Chan-Evans-Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem

Article abstract of DOI:10.1021/acs.joc.6b00466

The Chan-Evans-Lam reaction is a valuable C-N bond forming process. However, aryl boronic acid pinacol (BPin) ester reagents can be difficult coupling partners that often deliver low yields, in particular in reactions with aryl amines. Herein, we report effective reaction conditions for the Chan-Evans-Lam amination of aryl BPin with alkyl and aryl amines. A mixed MeCN/EtOH solvent system was found to enable effective C-N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amines.

Full text of DOI:10.1021/acs.joc.6b00466

Note
pubs.acs.org/joc
Chan−Evans−Lam Amination of Boronic Acid Pinacol (BPin) Esters:
Overcoming the Aryl Amine Problem
Julien C. Vantourout,† Robert P. Law,‡ Albert Isidro-Llobet,‡ Stephen J. Atkinson,‡
and Allan J. B. Watson*,†
†Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow, G1 1XL, U.K.
‡GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: The Chan−Evans−Lam reaction is a valuable
C−N bond forming process. However, aryl boronic acid
pinacol (BPin) ester reagents can be difficult coupling partners
that often deliver low yields, in particular in reactions with aryl
amines. Herein, we report effective reaction conditions for the
Chan−Evans−Lam amination of aryl BPin with alkyl and aryl
amines. A mixed MeCN/EtOH solvent system was found to
enable effective C−N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amines.
ransition metal-mediated C−N bond formation is an
In relation to this BPin problem, Hartwig has developed
specific reaction conditions for the CEL reaction of aryl BPins
that are moderately effective with alkyl amines but not with aryl
amines (Scheme 1a (i)).5 Koninobu has shown that alkyl BPin
substrates will undergo reaction with alkyl and aryl amines;
however, aryl BPin species are not tolerated (Scheme 1a (ii)).6
More recently, Clark has shown that substrates capable of
chelation can be used to facilitate CEL of specific substrates
(Scheme 1a (iii)).7 Herein, we report a simple set of general
reaction conditions that promote the efficient CEL reaction of
aryl BPin esters and aryl amines (Scheme 1b). These conditions
also operate effectively for the coupling of alkyl amines,
providing the first set of general conditions for this previously
troublesome process.
Our initial investigation of the aryl amine/aryl BPin coupling
was performed using a benchmark reaction between aniline
(1a) and biphenyl BPin (2a) (Table 1). We began with
standard CEL conditions (entry 1) to establish a general
reactivity profile for this process, which gave 16% yield of the
desired amine product 3a, highlighting the problem with these
substrates. In addition to 3a, we observed the expected
byproduct of this reaction, phenol 4 (1%). Conversion to
product almost doubled when heating under reflux in CH2Cl2
(entry 2).
T
essential transformation that enables the preparation of
valuable amine products.1 The Buchwald−Hartwig reaction2
(mediated by Pd) and Chan−Evans−Lam (CEL) reaction3,4
(mediated by Cu) are two related methods that are widely
practiced. The CEL reaction is particularly favored due to
several advantages it can offer versus its Pd counterpart, such as
the lower cost and toxicity of the metal as well as its tolerance
of aerobic conditions. This process typically couples a boronic
acid with an amine under mild conditions to deliver a new C−
N bond (Scheme 1) and has seen considerable development.
Despite this, a significant and routinely encountered problem
with the CEL amination reaction is that aryl boronic acid
pinacol (BPin) esters and aryl amines are generally very poor
substrates. Enabling the effective amination of aryl BPin esters
is highly desired due to the increased stability and accessibility
of these species with respect to the parent boronic acids.4
Scheme 1. Approaches to Chan−Evans−Lam Coupling of
RBPin
A survey of reaction solvents was useful (a broad range of
solvents was evaluated; see the Supporting Information).
Replacement of CH2Cl2 with MeCN allowed access to higher
reaction temperatures and provided a small increase in
conversion to 3a with increases in formation of 4 and the
emergence of 5, the product of protodeboronation, also noted
(Table 1, entries 3 and 4). Addition of molecular sieves reduced
the levels of phenolic byproduct 4 (entry 5), and increasing the
Received: March 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Reaction Optimization
Table 2. Inhibitory Effect of Pinacol on CEL Reactions of
Boronic Acid 1b
a
b
entry
pinacol
time (h)
3a (%)
b
1
2
3
4
5
6
6
24
6
41
70
11
12
46
50
entry
reaction conditions
CH2Cl2, 0.25 M, 25 °C
CH2Cl2, 0.25 M, 40 °C
MeCN, 0.25 M, 60 °C
MeCN, 0.25 M, 80 °C
MeCN, 0.25 M, 3 Å MS, 80 °C
MeCN, 1.0 M, 3 Å MS, 80 °C
EtOH, 0.25 M, 60 °C
MeCN:EtOH (20:1), 1.0 M, 3 Å MS, 80 °C
MeCN:EtOH (20:1), 1.0 M, 3 Å MS, O2, 80 °C
3a:4:5:6 (%)
1
2
3
4
5
6
7
8
9
16:1:0:--
31:2:5:--
39:8:6:--
44:14:11:--
58:6:3:--
71:2:0:--
43:12:15:38
82:6:3:7
1 equiv added at 0 h
1 equiv added at 0 h
1 equiv added at 6 h
1 equiv added at 6 h
24
6
24
a
1b (1.0 equiv, 0.25 mmol), 2a (2 equiv, 0.5 mmol), Cu(OAc)2 (1
equiv, 0.25 mmol), Et3N (2 equiv, 0.5 mmol), CH2Cl2 (1 mL), air, 20
b
°C. Determined by HPLC analysis using an internal standard.
c
21:2:0:0
a
On the basis of this, we proceeded to evaluate the generality
of the optimum stoichiometric conditions (Table 1, entry 8).
Application of the developed protocol to a range of ArBPin and
aniline substrates showed the conditions to be broadly
applicable (Scheme 2).
1a (1.0 equiv, 0.3 mmol), 2a (2 equiv, 0.6 mmol), Cu(OAc)2 (1
equiv, 0.3 mmol), Et3N (2 equiv, 0.6 mmol), solvent, air, 24 h.
b
Determined by HPLC analysis using an internal standard. Mass
c
balance is returned starting material. Using 10 mol % Cu(OAc)2.
The reaction conditions tolerated functionality on both the
aryl BPin and aryl amine components. Electron-rich (3c, 3h,
3j), electron-neutral (3a, 3b, 3l), and electron-withdrawing
groups (3d−g, 3i, 3k) were tolerated on the ArBPin (Scheme
reaction concentration boosted the yield of 3a further,
providing relatively good efficiency (entry 6). In addition to
lowering production of phenol byproduct 4, removal of H2O by
addition of molecular sieves was observed to decrease
formation of protodeboronation byproduct 5, as expected.8
During the solvent survey, use of alcoholic media such as EtOH
led to a significant quantity of the corresponding ether product
Scheme 2. Scope of the Developed CEL Reaction
Conditions to a Range of Aryl BPin and Aryl Amine
Substrates (Isolated Yields)
9
d,e,
6 as expected;3a,b,4
however, a competitive quantity of 3a
was produced and, more importantly, complete conversion of
1a was observed for the first time (entry 7). This increase in
reactivity may be attributable to an increase in mononuclear
Cu(OAc)2 from the paddlewheel dimer, [Cu(OAc)2]2.10 To
limit the production of 6 while attempting to retain this
increase in reactivity, mixtures of MeCN:EtOH were evaluated
(see the Supporting Information). At 20:1 MeCN:EtOH, the
formation of 6 was lowered significantly, and this provided an
efficient system for the coupling of 1a and 2a (entry 8).
Unfortunately, attempts to render the process catalytic were
unsuccessful; using 10 mol % Cu(OAc)2 under an O2
atmosphere led to only 21% conversion to 3a (entry 9).
The reason for the lack of efficiency under catalytic reaction
conditions was intriguing since several literature methods
report moderate to good efficiency using catalytic Cu(OAc)2
under an O2 atmosphere.11 In this regard, a series of control
experiments using boronic acid 1b, aniline 2a, and stoichio-
metric CEL reaction conditions were informative (Table 2).
The CEL reaction of 1b with 2a proceeds well in the absence
of pinacol, as expected (Table 2, entries 1 and 2). However,
addition of stoichiometric pinacol at various time points
immediately impedes the reaction. Specifically, addition of
pinacol at t = 0 h leads to ca. 10% conversion over 6 h and this
does not improve over an additional 18 h of reaction time
(entries 3 and 4). Similarly, addition of pinacol at t = 6 h
immediately halts the reaction at ca. 50% conversion (entries 5
and 6). The origin of this effect is unclear; however, diols are
known to form stable complexes with Cu(II).12 We, therefore,
speculate that pinacol, released as a byproduct as the reactions
of BPin substrates progress, inhibits catalyst turnover and,
therefore, reaction efficiency. Accordingly, stoichiometric
Cu(OAc)2 is required with BPin substrates.
B
DOI: 10.1021/acs.joc.6b00466
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The Journal of Organic Chemistry
Note
2). The aryl amine was also broadly tolerant of functionality
and substitution (3m−x). Yields were generally >70% with
some diminished yields observed with specific components, in
particular heterocycles (3u, 3w) and secondary aryl amines (3n,
3x).
Pleasingly, the developed conditions were also found to be
applicable to alkyl amines (Scheme 3). In this case, the addition
of EtOH was not necessary to achieve good levels of reaction
efficiency. Once more, a good diversity of BPin (7a−o) and
amine (7p−7al) components was tolerated. Similar trends were
observed with some heterocyclic (7l) and secondary amines
(7p) delivering lower yields. While the product 7ah was
isolated in relatively low yield due to competing arylation of the
lactam, the reactions of other amides and carbamates were
more chemoselective (e.g., 7i, 7m, 7aj). Taking the combined
scope of aryl and alkyl amine, the developed reaction
conditions allow the effective and general Chan−Evans−Lam
amination of aryl BPin.
In summary, a straightforward set of reaction conditions has
been developed that allow the efficient Chan−Evans−Lam
coupling of aryl BPin and aryl amines. These conditions are
also suitable for the coupling of alkyl amines. This provides the
first general set of reaction conditions for the CEL reaction of
aryl BPin reagents.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were obtained
from commercial suppliers and were used without further purification
unless otherwise stated. Purification was carried out according to
standard laboratory methods. EtOAc and petroleum ether 40−60° for
purification purposes were used as obtained from suppliers without
further purification. Reactions were carried out using capped 5 mL
microwave vials (reactions for Table 1, Schemes 2 and 3). Glassware
was oven-dried (150 °C) and purged with N2 before use. Purging
refers to a vacuum/nitrogen-refilling procedure. Room temperature
was generally ca. 20 °C. Reactions were carried out at elevated
temperatures using a temperature-regulated hot plate/stirrer. 3 Å
molecular sieves were purchased from Aldrich Chemical Co. in
powdered form, and activated and stored in an oven at 150 °C until
their use.
Scheme 3. Scope of the Developed CEL Reaction
Conditions to a Range of Aryl BPin and Alkyl Amine
Substrates (Isolated Yields)
Purification and Analysis. Thin layer chromatography was
carried out using silica plates coated with fluorescent indicator
UV254. These were analyzed under 254 nm UV light or developed
using potassium permanganate solution. 19F NMR spectra were
obtained at 282 MHz. 1H and 13C NMR spectra were obtained at 400
and 101 MHz, respectively. Chemical shifts are reported in ppm, and
coupling constants are reported in Hz with CDCl3 referenced at 7.27
ppm (1H) and 77.36 ppm (13C) and DMSO-d6 referenced at 2.50 ppm
(1H) and 39.52 ppm (13C). High-resolution mass spectra were
obtained using a quadrupole time-of-flight (Q-TOF) machine with
electrospray ionization. Reverse phase HPLC data were obtained using
a C18 column. Analysis was performed using a gradient method,
eluting with 5−80% MeCN/H2O over 16 min at a flow rate of 2 mL/
min. Samples for HPLC analysis were prepared through the addition
of 2 mL of caffeine standard to the reaction mixture. The resulting
solution was then stirred before the removal of a 200 μL aliquot. The
aliquot was diluted to 1 mL with MeCN. A 200 μL aliquot of the
diluted solution was then filtered and further diluted with 800 μL of
MeCN and 500 μL of H2O for HPLC analysis against established
conversion factors.
General Procedure for the Chan−Evans−Lam Amination of
Boronic Acid Pinacol (BPin) Esters with Aryl Amines. A solution
of aryl BPin (1 equiv, 0.30 mmol, 1 M), aryl amine (2 equiv, 0.60
mmol), Cu(OAc)2 (1 equiv, 0.30 mmol, 54 mg), Et3N (2 equiv, 0.60
mmol, 61 mg, 84 μL), and powdered activated 3 Å molecular sieves in
MeCN−EtOH (20:1 ratio, 300 μL) was sealed into an oven-dried
round-bottomed 5 mL microwave vial under air and stirred at 80 °C
(preheated sand bath, sand temperature) for 24 h. The reaction
mixture was allowed to cool to room temperature and filtered through
Celite, and the filtrate was evaporated to give a residue that was
purified by silica chromatography (EtOAc/petroleum ether with 1%
Et3N modifier). Appropriate fractions were evaporated to afford the
desired product.
General Procedure for the Chan−Evans−Lam Amination of
Boronic Acid Pinacol (BPin) Esters with Alkyl Amines. A solution
of aryl BPin (1 equiv, 0.20 mmol, 0.5 M), alkyl amine (2 equiv, 0.40
mmol), Cu(OAc)2 (1 equiv, 0.20 mmol, 36 mg), Et3N (2 equiv, 0.40
mmol, 41 mg, 56 μL), and powdered activated 3 Å molecular sieves in
MeCN (400 μL) was sealed in an oven-dried round-bottom 5 mL
microwave vial under air and stirred at 80 °C (preheated sand bath,
sand temperature) for 24 h. The reaction mixture was allowed to cool
C
DOI: 10.1021/acs.joc.6b00466
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The Journal of Organic Chemistry
Note
to room temperature and filtered through Celite, and the filtrate was
evaporated to give a residue that was purified by silica chromatography
(EtOAc/petroleum ether with 1% Et3N modifier). Appropriate
fractions were evaporated to afford the desired product.
121.4, 122.2, 129.3, 130.4, 141.7, 144.7. LCMS (ESI): tR = 1.15 min,
[M + H]+ 195.2. HRMS (ESI): (C13H11N2) [M + H]+ requires
195.0917, found [M + H]+ 195.0921. υmax (neat): 3338, 2233, 1592,
1533, 1495, 1482, 1416, 1338, 1303, 1153, 993, 962.1, 863, 778, 763,
711, 695, 677 cm−1.
N-Phenyl-[1,1′-biphenyl]-4-amine (3a).13 Orange solid (57 mg,
79% yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. M.p: 110−111 °C. 1H NMR (400 MHz;
DMSO-d6): δ 6.86 (t, J = 7.3 Hz, 1H), 7.12−7.17 (m, 4H), 7.27−7.28
(m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.55−7.63 (m, 4H), 8.30 (br. s.,
1H). 13C NMR (101 MHz, DMSO-d6): δ 117.2, 117.6, 119.6, 120.4,
126.2, 126.8, 127.8, 129.3, 129.7, 131.6, 140.5, 143.5. LCMS (ESI): tR
= 1.43 min, [M + H]+ 246.2. HRMS (ESI): (C18H16N) [M + H]+
requires 246.1277, found [M + H]+ 246.1279. υmax (neat): 3372, 1596,
1523, 1505, 1485, 1323, 846, 759, 745, 693 cm−1.
tert-Butyl-(3-(phenylamino)phenyl)carbamate (3h). Colorless
solid (57 mg, 67% yield). Purification: silica chromatography, 0−
10% (EtOAc + 1% Et3N)/petroleum ether. M.p.: 87−88 °C. 1H NMR
(400 MHz, DMSO-d6): δ 1.47 (s, 9H), 6.67 (t, J = 7.1 Hz, 1H), 6.80
(m, 1H), 6.90 (m, 1H), 7.04−7.07 (m, 3H), 7.19−7.23 (m, 2H), 7.32
(s, 1H), 8.08 (s, 1H), 9.18 (s, 1H). 13C NMR (101 MHz, DMSO-d6):
δ 28.1, 78.7, 106.6, 109.9, 110.7, 116.7, 119.4, 129.0, 140.3, 143.4,
143.6, 152.7 (1 signal not observed). LCMS (ESI): tR = 1.29 min, [M
+ H]+ 285.2. HRMS (ESI): (C17H21N2O2) [M + H]+ requires
285.1598, found [M + H]+ 285.1604. υmax (neat): 3331, 1692, 1595,
1526, 1497, 1450, 1398, 1368, 1275, 1247, 1153, 1053, 859, 761, 696
cm−1.
Diphenylamine (3b).14 White solid (38 mg, 74% yield).
Purification: silica chromatography, 0−3% (EtOAc + 1% Et3N)/
petroleum ether. M.p.: 51−52 °C. 1H NMR (400 MHz, DMSO-d6): δ
6.81 (t, J = 7.3 Hz, 2H), 7.05−7.07 (m, 4H), 7.20−7.24 (m, 4H), 8.10
(s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 116.7, 119.6, 129.1,
143.4. LCMS (ESI): tR = 1.21 min, [M + H]+ 170.2. HRMS (ESI):
(C12H12N) [M + H]+ requires 170.0964, found [M + H]+ 170.0965.
υmax (neat): 3407, 3383, 3042, 1595, 1519, 1494, 1458, 1418, 1316,
1242, 1172, 876, 743, 689 cm−1.
N-Phenyl-3-(trifluoromethyl)aniline (3i).18 Colorless oil (53 mg,
74% yield). Purification: silica chromatography, 0−5% (EtOAc + 1%
1
Et3N)/petroleum ether. H NMR (400 MHz, DMSO-d6): δ 6.93 (t, J
= 7.3 Hz, 1H), 7.07−7.14 (m, 3H), 7.27−7.32 (m, 4H), 7.40−7.42 (m,
1H), 8.51 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 111.5 (q, JC‑F
=
4.2 Hz), 115.0 (q, JC‑F = 4.2 Hz), 118.2, 118.9 (q, JC‑F = 1 Hz), 121.2,
125.6 (q, JC‑F = 273 Hz), 129.5, 129.8, 130.4 (q, JC‑F = 35 Hz), 142.0,
144.7. 19F NMR (282 MHz, DMSO-d6): δ −61.5 (s). LCMS (ESI): tR
= 1.34 min, [M + H]+ 238.2. HRMS (ESI): (C13H11F3N) [M + H]+
requires 238.0838, found [M + H]+ 238.0841. υmax (neat): 3404, 1658,
1049, 1023, 999, 824, 761 cm−1.
4-Methoxy-N-phenylaniline (3c).15 Yellow solid (42 mg, 70%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 104−105 °C. 1H NMR (400 MHz,
DMSO-d6): δ 3.71 (s, 3H), 6.70 (t, J = 7.3 Hz, 1H), 6.85−6.92 (m,
4H), 7.03−7.05 (m, 2H), 7.13−7.15 (m, 2H), 7.79 (s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 55.2, 114.5, 114.8, 118.2, 120.3, 129.0,
136.1, 145.1, 153.8. LCMS (ESI): tR = 1.17 min, [M + H]+ 200.3.
HRMS (ESI): (C13H14NO) [M + H]+ requires 200.1070, found [M +
H]+ 200.1073. υmax (neat): 3388, 1596, 1501, 1443, 1316, 1298, 1249,
1181, 1033, 812, 750, 695 cm−1.
3-Methyl-N-phenylaniline (3j).18 Yellow oil (30 mg, 55%).
Purification: silica chromatography, 0−3% (EtOAc + 1% Et3N)/
1
petroleum ether. H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H),
6.74 (t, J = 7.5 Hz, 1H), 6.86−6.91 (m, 3H), 7.10−7.19 (m, 5H), 7.33
(s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 17.9, 116.0, 118.7, 119.7
121.8, 126.4, 128.9, 129.4, 130.8, 141.3, 145.0. LCMS (ESI): tR = 1.29
min, [M + H]+ 184.2. HRMS (ESI): (C13H14N) [M + H]+ requires
184.1121, found [M + H]+ 184.1123. υmax (neat): 3407, 3383, 3042,
1595, 1519, 1494, 1458, 1418, 1318, 1242, 1172, 1083, 1023, 993, 876,
846 cm−1.
Methyl-4-(phenylamino)benzoate (3d).16 White solid (54 mg,
78% yield). Purification: silica chromatography, 0−10% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 108−109 °C. 1H NMR (400 MHz,
DMSO-d6): δ 3.78 (s, 3H), 6.99 (t, J = 7.3 Hz, 1H), 7.05−7.07 (m,
2H), 7.17−7.20 (m, 2H), 7.30−7.34 (m, 2H), 7.78−7.82 (m, 2H),
8.74 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 51.4, 113.9, 119.0,
119.4, 121.9, 129.2, 131.0, 141.2, 148.5, 165.9. LCMS (ESI): tR = 1.17
min, [M + H]+ 228.2. HRMS (ESI): (C14H14NO2) [M + H]+ requires
228.1019, found [M + H]+ 228.1023. υmax (neat): 3334, 1687, 1589,
1532, 1496, 1433, 1344, 1281, 1251, 1172, 1109, 851, 767, 747, 692
cm−1.
2-Fluoro-5-(phenylamino)benzonitrile (3k). Colorless solid (37
mg, 58% yield). Purification: silica chromatography, 0−10% (EtOAc +
1
1% Et3N)/petroleum ether. M.p.: 90−91 °C. H NMR (400 MHz,
DMSO-d6): δ 6.93 (t, J = 7.3 Hz, 1H), 7.07−7.10 (m, 2H), 7.26−7.30
(m, 2H), 7.35−7.37 (m, 3H), 8.43 (s, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 100.1 (d, JC‑F = 2.8 Hz), 114.2, 117.3 (d, JC‑F = 24 Hz),
117.6, 119.5 (d, JC‑F = 253 Hz), 123.3 (d, JC‑F = 8 Hz), 129.3, 141.1,
142.1, 154.7, 157.2. 19F NMR (282 MHz, DMSO-d6): δ −121.2 (s).
LCMS (ESI): tR = 1.18 min, [M + H]+ 213.2. HRMS (ESI):
(C13H10FN2) [M + H]+ requires 213.0828, found [M + H]+ 213.0823.
υmax (neat): 3345, 3039, 2243, 1595, 1533, 1493, 1402, 1348, 1241,
1226, 1171, 818, 755, 718, 693 cm−1.
4-Bromo-N-phenylaniline (3e).17 White solid (60 mg, 81% yield).
Purification: silica chromatography, 0−3% (EtOAc + 1% Et3N)/
petroleum ether. M.p.: 88−89 °C. 1H NMR (400 MHz, DMSO-d6): δ
6.87 (t, J = 7.5 Hz, 1H), 6.99−7.01 (m, 2H), 7.06−7.08 (m, 2H),
7.23−7.27 (m, 2H), 7.34−7.37 (m, 2H), 8.27 (s, 1H). 13C NMR (101
MHz, DMSO-d6): δ 110.0, 117.4, 118.0, 120.3, 129.2, 131.7, 142.6,
143.0. LCMS (ESI): tR = 1.34 min, [M + H]+ 250.1. HRMS (ESI):
(C12H11BrN) [M + H]+ requires 248.0069, found [M + H]+ 248.0076.
υmax (neat): 3401, 1579, 1500, 1481, 1312, 1070, 803, 748, 704, 690
cm−1.
N-Phenylnaphthalen-2-amine (3l).19 Colorless solid (51 mg, 77%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 107−108 °C. 1H NMR (400 MHz,
DMSO-d6): δ 6.89 (t, J = 7.2 Hz, 1H), 7.18−7.21 (m, 6H), 7.26−7.29
(m, 1H), 7.45 (d, J = 8.3 Hz 1H), 7.66 (d, J = 8.1 Hz 1H), 7.73−7.78
(m, 2H), 8.38 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 108.9,
117.3, 119.9, 120.1, 122.7, 126.1, 126.2, 127.3, 128.1, 128.7, 129.2,
134.3, 141.3, 143.0. LCMS (ESI): tR = 1.35 min, [M + H]+ 220.2.
HRMS (ESI): (C16H14N) [M + H]+ requires 220.1121, found [M +
H]+ 220.1127. υmax (neat): 3401, 1596, 1496, 1304, 854, 737, 690
cm−1.
4-Chloro-N-phenylaniline (3f).17 Colorless solid (48 mg, 78%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 65−66 °C. 1H NMR (400 MHz,
DMSO-d6): δ 6.86 (t, J = 7.2 Hz, 1H), 7.04−7.08 (m, 4H), 7.23−7.27
(m, 4 H), 8.25 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 117.2,
117.7, 120.2, 122.5, 128.9, 129.2, 142.5, 142.7. LCMS (ESI): tR = 1.32
min, [M + H]+ 204.2. HRMS (ESI): (C12H11ClN) [M + H]+ requires
204.0575, found [M + H]+ 204.0579. υmax (neat): 3402, 1585, 1500,
1482, 1443, 1394, 1307, 1298, 1171, 1069, 874, 804, 749, 710, 690
cm−1.
N-Methyl-N-phenylaniline (3m).20 Colorless oil (36 mg, 65%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
1
3-(Phenylamino)benzonitrile (3g).18 Colorless solid (49 mg, 84%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 95−96 °C. 1H NMR (400 MHz,
DMSO-d6): δ 6.95 (t, J = 7.4 Hz, 1H), 7.12−7.14 (m, 2H), 7.15−7.19
(m, 1H), 7.28−7.32 (m, 4H), 7.33−7.39 (m, 1H), 8.52 (s, 1H). 13C
NMR (101 MHz, DMSO-d6): δ 111.9, 117.6, 118.3, 119.1, 120.2,
Et3N)/petroleum ether. H NMR (400 MHz, DMSO-d6): δ 3.25 (s,
3H), 6.94 (t, J = 7.2 Hz, 2H), 6.97−7.00 (m, 4H), 7.25−7.29 (m, 4H).
13C NMR (101 MHz, DMSO-d6): δ 120.0, 121.1, 129.1, 148.6 (one
signal obscured by DMSO signals). LCMS (ESI): tR = 1.36 min, [M +
H]+ 184.2. HRMS (ESI): (C13H14N) [M + H]+ requires 184.1121,
found [M + H]+ 184.1123. υmax (neat): 3036, 1584, 1493, 1340, 1271,
D
DOI: 10.1021/acs.joc.6b00466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1251, 1185, 1156, 1130, 1091, 1074, 1023, 991, 864, 747, 722, 690
cm−1.
(q, JC‑F = 24 Hz), 123.1, 124.7, 125.7, 129.6, 130.3(dt, JC‑F = 168 Hz,
7.3 Hz), 139.0, 150.1, 168.9 (1 signal not observed). 19F NMR (282
MHz, DMSO-d6): δ −60.1 (s). LCMS (ESI): tR = 1.41 min, [M + H]+
282. HRMS (ESI): (C14H11F3NO2) [M + H]+ requires 282.0736,
found [M + H]+ 282.0739. υmax (neat): 3330, 2901, 1666, 1592, 1577,
1524, 1499, 1435, 1417, 1321, 1243, 1139, 1068, 904, 823, 792, 758,
745, 682, 662 cm−1.
N-Phenylbenzo[b]thiophen-5-amine (3u). Gray solid (33 mg, 51%
yield). Purification: silica chromatography, 0−10% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 120−121 °C. 1H NMR (400 MHz,
DMSO-d6): δ 6.81 (t, J = 7.3 Hz, 1H), 7.08−7.11 (m, 3H), 7.21−7.23
(m, 2H), 7.33 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 6.2 Hz, 1H), 6.67 (d, J
= 6.7 Hz, 1H), 7.81 (d, J = 6.7 Hz, 1H), 8.17 (s, 1H). 13C NMR (101
MHz, DMSO-d6): δ 110.1, 116.3, 117.1, 119.4, 122.9, 123.6, 127.7,
129.1, 130.9, 140.5, 143.9 (1 signal not observed). LCMS (ESI): tR =
1.33 min, [M + H]+ 226.1. HRMS (ESI): (C14H12NS) [M + H]+
requires 226.0685, found [M + H]+ 226.0686. υmax (neat): 3376, 3053,
1667, 1596, 1512, 1497, 1433, 1344, 1298, 1267, 1246, 1201, 1153,
1086, 1049, 1028, 892, 861, 825, 802, 745, 712, 670 cm−1.
N-Isopropyl-N-phenylaniline (3n).21 Colorless oil (15 mg, 24%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/petroleum ether. 1H NMR (400 MHz, DMSO-d6): δ 1.07 (d, J
= 4.1 Hz, 6H), 4.30 (sept, J = 2.3 Hz, 1H), 6.78−6.81 (m, 4H), 6.94−
6.98 (t, J = 7.5 Hz, 2H), 7.24−7.28 (m, 4H). 13C NMR (101 MHz,
DMSO-d6): δ 21.4, 48.3, 122.0, 123.1, 129.8, 146.8. LCMS (ESI): tR =
1.52 min, [M + H]+ 212.2. HRMS (ESI): (C15H18N) [M + H]+
requires 212.1434, found [M + H]+ 212.1425. υmax (neat): 3042, 1586,
1498, 1340, 1242, 1183, 1132, 1092, 1088, 993, 880, 777, 710, 690
cm−1.
Methyl-4-(phenylamino)benzoate (3o).15 White solid (54 mg,
69% yield). Purification: silica chromatography, 0−10% (EtOAc + 1%
Et3N)/petroleum ether.M.p.: 108−109 °C. 1H NMR (400 MHz,
DMSO-d6): δ 3.78 (s, 3H), 6.99 (t, J = 7.3 Hz, 1H), 7.05−7.07 (m,
2H), 7.17−7.20 (m, 2H), 7.30−7.34 (m, 2H), 7.78−7.82 (m, 2H),
8.74 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 51.4, 113.9, 119.0,
119.4, 121.9, 129.2, 131.0, 141.2, 148.5, 165.9. LCMS (ESI): tR = 1.17
min, [M + H]+ 228.2. HRMS (ESI): (C14H14NO2) [M + H]+ requires
228.1019, found [M + H]+ 228.1023. υmax (neat): 3334, 1687,1589,
1532, 1496, 1433, 1344, 1281, 1251, 1172, 1109, 851, 767, 747, 692
cm−1.
N-Phenylpyridin-3-amine (3v).23 White solid (20 mg, 40% yield).
Purification: silica chromatography, 0−50% (EtOAc + 1% Et3N)/
petroleum ether. M.p.: 140−141 °C. 1H NMR (400 MHz, DMSO-d6):
δ 6.72 (t, J = 7.2 Hz, 1H), 6.82−6.87 (m, 2H), 7.23−7.27 (m, 2H),
7.54 (m, 1H), 7.67 (m, 2H), 8.15 (s, 1H), 8.96 (s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 110.6, 114.1, 117.9, 120.2, 128.5, 137.1,
141.7, 147.1, 155.8. LCMS (ESI): tR = 0.36 min, [M + H]+ 171.2.
HRMS (ESI): (C11H11N2) [M + H]+ requires 171.0917, found [M +
H]+ 171.0915. υmax (neat): 3008, 1667, 1588, 1574, 1530, 1493, 1464,
1442, 1430, 1327, 1253, 1159, 1148, 1159, 992, 768, 747, 695 cm−1.
N-Phenylpyridin-2-amine (3w).24 White solid (17 mg, 34% yield).
Purification: silica chromatography, 0−50% (EtOAc + 1% Et3N)/
petroleum ether. M.p.: 140−141 °C. 1H NMR (400 MHz, DMSO-d6):
δ 6.71 (t, J = 7.2 Hz, 1H), 6.81−6.87 (m, 2H), 7.23−7.27 (m, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.66 (m, 2H), 8.14 (s, 1H), 8.95 (s, 1H). 13C
NMR (101 MHz, DMSO-d6): δ 110.6, 114.1, 117.9, 120.2, 128.5,
137.1, 141.7, 147.1, 155.8. LCMS (ESI): tR = 0.36 min, [M + H]+
171.2. HRMS (ESI): (C11H11N2) [M + H]+ requires 171.0917, found
[M + H]+ 171.0915. υmax (neat): 3088, 1589, 1537, 1494, 1464, 1444,
1327, 992, 770, 748, 696 cm−1.
4-Methoxy-N-phenylaniline (3p).16 Yellow solid (52 mg, 87%
yield). M.p.: 104−105 °C. Purification: silica chromatography, 0−3%
1
(EtOAc + 1% Et3N)/petroleum ether. H NMR (400 MHz, DMSO-
d6): δ 3.71 (s, 3H), 6.69 (t, J = 7.3 Hz, 1H), 6.85−6.92 (m, 4H), 7.03−
7.05 (m, 2H), 7.13−7.15 (m, 2H), 7.79 (s, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 55.2, 114.5, 114.8, 118.2, 120.3, 129.0, 136.1, 145.1,
153.8. LCMS (ESI): tR = 1.17 min, [M + H]+ 200.3. HRMS (ESI):
(C13H14NO) [M + H]+ requires 200.1070, found [M + H]+ 200.1073.
υmax (neat): 3388, 1596, 1501, 1443, 1316, 1298, 1249, 1181, 1033,
812, 750, 695 cm−1.
4-Bromo-N-phenylaniline (3q).17 White solid (53 mg, 71% yield).
M.p.: 88−89 °C. Purification: silica chromatography, 0−3% (EtOAc +
1
1% Et3N)/petroleum ether. H NMR (400 MHz, DMSO-d6): δ 6.87
(t, J = 7.5 Hz, 1H), 6.99−7.01 (m, 2H), 7.06−7.08 (m, 2H), 7.23−
7.27 (m, 2H), 7.34−7.36 (m, 2H), 8.27 (s, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 110.0, 117.4, 118.0, 120.3, 129.2, 131.7, 142.6, 143.0.
LCMS (ESI): tR = 1.34 min, [M + H]+ 250.1. HRMS (ESI):
(C12H11BrN) [M + H]+ requires 248.0069, found [M + H]+ 248.0076.
υmax (neat): 3401, 1579, 1500, 1481, 1312, 1070, 803, 748, 704, 690
cm−1.
4-(Indolin-1-yl)benzoic Acid (3x). Gray solid (20 mg, 31% yield).
Purification: silica chromatography, 0−40% (EtOAc + 1% AcOH)/
petroleum ether. M.p.: 139−140 °C. 1H NMR (400 MHz, DMSO-d6):
δ 3.09 (t, J = 7.2 Hz, 2H), 3.94 (t, J = 7.7 Hz, 2H), 6.71−6.75 (m, 1H),
7.13−7.15 (m, 1H), 7.16−7.19 (m, 4H), 7.85−7.88 (m, 2H) (1 signal
not observed). 13C NMR (101 MHz, DMSO-d6): δ 27.4, 51.4, 108.1,
115.3, 118.8, 125.0, 126.9, 130.2, 131.4, 144.4, 146.0, 169.1, 178.8.
LCMS (ESI): tR = 1.15 min, [M + H]+ 240.1. HRMS (ESI):
(C15H14NO2) [M + H]+ requires 240.1019, found [M]+ 240.1007. υmax
(neat): 3341, 2861, 1684, 1594, 1568, 1529, 1511, 1482, 1457, 1402,
1320, 1295, 1187, 1170, 928, 790, 740, 708 cm−1.
3-(Phenylamino)benzoic Acid (3r).22 White solid (53 mg, 83%
yield). Purification: silica chromatography, 0−30% (EtOAc + 1%
1
AcOH)/petroleum ether. M.p.: 140−141 °C. H NMR (400 MHz,
DMSO-d6): δ 6.88 (t, J = 7.1 Hz, 1H), 7.09−7.11 (m, 2H), 7.27−7.33
(m, 5H), 7.65 (s, 1H), 8.33 (s, 1H), 12.81 (s, 1H). 13C NMR (101
MHz, DMSO-d6): δ 116.5, 117.5, 120.1, 120.2, 120.4, 129.2, 129.3,
131.7, 142.7, 143.9, 167.4. LCMS (ESI): tR = 1.01 min, [M + H]+
214.2. HRMS (ESI): (C13H12NO2) [M + H]+ requires 214.0863,
found [M + H]+ 214.0865. υmax (neat): 3407, 2989, 1686, 1593, 1512,
1463, 1427, 1296, 1279, 996, 934, 882, 786, 749, 698, 681, 664 cm−1.
4-Chloro-2-nitro-N-phenylaniline (3s). Red solid (39 mg, 52%
yield). Purification: silica chromatography, 0−15% (EtOAc + 1%
Et3N)/petroleum ether. M.p.: 59−61 °C. 1H NMR (400 MHz,
DMSO-d6): δ 7.16−7−23 (m, 2H), 7.31−7.33 (m, 2H), 7.41−7.43
(m, 2H), 7.48−7.52 (m, 1H), 8.12 (s, 1H), 9.40 (s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 118.7, 120.8, 124.0, 125.0, 125.2, 129.5,
133.4, 135.6, 138.9, 141.0. LCMS (ESI): tR = 1.38 min, [M + H]+
249.1. HRMS (ESI): (C12H10ClN2O2) [M + H]+ requires 249.0425,
found [M + H]+ 249.0432. υmax (neat): 3338, 1618, 1593, 1566, 1526,
1498, 1456, 1407, 1345, 1246, 1213, 1148, 1074, 902, 885, 849, 819,
766, 759, 725, 694, 667 cm−1.
1-([1,1′-Biphenyl]-4-yl)piperidine (7a).25 White solid (35 mg, 74%
yield). Purification: silica chromatography, 0−1% (EtOAc + 1%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.55−1.64 (m,
2H), 1.67−1.76 (m, 4H), 3.20 (t, J = 5.1 Hz, 4H), 6.98 (d, J = 8.8 Hz,
2H), 7.25−7.27 (m, 1 H), 7.35−7.41 (m, 2H), 7.49 (d, J = 8.8 Hz,
2H) 7.54−7.56 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 24.4, 25.8,
50.4, 116.4, 126.3, 126.5, 127.6, 128.7, 131.6, 141.1, 151.4. LCMS
(ESI): tR = 0.89 min, [M + H]+ 238.3. υmax (neat): 2934, 2814, 1604,
1525, 1488, 1448, 1384, 1337, 1236, 1125, 917, 820, 760, 718, 691
cm−1.
1-Phenylpiperidine (7b). Colorless oil (23 mg, 71% yield).26
Purification: silica chromatography, 0−1% (EtOAc + 1% Et3N)/
1
cyclohexane. H NMR (400 MHz, CDCl3): δ 1.53−1.61 (m, 2H),
1.66−1.75 (m, 4H), 3.15 (t, J = 5.4 Hz, 4H), 6.78−6.84 (m, 1H), 6.93
(dd, J = 8.7, 0.9 Hz, 2H), 7.20−7.27 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 24.4, 25.9, 50.7, 116.5, 119.1, 129.0, 152.3. LCMS (ESI): tR
= 1.29 min, [M + H]+ 162.3. υmax (neat): 2932, 2853, 2805, 1597,
1493, 1450, 1384, 1334, 1235, 1220, 1131, 1025, 993, 916, 859, 753,
690 cm−1.
2-(Phenylamino)-5-(trifluoromethyl)benzoic Acid (3t). White solid
(36 mg, 43% yield). Purification: silica chromatography, 0−25%
1
(EtOAc + 1% AcOH)/petroleum ether. M.p.: 77−78 °C. H NMR
(400 MHz, DMSO-d6): δ 7.20−7.23 (m, 2H), 7.32−7.33 (m, 2H),
7.41−7.45 (m, 2H), 7.64−7.67 (m, 1H), 8.14 (s, 1H), 9.97 (s, 1H),
13.57 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 111.5, 113.7, 116.7
E
DOI: 10.1021/acs.joc.6b00466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1-(4-Methoxyphenyl)piperidine (7c).26 Off-white gum (30 mg,
78% yield). Purification: silica chromatography, 0−1.5% (EtOAc + 1%
LCMS (ESI): tR = 1.00 min, [M + H]+ 233.4. HRMS (ESI):
(C14H21N2O) [M + H]+ requires 233.1648, found [M + H]+ 233.1648.
υmax (neat): 2932, 2854, 1635, 1599, 1575, 1485, 1444, 1389, 1267,
1244, 1096, 994, 911, 749 cm−1.
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.50−1.58 (m,
2H), 1.67−1.75 (m, 4H), 3.02 (t, J = 5.4 Hz, 4H), 3.76 (s, 3H), 6.82
(d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H). 13C NMR (101 MHz,
CDCl3): δ 24.2, 26.2, 52.3, 55.6, 114.4, 118.7, 147.0, 153.6. LCMS
(ESI): tR = 1.21 min, [M + H]+ 121.3. υmax (neat): 2934, 2802, 1510,
1453, 1243, 1182, 1121, 1041, 920, 823 cm−1.
1-(o-Tolyl)piperidine (7k).31 Off-white gum (14 mg, 40% yield).
Purification: silica chromatography, 0−0.5% (EtOAc + 1% Et3N)/
1
cyclohexane. H NMR (400 MHz, CDCl3): δ 1.54−1.60 (m, 2H),
1.66−1.74 (m, 4H), 2.30 (s, 3H), 2.83 (t, J = 4.9 Hz, 4H), 6.94 (ddd, J
= 7.3, 1.0 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.11−7.18 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 17.8, 24.5, 26.6, 53.4, 119.0, 122.6, 126.4,
130.9, 132.7, 153.0. LCMS (ESI): tR = 1.52 min, [M + H]+ 176.3. υmax
(neat): 2933, 2852, 2801, 1599, 1491, 1451, 1442, 1379, 1326, 1227,
1124, 1106, 1028, 923, 759, 723 cm−1.
Methyl 4-(Piperidin-1-yl)benzoate (7d).27 White solid (32 mg, 73%
yield). Purification: silica chromatography, 0−1.5% (EtOAc + 1%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.59−1.72 (m,
6H), 3.32 (t, J = 4.6 Hz, 4H), 3.85 (s, 3H), 6.84 (d, J = 9.0 Hz, 2H),
7.89 (d, J = 9.0 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 24.4, 25.4,
48.8, 51.5, 113.6, 118.7, 131.2, 154.5, 167.2. LCMS (ESI): tR = 1.28
min, [M + H]+ 220.3. υmax (neat): 2847, 2843, 1704, 1606, 1516, 1436,
1287, 1247, 1191, 1110, 964, 916, 827, 771, 694 cm−1.
3-(Piperidin-1-yl)pyridine (7l).32 Brown gum (7 mg, 22% yield).
Purification: silica chromatography, 0−75% (EtOAc + 1% Et3N)/
1
cyclohexane. H NMR (400 MHz, CDCl3): δ 1.55−1.65 (m, 2H),
1-(4-Bromophenyl)piperidine (7e).28 White solid (41 mg, 85%
yield). Purification: silica chromatography, 0−1.5% (EtOAc + 1%
1.67−1.76 (m, 4H), 3.19 (t, J = 5.4 Hz, 4H), 7.13 (ddd, J = 8.6, 4.6,
0.7 Hz, 1H), 7.18 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 8.05 (dd, J = 4.5, 1.3
Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ
24.1, 25.6, 49.9, 122.6, 123.3, 139.0, 140.0, 147.7. LCMS (ESI): tR =
0.94 min, [M + H]+ 163.3. υmax (neat): 2935, 2854, 2810, 1582, 1488,
1451, 1424, 1384, 1346, 1245, 1131, 919, 859, 797, 707 cm−1.
tert-Butyl (3-(Piperidin-1-yl)phenyl)carbamate (7m). White solid
(42 mg, 76% yield). Purification: silica chromatography, 0−5%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.54−1.61 (m,
2H), 1.64−1.73 (m, 4H), 3.12 (t, J = 5.4 Hz, 4H), 6.79 (d, J = 9.0 Hz,
2H), 7.31 (d, J = 9.0 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 24.2,
25.7, 50.4, 111.1, 118.0, 131.7, 151.2. LCMS (ESI): tR = 1.46 min, [M
+ H]+ 240.2. υmax (neat): 2941, 2858, 2817, 1588, 1494, 1450, 1387,
1340, 1280, 1243, 1223, 1127, 992, 917, 860, 808 cm−1.
1-(4-Chlorophenyl)piperidine (7f).29 White solid (33 mg, 84%
yield). Purification: silica chromatography, 0−1.5% (EtOAc + 1%
Et3N)/cyclohexane. M.p.: 67−69 °C. 1H NMR (400 MHz, CDCl3): δ
1.51−1.61 (m, 2H), 1.65−1.74 (m, 4H), 3.11 (t, J = 5.4 Hz, 4H),
6.82−6.85(m, 2H), 7.15−7.20 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 24.2, 25.7, 50.6, 117.6, 123.9, 128.8, 150.8. LCMS (ESI): tR
= 1.43 min, [M + H]+ 196.3. υmax (neat): 2940, 2810, 1596, 1492,
1441, 1383, 1338, 1242, 1223, 1127, 993, 916, 858, 808, 747 cm−1.
1-(3-Cyanophenyl)piperidine (7g).30 Off-white gum (24 mg, 64%
yield). Purification: silica chromatography, 0−2.5% (EtOAc + 1%
(EtOAc + 1% Et3N)/cyclohexane. M.p.: 94−95 °C. H NMR (400
1
MHz, CDCl3): δ 1.51 (s, 9 H), 1.53−1.60 (m, 2H), 1.68 (dt, J = 11.2,
5.6 Hz, 4H), 3.14 (t, J = 5.6 Hz, 4H), 6.44 (br. s., 1H), 6.60 (dd, J =
8.2, 2.1 Hz, 1H), 6.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.08 (br. s., 1H),
7.09−7.14 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 24.4, 25.8, 28.4,
50.5, 80.2, 106.6, 109.3, 111.3, 129.3, 139.2, 152.7, 153.0. LCMS
(ESI): tR = 1.36 min, [M + H]+ 277.3. HRMS (ESI): (C16H25N2O2)
[M + H]+ requires 277.1911, found [M + H]+ 277.1914. υmax (neat):
3328, 2933, 1698, 1607, 1532, 1497, 1443, 1366, 1236, 1155, 1053,
1026, 979, 954, 901, 861, 768, 692 cm−1.
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.58−1.74 (m,
4-(4-(Piperidin-1-yl)benzyl)morpholine (7n). Colorless oil (38 mg,
6H), 3.19 (t, J = 5.4 Hz, 4H), 7.03 (d, J = 7.3 Hz, 1H), 7.07−7.12 (m,
2H), 7.25−7.31 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 24.1, 25.4,
49.7, 112.9, 118.6, 119.5, 120.1, 121.7, 129.7, 151.9. LCMS (ESI): tR =
1.25 min, [M + H]+ 187.3. υmax (neat): 2937, 2861, 2216, 1595, 1572,
1493, 1438, 1383, 1247, 1123, 996, 955, 784, 688 cm−1.
73% yield). Purification: silica chromatography, 0−45% (EtOAc + 2%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.53−1.61 (m,
2H), 1.66−1.75 (m, 4H), 2.42 (t, J = 4.6 Hz, 4H), 3.14 (t, J = 5.1 Hz,
4H), 3.41 (s, 2H), 3.69 (t, J = 4.9 Hz, 4H), 6.88 (d, J = 8.6 Hz, 2H),
7.17 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 24.3, 25.9,
1-(4-(Trifluoromethoxy)phenyl)piperidine (7h). Colorless oil (35
50.7, 53.6, 63.0, 67.1, 116.2, 128.0, 130.0, 151.4. LCMS (ESI): tR =
mg, 71% yield). Purification: silica chromatography, 0−1% (EtOAc +
1.17 min, [M + H]+ 261.4. HRMS (ESI): (C16H25N2O) [M + H]+
requires 261.1961, found [M + H]+ 261.1961. υmax (neat): 2932, 2853,
2804, 1613, 1515, 1453, 1237, 1118, 1006, 915, 866 cm−1.
1
2% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.52−1.62
(m, 2H), 1.65−1.74 (m, 4H), 3.13 (t, J = 5.4 Hz, 4H), 6.88 (d, J = 9.0
Hz, 2H), 7.08 (dd, J = 9.2, 0.9 Hz, 2H). 13C NMR (101 MHz,
CDCl3): δ 24.2, 25.8, 50.7, 116.9, 120.7 (q, JC‑F = 255.3 Hz), 121.8,
141.6 (q, JC‑F = 2.0 Hz), 151.0. 19F NMR (282 MHz, CDCl3): δ
−58.32 (s). LCMS (ESI) tR = 1.48 min, [M + H]+ 246.3. HRMS
(ESI): (C12H15F3NO) [M + H]+ requires 246.1100, found [M + H]+
246.1101. υmax (neat): 2938, 1509, 1260, 1232, 1206, 1155, 1131,
1026, 920, 835, 807 cm−1.
tert-Butyl 5-(Piperidin-1-yl)indoline-1-carboxylate (7o). Off-white
solid (39 mg, 65% yield). Purification: silica chromatography, 0−7%
1
(EtOAc + 1% Et3N)/cyclohexane. M.p.: 88−91 °C. H NMR (400
MHz, CDCl3): δ 1.51−1.56 (m, 2H), 1.55 (s, 9H), 1.66−1.76 (m,
4H), 2.98−3.08 (m, 6H), 3.94 (br. s., 2H), 6.75 (d, J = 8.6 Hz, 1H),
6.80 (s, 1H), 7.35 (d, J = 8.0 Hz, 0.5H), 7.74 (d, J = 8.2 Hz, 0.5H). 13C
NMR (126 MHz, CDCl3): δ 24.2, 26.0, 27.3, 27.8, 28.5, 47.5, 47.7,
52.2, 52.3, 80.0, 81.1, 114.7, 114.8, 114.9, 116.0, 116.4, 131.7, 132.7,
135.3, 136.4, 148.3, 152.5, 152.8. LCMS (ESI): tR = 1.50 min, [M +
H]+ 303.3. HRMS (ESI): (C18H27N2O2) [M + H]+ requires 303.2037,
found [M + H]+ 303.2069. υmax (neat): 2932, 2855, 2793, 1692, 1494,
1453, 1380, 1366, 1331, 1244, 1174, 1140, 1127, 1018, 950, 862, 813,
762 cm−1.
N-Methyl-3-(piperidin-1-yl)benzamide (7i). Off-white solid (27
mg, 62% yield). Purification: silica chromatography, 0−35% (EtOAc +
1% Et3N)/cyclohexane. M.p.: 96−98 °C. 1H NMR (400 MHz,
CDCl3): δ 1.53−1.62 (m, 2H), 1.64−1.73 (m, 4H), 2.98 (d, J = 4.9
Hz, 3H), 3.19 (t, J = 5.1 Hz, 4H), 6.27 (br. s., 1H), 7.02 (ddd, J = 8.3,
2.7, 1.0 Hz, 1H), 7.05−7.10 (m, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.35−
7.39 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 24.2, 25.7, 26.8, 50.3,
114.9, 116.5, 119.0, 129.0, 135.6, 152.3, 168.8. LCMS (ESI): tR = 0.91
min, [M + H]+ 219.3. HRMS (ESI): (C13H19N2O) [M + H]+ requires
219.1492, found [M + H]+ 219.1492. υmax (neat): 3315, 2934, 2854,
2806, 1636, 1598, 1576, 1543, 1489, 1443, 1365, 1343, 1239, 1127,
940, 755, 693 cm−1.
N,N-Dibutylaniline (7p).33 Brown oil (4 mg, 10% yield).
Purification: silica chromatography, 0−1% (EtOAc + 1% Et3N)/
cyclohexane. 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 6H),
1.29−1.40 (m, 4H), 1.52−1.62 (m, 4H), 3.22−3.29 (m, 4H), 6.58−
6.67 (m, 3H), 7.15−7.22 (m, 2H). LCMS (ESI): tR = 1.64 min, [M +
H]+ 206.4. Matches data from: Barker, T. J.; Jarvo, E. R. J. Am. Chem.
Soc. 2009, 131, 15598−15599, DOI: 10.1021/ja907038b.
N,N-Dimethyl-3-(piperidin-1-yl)benzamide (7j). Off-white gum
(38 mg, 82% yield). Purification: silica chromatography, 0−30%
N-Isopropylnaphthalen-2-amine (7q).34 Brown oil (27 mg, 73%
yield). Purification: silica chromatography, 0−1% (EtOAc + 1%
1
(EtOAc + 1% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ
1
1.51−1.63 (m, 2H), 1.65−1.74 (m, 4H), 2.97 (br. s., 3H), 3.09 (br. s.,
3H), 3.17 (t, J = 5.6 Hz, 4H), 6.79 (dd, J = 7.5, 1.1 Hz, 1H), 6.91−6.97
(m, 2H), 7.20−7.25 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 24.3,
25.7, 35.2, 39.5, 50.3, 114.7, 117.2, 117.2, 128.9, 137.2, 152.1, 172.2.
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.26 (d, J = 6.3
Hz, 6H), 3.58 (br. s., 1H), 3.75 (sept, J = 6.3 Hz, 1H), 6.78 (d, J = 2.4
Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (ddd, J = 8.1, 6.9, 1.1 Hz,
1H), 7.33 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.60
F
DOI: 10.1021/acs.joc.6b00466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H). 13C NMR (101 MHz,
CDCl3): δ 22.9, 44.3, 105.0, 118.3, 121.8, 125.8, 126.2, 127.3, 127.6,
128.9, 135.3, 145.1. LCMS (ESI): tR = 1.31 min, [M + H]+ 186.3. υmax
(neat): 3403, 2966, 1627, 1603, 1522, 1485, 1398, 1361, 1225, 1191,
828, 807, 744 cm−1.
3-(Phenethylamino)benzonitrile (7r). Off-white solid (25 mg, 56%
yield). Purification: silica chromatography, 0−3% (EtOAc + 1%
Et3N)/cyclohexane. M.p.: 61−63 °C. 1H NMR (400 MHz, CDCl3): δ
2.92 (t, J = 7.0 Hz, 2H), 3.35−3.45 (m, 2H), 3.88 (br. s., 1H), 6.73−
6.81 (m, 2H), 6.95 (dt, J = 7.5, 1.1 Hz, 1H), 7.17−7.28 (m, 4H),
7.30−7.36 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 35.2, 44.6, 113.0,
115.0, 117.3, 119.4, 120.8, 126.7, 128.7, 128.8, 129.9, 138.6, 148.2.
LCMS (ESI): tR = 1.26 min, [M + H]+ 223.3. HRMS (ESI):
(C15H15N2) [M + H]+ requires 223.1230, found [M + H]+ 223.1231.
υmax (neat): 3392, 3028, 2930, 2857, 2227, 1602, 1583, 1514, 1493,
1428, 1335, 1303, 780, 751, 700, 682 cm−1.
(t, J = 7.3 Hz, 2H), 6.63−6.72 (m, 3H), 7.18−7.26 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ 14.0, 20.4, 28.9, 38.3, 52.5, 112.1, 115.8, 129.2,
149.4. LCMS (ESI): tR = 1.42 min, [M + H]+ 164.3. υmax (neat): 2958,
2869, 1600, 1507, 1366, 1207, 746, 691 cm−1.
N-Methyl-N-(2-(methylsulfonyl)ethyl)aniline (7y). Colorless oil
(18 mg, 42% yield). Purification: silica chromatography, 0−35%
1
(EtOAc + 1% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ
2.91 (s, 3H), 2.98 (s, 3H), 3.25 (t, J = 6.8 Hz, 2H), 3.89 (t, J = 7.0 Hz,
2H), 6.76−6.84 (m, 3H), 7.25−7.31 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 38.8, 42.1, 46.7, 51.4, 113.2, 118.2, 129.6, 148.1. LCMS
(ESI): tR = 0.82 min, [M + H]+ 214.2. HRMS (ESI): (C10H16NO2S)
[M + H]+ requires 214.0896, found [M + H]+ 214.0899. υmax (neat):
2927, 1600, 1505, 1362, 1362, 1301, 1134, 955, 752, 695 cm−1.
N-Butylaniline (7z).36 Colorless oil (21 mg, 70% yield).
Purification: silica chromatography, 0−1% (EtOAc + 1% Et3N)/
cyclohexane. 1H NMR (400 MHz, CDCl3): δ 0.95 (t, J = 7.3 Hz, 3H),
1.37−1.48 (m, 2H), 1.55−1.64 (m, 2H), 3.10 (t, J = 7.1 Hz, 2H), 3.53
(br. s., 1H), 6.59 (d, J = 7.8 Hz, 2H), 6.67 (t, J = 7.3 Hz, 1H), 7.13−
7.20 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 13.9, 20.3, 31.7, 43.7,
112.7, 117.1, 129.2, 148.6. LCMS (ESI): tR = 1.26 min, [M + H]+
150.3. υmax (neat): 3414, 2958, 2869, 1603, 1506, 1320, 1262, 1179,
747, 692 cm−1.
2-Methyl-N-phenethylaniline (7s). Yellow gum (30 mg, 71%
yield). Purification: silica chromatography, 0−1.5% (EtOAc + 1%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 2.02 (s, 3H),
2.96 (t, J = 6.8 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 3.51 (br. s., 1H),
6.62−6.70 (m, 2H), 7.03 (d, J = 7.1 Hz, 1H), 7.09−7.16 (m, 1H),
7.20−7.27 (m, 3H), 7.28−7.35 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 17.3, 35.5, 45.0, 109.9, 117.0, 122.1, 126.4, 127.1, 128.6,
128.8, 130.1, 139.4, 145.9. LCMS (ESI): tR = 1.39 min, [M + H]+
212.3. HRMS (ESI): (C15H18N) [M + H]+ requires 212.1434, found
[M + H]+ 212.1435. υmax (neat): 3419, 3023, 2920, 2853, 1606, 1587,
1514, 1473, 1453, 1317, 1263, 1130, 1052, 746, 700 cm−1.
N-Isopropylaniline (7aa).37 Off-white oil (14 mg, 52% yield).
Purification: silica chromatography, 0−1% (EtOAc + 1% Et3N)/
cyclohexane. 1H NMR (400 MHz, CDCl3): δ 1.20 (d, J = 6.4 Hz, 6H),
3.37 (br. s., 1H), 3.62 (sept, J = 6.3 Hz, 1H), 6.58 (d, J = 7.6 Hz, 2H),
6.66 (t, J = 7.3 Hz, 1H), 7.11−7.18 (m, 2 H). 13C NMR (101 MHz,
CDCl3): δ 23.0, 44.2, 113.3, 117.0, 129.3, 147.5. LCMS (ESI): tR =
1.12 min, [M + H]+ 136.2. υmax (neat): 3397, 2696, 1603, 1506, 1317,
1256, 1179, 748, 693 cm−1.
Methyl 1-Phenylpiperidine-4-carboxylate (7t). Light yellow oil (27
mg, 62% yield). Purification: silica chromatography, 0−1% (EtOAc +
1
1% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.81−1.93
(m, 2H), 1.97−2.07 (m, 2H), 2.45 (tt, J = 11.1, 4.0 Hz, 1H), 2.78 (td, J
= 11.9, 2.9 Hz, 2H), 3.64 (dt, J = 12.7, 3.3 Hz, 2H), 3.70 (s, 3H), 6.84
(t, J = 7.2 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 7.21−7.28 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 28.1, 41.0, 49.3, 51.7, 116.7, 119.7, 129.1,
151.6, 175.3. LCMS (ESI): tR = 1.15 min, [M + H]+ 220.3. HRMS
(ESI): (C13H18NO2) [M + H]+ requires 220.1332, found [M + H]+
220.1338. υmax (neat): 2951, 2811, 1733, 1598, 1496, 1448, 1388,
1314, 1251, 1194, 1168, 1043, 922, 757, 694 cm−1.
tert-Butyl 4-(2-(Phenylamino)ethyl)piperidine-1-carboxylate
(7ab). Off-white solid (50 mg, 82% yield). Purification: silica
chromatography, 0−10% (EtOAc + 1% Et3N)/cyclohexane. M.p.:
1
92−94 °C. H NMR (400 MHz, CDCl3): δ 1.06−1.23 (m, 2H), 1.46
(s, 9H), 1.52−1.60 (m, 3H), 1.69 (d, J = 13.0 Hz, 2H), 2.69 (t, J =
12.2 Hz, 2H), 3.14 (t, J = 7.0 Hz, 2H), 3.53 (br. s., 1H), 4.01−4.16 (m,
2H), 6.59 (dd, J = 8.6, 1.0 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 7.17 (dd,
J = 8.4, 7.5 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 28.5, 32.2, 33.9,
36.3, 41.3, 44.0, 79.3, 112.7, 117.3, 129.3, 148.4, 154.9. LCMS (ESI):
tR = 1.39 min, [M + H]+ 305.3. HRMS (ESI): (C18H29N2O2) [M +
H]+ requires 305.2224, found [M + H]+ 305.2231. υmax (neat): 3375,
2922, 2850, 1675, 1602, 1507, 1423, 1365, 1278, 1244, 1166, 1143,
1090, 968, 866, 747, 693 cm−1.
N,N-Dimethyl-1-phenylpiperidin-4-amine (7u). Yellow solid (28
mg, 69% yield). Purification: silica chromatography, 0−7% (EtOAc +
1% Et3N)/cyclohexane. M.p.: 45−48 °C. 1H NMR (400 MHz,
CDCl3): δ 1.64 (qd, J = 12.1, 3.9 Hz, 2H), 1.89−1.97 (m, 2H), 2.24−
2.31 (m, 1H), 2.32 (s, 6H), 2.71 (td, J = 12.3, 2.6 Hz, 2H), 3.68−3.77
(m, 2H), 6.82 (t, J = 7.2 Hz, 1H), 6.94 (dd, J = 8.7, 0.9 Hz, 2H), 7.20−
7.28 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 28.3, 41.7, 49.2, 62.2,
116.5, 119.4, 129.0, 151.5. LCMS (ESI): tR = 0.97 min, [M + H]+
205.3. HRMS (ESI): (C13H21N2) [M + H]+ requires 205.1699, found
[M + H]+ 205.1701. υmax (neat): 2945, 2770, 1600, 1499, 1378, 1220,
1190, 1153, 1065, 1040, 994, 918, 757, 692 cm−1.
4-Phenylthiomorpholine 1,1-Dioxide (7v). White solid (23 mg,
54% yield). Purification: silica chromatography, 0−35% (EtOAc + 1%
Et3N)/cyclohexane. M.p.: 123−124 °C. 1H NMR (400 MHz, CDCl3):
δ 3.05−3.14 (m, 4H), 3.79−3.88 (m, 4H), 6.86−6.97 (m, 3H), 7.26−
7.34 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 47.7, 50.6, 116.4,
120.9, 129.8, 147.7. LCMS (ESI): tR = 0.78 min, [M + H]+ 212.3.
HRMS (ESI): (C10H14NO2S) [M + H]+ requires 212.0740, found [M
+ H]+ 212.0737. υmax (neat): 2930, 1598, 1498, 1309, 1384, 1276,
1227, 1176, 1121, 975, 858, 756, 694 cm−1.
N-Cyclopentylaniline (7ac).38 Off-white gum (24 mg, 74% yield).
Purification: silica chromatography, 0−1% (EtOAc + 1% Et3N)/
1
cyclohexane. H NMR (400 MHz, CDCl3): δ 1.40−1.53 (m, 2H),
1.55−1.78 (m, 4H), 1.95−2.08 (m, 2H), 3.61 (br. s., 1H), 3.73−3.82
(m, 1H), 6.59 (dd, J = 8.6, 1.0 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 7.10−
7.20 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 24.1, 33.6, 54.7, 113.2,
116.9, 129.2, 148.1. LCMS (ESI): tR = 1.27 min, [M + H]+ 162.3. υmax
(neat): 3397, 2955, 2868, 1602,1504, 1429, 1313, 1180, 747, 692
cm−1.
N-((Tetrahydro-2H-pyran-4-yl)methyl)aniline (7ad).39 Off-white
oil (33 mg, 86% yield). Purification: silica chromatography, 0−9%
1
(EtOAc + 1% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ
1.30−1.43 (m, 2H), 1.66−1.75 (m, 2H), 1.78−1.91 (m, 1H), 3.03 (d, J
= 6.6 Hz, 2H), 3.39 (td, J = 11.8, 2.1 Hz, 2H), 3.71 (br. s., 1H), 3.94−
4.03 (m, 2H), 6.60 (dd, J = 8.6, 1.0 Hz, 2H), 6.66−6.72 (m, 1H),
7.13−7.20 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 31.1, 34.9, 50.0,
67.8, 112.7, 117.3, 129.3, 148.3. LCMS (ESI): tR = 1.02 min, [M + H]+
192.3. υmax (neat): 3372, 2929, 2843, 1603, 1508, 1327, 1264, 1141,
1091, 1014, 984, 853, 749, 693 cm−1.
4-Phenylmorpholine (7w).35 White solid (23 mg, 71% yield).
Purification: silica chromatography, 0−2% (EtOAc + 1% Et3N)/
cyclohexane. M.p.: 54−55 °C. 1H NMR (400 MHz, CDCl3): δ 3.16 (t,
J = 4.9 Hz, 4H), 3.86 (t, J = 4.9 Hz, 4H), 6.85−6.94 (m, 3H), 7.26−
7.31 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 49.4, 67.0, 115.7,
120.0, 129.2, 151.3. LCMS (ESI): tR = 0.92 min, [M + H]+ 164.3. υmax
(neat): 2953, 2844, 1603, 1501, 1453, 1331, 1263, 1239, 1123, 1067,
925, 758, 695 cm−1.
N-Phenethylaniline (7ae).40 Off-white gum (34 mg, 86% yield).
Purification: silica chromatography, 0−1.5% (EtOAc + 1% Et3N)/
cyclohexane. 1H NMR (400 MHz, CDCl3): δ 2.91 (t, J = 7.0 Hz, 2H),
3.40 (t, J = 7.0 Hz, 2H), 3.66 (br. s., 1H), 6.61 (dd, J = 8.6, 1.0 Hz,
2H), 6.70 (tt, J = 7.3, 1.0 Hz, 1H), 7.14−7.26 (m, 5H), 7.28−7.34 (m,
2H). 13C NMR (101 MHz, CDCl3): δ 35.6, 45.1, 113.0, 117.5, 126.4,
128.6, 128.8, 129.3, 139.3, 148.0. LCMS (ESI): tR = 1.31 min, [M +
N-Butyl-N-methylaniline (7x).33 Off-white gum (14 mg, 43%
yield). Purification: silica chromatography, 0−1% (EtOAc + 1%
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 0.94 (t, J = 7.3
Hz, 3H), 1.29−1.40 (m, 2H), 1.49−1.60 (m, 2H), 2.91 (s, 3H), 3.30
G
DOI: 10.1021/acs.joc.6b00466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
H]+ 198.3. υmax (neat): 3409, 3025, 2928, 2861, 1602, 1506, 1454,
1319, 1262, 1180, 748, 693 cm−1.
1470, 1436, 1384, 1317, 1256, 1177, 1150, 1098, 1069, 990, 870, 750,
697 cm−1.
N-(4-Methoxybenzyl)aniline (7af).41 Yellow oil (36 mg, 84%
yield). Purification: silica chromatography, 0−2% (EtOAc + 1%
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00466.
■
1
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 3.80 (s, 3H),
S
3.92 (br. s., 1H), 4.25 (s, 2H), 6.63 (d, J = 7.8 Hz, 2H), 6.71 (t, J = 7.3
Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.14−7.20 (m, 2H), 7.28 (d, J = 8.6
Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 47.8, 55.3, 112.9, 114.1,
117.5, 128.8, 129.2, 131.4, 148.2, 158.9. LCMS (ESI): tR = 1.22 min,
[M − H]− 212.2. υmax (neat): 3416, 3011, 2927, 2835, 1603, 1509,
1465, 1431, 1302, 1246, 1177, 1033, 824, 750, 693 cm−1.
Data from solvent and concentration optimization and
NMR, LCMS, HRMS, and IR spectra for characterization
(PDF)
N-(4,4,4-Trifluorobutyl)aniline (7ag).39 Yellow oil (28 mg, 69%
yield). Purification: silica chromatography, 0−1% (EtOAc + 1%
AUTHOR INFORMATION
Corresponding Author
*E-mail: allan.watson.100@strath.ac.uk.
1
■
Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 1.81−1.93 (m,
2H), 2.12−2.28 (m, 2H), 3.21 (t, J = 7.0 Hz, 2H), 3.59 (br. s., 1H),
6.60 (dd, J = 8.7, 0.9 Hz, 2H), 6.68−6.76 (m, 1H), 7.13−7.22 (m,
2H). 13C NMR (101 MHz, CDCl3): δ 22.2 (q, JC‑F = 2.7 Hz), 31.5 (q,
JC‑F = 28.6 Hz), 42.7, 112.8, 117.8, 127.1 (q, JC‑F = 275.8 Hz), 129.4,
147.8. 19F NMR (282 MHz, CDCl3): δ −66.14 (t, J = 10.4 Hz, 3F).
LCMS (ESI): tR = 1.21 min, [M + H]+ 204.3. υmax (neat): 3414, 2948,
1604, 1508, 1391, 1316, 1295, 1250, 1225, 1144, 1028, 750, 693 cm−1.
4-((Phenylamino)methyl)pyrrolidin-2-one (7ah). Off-white solid
(12 mg, 32% yield). Purification: silica chromatography, 0−100%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank GlaxoSmithKline for Ph.D. studentships (J.C.V.,
R.P.L.), the EPSRC UK National Mass Spectrometry Facility at
Swansea University for analyses, and GlaxoSmithKline for
chemical and analytical resources.
1
(EtOAc + 1% Et3N)/cyclohexane. M.p.: 95−98 °C. H NMR (400
MHz, CDCl3): δ 2.16 (dd, J = 17.1, 6.1 Hz, 1H), 2.51 (dd, J = 16.9, 8.8
Hz, 1H), 2.72−2.85 (m, 1H), 3.15−3.26 (m, 3H), 3.55 (dd, J = 9.5,
8.1 Hz, 1H), 3.77 (br. s., 1H), 6.28 (br. s., 1H), 6.61 (d, J = 7.8 Hz,
2H), 6.73 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.8 Hz, 2H). 13C NMR (101
MHz, CDCl3): δ 34.3, 34.6, 45.9, 47.7, 112.8, 117.9, 129.4, 147.7,
177.6. LCMS (ESI): tR = 0.71 min, [M + H]+ 191.3. HRMS:
(C11H15N2O) [M + H]+ requires 191.1179, found [M + H]+ 191.1176.
υmax (neat): 3335, 2924, 1682, 1602, 1499, 1321, 1262, 750, 694 cm−1.
N-(2-Methoxyethyl)aniline (7ai).37 Yellow oil (23 mg, 76% yield).
Purification: silica chromatography, 0−6% (EtOAc + 1% Et3N)/
cyclohexane. 1H NMR (400 MHz, CDCl3): δ 3.28 (t, J = 5.3 Hz, 2H),
3.38 (s, 3H), 3.60 (t, J = 5.3 Hz, 2H), 4.00 (br. s., 1H), 6.60−6.66 (m,
2H), 6.71 (t, J = 7.3 Hz, 1H), 7.13−7.20 (m, 2H). 13C NMR (101
MHz, CDCl3): δ 43.5, 58.7, 71.1, 113.1, 117.6, 129.2, 148.2. LCMS
(ESI): tR = 0.90 min, [M + H]+ 152.3. υmax (neat): 3401, 2891, 1603,
1507, 1459, 1320, 1277, 1193, 1117, 749, 693 cm−1.
REFERENCES
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tert-Butyl (2-(Phenylamino)ethyl)carbamate (7aj). Off-white solid
(33 mg, 70% yield). Purification: silica chromatography, 0−12%
1
(EtOAc + 1% Et3N)/cyclohexane. M.p.: 83−85 °C. H NMR (400
MHz, CDCl3): δ 1.45 (s, 9H), 3.22−3.29 (m, 2H), 3.32−3.41 (m,
2H), 3.94 (br. s., 1H), 4.77 (br. s., 1H), 6.61 (d, J = 8.3 Hz, 2H), 6.71
(t, J = 7.3 Hz, 1H), 7.13−7.21 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 28.4, 40.2, 44.4, 79.6, 112.8, 117.6, 129.3, 148.0, 156.4.
LCMS (ESI): tR = 1.11 min, [M + H]+ 237.4. HRMS: (C13H21N2O2)
[M + H]+ requires 237.1598, found [M + H]+ 237.1602. υmax (neat):
3380, 2977, 1691, 1604, 1509, 1366, 1253, 1169, 989, 749, 693 cm−1.
N-(2-(1,3-Dioxolan-2-yl)ethyl)aniline (7ak). Light brown oil (30
mg, 78% yield). Purification: silica chromatography, 0−6% (EtOAc +
1
1% Et3N)/cyclohexane. H NMR (400 MHz, CDCl3): δ 2.01 (td, J =
6.4, 4.5 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 3.83−3.91 (m, 2H), 3.93−
4.01 (m, 2H), 4.05 (br. s., 1H), 4.98 (t, J = 4.5 Hz, 1H), 6.61 (d, J =
7.8 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 7.16 (dd, J = 8.3, 7.3 Hz, 2H).
13C NMR (101 MHz, CDCl3): δ 33.1, 39.3, 64.9, 103.8, 112.8, 117.3,
129.2, 148.4. LCMS (ESI): tR = 0.95 min, [M + H]+ 194.3. HRMS
(ESI): (C11H16NO2) [M + H]+ requires 194.1176, found [M + H]+
194.1177. υmax (neat): 3400, 2884, 1603, 1508, 1413, 1319, 1266,
1180, 1139, 1031, 944, 750, 694 cm−1.
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N-((1,3,5-Trimethyl-1H-pyrazol-4-yl)methyl)aniline (7al).42 White
solid (39 mg, 91% yield). Purification: silica chromatography, 0−100%
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1
(EtOAc + 1% Et3N)/cyclohexane. M.p.: 106−107 °C. H NMR (400
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3H), 3.99 (s, 2H), 6.65 (dd, J = 8.4, 0.9 Hz, 2H), 6.69−6.75 (m, 1H),
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38.1, 112.7, 113.5, 117.4, 129.3, 137.6, 146.3, 148.4. LCMS (ESI): tR =
0.98 min, [M + H]+ 216.3. υmax (neat): 3300, 2925, 2823, 1601, 1511,
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