a di-ortho-substituted aryl bromide fails to
deliver cross-coupled product (entry 8). A variety of
substituents at the carbinol carbon of the benzocyclobutenol
(R2) are also tolerated, including methyl (entries 1−10, 18, and
19), cyclohexyl (entries 11 and 12), isopropyl (entries 13 and
14), and 4-anisyl (entries 15−17) groups. Although the
majority of the examples explored include a benzocyclobutenol
bearing a methoxy group (entries 1−14), this substituent is not
necessary for the success of the reaction (entries 15−22). It is
worth noting that the base-catalyzed ring cleavage of
unsubstituted benzocyclobutenols results in mixtures of
products arising from proximal and distal bond cleavage.
Finally, it is also possible to generate cyclic ketones using this
protocol (entries 20−22).
We surmised that using aryl bromides bearing electrophilic
functional groups at the ortho position could provide an
expedient route to functionalized phenanthrenes48,49 via
condensation with the enolate of the resulting ketone group.
Indeed, the use of ortho-bromobenzonitrile and ortho-
bromobenzaldehyde results in the formation of the correspond-
ing phenanthrenes in good yield simply by using an excess of
base and allowing the reaction mixture to be stirred for an
extended period of time (Scheme 2, eqs 2 and 3). In contrast,
chemistry can be extended to the synthesis of functionalized
phenanthrenes and cyclic imines.
EXPERIMENTAL SECTION
■
General Preparation of Benzocyclobutenols. Benzocyclobu-
tenols were prepared by addition of the required organometallic
reagent to the corresponding benzocyclobutenone19,21 or by addition
of ketone enolates to benzyne.2
5-Methoxy-7-methylbicyclo[4.2.0]octa-1,3,5-trienol (Table 1,
Table 2, entries 1−13, and Scheme 2, eq 5). Isolated as a beige
powder (73%) using a 17% solution of EtOAc in hexanes: mp 70−73
°C; 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.8 Hz, 1 H), 6.77 (d, J
= 7.8, 1 H), 6.72 (d, J = 7.8 Hz, 1 H), 3.95 (s, 3 H), 3.33 (d, J = 14 Hz,
1 H), 3.21 (d, J = 14.0 Hz, 1 H), 2.39 (s, 1 H), 1.77 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 153.5, 142.7, 134.5, 130.8, 116.1, 112.8,
77.7, 56.6, 47.9, 26.6; IR 3312, 2922, 1597, 1575, 1263, 1169 cm−1
;
HRMS (EI) m/z calcd for C10H12O2 (M+) 164.0837, found 164.0799.
5-Methoxy-7-cyclohexylbicyclo[4.2.0]octa-1,3,5-trienol (Table 2,
entries 11 and 12). Isolated as a beige powder (73%) using a 13%
solution of EtOAc in hexanes: mp 93 °C; 1H NMR (400 MHz,
CDCl3) δ 7.24 (dd, J = 8.0, 8.0 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H),
6.72 (d, J = 8.0 Hz, 1 H), 3.87 (s, 3 H), 3.38 (d, J = 14.0 Hz, 1 H), 2.95
(d, J = 14.0 Hz, 1 H), 2.31 (br s, 1 H), 2.17 (m, 1 H), 1.88−1.07 (m, 5
H), 1.31−1.08 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 153.6,
143.6, 134.3, 130.5, 116.0, 111.0, 83.6, 55.9, 45.5, 43.3, 27.7, 26.3, 26.2;
IR 3436, 2925, 1579, 1477, 1265, 1070 cm−1; HRMS (EI) m/z calcd
for C15H20O2 (M+) 232.1463, found 232.1456.
Scheme 2. Synthesis of Phenanthrenes and Cyclic Imines
Using a Cross-Coupling and Condensation Sequence
5-Methoxy-7-(4-anisyl)bicyclo[4.2.0]octa-1,3,5-trienol (Table 2,
entries 15−17). Isolated as a clear oil (65%) using a 14% solution
of EtOAc in hexanes: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4
Hz, 2 H), 7.37−7.30 (m, 3 H), 7.25 (d, J = 7.2 Hz, 1 H), 6.89 (d, J =
8.4 Hz, 2 H), 3.82 (s, 3 H), 3.66 (d, J = 14.0 Hz, 1 H), 3.59 (d, J =
14.0 Hz, 1 H), 2.60 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 158.9,
149.2, 142.0, 135.7, 129.5, 127.5, 126.9, 124.1, 121.5, 113.5, 81.2, 55.2,
49.7; IR 3427, 1511, 1248, 1176, 1034 cm−1; HRMS (EI) m/z calcd
for C15H14O2 (M+) 226.0994, found 226.1003.
5-Methoxy-7-isopropylbicyclo[4.2.0]octa-1,3,5-trienol (Table 2,
entries 13 and 14, and Scheme 2, entry 3). Isolated as an oil
1
(73%) using a 20% solution of EtOAc in hexanes: H NMR (400
MHz, CDCl3) δ 7.24 (dd, J = 8.0, 8.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1
H), 6.71 (d, J = 8.0 Hz), 3.83 (s, 3 H), 3.33 (d, J = 14.0 Hz, 1 H), 2.94
(d, J = 14.0 Hz, 1 H), 2.74 (bs, 1 H), 2.16 (m, J = 6.8 Hz, 1 H), 1.14
(d, J = 6.8 Hz, 1 H), 0.95 (d, J = 6.8 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 153.4, 143.6, 134.4, 130.5, 116.0, 110.9, 84.1, 55.7, 42.7,
33.5, 17.8, 17.6; IR 1602, 1579, 1478, 1435, 1265, 1070 cm−1; HRMS
(EI) m/z calcd for C12H16O2 (M+) 192.1150, found 192.1156.
General Procedure for the Cross Coupling of Benzocyclo-
butenols with Aryl Bromides. 1-(6-Methoxy-4′-methylbiphenyl-
2-yl)propan-2-one (entry 1). A 10 mL round-bottomed flask
equipped with a stir bar and condenser was charged with 5-
methoxy-7-methylbicyclo[4.2.0]octa-1,3,5-trienol (0.030 g, 1.0 equiv,
0.18 mmol), Dave-Phos (0.007 g, 0.10 equiv, 0.018 mmol), Pd2dba3
(0.004 g, 0.025 equiv, 0.005 mmol), Ag2CO3 (0.074 g, 1.5 equiv, 0.27
mmol), and toluene. After the mixture had been stirred for 5 min, 4-
bromotoluene (0.037 g, 1.2 equiv, 0.22 mmol) was added via syringe
and the mixture was heated to 65 °C. Upon completion, the reaction
mixture was diluted with EtOAc, filtered through a plug of silica gel,
and concentrated. Column chromatography of the crude reaction
mixture using an 11% solution of EtOAc in hexanes provided the title
the use of methyl ortho-bromobenzoate requires isolation of the
cross-coupled product before the phenanthrene synthesis can
be conducted (Scheme 2, eq 4). Finally, we have also shown
that formation of cylic imines is possible using an ortho-
bromoaniline as the cross-coupling partner (Scheme 2, eq 5).
In conclusion, we have developed an efficient protocol for
the cross-coupling reaction of benzocyclobutenols with aryl
bromides. To the best of our knowledge, these are the first
examples of carbon−carbon bond-forming processes involving
controlled cleavage of the proximal bond of benzocyclobute-
nols. These reactions proceed in good to excellent yields and
tolerate a variety of oxidative addition partners. Finally, this
1
compound (0.043 g, 0.017 mmol) as a yellow oil (94%): H NMR
(300 MHz, CDCl3) δ 7.33 (dd, J = 7.8, 7.8 Hz, 1 H), 7.25 (d, J = 7.8
Hz, 2 H), 7.08 (d, J = 7.8 Hz, 2 H), 6.93 (d, J = 7.8 Hz, 1 H), 6.88 (d, J
= 7.8 Hz, 1 H), 3.74 (s, 3 H), 3.54 (s, 2 H), 2.43 (s, 3 H), 1.96 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 7.33 (dd, J = 7.8, 7.8 Hz, 1 H),
7.25 (d, J = 7.8 Hz, 2 H), 7.08 (d, J = 7.8 Hz, 2 H), 6.93 (d, J = 7.8 Hz,
1 H), 6.88 (d, J = 7.8 Hz, 1 H), 3.74 (s, 3 H), 3.54 (s, 2 H), 2.43 (s, 3
H), 1.96 (s, 3 H); IR 1717, 1575, 1464, 1352, 1254, 1156, 1076 cm−1
;
HRMS (EI) m/z calcd for C17H18O2 (M+) 254.1307, found 254.1301.
1-(4′-Fluoro-6-methoxybiphenyl-2-yl)propan-2-one (entry 2).
Isolated as a colorless oil (97%) using a 10% solution of EtOAc in
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1
hexanes: H NMR (300 MHz, CDCl3) δ 7.34 (dd, J = 8.1, 8.1 Hz, 1
tert-Butyl-5-[2-methoxy-6-(2-oxopropyl)phenyl]-1H-indole-1-car-
boxylate (entry 10). Isolated as a yellow oil (92%) using a 10%
H), 7.18−7.08 (m, 4 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.87 (d, J = 8.1 Hz,
1
1 H), 3.74 (s, 3 H), 3.53 (s, 2 H), 1.97 (s, 3 H); 13C NMR (75 MHz,
solution of ethyl acetate in hexanes: H NMR (300 MHz, CDCl3) δ
1
8.20 (d, J = 8.1 Hz, 1 H), 7.66 (d, J = 3.6 Hz, 1 H), 7.38 (s, 1 H), 7.35
(dd, J = 8.1, 8.1 Hz, 1 H), 7.14 (d, J = 8.1 Hz, 1 H), 6.95 (d, J = 8.1
Hz, 1 H), 6.89 (d, J = 8.1 Hz, 1 H), 6.60 (d, J = 3.6 Hz, 1 H), 3.73 (s,
3 H), 3.55 (s, 2 H), 1.93 (s, 3 H), 1.72 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 206.6, 157.5, 149.8, 134.8, 134.2, 131.6, 131.3, 130.6, 128.3,
126.2, 126.2, 122.5, 122.2, 114.9, 109.6, 107.4, 83.7, 55.8, 48.5, 29.7,
28.2; IR 1730, 1579, 1454, 1255, 1157, 1080, 1024, 735 cm−1; HRMS
(EI) m/z calcd for C23H25NO4 (M+) 379.1784, found 379.1773.
1-Cyclohexyl-2-(6-methoxy-4′-methylbiphenyl-2-yl)ethanone
(entry 11). Isolated as a clear oil (91%) using a 4% solution of ethyl
CDCl3) δ 206.2, 162.0 (d, JC−F = 244.5 Hz), 157.2, 134.6, 132.7 (d,
4JC−F = 3.0 Hz), 131.6 (d, JC−F = 7.5 Hz), 130.2, 128.6, 122.7, 115.1
3
(d, JC−F = 21.0 Hz), 109.7, 55.7, 48.4, 29.6; 19F NMR (282 MHz,
2
CDCl3) δ −114.9; IR 1720, 1468, 1257, 1220, 1159, 1078, 1008 cm−1
;
HRMS (EI) m/z calcd for C16H15FO2 (M+) 258.1056, found
258.1047.
2′-Methoxy-6′-(2-oxopropyl)biphenyl-4-carbonitrile (entry 3).
Isolated as a pale yellow crystalline solid (69%) using a 15% solution
of ethyl acetate in hexanes: mp 74 °C; 1H NMR (300 MHz, CDCl3) δ
7.71 (d, J = 8.4 Hz, 2 H), 7.37 (dd, J = 8.1, 8.1 Hz, 1 H), 7.31 (d, J =
8.4 Hz, 2 H), 6.94 (d, J = 8.1 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 3.73
(s, 3 H), 3.51 (s, 2 H), 1.99 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
205.7, 156.7, 142.3, 133.8, 131.9, 131.0, 129.4, 129.4, 122.8, 118.9,
1
acetate in hexanes: H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.0,
8.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 6.91
(d, J = 8.0 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 3.73 (s, 3 H), 3.57 (s, 2
H), 2.42 (s, 3 H), 2.12 (m, 1 H), 1.71 (m, 2 H), 1.61 (m, 3 H), 1.25−
1.17 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 211.1, 157.1, 136.5,
134.8, 133.9, 131.2, 129.8, 128.7, 128.0, 122.7, 109.4, 55.7, 50.2, 45.5,
28.3, 25.7, 25.5, 21.2; IR 2929, 1711, 1468, 1253, 1072 cm−1; HRMS
(EI) m/z calcd for C22H26O2 (M+) 322.1933, found 322.1944.
1-Cyclohexyl-2-(3′,4′,5′,6-tetramethoxybiphenyl-2-yl)ethanone
(entry 12). Isolated as a crystalline solid (84%) using a 27% solution
of ethyl acetate in hexanes: mp 117 °C; 1H NMR (300 MHz, CDCl3)
δ 7.31 (dd, J = 8.1, 8.1 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.82 (d, J =
8.1 Hz, 1 H), 6.38 (s, 2 H), 3.90 (s, 3 H), 3.82 (s, 6 H), 3.76 (s, 3 H),
3.57 (s, 2 H), 2.19 (m, 1 H), 1.70−1.61 (m, 5 H), 1.28−1.14 (m, 5
H); 13C NMR (75 MHz, CDCl3) δ 211.36, 157.0, 152.8, 136.7, 134.9,
132.7, 131.2, 128.3, 122.8, 109.5, 106.9, 60.8, 56.0, 55.8, 50.4, 45.6,
28.4, 25.7, 25.5; IR 2935, 1704, 1581, 1238, 1074 cm−1; HRMS (EI)
m/z calcd for C24H30O5 (M+) 398.2093, found 398.2081.
1-[4′-(2-Chloroethyl)-6-methoxybiphenyl-2-yl]-3-methylbutan-2-
one (entry 13). Isolated as a yellow oil (60%) using a 10% solution of
ethyl acetate in hexanes: 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J =
8.0, 8.0 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H),
6.87 (d, J = 8.0 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 4.28 (t, J = 6 Hz, 2
H), 3.85 (t, J = 6 Hz, 2 H), 3.72 (s, 3 H), 3.59 (s, 2 H), 2.43 (h, J = 6.8
Hz, 1 H), 0.94 (d, J = 6.8 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ
211.9, 157.2, 157.1, 134.8, 131.1, 130.7, 129.9, 128.1, 122.7, 114.3,
109.4, 67.9, 55.7, 45.3, 41.8, 40.2, 18.1; IR 1708, 1575, 1512, 1463,
1254 cm−1; HRMS (EI) m/z calcd for C20H23ClO3 (M+) 346.1336,
found 346.1325.
111.1, 109.7, 55.7, 48.3, 29.6; IR 2228, 1718, 1608, 1257, 1078 cm−1
;
HRMS (EI) m/z calcd for C17H15NO2 (M+) 265.1103, found
265.1109.
Methyl 2′-Methoxy-6′-(2-oxopropyl)biphenyl-4-carboxylate
(entry 4). Isolated as a brown powder (89%) using a 14% solution
of ethyl acetate in hexanes: mp 105 °C; 1H NMR (300 MHz, CDCl3)
δ 8.10 (d, J = 8.4 Hz, 2 H), 7.35 (dd, J = 8.1 Hz, 1 H), 7.27 (d, J = 8.4
Hz, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 3.95 (s,
3 H), 3.72 (s, 3 H), 3.51 (s, 2 H), 1.95 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 206.0, 167.0, 156.9, 142.2, 134.0, 130.3, 130.1, 129.4, 128.9,
128.9, 122.7, 109.7, 55.7, 52.1, 48.3, 29.6; IR 1722, 1610, 1279, 1257,
1078, 1007 cm−1; HRMS (EI) m/z calcd for C18H18O4 (M+)
298.1205, found 298.1215.
1-(4′,6-Dimethoxybiphenyl-2-yl)propan-2-one (entry 5). Isolated
as a yellow oil (88%) using a 10% solution of ethyl acetate in hexanes:
1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J = 8.1, 8.1 Hz, 1 H), 7.11
(d, J = 8.7 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 8.1 Hz, 1
H), 6.87 (d, J = 8.1 Hz, 1 H), 3.87 (s, 3 H), 3.74 (s, 3 H), 3.55 (s, 2
H), 1.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 206.6, 158.6, 157.4,
134.9, 131.0, 130.9, 129.0, 128.3, 122.6, 113.6, 109.7, 55.8, 55.2, 48.5,
29.6; IR 1714, 1579, 1288, 1248, 1078, 1018 cm−1; HRMS (EI) m/z
calcd for C17H18O3 (M+) 270.1256, found 270.1266.
1-(6-Methoxy-2′-methylbiphenyl-2-yl)propan-2-one (entry 6).
Isolated as a slightly yellow crystalline solid (99%) using a 5%
solution of ethyl acetate in hexanes: mp 53 °C; H NMR (300 MHz,
1
1-[3-Methoxy-2-(naphthalen-2-yl)phenyl]-3-methylbutan-2-one
CDCl3) δ 7.35 (dd, J = 8.1, 8.1 Hz, 1 H), 7.29 (m, 2 H), 7.25 (dd, J =
7.8, 7.8 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.93 (d, J = 8.1 Hz, 1 H),
6.90 (d, J = 8.1 Hz, 1 H), 3.74 (s, 3 H), 3.54 (d, J = 16.2 Hz, 1 H), 3.34
(d, J = 16.2 Hz, 1 H), 2.03 (s, 3 H), 1.89 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 206.3, 157.0, 137.0, 136.6, 134.5, 130.4, 129.8, 129.8
128.4, 127.5, 125.6, 122.7, 109.5, 55.7, 48.0, 29.7, 19.5; IR 1720, 1641,
1255, 1078, 1007 cm−1; HRMS (EI) m/z calcd for C17H18O2 (M+)
254.1307, found 254.1315.
1-(2′,6-Dimethoxybiphenyl-2-yl)propan-2-one (entry 7). Isolated
as a clear oil (86%) using a 13% solution of ethyl acetate in hexanes:
1H NMR (300 MHz, CDCl3) δ 7.37 (dt, J = 8.1, 2.1 Hz, 1 H), 7.34
(dd, J = 7.8, 7.8 Hz, 1 H), 7.08 (dd, J = 8.1, 2.1 Hz, 1 H), 7.04 (dd, J =
8.1 Hz, 1 H), 7.00 (d, J = 8.1 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 6.92
(d, J = 7.8 Hz, 1 H), 3.74 (s, 3 H), 3.48 (d, J = 16.2 Hz, 1 H), 3.42 (d,
J = 16.2 Hz, 1 H), 2.03 (s, 3 H), 1.89 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 206.7, 157.5, 156.8, 135.2, 131.7, 129.0, 128.5, 127.7, 125.5,
122.4, 120.5, 110.9, 109.8, 55.9, 55.3, 48.6, 29.2; IR 1711, 1581, 1253,
1078, 1051 cm−1; HRMS (EI) m/z calcd for C17H18O3 (M+)
270.1256, found 270.1250.
(entry 14). Isolated as a yellow oil (78%) using a 12% solution of
1
ethyl acetate in hexanes: H NMR (400 MHz, CDCl3) δ 7.87 (m, 2
H), 7.81 (m, 1 H), 7.62 (s, 1 H), 7.50 (m, 2 H), 7.34 (m, 2 H), 6.95
(d, J = 8 Hz, 1 H), 6.88 (d, J = 8 Hz, 1 H), 3.72 (s, 3 H), 3.62 (d, J =
17.0 Hz, 1 H), 3.56 (d, J = 17.0 Hz, 1 H), 2.35 (h, J = 6.8 Hz, 1 H),
0.85 (d, J = 5.0 Hz, 3 H), 0.82 (d, J = 5.0 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 211.9, 157.2, 134.7, 134.6, 133.2, 132.4, 131.1, 128.5,
128.4, 128.3, 127.9, 127.6, 127.4, 125.9, 125.7, 122.8, 109.5, 55.7, 45.4,
40.2, 18.0; IR 2963, 2928, 1708, 1575, 1464, 1254, 1085, 1067 cm−1
;
HRMS (EI) m/z calcd for C22H22O2 (M+) 318.1620, found 318.1611.
1-(4-Methoxyphenyl)-2-[4′-(trifluoromethyl)biphenyl-2-yl]-
ethanone (entry 15). Isolated as a clear oil (81%) using a 10%
1
solution of ethyl acetate in hexanes: H NMR (400 MHz, CDCl3) δ
7.80 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz,
2 H), 7.39 (m, 2 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1
H), 6.89 (d, J = 8.8 Hz, 2 H), 4.20 (s, 2 H), 3.87 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 196.3, 163.5, 145.0, 140.9, 132.6, 130.9, 130.4,
130.0 (q, 2JC−F = 32.0 Hz), 129.8, 129.4, 128.1, 127.0, 125.0 (q, 3JC−F
=
4.0 Hz), 124.1 (q, 1JC−F = 271.0 Hz), 113.6, 55.3, 42.5; 19F NMR (282
MHz, CDCl3) δ −62.4; IR 1675, 1600, 1324, 1263, 1168, 1068 cm−1
;
1-[3-Methoxy-2-(thiophen-3-yl)phenyl]propan-2-one (entry 9).
Isolated as a clear oil (99%) using an 11% solution of ethyl acetate in
HRMS (EI) m/z calcd for C22H17F3O2 (M+) 370.1181, found
370.1169.
1
hexanes: H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 4.8, 2.4 Hz, 1
H), 7.32 (t, J = 8.0 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 6.99 (d, J = 4.8
Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 3.76 (s,
3 H), 3.60 (s, 2 H), 2.00 (s, 3 H); 13C NMR (282 MHz, CDCl3) δ
206.5, 157.6, 136.4, 135.2, 129.5, 128.5, 126.1, 124.8, 123.5, 122.6,
109.6, 55.7, 48.5, 29.5; IR 1712, 1643, 1360, 1223, 1076 cm−1; HRMS
(EI) m/z calcd for C14H14O2S (M+) 246.0715, found 246.0721.
2-[2-(Benzo[b]thiophen-3-yl)phenyl]-1-(4-methoxyphenyl)-
ethanone (entry 16). Isolated as a yellow oil (76%) using a 10%
1
solution of ethyl acetate in hexanes: H NMR (300 MHz, CDCl3) δ
7.91 (d, J = 7.8 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 7.8 Hz,
1 H), 7.44−7.29 (m, 7 H), 6.78 (d, J = 8.7 Hz, 2 H), 4.13 (s, 2 H),
3.83 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 196.7, 163.3, 139.9,
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The Journal of Organic Chemistry
Note
139.1, 136.5, 135.5, 134.6, 130.8, 130.7, 130.5, 129.6, 128.1, 126.9,
124.7, 124.4, 124.3, 123.0, 122.6, 113.5, 55.4, 42.8; IR 1673, 1599,
1259, 1168, 1027 cm−1; HRMS (EI) m/z calcd for C23H18O2S (M+)
358.1028, found 358.1011.
1-(4-Methoxyphenyl)-2-(4′-nitrobiphenyl-2-yl)ethanone (entry
17). Isolated as a yellow oil (79%) using a 13% solution of ethyl
acetate in hexanes: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz,
2 H), 7.82 (d, J = 8.7 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.41 (m, 2
H), 7.32 (m, 2 H), 6.89 (d, J = 8.4 Hz, 2 H), 4.20 (s, 2 H), 3.87 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 196.0, 163.7, 148.3, 147.0, 140.2,
132.6, 131.2, 130.4, 130.1, 129.6, 129.4, 128.6, 127.2, 123.4, 113.8, 55.5
42.7; IR 1664, 1523, 1344, 1225, 1111, 1029 cm−1; HRMS (EI) m/z
calcd for C21H17NO4 (M+) 347.1158, found 347.1149.
1-(4′-tert-Butylbiphenyl-2-yl)propan-2-one (entry 18). Isolated as
a white solid (74%) using a 7% solution of ethyl acetate in hexanes:
mp 54−57 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2
H), 7.35−7.31 (m, 3 H), 7.24 (m, 1 H), 7.19 (d, J = 8.4 Hz, 2 H), 3.73
(s, 2 H), 2.01 (s, 3 H), 1.39 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ
206.8, 150.0, 142.3, 138.1, 132.2, 130.4, 130.2, 128.6, 127.3, 127.0,
125.1, 48.3, 34.3, 31.3, 29.6; IR 1712, 1481, 1361 cm−1; HRMS (EI)
m/z calcd for C19H22O (M+) 266.1671, found 266.1663.
6.9 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 209.8, 158.8, 136.8,
131.1, 130.7, 129.0, 128.6, 127.9, 127.5, 127.1, 126.3, 121.3, 118.7,
108.9, 55.7, 40.3, 18.4; IR 1688, 1571, 1445, 1251 cm−1; HRMS (EI)
m/z calcd for C19H18O2 (M+) 278.1307, found 278.1295
Methyl 2′-(2-Oxopropyl)biphenyl-2-carboxylate (eq 4, first
step). Prepared using the general cross-coupling procedure and
isolated as a yellow oil (88%) using a 7% solution of ethyl acetate
in hexanes: 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 1 H),
7.57 (dd, J = 7.0, 7.0 Hz, 1 H), 7.46 (dd, J = 7.0, 7.0 Hz, 1 H), 7.34
(dd, J = 8.0, 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 6.89 (d, J = 7.0
Hz, 1 H), 6.88 (d, J = 7.0 Hz, 1H), 3.69 (s, 3 H), 3.65 (s, 3 H), 3.50
(d, J = 16.0 Hz, 1 H), 3.40 (d, J = 16.0 Hz, 1 H), 1.95 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 206.5, 167.3, 156.6, 137.8, 133.4, 131.7,
131.4, 130.9, 130.6, 130.1, 128.3, 127.4, 122.4, 109.1, 55.6, 51.7, 48.5,
29.3; IR 3432.7, 3066.3, 3002.6, 2950.6, 2836.8, 1710.6, 1600.6,
1581.4, 1467.6, 1434.8, 1292.1, 1253.5, 1079.9 cm−1; HRMS (EI) m/z
calcd for C18H18O4 (M+) 298.1205, found 298.1213.
1-(10-Hydroxyphenanthren-9-yl)ethanone (eq 4, second step).
The above biaryl was dissolved in a solution of NaOMe (20 equiv) in
MeOH. The phenanthrene product was isolated as a yellow solid
(76%) using a 17% solution of ethyl acetate in hexanes: mp 106−108
°C; 1H NMR (400 MHz, CDCl3) δ 14.24 (s, 1 H), 9.53 (d, J = 8.0 Hz,
1 H), 8.61 (dd, J = 8.0, 1.0 Hz, 1 H), 7.78 (dd, J = 8.0, 8.0 Hz, 1 H),
7.64 (dd, J = 8.0, 8.0 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.53 (dd, J =
8.0, 8.0 Hz, 1 H), 7.07 (d, J = 8.0 Hz, 1 H), 4.13 (s, 3 H), 2.80 (s, 3
H); 13C NMR (100 MHz, CDCl3) δ 204.0, 161.9, 158.8, 133.6, 132.1,
130.5, 128.5, 127.0, 126.3, 125.6, 124.5, 118.4, 116.6, 112.7, 106.9,
55.6, 31.3; IR 1599, 1579, 1530, 1348, 1254, 1080 cm−1; HRMS (EI)
m/z calcd for C17H14O3 (M+) 266.0943, found 266.0949.
(Z)-11-Methoxy-6-methyl-7H-dibenzo[b,d]azepine (eq 5). Pre-
pared using the general cross-coupling procedure and isolated as a
red oil (53%) using a 9% solution of ethyl acetate in hexanes: 1H NMR
(400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1 H), 7.39−7.32 (m, 3 H),
7.32 (m, 2 H), 7.17 (dd, J = 7.6, 7.6 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1
H), 6.91 (d, J = 8.0 Hz, 1 H), 3.83 (s, 3 H), 3.38 (d, J = 11.6 Hz, 1 H),
2.85 (d, J = 11.6 Hz, 1 H), 2.30 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 168.7, 157.0, 146.9, 139.3, 131.5, 128.8, 127.2, 127.1, 124.9,
124.3, 122.2, 119.1, 109.9, 55.7, 40.5, 26.6; IR 1643, 1592, 1456, 1263,
1076 cm−1; HRMS (EI) m/z calcd for C16H15NO (M+) 237.1154,
found 237.1147.
1-(3′,4′,5′-Trimethoxybiphenyl-2-yl)propan-2-one (entry 19).
Isolated as a white solid (73%) using a 25% solution of ethyl acetate
in hexanes: mp 108−111 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 (m,
3 H), 7.24 (d, J = 8.4 Hz, 1 H), 6.47 (s, 2 H), 3.92 (s, 3 H), 3.85 (s, 6
H), 3.73 (s, 2 H), 2.10 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
206.6, 152.8, 142.4, 137.0, 136.8, 132.1, 130.5, 129.8, 127.8, 126.9,
106.1, 60.8, 56.0, 48.4, 29.7; IR 1717, 1575, 1406, 1241 cm−1; HRMS
(EI) m/z calcd for C18H20O4 (M+) 300.1362, found 300.1371.
2-(4′-Methylbiphenyl-2-yl)cyclohexanone (entry 20). Isolated as a
white solid (70%) using a 5% solution of ethyl acetate in hexanes: mp
67−69 °C; 1H NMR (300 MHz, CDCl3) δ 7.42−7.24 (m, 4 H), 7.21
(d, J = 7.8 Hz, 2 H), 7.13 (d, J = 7.8 Hz, 2 H), 3.74 (dd, J = 12.9, 5.4
Hz, 1 H), 2.53−2.47 (m, 1 H), 2.43 (s, 3 H), 2.35−1.61 (m, 7 H); 13
C
NMR (75 MHz, CDCl3) δ 211.0, 142.0, 138.5, 136.7, 130.0, 128.9,
128.5, 127.2, 126.5, 54.2, 42.3, 35.8, 27.7, 25.6, 21.2; IR 2932, 2856,
1704, 1481, 1446, 1121 cm−1; HRMS (EI) m/z calcd for C19H20O
(M+) 264.1514, found 264.1524.
Methyl 2′-(2-Oxocycloheptyl)biphenyl-4-carboxylate (entry 21).
Isolated as a yellow oil (85%) using a 9% solution of ethyl acetate in
1
hexanes: H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2 H),
7.41−7.28 (m, 5 H), 7.21 (d, J = 7.6 Hz, 1 H), 3.97 (s, 3 H), 3.87 (dd,
J = 10.0, 3.0 Hz, 1 H), 2.55−2.49 (m, 1 H), 2.44−2.38 (m, 1 H),
2.03−1.84 (m, 5 H), 1.48−1.29 (m, 3 H); 13C NMR (75 MHz,
CDCl3) δ 213.6, 166.9, 146.4, 140.4, 139.1, 129.5, 129.4, 128.9, 128.2,
128.1, 126.4, 54.1, 52.2, 43.9, 33.3, 29.6, 29.4, 24.0; IR 1717, 1606,
1432, 1277, 1112 cm−1; HRMS (EI) m/z calcd for C21H22O3 (M+)
322.1569, found 322.1561.
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete reaction optimization and H and 13C NMR spectra
1
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
2-(4′-Methoxybiphenyl-2-yl)cycloheptanone (entry 22). Isolated
as a yellow oil (56%) using a 6% solution of ethyl acetate in hexanes:
1H NMR (400 MHz, CDCl3) δ 7.39−7.22 (m, 4 H), 7.19 (d, J = 8.6
Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 3.98 (dd, J = 11.0, 3.0 Hz, 1 H),
3.88 (s, 3 H), 2.57−2.38 (m, 2 H), 2.03−1.84 (m, 5 H), 1.50−1.28
(m, 3 H); 13C NMR (100 MHz, CDCl3) δ 214.1, 158.6, 141.0, 139.5,
133.8, 130.3, 129.9, 127.9, 127.2, 126.2, 113.4, 55.2, 54.0, 43.8, 33.1,
29.6, 29.3, 24.0; IR 1700, 1609, 1513, 1481, 1441, 1294, 1245, 1175,
1035 cm−1; HRMS (EI) m/z calcd for C20H22O2 (M+) 294.1620,
found 294.1627.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aorellan@yorku.ca.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support of this work by York
University and the Natural Sciences and Engineering Research
Council of Canada. We thank Dr. Howard N. Hunter (York
University) for assistance in conducting NMR spectroscopy
experiments, Professor Michael Organ (York University) for
generous sharing of resources, and a previous reviewer for
suggested improvements to the manuscript.
1-(10-Aminophenanthren-9-yl)ethanone (Scheme 2, eq 2). This
compound was prepared following the general procedure and using 2.5
equiv of Ag2CO3. 1H and 13C NMR data were identical to that
previously reported.48
1-(5-Methoxyphenanthren-9-yl)-2-methylpropan-1-one (eq 3).
Prepared following the general cross-coupling procedure and using 2.5
equiv of Ag2CO3 and isolated as a white solid (78%) using a 17%
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