Chan-Lam Amination of Secondary and Tertiary Benzylic Boronic Esters

Article abstract of DOI:10.1021/acs.joc.1c00976

We report a Chan-Lam coupling reaction of benzylic and allylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition-metal-mediated transformation of a tertiary alkylboron reagent. Initial investigation into the reaction mechanism suggests that transmetalation from B to Cu occurs through a single-electron, rather than a two-electron process.

Full text of DOI:10.1021/acs.joc.1c00976

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Note
Chan−Lam Amination of Secondary and Tertiary Benzylic Boronic
Esters
James D. Grayson, Francesca M. Dennis, Craig C. Robertson, and Benjamin M. Partridge*
Cite This: J. Org. Chem. 2021, 86, 9883−9897
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ABSTRACT: We report a Chan−Lam coupling reaction of benzylic and allylic
boronic esters with primary and secondary anilines to form valuable alkyl amine
products. Both secondary and tertiary boronic esters can be used as coupling
partners, with mono-alkylation of the aniline occurring selectively. This is a rare
example of a transition-metal-mediated transformation of a tertiary alkylboron
reagent. Initial investigation into the reaction mechanism suggests that trans-
metalation from B to Cu occurs through a single-electron, rather than a two-electron
process.
dvances in catalysis have enabled chemists to prepare aryl
Aamines in a reliable and predictable manner, using methods
such as the Buchwald−Hartwig,1 Chan−Lam,2 and Ullmann
reactions.1c,2b,3 These reactions allow amine formation from
common chemical building blocks (e.g., aryl halides or
arylboronic acids) and are typically operationally simple to
carry out. As a result, they have found application in a range of
disciplines from drug discovery and manufacture to materials
science.1b
While highly desirable, the corresponding coupling methods
that form alkyl C−N bonds are underdeveloped.4 For Pd
catalysis, the reductive elimination step to form alkyl−N bonds
is challenging.5 More progress has been made using Cu catalysis,
through the coupling of amines with alkyl radicals, generated
under photoredox catalysis from alkyl halides6 and carboxylic
acids.7
the coupling of cyclopropyl boronic acid,8 but the reaction of
alkylboronic esters has only been rarely reported.9 Advances in
this area would complement traditional methods to form alkyl
amines, such as nucleophilic substitution and reductive
amination.10 These often suffer from the necessity of protecting
group strategies, over-alkylation, and, in the case of nucleophilic
substitution, the need for toxic alkylating agents.
Herein, we report a Chan−Lam coupling of secondary and
tertiary benzylic boronic esters with anilines. This complements
a recent report of Cu-catalyzed decarboxylative amination of
benzylic carboxylic acids which was proposed to occur through a
Chan−Lam type mechanism.11,12
As part of the ongoing investigation into Cu-catalyzed
oxidative transformations of boronic esters,13 we explored the
reaction of boronic ester 1 with aniline 2a in the presence of
Cu(OAc)2 and Cs2CO3 (see Table 1).14 Heating these reagents
in a mixture of MeOH and pyridine at 50 °C under air gave
amine 3a, alongside oxidation products 4 and 5 which are
consistent with our previous observations.13 The remainder of
the mass is likely to be accounted for by protodeboronation of
boronic ester 1 to give ethylbenzene, whose volatility means it
was unable to be detected after workup. Reducing the loading of
base led to an increase in amine 3a and a decrease in the amount
of alcohol 5 formed. However, in the absence of Cs2CO3,
formation of ketone 4 dominated. Pleasingly, oxidation side
products could be minimized by conducting the reaction under
an inert atmosphere. However, this requires the use of
stoichiometric loadings of Cu(OAc)2, to act as both catalyst
Because of the versatility of organoboron reagents, we are
interested in developing an alkyl variant of the Chan−Lam
reaction (Scheme 1). This reaction has been studied in detail for
a
Scheme 1. Context of This Research
Received: April 26, 2021
Published: June 25, 2021
a
pin = pinacol boronic ester.
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c00976
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Note
a
Table 1. Evaluation of Reaction Conditions on the Yield of 3a
b
yield (%)
entry
equiv [Cu]
equiv 2a
MeOH:Pyr
equiv Cs2CO3
1
3a
4
5
c
1
2
2
2
2
2
2
2
1
2
2
2
2
4
4
4
2
3
1
4
4
3:2
3:2
3:2
3:2
3:2
3:1
3:1
3:1
3:1
3:1
3:1
1:0
2
0.5
0
0
0
0
23
51
16
30
6
34
32
60
6
<5
<5
48
5
<5
6
6
<5
c
2
c
3
4
5
6
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
39
48
38
de
,
f
7
73
36
67
46
0
de
,
f
f
f
8
de
,
9
1.5
2
0
de
,
10
11
12
d
d
n.d.
45
<5
<5
33
0
2
37
a
b
1
Reactions performed using 0.05 mmol of 1a. Determined using H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
c
d
e
f
Reaction conducted under air. 16 h reaction time. Reactions performed using 0.50 mmol of 1a. Yield is of isolated material. n.d. = not
determined.
and oxidant in the reaction. Because of the relatively low cost
and benign safety profile of Cu(OAc)2, we chose this
compromise rather than using other chemical oxidants that
have been used previously in Chan−Lam reactions.9a,c,15
Increasing the amount of aniline 2a led to an improved yield
of 3a, with a ratio of 2a:Cu(OAc)2 of 2:1 found to be best.
Lowering the amount of pyridine in the solvent mixture gave a
better mass balance, presumably due to lower levels of
protodeboronation. Finally, extending the reaction time led to
complete conversion of boronic ester 1, giving amine 3a in
excellent yield. A series of control experiments showed the
necessity of Cu(OAc)2 for amination to occur (entry 11). In the
absence of pyridine, the efficiency of amination is reduced (entry
12). This suggests that pyridine acts to break up aggregates of
Cu(OAc)2, providing a higher concentration of active catalyst in
solution.16 Switching the stoichiometry to make the amine the
limiting reagent did lead to coupling, albeit in moderate yield
(entry 10). However, these conditions would allow an isolable
amount of coupling product to be obtained if the aniline
substrate is prohibitively expensive.
Scheme 2 details the scope of the reaction of boronic ester 1
with a variety of anilines. In all cases, only mono-substitution of
the aniline was observed. There is a clear trend that electron rich
anilines react in higher yield over a 16 h time frame. Anilines
substituted with electron withdrawing groups did react
successfully but often required higher temperatures and
prolonged reaction times for acceptable yields. Functional
groups tolerated include alkenes (3j), amides (3g), aryl halides
(3e, 3k, 3n), esters (3h), sulfides (3d), and trifluoromethyl
groups (3f, 3i). Importantly, no Ullmann coupling was observed
when using substrates containing an aryl bromide or chloride.3
C−N coupling also occurred exclusively at the aniline in the
presence of a primary amide, which complements reports of
amide coupling from Watson and co-workers.9a,17 Hetero-
aromatic anilines were successfully coupled in modest to good
yield (3p, 3q). Secondary anilines can also be coupled
successfully, with examples including methyl- and isopropyl-
substituted anilines (3r, 3s), and tetrahydroquinoline (3t).
However, amine 3b, when resubjected to the coupling
conditions, reacted in low conversion after 48 h (3u). This
suggests why only the product of monoalkylation is typically
observed as the rate of the second alkylation is much slower by
comparison. We have briefly explored the generality of our
conditions with alkylamines. Morpholine did undergo coupling
to form amine 3v, though with low efficiency. However, primary
alkyl amines 6 and 7 were found to be unreactive.
We next explored the scope of the boronic ester using p-
anisidine as the coupling partner (Scheme 3). Benzylic boronic
esters containing both electron donating and electron with-
drawing groups on the arene are tolerated. Trifluoromethyl-
substituted boronic ester 8f, however, reacted slowly. Aryl
halides and ortho substituents on the arene are also tolerated.
Extension of the alkyl chain was possible, with groups containing
ethers, azides, and alcohols tolerated (9l−9o). Primary benzylic
boronic ester 8p reacted smoothly and only gave the product of
monoalkylation. The reaction conditions were successfully
applied to allylic boronic esters 8q and 8r to form allylic amines
in good yield. The reaction of 2-methylallylboronic ester 8r with
p-anisidine did give a mixture of mono- and dialkylated
products, but this is the only boronic ester for which we have
observed dialkylation. In comparison, aliphatic boronic ester 8s
showed low reactivity under these conditions.
Methods using tertiary boronic esters to form C−N bonds are
currently limited to the preparation of primary amines.18 Using
our conditions, we were pleased to observe the successful
coupling of boronic ester 10a with a range of primary anilines
(Scheme 4). This is a rare example of a tertiary boronic ester
reacting under transition metal catalysis.19 Unlike secondary
boronic esters, no reaction occurred between N-methylaniline
and boronic ester 10a, presumably due to the increased steric
congestion from these substrates. Interestingly, amination of
dibenzylboronic esters proceeded at room temperature, except
CF3-containing boronic ester (11f). Monobenzylic tertiary
boronic ester, however, required a reaction temperature of 50 °C
to give 11g in reasonable yield within 16 h. In contrast, tert-butyl
pinacol boronic ester was unreactive under the reaction
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Note
Scheme 2. Scope of Anilines in the Amination of Boronic
Ester 1
Scheme 3. Scope of Boronic Esters in the Amination with p-
Anisidine
a
a
a
b
Yields reported are of isolated material. Reaction conducted at 65
c
d
e
°C. Reaction time of 48 h. Reaction time of 32 h. Reaction
conducted with N-methylaniline instead of p-anisidine.
a
Scheme 4. Amination of Tertiary Boronic Esters
a
Reactions were conducted on a 0.5 mmol scale. Yields reported are
b
of isolated material of the corresponding product. Oxidation of
remaining boronic ester using H2O2/NaOH was performed prior to
c
isolation of the amine product. Reaction conducted at 65 °C.
d
e
Reaction time of 48 h. Reaction time of 36 h.
conditions. While the yields of coupling are generally lower than
with secondary boronic esters, the method can produce useful
amounts of these otherwise hard to make C-tertiary amines.
Interestingly, when p-anisidine was reacted with tertiary
boronic ester 13, alongside C-N coupling product 14, we also
observed a product of C-C coupling (15, isolated as thiourea 16,
Scheme 5). While this reactivity was not seen between p-
anisidine and secondary boronic esters, a reaction of 4-
aminophenol with 1 did give a mixture of products from C-N
(17), C-O (18), and C-C (19) coupling. Single isomers of both
15 and 19 were observed, with X-ray crystallography of the
corresponding thiourea of 19 confirming arylation occurs ortho
to nitrogen.20 We have assigned 16 through analogy. The
selectivity is consistent with electrophilic aromatic substitution
reactions, suggesting the formation of 15 and 19 may involve a
carbocation intermediate.
a
Reactions were conducted on a 0.5 mmol scale. Yields reported are
b
of isolated material. Reaction conducted at 50 °C.
We wanted to learn more about the reaction mechanism, as
little information is available about the reaction of alkylboronic
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Note
a
is likely to occur through a single-electron process. Further C−
heteroatom bond forming processes from alkylboronic esters are
under development and will be reported in due course.
Scheme 5. Observation of C−C Bond Formation
EXPERIMENTAL SECTION
■
General. All reagents and solvents used were supplied by
commercial sources without further purification unless specified.
Aniline (distillation) and p-anisidine (recrystallization from ethanol)
were purified before use. All air-sensitive reactions were carried out
under a nitrogen or argon atmosphere using oven-dried apparatus.
Anhydrous Et2O, THF, and toluene were dried and purified by passage
through activated alumina columns using a solvent purification system.
All petroleum ether used was 40−60 °C petroleum ether. All reactions
which required elevated temperatures were heated using a stirrer hot
plate and oil bath with an external probe to control the temperature.
Thin layer chromatography (TLC) was performed on aluminum-
backed plates precoated with silica. Compounds were visualized by
exposure to UV light or by dipping the plates into solutions of vanillin or
KMnO4, followed by heating. All flash chromatography was carried out
using silica gel mesh 40−63. It should be noted that the time taken for
chromatography of boronic esters should be kept to a minimum to
avoid extensive decomposition and reduced yields.
a
Reaction conditions for amination reactions: Cu(OAc)2 (2 equiv),
Cs2CO3 (0.5 equiv), MeOH/Pyr (3:1), 25 °C (reaction with 13) or
50 °C (reaction with 1). Yields reported are of isolated material.
b
Phenyl isothiocyanate (1.1 equiv), hexane:MeCN:Et3N (1:0.1:0.1).
Infrared spectra were recorded on a PerkinElmer 100 FT instrument
on the neat compound. NMR spectra were recorded on Bruker
Advance 400 and 500 instruments at the indicated 101, 128, 126, 377,
400, and 500 MHz as dilute solutions in the indicated deuterated
solvent. NMR spectra were recorded at ambient temperature unless
otherwise stated. All chemical shifts (δ) are reported in parts per million
(ppm) relative to the residual protio solvent (δH: CHCl3 = 7.27 ppm,
DMSO = 2.50 ppm, or CH3CN = 1.94 ppm) or the solvent itself (δC:
CDCl3 = 77.0 ppm, DMSO = 39.5 ppm, or CH3CN = 1.32, 118.3 ppm).
All multiplets are designated by the following abbreviations: s = singlet,
br s = broad singlet, d = doublet, dt = doublet triplet, td = triplet
doublet, ddd = doublet of doublets of doublets, q = quartet, br q = broad
quartet, m = multiplet. All coupling constants (J) are reported in Hertz
esters with Cu salts. We started by performing a radical clock
experiment, using cyclopropane containing boronic ester 20 (eq
1). This reacted to give amine 21, with ring opening of the
cyclopropane, without observation of the corresponding benzyl
amine 22. This suggests that the boronic ester serves as a radical
precursor,21 with a two-electron transmetalation to Cu unlikely.
This is in contrast to our previous investigation into the Cu-
catalyzed oxidation of benzylic boronic esters, where oxidation
of 20 occurred without ring opening of the cyclopropane.13
While we cannot rule out further oxidation of the radical to a
carbocation, the observed product distribution indicates this is
likely to be a minor pathway, due to stability of cyclo-
propylcarbinyl cations which would presumably promote
formation of 22.
1
(Hz). Assignments of H NMR signals were made using 2D NMR
spectra, typically HSQC and HMBC experiments. 13C NMR data were
acquired as DEPT-Q experiments as standard. For samples where
quaternary carbons were not observed by DEPT-Q, 13C NMR spectra
were acquired as decoupled spectra. 19F NMR spectra were acquired as
decoupled spectra. High-resolution mass spectra were recorded using
either electrospray ionization (ESI) or electron ionization (EI) by the
Chemistry Mass Spectrometry Facility in the Faculty of Science,
University of Sheffield. HPLC analysis was carried out using the
Chromatography Facility at the Department of Chemistry, University
of Sheffield. Melting points were measured using a Linkam HFs91
heating stage, used in conjunction with a TC92 controller, and are
uncorrected.
Single crystal X-ray intensity data were collected at 100 K on a Bruker
D8 Venture diffractometer equipped with a Photon 100 CMOS
detector using a Cu Kα microfocus X-ray source from crystals mounted
in fomblin oil on a MiTiGen microloop and cooled in a stream of cold
N2. Data were corrected for absorption using empirical methods
(SADABS)23 based upon symmetry equivalent reflections combined
with measurements at different azimuthal angles.24 The crystal
structures were solved and refined against F2 values using ShelXT25
for solution and ShelXL26 for refinement accessed via the Olex2
program.27 Non-hydrogen atoms were refined anisotropically. Hydro-
gen atoms were placed in calculated positions with idealized geometries
and then refined by employing a riding model and isotropic
displacement parameters.
Consistent with the formation of a benzyl radical is the reaction
of enantiomerically enriched boronic ester (S)-1a (eq 2). This
reacted smoothly to form amine 3a, but with complete loss of
stereochemical information. However, we cannot rule out
whether configurational instability of an alkyl-Cu intermediate is
the cause of stereoablation.22
In conclusion, we have developed an operationally simple
Chan−Lam coupling of secondary and tertiary boronic esters
with anilines. The amination reaction is a rare example of a
transition-metal-mediated reaction using a tertiary alkylboron
coupling partner. Monoalkylation of the amine occurs
selectively, and the conditions tolerate a diverse range of
functional groups. Initial investigation into the reaction
mechanism suggests that transmetalation from boron to copper
Synthesis of Substrates. Boronic esters (1, 8a−p, 20)13 and
boronic esters (8q, 8r)28 were prepared by literature methods.
3-Methoxypropyl N,N-Bis(propan-2-yl)carbamate (S1).
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Note
N,N-Diisopropylcarbamoyl chloride (3.96 g, 24.2 mmol) was added to
a solution of 3-methoxy propanol (2.2 mL, 23 mmol) and triethylamine
(3.4 mL, 24 mmol) in CH2Cl2 (77 mL). The mixture was heated at
reflux for 18 h, cooled to room temperature, and diluted with H2O (30
mL). The mixture was extracted with DCM (3 × 20 mL). The
combined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The crude material was
purified by flash chromatography (10% EtOAc/petroleum ether) to
give carbamate S1 (3.88 g, 77%) as a yellow oil. IR 2969, 2932, 1687,
1435, 1289 cm−1. 1H NMR (400 MHz, CDCl3) δ 4.16 (2H, t, J = 6.4
Hz, C(O)OCH2), 4.13−3.55 (2H, m, 2 × CH3CH), 3.47 (2H, t, J = 6.4
Hz, CH2OCH3), 3.34 (3H, s, OCH3), 1.92 (2H, p, J = 6.4 Hz,
OCH2CH2), 1.25−1.15 (12H, m, 4 × CHCH3). 13C{1H} NMR (101
MHz, CDCl3) δ 155.7 (C), 69.6 (CH2), 61.7 (CH2), 58.6 (CH3), 46.3
(br, 2 × CH), 29.4 (CH2), 20.9 (4 × CH3). HRMS (Q-TOF) m/z: [M
+ H]+ Calcd for C11H24NO3+ 218.1756; found 218.1751.
(3H, d, J = 7.5 Hz, CHCH3), 1.22 (6H, s, 2 × CCH3), 1.21 (6H, s, 2 ×
CCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 144.9 (C), 128.3 (2 ×
CH), 127.8 (2 × CH), 125.1 (CH), 83.3 (2 × C), 24.6 (2 × CH3), 24.6
(2 × CH3), 17.0 (CH3). 11B NMR (128 MHz, CDCl3) δ 33.5. e.r. =
97:3, measured through chiral HPLC analysis of the corresponding
alcohol obtained after oxidation. HPLC (Phenomenex Cellulose-1
column (250 × 4.6 mm), IPA/hexane 10/90, flow rate = 1.0 mL/min, l
= 254 nm), tR = 6.2 min (minor), 7.1 min (major).
General Procedure 1: Lithiation-Borylation. Using a modification
of the procedure by Aggarwal and co-workers,29 a Schlenk flask
containing the corresponding carbamate (1.2 equiv) was backfilled with
nitrogen three times. Anhydrous Et2O (0.2 M) was added, and the
mixture was cooled to −78 °C. s-BuLi (1.3 equiv) was added dropwise,
and the mixture was stirred at −78 °C for 1 h. The boronic ester (1
equiv) was added dropwise, and the mixture was stirred at −78 °C for 1
h and then at room temperature for 2 h. H2O (20 mL) and Et2O (15
mL) were added, and the mixture was extracted with Et2O (3 × 15 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo.
( )-tert-Butyl 3-[3-Methoxy-1-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)propyl]-1H-indole-1-carboxylate (8l).
( )-2-[1-(4-Methoxyphenyl)-1-phenylethyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (10a).
Using a modification of the procedure by Aggarwal and co-workers,29
a
Schlenck flask containing carbamate S1 (0.576 g, 2.65 mmol) was
backfilled with nitrogen three times. TMEDA (0.55 mL, 3.7 mmol) and
anhydrous Et2O (10.2 mL) were added, and the mixture was cooled to
−78 °C. s-BuLi (1.3 M in cyclohexane, 2.8 mL, 3.7 mmol) was added
dropwise, and the mixture was stirred at −78 °C for 4 h. t-Butyl 3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate
(0.700 g, 2.04 mmol) was added dropwise. A solution of MgBr2 in Et2O
(0.378 g, 2.04 mmol, 1 M) was added dropwise, and the mixture was
stirred at 34 °C for 18 h. Toluene (10 mL) was added, and the mixture
was heated to 90 °C for 18 h. H2O (20 mL) and Et2O (15 mL) were
added, and the mixture was extracted with Et2O (3 × 15 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography (5% EtOAc/petroleum ether) to give boronic ester 8l
(0.422 g, 50%) as a colorless oil. IR 2977, 2930, 1729, 1452, 1368, 1142
cm−1. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.66−7.61 (1H, m,
ArH), 7.41 (1H, s, ArH), 7.31−7.27 (1H, m, ArH), 7.24−7.17 (1H, m,
ArH), 3.48−3.36 (2H, m, CH2OCH3), 3.33 (3H, s, OCH3), 2.66−2.57
(1H, m, BCH), 2.25−2.14 (1H, m, BCHCHACHB), 2.05−1.93 (1H, m,
BCHCHACHB), 1.66 (9H, s, 3 × C(O)OCCH3), 1.22 (6H, s, 2 ×
BOCCH3), 1.21 (6H, s, 2 × BOCCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 149.8 (C), 135.6 (C), 130.7 (C), 124.0 (CH), 122.3 (C),
122.0 (CH), 121.5 (CH), 119.6 (CH), 115.0 (CH), 83.5 (2 × C), 83.0
(C), 72.0 (CH2), 58.5 (CH3), 31.0 (CH2), 28.2 (3 × CH3), 24.7 (4 ×
CH3), 18.4 (BCH). 11B NMR (128 MHz, CDCl3) δ 33.7. HRMS (Q-
The title compound was prepared according to General Procedure 1
using 1-phenylethyl diisopropylcarbamate33 (1.60 g, 6.42 mmol), s-
BuLi (1.3 M in cyclohexane, 5.6 mL, 7.3 mmol), and 4-
methoxyphenylboronic acid pinacol ester (1.00 g, 4.27 mmol) added
in Et2O (2 mL). Flash chromatography (2% EtOAc/petroleum ether)
of the crude material gave boronic ester 10a (1.25 g, 87%) as a white
solid. The data were consistent with the literature.29 m.p. 64−66 °C
(petroleum ether); no literature value available. 1H NMR (400 MHz,
CDCl3) δ 7.31−7.24 (2H, m, ArH), 7.25−7.20 (2H, m, ArH), 7.20−
7.15 (3H, m, ArH), 6.86−6.80 (2H, m, ArH), 3.81 (3H, s, OCH3), 1.68
(3H, s, CCH3), 1.22 (12H, s, 4 × OCCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 157.3 (C), 148.1 (C), 139.4 (C), 129.4 (2 × CH), 128.4 (2 ×
CH), 127.9 (2 × CH), 125.3 (CH), 113.3 (2 × CH), 83.7 (2 × C), 55.1
(CH3), 25.9 (CH3), 24.4 (4 × CH3). 11B NMR (128 MHz, CDCl3) δ
33.6.
( )-2-[1-(4-Chlorophenyl)-1-phenylethyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (10b).
+
TOF) m/z: [M + Na]+ Calcd for C23H34BNNaO5 438.2428; found
438.2422.
(S)-4,4,5,5-Tetramethyl-2-(1-phenylethyl)-1,3,2-dioxaborolane
((S)-1). Following the procedure by Yun and co-workers,30 a mixture of
CuCl (20.8 mg, 0.211 mmol), KOtBu (56.7 mg, 0.506 mmol), and (R)-
DTBM-Segphos (250.0 mg, 0.211 mmol) in anhydrous toluene (5.0
mL) was stirred for 30 min under an atmosphere of nitrogen.
Pinacolborane (10.1 mmol, 1.46 mL) was added to the reaction mixture
and stirred for 10 min. Styrene (8.44 mmol, 0.97 mL) was added, and
the mixture was stirred at 60 °C for 18 h. The reaction mixture was
cooled, filtered through a pad of Celite eluting with EtOAc, and
concentrated in vacuo. The product was purified by column
chromatography (5% Et2O/petroleum ether) to give boronic ester
(S)-1 (1.10 g, 54%) as a colorless oil. The data were consistent with the
literature.31 [α]D21 +12.0 (c 1.00, CHCl3); lit. [α]2D3 +11.9 (c 1.08,
CHCl3) 97:3 e.r. (S).32 1H NMR (400 MHz, CDCl3) δ 7.33−7.19 (4H,
m, ArH), 7.19−7.08 (1H, m, ArH), 2.45 (1H, q, J = 7.5 Hz, CH), 1.34
The title compound was prepared according to General Procedure 1
using 1-phenylethyl diisopropylcarbamate33 (1.25 g, 5.03 mmol), s-
BuLi (1.3 M in cyclohexane, 4.2 mL, 5.5 mmol), and 4-
chlorophenylboronic acid pinacol ester (1.00 g, 4.19 mmol) added in
Et2O (2 mL). Flash chromatography (4% EtOAc/petroleum ether) of
the crude material gave boronic ester 10b (1.38 g, 96%) as an off-white
solid. The data were consistent with the literature.29 m.p. 74−75 °C
(petroleum ether); no literature value available. 1H NMR (400 MHz,
CDCl3) δ 7.30−7.27 (1H, m, ArH), 7.26−7.15 (8H, m, ArH), 1.67
(3H, s, CCH3), 1.21 (6H, s, 2 × OCCH3), 1.21 (6H, s, 2 × OCCH3).
13C{1H} NMR (101 MHz, CDCl3) δ 147.2 (C), 146.2 (C), 131.1 (C),
129.9 (2 × CH), 128.4 (2 × CH), 128.1 (2 × CH), 128.0 (2 × CH),
125.6 (CH), 83.9 (2 × C), 25.7 (CH3), 24.4 (4 × CH3). 11B NMR (128
MHz, CDCl3) δ 33.1.
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Note
( )-2-[1-(4-Trifluoromethylphenyl)-1-phenylethyl]-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (10c).
m, CCH2), 1.36 (3H, s, BCCH3), 1.22 (6H, s, 2 × OCCH3), 1.21 (6H,
s, 2 × OCCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 146.4 (C), 128.2
(2 × CH), 126.8 (2 × CH), 125.3 (CH), 83.5 (2 × C), 52.1 (CH2),
36.5 (CH2), 24.9 (CH2), 24.6 (2 × CH3), 24.5 (2 × CH3), 21.3 (CH3).
11B NMR (128 MHz, CDCl3) δ 33.7. HRMS (Q-TOF) m/z: [M +
Na]+ Calcd for C17H26BN3O2Na+ 338.2016; found 338.2017.
Experimental Procedure for the Cu-Promoted Amination of
Alkylboronic Esters. General Procedure 2: Preparative Scale Cu-
Catalyzed Amination of Alkylboronic Esters. A flask containing the
corresponding boronic ester (0.50 mmol, 1 equiv), aniline (2.00 mmol,
4 equiv), Cu(OAc)2 (0.182 g, 1.00 mmol), and Cs2CO3 (0.0820 g,
0.252 mmol) was purged with argon. Methanol (1.0 mL) and pyridine
(0.33 mL) were added, and the mixture was stirred at 50 or 65 °C until
the reaction was complete (as determined by TLC). The mixture was
cooled to room temperature, NH4OH (10 mL) was added, and the
mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered,
and concentrated in vacuo. The crude material was purified by column
chromatography.
General Procedure 3: Preparative Scale Cu-Catalyzed Amination
of Alkylboronic Esters with Oxidative Workup. A flask containing the
corresponding boronic ester (0.50 mmol, 1 equiv), aniline (2.00 mmol,
4 equiv), Cu(OAc)2 (0.182 g, 1.00 mmol), and Cs2CO3 (0.082 g, 0.25
mmol) was purged with argon. Methanol (1.0 mL) and pyridine (0.33
mL) were added, and the mixture was stirred at 50 or 65 °C until the
reaction was complete (as determined by TLC). The mixture was
cooled to room temperature, NH4OH (10 mL) was added, and the
mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered,
and concentrated in vacuo. THF (1 mL), H2O (1 mL), and sodium
perborate (0.382 g, 2.50 mmol) were added, and the mixture was stirred
at RT for 1 h. The mixture was diluted with H2O (10 mL) and extracted
with EtOAc (3 × 10 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. The crude material was
purified by column chromatography.
The title compound was prepared according to General Procedure 1
using 1-phenylethyl diisopropylcarbamate33 (0.551 g, 2.21 mmol), s-
BuLi (1.3 M in cyclohexane, 1.8 mL, 2.4 mmol), and 4-
trifluoromethlphenylboronic acid pinacol ester (0.50 g, 1.84 mmol)
added in Et2O (2 mL). Flash chromatography (4% EtOAc/petroleum
ether) of the crude material gave boronic ester 10c (0.575 g, 83%) as an
off white solid. m.p. 65−66 °C (petroleum ether). IR 2977, 2932, 1616,
1317, 1113 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.53−7.49 (2H, m,
ArH), 7.36−7.28 (4H, m, ArH), 7.22−7.18 (3H, m, ArH), 1.71 (3H, s,
CCH3), 1.22 (6H, s, 2 × OCCH3), 1.21 (6H, s, 2 × OCCH3). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.2 (C), 146.6 (C), 128.8 (2 × CH),
128.4 (2 × CH), 128.2 (2 × CH), 127.6 (q, JF = 32.2 Hz, C), 125.8
(CH), 124.8 (q, JF = 3.8 Hz, 2 × CH), 124.4 (q, JF = 271.6 Hz, CF3),
84.0 (2 × C), 25.6 (CH3), 24.5 (2 × CH3), 24.4 (2 × CH3). 11B NMR
(128 MHz, CDCl3) δ 33.3. 19F NMR (377 MHz, CDCl3) δ −62.2.
HRMS (Q-TOF) m/z: [M + H]+ Calcd for C21H25BF3O2+ 377.1900;
found 377.1894.
( )-2-(2-Phenylbut-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (10d).
General Procedure 4: Preparative Scale Tertiary Alkyl Chan−Lam
Coupling. A flask containing the corresponding boronic ester (0.50
mmol, 1 equiv), aniline (2.00 mmol, 4 equiv), Cu(OAc)2 (0.182 g, 1.00
mmol), and Cs2CO3 (0.0820 g, 0.252 mmol) was purged with argon.
Methanol (1.0 mL) and pyridine (0.33 mL) were added, and the
mixture was stirred at RT for 16 h. NH4OH (10 mL) was added, and the
mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered,
and concentrated in vacuo. The crude material was purified by column
chromatography.
The title compound was prepared according to General Procedure 1
using 1-phenylethyl diisopropylcarbamate33 (1.92 g, 7.69 mmol), s-
BuLi (1.3 M in cyclohexane, 6.4 mL, 8.3 mmol), and ethylboronic acid
pinacol ester (1.00 g, 6.41 mmol). Flash chromatography (4% EtOAc/
petroleum ether) of the crude material gave boronic ester 10d (1.51 g,
90%) as a yellow oil. The data were consistent with the literature.29 1H
NMR (400 MHz, CDCl3) δ 7.34−7.26 (4H, m, ArH), 7.17−7.11 (1H,
m, ArH)), 1.89 (1H, dq, J = 14.7, 7.4 Hz, CCHAHB), 1.72 (1H, dq, J =
14.7, 7.4 Hz, CCHAHB), 1.34 (3H, s, BCCH3), 1.22 (6H, s, 2 ×
OCCH3), 1.22 (6H, s, 2 × OCCH3), 0.84 (3H, t, J = 7.4 Hz, CH2CH3).
13C{1H} NMR (101 MHz, CDCl3) δ 147.3 (C), 128.0 (2 × CH), 126.9
( )-N-(1-Phenylethyl)aniline (3a). The title compound was
prepared according to General Procedure 3 using boronic ester 1
(0.116 g, 0.501 mmol) and aniline (0.18 mL, 2.0 mmol), heating at 50
°C for 16 h. Flash chromatography (2% EtOAc/petroleum ether) of the
crude material gave amine 3a (0.0719 g, 73%) as a brown oil. The data
were consistent with the literature.35 1H NMR (400 MHz, CDCl3) δ
7.41−7.36 (2H, m, ArH), 7.36−7.30 (2H, m, ArH), 7.26−7.21 (1H, m,
ArH), 7.14−7.06 (2H, m, ArH), 6.69−6.61 (1H, m, ArH), 6.56−6.48
(2H, m, ArH), 4.50 (1H, q, J = 6.7 Hz, CH), 4.05 (1H, s, NH), 1.53
(3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
147.2 (C), 145.2 (C), 129.1 (2 × CH), 128.6 (2 × CH), 126.8 (CH),
125.8 (2 × CH), 117.2 (CH), 113.2 (2 × CH), 53.4 (CH), 25.0 (CH3).
( )-4-Methoxy-N-(1-phenylethyl)aniline (3b). The title compound
was prepared according to General Procedure 2 using boronic ester 1
(0.116 g, 0.501 mmol) and p-anisidine (0.246 g, 2.00 mmol), heating at
50 °C for 16 h. Flash chromatography (4% EtOAc/petroleum ether) of
the crude material gave amine 3b (0.0823 g, 72%) as a yellow oil. The
data were consistent with the literature.35 1H NMR (400 MHz, CDCl3)
δ 7.45−7.39 (2H, m, ArH), 7.39−7.33 (2H, m, ArH), 7.39−7.33 (1H,
m, ArH), 6.75 (2H, d, J = 8.9 Hz, ArH), 6.52 (2H, d, J = 8.9 Hz, ArH),
4.46 (1H, q, J = 6.7 Hz, CH), 3.82 (1H, s, NH), 3.74 (3H, s, OCH3),
1.54 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
151.8 (C), 145.4 (C), 141.5 (C), 128.5 (2 × CH), 126.8 (CH), 125.8
(2 × CH), 114.7 (2 × CH), 114.5 (2 × CH), 55.7 (CH3), 54.2 (CH),
25.1 (CH3).
(2 × CH), 125.0 (CH), 83.2 (2 × C), 31.9 (CH2), 24.6 (4 × CH3), 21.0
(CH3), 10.0 (CH3). 11B NMR (128 MHz, CDCl3) δ 33.7.
( )-2-(5-Azido-2-phenylpentan-2-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (13).
The title compound was prepared according to General Procedure 1
using 1-phenylethyl diisopropylcarbamate33 (1.19 g, 4.77 mmol), s-
BuLi (1.3 M in cyclohexane, 4.2 mL, 5.4 mmol), and 2-(3-
bromopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane34 (0.700 g,
3.32 mmol). Flash chromatography (1% EtOAc/petroleum ether) of
the crude material gave boronic ester 13 (0.540 g, 52%) as a colorless oil.
1
IR 2977, 2932, 2092, 1350, 1312, 1145 cm−1. H NMR (400 MHz,
( )-4-Methyl-N-(1-phenylethyl)aniline (3c). The title compound
was prepared according to General Procedure 3 using boronic ester 1
(0.116 g, 0.499 mmol) and p-toluidine (0.216 g, 2.00 mmol), heating at
CDCl3) δ 7.33−7.28 (4H, m, ArH), 7.18−7.12 (1H, m, ArH), 3.25−
3.17 (2H, m, CH2N), 1.88−1.72 (2H, m, CH2CH2N), 1.55−1.42 (2H,
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Note
50 °C for 16 h. Flash chromatography (2% EtOAc/petroleum ether) of
the crude material gave amine 3c (0.0729 g, 69%) as a brown oil. The
data were consistent with the literature.35 1H NMR (400 MHz, CDCl3)
δ 7.41−7.34 (2H, m, ArH), 7.35−7.29 (2H, m, ArH), 7.25−7.18 (1H,
m, ArH), 6.91 (2H, d, J = 8.3 Hz, ArH), 6.45 (2H, d, J = 8.3 Hz, ArH),
4.47 (1H, q, J = 6.7 Hz, NCH), 3.92 (1H, s, NH), 2.20 (3H, s, CCH3),
1.51 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
145.4 (C), 145.0 (C), 129.6 (2 × CH), 128.6 (2 × CH), 126.8 (CH),
126.3 (C), 125.8 (2 × CH), 113.3 (2 × CH), 53.6 (CH), 25.1 (CH3),
20.3 (CH3).
( )-4-(Methylthio)-N-(1-phenylethyl)aniline (3d). The title com-
pound was prepared according to General Procedure 2 using boronic
ester 1 (0.115 g, 0.495 mmol) and 4-(methylthio)aniline (0.25 mL, 2.0
mmol), heating at 50 °C for 16 h. Flash chromatography (5% EtOAc/
petroleum ether) of the crude material gave amine 3d (0.0743 g, 62%)
as a brown oil. The data were consistent with the literature.36 1H NMR
(400 MHz, CDCl3) δ 7.28−7.20 (4H, m, ArH), 7.17−7.12 (1H, m,
ArH), 7.04 (2H, d, J = 8.7 Hz, ArH), 6.37 (2H, d, J = 8.7 Hz, ArH), 4.37
(1H, q, J = 6.7 Hz, NCH), 3.96 (1H, s, NH), 2.27 (3H, s, SCH3), 1.42
(3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
146.1 (C), 144.9 (C), 131.3 (2 × CH), 128.7 (2 × CH), 126.9 (CH),
125.8 (2 × CH), 124.0 (C), 113.8 (2 × CH), 53.5 (CH), 25.0 (CH3),
19.1 (CH3).
( )-4-Chloro-N-(1-phenylethyl)aniline (3e). The title compound
was prepared according to General Procedure 3 using boronic ester 1
(0.116 g, 0.501 mmol) and 4-chloroaniline (0.256 g, 2.01 mmol),
heating at 65 °C for 16 h. Flash chromatography (2% EtOAc/
petroleum ether) of the crude material gave amine 3e (0.0672g, 58%) as
a brown oil. The data were consistent with the literature.35 1H NMR
(400 MHz, CDCl3) δ 7.40−7.30 (4H, m, ArH), 7.27−7.21 (1H, m,
ArH), 7.10−7.01 (2H, m, ArH), 6.52−6.32 (2H, m, ArH), 4.45 (1H, q,
J = 6.7 Hz, NCH), 4.06 (1H, s, NH), 1.52 (2H, d, J = 6.7 Hz, CHCH3).
13C{1H} NMR (101 MHz, CDCl3) δ 145.8 (C), 144.7 (C), 128.9 (2 ×
CH), 128.8 (2 × CH), 127.0 (CH), 126.3 (2 × CH), 121.4 (C), 111.9
(2 × CH), 52.2 (CH), 24.9 (CH3).
( )-Methyl 4-(1-Phenylethylamino)benzoate (3h). The title
compound was prepared according to General Procedure 2 using
boronic ester 1 (0.117 g, 0.503 mmol) and 4-methoxycarbonylaniline
(0.302 g, 2.01 mmol), heating at 65 °C for 48 h. Flash chromatography
(10% EtOAc/petroleum ether) of the crude material gave amine 3h
(0.0648 g, 53%) as a white solid. The data were consistent with the
literature.38 m.p. 101−103 °C (petroleum ether); no literature value
available. 1H NMR (400 MHz, CDCl3) δ 7.79 (2H, d, J = 8.8 Hz, ArH),
7.35−7.33 (4H, m, ArH), 7.27−7.22 (1H, m, ArH), 6.48 (2H, d, J = 8.8
Hz, ArH), 4.57 (1H, q, J = 6.6, NCH), 4.48 (1H, s, NH), 4.48 (1H, s,
OCH3), 1.56 (3H, d, J = 6.6 Hz, CHCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 167.2 (C), 150.9 (C), 144.1 (C), 131.4 (2 × CH), 128.8 (2 ×
CH), 127.1 (CH), 125.7 (2 × CH), 118.3 (C), 112.1 (2 × CH), 53.0
(CH), 51.5 (CH3), 24.7 (CH3).
( )-N-(1-Phenylethyl)-4-(trifluoromethyl)aniline (3i). The title
compound was prepared according to General Procedure 3 using
boronic ester 1 (0.116 g, 0.501 mmol) and 4-trifluoromethylaniline
(0.25 mL, 2.0 mmol), heating at 65 °C for 48 h. Flash chromatography
(2% EtOAc/petroleum ether) of the crude material gave amine 3i
(0.0479 g, 36%) as a colorless oil. The data were consistent with the
literature.39 1H NMR (400 MHz, CDCl3) δ 7.39−7.34 (6H, m, ArH),
7.32−7.27 (1H, m, ArH), 6.57−6.53 (2H, m, ArH), 4.55 (1H, q, J = 6.7
Hz, NCH), 4.42 (1H, s, NH), 1.58 (3H, d, J = 6.7 Hz, CHCH3).
13C{1H} NMR (101 MHz, CDCl3) δ 149.6 (C), 144.2 (C), 128.8 (2 ×
CH), 127.2 (CH), 126.4 (2 × CH, q, JF = 3.8 Hz), 125.7 (2 × CH),
125.0 (C, q, JF = 270.4 Hz), 118.6 (C, q, JF = 32.5 Hz), 112.4 (2 × CH),
53.2 (CH), 24.8 (CH3). 19F NMR (377 MHz, CDCl3) δ −61.1.
( )-N-(1-Phenylethyl)-4-(prop-2-en-1-yloxy)aniline (3j). The title
compound was prepared according to General Procedure 2 using
boronic ester 1 (0.116 g, 0.500 mmol) and 4-[(prop-2-en-1-
yl)oxy]aniline (0.299 g, 2.00 mmol), heating at 50 °C for 48 h. Flash
chromatography (6% EtOAc/petroleum ether) of the crude material
gave amine 3j (0.0863 g, 68%) as a yellow oil. IR 3404, 3025, 2866,
1508, 1229 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.40−7.36 (2H, m,
ArH), 7.36−7.30 (2H, m, ArH), 7.26−7.21 (1H, m, ArH), 6.72 (2H, d,
J = 8.9 Hz, ArH), 6.47 (2H, d, J = 8.9 Hz, ArH), 6.03 (1H, ddt, J = 17.2,
10.6, 5.4 Hz, CHCH2), 5.37 (1H, dd, J = 17.2, 1.5 Hz, CH
CHAHB), 5.24 (1H, dd, J = 10.6, 1.5 Hz, CHCHAHB), 4.46−4.39
(3H, m, NCH, OCH2), 3.80 (1H, s, NH), 1.51 (3H, d, J = 6.7 Hz,
CH3). 13C{1H} NMR (101 MHz, CDCl3) δ 150.8 (C), 145.4 (C),
141.7 (C), 133.9 (CH), 128.6 (2 × CH), 126.8 (CH), 125.9 (2 × CH),
117.3 (CH2), 115.8 (2 × CH), 114.4 (2 × CH), 69.6 (CH2), 54.2
(CH), 25.1 (CH3). HRMS (Q-TOF) m/z: [M + H]+ Calcd for
C17H20NO+ 254.1545; found 254.1539.
( )-3-Bromo-N-(1-phenylethyl)aniline (3k). The title compound
was prepared according to General Procedure 3 using boronic ester 1
(0.116 g, 0.501 mmol) and 3-bromoaniline (0.344 g, 2.00 mmol),
heating at 65 °C for 16 h. Flash chromatography (2% EtOAc/
petroleum ether) of the crude material gave amine 3k (0.0613 g, 44%)
as a brown oil. The data were consistent with the literature.40 1H NMR
(400 MHz, CDCl3) δ 7.38−7.31 (4H, m, ArH), 7.29−7.23 (1H, m,
ArH), 6.96−6.90 (1H, m, ArH), 6.78−6.74 (1H, m, ArH), 6.70−6.67
(1H, m, ArH), 6.44−6.37 (1H, m, ArH), 4.47 (1H, q, J = 6.6 Hz, CH),
4.10 (1H, s, NH), 1.53 (3H, d, J = 6.6 Hz, CHCH3). 13C{1H} NMR
(101 MHz, CDCl3) δ 148.4 (C), 144.4 (C), 130.4 (CH), 128.7 (2 ×
CH), 127.1 (CH), 125.7 (2 × CH), 123.0 (C), 120.0 (CH), 116.0
(CH), 111.8 (CH), 53.3 (CH), 24.8 (CH3).
( )-3-Methoxy-N-(1-phenylethyl)aniline (3l). The title compound
was prepared according to General Procedure 3 using boronic ester 1
(0.120 g, 0.519 mmol) and m-methoxyaniline (0.251 g, 2.04 mmol),
heating at 50 °C for 48 h. Flash chromatography (5% EtOAc/
petroleum ether) of the crude material gave amine 3l (0.0552 g, 47%) as
a yellow oil. The data were consistent with the literature.41 1H NMR
(400 MHz, CDCl3) δ 7.39−7.31 (4H, m, ArH), 7.24 (1H, t, J = 7.1 Hz,
ArH), 7.01 (1H, t, J = 8.1 Hz, ArH), 6.23 (1H, dd, J = 8.1, 2.1 Hz, ArH),
6.16 (1H, dd, J = 8.1, 1.8 Hz, ArH), 6.08 (1H, dd, J = 2.1, 1.8 Hz, ArH),
4.49 (1H, q, J = 6.7 Hz, CH), 4.11 (1H, s, NH), 3.70 (3H, s, OCH3),
1.53 (3H, d, J = 6.7 Hz, CH3). 13C{1H} NMR (101 MHz, CDCl3) δ
CH), 128.7 (2 × CH), 127.0 (CH), 125.8 (2 × CH), 121.8 (C), 114.4
(2 × CH), 53.6 (CH), 25.0 (CH3).
( )-α-Methyl-N-[4-(trifluoromethoxy)phenyl]-benzenemethan-
amine (3f). The title compound was prepared according to General
Procedure 2 using boronic ester 1 (0.116 g, 0.499 mmol) and 4-
(trifluoromethoxy)aniline (0.27 mL, 2.01 mmol), heating at 65 °C for
48 h. Flash chromatography (2% EtOAc/petroleum ether) of the crude
material gave amine 3f (0.0853g, 61%) as a yellow oil. IR 3420, 2968,
1613, 1512, 1248, 1153 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.38−
7.31 (4H, m, ArH), 7.27−7.24 (1H, m, ArH), 6.95 (2H, d, J = 8.9 Hz,
ArH), 6.46 (2H, d, J = 8.9 Hz, ArH), 4.45 (1H, q, J = 6.9 Hz, NCH),
4.10 (1H, s, NH), 1.53 (3H, d, J = 6.9 Hz, CH3). 13C{1H} NMR (101
MHz, CDCl3) δ 146.0 (C), 144.7 (C), 140.3 (C, q, JF = 1.9 Hz), 128.7
(2 × CH), 127.1 (CH), 125.7 (2 × CH), 122.2 (2 × CH), 120.64
(OCF3, q, JF = 255.2 Hz), 113.4 (2 × CH), 53.7 (CH), 25.0 (CH3). 19F
NMR (377 MHz, CDCl3) δ −58.5. HRMS (Q-TOF) m/z: [M + H]+
Calcd for C15H15F3NO+ 282.1106; found 282.1095.
( )-4-(1-Phenylethylamino)benzamide (3g). The title compound
was prepared according to a modification of General Procedure 3 using
boronic ester 1 (0.117 g, 0.502 mmol) and 4-aminobenzamide (0.272 g,
2.01 mmol), heating at 65 °C for 36 h. The mixture was cooled to room
temperature, Et2O (5 mL) was added, and the mixture was passed
through a plug of Celite. Flash chromatography (3% MeOH/DCM) of
the crude material gave a mixture of amine 3g and pinacol (1:0.3,
0.0623 g). THF (1 mL), H2O (1 mL), and sodium periodate (0.060 g,
0.281 mmol) were added, and the mixture was stirred at RT for 16 h.
The mixture was diluted with H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography (3% MeOH/
DCM) of the crude material gave amine 3g (0.0526 g, 44%) as an off-
white solid. The data were consistent with the literature.37 m.p 153−
155 °C (CH2Cl2). No literature value. 1H NMR (400 MHz, DMSO) δ
7.53 (2H, d, J = 8.6 Hz, ArH), 7.46 (1H, s, NH), 7.39−7.33 (2H, m,
ArH), 7.33−7.25 (2H, m, ArH), 7.22−7.14 (1H, m, ArH), 6.81 (1H, s,
NH), 6.72−6.66 (1H, m, NH), 6.47 (2H, d, J = 8.6 Hz, ArH), 4.54 (1H,
q, J = 6.8 Hz, NCH), 1.42 (3H, d, J = 6.8 Hz, CH3). 13C{1H} NMR
(101 MHz, DMSO) δ 168.4 (C), 150.8 (C), 146.1 (C), 129.3 (2 ×
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Note
160.6 (C), 148.6 (C), 145.1 (C), 129.8 (CH), 128.6 (2 × CH), 126.9
(CH), 125.8 (2 × CH), 106.4 (CH), 102.4 (CH), 99.3 (CH), 54.9
(CH3), 53.5 (CH), 24.9 (CH3).
(101 MHz, CDCl3) δ 165.5 (C), 155.4 (C), 144.9 (C), 132.0 (CH),
128.7 (2 × CH), 127.1 (CH), 125.7 (2 × CH), 117.2 (CH), 98.9 (C),
54.8 (CH3), 51.1 (CH), 24.9 (CH3). HRMS (Q-TOF) m/z: [M + H]+
Calcd for C14H16NO2S+ 262.0896; found 262.0905.
( )-2-Methoxy-N-(1-phenylethyl)aniline (3m). The title com-
pound was prepared according to General Procedure 3 using boronic
ester 1 (0.116 g, 0.499 mmol) and o-methoxyaniline (0.23 mL, 2.0
mmol), heating at 50 °C for 16 h. Flash chromatography (4% EtOAc/
petroleum ether) of the crude material gave amine 3m (0.0801 g, 71%)
as a colorless oil. The data were consistent with the literature.42 1H
NMR (400 MHz, CDCl3) δ 7.41−7.37 (2H, m, ArH), 7.36−7.30 (2H,
m, ArH), 7.26−7.21 (1H, m, ArH), 6.81−6.76 (1H, m, ArH), 6.75−
6.69 (1H, m, ArH), 6.66−6.59 (1H, m, ArH), 6.39−6.33 (1H, m, ArH),
4.65 (1H, s, NH), 4.50 (1H, q, J = 6.6 Hz, CH), 3.91 (3H, s, OCH3),
1.57 (3H, d, J = 6.6 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
146.5 (C), 145.4 (C), 137.2 (C), 128.6 (2 × CH), 126.7 (CH), 125.8
(2 × CH), 121.1 (CH), 116.3 (CH), 111.0 (CH), 109.2 (CH), 55.4
(CH3), 53.3 (CH), 25.2 (CH3).
( )-N-Methyl-N-(1-phenylethyl)aniline (3r). The title compound
was prepared according to General Procedure 2 using boronic ester 1
(0.116 g, 0.501 mmol) and N-methylaniline (0.22 mL, 2.0 mmol),
heating at 65 °C for 16 h. Flash chromatography (2% EtOAc/
petroleum ether) of the crude material gave amine 3r (0.0877 g, 83%)
as a yellow oil. The data were consistent with the literature.44 1H NMR
(400 MHz, CDCl3) δ 7.40−7.35 (4H, m, ArH), 7.33−7.27 (3H, m,
ArH), 6.92−6.87 (2H, m, ArH), 6.81−6.75 (1H, m, ArH), 5.18 (1H, q,
J = 6.9 Hz, CH), 2.73 (3H, s, NCH3), 1.60 (3H, d, J = 6.9 Hz, CHCH3).
13C{1H} NMR (101 MHz, CDCl3) δ 150.2 (C), 142.8 (C), 129.2 (2 ×
CH), 128.4 (2 × CH), 126.9 (2 × CH), 126.8 (CH), 116.6 (CH),
113.0 (2 × CH), 56.5 (CH), 31.8 (CH3), 16.3 (CH3).
( )-N-(1-Phenylethyl)-N-(propan-2-yl)aniline (3s). The title com-
pound was prepared according to General Procedure 3 using boronic
ester 1 (0.116 g, 0.498 mmol) and N-isopropylaniline (0.29 mL, 2.0
mmol), heating at 65 °C for 48 h. Flash chromatography (100%
pentane) of the crude material gave amine 3s (0.0525 g, 44%) as a
( )-4-Bromo-2-methoxy-N-(1-phenylethyl)aniline (3n). The title
compound was prepared according to General Procedure 3 using
boronic ester 1 (0.119 g, 0.514 mmol) and 4-bromo-2-methoxyaniline
(0.409 g, 2.02 mmol), heating at 50 °C for 16 h. Flash chromatography
(2% EtOAc/petroleum ether) of the crude material gave amine 3n
(0.0843 g, 54%) as a light brown solid. m.p. 95−97 °C (petroleum
1
colorless oil. IR 2670, 2931, 1595, 1500, 1263 cm−1. H NMR (400
MHz, CDCl3) δ 7.47−7.40 (2H, m, ArH), 7.38−7.30 (2H, m, ArH),
7.26−7.21 (1H, m, ArH), 7.20−7.11 (2H, m, ArH), 6.85−6.74 (3H, m,
ArH), 4.79 (1H, q, J = 6.9 Hz, NCHAr), 3.89 (1H, sept, J = 6.7 Hz, CH
(CH3)2), 1.53 (3H, d, J = 6.9 Hz, NCHCH3), 1.20 (3H, d, J = 6.7 Hz,
CH(CH3CH3)), 1.16 (3H, d, J = 6.7 Hz, CH(CH3CH3)). 13C{1H}
NMR (101 MHz, CDCl3) δ 147.0 (C), 144.9 (C), 128.3 (2 × CH),
128.3 (2 × CH), 126.8 (CH), 126.3 (2 × CH), 119.5 (2 × CH), 118.4
(CH), 54.1 (CH), 48.7 (CH), 20.4 (CH3), 20.3 (CH3), 19.4 (CH3).
HRMS (Q-TOF) m/z: [M + H]+ Calcd for C17H22N+ 240.1752; found
240.1747.
1
ether). IR 3425, 2963, 2933, 1590, 1506, 1223 cm−1. H NMR (400
MHz, CDCl3) δ 7.36−7.29 (4H, m, ArH), 7.26−7.20 (1H, m, ArH),
6.85 (1H, d, J = 2.1 Hz, ArH), 6.79 (1H, dd, J = 8.4, 2.1 Hz, ArH), 6.17
(1H, d, J = 8.4 Hz, ArH), 4.60 (1H, s, NH), 4.49−4.39 (1H, m, CH),
3.88 (3H, s, OCH3), 1.55 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR
(101 MHz, CDCl3) δ 147.1 (C), 144.8 (C), 136.2 (C), 128.6 (2 ×
CH), 126.9 (CH), 125.7 (2 × CH), 123.6 (CH), 112.6 (CH), 111.8
(CH), 107.7 (C), 55.7 (CH3), 53.2 (CH), 25.1 (CH3). HRMS (Q-
TOF) m/z: [M + H]+ Calcd for C15H1879BrNO+ 306.0494; found
306.0488.
( )-1-(1-Phenylethyl)-1,2,3,4-tetrahydroquinoline (3t). The title
compound was prepared according to General Procedure 3 using
boronic ester 1 (0.116 g, 0.499 mmol) and 1,2,3,4-tetrahydroquinoline
(0.266 mg, 2.00 mmol), heating at 65 °C for 16 h. Flash
chromatography (2% EtOAc/petroleum ether) of the crude material
gave amine 3t (0.0789 g, 67%) as a clear oil. The data were consistent
with the literature.45 1H NMR (400 MHz, CDCl3) δ 7.40−7.33 (4H, m,
ArH), 7.29−7.24 (1H, m, ArH), 7.08−7.03 (1H, m, ArH), 7.03−6.98
(1H, m, ArH), 6.75−6.69 (1H, m, ArH), 6.63−6.57 (1H, m, ArH), 5.16
(1H, q, J = 6.9 Hz, NCH), 3.21−3.14 (1H, m, NCHACHB), 3.10−3.02
(1H, m, NCHACHB), 2.86−2.74 (2H, m, ArCH2), 1.94−1.85 (2H, m,
NCH2CH2), 1.61 (3H, d, J = 6.9 Hz, CH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 145.6 (C), 142.7 (C), 129.2 (CH), 128.4 (2 × CH), 127.1
(CH), 126.9 (2 × CH), 126.7 (CH), 122.8 (C), 115.4 (CH), 110.6
(CH), 54.6 (CH), 42.5 (CH2), 28.5 (CH2), 22.2 (CH2), 16.0 (CH3).
( )-4-Methoxy-N,N-bis(1-phenylethyl)aniline (3u). The title com-
pound was prepared according to General Procedure 2 using boronic
ester 1 (0.0603 g, 0.260 mmol) and ( )-4-methoxy-N-(1-phenylethyl)-
aniline (3b) (0.226 g, 1.00 mmol), heating at 50 °C for 48 h. Flash
chromatography (5% EtOAc/petroleum ether) of the crude material
(d.r. 1:1) gave amine 3u (0.0016 g, 18%, isolated d.r = 1.8:1 A:B) as a
yellow oil, and amine 3b was recovered (182.8 mg, 80%). Upon further
purification, diastereomer B was isolated as a single diastereomer. IR
3028, 2971, 1507, 1243, 1036, 699 cm−1. 1H NMR (diastereomer A)
(400 MHz, CDCl3) 7.33−7.29 (4H, m, ArH), 7.25−7.19 (6H, m,
ArH), 6.73−6.71 (4H, m, ArH), 4.26 (2H, q, J = 6.8 Hz, 2 × CH), 3.80
(3H, s, OCH3), 1.18 (6H, d, J = 6.8 Hz, 2 × CH3). 1H NMR
(diastereomer B) (400 MHz, CDCl3) δ 7.30−7.29 (8H, m, ArH),
7.24−7.20 (2H, m, ArH), 6.71 (2H, d, J = 9.0 Hz, ArH), 6.65 (2H, d, J =
9.0 Hz, ArH), 4.45 (2H, q, J = 6.7 Hz, 2 × CH), 3.74 (3H, s, CH3), 1.27
(6H, d, J = 6.7 Hz, 2 × CH3). 13C{1H} NMR (mixed diastereomer A
+B) (101 MHz, CDCl3) δ 156.4 (C), 155.5 (C), 145.0 (2 × C), 143.7
(2 × C), 138.9 (C), 138.0 (C), 130.8 (CH), 128.7 (2 × CH), 128.0 (4
× CH), 128.0 (2 × CH), 127.9 (4 × CH), 127.8 (2 × CH), 126.7
(CH), 126.6 (CH), 112.8 (2 × CH), 112.5 (2 × CH), 58.3 (CH), 57.9
(CH), 55.2 (CH3), 22.0 (CH3), 18.2 (CH3). HRMS (Q-TOF) m/z:
[M + H]+ Calcd for C23H25NO+ 332.2009; found 332.2007.
( )-N-(1-Phenylethyl)-2,6-dimethylbenzenamine (3o). The title
compound was prepared according to General Procedure 3 using
boronic ester 1 (0.116 g, 0.501 mmol) and 2,6-dimethylaniline (0.25
mL, 2.0 mmol), heating at 65 °C for 48 h. Flash chromatography (2%
EtOAc/petroleum ether) of the crude material gave amine 3o (0.0339
g, 30%) as a red oil. The data were consistent with the literature.43 1H
NMR (400 MHz, CDCl3) δ 7.33−7.28 (4H, m, ArH), 7.26−7.21 (1H,
m, ArH), 6.96 (2H, d, J = 7.4 Hz, ArH), 6.79 (1H, t, J = 7.4 Hz, ArH),
4.33 (1H, q, J = 6.7 Hz, NCH), 3.21 (1H, s, NH), 2.28 (6H, s, 2 ×
CCH3), 1.52 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 145.3 (C), 144.9 (C), 129.4 (C), 128.8 (2 × CH), 128.4 (2 ×
CH), 126.9 (CH), 126.1 (2 × CH), 121.5 (CH), 56.7 (CH3), 22.6
(CH), 18.9 (2 × CH3).
( )-1-Methyl-N-(1-phenylethyl)-1H-pyrazol-5-amine (3p). The
title compound was prepared according to General Procedure 2 using
boronic ester 1 (0.116 g, 0.499 mmol) and 1H-pyrazol-5-amine (0.194
g, 2.01 mmol), heating at 65 °C for 16 h. Flash chromatography (1:1 →
2:1 EtOAc/petroleum ether) of the crude material gave amine 3p
(0.0589 g, 59%) as a colorless oil. IR 3293, 2967, 2926, 1550, 1501
cm−1. 1H NMR (400 MHz, CDCl3) δ 7.42−7.37 (2H, m, ArH), 7.35−
7.30 (2H, m, ArH), 7.26−7.20 (1H, m, ArH), 7.00 (1H, d, J = 2.3 Hz,
ArH), 5.29 (1H, d, J = 2.3 Hz, ArH), 4.46 (1H, q, J = 6.7 Hz, NCH),
4.07 (1H, s, NH), 3.68 (3H, s, NCH3), 1.50 (3H, d, J = 6.7 Hz,
CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 156.6 (C), 145.6 (C),
130.8 (CH), 128.4 (2 × CH), 126.8 (CH), 126.0 (2 × CH), 91.3 (CH),
54.7 (CH), 38.4 (CH3), 24.5 (CH3). HRMS (Q-TOF) m/z: [M + H]+
Calcd for C12H16N3+ 202.1344; found 202.1339.
( )-Methyl 3-[(1-Phenylethyl)amino]thiophene-2-carboxylate
(3q). The title compound was prepared according to General Procedure
3 using boronic ester 1 (0.117 g, 0.504 mmol) and methyl 3-amino-2-
thiophenecarboxylate (0.316 g, 2.01 mmol), heating at 65 °C for 48 h.
Flash chromatography (6% EtOAc/petroleum ether) of the crude
material gave amine 3q (0.0595 g, 45%) as a yellow oil. IR 3364, 2950,
1
1663, 1566, 1246 cm−1. H NMR (400 MHz, CDCl3) δ 7.34−7.32
(4H, m, ArH), 7.25−7.23 (1H, m, ArH), 7.19−7.18 (1H, d, J = 5.4 Hz,
ArH), 6.36 (1H, d, J = 5.4 Hz, ArH), 4.60 (1H, p, J = 6.8 Hz, NHCH),
3.86 (3H, s, OCH3), 1.58 (3H, d, J = 6.8 Hz, CHCH3). 13C{1H} NMR
9890
https://doi.org/10.1021/acs.joc.1c00976
J. Org. Chem. 2021, 86, 9883−9897

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
( )-4-(1-Phenylethyl)-morpholine (3v). The title compound was
prepared according to General Procedure 2 using boronic ester 1 (0.116
g, 0.502 mmol) and morpholine (0.18 mL, 2.0 mmol), heating at 65 °C
for 48 h. Flash chromatography (5−10% EtOAc/petroleum ether) of
the crude material gave amine 3v (0.0301 g, 31%) as a yellow oil. The
data were consistent with the literature.46 1H NMR (400 MHz, CDCl3)
δ 7.34−7.29 (4H, m, ArH), 7.26−7.21 (1H, m, ArH), 3.73−3.66 (4H,
m, 2 × OCH2), 3.31 (1H, q, J = 6.6 Hz, NCH), 2.56−2.44 (2H, m, 2 ×
NCHAHB), 2.41−2.34 (2H, m, 2 × NCHAHB), 1.36 (3H, d, J = 6.6 Hz,
CH3). 13C{1H} NMR (101 MHz, CDCl3) δ 143.9 (C), 128.3 (2 ×
CH), 127.6 (2 × CH), 127.0 (CH), 67.2 (2 × CH2), 65.4 (H), 51.3 (2
× CH2), 19.8 (CH3).
( )-4-Methoxy-N-(1-(4-methoxyphenyl)ethyl)aniline (9a). The
title compound was prepared according to General Procedure 2 using
boronic ester 8a (0.143 g, 0.507 mmol) and p-anisidine (0.249 g, 2.02
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9a (0.0899 g, 69%)
as a yellow oil. The data were consistent with the literature.35 1H NMR
(400 MHz, CDCl3) δ 7.29 (2H, d, J = 8.7 Hz, ArH), 6.87 (2H, d, J = 8.7
Hz, ArH), 6.71 (2H, d, J = 8.9 Hz, ArH), 6.49 (2H, d, J = 8.9 Hz, ArH),
4.39 (1H, q, J = 6.7 Hz, CH), 3.80 (3H, s, OCH3), 3.71 (3H, s, OCH3),
1.48 (3H, d, J = 6.7 Hz, CH3). 13C{1H} NMR (101 MHz, CDCl3) δ
158.4 (C), 151.8 (C), 141.6 (C), 137.5 (C), 126.9 (2 × CH), 114.7 (2
× CH), 114.6 (2 × CH), 113.9 (2 × CH), 55.7 (CH3), 55.2 (CH3),
53.6 (CH), 25.1 (CH3).
( )-4-Methoxy-N-(1-p-tolylethyl)aniline (9b). The title compound
was prepared according to General Procedure 2 using boronic ester 8b
(0.123 g, 0.500 mmol) and p-anisidine (0.246 g, 2.00 mmol), heating at
50 °C for 16 h. Flash chromatography (6% EtOAc/petroleum ether) of
the crude material gave amine 9b (0.0853 g, 71%) as an orange oil. The
data were consistent with the literature.35 1H NMR (400 MHz, CDCl3)
δ 7.26 (2H, d, J = 7.9 Hz, ArH), 7.14 (2H, d, J = 7.9 Hz, ArH), 6.70 (2H,
d, J = 8.9 Hz, ArH), 6.49 (2H, d, J = 8.9 Hz, ArH), 4.40 (1H, q, J = 6.7
Hz, NCH), 3.75 (1H, br. s, NH), 3.71 (3H, s, OCH3), 2.33 (3H, s,
CCH3), 1.49 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 151.8 (C), 142.4 (C), 141.6 (C), 136.3 (C), 129.3 (2 × CH),
125.8 (2 × CH), 114.7 (2 × CH), 114.5 (2 × CH), 55.7 (CH3), 53.9
(CH), 25.2 (CH3), 21.1 (CH3).
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9e (0.0729 g, 56%)
as an orange oil. The data were consistent with the literature.48 1H
NMR (400 MHz, CDCl3) δ 7.33−7.27 (4H, m, ArH), 6.70 (2H, d, J =
8.9 Hz, ArH), 6.44 (2H, d, J = 8.9 Hz, ArH), 4.39 (1H, q, J = 6.7 Hz,
NCH), 3.70 (3H, s, OCH3), 1.48 (3H, d, J = 6.7 Hz, CHCH3).
13C{1H} NMR (101 MHz, CDCl3) δ 152.1 (C), 144.1 (C), 141.3 (C),
132.4 (C), 128.8 (2 × CH), 127.3 (2 × CH), 114.8 (2 × CH), 114.6 (2
× CH), 55.7 (CH3), 53.8 (CH), 25.1 (CH3).
( )-4-Methoxy-N-(1-(4-(trifluoromethyl)phenyl)ethyl)aniline (9f).
The title compound was prepared according to General Procedure 2
using boronic ester 8f (0.148 g, 0.493 mmol) and p-anisidine (0.249 g,
2.02 mmol), heating at 65 °C for 48 h. Flash chromatography (6%
EtOAc/petroleum ether) of the crude material gave amine 9f (0.0609 g,
42%) as a yellow oil. The data were consistent with the literature.35 1H
NMR (400 MHz, CDCl3) δ 7.58 (2H, d, J = 8.2 Hz, ArH), 7.49 (d, J =
8.2 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 6.43 (d, J = 8.9 Hz, 2H), 4.46 (q, J
= 6.8 Hz, 1H), 3.70 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 152.2 (C), 149.8 (C), 141.0 9 (C), 129.1 (C, q, JF
= 32.3 Hz), 126.2 (2 × CH), 125.6 (2 × CH q, JF = 3.7 Hz), 124.2 (C, q,
JF = 270.4 Hz), 114.8 (2 × CH), 114.5 (2 × CH), 55.7 (CH3), 54.0
(CH), 25.1 (CH3). 19F NMR (377 MHz, CDCl3) δ −62.4.
( )-N-[1-(3-Chlorophenyl)ethyl]-4-methoxyaniline (9g). The title
compound was prepared according to General Procedure 2 using
boronic ester 8g (0.133 g, 0.497 mmol) and p-anisidine (0.247 g, 2.00
mmol), heating at 65 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9g (0.0792 g, 61%)
as an orange oil. The data were consistent with the literature.48 1H
NMR (400 MHz, CDCl3) δ 7.38 (1H, s, ArH), 7.27−7.24 (2H, m,
ArH), 7.24−7.19 (1H, m, ArH), 6.71 (2H, d, J = 8.8 Hz, ArH), 6.46
(2H, d, J = 8.8 Hz, ArH), 4.38 (1H, q, J = 6.7 Hz, CH), 3.77 (1H, s,
NH), 3.71 (3H, s, OCH3), 1.49 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.1 (C), 147.9 (C), 141.2 (C), 134.5
(C), 129.9 (CH), 127.0 (CH), 126.1 (CH), 124.1 (CH), 114.8 (2 ×
CH), 114.5 (2 × CH), 55.7 (CH3), 54.0 (CH), 25.1 (CH3).
( )-N-[1-(3-Bromophenyl)ethyl]-4-methoxyaniline (9h). The title
compound was prepared according to General Procedure 2 using
boronic ester 8h (0.153 g, 0.490 mmol) and p-anisidine (0.252 g, 2.04
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9h (0.0738 g, 49%)
as a brown oil. The data were consistent with the literature.49 1H NMR
(400 MHz, CDCl3) δ 7.53 (1H, s, ArH), 7.36 (1H, d, J = 7.7 Hz, ArH),
7.30 (1H, d, J = 7.7 Hz, ArH), 7.19 (t, J = 7.7 Hz, ArH), 6.71 (2H, d, J =
8.9 Hz, ArH), 6.45 (2H, d, J = 8.9 Hz, ArH), 4.37 (1H, q, J = 6.7 Hz,
CH), 3.79 (1H, s, NH), 3.71 (3H, s, OCH3), 1.49 (3H, d, J = 6.7 Hz,
CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 152.1 (C), 148.2 (C),
141.1 (C), 130.2 (CH), 130.0 (CH), 129.0 (CH), 124.5 (CH), 122.8
(C), 114.8 (2 × CH), 114.5 (2 × CH), 55.7 (CH3), 54.0 (CH), 25.2
(CH3).
( )-4-Methoxy-N-(1-(3-methoxyphenyl)ethyl)aniline (9i). The
title compound was prepared according to General Procedure 2 using
boronic ester 8i (0.129 g, 0.493 mmol) and p-anisidine (0.246 g, 2.03
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9i (0.0998 g, 79%) as
a yellow oil. The data were consistent with the literature.42 1H NMR
(400 MHz, CDCl3) δ 7.27−7.22 (1H, m, ArH), 7.00−6.96 (1H, m,
ArH), 6.94 (1H, s, ArH), 6.80−6.75 (1H, m, ArH), 6.71 (2H, d, J = 8.8
Hz, ArH), 6.49 (2H, d, J = 8.8 Hz, ArH), 4.39 (1H, q, J = 6.7 Hz, NCH),
3.80 (3H, s, CCHCOCH3), 3.71 (3H, s, CHCHCOCH3), 1.50 (3H, d,
J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 159.9 (C),
151.8 (C), 147.4 (C), 141.5 (C), 129.6 (CH), 118.2 (CH), 114.7 (2 ×
CH), 114.5 (2 × CH), 111.9 (CH), 111.6 (CH), 55.7 (CH3), 55.1
(CH3), 54.3 (CH), 25.1 (CH3).
( )-4-Methoxy-N-(1-o-tolylethyl)aniline (9j). The title compound
was prepared according to General Procedure 2 using boronic ester 8j
(0.120 g, 0.487 mmol) and p-anisidine (0.251 g, 2.04 mmol), heating at
50 °C for 16 h. Flash chromatography (6% EtOAc/petroleum ether) of
the crude material gave amine 9j (0.0809 g, 69%) as a brown oil. The
data were consistent with the literature.50 1H NMR (400 MHz, CDCl3)
δ 7.46−7.40 (1H, m, ArH), 7.20−7.10 (3H, m, ArH), 6.70 (2H, d, J =
( )-N-(1-(Biphenyl-4-yl)ethyl)-4-methoxyaniline (9c). The title
compound was prepared according to General Procedure 2 using
boronic ester 8c (0.156 g, 0.507 mmol) and p-anisidine (0.247 g, 2.01
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9c (0.0975 g, 63%)
as an orange solid. The data were consistent with the literature.47 m.p.
1
85−86 °C (petroleum ether); no literature value available. H NMR
(400 MHz, CDCl3) δ 7.64−7.50 (4H, m, ArH), 7.48−7.38 (4H, m,
ArH), 7.37−7.31 (1H, m, ArH), 6.72 (2H, d, J = 8.9 Hz, ArH), 6.51
(2H, d, J = 8.9 Hz, ArH), 4.47 (1H, q, J = 6.7 Hz, NCH), 3.79 (1H, s,
NH), 3.71 (3H, s, OCH3), 1.55 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.0 (C), 144.6 (C), 141.6 (C), 141.0
(C), 139.7 (C), 128.7 (2 × CH), 127.4 (2 × CH), 127.1 (CH), 127.0 (2
× CH), 126.3 (2 × CH), 114.8 (2 × CH), 114.6 (2 × CH), 55.7 (CH3),
54.0 (CH), 25.1 (CH3).
( )-N-(1-(4-Fluorophenyl)ethyl)-4-methoxyaniline (9d). The title
compound was prepared according to General Procedure 2 using
boronic ester 8d (0.122 g, 0.488 mmol) and p-anisidine (0.246 g, 2.00
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9d (0.0839 g, 70%)
as an orange oil. The data were consistent with the literature.35 1H
NMR (400 MHz, CDCl3) δ 7.36−7.30 (2H, m, ArH), 7.04−6.97 (2H,
m, ArH), 6.70 (2H, d, J = 8.7 Hz, ArH), 6.45 (2H, d, J = 8.7 Hz, ArH),
4.40 (1H, q, J = 6.7 Hz, CH), 3.77 (1H, s, NH), 3.71 (3H, s, OCH3),
1.48 (3H, d, J = 6.7 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
161.7 (C, d, JF = 244.1 Hz), 151.9 (C), 141.1 (C, d, JF = 3.0 Hz), 127.3
(2 × CH, d, JF = 8.0 Hz), 115.4 (2 × CH, JF = 21.3 Hz), 114.7 (2 × CH),
114.5 (2 × CH), 55.7 (CH3), 53.6 (CH), 25.3 (CH3). 19F NMR (377
MHz, CDCl3) δ −116.3.
( )-4-Methoxy-N-(1-4-chlorophenylethyl)aniline (9e). The title
compound was prepared according to General Procedure 2 using
boronic ester 8e (0.133 g, 0.499 mmol) and p-anisidine (0.246 g, 2.00
9891
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Note
8.9 Hz, ArH), 6.42 (2H, d, J = 8.9 Hz, ArH), 4.62 (1H, q, J = 6.6 Hz,
NCH), 3.77 (1H, s, NH), 3.70 (3H, s, OCH3), 2.44 (3H, s, CCH3),
1.47 (3H, d, J = 6.6 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
151.8 (C), 143.0 (C), 141.6 (C), 134.6 (C), 130.6 (CH), 126.6 (CH),
126.5 (CH), 124.6 (CH), 114.8 (2 × CH), 114.1 (2 × CH), 55.7
(CH3), 50.4 (CH), 23.1 (CH3), 19.0 (CH3).
(CH2), 25.8 (CH2). HRMS (Q-TOF) m/z: [M + H]+ Calcd for
C17H21N4O+ 297.1715; found 297.1717.
( )-(1-{4-[(4-Methoxyphenyl)amino]-4-phenylbutyl}-1H-1,2,3-
triazol-4-yl)methanol (9o). The title compound was prepared
according to a modification of General Procedure 2 using boronic
ester 8o (0.0899 g, 0.252 mmol), p-anisidine (0.124 g, 1.00 mmol),
Cu(OAc)2 (0.0910 g, 0.501 mmol), Cs2CO3 (0.0410 g, 0.126 mmol),
methanol (0.5 mL), and pyridine (0.17 mL). The mixture was stirred at
65 °C for 48 h. Flash chromatography (2%−5% EtOAc/petroleum
ether) of the crude material gave amine 9o (0.0457 g, 52%) as an off
white solid. m.p. 135−136 °C (CHCl3). IR 3333, 3207, 2928, 2858,
1737, 1513, 1234 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, s,
ArH), 7.35−7.28 (4H, m, ArH), 7.26−7.20 (1H, m, ArH), 6.68 (2H, d,
J = 8.8 Hz, ArH), 6.48 (2H, d, J = 8.8 Hz, ArH), 4.78 (2H, s, CH2OH),
4.38−4.32 (2H, m, CH2N), 4.29−4.24 (1H, m, CHN), 3.69 (3H, s,
OCH3), 2.10−2.02 (1H, m, CHCHACHB), 1.96−1.89 (1H, m,
CHCHACHB), 1.85−1.75 (2H, m, CH2CH2N). 13C{1H} NMR (101
MHz, CDCl3) δ 152.4 (C), 147.7 (C), 142.9 (C), 140.6 (C), 128.7 (2 ×
CH), 127.3 (CH), 126.4 (2 × CH), 121.5 (CH), 115.1 (2 × CH),
114.8 (2 × CH), 58.8 (CH), 56.6 (CH2), 55.7 (CH3), 50.0 (CH2), 35.0
(CH2), 27.1 (CH2). HRMS (Q-TOF) m/z: [M + H]+ Calcd for
C20H25N4O2+ 353.1978; found 353.1972.
( )-N-(4-Methoxyphenyl)-α-methyl-1-naphthalenemethan-
amine (9k). The title compound was prepared according to General
Procedure 2 using boronic ester 8k (0.141 g, 0.499 mmol) and p-
anisidine (0.249 g, 2.02 mmol), heating at 65 °C for 16 h. Flash
chromatography (6% EtOAc/petroleum ether) of the crude material
gave amine 9k (0.0623 g, 45%) as a yellow solid. The data were
consistent with the literature.51 1H NMR (400 MHz, CDCl3) δ 8.20−
8.18 (1H, m, ArH), 7.93−7.91 (1H, m, ArH), 7.77−7.75 (1H, m, ArH),
7.68−7.66 (1H, m, ArH), 7.60−7.51 (2H, m, ArH), 7.44−7.41 (1H, m,
ArH), 6.67 (2H, d, J = 8.8 Hz, ArH), 6.45 (2H, d, J = 8.8 Hz ArH), 5.23
(1H, q, J = 6.6 Hz, NCH), 3.96 (1H, br s, NH), 3.69 (3H, s, OCH3),
1.66 (3H, d, J = 6.6 Hz, CHCH3). 13C{1H} NMR (101 MHz, CDCl3) δ
151.8 (C), 141.3 (C), 140.1 (C), 134.1 (C), 130.7 (C), 129.1 (CH),
127.3 (CH), 126.0 (CH), 125.9 (CH), 125.4 (CH), 122.6 (CH), 122.3
(CH), 114.7 (2 × CH), 114.2 (2 × CH), 55.7 (CH3), 50.1 (CH), 23.8
(CH3).
4-Methoxy-N-(naphthalen-2-ylmethyl)aniline (9p). The title
compound was prepared according to General Procedure 2 using
boronic ester 8p (0.135 g, 0.505 mmol) and p-anisidine (0.249 g, 2.02
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9p (0.0825 g, 62%)
as a yellow solid. The data were consistent with the literature.52 m.p.
106−108 °C (petroleum ether); no literature value available. 1H NMR
(400 MHz, CDCl3) δ 7.88−7.78 (4H, m, ArH), 7.54−7.42 (3H, m,
ArH), 6.79 (2H, d, J = 8.9 Hz, ArH), 6.66 (2H, d, J = 8.9 Hz, ArH), 4.46
(2H, s, CH2), 3.75 (3H, s, OCH3). 13C{1H} NMR (101 MHz, CDCl3)
δ 152.2 (C), 142.4 (C), 137.2 (C), 133.5 (C), 132.7 (C), 128.3 (CH),
127.7 (CH), 127.7 (CH), 126.1 (CH), 125.9 (CH), 125.8 (CH), 125.7
(CH), 114.9 (2 × CH), 114.2 (2 × CH), 55.8 (CH3), 49.4 (CH2).
( )-N-(4-Methoxybenzyl)cyclohex-2-enamine (9q). The title
compound was prepared according to General Procedure 2 using
boronic ester 8q (0.104 g, 0.501 mmol) and p-anisidine (0.247 g, 2.00
mmol), heating at 65 °C for 48 h. Flash chromatography (3% EtOAc/
petroleum ether) of the crude material gave amine 9q (0.0498 g, 49%)
as a yellow oil. The data were consistent with the literature.53 1H NMR
(400 MHz, CDCl3) δ 6.79 (2H, d, J = 9.0 Hz, ArH), 6.61 (2H, d, J = 9.0
Hz, ArH), 5.88−5.79 (1H, m, CHCHCH), 5.80−5.72 (1H, m,
CHCHCH), 3.92 (1H, s, NCH), 3.76 (3H, s, OCH3), 3.34 (1H, s,
NH), 2.13−1.99 (2H, m, CHCHCH2), 1.95−1.85 (1H, m,
NCHCHAHB), 1.81−1.69 (1H, m, NCHCH2CHAHB), 1.67−1.52
(2H, m, NCHCH2CHAHB + NCHCHAHB). 13C{1H} NMR (101
MHz, CDCl3) δ 152.0 (C), 141.3 (C), 129.9 (CH), 128.9 (CH), 115.0
(2 × CH), 114.9 (2 × CH), 55.8 (CH3), 49.0 (CH), 29.0 (CH2), 25.2
(CH2), 19.8 (CH2).
N-Methyl-N-(3-methylbut-2-en-1-yl)aniline (9r). The title com-
pound was prepared according to General Procedure 2 using boronic
ester 8r (0.093 g, 0.509 mmol) and N-methyl aniline (0.216 g, 2.01
mmol), heating at 50 °C for 16 h. Flash chromatography (6% EtOAc/
petroleum ether) of the crude material gave amine 9r (0.0464 g, 57%)
as a yellow oil. The data were consistent with the literature.54 1H NMR
(400 MHz, CDCl3) δ 7.25−7.21 (2H, m, ArH), 6.71−6.68 (3H, m,
ArH), 4.86 (1H, s, CCHAHB), 4.81 (1H, s, CCHAHB) 3.81 (2H, s,
NCH2), 2.97 (3H, s, NCH3), 1.74 (3H, s, CCH3). 13C{1H} NMR (101
MHz, CDCl3) δ 149.6 (C), 141.5 (C), 129.0 (2 × CH), 116.1 (CH),
111.9 (2 × CH), 110.7 (CH2), 58.8 (CH2), 38.2 (CH3), 20.0 (CH3).
N-Cyclohexyl-4-methoxyaniline (9s). Methanol (1.0 mL) and
pyridine (0.33 mL) were added to a flask containing cyclohexylboronic
acid pinacol ester (0.106 g, 0.503 mmol), p-anisidine (0.248 g, 2.03
mmol), Cu(OAc)2 (0.182 g, 1.00 mmol), and Cs2CO3 (0.0820 g, 0.252
mmol), and the mixture was stirred at 80 °C for 16 h. The mixture was
cooled to room temperature, NH4OH (10 mL) was added, and the
mixture was extracted with Et2O (3 × 10 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography (5% EtOAc/petroleum ether) of the crude material
( )-tert-Butyl 3-(3-Methoxy-1-[(4-methoxyphenyl)amino]-
propyl)-1H-indole-1-carboxylate (9l). The title compound was
prepared according to General Procedure 2 using boronic ester 8l
(0.208 g, 0.500 mmol) and p-anisidine (0.249 g, 2.02 mmol), heating at
65 °C for 48 h. Flash chromatography (10% EtOAc/petroleum ether)
of the crude material gave amine 9l (0.151 g, 73%) as a dark yellow oil.
1
IR 2932, 2832, 2248, 1726, 1510, 906 cm−1. H NMR (400 MHz,
CDCl3) δ 8.15 (1H, s, ArH), 7.65 (1H, d, J = 7.7 Hz, ArH), 7.53 (1H, s,
ArH), 7.36−7.32 (1H, m, ArH), 7.26−7.24 (1H, m, ArH), 6.73 (2H, d,
J = 8.9 Hz, ArH), 6.60 (2H, d, J = 8.9 Hz, ArH), 4.77 (1H, t, J = 6.3 Hz,
NCH), 3.72 (3H, s, ArOCH3), 3.60−3.55 (1H, m, CHAHBO), 3.51−
3.46 (1H, m, CHAHBO), 3.37 (3H, s, CH2OCH3), 2.26−2.18 (2H, m,
CHCH2), 1.67 (9H, s, 3 × CCH3). 13C{1H} NMR (101 MHz, CDCl3)
δ 152.0 (C), 149.7 (C), 141.7 (C), 135.8 (C), 129.0 (C), 124.4 (2 ×
CH), 123.0 (CH), 122.4 (2 × CH), 119.3 (CH), 115.4 (CH), 114.7 (2
× CH), 83.6 (C), 70.3 (CH2), 58.8 (CH3), 55.7 (CH3), 50.4 (CH),
36.3 (CH2), 28.2 (3 × CH3). HRMS (Q-TOF) m/z: [M + Na]+ Calcd
for C24H30N2O4+ 433.2106; found 433.2098.
( )-N-[3-(Benzyloxy)-1-phenylpropyl]-4-methoxyaniline (9m).
The title compound was prepared according to General Procedure 2
using boronic ester 8m (0.177 g, 0.501 mmol) and p-anisidine (0.247 g,
2.02 mmol), heating at 65 °C for 32 h. Flash chromatography (8%
EtOAc/petroleum ether) of the crude material gave amine 9m (0.103 g,
59%) as an orange oil. IR 3385, 3028, 2857, 1510, 1235 cm−1. 1H NMR
(400 MHz, CDCl3) δ 7.38−7.28 (9H, m, ArH), 7.25−7.19 (1H m,
ArH), 6.67 (2H, d, J = 8.9 Hz, ArH), 6.42 (2H, d, J = 8.9 Hz, ArH), 4.61
(1H, s, NH), 4.51 (2H, s, ArCH2), 4.49−4.45 (1H, m, NCH), 3.69
(3H, s, OCH3), 3.63−3.52 (2H, m, CH2CH2O), 2.12−2.05 (2H, m,
CHCH2). 13C{1H} NMR (101 MHz, CDCl3) δ 151.6 (C), 144.0 (C),
141.9 (C), 138.1 (C), 128.5 (2 × CH), 128.4 (2 × CH), 127.7 (2 ×
CH), 127.7 (CH), 126.8 (CH), 126.4 (2 × CH), 114.6 (2 × CH),
114.3 (2 × CH), 73.2 (CH2), 68.1 (CH2), 57.8 (CH3), 55.7 (CH), 38.3
+
(CH2). HRMS (Q-TOF) m/z: [M + H]+ Calcd for C23H26NO2
348.1964; found 348.1958.
( )-N-(4-Azido-1-phenylbutyl)-4-methoxyaniline (9n). The title
compound was prepared according to General Procedure 2 using
boronic ester 8n (0.151 g, 0.500 mmol)and p-anisidine (0.247 g, 2.01
mmol), heating at 65 °C for 16 h. Flash chromatography (5% EtOAc/
petroleum ether) of the crude material gave amine 9n (0.0869 g, 59%)
as a brown oil. IR 3396, 2930, 2093, 1509, 1451, 1233 cm−1. 1H NMR
(400 MHz, CDCl3) δ 7.36−7.29 (4H, m, ArH), 7.26−7.21 (1H, m,
ArH), 6.70 (2H, d, J = 8.9 Hz, ArH), 6.49 (2H, d, J = 8.9 Hz, ArH),
4.32−4.23 (1H, m, NCH), 3.70 (3H, s, OCH3), 3.34−3.25 (2H, m,
CH2), 1.96−1.81 (2H, m, CH2), 1.77−1.69 (1H, m, CH2), 1.66−1.59
(1H, m, CH2). 13C{1H} NMR (101 MHz, CDCl3) δ 152.0 (C), 143.6
(C), 141.3 (C), 128.7 (2 × CH), 127.1 (CH), 126.4 (2 × CH), 114.8 (2
× CH), 114.6 (2 × CH), 58.6 (CH3), 55.7 (CH), 51.2 (CH2), 35.7
9892
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Note
gave amine 9s (0.0114 g, 11%) as an orange oil. The data were
consistent with the literature.55 1H NMR (400 MHz, CDCl3) δ 6.77
(2H, d, J = 8.2 Hz, ArH), 6.58 (2H, d, J = 8.2 Hz, ArH), 3.75 (3H, s,
OCH3), 3.21−3.13 (1H, m, NCH), 2.08−2.02 (2H, m, CHCHAHB),
1.80−1.69 (2H, m, CHCH2CHAHB), 1.69−1.63 (1H, m,
CHCH2CH2CHAHB), 1.40−1.31 (2H, m, CHCH2CHAHB), 1.27
(1H, s, NH), 1.25−1.18 (1H, m, CHCH2CH2CHAHB), 1.18−1.08
(2H, m, CHCHAHB). 13C{1H} NMR (101 MHz, CDCl3) δ 151.9 (C),
141.6 (C), 114.9 (2 × CH), 114.8 (2 × CH), 55.8 (CH3), 52.8 (CH),
33.6 (2 × CH2), 26.0 (CH2), 25.1 (2 × CH2).
( )-4-Methoxy-N-[1-(4-methoxyphenyl)-1-phenylethyl]aniline
(11a). The title compound was prepared according to General Procedure
4 using boronic ester 10a (0.168 g, 0.498 mmol) and p-anisidine (0.246
g, 2.00 mmol). Flash chromatography (2% EtOAc/petroleum ether) of
the crude material gave amine 11a (0.0977 g, 59%) as a yellow oil. IR
3396, 2991, 2932, 2833, 1608, 1507, 1237 cm−1. 1H NMR (400 MHz,
CDCl3) δ 7.49−7.43 (2H, m, ArH), 7.37 (2H, d, J = 8.8 Hz, ArH),
7.35−7.29 (2H, m, ArH), 7.26−7.20 (1H, m, ArH), 6.85 (2H, d, J = 8.8
Hz, ArH), 6.64 (2H, d, J = 8.9 Hz, ArH), 6.41 (2H, d, J = 8.9 Hz,
ArHH), 4.03 (1H, s, NH), 3.80 (3H, s, OCH3), 3.70 (3H, s, OCH3),
2.03 (3H, s, CCH3). 13C{1H} NMR (101 MHz, CDCl3) δ 158.2 (C),
152.4 (C), 147.7 (C), 139.8 (C), 139.7 (C), 128.3 (2 × CH), 128.0 (2
× CH), 126.8 (2 × CH), 126.6 (CH), 118.2 (2 × CH), 114.2 (2 ×
CH), 113.6 (2 × CH), 62.2 (C), 55.6 (CH3), 55.2 (CH3), 26.7 (CH3).
HRMS (Q-TOF) m/z: [M]+ Calcd for C22H23NO2+ 333.1723; found
333.1719.
( )-4-Chloro-N-[1-(4-methoxyphenyl)-1-phenylethyl]aniline
(11b). The title compound was prepared according to General Procedure
4 using boronic ester 10a (0.170 g, 0.501 mmol) and 4-chloroaniline
(0.257 g, 2.01 mmol). Flash chromatography (2% EtOAc/petroleum
ether) of the crude material gave amine 11b (0.0710 g, 42%) as a yellow
oil. IR 3473, 3383, 3006, 1601, 1493, 1247 cm−1. 1H NMR (400 MHz,
CDCl3) δ 7.46−7.40 (2H, m, J = 8.9 Hz, ArH), 7.37−7.31 (4H, m,
ArH), 7.27−7.23 (1H, m, ArH), 6.97 (2H, d, J = 8.9 Hz, ArH), 6.86
(2H, d, J = 8.9 Hz, ArH), 6.35 (2H, d, J = 8.9 Hz, ArH), 4.39 (1H, s,
NH), 3.81 (3H, s, OCH3), 2.07 (3H, s, CCH3). 13C{1H} NMR (101
MHz, CDCl3) δ 158.4 (C), 146.8 (C), 144.5(C), 138.7 (C), 128.5 (2 ×
CH), 128.5 (2 × CH), 128.0 (2 × CH), 126.9 (CH), 126.7 (2 × CH),
122.2 (C), 117.0 (2 × CH), 113.7 (2 × CH), 62.0 (C), 55.2 (CH3),
26.9 (CH3). HRMS (Q-TOF) m/z: [M + Na]+ Calcd for
C21H2035ClNNaO+ 360.1131; found 360.1135.
( )-N-[1-(4-Methoxyphenyl)-1-phenylethyl]-1-methyl-1H-pyra-
zol-5-amine (11c). The title compound was prepared according to
General Procedure 4 using boronic ester 10a (0.169 g, 0.501 mmol) and
1-methyl-1H-pyrazol-3-amine (0.194 g, 2.00 mmol). Flash chromatog-
raphy (1:5 EtOAc/petroleum ether) of the crude material gave amine
11c (0.0522 g, 34%) as a yellow oil. IR 3267, 2933, 2835, 1547, 1509,
1249 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.50−7.45 (2H, m, ArH),
7.39 (2H, d, J = 8.9 Hz, ArH), 7.33−7.28 (2H, m, ArH), 7.25−7.19
(1H, m, ArH), 6.92 (1H, d, J = 2.3 Hz, ArH), 6.84 (2H, d, J = 8.9 Hz,
ArH), 4.84 (1H, d, J = 2.3 Hz, ArH), 4.58 (1H, s, NH), 3.79 (3H, s,
OCH3), 3.68 (3H, s, NCH3), 2.00 (3H, s, CCH3). 13C{1H} NMR (126
MHz, CDCl3) δ 158.1 (C), 155.0 (C), 147.7 (C), 139.6 (C), 130.3
(CH), 128.2 (2 × CH), 128.0 (2 × CH), 126.7 (2 × CH), 126.5 (CH),
113.4 (2 × CH), 94.0 (CH), 61.8 (C), 55.2 (CH3), 38.3 (CH3), 27.7
(CH3). HRMS (Q-TOF) m/z: [M + H]+ Calcd for C19H22N3O+
308.1763; found 308.1757.
(CH3). HRMS (Q-TOF) m/z: [M + Na]+ Calcd for C21H21NNaO+
326.1521; found 326.1536.
( )-N-[1-(4-Chlorophenyl)-1-phenylethyl]aniline (11e). The title
compound was prepared according to General Procedure 4 using
boronic ester 10b (0.171 g, 0.499 mmol) and aniline (0.18 mL, 2.0
mmol), heating at 25 °C. Flash chromatography (2% EtOAc/
petroleum ether) of the crude material gave amine 11e (0.0681 g,
44%) as a yellow oil. IR 3150, 1492, 1097, 1012, 750 cm−1. 1H NMR
(400 MHz, CDCl3) δ 7.46−7.41 (4H, m, ArH), 7.37−7.28 (5H, m,
ArH), 7.08−7.03 (2H, m, ArH), 6.73−6.66 (1H, m, ArH), 6.47−6.42
(2H, m, ArH), 4.34 (1H, s, NH), 2.11 (3H, s, CH3). 13C{1H} NMR
(101 MHz, CDCl3) δ 146.8 (C), 145.6 (C), 145.4 (C), 132.6 (C),
128.7 (2 × CH), 128.5 (6 × CH), 127.1 (CH), 126.6 (2 × CH), 117.8
(CH), 116.1 (2 × CH), 62.1 (C), 26.7 (CH3). HRMS (ESI) m/z: [M +
H]+ Calcd for C20H1835ClN+ 308.1201; found 308.1194.
( )-N-{1-Phenyl-1-[4-(trifluoromethyl)phenyl]ethyl}aniline (11f).
The title compound was prepared according to General Procedure 4
using boronic ester 10c (0.189 g, 0.502 mmol) and aniline (0.18 mL,
2.0 mmol), heating at 50 °C. Flash chromatography (2% EtOAc/
petroleum ether) of the crude material gave amine 11f (0.0432 g, 25%)
as a yellow oil. IR 3450, 2928, 1600, 1497, 1325 cm−1. 1H NMR (400
MHz, CDCl3) δ 7.56−7.48 (4H, m, ArH), 7.34 (2H, d, J = 7.7 Hz,
ArH), 7.28−7.23 (2H, m, ArH), 7.20−7.16 (1H, m, ArH), 7.00−6.93
(2H, m, ArH), 6.64−6.57 (1H, m, ArH), 6.34 (2H, d, J = 7.7 Hz, ArH),
4.27 (1H, s, NH), 2.05 (3H, s, CH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 150.7 (C), 146.5 (C), 145.5 (C), 129.0 (C, q, JF = 32.6 Hz),
128.7 (2 × CH), 128.6 (2 × CH), 127.4 (2 × CH), 127.2 (CH), 126.6
(2 × CH), 125.4 (2 × CH, q, JF = 3.7 Hz), 124.2 (CF3, q, JF = 271.8
Hz,), 118.0 (CH), 116.2 (2 × CH), 62.4 (C), 26.6 (CH3). 19F NMR
(377 MHz, CDCl3) δ −62.3. HRMS (EI) m/z: [M]+ Calcd for
C21H18F3N+ 341.1386; found 341.1399.
( )-N-(2-Phenylbutan-2-yl)aniline (11g). The title compound was
prepared according to General Procedure 4 using boronic ester 10d
(0.130 g, 0.500 mmol) and aniline (0.18 mL, 2.0 mmol), heating at 50
°C. Flash chromatography (1% EtOAc/petroleum ether) of the crude
material gave amine 11g (0.0466 g, 41%) as a yellow oil. The data were
consistent with the literature.56 IR 3359, 2918, 2850, 1600, 1468, 1263.
1H NMR (400 MHz, CDCl3) δ 7.52−7.45 (2H, m, ArH), 7.36−7.30
(2H, m, ArH), 7.26−7.21 (1H, m, ArH), 7.04−6.95 (2H, m, ArH),
6.65−6.56 (1H, m, ArH), 6.38−6.30 (2H, m, ArH), 4.01 (1H, s, NH),
1.92 (2H, q, J = 7.4, CH2), 1.63 (3H, s, CCH3), 0.83 (3H, t, J = 7.4 Hz,
CH2CH3). 13C{1H} NMR (400 MHz, CDCl3) δ 146.3 (C), 146.0 (C),
128.7 (2 × CH), 128.3 (2 × CH), 126.2 (3 × CH), 116.9 (CH), 115.1
(2 × CH), 58.4 (C), 36.4 (CH2), 25.3 (CH3), 8.2 (CH3). HRMS (ESI)
m/z: [M + H]+ Calcd for C16H19N+ 226.1590; found 226.1597.
Reaction of Boronic Ester 13 with p-Anisidine. (See Scheme S1
in the Supporting Information.)
According to General Procedure 4, boronic ester 13 (0.159 g, 0.503
mmol) and p-anisidine (0.246 g, 2.00 mmol) were heated at 25 °C.
Flash chromatography (5% EtOAc/petroleum ether) of the crude
material gave amine 14 (0.0365 g, 23%) as a yellow oil, and an
inseparable mixture of alcohol S2 and amine 15 (40.9 mg).
Phenyl isothiocyanate (1.1 equiv) was added to a solution of a
mixture of S2 and 15 in hexane:Et3N:MeCN (1:0.1:0.1, 0.1 M), and the
mixture was stirred for 16 h at room temperature. The precipitate was
collected and washed with hexane (2 × 5 mL) to give thiourea 16 (16.0
mg, 7%). Flash chromatography (petroleum ether → 20% EtOAc/
petroleum ether) of the mother liquor gave alcohol S2 (18.1 mg, 18%).
( )-N-(5-Azido-2-phenylpentan-2-yl)-4-methoxyaniline (14). IR
3390, 2932, 2831, 2093, 1508, 1235, cm−1. 1H NMR (400 MHz,
CDCl3) δ 7.53−7.45 (2H, m, ArH), 7.39−7.32 (2H, m, ArH), 7.27−
7.23 (1H, m, ArH), 6.62 (2H, d, J = 8.8 Hz, ArH), 6.31 (2H, d, J = 8.8
Hz, ArH), 3.69 (4H, s, NH, OCH3), 3.26−3.12 (2H, m, CH2N), 2.01−
1.88 (2H, m, CH2CH2N), 1.61 (3H, s, CCH3), 1.55−1.47 (2H, m,
CCH2). 13C{1H} NMR (101 MHz, CDCl3) δ 152.0 (C), 146.2 (C),
139.7 (C), 128.5 (2 × CH), 126.5 (CH), 126.2 (2 × CH), 117.0 (2 ×
CH), 114.3 (2 × CH), 58.3 (C), 55.6 (CH3), 51.6 (CH2), 40.6 (CH2),
26.3 (CH3), 23.5 (CH2). HRMS (Q-TOF) m/z: [M + H]+ Calcd for
C18H23N4O+ 311.1872; found 311.1866.
( )-N-[1-(4-Methoxyphenyl)-1-phenylethyl]aniline (11d). The
title compound was prepared according to General Procedure 4 using
boronic ester 10a (0.169 g, 0.499 mmol) and aniline (0.18 mL, 2.0
mmol). Flash chromatography (2% EtOAc/petroleum ether) of the
crude material gave amine 11d (0.0642 g, 42%) as a yellow oil. IR 3409,
1
2989,2834, 1599, 1497, 1249 cm−1. H NMR (400 MHz, CDCl3) δ
7.46 (2H, d, J = 8.8 Hz, ArH), 7.38−7.30 (4H, m, ArH), 7.26−7.21
(1H, m, ArH), 7.07−7.00 (2H, m, ArH), 6.86 (2H, d, J = 8.8 Hz, ArH),
6.68−6.63 (1H, m, ArH), 6.47−6.41 (2H, m, ArH), 4.36 (1H, s, NH),
3.80 (3H, s, OCH3), 2.10 (3H, s, CCH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.3 (C), 147.3 (C), 146.0 (C), 139.3 (C), 128.6 (2 × CH),
128.4 (2 × CH), 128.0 (2 × CH), 126.8 (2 × CH), 126.7 (CH), 117.4
(CH), 116.0 (2 × CH), 113.6 (2 × CH), 61.9 (C), 55.2 (CH3), 26.6
9893
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J. Org. Chem. 2021, 86, 9883−9897

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
( )-1-[2-(5-Azido-2-phenylpentan-2-yl)-4-methoxyphenyl]-3-
phenylthiourea (16). m.p. 150−151 °C (hexane). IR 3334, 3170,
2959, 2096, 1508, 1214 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.57 (1H,
s, NH), 7.35−7.29 (1H, m, ArH), 7.26−7.21 (2H, m, ArH), 7.18−7.13
(2H, m, ArH), 7.04 (6H, m, ArH), 6.90−6.87 (1H, m, ArH), 6.38 (1H,
s, ArH), 3.90 (3H, s, OCH3), 3.38−3.28 (1H, m, CHAHBN), 3.28−3.18
(1H, m, CHAHBN), 2.23−2.03 (2H, m, CH2CH2N3), 1.57 (3H, s,
CCH3), 1.44−1.31 (2H, m, CCH2). 13C{1H} NMR (101 MHz,
CDCl3) δ 179.7 (C), 158.5 (C), 148.2 (C), 145.1 (C), 136.8 (C), 131.9
(CH), 129.6 (CH), 128.8 (4 × CH), 126.6 (2 × CH), 126.3 (2 × CH),
125.4 (CH), 123.8 (C), 115.4 (CH), 110.8 (CH), 55.5 (CH3), 51.9
(CH2), 45.5 (C), 36.1 (CH2), 27.8 (CH3), 24.8 (CH2). HRMS (Q-
TOF) m/z: [M + H]+ Calcd for C25H28N5OS+ 446.2015; found
446.2009.
( )-5-Azido-2-phenylpentan-2-ol (S2). IR 3420, 2930, 2092, 1602,
1146, 1260 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.48−7.39 (2H, m,
ArH), 7.40−7.33 (2H, m, ArH), 7.29−7.24 (1H, m, ArH), 3.26−3.19
(2H, m, CH2N3), 1.95−1.83 (2H, m, CH2CH2N3), 1.80 (1H, s, OH),
1.64−1.57 (4H, m, CH3, CCHAHB), 1.53−1.38 (1H, m, CCHAHB).
13C{1H} NMR (101 MHz, CDCl3) δ 147.2 (C), 128.3 (2 × CH), 126.7
(CH), 124.6 (2 × CH), 74.3 (C), 51.6 (CH2), 41.1 (CH2), 30.5 (CH3),
23.7 (CH2). HRMS (Q-TOF) m/z: [M + Na]+ Calcd for
C11H15N3ONa+ 228.1113; found 228.1107.
Reaction of Boronic Ester 1 with p-Aminophenol. The title
compounds were prepared according to General Procedure 2 using
boronic ester 1 (0.116 g, 0.500 mmol) and 4-aminophenol (0.218 g,
2.00 mmol), heating at 65 °C for 48 h. Flash chromatography (20%
EtOAc/petroleum ether) of the crude material gave amine 17 (0.0499
g, 47%), amine 18 (0.0023 g, 2%), and amine 19 (0.0338 g, 32%) as red
oils.
(CH), 114.8 (CH), 40.4 (CH), 21.6 (CH3). HRMS (Q-TOF) m/z: [M
+ H]+ Calcd for C21H21N2OS+ 349.1375; found 349.1369. Crystals
suitable for X-ray diffraction were obtained through recrystallization of
S3 from hexane and slow evaporation.
Reaction of Cyclopropane-Containing Boronic Ester 12. A
flask containing boronic ester 20 (0.131 g, 0.507 mmol), p-anisidine
(0.251 g, 2.04 mmol), Cu(OAc)2 (0.184 g, 1.01 mmol), and Cs2CO3
(0.0858 g, 0.263 mmol) was purged with argon. Methanol (1.0 mL) and
pyridine (0.33 mL) were added, and the mixture was stirred at 65 °C for
48 h. The mixture was cooled to room temperature, NH4OH (10 mL)
was added, and the mixture was extracted with Et2O (3 × 10 mL), dried
(MgSO4), filtered, and concentrated in vacuo. Flash chromatography
(6% EtOAc/petroleum ether) of the crude material gave amine 21
(0.0501g, 39%) as an orange oil. IR 3390, 2929, 2831, 1510, 1233 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.41−7.35 (2H, m, ArH), 7.36−7.29
(2H, m, ArH), 7.27−7.20 (1H, m, ArH), 6.81 (2H, d, J = 8.9 Hz, ArH),
6.62 (2H, d, J = 8.9 Hz, ArH), 6.51 (1H, d, J = 15.9 Hz, PhCH), 6.24
(1H, dt, J = 15.9 7.1 Hz, PhCHCH), 3.77 (3H, s, OCH3), 3.47 (1H,
s, NH), 3.25 (2H, t, J = 6.7 Hz, CH2N), 2.55 (2H, dtd, J = 7.1, 6.7, 1.1
Hz, CH2CH2N). 13C{1H} NMR (101 MHz, CDCl3) δ 152.2 (C),
142.5 (C), 137.3 (C), 132.2 (CH), 128.5 (2 × CH), 127.5 (CH), 127.2
(CH), 126.1 (2 × CH), 115.0 (2 × CH), 114.3 (2 × CH), 55.8 (CH3),
44.3 (CH2), 33.0 (CH2). HRMS (Q-TOF) m/z: [M + H]+ Calcd for
C17H20NO+ 254.1545; found 254.1539.
Reaction of Enantiomerically Enriched Boronic Ester (S)-1.
According to General Procedure 2, boronic ester (S)-1 (0.0502 g, 0.216
mmol) and aniline (0.0803 g, 0.862 mmol) were reacted, heating at 50
°C for 16 h. Flash chromatography (4% EtOAc/petroleum ether) of the
crude material gave amine 3a (0.0311 g, 73%) as a yellow oil. The data
were consistent with the literature.35 See above for data. e.r. = 50:50.
HPLC (Phenomenex Cellulose-1 column (250 × 4.6 mm), IPA/
hexane 6/94, flow rate = 1.0 mL/min, l = 254 nm), tR = 6.5 min
(minor), 8.0 min (major).
( )-4-[(1-Phenylethyl)amino]phenol (17). The data were consis-
tent with the literature.57 1H NMR (400 MHz, CDCl3) δ 7.38−7.30
(4H, m, ArH), 7.25−7.21 (1H, m, ArH), 6.62 (2H, d, J = 8.8 Hz, ArH),
6.43 (2H, d, J = 8.8 Hz, ArH), 4.41 (1H, q, J = 6.7 Hz, CH), 2.19 (1H, s,
NH), 1.50 (3H, d, J = 6.7 Hz, CH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 147.4 (C), 145.4 (C), 141.6 (C), 128.6 (2 × CH), 126.8
(CH), 125.9 (2 × CH), 116.0 (2 × CH), 114.7 (2 × CH), 54.3 (CH),
25.1 (CH3).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00976.
( )-4-(1-Phenylethoxy)aniline (18). IR 3446, 3360, 2920, 2850,
1
1624, 1508, 1230 cm−1. H NMR (400 MHz, CDCl3) δ 7.39−7.30
(4H, m, ArH), 7.27−7.21 (1H, m, ArH), 6.70 (2H, d, J = 8.7 Hz, ArH),
6.56 (2H, d, J = 8.7 Hz, ArH), 5.17 (1H, q, J = 6.5 Hz, CH), 3.44 (2H, s,
NH2), 1.60 (3H, d, J = 6.5 Hz, CH3). 13C{1H} NMR (101 MHz,
CDCl3) δ 151.1 (C), 143.6 (C), 139.9 (C), 128.5 (2 × CH), 127.3
(CH), 125.7 (2 × CH), 117.4 (2 × CH), 116.3 (2 × CH), 76.9 (CH),
24.3 (CH3). HRMS (Q-TOF) m/z: [M + H]+ Calcd for C14H16NO+
214.1232; found 214.1226.
Experimental details and characterization data (PDF)
Accession Codes
CCDC 2073100 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
( )-4-Amino-3-(1-phenylethyl)phenol (19). IR 3363, 2966, 2929,
1600, 1498, 1450, 1214 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.32−
7.27 (2H, m, ArH), 7.23−7.18 (3H, m, ArH), 6.82 (1H, d, J = 2.7 Hz,
ArH), 6.60 (1H, dd, J = 8.4, 2.7 Hz, ArH), 6.55 (1H, d, J = 8.4 Hz, ArH),
4.09 (1H, q, J = 7.2 Hz, CH), 1.59 (3H, d, J = 7.2 Hz, CH3). 13C{1H}
NMR (101 MHz, CDCl3) δ 148.8 (C), 145.3 (C), 137.5 (C), 132.1
(C), 128.7 (2 × CH), 127.5 (2 × CH), 126.4 (CH), 117.6 (CH), 114.6
(CH), 113.8 (CH), 40.1 (CH), 21.7 (CH3). HRMS (Q-TOF) m/z: [M
+ H]+ Calcd for C14H16NO+ 214.1232; found 214.1226.
AUTHOR INFORMATION
■
Corresponding Author
Benjamin M. Partridge − Department of Chemistry, University
of Sheffield, Sheffield S3 7HF, United Kingdom; orcid.org/
0000-0002-8550-9994; Email: b.m.partridge@
sheffield.ac.uk
( )-3-[4-Hydroxy-2-(1-phenylethyl)phenyl]-1-phenylthiourea
(S3). (See Scheme S2 in the Supporting Information.)
Phenyl isothiocyanate (23.8 mg, 0.176 mmol) was added to a
solution of amine 19 (33.8 mg, 0.158 mmol) in hexane (1.6 mL), Et3N
(0.16 mL), and MeCN (0.16 mL), and the mixture was stirred for 16 h
at room temperature. The precipitate was collected and washed with
hexane (2 × 5 mL) to give thiourea S3 (37.2 mg, 68%). m.p. 155−157
°C (hexane). IR 3339, 3152, 2967, 1747, 1533, 1275 cm−1. 1H NMR
(400 MHz, CD3CN) δ 7.73 (1H, s, NH), 7.33−7.23 (8H, m, ArH),
7.21−7.15 (2H, m, ArH), 7.09−7.06 (1H, m, ArH), 6.79 (1H, s, ArH),
6.73−6.68 (1H m, ArH), 4.33 (1H, q, J = 7.2 Hz, CH), 1.55 (3H, d, J =
7.2 Hz, CHCH3). 13C{1H} NMR (101 MHz, CD3CN) δ 182.8 (C),
157.9 (C), 147.0 (C), 146.4 (C), 131.6 (CH), 129.6 (C), 129.4 (4 ×
CH), 128.5 (4 × CH), 127.1 (CH), 126.9 (C), 126.8 (CH), 115.5
Authors
James D. Grayson − Department of Chemistry, University of
Sheffield, Sheffield S3 7HF, United Kingdom
Francesca M. Dennis − Department of Chemistry, University of
Sheffield, Sheffield S3 7HF, United Kingdom
Craig C. Robertson − Department of Chemistry, University of
Sheffield, Sheffield S3 7HF, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00976
9894
https://doi.org/10.1021/acs.joc.1c00976
J. Org. Chem. 2021, 86, 9883−9897

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Am. Chem. Soc. 2017, 139 (49), 17707−17710. (d) Kainz, Q. M.;
Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C.
Asymmetric Copper-Catalyzed C-N Cross-Couplings Induced by
Visible Light. Science 2016, 351 (6274), 681−684. (e) Ahn, J. M.;
Ratani, T. S.; Hannoun, K. I.; Fu, G. C.; Peters, J. C. Photoinduced,
Copper-Catalyzed Alkylation of Amines: A Mechanistic Study of the
Cross-Coupling of Carbazole with Alkyl Bromides. J. Am. Chem. Soc.
2017, 139 (36), 12716−12723.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(7) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Decarboxylative Sp3 C-
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559 (7712), 83−88.
We thank the EPSRC (Grant EP/T009292/1), the Royal
Society (Grant RSG\R1\180065), and the University of
Sheffield for financial support.
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