Synthesis of Biaryl Ethers by the Copper-Catalyzed Chan-Evans-Lam Etherification from Benzylic Amine Boronate Esters

Article abstract of DOI:10.1021/acs.joc.6b01254

The copper-catalyzed etherification of ortho-borylated benzylic amines with phenols has been achieved to provide biaryl ethers that are prevalent in biologically active compounds. A variety of substitution patterns on the aryl boronate ester and the phenol are tolerated under the reaction conditions, providing moderate to high yields. A competition reaction between phenol and aniline revealed condition-dependent selectivity in which the phenol could be highly favored over the aniline.

Full text of DOI:10.1021/acs.joc.6b01254

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Note
Synthesis of Biaryl Ethers by the Copper-Catalyzed Chan-
Evans-Lam Etherification from Benzylic Amine Boronate Esters
Justin S Marcum, Kathryn A. McGarry, Carl J Ferber, and Timothy Bryan Clark
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01254 • Publication Date (Web): 04 Aug 2016
Downloaded from http://pubs.acs.org on August 5, 2016
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The Journal of Organic Chemistry
Synthesis of Biaryl Ethers by the Copper-Catalyzed Chan-Evans-Lam Etherification from Benzylic
Amine Boronate Esters
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Justin S. Marcum, Kathryn A. McGarry, Carl J. Ferber, Timothy B. Clark*
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Department of Chemistry & Biochemistry, University of San Diego, 5998 Alcalá Park, San Diego, CA 92110,
United States
*clarkt@sandiego.edu
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NMe2
R
OH
10 mol % Cu(CO2CF3)2
KF, 3Å MS, CH3CN
NMe2
Bpin
O
R
R'
O2, 80 °C, 2h
R'
18 examples, 42-77% yield
ABSTRACT: The copper-catalyzed etherification of ortho-borylated benzylic amines with phenols has been
achieved to provide biaryl ethers that are prevalent in biologically active compounds. A variety of substitution
patterns on the aryl boronate ester and the phenol are tolerated under the reaction conditions, providing
moderate to high yields. A competition reaction between phenol and aniline revealed condition-dependent
selectivity in which the phenol could be highly favored over the aniline.
Metal-catalyzed C–H borylation reactions have undergone exceptional growth since the initial discovery about
twenty years ago.1-3 Both arenes and alkanes are successfully borylated using a variety of reaction conditions
and pre-catalysts.4-8 Two complimentary approaches to the C–H borylation of arenes have been developed: 1)
sterically controlled C–H borylation that results in borylation meta- and para- to substituents in arenes;4,5 2)
substrate-directed C–H borylation with numerous examples of ortho-directed borylation and recent select
examples of meta-directed borylation.9-11 Distinct approaches to ortho-directed C–H borylation reactions have
been developed using a variety of directing groups (halides,12 ethers,12-14 carbonyls,12-17 amines,13,18-23
imines,24-26 silanes,27,28 and phosphines29) and strategies (covalent interactions with the metal catalyst,27,28 H-
bonding interactions,22 and Lewis base coordination12-20,23-26,29). Although efficient approaches to access ortho-
borylated arenes have been developed, reactions that explicitly utilize the resulting C–B bond with these
products have been limited. Since much of the value of the C–H borylation methodology comes from the
versatility of the C–B bond in synthesis,30-38 it is important to determine if the presence of the directing group
allows reactions of the C–B bond to take place efficiently. To this end, we have recently shown ortho-borylated
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benzylic amines can be used in Suzuki-Miyaura coupling reactions to form biphenyl benzylic amines39 and
Chan-Evans-Lam type amination with anilines to form diamines40 (Scheme 1).
Scheme 1. Formation and Utility of ortho-Borylated Benzylic Amines
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The Chan-Evans-Lam etherification of ortho-borylated benzylic amines was recognized as a valuable synthetic
reaction based on the prevalence of biaryl ethers, with a benzylic amine in the ortho position, in biologically
active compounds.41-46 For example, tetrandrine, a bisbenzylisoquinoline alkaloid with extensive bioactivity is a
cyclic diaryl ether with built-in benzylic amines (Figure 1).47 Although this class of ethers has been accessed by
the Ullman reaction or by nucleophilic aromatic substitution,48 the Chan-Evans-Lam etherification49-56 was
envisioned to have significant advantages over these methods including the ability to selectively incorporate
the boronate ester into a readily available amine, and the orthogonal reactivity of the boronate ester to any
other halides present in the arene. One challenge that was recognized in developing this reaction is the typical
need to utilize the boronic acid rather than the boronate ester in Chan-Evans-Lam couplings.57-59 Four
examples of the direct coupling of amines or alcohols to organoboronate esters have been reported in the
literature. Hartwig developed the amination of aryl boronate esters with alkylamines in 2007,57 but boronic
acids were required for anilines and alcohols. Kuninobu reported the direct coupling of anilines and phenols to
sp3-hybridized alkyl boronate esters in 2013,59 requiring tert-butylperoxide as the oxidant. In 2016, Watson
found that aryl and alkylamines could be coupled to aryl boronate esters,58 but a stoichiometric amount of
copper was required for the transformation. Finally, our recent work on the coupling of anilines to benzylic
amine boronate esters40 (see Scheme 1) revealed an alternative method to direct Chan-Evans-Lam coupling to
arylboronate esters in which an adjacent Lewis base could facilitate the amination. Based on this work in
amination reactions, we were optimistic that the pendent benzylic amine would allow for direct coupling of the
aryl boronate ester to phenols. We herein describe the copper-catalyzed Chan-Evans-Lam etherification of
ortho-borylated benzylic amines with phenols.
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Figure 1. Structure of (+)-Tetrandrine
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Examination of the desired etherification reaction was initiated using the parent boronate ester with phenol.
Copper salts and bases that have been shown to mediate the Chan-Evans-Lam coupling,49-54 and in particular
the amination of ortho-borylated benzylic amines,40 were explored. Early reactions with copper(II) acetate and
a series of bases resulted in good conversion of the starting material to 1 and 2, but significant quantities of
homocoupled product 2 was observed (Table 1, entries 1–4). In contrast to the amination reaction, the
absence of added base provided an increased quantity of 2 with copper(II) acetate (entry 4). The copper salt
had a significant impact on the distribution of 1:2 as well, favoring homocoupled product 2 when copper(II)
acetylacetonate was employed (entry 5). Weakly coordinating copper counterions improved the selectivity
toward 1 (entries 6, 7), providing high conversion and selectivity with copper(II) trifluoroacetate and copper(II)
trifluoromethanesulfonate.
NMe2
NMe2
+
NMe2 10 mol % [Cu]
phenol, base
NMe2
O
(1)
3Å MS, CH3CN
O2, 80 °C, 2h
Bpin
1
2
Table 1. Optimization of the Copper‐Catalyzed Etherification of ortho‐Borylated Benzylic Amines (eq 1)
Entrya
Catalyst
Base
KF
Conversionb
100%
95%
1:2b
1
2
3
4
5
6
7
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(acac)2
85:15
85:15
70:30
60:40
36:64
>99:1
>99:1
LiF
Na2CO3
none
KF
100%
21%
92%
Cu(CO2CF3)2•H2O
Cu(SO3CF3)2•H2O
KF
100%
100%
KF
a
Yield based on boronate ester. Conditions: 3 equiv. phenol, 1.03
equiv. base, 0.2 M in CH3CN, 1 atm O2. b Determined by 1H NMR
spectroscopy of the unpurified reaction mixture.
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The increased reactivity of benzylic amine boronate esters toward Chan-Evans-Lam coupling with phenols and
anilines (previously reported) is consistent with the pendant amine activating the boronate ester toward
coupling. To further examine this hypothesis, the optimized reaction conditions were applied to the coupling of
phenol to 2-(pinacolboryl)-toluene (eq 2), which lacks the pendant benzylic amine. As expected, this simple
boronate ester was nearly unreactive under the optimized conditions, resulting in 5% conversion to the
corresponding ether, as determined by 1H NMR spectroscopy.60 This divergent reactivity supports the assertion
that the amine coordinates to the catalyst to facilitate the coupling reaction, likely during the transmetallation of
the copper salt with the carbon–boron bond.
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The optimized reaction conditions were examined with a variety of substituted phenols. Copper(II)
trifluoroacetate was found to be more general than copper(II) trifluoromethanesulfonate, providing increased
selectivity and yields with the phenols examined. Moderate to good yields were obtained in all cases (Scheme
2), including phenols with strongly electron-donating (7 and 10) and electron-withdrawing (8 and 9)
substituents on the phenol. Electron-deficient phenols were found to be sluggish in the reaction, requiring 6 h
to proceed to completion for 8 (4–CF3). In the case of 3-nitrophenol, incomplete conversion was observed,
even after 24 h, but the addition of sodium tert-butoxide in place of potassium fluoride provided 9 in 2 h. The
presence of a chlorine substituent in the ortho-, meta-, and para- positions was tolerated (3–5), providing an
additional synthetic handle for coupling reactions. The facile formation of 3–5 is notable in that they have been
found to be active in serotonin/noradrenaline reuptake inhibition.42 Remarkably, a styrene-derived phenol
provided a 77% yield of 10 without any evidence of significant side reactions involving the olefin.
Scheme 2. Scope of Substituted Phenols in Etherificationa
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a
Yield based on boronate ester. Conditions: 3 equiv. phenol,
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1.03 equiv. base, 0.2 M in CH3CN, 1 atm O2. >99:1 selectivity of
1, 3–10:2 for all substrates. b 6 h reaction time. c NaOt-Bu used in
place of KF.
The effect of substituents on the aryl boronate ester was examined next with phenol, providing similar yields
and selectivity for the desired ethers (Scheme 3). Electron-donating and electron-withdrawing substituents on
the boronate ester were also readily tolerated (13–15).
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Scheme 3. Scope of Substituted Aryl Boronate Estersa
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a Yield based on boronate ester. Conditions: 3 equiv. phenol, 1.03
equiv. base, 0.2 M in CH3CN, 1 atm O2. >99:1 selectivity of 11–
16:2 for all substrates.
Several examples of etherifications were conducted with both substituted benzylic amines and phenols to
provide 17–19 in moderate yields (Figure 2). The rapid formation of 17–19 from readily available starting material
demonstrates the utility of this C–H borylation/etherification sequence.
Figure 2. Examples of Multi-Substituted Biaryl Ethers under Standard Reaction Conditions. 17 required a 4 h
reaction time to proceed to completion.
The ability to couple phenols and anilines40 to aryl boronate esters under similar reaction conditions led us to
probe the relative reactivity of these two coupling partners. A competition reaction was performed with three
equivalents of both phenol and aniline with the parent boronate ester (Scheme 4). Two sets of reaction
conditions were utilized for the competition, those utilized for anilines [Cu(OAc)2 with no added base] and those
utilized for phenols [Cu(O2CCF3)2 with KF]. Using Cu(O2CCF3)2 with KF, the ratio of 1 to 20 was 37:63.
Unexpectedly, however, with Cu(OAc)2 with no added base provided ether 1 as the only observed product.
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The Journal of Organic Chemistry
While the source of this selectivity is not understood, it likely results from the increased acidity of phenol over
1
2
3
aniline.
4
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Scheme 4. Competition Experiment between Phenol and Aniline
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NMe2
O
NMe2
NH
10 mol % Cu(CO2CF3)2
KF, 3Å MS, CH3CN
OH
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O2, 80 °C, 2h
NMe2
Bpin
3 equiv.
NH2
1
20
37:63 of 1:20
NMe2
NMe2
NH
10 mol % Cu(OAc)2
3Å MS, CH3CN
O
3 equiv.
O2, 80 °C, 2h
1
20
>99:1 of 1:20
In summary, the Chan-Evans-Lam etherification of aryl boronate esters derived from benzylic amines has been
achieved in moderate to high yields. The adjacent benzylic amine allows for direct coupling with the boronate
ester without hydrolysis to the more reactive boronic acid. A variety of aryl boronate esters and phenols are
tolerated under the reaction conditions. A competition experiment between phenol and aniline with a boronate
ester revealed high selectivity for the phenol, which was utilized to selectively couple an aminophenol without
protecting the aniline functionality.
Experimental Section
General Methods
All procedures were performed in oven-dried glassware under purified nitrogen until O2 gas was introduced. N,N-
Dimethylbenzylamines and the corresponding boronate esters were synthesized following the published
procedures.20,21 All other materials, including solvents, were purchased and used as received. Concentration
was performed by rotary evaporation. TLC analysis was performed on 60 Å silica layer fluorescence UV plates.
Flash column chromatography was carried out on hand-packed columns of silica gel, 40-63 µm, 60 Å or
aluminum oxide, basic, Brockman I, 50-200 µm, 60 Å. NMR spectra were collected at 500 MHz or 400 MHz for
1H
NMR,
125
MHz
or
100
MHz
for
13C{1H}
1
NMR. H NMR spectra are referenced to CDCl3 at 7.26 ppm, or to an internal tetramethylsilane (TMS) standard
at 0.00 ppm. The 1H NMR spectral data are reported as follows: chemical shift ppm, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, qn = quintet, hex = hextet, sep = septet, oct = octet, m = multiplet), coupling
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constants (Hz), and integration. C{1H} NMR spectra are referenced to CDCl3 at 77.0 ppm. Fourier transform
infrared (FTIR) spectra were obtained from thin film in dichloromethane or chloroform-d and absorptions reported
in cm−1. High-resolution mass spectrometry was obtained by time-of-flight electrospray ionization.
Representative Procedure A:
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N,N-dimethyl-1-(2-phenoxyphenyl)methanamine, 1: To a Schlenk flask containing 4 Å molecular sieves (0.300
g) was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol),
potassium fluoride (0.0114 g, 0.197 mmol), phenol (0.0540 g, 0.574 mmol), copper(II) trifluoroacetate
monohydrate (0.0055 g, 0.0191 mmol) and acetonitrile (2.0 mL). Oxygen gas was bubbled through the mixture
for 5 minutes, followed by heating to 80 °C under positive oxygen pressure. After 2 hours the mixture was allowed
to cool to room temperature, then transferred using acetonitrile (10 ml) and concentrated in vacuo to give a dark
brown oil. The crude product was purified by silica gel column chromatography (90:10 dichloromethane/ethyl
acetate). The concentrated fractions were diluted with 95% ethanol and concentrated in vacuo (3 × 2 mL), to
remove pinacol impurities azeotropically, providing 1 as a brown oil (0.0476 g, 0.1047 mmol, 53%). 1H NMR (400
MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 8.2 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H),
7.05 (t, J = 7.4 Hz, 1H), 6.93–6.90 (m, 3H), 3.46 (s, 2H), 2.26 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 157.9,
154.7, 131.2, 130.4, 129.6, 128.3, 123.9, 122.5, 119.7, 117.7, 57.4, 45.5; IR (thin film, CH2Cl2) 3038, 2941, 2855,
2817, 2769, 1682, 1582.3, 1485, 1453, 1234, 751 cm−1; HRMS (ESI): m/z calcd for (C15H17NO)+ 227.1310, found
227.1317.
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1-(2-(2-chlorophenoxy)phenyl)-N,N-dimethylmethanamine, 3: Following representative procedure A with
substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and
2-chlorophenol (0.0586 mL, 0.574 mmol), the crude mixture was purified by silica gel column chromatography
(96.8:3:0.2) dichloromethane/ethyl acetate/triethylamine) to afford 3 as a yellow oil (0.0307g, 0.117 mmol, 58%).
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.23–7.12 (m, 3H), 7.04 (t, J =
8.0 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 3.53 (s, 2H), 2.29 (s, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δ 154.4, 153.0, 131.3, 130.7, 129.5, 128.2, 127.8, 124.8, 123.94, 123.90, 119.2, 118.2, 57.1, 45.4; IR
(thin film, CH2Cl2) 3067, 2974, 2942, 2855, 2817, 2770, 1578, 1476, 1476, 1445, 1242, 751 cm-1; HRMS (ESI):
m/z calcd for (C15H16ClNO)+ 261.0920, found 261.0918.
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1-(2-(3-chlorophenoxy)phenyl)-N,N-dimethylmethanamine, 4: Following representative procedure A with
substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and
3-chlorophenol (0.0734 g, 0.574 mmol), the crude mixture was purified by silica gel column chromatography
(94.8:5:0.2 dichloromethane/ethyl acetate/triethylamine) to afford 4 as a yellow oil (0.0285 g, 0.109 mmol, 57%).
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 1H), 7.28–7.15 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.94 (d, J =
8.0 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.42 (s, 2H), 2.25 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ
158.9, 153.8, 135.0, 131.4, 130.7, 130.4, 128.5, 124.6, 122.6, 120.2, 117.6, 115.5, 57.4, 45.5; IR (thin film,
CH2Cl2) 3066, 2974, 2942, 2856, 2818, 2770, 1580, 1471, 1233, 912, 767 cm-1; HRMS (ESI): m/z calcd for
(C15H16ClNO)+ 261.0920, found 261.0925.
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1-(2-(4-chlorophenoxy)phenyl)-N,N-dimethylmethanamine, 5: Following the representative procedure A with
substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and
4-chlorophenol (0.0734 g, 0.574 mmol), the crude mixture was purified by silica gel column chromatography
(89.8:10:0.2 dichloromethane/ethyl acetate/triethylamine) to afford 5 as a yellow oil (0.0272 g, 0.104 mmol, 53%).
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 1H), 7.27–7.20 (m, 3H), 7.15 (t, J = 7.3 Hz, 1H), 6.89 (d, J =
8.0 Hz, 1H), 6.85 (d, J = 7.9 Hz, 2H), 3.44 (s, 2H) 2.25 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 156.6, 154.3,
131.3, 130.4, 129.6, 128.4, 127.4, 124.3, 119.7, 118.7, 57.4, 45.5; IR (thin film, CH2Cl2) 2974, 2942, 2856, 2817,
2770, 1581, 1483, 1452, 1238 cm-1; HRMS (ESI): m/z calcd for (C15H16ClNO)+ 261.0920, found 261.0916.
N,N-dimethyl-1-(2-(p-tolyloxy)phenyl)methanamine, 6: Following representative procedure A with substrate 2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and para-cresol
(0.0603 mL, 0.574 mmol), the crude mixture was purified by silica gel column chromatography (87.99:12:0.01
dichloromethane/ethyl acetate/triethylamine) to afford 6 as a brown oil (0.0242 g, 0.100 mmol, 54%). 1H NMR
(400 MHz, CDCl3) δ 7.46 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.30–7.05 (m, 3H), 6.87–6.82 (m, 3H), 3.50
(s, 2H), 2.32 (s, 3H), 2.27 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.5, 155.3, 132.1, 131.2, 130.1, 129.9,
128.2, 123.5, 119.1, 117.9, 57.3, 45.4, 20.6; IR (thin film, CH2Cl2) 3030, 2973, 2941, 2856, 2817, 2769, 1506,
1486, 1452, 1236 cm-1; HRMS (ESI): m/z calcd for (C16H19NO)+ 241.1467, found 241.1471.
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3-(2-((dimethylamino)methyl)phenoxy)-N,N-dimethylaniline, 7: Following representative procedure A with
substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and
3-dimethylamino phenol (0.079 g, 0.574 mmol), the crude mixture was purified by silica gel column
chromatography (94.7:5:0.3 dichloromethane/ethyl acetate/triethylamine) to afford 7 as a brown oil (0.0269 g,
0.0996 mmol, 54%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.3Hz, 1H), 7.16–7.08 (m,
2H) , 6.93 (d, J = 8.0 Hz, 1H) 6.45 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 6.19 (d, J = 8.0 Hz, 1H), 3.50 (s, 2H), 2.92
(s, 6H), 2.28 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 158.9, 155.0, 152.1, 131.0, 130.0, 129.8, 128.2, 123.5,
119.5, 107.1, 105.6, 102.5, 57.3, 45.5, 40.5; IR (thin film, CH2Cl2) 2940, 2854, 2814, 2769, 1613, 1572, 1502,
1486, 1450, 1236 cm-1; HRMS (ESI): m/z calcd for (C17H22N2O)+ 270.1732, found 270.1742.
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N,N-dimethyl-1-(2-(4-(trifluoromethyl)phenoxy)phenyl)methanamine, 8: Following representative procedure A
with substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol)
and 4-trifluoromethyl phenol (0.0931 g, 0.574 mmol), the crude mixture was purified by silica gel column
chromatography (94.5:5:0.5 dichloromethane/ethyl acetate/triethylamine) to afford 8 as a yellow oil (0.0312 g,
0.106 mmol, 56%): 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.28 (t, J =
7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 6.98–6.94 (m, 3H) 3.40 (s, 2H), 2.24 (s, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 160.9, 153.4, 131.5, 130.9, 128.7, 127.1 (q, JF = 4.0 Hz), 125.1, 124.3 (q, JF = 33.0 Hz), 124.2 (q, JF =
270.0 Hz), 120.7, 116.8, 57.4, 45.4; IR (thin film, CH2Cl2) 2975, 2944, 2857, 2819, 2772, 1617, 1512, 1486,
1454, 1323, 1243, 1165 cm-1; HRMS (ESI): m/z calcd for (C16H16F3NO)+ 295.1184, found 295.1192.
N,N-dimethyl-1-(2-(3-nitrophenoxy)phenyl)methanamine, 9: Following the representative procedure A with
substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol) and
3-nitrophenol (0.0799 g, 0.574 mmol), the crude mixture was purified by silica gel column chromatography
(94.8:5:0.2 dichloromethane/ethyl acetate/triethylamine) to afford 9 as a brown oil (0.0276 g, 0.101 mmol,
53%).1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.2
Hz, 1H), 7.31–7.22 (m, 3H), 6.97 (d, J = 7.9 Hz, 1H) 3.41 (s, 2H), 2.23 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3)
δ 159.0, 153.2, 149.2, 131.7, 131.0, 130.2, 128.9, 125.4, 123.1, 120.5, 117.1, 111.8, 57.6, 45.4; IR (thin film,
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CH2Cl2) 2942, 2857, 2818, 2770, 1532, 1351, 1238, 737 cm-1; HRMS (ESI): m/z calcd for (C15H16N2O3)+
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272.1161, found 272.1153.
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(E)-1-(2-(2-ethoxy-5-(prop-1-en-1-yl)phenoxy)phenyl)-N,N-dimethylmethanamine, 10: Following representative
procedure A with substrate 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g,
0.191 mmol) and 2-ethoxy 5-(1-propenyl)phenol (0.1024 g, 0.574 mmol), the crude mixture was purified by silica
gel column chromatography (95:5 to 0:1 dichloromethane/ethyl acetate) to afford 10 as a yellow oil (0.0444 g,
0.143 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.0 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.08–6.98 (m,
2H), 6.93 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 6.03 (m, 1H), 4.01
(q, J = 6.9 Hz, 2H), 3.62 (s, 2H), 2.32 (s, 6H), 1.82 (d, J = 6.5 Hz, 3H), 1.24 (t, J = 6.9 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 156.2, 149.4, 145.7, 131.5, 131.0, 130.0, 128.0, 124.3, 122.5, 122.0, 118.0, 116.4, 114.3, 64.6,
57.1, 45.4, 18.3, 14.7 (one overlapping peak); IR (thin film, CH2Cl2) 3021, 2977, 2937, 2912, 2817, 2770, 1509,
1263, 1222, 1043 cm-1; HRMS (ESI): m/z calcd for (C20H25NO2)+ 311.1885, found 311.1875.
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N,N-dimethyl-1-(5-methyl-2-phenoxyphenyl)methanamine, 11: Following representative procedure A with
substrate 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.182
mmol) and phenol (0.0513 g, 0.545 mmol), the crude mixture was purified by silica gel column chromatography
(85:15 dichloromethane/ethyl acetate) to afford 11 as a brown oil (0.0266 g, 0.110 mmol, 65%). 1H NMR (400
MHz, CDCl3) δ 7.32–7.25 (m, 3H), 7.03–7.00 (m, 2H), 6.89 (d, J = 7.8 Hz, 2H), 6.82 (d, J = 8.2 Hz, 1H), 3.41 (s,
2H), 2.34 (s, 3H), 2.25 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 158.4, 152.1, 133.7, 131.6, 130.3, 129.6, 128.9,
122.2, 120.0, 117.2, 57.3, 45.6, 20.8; IR (thin film, CH2Cl2) 3038, 2972, 2941, 2857, 2817, 2768, 1589, 1487,
1245, 1217, 853, 752, 691 cm-1; HRMS (ESI): m/z calcd for (C16H19NO)+ 241.1467, found 241.1463.
N,N-dimethyl-1-(2-methyl-6-phenoxyphenyl)methanamine, 12: Following representative procedure A with
substrate 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.1717
mmol) and phenol (0.0485 g, 0.5151 mmol), the crude mixture was purified by silica gel column chromatography
(89.9:10:0.1 dichloromethane/ethyl acetate/triethylamine) to afford 14 as a brown oil (0.0239 g, 0.0929 mmol,
54%). 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J = 8.4 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.98
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(d, J = 7.5 Hz, 1H), 6.92 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 8.1 Hz, 1H), 3.43 (s, 2H), 2.45 (s, 3H), 2.25 (s, 6H); δ
13C NMR (125 MHz, CDCl3) δ 158.1, 155.2, 140.7, 129.6, 129.0, 128.0, 126.0, 122.4, 117.7, 117.0, 54.2, 45.6,
19.4; IR (thin film, CH2Cl2) 2941, 2855, 2815, 2767, 1578, 1490, 1465, 1241, 1214 cm-1; HRMS (ESI): m/z calcd
for (C16H19NO)+ 241.1467, found 241.1461.
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1-(2-fluoro-6-phenoxyphenyl)-N,N-dimethylmethanamine, 13: Following representative procedure A with
substrate 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.179
mmol) and phenol (0.0506 g, 0.537 mmol), the crude mixture was purified by silica gel column chromatography
(89.9:10:0.1 dichloromethane/ethyl acetate/triethylamine) to afford product 13 as a brown oil (0.0196 g, 0.080
mmol, 44%). 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.6 Hz, 2H), 7.20–7.15 (m, 1H), 7.11 (t, J = 7.4 Hz, 1H)
6.98 (d, J = 7.8 Hz, 2H), 6.85 (t, J = 8.1 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 3.60 (s, 2H), 2.31 (s, 6H); 13C NMR
(101 MHz, CDCl3) δ 162.6 (d, JF = 246.0 Hz), 157.11, 157.0 (d, JF = 7.0 Hz), 129.8, 128.9 (d, JF = 10.0 Hz),
123.4, 118.6, 117.3 (d, JF = 18.0 Hz), 114.2 (d, JF = 3.0 Hz), 110.4 (d, JF = 23.0 Hz), 50.3, 45.2; IR (thin film,
CH2Cl2) 3041, 2974, 2942, 2859, 2819, 2770, 1587, 1491, 1464, 1235, 1213, 1035 cm-1; HRMS (ESI): m/z calcd
for (C15H16FNO)+ 245.1216, found 245.1207.
1-(5-methoxy-2-phenoxyphenyl)-N,N-dimethylmethanamine, 14: Following representative procedure A with
substrate 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.1717
mmol) and phenol (0.0485 g, 0.5151 mmol), the crude mixture was purified by silica gel column chromatography
(89.9:10:0.1 dichloromethane/ethyl acetate/triethylamine) to afford 14 as a brown oil (0.0239 g, 0.0929 mmol,
54%). 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 2H), 7.06 (br s, 1H), 7.00 (t, J = 6.9 Hz, 1H), 6.92-6.84
(m, 3H), 6.79 (m, 1H), 3.82 (s, 3H), 3.41 (s, 2H), 2.25 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 158.8, 156.3, 147.5,
131.9, 129.6, 121.9, 121.8, 116.5, 115.3, 114.1, 57.5, 55.7, 45.47; IR (thin film, CH2Cl2) 2941, 2817, 2770, 1487,
1217, 1040, 852, 753 cm-1; HRMS (ESI): m/z calcd for (C16H19NO2)+ 257.1416, found 257.1405.
Ethyl 4-((dimethylamino)methyl)-3-phenoxybenzoate, 15: Following representative procedure A with substrate
4-(dimethylaminomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylbenzoate (0.0840 g, 0.2535 mmol)
and phenol (0.0716 g, 0.7608 mmol), the crude mixture was purified by silica gel column chromatography
(89.8:10:0.2 dichloromethane/ethyl acetate/triethylamine) to afford 15 as a yellow oil (0.0376 g, 0.126 mmol,
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77%). δ 7.82 (d, J = 7.8 Hz, 1H), 7.60-7.58 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 6.93 (d, J =
7.9 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 2.28 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 166.0, 157.4, 154.6, 135.7, 130.8, 130.7, 129.8, 124.9, 123.0, 120.5, 117.7, 61.0, 57.2, 45.6, 14.3; IR
(thin film, CH2Cl2) 2977, 2942, 2858, 2819, 2770, 1720, 1490, 1283, 1225, 762 cm-1; HRMS (ESI): m/z calcd for
(C18H21NO3)+ 299.1521, found 299.1512.
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1-(2-phenoxybenzyl)piperidine, 16: Following representative procedure A with substrate 1-(2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine (0.050 g, 0.166 mmol) and phenol (0.0468 g, 0.498 mmol),
the crude mixture was purified by silica gel column chromatography (90:10 dichloromethane/ethyl acetate) to
afford 16 as a brown oil (0.0342 g, 0.128 mmol, 72%). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.3 Hz, 1H),
7.30 (t, J = 7.9 Hz, 2H), 7.20 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.94–6.87 (m,
3H), 3.54 (br s, 2H), 2.43 (br s, 4H), 1.56 (br s, 4H), 1.40 (br s, 2H); 13C NMR (101 MHz, CDCl3) δ 158.0, 154.7,
131.2, 129.6, 128.1, 123.8, 122.4, 119.6, 118.3, 117.6, 56.7, 54.4, 25.9, 24.2; IR (thin film, CH2Cl2) 3064, 3037,
2933, 2852, 2795, 2756, 1581, 1486, 1235, 750 cm-1; HRMS (ESI): m/z calcd for (C18H21NO)+ 267.1623, found
267.1615.
N,N-dimethyl-1-(5-methyl-2-(4-(trifluoromethyl)phenoxy)phenyl)methanamine, 17: Following representative
procedure A with substrate 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine
(0.100 g, 0.363 mmol) and 4-trifluoromethylphenol (0.1767 g, 1.090 mmol), the crude mixture was purified by
silica gel column chromatography (90:10 dichloromethane/ethyl acetate) to afford product 17 as a yellow oil
(0.0610 g, 0.197 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.6 Hz, 2H), 7.32 (s, 1H), 7.09 (d, J =
8.2 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.2 Hz, 1H), 3.35 (s, 2H), 2.36 (s, 3H), 2.24 (s, 6H); 13C NMR
(101 MHz, CDCl3) δ 161.2, 150.9, 134.9, 131.9, 130.6, 129.3, 127.0 (q, JF = 4.0 Hz), 124.3 (q, JF = 270.0 Hz),
124.0 (q, JF = 32.5 Hz), 120.7, 116.4, 57.4, 45.5, 20.8; IR (thin film, CH2Cl2) 2975, 2944, 2859, 2819, 2771, 1616,
1514, 1493, 1327, 1250, 1163, 1121, 840 cm-1; HRMS (ESI): m/z calcd for (C17H18F3NO)+ 309.1341, found
309.1339.
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N,N-dimethyl-3-(2-(piperidin-1-ylmethyl)phenoxy)aniline, 18: Following representative procedure A with
substrate 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine (0.050 g, 0.161 mmol) and 3-
dimethylaminophenol (0.0683 g, 0.498 mmol), the crude mixture was purified by silica gel column
chromatography (84.9:15:0.1 dichloromethane/ethyl acetate/triethylamine) to afford 18 as a brown oil (0.0215
g, 0.069 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.3 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.14–7.08
(m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.3 Hz, 1H), 6.35 (s, 1H), 6.19 (d, J = 7.8 Hz, 1H), 3.56 (s, 2H),
2.92 (s, 6H), 2.43 (br s, 4H), 1.55 (br s, 4H), 1.38 (br s, 2H); 13C NMR (101 MHz, CDCl3) δ 158.9, 155.0, 152.0,
130.8, 129.8, 127.9, 125.8, 119.4, 107.0, 105.6, 102.4, 56.7, 54.4, 40.5, 26.0, 24.3 (one overlapping peak); IR
(thin film, CH2Cl2) 2933, 2850, 2780, 2755, 1615, 1573, 1501, 1235, 1000, 756 cm-1; HRMS (ESI): m/z calcd for
(C20H26N2O)+ 310.2045, found 310.2035.
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(E)-1-(2-(2-ethoxy-5-(prop-1-en-1-yl)phenoxy)-6-fluorophenyl)-N,N-dimethylmethanamine,
19:
Following
representative procedure A with substrate 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-
dimethylbenzylamine (0.050 g, 0.363 mmol) and 2-ethoxy 5-(1-propenyl)phenol (0.0958 g, 0.537 mmol), the
crude mixture was purified by silica gel column chromatography (200 ml DCM then 75:25 dichloromethane/ethyl
acetate) to afford 19 as a brown oil (0.0243 g, 0.0737 mmol, 44%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.05 (m,
3H), 6.89 (d, J = 8.2 Hz, 1H), 6.75 (t, J = 8.7, 1H), 6.44 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 15.8 Hz, 1H), 6.10-6.02
(m, 1H), 3.97 (q, J = 7.0 Hz, 2H), 3.71 (s, 2H), 2.36 (s, 6H), 1.84 (d, J = 6.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ163.8, 161.3, 158.3, 149.7, 131.5, 129.8, 128.4 (d, JF = 11.1 Hz), 124.5, 122.8, 119.0,
114.1, 110.8 (d, JF = 3.0 Hz), 109.0 (d, JF = 23.2), 64.4, 50.1, 45.2, 18.4, 14.6; IR (thin film, CH2Cl2) 3021, 2978,
2938, 2820, 2772, 1616, 1506, 1464, 1268, 1130, 1036 cm-1; HRMS (ESI): m/z calcd for (C20H24FNO2)+
329.1791, found 329.1789.
Competition Experiments
Representative Procedure of the Competition Reaction of Phenol and Aniline.
To an oven dried Schlenk flask containing 4 Å molecular sieves (0.300 g) was added 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-N,N-dimethylbenzylamine (0.050 g, 0.191 mmol), a solution of phenol (0.0540 g, 0.574
mmol) and aniline (0.574 mmol) in acetonitrile (2 mL), and copper (II) acetate (0.0038 g, 0.0191 mmol). Oxygen
gas was bubbled through the mixture for 5 minutes, followed by heating to 80 °C under positive oxygen pressure.
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After 2 hours the mixture was allowed to cool to room temperature, then transferred using acetonitrile (10 mL)
and concentrated in vacuo to give a dark brown oil. The unpurified reaction mixture was analyzed by 1H NMR
spectroscopy (500 Mhz, CDCl3, 10 s relaxation delay), comparing the characteristic benzyl hydrogen peaks of
the characterized ether 1 and aniline 20. Characteristic peaks for analysis: 1 δ 3.46 (s, 2H); 20 δ 3.50 (s, 2H).
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Supporting Information
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Copies of all 1H and 13C NMR spectra. The Supporting Information is available free of charge on the ACS
Publications website.
Acknowledgements
UCI Mass Spectrometry facility, National Science Foundation (CHE-1151092 and CHE-1339149), University of
San Diego, and Research Corporation for Science Advancement Department Development Award. JSM
thanks the Doheny Foundation and Farrell Family for a University of San Diego Summer Undergraduate
Research Experience Fellowship.
References
(1)
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(7)
Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder, T. B. J. Am. Chem. Soc. 1993, 115, 9329.
Waltz, K. M.; He, X.; Muhoro, C.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11357.
Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 1999, 121, 7696.
Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992.
Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864.
Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am.
Chem. Soc. 2013, 135, 7572.
(8)
(9)
Mankad, N. P. Synlett 2014, 25, 1197.
Ros, A.; Fernández, R.; Lassaletta, J. M. Chem. Soc. Rev. 2014, 43, 3229.
(10)
(11)
(12)
(13)
Bisht, R.; Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84.
Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. Nat. Chem. 2015, 7, 712.
Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am. Chem. Soc. 2009, 131, 5058.
Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E.,
Jr.; Smith, M. R., III J. Am. Chem. Soc. 2014, 136, 14345.
(14)
(15)
(16)
(17)
(18)
Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3978.
Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46, 159.
Kawamorita, S.; Ohmiya, H.; Sawamura, M. J. Org. Chem. 2010, 75, 3855.
Itoh, H.; Kikuchi, T.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2011, 40, 1007.
Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc.
2006, 128, 15552.
(19)
(20)
Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2011, 133, 19310.
Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Org. Lett. 2012,
14, 3558.
(21)
(22)
Hale, L. V. A.; McGarry, K. A.; Ringgold, M. A.; Clark, T. B. Organometallics 2015, 34, 51.
Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr.; Smith, M. R., III J.
Am. Chem. Soc. 2012, 134, 11350.
(23) Okada, S.; Namikoshi, T.; Watanabe, S.; Murata, M. ChemCatChem 2015, 7, 1531.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
(24)
Ros, A.; Estepa, B.; López‐Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Angew. Chem., Int.
1
2
3
4
5
6
7
8
Ed. 2011, 50, 11724.
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
López‐Rodríguez, R.; Ros, A.; Fernández, E.; Lassaletta, J. M. J. Org. Chem. 2012, 77, 9915.
Sasaki, I.; Amou, T.; Ito, H.; Ishiyama, T. Org. Biomol. Chem. 2014, 12, 2041.
Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534.
Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068.
Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B. Angew. Chem., Int. Ed. 2014, 53, 7589.
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Matteson, D. S. Tetrahedron 1998, 54, 10555.
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
Crudden, C. M.; Edwards, D. Eur. J. Org. Chem 2003, 4695.
Scott, H. K.; Aggarwal, V. K. Chem. Eur. J. 2011, 17, 13124.
Brown, H. C.; Kramer, G. W.; Levy, A. B.; Middland, M. M. Organic Syntheses via Boranes; Wiley‐
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Interscience: New York, 1975; Vol. 1.
(36)
Brown, H. C.; Zaidlewicz, M. Organic Syntheses via Boranes‐Recent Developments; Aldrich Chemical
Company: Milwaukee, 2001; Vol. 2.
(37)
Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Hall, D. G.,
Ed.; Wiley‐VCH: Weinheim, 2011; Vol. 1.
(38)
Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Hall, D. G.,
Ed.; Wiley‐VCH: Weinheim, 2011; Vol. 2.
(39)
2015, 2, 661.
(40)
Hale, L. V. A.; Emmerson, D. G.; Ling, E. F.; Roering, A. J.; Ringgold, M. A.; Clark, T. B. Org. Chem. Frontiers
McGarry, K. A.; Duenas, A. A.; Clark, T. B. J. Org. Chem. 2015, 80, 7193.
Gözler, B.; Shamma, M. J. Nat. Prod. 1984, 47, 753.
Whitlock, G. A.; Blagg, J.; Fish, P. V. Bioorg. Med. Chem. Lett. 2008, 18, 596.
Freundlich, J. S.; Yu, M.; Lucumi, E.; Kuo, M.; Tsai, H.‐C.; Valderramos, J.‐C.; Karagyozov, L.; Jacobs, W. R.,
(41)
(42)
(43)
Jr.; Schiehser, G. A.; Fidock, D. A.; Jacobus, D. P.; Sacchettini, J. C. Bioorg. Med. Chem. Lett. 2006, 16, 2163.
(44) Kung, H. F.; Newman, S.; Choi, S.‐R.; Oya, S.; Hou, C.; Zhuang, Z.‐P.; Acton, P. D.; Plössl, K.; Winkler, J.;
Kung, M.‐P. J. Med. Chem. 2004, 47, 5258.
(45)
Vercouillie, J.; Mavel, S.; Galineau, L.; Ragusa, T.; Innis, R.; Kassiou, M.; Chalon, S.; Dollé, F.; Besnard, J.‐
C.; Guilloteau, D.; Emond, P. Bioorg. Med. Chem. Lett. 2006, 16, 1297.
(46)
(47)
(48)
(49)
(50)
(51)
(52)
(53)
Papastephanou, C. Anal. Profiles Drug Subst. 1978, 7, 477.
Bhagya, N.; Chandrashekar, K. R. Phytochemistry 2016, 125, 5.
Pitsinos, E. N.; Vidali, V. P.; Couladouros, E. A. Eur. J. Org. Chem. 2011, 1207.
Allen, S. E.; Walvoord, R. R.; Padilla‐Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234.
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
Chan, D. M. T.; Monaco, K. L.; Wang, R.‐P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 29, 2941.
(54)
(55)
(56)
(57)
(58)
Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415.
Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829.
Sanjeeva Rao, K.; Wu, T.‐S. Tetrahedron 2012, 68, 7735.
Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761.
Vantourout, J. C.; Law, R. P.; Isidro‐Llobet, A.; Atkinson, S. J.; Watson, A. J. B. J. Org. Chem. 2016, 81,
3942.
(59)
(60)
Sueki, S.; Kuninobu, Y. Org. Lett. 2013, 15, 1544.
Jamni, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 1971.
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