Ruthenium-Catalyzed C-H Arylation of 1-Naphthol with Aryl and Heteroaryl Halides

Article abstract of DOI:10.1021/acs.joc.9b02075

While 8-aryl-1-napthols are promising dye molecules and useful intermediates in the synthesis of polycyclic aromatic hydrocarbons, they can be difficult to access. A new, ruthenium-catalyzed method for peri-C-H arylation of 1-naphthol with a variety of aryl and heteroaryl halides (iodides, bromides) is reported that overcomes the limitations of previous palladium-catalyzed approaches. Yields for the 21 examples range from 16 to 99%, with an average of 71%, and the reaction tolerates a variety of functional groups: pyridine, pyrimidine, primary aniline, aldehyde, and ester.

Full text of DOI:10.1021/acs.joc.9b02075

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Note
Ruthenium-Catalyzed C-H Arylation of 1-
Naphthol with Aryl and Heteroaryl Halides
Amanda M Spiewak, and Daniel J. Weix
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02075 • Publication Date (Web): 14 Nov 2019
Downloaded from pubs.acs.org on November 14, 2019
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Ruthenium-Catalyzed C-H Arylation of 1-Naphthol
with Aryl and Heteroaryl Halides
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Amanda M. Spiewak and Daniel J. Weix*
Department of Chemistry, University of Wisconsin, Madison, WI 53706 USA
ABSTRACT While 8-aryl-1-napthols are promising dye molecules and useful intermediates in
the synthesis of polycyclic aromatic hydrocarbons, they can be difficult to access. A new,
ruthenium-catalyzed method for peri C-H arylation of 1-naphthol with a variety of aryl and
heteroaryl halides (iodides, bromides) is reported that overcomes the limitations of previous
palladium-catalyzed approaches. Yields for the 21 examples range from 16-99%, with an average
of 71%, and the reaction tolerates a variety of functional groups: pyridine, pyrimidine, primary
aniline, aldehyde, and ester.
R
X
X
R
OH
OH
cat. Ru (II)
base, NMP
or
+
R
N
21 examples
up to 99% yield
X = I or Br
Transition metal catalyzed C-H arylation can streamline synthesis by avoiding the need for
prefunctionalization, but selective reaction with one C-H out of many can be challenging.1,2
Directed C-H arylation has proven to be one of the most robust approaches to solving this
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problem.2 Methods that rely upon innate functional groups as directing groups rather than the
introduction and removal of specialized groups can be especially efficient, albeit often at the
expense of more narrow applicability.3 These methods can nonetheless open up new chemical
space for exploration. For example, the development of a method to access 8-aryl-1-naphthol
derivatives from 1-naphthol by Miura (Scheme 1a)4 enabled exploration of these derivatives for
organic light emitting diode (OLED) applications.5 In addition, easy access to these 8-arylated
naphthols simplified access to fluoranthenes.6,7
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While the palladium-catalyzed C-H arylation procedure was a powerful advance, the method
only provided high yields with aryl iodides and functional-group tolerance was limited: no
examples with aniline functional groups or heteroaromatic halides were provided.8 This is
problematic because the more promising 8-aryl-1-naphthol dyes contain heteroaromatic or highly
substituted aryl groups, requiring lengthy cross-coupling approaches involving
protection/deprotection steps.5 Ruthenium-catalyzed C-H arylation in some cases has been
demonstrated to be superior to the analogous palladium-catalyzed methods.2c,g,3g For example, our
group, along with Gooßen, Ackermann, and Larossa, found that ruthenium catalysts are more
tolerant of heteroaromatic halides and less reactive aryl halides in the ortho-arylation of benzoic
acids.9 peri-Arylation with naphthols has not been reported, but ortho-alkylation of phenols and
naphthols10 and ortho-arylation of 2-pyridyl-protected phenols has been reported.11 We show here
how standard ruthenium C-H arylation conditions allow the use of aryl bromides and
heteroaromatic halides in 1-naphthol peri-C-H arylation (Scheme 1b).
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Scheme 1. Synthesis of 8-(Hetero)Aryl-1-Naphthols.
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Previous studies - Pd-catalyzed arylation with aryl iodides
OH
Ar
OH
cat. Pd
base
8
9
(a)
Ar-I
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This study - Ru catalysis enables expanded scope
OH
Ar
OH
cat. Ru
X = I and Br
Ar = aryl and
heteroaryl
base
(b)
Ar-X
The optimal conditions (Table 1, entries 1, 10, and 12) do not require an ancillary ligand, but ,
similar to what Miura reported with palladium catalysis, both a carbonate and acetate base are
essential.4,12 Aryl bromides and iodides are both coupled under essentially the same conditions, but
at lower temperature with cesium carbonate, activated aryl iodides can be coupled while aryl
bromides provide low yields (entries 1, 6, 7, and 12). In cases with challenging aryl iodides, the
higher-temperature conditions worked best, and these conditions appear to be the most general
(Scheme 2). See the Supporting Information for additional details on the conditions tested. Even
though unactivated aryl bromides could be coupled, chlorobenzene could not be coupled (entry
13).
Table 1. Optimization of Intermolecular C−H Arylation of 1-Naphthol with Halobenzenes
OH
Ph OH
[Ru(p-cymene)Cl2]2 (4 mol%)
Base(s) (2 equiv total)
Ph–X (2, 1.25 equiv)
NMP (0.25 M), T °C, 24 h
1
3
entrya
X
I
base(s)b
T (°C)
yieldc (%)
1
2
3
4
5
Cs2CO3, KOAc 100
98 (93)
I
KOAc
100
100
45
50
96
0
I
Cs2CO3
Id
Ie
Cs2CO3, KOAc 100
Cs2CO3, KOAc 100
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Br Cs2CO3, KOAc 100
Br K2CO3, KOAc 130
35
72
12
71
84
0
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Br KOAc
Br K2CO3
130
130
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Brd K2CO3, KOAc 130
Bre K2CO3, KOAc 130
I
K2CO3, KOAc 130
96
6
Cl K2CO3, KOAc 130
a Reactions were run on a 0.25 mmol scale in 1 mL of solvent for 24 h. A total of 2 equiv of
base was used in each case. When two bases were used together, 1 equiv of each was used. c GC
yield vs internal standard (dodecane), isolated yields in parenthesis. d1.5 equiv of aryl halide used.
e Ruthenium catalyst omitted.
b
Application of these conditions to a variety of aryl halides is demonstrated in Scheme 2. Both
electron-rich and electron-poor aryl iodides and bromides can be coupled in useful yields, but for
electron-rich aryl iodides the higher temperature conditions were found to be optimal. Important
improvements over previously reported methods are tolerance for reactive functional groups: an
unprotected aniline (3b), an ester (3m), and an aldehyde (3j); and the ability to couple heteroaryl
halides (3p, 3r, 3s). Substitution at the ortho-position of the aryl halide generally resulted in
diminished yields (compare 3g to 3i), but bromopyrene was coupled in 73% yield (3q). In addition,
dihalide substrates were also tolerated, with the more reactive carbon-halide bond being selectively
arylated (3l, 3r, 3s), although selectivity was not always perfect, resulting in diminished yields
(3s). While chlorobenzene had been unsuccessful (Table 1, entry 13), 2-chloropyrimidine was
reactive (3s). This selectivity allows for the use of different halides as orthogonal functional group
handles for further chemical elaboration. Finally, the reaction could be scaled to 10 mmol scale
without difficulty using standard Schlenk techniques (3d, 2.66 g of product).
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Scheme 2. Intermolecular C−H Arylation of 1-Naphthol with (Hetero)aromatic Halidesa
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Condition A (X = I)
Condition B (X = Br, I)
R
R
OH
OH
OH
R
[Ru(p-cymene)Cl2]2 (4 mol%)
[Ru(p-cymene)Cl2]2 (4 mol%)
X
+
KOAc (1 equiv)
Cs2CO3 (1 equiv)
NMP, 100 °C, 24 h
KOAc (1 equiv)
K2CO3 (1 equiv)
NMP, 130 °C, 24 h
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3
1
2
3
(1.25 equiv)
NH2
CH3
O
CF3
F
CF3
OH
OH
OH
OH
OH
OH
X = I, 3a, 93% (A)
Br, 3a, >99% (B)
X = I, 3b, 71% (A)
X = I, 3c, 72% (A)
X = I, 3d, 92%b (A)
X = I, 3e, 96% (A)
X = I, 3f, 71% (B)
O
F
CH3
Cl
F
H3C
OH
H3C
OH
OH
OH
OH
OH
X = I, 3g, 95% (A)
X = I, 3h, 63% (A)
X = I, 3i, 16% (A)
X = Br, 3j, 57% (B)
X = I, 3k, 87% (A)
X = I, 3l, 55% (A)
EtO
O
Br
Cl
O
O
O
O
N
N
N
N
OH
OH
OH
OH
OH
OH
OH
X = Br, 3m, 68%c (B) X = Br, 3n, 90%c (B)
X = Br, 3o, 94% (B)
X = Br, 3p, 63% (B)
X = Br, 3q, 73% (B)
X = Br, 3r, 76% (B)
X = Cl, 3s, 51% (B)
a Reactions were run on a 0.5 mmol scale in 2 mL of solvent for 24 h. b Reaction was run on a
10.0 mmol scale using standard Schlenk line techniques on the benchtop. c Product was inseparable
from a small amount (<8%) of naphthol impurity. The yield has been adjusted based upon NMR.
Although we have not conducted any mechanistic investigations on this system, it appears to
proceed in analogy to other, related, palladium and ruthenium catalyzed methods.4,9,13
Deprotonation of the phenol, coordination to ruthenium, and concerted metalation deprotonation
activates the C-H bond and sets the regioselectivity. Subsequent oxidative addition of the aryl
halide and reductive elimination to form the new C-C bond would then complete the cycle.
This new approach to peri-substituted naphthols expands the pool of 8-arylated naphthol
derivatives that can be accessed in a single step to include nitrogen-substitution, a common
component in some of the most promising dyes.5 This result mirrors our findings for the arylation
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of benzoic acids,9 demonstrating again how ruthenium C-H arylation is a useful complement to
palladium catalyzed methods.2c,3g While we have no plans to further investigate this methodology,
it is likely that other electrophiles could be used in this chemistry as well.
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Experimental Section
General Methods. Dry NMP (1-Methyl-2-pyrrolidinone, anhydrous, 99.5%) was purchased and
used without purification. 1H nuclear magnetic resonance (NMR) spectroscopy chemical shifts are
reported in ppm and referenced to TMS (tetramethylsilane) in CDCl3 (δ = 0 ppm) or the residual
solvent peak for CDCl3 (δ = 7.26 ppm). For 13C NMR and 19F NMR chemical shifts, the residual
solvent peak (CDCl3, δ= 77.00 ppm) and TMS (δ = 0 ppm) were used as references. Chemical
shifts are reported in parts per million (ppm), multiplicities are indicated by s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet) and br (broad). Coupling constants (J) are reported in Hertz.
GC analyses were performed on an Agilent 7890A GC equipped with dual DB-5 columns (20 m
× 180 µm × 0.18 µm), dual FID detectors, and hydrogen as the carrier gas. Chromatography was
performed on silica gel (EMD, silica gel 60, particle size 0.040-0.063 mm) using standard flash
techniques or on 40 g HP Silica column (catalog 69-2203-347) using a Teledyne Isco Rf- 200
(detection at 210 nm and 340 nm). Products were visualized by UV-vis. GCMS data was collected
with a Shimadzu GCMS-2010S. For non-volatile compounds, high resolution mass spectra
(HRMS) data was collected on a Thermo Q Exactive Plus (ESI-Q-IT-MS) (thermofisher.com) via
flow injection with electrospray ionization. An ASAP-MS source (ionSence, Saugus, MA) on the
Thermo Q Exactive Plus was used to obtain HRMS for volatile compounds analyzed by GCMS.
This HRMS data was acquired by the chemistry mass spectrometry facility at the University of
Wisconsin – Madison.
General Procedure for the Arylation of 1-Naphthol and Aryl Iodides (Condition A)
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Glovebox procedure: On the bench, an oven-dried 1-dram vial fitted with a Teflon-coated stir-bar
was charged with [Ru(p-cymene)Cl2]2 (12.3 mg, 0.02 mmol, 4 mol%), 1-naphthol (72.1 mg, 0.50
mmol, 1.0 equiv), and potassium acetate (49.1 mg, 0.50 mmol, 1.0 equiv). The vial was moved
into a nitrogen filled glove box and Cs2CO3 (162.9 mg, 0.50 mmol, 1.0 equiv), dodecane (as an
internal standard, 10.0 µL), aryl iodide (0.625 mmol, 1.25 equiv), and NMP (2.00 mL) were
sequentially added. The vial was capped with a screw cap fitted with a PTFE-faced silicone
septum, removed from the glove box, and heated in a reaction block set to 100 °C on the benchtop
with stirring at 1250 rpm until the reaction was judged complete (<5% 1-naphthol or aryl iodide
remaining) by GC analysis, typically 24 h.
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Benchtop procedure: An oven-dried 100 mL Schlenk flask containing a PTFE-coated stir-bar was
charged with [Ru(p-cymene)Cl2]2 (0.24 g, 0.4 mmol, 4 mol %), 1-naphthol (1.44 g, 10.0 mmol,
1.0 equiv), potassium acetate (0.98 g, 10.0 mmol, 1.0 equiv), and Cs2CO3 (3.26 g, 10.0 mmol, 1.0
equiv). 50 mL of anhydrous NMP was then added to the flask, which was subsequently attached
to a nitrogen manifold. The headspace was purged with N2 (through the stopcock with venting
through a needle in the septa). After 10 min, the vent needle was removed from the septa and 4-
iodobenzotrifluoride (1.47 mL, 12.5 mmol, 1.25 equiv) was added via syringe. The flow of N2 into
the vessel was turned off and the sealed (septum) reaction vessel was stirred (1250 rpm) in a 100
°C oil bath for 24 h.
General Procedure for the Arylation of 1-Naphthol and Aryl Bromides (Condition B)
Glovebox procedure: As for condition A, except that K2CO3 (69.1 mg, 0.50 mmol, 1.0 equiv) and
aryl bromide (0.625 mmol, 1.25 equiv), and NMP (2.00 mL) were used in place of Cs2CO3 and
aryl iodide. The reaction was stirred at 130 °C instead of 100 °C.
Isolation and purification
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Upon reaction completion, the reaction mixture was diluted with dichloromethane (50 mL). The
mixture was poured into a separatory funnel and the organic layer was washed with 1 M LiBraq
(50 mL), 1 M HClaq (50 mL), and saturated NaClaq (50 mL). The combined aqueous layers were
then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over
MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel to afford the pure product.
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8-Phenylnaphthalen-1-ol (3a)6 Condition A from iodobenzene (127.5 mg, 69.7 µL): 93% yield
(102.4 mg). Yellow oil. Condition B from bromobenzene (98.1 mg, 66.6 µL): >99% yield (110.1
mg). Yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.3, 1.3 Hz, 1H), 7.52 (m, 6H), 7.43
(dt, J = 17.2, 7.6 Hz, 2H), 7.21 (dd, J = 7.1, 1.3 Hz, 1H), 6.91 (dd, J = 7.6, 1.3 Hz, 1H), 5.40 (s,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.0, 141.4, 136.2, 135.7, 129.5, 129.0, 128.7, 128.6,
128.5, 126.9, 124.8, 121.3, 121.0, 111.8. HRMS (ESI) m/z calculated for C16H11O [M – H]-
219.0815, found 219.0814. Our characterization data is consistent with those previously reported.
8-(4-Aminophenyl)naphthalen-1-ol (3b) Condition A from 4-iodoaniline (136.9 mg): 71% yield
(83.5 mg). Brick red oil. 1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.3, 1.2 Hz, 1H), 7.47 (dd, J
= 8.2, 1.2 Hz, 1H), 7.39 (dt, J = 15.3, 7.5 Hz, 2H), 7.32 – 7.27 (m, 2H), 7.17 (dd, J = 7.0, 1.3 Hz,
1H), 6.90 (dd, J = 7.5, 1.2 Hz, 1H), 6.83 – 6.77 (m, 2H), 5.93 (s, 1H), 3.87 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 153.4, 146.9, 136.3, 135.7, 130.6, 130.3, 128.7, 128.3, 126.8, 124.9, 121.6,
120.7, 115.2, 111.4. HRMS (ESI) m/z calculated for C16H12NO [M – H]- 234.0924, found
234.0923.
8-(3-Fluoro-4-Methylphenyl)naphthalen-1-ol (3c) Condition A from 2-fluoro-4-iodotoluene
(147.5 mg): 72% yield (90.8 mg). Amber oil. 1H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 8.2, 1.3
Hz, 1H), 7.51 (dd, J = 8.2, 1.2 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.21 – 7.18
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(m, 2H), 7.18 – 7.17 (m, 1H), 6.93 (dd, J = 7.6, 1.3 Hz, 1H), 5.41 (s, 1H), 2.38 (d, J = 2.0 Hz, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 161.0 (d, J = 248.2 Hz), 152.8, 140.7 (d, J = 7.5 Hz), 135.6,
134.9 (d, J = 1.8 Hz), 131.9 (d, J = 5.7 Hz), 128.9, 128.5, 126.9, 125.4 (d, J = 17.2 Hz), 124.8,
124.8, 121.2, 121.1, 116.3 (d, J = 22.4 Hz), 111.9, 14.4 (d, J = 3.4 Hz). 19F{1H} NMR (377 MHz,
CDCl3) δ 9.42. HRMS (ASAP-MS) m/z calculated for C17H12FO [M – H]- 251.0878, found
251.0878.
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8-(4-Trifluoromethylphenyl)naphthalen-1-ol (3d)6 Condition A, benchtop procedure (10.0
mmol scale) from 4-iodobenzotrifluoride (3.4 g, 1.84 mL): 92% yield (2.66 g). Brown solid. Mp.
1
71.4-74.1 ℃ (lit.6 72.8-74.0 ℃). H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 8.3, 1.3 Hz, 1H),
7.74 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 (dd, J = 8.2, 1.2 Hz, 1H), 7.48 (d, J = 7.0
Hz, 1H), 7.47 (d, J = 7.0 Hz, 0H), 7.41 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 7.0, 1.3 Hz, 1H), 6.90 (dd,
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J = 7.5, 1.2 Hz, 1H), 5.00 (s, 1H). C{1H} NMR (126 MHz, CDCl3) δ 152.4, 146.16, 146.15,
135.8, 135.4, 130.5 (q, J = 32.6 Hz), 129.8, 129.1, 128.8, 127.4 (q, J = 274.5 Hz), 126.9, 125.3 (q,
1
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J = 3.8 Hz), 125.2, 125.0, 121.5, 121.2, 112.0, 29.7. F{ H} NMR (377 MHz, CDCl3) δ 62.52.
HRMS (ESI) m/z calculated for C17H10F3O [M – H]- 287.0689, found 287.0688. Our
characterization data is consistent with those previously reported.
8-(3-Trifluoromethylphenyl)naphthalen-1-ol (3e)6 Condition A from 3-iodobenzotrifluoride
(170.0 mg, 90.1 µL): 96% yield (136.4 mg). Dark brown oil. 1H NMR (400 MHz, CDCl3) δ 7.89
(dd, J = 8.3, 1.1 Hz, 1H), 7.77 (dd, J = 7.3, 1.2 Hz, 1H), 7.70 (dd, J = 15.6, 7.7 Hz, 2H), 7.60 (t, J
= 7.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 7.1 Hz, 1H), 7.46 (d, J = 6.9 Hz, 0H), 7.40 (t,
J = 7.9 Hz, 1H), 7.22 (dd, J = 5.9, 1.2 Hz, 1H), 6.88 (dd, J = 7.6, 1.2 Hz, 1H), 4.92 (s, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 152.5, 143.4, 140.2, 136.0, 135.4, 132.8, 130.8 (q, J = 32.4 Hz), 129.2,
129.1, 128.8, 126.9, 126.4 (q, J = 3.8 Hz), 125.2, 124.7 (q, J = 3.8 Hz), 124.4 (q, J = 273.9 Hz),
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121.6, 121.4, 112.0. F{ H} NMR (377 MHz, CDCl3) δ 62.39. HRMS (ESI) m/z calculated for
C17H10F3O [M – H]- 287.0688, found 287.0689. Our characterization data is consistent with those
previously reported.
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8-(4-Methoxyphenyl)naphthalen-1-ol (3f)6 Condition B from 4-iodoanisole (146.3 mg): 71%
yield (88.9 mg). Brick red solid. Mp. 114.2-116.4 ℃ (lit.6 114.1-114.9 ℃). 1H NMR (500 MHz,
CDCl3) δ 7.84 (dd, J = 8.2, 1.4 Hz, 1H), 7.49 (dd, J = 8.1, 1.3 Hz, 1H), 7.46 – 7.41 (m, 3H), 7.42
– 7.36 (m, 1H), 7.18 (dd, J = 7.0, 1.3 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.91 (dd, J = 7.6, 1.2 Hz, 1H),
5.65 (s, 1H), 3.89 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.9, 153.2, 135.8, 135.7, 133.0,
130.7, 128.7, 128.5, 126.8, 124.9, 121.5, 120.9, 114.4, 111.6, 55.4. HRMS (ESI) m/z calculated
for C17H13O2 [M – H]- 249.0921, found 249.0922. Our characterization data is consistent with those
previously reported.
8-(4-Methylphenyl)naphthalen-1-ol (3g)6 Condition A from 4-iodotoluene (136.3 mg): 95%
yield (111.3 mg). Brown oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 1H), 7.49 (d, J =
8.1 Hz, 1H), 7.41 (p, J = 8.5, 7.9 Hz, 4H), 7.33 (d, J = 7.7 Hz, 2H), 7.22 – 7.16 (m, 1H), 6.91 (d,
13
J = 7.5 Hz, 1H), 5.55 (s, 1H), 2.46 (s, 3H). C{1H} NMR (126 MHz, CDCl3) δ 153.4, 138.8,
138.3, 136.3, 135.9, 129.9, 129.5, 128.8, 128.7, 127.0, 125.0, 121.6, 121.1, 111.9, 21.5. HRMS
(ESI) m/z calculated for C17H13O [M – H]- 233.0972, found 233.0972. Our characterization data is
consistent with those previously reported excepting morphology (lit.6 reports a yellow solid).
8-(3-Methylphenyl)naphthalen-1-ol (3h)6 Condition A from 3-iodotoluene (136.3 mg, 80.3 µL):
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63% yield (73.6 mg). Amber solid. Mp. 81.6-84.0. H NMR (500 MHz, CDCl3) δ 7.85 (dd, J =
8.2, 1.3 Hz, 1H), 7.51 – 7.42 (m, 2H), 7.42 – 7.31 (m, 5H), 7.12 (dd, J = 6.9, 1.3 Hz, 1H), 6.87
13
(dd, J = 7.6, 1.2 Hz, 1H), 5.54 (s, 1H), 2.08 (s, 3H). C{1H} NMR (126 MHz, CDCl3) δ 153.4,
140.3, 137.6, 135.6, 135.4, 130.6, 130.0, 129.2, 128.6, 127.6, 126.8, 126.5, 125.1, 121.6, 121.0,
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111.4, 20.1. HRMS (ESI) m/z calculated for C17H13O [M – H]- 233.0972, found 233.0971. Our
characterization data is consistent with those previously reported excepting morphology (lit.6
reports a yellow oil).
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8-(2-Methylphenyl)naphthalen-1-ol (3i) Condition A from 2-iodotoluene (136.3 mg, 79.5 µL):
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59% yield (69.1 mg). Amber oil. H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 8.2, 1.3 Hz, 1H),
7.37 (dd, J = 8.2, 1.2 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.30 – 7.25 (m, 2H), 7.25 – 7.18 (m, 2H), 7.00
(dd, J = 7.0, 1.3 Hz, 1H), 6.77 (dd, J = 7.6, 1.2 Hz, 1H), 5.45 (s, 1H), 1.96 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 153.4, 140.3, 137.6, 135.7, 135.4, 130.7, 130.0, 129.2, 128.6, 127.3, 126.9,
126.5, 125.2, 121.7, 121.0, 111.4, 20.2. HRMS (ESI) m/z calculated for C17H13O [M – H]-
233.0972, found 233.0972.
4-(8-hydroxynaphthalen-1-yl)benzaldehyde (3j) Condition B from 4-bromobenzaldehyde
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(115.6 mg): 57% yield (71 mg). Pale yellow oil. H NMR (500 MHz, CDCl3) δ 8.03 – 7.98 (m,
2H), 7.85 (dd, J = 8.3, 1.2 Hz, 1H), 7.56 – 7.52 (m, 2H), 7.49 (dd, J = 8.1, 1.1 Hz, 1H), 7.43 (dd, J
= 8.3, 7.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.0, 1.3 Hz, 1H), 6.90 (dd, J = 7.6, 1.2
13
Hz, 1H), 5.75 (s, 1H). C{1H} NMR (126 MHz, CDCl3) δ 200.4, 162.9, 137.2, 136.3, 130.6,
129.3, 128.1, 127.3, 126.4, 126.3, 124.9, 124.3, 123.5, 116.8, 111.5. HRMS (ASAP-MS) m/z
calculated for C17H11O2 [M – H]- 247.0765, found 247.0764.
8-(4-Fluorophenyl)naphthalen-1-ol (3k) Condition A from 4-fluoroiodobenzene (138.8 mg, 72.1
µL): 87% yield (103.6 mg). Brown oil. 1H NMR (500 MHz, CDCl3) δ 7.74 (dd, J = 8.3, 1.2 Hz,
1H), 7.39 (dd, J = 8.2, 1.2 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.29 (t, J = 7.3 Hz, 1H), 7.12 – 7.04 (m,
3H), 6.79 (dd, J = 7.6, 1.2 Hz, 1H), 5.21 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (d, J =
248.6 Hz), 152.9, 137.5 (d, J = 3.6 Hz), 135.8, 135.3, 131.3 (d, J = 8.1 Hz), 128.9 (d, J = 1.2 Hz),
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127.0, 125.0, 121.4, 121.2, 115.8 (d, J = 21.5 Hz), 111.9. F{ H} NMR (377 MHz, CDCl3) δ -
113.13. HRMS (ESI) m/z calculated for C16H10FO [M – H]- 237.0721, found 237.0722.
8-(2-Fluoro-4-bromophenyl)naphthalen-1-ol (3l) Condition A from 1-chloro-2-fluoro-4-
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iodobenzene (160.3 mg, 79.8 µL): 55% yield (74.9 mg). Brown oil. H NMR (500 MHz, CDCl3)
δ 7.85 (dd, J = 8.3, 1.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.37 (t, J = 7.8 Hz,
1H), 7.25 (dd, J = 9.5, 2.0 Hz, 1H), 7.17 (dt, J = 7.9, 1.8 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 1H),
5.18 (s, 1H). C{1H} NMR (126 MHz, CDCl3) δ 157.5 (d, J = 250.8 Hz), 152.3, 135.8, 134.6,
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130.3, 129.1, 128.7, 126.8, 125.8 (d, J = 3.6 Hz), 125.0, 121.4, 121.2, 117.8 (d, J = 21.2 Hz), 111.9.
19F{1H} NMR (377 MHz, CDCl3) δ -114.70. HRMS (ESI) m/z calculated for C16H9ClOF [M – H]-
271.0331, found 271.0331.
8-(4-Ethylbenzoate)naphthalen-1-ol (3m) Condition B from ethyl 4-bromobenzoate (143.2 mg,
102.0 µL): 68% yield (99.4 mg). This compound could not be separated from a small amount of
1-naphthol. The yield reported has been adjusted to account for this impurity based upon 1H NMR
integration. Light brown solid. Mp. 132.4-133.0℃; 1H NMR (500 MHz, CDCl3) δ 8.21 – 8.13 (m,
2H), 7.88 (dd, J = 8.2, 1.2 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.55 – 7.51 (m, 1H), 7.46 (dd, J = 8.3, 7.0
Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.0, 1.3 Hz, 1H), 6.91 (dd, J = 7.5, 1.2 Hz, 1H),
5.12 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 166.2, 152.6, 146.7, 135.7, 135.6, 130.2, 129.8, 129.7, 129.4 (d, J = 3.5 Hz), 129.1, 128.5, 126.9,
124.9, 121.3, 121.2, 112.0, 61.2, 14.4. HRMS (ASAP-MS) m/z calculated for C19H15O3 [M – H]-
291.1027, found 291.1026.
8-(3,4-dimethoxyphenyl)naphthalen-1-ol (3n) Condition B from 4-bromoveratrole (135.7 mg,
89.9 µL): 90% yield (126.0 mg). This compound could not be separated from a small amount of
1-naphthol. The yield reported has been adjusted to account for this impurity based upon 1H NMR
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integration. Amber oil. 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 8.3, 1.3 Hz, 1H), 7.49 (dd, J =
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8.2, 1.2 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.22 (dd, J = 6.9, 1.3 Hz, 1H), 6.93 (dd, J = 7.6, 1.2 Hz, 1H),
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6.62 (d, J = 2.3 Hz, 2H), 6.57 (t, J = 2.3 Hz, 1H), 5.84 (s, 1H), 3.82 (s, 6H). C{1H} NMR (126
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MHz, CDCl3) δ 153.2, 149.3, 149.1, 135.8, 135.7, 133.3, 128.64, 128.58, 126.9, 124.8, 121.6,
120.9, 112.6, 111.7, 111.3, 56.02, 55.99. HRMS (ESI) m/z calculated for C18H15O3 [M – H]-
279.1027, found 279.1026.
8-(3,5-dimethoxyphenyl)naphthalen-1-ol
(3o)
Condition
B
from
1-bromo-3,5-
dimethoxybenzene (135.7 mg): 94% yield (131.7 mg). Brown oil. 1H NMR (500 MHz, CDCl3) δ
7.86 (dd, J = 8.3, 0.9 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.46 – 7.37 (m, 2H), 7.27 – 7.20 (m, 1H), 6.93
(dd, J = 7.6, 1.1 Hz, 1H), 6.63 (d, J = 2.3 Hz, 2H), 6.57 (t, J = 2.3 Hz, 1H), 5.81 (s, 1H), 3.82 (s,
6H). 13C{1H} NMR (126 MHz, CDCl3) δ 161.0, 153.0, 143.3, 136.0, 135.6, 128.8, 127.9, 126.9,
124.8, 121.2, 120.9, 112.0, 107.4, 100.7, 55.5. HRMS (ASAP-MS) m/z calculated for C18H15O3
[M – H]- 279.1027, found 279.1027.
8-(Quinolin-3-yl)naphthalen-1-ol (3p) Condition B from 3-bromoquinoline (130.0 mg, 84.8 µL):
63% yield (85.5 mg). Amber oil. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.0 Hz, 1H), 8.06 (d,
J = 8.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.3 Hz, 3H), 7.60 (t, J = 7.8 Hz, 1H), 7.52 (t,
J = 8.1 Hz, 2H), 7.43 (q, J = 8.0 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H). 13C{1H}
(126 MHz, CDCl3) δ 162.2, 149.9, 146.6, 140.0, 135.0, 129.8, 128.0, 127.9, 127.5, 127.3, 126.4,
126.1, 125.73, 125.70, 125.0, 124.9, 122.1, 117.3, 112.1. HRMS (ASAP-MS) m/z calculated for
C19H14NO [M + H]+ 272.1070, found 272.1067.
8-(Pyren-2-yl)naphthalen-1-ol (3q) Condition B from 1-bromopyrene (175.7 mg): 73% yield
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(125.7 mg). Off-white solid. Mp. 90.4-91.6 ℃; H NMR (500 MHz, benzene-d6) δ 8.46 (d, J =
9.2 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.89 – 7.78 (m, 6H), 7.78 – 7.66
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(m, 4H), 7.61 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H). 13C{1H} NMR (126 MHz, benzene-d6)
δ 131.23 131.2, 131.0, 130.6, 129.9, 129.8, 129.0, 127.9, 127.74, 127.68, 127.6, 127.5, 126.3,
126.0, 125.9, 125.7, 125.6, 125.5, 124.93, 124.91, 124.2, 119.9. HRMS (ASAP-MS) m/z
calculated for C26H15O [M – H]- 343.1128, found 343.1127. The product was not sufficiently
soluble in CDCl3 to obtain a 13C NMR spectrum with sufficient signal to noise.
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8-(2-Chloro-pyridin-5-yl)naphthalen-1-ol (3r) Condition B from 5-bromo-2-chloropyridine
(120.3 mg): 76% yield (97.2 mg). Amber oil. 1H (500 MHz, Chloroform-d) δ 8.19 (d, J = 2.5 Hz,
1H), 7.93 (dd, J = 8.4, 1.2 Hz, 1H), 7.88 (dd, J = 8.1, 1.3 Hz, 1H), 7.79 – 7.70 (m, 2H), 7.55 – 7.40
(m, 3H), 7.22 (dd, J = 7.5, 1.0 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H, OH, exchangeable in D2O). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 163.1, 149.6, 148.6, 142.0, 135.0, 128.0, 127.3, 126.5, 126.3,
125.7, 125.4, 121.8, 117.2, 113.5, 112.4. HRMS (ESI) m/z calculated for C15H9ClNO [M – H]-
254.0378, found 254.0380.
8-(3-Bromo-pyrimidin-5-yl)naphthalen-1-ol
(3s)
Condition
B
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5-bromo-2-
chloropyrimidine (120.9 mg): 51% yield (65.5 mg). Amber oil. 1H NMR (500 MHz, Chloroform-
d) δ 8.55 (s, 2H), 7.93 – 7.86 (m, 2H), 7.82 – 7.77 (m, 1H), 7.51 (ddd, J = 8.5, 7.1, 1.7 Hz, 2H),
7.46 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.30 (dd, J = 7.5, 1.0 Hz, 1H). 13C{1H}(126 MHz, Chloroform-
d) δ 164.4, 160.2, 148.7, 134.8, 128.1, 126.9, 126.5, 126.5, 126.1, 125.6, 121.5, 117.7, 113.2.
HRMS (ASAP-MS) m/z calculated for C14H10BrN2O [M + H]+ 300.9971, found 300.9977.
ASSOCIATED CONTENT
Supporting Information. Copies of NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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*dweix@wisc.edu
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
This work was supported by the NIH (R01GM097243). The authors thank Prof. Liangbin Huang
(S. China Univ. of Technology) for help with initial experiments. The purchase of the Thermo Q
Exactive Plus in 2015 was funded by NIH Award 1S10 OD020022-1 to the Department of
Chemistry
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metal-catalyzed C-H activation of simple arenes. Angew. Chem. Int. Ed. 2012, 51, 10236.
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Ackermann, L. Carboxylate-Assisted Transition-Metal-Catalyzed C−H Bond Functionalizations:
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Mechanism and Scope. Chem. Rev. 2011, 111, 1315-1345. (c) Arockiam, P. B.; Bruneau, C.;
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(3) For applications of directed C-H arylation approaches, see above references and: (a)
McMurray, L.; O’Hara, F.; Gaunt, M. Recent developments in natural product synthesis using
metal-catalysed C–H bond functionalization. J. Chem. Soc. Rev. 2011, 40, 1885. (b) Yamaguchi,
J.; Yamaguchi, A. D.; Itami, K. C-H bond functionalization: emerging synthetic tools for natural
products and pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960. (c) Chen, D. Y. K.; Youn,
S. W. C–H Activation: A Complementary Tool in the Total Synthesis of Complex Natural
Products. Chem. -Eur. J. 2012, 18, 9452. (d) Wencel-Delord, J.; Glorius, F. C–H bond activation
enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem.
2013, 5, 369. (e) Segawa, Y.; Maekawa, T.; Itami, K. Synthesis of Extended π-Systems through
C–H Activation. Angew. Chem. Int. Ed. 2015, 54, 66. (f) Cernak, T.; Dykstra, K.D.; Tyagarajan,
S.; Vachal, P.; Krska, S. W. The medicinal chemist's toolbox for late stage functionalization of
drug-like molecules. Chem. Soc. Rev. 2016, 45, 546. (g) Seki, M A New Catalytic System for Ru-
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Catalyzed C–H Arylation Reactions and Its Application in the Practical Syntheses of
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Pharmaceutical Agents. Org. Process Res. Dev. 2016, 20, 867.
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(4) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Palladium-Catalyzed Regioselective
Mono- and Diarylation Reactions of 2-Phenylphenols and Naphthols with Aryl Halides. Angew.
Chem. Int. Ed. 1997, 36, 1740. (b) Satoh, T.; Inoh, J. -I.; Kawamura, Y.; Miura, M.; Nomura, M.
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(5) Mun, S. Y.; Lee, B. S.; Park, J. C.; Ji, H. S.; Lee, S. H.; Kwon, J. T., Compound For Organic
Electronic Element, Organic Electronic Element Using The Same, And An Electronic Device
Thereof. Korean Patent KR20140170768, Feb 12, 2014. US Patent US 2016/0005981 A1, Jan. 7,
2016.
(6) Yamaguchi, M.; Higuchi, M.; Tazawa, K.; Manabe, K. Three-Step Synthesis of
Fluoranthenes through Pd-Catalyzed Inter- and Intramolecular C−H Arylation. J. Org. Chem.
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(7) For another application of the Miura protocol, see: Cadman, C. J.; Croft, A. K. Anion–π
interactions influence pKa values. Beilstein J. Org. Chem. 2011, 7, 320-328;
(8) We could find no examples of naphthol arylation with heteroaryl halides under the palladium-
catalyzed conditions from reference 4. We tested the conditions from reference 4(a) for substrates
2p and 2s. The reaction with 3-bromoquinoline (2p) (for which the corresponding iodide is not
commercially available) resulted in no formation of the C-H arylated product. The reaction with
5-bromo-2-chloropyrimidine (2s) gave a 14% yield (NMR yield versus ferrocene as an internal
standard).
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Acids with Aryl and Heteroaryl Halides. Org. Lett. 2016, 18, 5432-5435. (b) Biafora, A.; Krause,
T.; Hackenberger, D.; Belitz, F.; Gooßen, L. J. Ortho-C−H Arylation of Benzoic Acids with Aryl
Bromides and Chlorides Catalyzed by Ruthenium. Angew. Chem., Int. Ed. 2016, 55, 14752-14755.
(c) Mei, R.; Zhu, C.; Ackermann, L. Ruthenium(II)-catalyzed C–H functionalizations on benzoic
acids with aryl, alkenyl and alkynyl halides by weak-O-coordination. Chem. Commun. 2016, 52,
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13171-13174. (d)
Simonetti, M.; Cannas, D. M.; Panigrahi, A.; Kujawa, S.; Kryjewski, M.;
Xie, P.; Larrosa, I. Ruthenium-Catalyzed C−H Arylation of Benzoic Acids and Indole Carboxylic
Acids with Aryl Halides. Chem.–Eur. J. 2017, 23, 549-553.
(10) (a) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. Dehydrative C–H Alkylation and Alkenylation of
Phenols with Alcohols: Expedient Synthesis for Substituted Phenols and Benzofurans. J. Am.
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C. S. Experimental and Computational Study of the (Z)-Selective Formation of Trisubstituted
Olefins and Benzo-Fused Oxacycles from the Ruthenium-Catalyzed Dehydrative C–H Coupling
of Phenols with Ketones. J. Am. Chem. Soc. 2018, 140, 10289-10296.
(11) Ackermann, L.; Diers, E.; Manvar, A. Ruthenium-Catalyzed C–H Bond Arylations of
Arenes Bearing Removable Directing Groups via Six-Membered Ruthenacycles. Org. Lett. 2012,
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(12) Selected reports about base identity in C-H activation: (a) Neufeldt, S. R.; Sanford, M. S.
Controlling Site Selectivity in Palladium-Catalyzed C–H Bond Functionalization. Acc. Chem. Res.
2012, 45, 936. (b) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. Investigation of
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Adjacent to Amides and Sulfonamides. J. Am. Chem. Soc. 2010, 132, 10692. (c) Maleckis, A.;
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(13) (a) Shan, C.; Zhu, L.; Qu, L.-B.; Bai, R.; Lan, Y. Mechanistic view of Ru-catalyzed C–H
bond activation and functionalization: computational advances. Chem. Soc. Rev. 2018, 47, 7552-
7576. (b) Warratz, S.; Kornhaaß, C.; Cajaraville, A.; Niepötter, B.; Stalke, D.; Ackermann, L.
Ruthenium(II)-Catalyzed C–H Activation/Alkyne Annulation by Weak Coordination with O2 as
the Sole Oxidant. Angew. Chem., Int. Ed. 2015, 54, 5513-5517.
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