Selective Formation of ortho -Aminobenzylamines by the Copper-Catalyzed Amination of Benzylamine Boronate Esters

Article abstract of DOI:10.1021/acs.joc.5b01074

The copper-catalyzed coupling between benzylamino boronate esters and aryl amines has been investigated. Formation of ortho-aminobenzylamines was achieved under oxidative conditions in the presence of copper(II) acetate. The major side product of the tran

Full text of DOI:10.1021/acs.joc.5b01074

Article
pubs.acs.org/joc
Selective Formation of ortho-Aminobenzylamines by the Copper-
Catalyzed Amination of Benzylamine Boronate Esters
Kathryn A. McGarry, Alexi A. Duenas, and Timothy B. Clark*
́
Department of Chemistry & Biochemistry, University of San Diego, 5998 Alcala Park, San Diego, California 92110, United States
S
* Supporting Information
ABSTRACT: The copper-catalyzed coupling between benzylami-
no boronate esters and aryl amines has been investigated.
Formation of ortho-aminobenzylamines was achieved under
oxidative conditions in the presence of copper(II) acetate. The
major side product of the transformation is the homocoupling of
the aryl boronate ester. The formation of the desired diamines was
found to be improved in the absence of base, increasing selectivity
over the homocoupled product. Both electron-donating and electron-withdrawing substituents are tolerated on both the
boronate ester substrate and the aniline coupling partner under the reaction conditions. The presence of the adjacent
benzylamine moiety appears to enhance the reactivity of the boronate ester and influence the resulting product distribution, likely
by affecting the competing rates of transmetalation in the catalytic cycles.
through iridium-catalyzed C−H borylation,30,31 we sought to
INTRODUCTION
■
develop copper-catalyzed conditions to ortho-aminobenzyl-
Owing to the ubiquitous nature of C−N bonds in natural
products and pharmaceuticals, a huge portion of synthetic
research has been invested into new methods to install amines
into organic substrates. The transformation of C−N bonds
from C−B bonds under copper-mediated conditions, first
discovered by Chan1 and Lam2 and later shown to proceed
under catalytic conditions from boronic acids,3−7 has proven
invaluable in the synthesis of biologically relevant molecular
structures, with many examples occurring in the past few
years.8−16 The majority of transformations that describe this
reaction utilize boronic acid coupling partners, while limited
examples employ trifluoroborates17 and boronate esters.18,19
With the development of iridium-catalyzed aryl C−H
borylation reactions, resulting in the facile installation of a
boronate ester functional group,20−23 additional methods that
allow the formation of C−N bonds from boronate esters would
expand applications of this valuable process.
Substrate-directed C−H borylation has received a great deal
of attention over the past decade as a powerful way to
selectively form new C−B bonds from unreactive C−H
bonds.24−29 One such method has employed a pendant
amine to achieve directed ortho-C−H borylation, yielding
benzylamine boronate esters.30−32 The conversion of these
boronate esters into aminobenzylamines has not yet been
reported but appeared to be feasible under copper-catalyzed
conditions. While the coupling between an aryl halide and an
amine in the presence of a pendant amine is known,33 the use
of a pendant coordinating group in the copper-catalyzed
coupling of a boronate ester with an amine has not been
reported. Furthermore, no examples could be found on the
direct conversion of benzylamines into ortho-aminobenzyl-
amines, compounds which have potential as effective ligands.34
Having successfully synthesized benzylamine boronate esters
amines from these boronate ester substrates (eq 1).
RESULTS AND DISCUSSION
■
Initial conditions were chosen which employed a boronate ester
as the limiting reagent in an amine coupling reaction.19 The
investigation began with the coupling of aryl boronate ester 1
with alkyl amines since alkyl amines were shown to have better
reactivity than anilines in the amination of aryl boronate esters.
Upon coupling compound 1 with isopropylamine using 10 mol
% of copper(II) acetate at 80 °C for 2 h, we were gratified to
find that 2-((dimethylamino)methyl)-N-isoproylaniline (2a)
was produced (eq 2). Analysis of the crude reaction mixture
revealed complete consumption of the starting boronate ester
and evidence of an additional product, identified as biaryl 2b.
Formation of this product was foreseeable as the homocoupling
of arylboronic acids and boronate esters has been observed
under oxidative palladium-catalyzed conditions35−38 and under
copper-catalyzed conditions.39−42 The synthesis of compound
2b has previously been achieved under stoichiometric copper-
mediated conditions from an arylcuprate43 or aryl halide,44
although catalytic methods from benzylamine boronate ester
substrates to the corresponding biphenyls have not been
reported. The product distribution, however, was unanticipated,
which was found to consist of 51% of 2b with the remaining
Received: May 13, 2015
© XXXX American Chemical Society
A
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Table 1. Product Selectivity for Initial Analysis of the Amine
a
Coupling Reaction
49% of 2a.45 Alternative conditions which were reported to
successfully couple aliphatic amines with aryl boronic acids or
trifluoroborates17 were also investigated,46 but the reaction only
progressed to 55% conversion with 27% selectivity for 2a. The
initial reaction conditions chosen were used as a starting point
to optimize for the formation of a and avoid the formation of
the homcoupling product b.
Other alkyl amines were investigated, and in both cases, the
formation of the diamine a was found to be the minor product
(Table 1, entries 1−2). Anilines were then investigated to
determine their effect on the selectivity of a, although simple
boronate esters were previously found to not be reactive
enough to couple with aryl amines.19 Remarkably, the coupling
of substrate 1 and aniline led to significant improvement in the
formation of the ortho-aminobenzylamine 5a with 98%
selectivity over 2b (Table 1, entry 3). This outcome was
found to be consistent with that of other aryl amines (Table 1,
entries 4−5), indicating that the nature of the amine coupling
partner influences the rate of the coupling reaction and thus the
product distribution. Previous studies on copper-mediated C−
N bond forming reactions have revealed that the pKa of the N−
H bond plays a role in the rate of the coupling reaction, with
more acidic substrates exhibiting faster reactivity.47 Alter-
natively, alkyl amines may also undergo oxidative deamination
under the copper-mediated conditions,48,49 thus limiting the
formation of the desired product a.50 Since the inherent
selectivity of the aryl amine coupling favors the desired diamine
a, optimization of the reaction conditions focused on anilines.
In the reaction between boronate ester 1 and aniline in the
presence of KF (1.0 equiv), the initial concentration of 0.2 M
provided the best selectivity of 5a using the least amount of
solvent. At room temperature, lower conversion and selectivity
of 5a was observed even with a longer reaction time (87%
conversion and 66% selectivity for 5a, 18 h) as compared to the
reaction at 80 °C, indicating that heat is beneficial for both the
conversion and selectivity of a. Using the optimized
concentration and temperature, the effect of the copper
precatalyst was then examined (eq 3). Replacing copper(II)
acetate with copper(II) trifluoroacetate, copper(II) acetylacet-
onate, or copper(II) methoxide shifted the product distribution
to favor compound 2b over the ortho-aminobenzylamine 5a,
while the use of copper(II) trifluoromethanesulfonate improved
the selectivity toward 5a (Table 2, entries 2−5). Although
copper(II) trifluoromethanesulfonate appeared to shift the
product distribution toward 5a, this trend was not extended to
substituted systems;51 consequently, copper(II) acetate was
chosen as the optimal catalyst for the reaction.
a
Reaction conditions: 1, H2NR2 (2.0 equiv), Cu(OAc)2·H2O (10 mol
%), KF (1.0 equiv), 3 Å MS, CH3CN (0.2 M), O2, 80 °C, 2 h.
b
Determined by integration of product peaks in a crude mixture by 1H
NMR spectroscopy.
emerged that related the counterion of the base to the product
distribution. The smaller counterion of NaF improved the
product ratio to favor the diamine product 5a (>99:1)
compared to that of KF (98:2), while the larger counterion
A brief base screen was used to investigate the influence of
carbonate and fluoride salts on the selectivity of 5a formation
(Table 2, entries 1, 6−12). Interestingly, a distinct trend
B
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when coupling anilines led us to reexamine the coupling of
substrate 1 and alkyl amines (see eq 2) under these conditions.
Although improved selectivity of a was observed, these
reactions did not reach the highly selective ratios seen in the
aryl amine couplings.55
While the couplings of a range of boronate esters proceeded
in good conversion and high chemoselectivity for the desired
diamine a, isolation of the ortho-aminobenzylamines was
challenging, resulting in moderate to good yields (Figure 1).
Table 2. Copper Catalyst and Base Screen for the Amine
Coupling Reaction (Eq 3)
a
entry
1
[Cu]
[base]
KF
selectivity of 5a
Cu(OAc)2·H2O
Cu(OCOCF3)2·XH2O
Cu(acac)2
98%
b
2
KF
44%
3
KF
26%
b
4
Cu(OCH3)2
KF
21%
5
6
7
Cu(OTf)2
KF
>99%
94%
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CsF
NaF
>99%
35%
b
8
Cs2CO3
K2CO3
Na2CO3
Li2CO3
none
b
9
94%
10
11
12
99%
>99%
>99%
a
Determined by integration of product peaks in a crude mixture by 1H
NMR spectroscopy; the remaining percentage corresponds to 2b;
b
Reaction did not proceed to completion.
of CsF (94:6) showed a slight decrease in the selectivity of 5a
(Table 2, entries 6−7), demonstrating a dependence on
counterion size. Changing to carbonate bases showed a more
drastic influence on product distribution. Cesium carbonate
significantly impacted the selectivity of 5a (35:65), shifting the
distribution in favor of compound 2b (Table 2, entry 8).
Incremental changes in the selectivity which favored diamine 5a
were observed by changing the counterion from potassium to
sodium to lithium (Table 2, entries 9−11). A smaller
counterion, which would bind more tightly to the base,
appeared to favor the formation of product 5a over compound
2b. The counterion of the base may influence the rate of
transmetalation of the boronate ester substrate,52,53 thus
influencing the product distribution. To examine whether the
base was necessary for the reaction to occur, the reaction was
performed without the addition of base and found to proceed
fully to the desired diamine 5a (Table 2, entry 12), implicating
the benzylamine moiety in the transmetalation step.
With several effective sets of conditions for the coupling
reaction in hand, a full investigation of the substrate scope was
initiated to provide a practical method for the synthesis of
complex diamines and to probe how electronic effects influence
the distribution of the corresponding diamine (a) to
homocoupled product (b). Although multiple bases proved
advantageous in the coupling reaction between substrate 1 and
aniline, the reported sensitivity of copper-catalyzed amination
reactions to steric and electronic effects54 led us to investigate
the scope of the reaction using three sets of conditions
(Cu(OAc)2 with KF, Li2CO3, or no base) to determine the
most general system for electronically diverse substrates. For
most of the substrates investigated, the selectivity of a was
maintained or improved as the base was changed from KF to
Li2CO3 to the absence of base (Table 3). Using these
conditions, some clear trends of selectivity emerged. In most
cases, the diamine could be accessed as the only observed
product when the reaction was performed in the absence of
base. Interestingly, halogens had a significant impact on the
distribution of diamine (11a and 13a) to the homocoupled
product (11b and 13b, respectively), which is not observed
with other electron withdrawing substituents, suggesting that
the role of inductive and resonance effects on the relative rate
of the key steps is not straightforward. The improved selectivity
of diamines (a) observed with Li2CO3 or in the absence of base
Figure 1. Yields of ortho-aminobenzylamine products from copper-
catalyzed couplings without base. H NMR spectroscopy of a crude
reaction mixture used to determine the selectivity of a is shown in
parentheses. a: Reaction performed with KF. b: Reaction performed
with Li2CO3. c: 1H NMR spectroscopy peaks of 13a/13b were poorly
resolved.
1
Although attempts to isolate a from the crude reaction mixture
using extraction and Kugelrohr distillation were unsuccessful,
column chromatography using either silica gel or basic alumina
provided compounds a in high purity. The use of
tetramethylethylenediamine to complex with the residual
copper prior to silica gel column chromatography proved to
enhance the yield of certain compounds, while for other
compounds the use of triethylamine in the elution solvent
worked well. In some cases, pinacol was observed along with
product a, but removal of this impurity was achieved
azeotropically with ethanol. The challenging isolation is likely
due to the diamine moiety in the products being strongly
absorbed to the silica during purification or by the formation of
stable complexes with the residual copper in the crude reaction
mixture. Regardless, a range of novel ortho-aminobenzylamines
has been achieved in moderate to good yields and high purity.
The reaction tolerates a variety of substituents on the
benzylamine boronate ester substrate, including electron-
donating groups (−OCH3 and −CH3) and electron-with-
drawing (−CO2Et, −F, −Cl, and −Br) groups at different
positions on the aromatic ring, all of which selectively produce
the diamine a over the homocoupled product b. The reaction
also proceeded well when the dimethylamine moiety was
changed to a piperidine group, proceeding without base in full
conversion to N-phenyl-2-(piperidin-1-ylmethyl)aniline (15a).
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Crude benzylamine boronate ester 1 could also be used under
the reaction conditions with aniline and KF to provide desired
product 5a, albeit in lower yield (47%).
Table 3. Crude Product Ratios of Optimized Base Systems
Substituted Aryl Boronate Esters and Aniline (Eq 4)
Substitution on the aniline was also tolerated under the
reaction conditions leading to predominant formation of a in all
cases (Figure 2). As in the case of substituents on the aryl
boronate ester, change, or removal of the base improved the
selectivity of product a.56 Increasing the steric bulk around the
amine did not appear to impact the product distribution
providing compound 6a when 1 was coupled with 2,4,6-
trimethylaniline; electron-withdrawing (−CO2Et) and electron-
donating (−OCH3) groups also resulted in predominant
formation of the desired aminobenzylamines 7a and 16a,
respectively. While para−Cl and −Br aniline proceeded with
high conversion to diamines 17a and 20a, a significant shift
toward product b was observed with the proximity of Cl from
para to meta to ortho, indicating the amination is strongly
influenced by the electronics of the amine. While both
resonance and induction of Cl on the aniline may play a role,
it appears that the inductive effect has the strongest impact on
the product distribution. The coupling of 2-aminopyridine
proceeded in high conversion to compound 20a, showing a
tolerance of the reaction for heteroaromatic amines. The broad
utility of this reaction was further demonstrated through the
coupling of substituted boronate ester substrates with various
aryl amines.57 The product selectivity for compounds 21a, 22a,
and 23a are consistent with the previous results for each
coupling partner, while in the case of product 24a more 15b
was produced than expected. The successful coupling of varying
anilines and benzylamine boronate esters conveys the robust
nature of this reaction in synthesizing ortho-aminobenzyl-
amines.
The biaryl coupling reaction to form product b was also
investigated in the absence of the added aniline. While the
identity of the counterion in the precatalyst proved important
in the amination reaction, the use of copper(II) acetate
monohydrate and copper(II) acetylacetonate in the presence of
KF both led to the biaryl 2b after 2 h.58 The biaryl coupling
transformation worked well with a variety of substituted
benzylamine boronate esters (Scheme 1).59 \Similar to the
ortho-aminobenzylamines, purification of the homocoupling
products b was rather challenging; the use of column
chromatography on basic alumina proved successful in most
cases. In the case of biaryl 2b, the coupling was also performed
without the base in the presence of copper(II) acetate
monohydrate yielding the product in full conversion, suggesting
a
Determined by integration of product peaks in a crude mixture by 1H
NMR spectroscopy; the remaining percentage corresponds to 8b−
13b, respectively.
that the benzylamine moiety may assist in both transmetalation
steps of the catalytic cycle.
While detailed mechanistic studies on the copper-catalyzed
amination reaction between an aryl amine and aryl boronic acid
or boronate ester have yet to be disclosed, mechanisms based
on preliminary studies exclude radical pathways and instead
focus on CuII and CuIII pathways.48,60 To gain more insight into
the catalytic cycle, experiments were performed in the absence
of oxygen. Under the optimized conditions, the amine coupling
reaction resulted in five percent conversion to diamine a (eq 5),
while the homocoupling reaction gave 10% conversion to
product b (eq 6).61 Both of these reactions reveal a CuII/
product stoichiometry of 2:1, which is consistent with previous
mechanistic reports on Chan, Evans,62 and Lam reactions63,64
and a previously proposed mechanism for the copper-catalyzed
homocoupling reaction.40 The results support disproportiona-
tion of CuII into CuI and CuIII complexes in the catalytic cycle,
D
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Scheme 1. Yields of Select Homocoupling Products Formed
a
from Benzylamine Boronate Esters in the Presence of KF
a
The reaction was performed without a base.
Drawing from previously proposed mechanisms4,63−65 and
our experimental results, a two-pathway catalytic cycle has been
proposed (Scheme 2) that accounts for the formation of the
diamine (a) and the homocoupled product (b). The catalytic
cycle is initiated with transmetalation of the boronate ester 1
with Cu(OAc)2 to form complex I. The two mechanisms
diverge from intermediate I depending on whether the amine
coordinates (I to II) or a second transmetalation takes place (I
to IV). Upon coordination of the aryl amine to copper to form
II, the complex is oxidized from CuII to CuIII via
disproportionation with CuII, forming complex III which is
poised to undergo reductive elimination to provide the diamine
product a and CuIX. Oxidation of CuI to CuII by O2 regenerates
the active catalyst. If intermediate I undergoes a second
transmetalation instead of being captured by an aniline,
intermediate IV will form, followed by disproportionation to
form the CuIII complex V, which upon reductive elimination
would then produce the homocoupling product b. The CuI
intermediate is then oxidized to the active catalyst.66 In the
formation of diamine a, a pathway in which coordination of the
amine occurs prior to transmetalation cannot be ruled out.65
The presented results reveal a complex dual catalytic process
for the formation of diamine a and biaryl b. The observed
dependence of product distributions on the boronate ester and
aniline electronics likely arises from the competing rates of
coordination (to form complex II)/oxidation to form complex
III versus transmetalation to form complex IV. The different
product distributions observed for alkyl amine versus aryl
amine couplings indicates that the nucleophilicity and acidity of
the amine coupling partner plays a significant role in the
pathway toward diamine a.47 In the aryl amine couplings done
without base, the benzylamine moiety likely assists in
transmetalation of the boronate ester, which is supported by
Figure 2. Yields of ortho-aminobenzylamines from copper-catalyzed
couplings without base. H NMR spectroscopy of a crude reaction
mixture used to determine the selectivity of a is shown in parentheses.
a: Reaction performed with KF.
1
while O2 serves to turn over the catalyst through the oxidation
of CuI to CuII.63,64
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on the benzylamine boronate ester substrates and aniline
coupling partners, resulting in optimized conditions for a large
array of ortho-aminobenzylamines. The selective formation of
the homocoupled product could also be achieved in the
absence of an added amine. Overall, the presence of the ortho-
benzylic amine significantly alters the reactivity of aryl boronate
esters, providing divergent reactivity profiles from typical
systems. This work demonstrates how the reactivity of an
aryl boronate ester can be modified through the use of a
pendant amine to achieve coupling of aryl boronate esters.
Scheme 2. Proposed Catalytic Cycles for the Formation of
the ortho-Aminobenzylamine (a, Top) and the
Homocoupling Product (b, Bottom)
EXPERIMENTAL SECTION
■
General Experimental Details. All procedures were performed in
oven-dried glassware under purified nitrogen until O2 gas was
introduced. N,N-Dimethylbenzylamine boronate esters were synthe-
sized following the published procedures.30,31 All other materials,
including solvents, were purchased and used as received. Concen-
tration was performed by rotary evaporation. TLC analysis was
performed on 60 Å silica layer fluorescence UV plates. Flash column
chromatography was carried out on hand-packed columns of silica gel,
40−63 μm, 60 Å or aluminum oxide, basic, Brockman I, 50−200 μm,
60 Å. NMR spectra were collected at 500 MHz for 1H NMR and 125
MHz for 13C{1H} NMR, or at 400 MHz for H NMR and 100 MHz
1
1
for 13C{1H} NMR. H NMR spectra are referenced to CDCl3 at 7.26
ppm or to an internal tetramethylsilane (TMS) standard at 0.00 ppm.
1
The H NMR spectral data are reported as follows: chemical shift
ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn =
quintet, hex = hextet, sep = septet, oct = octet, m = multiplet),
coupling constants (Hz), and integration. 13C{1H} NMR spectra are
referenced to CDCl3 at 77.0 ppm. In some of the spectra, interference
from the NMR spectrometer is visible at 5.96 ppm for 1H NMR
spectra and 104.9 ppm for 13C{1H} NMR spectra, and this
interference is likely the result of a problematic component of the
probe that failed during this study and has not been repaired to date.
Fourier transform infrared (FTIR) spectra were obtained from thin
film in dichloromethane or chloroform-d and absorptions reported in
cm−1. High-resolution mass spectrometry was obtained by time-of-
flight electrospray ionization.
Representative Procedure A. To a Schlenk flask was added 3 Å
molecular sieves (0.300 g), substrate 1 (0.100 g, 0.383 mmol),
potassium fluoride (0.0220 g, 0.394 mmol), aniline (0.070 mL, 0.766
mmol), and acetonitrile (1.9 mL). Oxygen was bubbled through the
mixture for 5 min, then copper(II) acetate monohydrate (0.0077 g,
0.0385 mmol) was added. After 2 h at 80 °C under positive oxygen
pressure, the mixture was allowed to cool to room temperature, then
transferred and concentrated in vacuo to give a black oil (0.1532 g).
The crude product (ratio45 5a/2b 98:2) was purified by silica gel
column chromatography using ethyl acetate, followed by treatment
with ethanol and concentration to remove pinacol impurities
azeotropically (3 × 2 mL) to afford product 5a as a brown oil
(0.0495 g, 0.219 mmol, 57%).
previous reports of dative bonds between benzylamines and
ortho-boronic acids and boronate esters.26,67 Furthermore, the
amination of PhBpin with aniline under base-free conditions
proceeded in less than 10% conversion, supporting the
assertion that the adjacent benzylic amine plays an important
role in the catalytic cycle. The high selectivity of a observed in
the absence of base likely results from the formation of a
copper species with counterion X that is more reactive toward
the coordination of the amine, leading to complexes II and III,
rather than a second transmetalation, leading to complex IV.
The identity of the counterion (X) has been shown to have a
significant influence on the rate of the transmetalation step of
the Suzuki−Miyaura coupling reaction.68 Although further
studies were beyond the scope of this investigation, experi-
ments that elucidate the active catalytic species and kinetics of
these reactions would provide great insight into the copper-
catalyzed transformations between aryl boronate esters and
amines.
Representative Procedure B. To a Schlenk flask was added 3 Å
molecular sieves (0.304 g), substrate 1 (0.100 g, 0.383 mmol),
potassium fluoride (0.0220 g, 0.394 mmol), copper(II) acetate (0.0075
g, 0.0383 mmol), and acetonitrile (2.00 mL). Oxygen was bubbled
through the mixture for 5 min. After 2 h at 80 °C under oxygen, the
mixture was allowed to cool to room temperature, then transferred and
concentrated in vacuo to give a light green solid (0.0942 g). The crude
mixture was purified by Kugelrohr distillation (0.5 mmHg, up to 80
°C) to afford 2b as a colorless solid (0.025 g, 0.0931 mmol, 49%).
2-((Dimethylamino)methyl)-N-isopropylaniline (2a). Following
representative procedure A using substrate 1 (0.100 g, 0.343 mmol)
and isopropyl amine (0.063 mL, 0.766 mmol), the crude mixture
(ratio45 2a:2b 28:72) was purified by column chromatography on
basic alumina (25:75 ethyl acetate/hexanes) to afford 2a as a tan oil
CONCLUSIONS
■
The synthesis of novel ortho-aminobenzylamines 2a−24a have
been achieved through the copper-catalyzed coupling of
benzylamine boronate esters and anilines. The coupling
reaction was initially plagued by the competitive formation of
homocoupled biaryl products. The formation of these biaryl
products was largely suppressed when the conditions were
modified to remove the base additive. The reaction tolerates
both electron-donating and electron-withdrawing substituents
1
(0.0042 g, 0.0218 mmol, 6%). H NMR (400 MHz, CDCl3) δ 7.18−
7.13 (m, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.57
(t, J = 7.3 Hz, 1H), 3.61 (sep, J = 6.2 Hz, 1H), 3.38 (s, 2H), 2.17 (s,
F
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6H), 1.21(d, J = 6.2 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ
147.9, 130.1, 128.3, 122.7, 115.3, 110.4, 63.8, 44.6, 43.4, 23.0; IR (thin
film, CDCl3) 3268 (br), 2967 (s), 2855 (m), 2818 (m), 2772 (m),
1606 (s), 1589 (s), 1523 (s), 1463 (s), 1382 (m), 1363 (s), 1325 (s)
cm−1. HRMS (ESI): m/z calcd for C12H21N2 [M + H]+ 193.1705,
found 193.1707.
Ethyl 4-((2-((dimethylamino)methyl)phenyl)amino)benzoate
(7a). Following representative procedure A using substrate 1 (0.100
g, 0.383 mmol) and ethyl 4-aminobenzoate (0.127 g, 0.766 mmol), the
crude mixture (ratio45 7a/2b 100:0) was treated with trimethylethy-
lenediamine (0.15 mL), then purified by silica gel column
chromatography (99:1 to 90:10 dichloromethane/EtOAc), and the
resulting product residue was azeotroped with ethanol (3 × 2 mL) to
afford product 7a as a red/brown oil (0.0744 g, 0.249 mmol, 65%). 1H
NMR (500 MHz, CDCl3) δ 9.01 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H),
7.44 (d, J = 8.1 Hz, 1H), 7.26−7.22 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H),
7.04 (d, J = 8.8 Hz, 2H), 6.90 (td, J = 7.4, 0.9 Hz, 1H), 4.34 (q, J = 7.1
Hz, 2H), 3.45 (s, 2H), 2.24 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 166.6, 147.7, 141.8, 131.3, 130.6, 128.1,
127.3, 121.1, 120.7, 117.3, 114.8, 63.4, 60.3, 44.8, 14.4; IR (thin film,
CDCl3) 3237 (br), 3183 (m), 3057 (m), 2980 (m), 2948 (m), 2903
(m) 2859 (m), 2822 (m), 2776 (m), 1706 (s), 1591 (s), 1525 (s),
1457 (s), 1275 (s) cm−1. HRMS (CI): m/z calcd for C18H23N2O2 [M
+ H]+ 299.1760, found 299.1768.
2-((Dimethylamino)methyl)-3-fluoro-N-phenylaniline (8a). Fol-
lowing representative procedure A, without base, using substrate
2769 (0.0943 g, 0.338 mmol), the crude mixture (ratio45 8a/8b 100:0)
was purified by silica gel column chromatography (99:1 to 95:5
dichloromethane/EtOAc) to afford product 8a as a light violet solid
(0.0471 g, 0.155 mmol, 46%): mp 83.5−89.5 °C; 1H NMR (500 MHz,
CDCl3) δ 8.62 (s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.10−7.05 (m, 4H),
6.93 (t, J = 7.3 Hz, 1H), 6.55−6.51 (m, 1H), 3.53 (d, JH−F = 1.3 Hz,
2H), 2.26 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9 (d, JC−F
2-((Dimethylamino)methyl)-N-(3-methoxypropyl)aniline (3a).
Following representative procedure A without base using substrate 1
(0.100 g, 0.343 mmol) and 3-methoxypropylamine (0.078 mL, 0.766
mmol), the crude mixture (ratio45 3a:2b 52:48) was purified by
column chromatography on basic alumina (4:1 to 1:1 hexanes/ethyl
1
acetate) to afford 3a as a tan oil (0.0118 g, 0.053 mmol, 14%). H
NMR (500 MHz, CDCl3) δ 7.17 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.2
Hz, 1H), 6.63−6.58 (m, 2H), 6.16 (br s, 1H), 3.50 (t, J = 6.2 Hz, 2H),
3.38 (s, 2H), 3.36 (s, 3H), 3.22 (t, J = 6.7 Hz, 2H), 2.17 (s, 6H), 1.91
(q, J = 6.4 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 129.9,
128.4, 122.7, 115.6, 109.7, 70.7, 63.8, 58.7, 44.8, 40.2, 29.4; IR (thin
film, CDCl3) 3281 (br), 3044 (m), 2975 (m), 2942 (s), 2854 (s), 2817
(s), 2771 (s), 1607 (s), 1589 (s), 1523 (s), 1468 (s), 1389 (m), 1362
(m), 1332 (m), 1313 (m) cm−1. HRMS (ESI): m/z calcd for
C13H22N2ONa [M + Na]+ 245.1630, found 245.1637.
N-(2,2-Diethoxyethyl)-2-((dimethylamino)methyl)aniline (4a).
Following representative procedure A using substrate 1 (0.100 g,
0.383 mmol), aminoacetaldehydediethyl acetate (0.111 mL, 0.766
mmol), and Li2CO3 (0.0291 g, 0.394 mmol), the crude mixture
(ratio45 4a/2b 40:60) was purified by silica gel column chromatog-
raphy (99:1 to 85:15 dichloromethane/ethyl acetate, then 80:19.5:0.5
dichloromethane/ethyl acetate/triethylamine) to afford 4a as a yellow
oil (0.0083 g, 0.0312 mmol, 8%). 1H NMR (500 MHz, CDCl3) δ 7.17
(td, J = 7.8, 1.6 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 6.63−6.60 (m, 2H),
4.76 (t, J = 5.9 Hz, 1H), 3.72 (ddd, J = 7.1, 9.4, 14.2 Hz, 2H), 3.59
(ddd, J = 7.1, 9.4, 14.2 Hz, 2H), 3.39 (s, 2H), 3.26 (d, J = 5.9 Hz, 2H),
2.17 (s, 6H), 1.24 (t, J = 7.1 Hz, 6H) (N−H resonance could not be
identified); 13C{1H} NMR (100 MHz, CDCl3) δ 148.1, 129.9, 128.4,
123.3, 116.1, 109.9, 100.9, 63.6, 61.7, 45.7, 44.8, 15.3; IR (thin film,
CDCl3) 3270 (br), 3045 (s), 2975 (s), 2929 (s), 2854 (s), 2817 (s),
2770 (s), 1729 (s), 1684 (m), 1607 (s), 1588 (s), 1520 (s), 1456 (s),
1373 (m) cm−1. HRMS (CI): m/z calcd for C15H27N2O2 [M + H]+
267.2072, found 267.2076.
= 241.8 Hz), 146.0 (d, JC−F = 6.0 Hz), 142.7, 129.3, 128.5 (d, JC−F
=
10.5 Hz), 120.9, 118.7, 112.3 (d, JC−F = 15.6 Hz), 110.1 (d, JC−F = 2.8
Hz), 105.9 (d, JC−F = 23.4 Hz), 53.4−53.3 (m), 44.7; IR (thin film,
CDCl3) 3237 (br), 3051 (m), 2981 (m), 2949 (m), 2864 (m), 2826
(m), 2779 (m), 1620 (s), 1596 (s), 1524 (m), 1498 (s), 1472 (s),
1365 (m), 1325 (m), 1265 (s), 1236 (s) cm−1. HRMS (CI): m/z calcd
for C15H18FN2 [M + H]+ 245.1454, found 245.1447.
2-((Dimethylamino)methyl)-4-methyl-N-phenylaniline (9a). Fol-
lowing representative procedure A using substrate 2869 (0.100 g, 0.363
mmol), the crude mixture (ratio45 9a/9b 97:3) was purified by silica
gel column chromatography (100:0 to 50:50 dichloromethane/
EtOAc), and the resulting product residue was azeotroped with
ethanol (3 × 2 mL) to afford product 9a as a brown oil (0.0631 g,
2-((Dimethylamino)methyl)-N-phenylaniline (5a). Following rep-
resentative procedure A, without base, using substrate 1 (0.1032 g,
0.395 mmol), the crude mixture (ratio45 5a/2b 100:0) was purified by
silica gel column chromatography (99:1 to 90:10 dichloromethane/
1
0.263 mmol, 72%). H NMR (500 MHz, CDCl3) δ 8.31 (br s, 1H),
7.27−7.21 (m, 3H), 7.05 (d, J = 7.8 Hz, 2H), 6.99 (d, J = 8.2 Hz, 1H),
6.90 (s, 1H), 6.83 (t, J = 7.3 Hz, 1H), 3.40 (s, 2H), 2.27 (s, 3H), 2.22
(s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 143.9, 140.9, 131.2,
129.2, 128.9, 128.4, 126.4, 119.6, 117.1, 116.0, 63.5, 44.8, 20.6; IR
(thin film, CDCl3) 3255 (br), 3105 (m), 3026 (m), 2975 (m), 2944
(m), 2915 (m), 2855 (m), 2819 (m), 2772 (m), 1598 (s), 1520 (s),
1497 (s), 1467 (m), 1455 (m), 1413 (m), 1358 (m), 1320 (s) cm−1.
HRMS (CI): m/z calcd for C16H21N2 [M + H]+ 241.1705, found
241.1702.
1
EtOAc) to afford 5a as a tan oil (0.0618 g, 0.273 mmol, 69%). H
NMR (500 MHz, CDCl3) δ 8.57 (br s, 1H), 7.40 (d, J = 8.1 Hz, 1H),
7.29 (t, J = 7.7 Hz, 2H), 7.23−7.19 (m, 1H), 7.14−7.12 (m, 3H), 6.92
(t, J = 7.4 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 3.49 (s, 2H), 2.27 (s, 6H);
13C{1H} NMR (125 MHz, CDCl3) δ 143.7, 143.2, 130.5, 129.2, 128.0,
125.8, 120.2, 119.2, 117.8, 115.0, 63.6, 44.8; IR (thin film, CDCl3)
3250 (br), 3045 (m), 2977 (m), 2945 (m), 2857 (m), 2820 (s), 2774
(s), 1594 (s), 1523 (s), 1497 (s), 1476 (s), 1462 (s), 1362 (m), 1326
(s), 1308 (s) cm−1. HRMS (ESI): m/z calcd for C15H19N2 [M + H]+
227.1548, found 227.1552.
2-((Dimethylamino)methyl)-4-methoxy-N-phenylaniline (10a).
Following representative procedure A using substrate 2969 (0.075 g,
0.258 mmol) and Li2CO3 (0.0197 g, 0.266 mmol), the crude mixture
(ratio45 10a/10b 100:0) was purified by silica gel column
chromatography (99:1 to 50:50 dichloromethane/EtOAc), and the
resulting product residue was azeotroped with ethanol (3 × 2 mL) to
N-(2-((Dimethylamino)methyl)phenyl)-2,4,6-trimethylaniline
(6a). Following representative procedure A using substrate 1 (0.100 g,
0.383 mmol) and 2,4,6-trimethylaniline (0.108 mL, 0.766 mmol), the
crude mixture (ratio45 6a/2b 89:11) was purified by basic alumina
column chromatography (100% dichloromethane), then silica gel
column chromatography (100:0 to 95:5 dichloromethane/EtOAc) to
1
afford product 10a as a brown oil (0.0328 g, 0.133 mmol, 52%). H
NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H),
7.22 (t, J = 7.5 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.82−6.76 (m, 2H),
6.72 (s, 1H), 3.78 (s, 3H), 3.38 (s, 2H), 2.22 (s, 6H); 13C{1H} NMR
(125 MHz, CDCl3) δ 153.5, 144.6, 136.6, 129.2, 129.0, 119.0, 118.7,
116.6, 116.0, 112.6, 63.4, 55.5, 44.9; IR (thin film, CDCl3) 3263 (br),
3033 (m), 2976 (m), 2945 (m), 2907 (m), 2854 (m), 2820 (m), 2773
(m), 1599 (s), 1515 (s), 1498 (s), 1267 (s) cm−1. HRMS (CI): m/z
calcd for C16H20N2O [M]+ 256.1576, found 256.1575.
4-Chloro-2-((dimethylamino)methyl)-N-phenylaniline (11a). Fol-
lowing representative procedure A, without base, using substrate 3069
(0.1051 g, 0.356 mmol), the crude mixture (ratio45 11a/11b 87:13)
was purified by silica gel column chromatography (95:5 dichloro-
methane/EtOAc), then again by silica gel column chromatography
1
afford 6a as a tan oil (0.0679 g, 0.253 mmol, 66%). H NMR (500
MHz, CDCl3) δ 8.00 (br s, 1H), 7.08−7.03 (m, 2H), 6.96 (s, 2H),
6.66 (dd, J = 7.3, 1.1 Hz, 1H), 6.17 (d, J = 8.0 Hz, 1H), 3.56 (s, 2H),
2.33 (s, 3H), 2.28 (s, 6H), 2.16 (s, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δ 146.4, 136.6, 134.6, 134.1, 129.8, 129.0, 128.1, 122.9, 116.5,
111.2, 63.7, 44.7, 20.9, 18.2; IR (thin film, CDCl3) 3244 (br), 3007
(m), 2973 (s), 2943 (s), 2915 (s), 2854 (s), 2818 (s), 2772 (s), 1604
(s), 1505 (s), 1485 (s), 1467 (s), 1375 (m), 1362 (m), 1325 (s), 1309
(s) cm−1. HRMS (ESI): m/z calcd for C18H25N2 [M + H]+ 269.2018,
found 269.2019.
G
DOI: 10.1021/acs.joc.5b01074
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(99.5:0.5 to 95:5 dichloromethane/EtOAc) to afford product 11a as a
tan oil (0.0441 g, 0.169 mmol, 48%). H NMR (500 MHz, CDCl3) δ
(s), 1308 (s) cm−1. HRMS (ESI): m/z calcd for C18H23N2 [M + H]+
267.1861, found 267.1860.
1
2-((Dimethylamino)methyl)-N-(4-methoxyphenyl)aniline (16a).
Following representative procedure A using substrate 1 (0.0996 g,
0.381 mmol) and p-anisidine (0.0943 g, 0.766 mmol), the crude
mixture (ratio45 16a/2b 94:6) was purified by silica gel column
chromatography (98:2 dichloromethane/EtOAc then switching to
89:10:1 dichloromethane/EtOAc/triethylamine) to afford product 16a
8.50 (br s, 1H), 7.28−7.24 (m, 3H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H),
7.06−7.05 (m, 3H), 6.91 (t, J = 7.4 Hz, 1H), 3.41 (s, 2H), 2.24 (s,
6H); 13C{1H} NMR (125 MHz, CDCl3) δ 142.8, 142.5, 130.1, 129.3,
127.8, 127.2, 123.5, 120.7, 118.1, 115.9, 63.1, 44.8; IR (thin film,
CDCl3) 3244 (br), 3029 (m), 2978 (m), 2947 (m), 2855 (m), 2822
(m), 2775 (m), 1592 (s), 1514 (s), 1474 (s), 1408 (s), 1321 (s) cm−1.
HRMS (CI): m/z calcd for C15H18ClN2 [M + H]+ 261.1158, found
261.1149.
Ethyl 4-((dimethylamino)methyl)-3-(phenylamino)benzoate
(12a). Following representative procedure A, without base, using
substrate 3169 (0.100 g, 0.300 mmol), the crude mixture (ratio45 12a/
12b 100:0) was purified by silica gel column chromatography (99:1 to
90:10 dichloromethane/EtOAc) to afford product 12a as a yellow oil
(0.0675 g, 0.226 mmol, 75%). 1H NMR (500 MHz, CDCl3) δ 8.67 (br
s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 (t,
J = 8.4 Hz, 2H), 7.14−7.10 (m, 3H), 6.93 (t, J = 7.4 Hz, 1H), 4.33 (q,
J = 7.2 Hz, 2H), 3.49 (s, 2H), 2.24 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 166.8, 143.9, 142.6, 130.4, 130.3,
1
as a tan solid (0.0496 g, 0.193 mmol, 51%): mp 65.5−67.7 °C; H
NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 7.17−7.07 (m, 5H), 6.88
(d, J = 8.8 Hz, 2H), 6.74 (ddd, J = 7.0, 7.0, 2.0 Hz, 1H), 3.82 (s, 3H),
3.49 (s, 2H), 2.26 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 154.5,
145.5, 136.3, 130.4, 128.1, 124.3, 121.6, 118.1, 114.5, 113.2, 63.6, 55.5,
44.7; IR (thin film, CDCl3) 3249 (br), 3105 (m), 3040 (m), 2976 (m),
2946 (s), 2904 (m), 2855 (m), 2820 (s), 2773 (s), 1601 (s), 1510 (s),
1458 (s), 1405 (m), 1362 (m), 1328 (s) cm−1. HRMS (ESI): m/z
calcd for C16H21N2O [M + H]+ 257.1654, found 257.1647.
N-(4-Chlorophenyl)-2-((dimethylamino)methyl)aniline (17a).
Following representative procedure A using substrate 1 (0.075 g,
0.287 mmol) and 4-chloroaniline (0.0732 g, 0.574 mmol), the crude
mixture (ratio45 17a/2b 97:3) was purified by silica gel column
chromatography (9:1 dichloromethane/EtOAc) to afford product 17a
130.2, 129.3, 120.8, 120.2, 118.1, 115.3, 63.3, 60.8, 44.8, 14.3; IR (thin
film, CDCl3) 3238 (br), 3109 (m), 3020 (m), 2979 (m), 2947 (m),
2904 (m), 2856 (m), 2822 (m), 2777 (m), 1715 (s), 1595 (s), 1577
(s), 1530 (s), 1497 (s), 1445 (s), 1423 (s) cm−1. HRMS (CI): m/z
calcd for C18H23N2O2 [M + H]+ 299.1760, found 299.1753.
1
as a brown oil (0.0467 g, 0.179 mmol, 62%). H NMR (500 MHz,
CDCl3) δ 8.28 (br s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.20−7.16 (m,
3H), 7.08 (dd, J = 7.4, 1.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.81
(ddd, J = 7.4, 7.4, 0.8 Hz, 1H), 3.44 (s, 2H), 2.23 (s, 6H); 13C{1H}
NMR (125 MHz, CDCl3) δ 143.3, 141.9, 130.6, 129.1, 128.1, 125.9,
124.5, 119.7, 118.8, 115.1, 63.5, 44.8; IR (thin film, CDCl3) 3238 (br),
3178 (m), 3097 (m), 3025 (m), 2978 (m), 2946 (m), 2856 (m), 2821
(m), 2775 (m), 1591 (s), 1520 (s), 1492 (s), 1327 (s), 1310 (s) cm−1.
HRMS (CI): m/z calcd for C15H18ClN2 [M + H]+ 261.1158, found
261.1166.
5-Bromo-2-((dimethylamino)methyl)-N-phenylaniline (13a). Fol-
lowing representative procedure A, without base, using substrate 3269
(0.100 g, 0.294 mmol), the crude mixture (ratio45 13a/13b 64:36) was
purified by silica gel column chromatography (99:1 to 95:5
dichloromethane/EtOAc) to afford product 13a as a yellow oil
(0.0405 g, 0.133 mmol, 45%). 1H NMR (500 MHz, CDCl3) δ 8.69 (br
s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.29 (t, J = 8.2 Hz, 2H), 7.09 (d, J =
7.7 Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.87
(dd, J = 7.9, 1.8 Hz, 1H), 3.40 (s, 2H), 2.22 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 145.5, 142.2, 131.6, 129.4, 123.9, 122.1, 121.5,
121.4, 119.0, 116.7, 63.1, 44.7; IR (thin film, CDCl3) 3233 (br), 3092
(m), 3030 (m), 2977 (s), 2945 (s), 2857 (m), 2821 (s), 2774 (s),
1591 (s), 1576 (s), 1516 (s), 1497 (s), 1470 (s), 1411 (s), 1361 (m),
1324 (m) cm−1. HRMS (CI): m/z calcd for C15H18BrN2 [M + H]+
305.0653, found 305.0640.
N-(3-Chlorophenyl)-2-((dimethylamino)methyl)aniline (18a).
Following representative procedure A using substrate 1 (0.100 g,
0.383 mmol) and 3-chloroaniline (0.081 mL, 0.766 mmol), the crude
mixture (ratio45 18a/2b 89:11) was purified by silica gel column
chromatography (95:5 dichloromethane/EtOAc) to afford product
1
18a as a tan oil (0.0486 g, 0.186 mmol, 49%). H NMR (500 MHz,
CDCl3) δ 8.68 (br s, 1H), 7.35 (dd, J = 8.1, 0.6 Hz, 1H), 7.20 (td, J =
7.7, 1.6 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 7.09 (dd, J = 7.4, 1.3 Hz,
1H), 7.06 (t, J = 2.1 Hz, 1H), 6.95−6.93 (m, 1H), 6.85−6.80 (m, 2H),
3.43 (s, 2H), 2.22 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.7,
142.7, 134.8, 130.5, 130.2, 128.1, 126.4, 120.2, 119.7, 116.8, 115.9,
115.2, 63.5, 44.8; IR (thin film, CDCl3) 3237 (br), 3178 (m), 3099
(m), 3057 (m), 3025 (m), 2946 (m), 2858 (m), 2822 (m), 2776 (m),
1589 (s), 1523 (s), 1480 (s), 1329 (s), 1309 (s) cm−1. HRMS (CI):
m/z calcd for C15H18ClN2 [M + H]+ 261.1158, found 261.1151.
2-Chloro-N-(2-((dimethylamino)methyl)phenyl)aniline (19a).
Following representative procedure A, without base, using substrate
1 (0.100 g, 0.383 mmol) and 2-chloroaniline (0.081 mL, 0.766 mmol),
the crude mixture (ratio45 19a/2b 66:33) was purified by silica gel
column chromatography (99:1 to 98:2 dichloromethane/EtOAc) to
afford product 19a as a tan oil (0.0355 g, 0.136 mmol, 36%). 1H NMR
(400 MHz, CDCl3) δ 9.18 (br s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.35
(d, J = 7.9 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.13−7.09 (m, 2H), 6.86
(t, J = 7.4 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 3.44 (s, 2H), 2.25 (s, 6H);
13C{1H} NMR (125 MHz, CDCl3) δ 142.3, 140.3, 130.5, 129.9, 127.9,
127.4, 127.1, 122.1, 120.3, 119.7, 116.4, 115.7, 63.1, 44.5; IR (thin film,
CDCl3) 3218 (br), 3038 (m), 2976 (m), 2945 (m), 2857 (m), 2820
(m), 2774 (m), 1590 (s), 1525 (s), 1482 (m), 1466 (s), 1361 (m),
1329 (m), 1309 (m) cm−1. HRMS (ESI): m/z calcd for C15H18ClN2
[M + H]+ 261.1158, found 261.1166.
2-((Dimethylamino)methyl)-5-methyl-N-phenylaniline (14a). Fol-
lowing representative procedure A, without base, using substrate 3369
(0.100 g, 0.343 mmol), the crude mixture (ratio45 14a/14b 100:0) was
treated with trimethylethylenediamine (0.15 mL), then purified by
column chromatography (99:1 to 90:10 dichloromethane/EtOAc) to
1
afford product 14a as an orange oil (0.0517 g, 0.215 mmol, 59%). H
NMR (400 MHz, CDCl3) δ 8.46 (br s, 1H), 7.25 (t, J = 7.5 Hz, 2H),
7.18 (s, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.87 (t,
J = 7.3 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 3.40 (s, 2H), 2.27 (s, 3H),
2.21 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 143.3, 137.8,
130.4, 129.2, 122.9, 120.1, 120.0, 117.9, 115.6, 63.2, 44.7, 21.4; IR
(thin film, CDCl3) 3250 (br), 3044 (m), 2976 (m), 2945 (m), 2855
(m), 2819 (m), 2773 (m), 1616 (m), 1593 (s), 1529 (s), 1497 (s),
1454 (s), 1417 (s), 1360 (m), 1325 (m), 1307 (m) cm−1. HRMS
(ESI): m/z calcd for C16H21N2 [M + H]+ 241.1705, found 241.1708.
N-Phenyl-2-(piperidin-1-ylmethyl)aniline (15a). Following repre-
sentative procedure A, without base, using substrate 2669 (0.104 g,
0.345 mmol), the crude mixture (ratio45 15a/15b 100:0) was purified
by silica gel column chromatography (99:1 to 90:10 dichloromethane/
EtOAc) to afford product 15a as a tan oil (0.0537 g, 0.202 mmol,
58%). 1H NMR (500 MHz, CDCl3) δ 9.02 (br s, 1H), 7.35 (d, J = 8.1
Hz, 1H), 7.28−7.24 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.3
Hz, 2H), 7.07 (d, J = 7.4 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.77 (t, J =
7.4 Hz, 1H), 3.51 (s, 2H), 2.51−2.27 (m, 4H), 1.61 (qn, J = 5.6 Hz,
4H), 1.57−1.44 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 143.8,
143.2, 130.5, 129.2, 127.9, 124.9, 120.2, 117.9, 114.1, 62.9, 53.8, 26.3,
24.4; IR (thin film, CDCl3) 3236 (br), 3106 (m), 3045 (m), 2934 (s),
2851 (m), 2802 (m), 2758 (m), 1727 (m), 1593 (s), 1523 (s), 1497
(s), 1476 (s), 1462 (s), 1442 (s), 1390 (s), 1367 (s), 1342 (s), 1325
N-(4-Bromophenyl)-2-((dimethylamino)methyl)aniline (20a).
Following representative procedure A using substrate 1 (0.075 g,
0.287 mmol) and 4-bromoaniline (0.0987 mg, 0.574 mmol), the crude
mixture (ratio45 20a/2b 96:4) was purified by silica gel column
chromatography (9:1 dichloromethane/EtOAc then 99:1 EtOAc/
triethylamine) to afford product 20a as a brown solid (0.0510 g, 0.167
mmol, 58%): mp 95.4−96.8 °C; 1H NMR (500 MHz, CDCl3) δ 8.59
(br s, 1H), 7.34−7.28 (m, 3H), 7.18 (app t, J = 8.3 Hz, 1H), 7.09 (d, J
H
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= 7.4 Hz, 1H), 6.97−6.94 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 3.44 (s,
2H), 2.23 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 143.2, 142.5,
132.0, 130.6, 128.1, 126.1, 119.9, 119.1, 115.3, 111.7, 63.5, 44.8; IR
(thin film, CDCl3) 3241 (br), 3045 (m), 2977 (m), 2945 (m), 2856
(m), 2821 (m), 2774 (m), 1587 (s), 1521 (s), 1488 (s), 1473 (s),
1455 (s) cm−1. HRMS (CI): m/z calcd for C15H18BrN2 [M + H]+
305.0653, found 305.0646.
26.3, 24.3; IR (thin film, CDCl3) 3228 (br), 3174 (m), 3055 (m),
2935 (s), 2851 (m), 2805 (m), 2759 (m), 1726 (m), 1589 (s), 1523
(s), 1479 (s), 1442 (m), 1417 (m), 1367 (m), 1341 (s) cm−1. HRMS
(ESI): m/z calcd for C18H22ClN2 [M + H]+ 301.1472, found
301.1469.
Ethyl 3-((4-bromophenyl)amino)-4-((dimethylamino)methyl)-
benzoate (25a). Following representative procedure A, without
base, using substrate 3169 (0.100 g, 0.300 mmol) and 4-bromoaniline
(0.1032 mL, 0.600 mmol), the crude mixture (ratio45 25a/12b 74:26)
was treated with trimethylethylenediamine (0.1 mL), concentrated
onto Celite, and purified by silica gel column chromatography (99:1 to
90:10 dichloromethane/EtOAc) to afford product 25a as a brown oil
(0.0623 g, 0.165 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 8.75 (br
s, 1H), 7.95 (s, 1H), 7.49 (dd, J = 7.6, 1.0 Hz, 1H), 7.37 (d, J = 8.7 Hz,
2H), 7.15 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 7.1
Hz, 2H), 3.49 (s, 2H), 2.24 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 166.6, 143.3, 141.8, 132.1, 130.5, 130.5,
130.4, 120.7, 119.4, 115.4, 112.4, 63.3, 60.9, 44.8, 14.3; IR (thin film,
CDCl3) 3231 (br), 2979 (m), 2904 (m), 2859 (m), 2823 (m), 2778
(m), 1716 (s), 1586 (s), 1526 (s), 1489 (s), 1439 (s), 1392 (m), 1363
(m), 1333 (s), 1301 (s) cm−1. HRMS (ESI): m/z calcd for
C18H21BrN2O2Na [M + Na]+ 399.0684, found 399.0677.
2,2′-(N,N-Dimethylaminomethyl)-1,1′-biphenyl (2b). See repre-
sentative procedure B: mp 35.0−37.1 °C; 1H NMR (500 MHz,
CDCl3) δ 7.57 (dd, J = 7.8, 0.7 Hz, 2H), 7.35 (td, J = 5.1, 1.4 Hz, 2H),
7.25 (td, J = 4.6, 1.4 Hz, 2H), 7.08 (dd, J = 7.6, 1.4 Hz, 2H), 3.17 (d, J
= 13.7 Hz, 2H), 3.06 (d, J = 13.8 Hz, 2H), 2.10 (s, 12 H); 13C{1H}
NMR (125 MHz, CDCl3) δ 140.7, 137.2, 129.6, 128.7, 127.3, 126.1,
60.9, 45.5; IR (thin film, CH2Cl2) 3056 (m), 3021 (m), 2972 (m),
2940 (m), 2853 (m), 2815 (m), 2767 (br), 1455 (s), 1442 (s), 1403
(s), 1362 (s), 1303 (m), 1264 (m), 1174 (s), 1147 (s), 1097 (s), 1029
(m), 1007 (s) cm−1. HRMS (CI): m/z calcd for C18H24N2 [M + H]+
269.2018, found 269.2014. This data corresponds to previously
reported data.70
1,1′-(3,3′-Difluoro-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethylme-
thanamine) (8b). Following representative procedure B using
substrate 2769 (0.100 g, 0.358 mmol), the crude mixture was purified
by Kugelrohr distillation (0.5 mmHg, 60 °C, 45 min; 0.5 mmHg, 80
°C, 80 min) to yield product 8b as a colorless oil (0.043 g, 0.128
mmol, 71%). 1H NMR (500 MHz, CDCl3) δ 7.28−7.24 (m, 2H), 7.07
(td, J = 8.2, 1.2 Hz, 2H), 7.02 (dd, J = 7.5, 1.2 Hz, 2H), 3.38 (dd, J =
12.4, 1.9 Hz, 2H), 2.90 (dd, J = 12.4, 1.5 Hz, 2H), 2.01 (s, 12 H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.6 (d, JC−F = 245.5 Hz),
142.8, 127.8 (d, JC−F = 9.5 Hz), 126.0, 124.9 (d, JC−F = 14.7 Hz), 114.6
(d, JC−F = 22.7 Hz), 54.1, 45.2; IR (thin film, CH2Cl2) 2971 (m), 2942
(m), 2858 (s), 2817 (m), 2769 (m), 1610 (s), 1577 (s), 1486 (m),
1364 (s), 1310 (s), 1258 (s), 1237 (s), 1184 (s), 1117 (s), 1096 (s),
1043 (s), 1023 (s) cm−1. HRMS (CI): m/z calcd for C18H22F2N2 [M
+ H]+ 305.1829, found 305.1830.
N-(2-((dimethylamino)methyl)phenyl)pyridin-2-amine (21a). Fol-
lowing representative procedure A, without base, using substrate 1
(0.100 g, 0.383 mmol) and 2-aminopyridine (0.0721 mL, 0.766
mmol), the crude mixture (ratio45 21a/2b 100:0) was purified by silica
gel column chromatography (1:1 hexanes/EtOAc), and the resulting
product residue was azeotroped with ethanol (3 × 2 mL) to afford
1
product 21a as a yellow oil (0.0350 g, 0.154 mmol, 40%). H NMR
(500 MHz, CDCl3) δ 9.40 (br s, 1H), 8.23 (d, J = 4.2 Hz, 1H), 7.89
(d, J = 8.2 Hz, 1H), 7.49−7.45 (m, 1H), 7.28−7.25 (m, 1H), 7.11 (d, J
= 7.3 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H),
6.71−6.68 (m, 1H), 3.48 (s, 2H), 2.26 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 155.8, 148.3, 141.2, 137.3, 130.2, 128.1, 126.6, 120.8,
118.0, 114.5, 109.6, 63.5, 44.8; IR (thin film, CDCl3) 3252 (br), 3015
(m), 2978 (m), 2946 (m), 2858 (m), 2822 (m), 2776 (m), 1595 (s),
1571 (s), 1525 (s), 1481 (s), 1455 (s), 1418 (s), 1348 (s), 1308 (s)
cm−1. HRMS (ESI): m/z calcd for C14H17N3Na [M + Na]+ 250.1320,
found 250.1328.
N-(2-((Dimethylamino)methyl)-4-methoxyphenyl)-2,4,6-trime-
thylaniline (22a). Following representative procedure A using
substrate 2969 (0.0871 g, 0.299 mmol) and 2,4,6-trimethylaniline
(0.084 mL, 0.598 mmol), the crude mixture (ratio45 22a/10b 100:0)
was purified by silica gel column chromatography (100% dichloro-
methane then switching to 100% EtOAc) to afford product 22a as a
brown oil (0.0442 g, 0.148 mmol, 49%). 1H NMR (500 MHz, CDCl3)
δ 7.61 (br s, 1H), 6.93 (s, 2H), 6.70 (d, J = 2.9 Hz, 1H), 6.60 (dd, J =
8.7, 3.0 Hz, 1H), 6.09 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H), 3.51 (s, 2H),
2.31 (s, 3H), 2.26 (s, 6H), 2.13 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 151.3, 140.4, 137.3, 134.2, 133.6, 129.0, 124.5, 116.7, 112.4,
112.1, 63.6, 55.7, 44.8, 20.8, 18.2; IR (thin film, CDCl3) 3250 (br),
2973 (s), 2943 (s), 2914 (s), 2853 (s), 2819 (s), 2772 (s), 1505 (s),
1486 (s), 1465 (s), 1425 (m), 1376 (m), 1358 (m), 1309 (m), 1292
(m), 1264 (m), 1231 (s), 1292 (s) cm−1. HRMS (CI): m/z calcd for
C19H26N2O [M]+ 298.2045, found 298.2036.
2-((Dimethylamino)methyl)-3-fluoro-N-(4-methoxyphenyl)-
aniline (23a). Following representative procedure A, without base,
using substrate 2769 (0.0811 g, 0.291 mmol) and 4-anisidine (0.0717
g, 0.582 mmol), the crude mixture (ratio45 23a:8b 100:0) was treated
with tetramethylethylenediamine (0.15 mL), concentrated onto Celite,
and purified by silica gel column chromatography (99:1 to 80:20
dichloromethane/EtOAc) to afford product 23a as an orange oil
(0.0332 g, 0.121 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ 8.38 (br
s, 1H), 7.08−7.01 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.2
Hz, 1H), 6.47 (t, J = 8.9 Hz, 1H), 3.82 (s, 3H), 3.57 (s, 2H), 2.28 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.9 (d, JC−F = 241.1 Hz),
155.0, 147.9 (d, JC−F = 5.9 Hz), 135.7, 128.5 (d, JC−F = 11.0 Hz),
122.5, 114.6, 110.8 (d, JC−F = 15.4 Hz), 108.5, 104.8 (d, JC−F = 23.4
Hz), 55.6, 53.3 (d, JC−F = 4.4 Hz), 44.6; IR (thin film, CDCl3) 3238
(br), 3033 (m), 2947 (m), 2859 (m), 2826 (m), 2776 (m), 1620 (s),
1597 (s), 1583 (s), 1510 (s), 1471 (s), 1442 (m), 1365 (m), 1331
(m), 1288 (m), 1236 (s) cm−1. HRMS (CI): m/z calcd for
C16H19FN2O [M]+ 274.1481, found 274.1487.
1,1′-(4,4′-Dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethylme-
thanamine) (9b). Following representative procedure B using
substrate 2869 (0.100 g, 0.363 mmol), the crude mixture was purified
by basic alumina column chromatography (90:10 dichloromethane/
ethyl acetate to 99:1 ethyl acetate/triethylamine) to afford product 9b
as a colorless solid (0.0214 g, 0.0722 mmol, 40%): mp 99.3−101.0 °C;
1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.05 (d, J = 7.6 Hz, 2H),
6.95 (d, J = 7.7 Hz, 2H), 3.15 (d, J = 13.7 Hz, 2H), 3.05 (d, J = 13.6
Hz, 2H) 2.40 (s, 6 H), 2.10 (s, 12H); 13C{1H} NMR (400 MHz,
CDCl3) δ 137.7, 137.0, 136.8, 129.8, 129.1, 126.9, 60.8, 45.6, 21.2; IR
(thin film, CH2Cl2) 3019 (br), 2972 (m), 2940 (m), 2854 (s), 2814
(s), 2765 (m), 1611 (s), 1485 (s), 1455 (m), 1361 (s), 1299 (m),
1262 (m), 1175 (s), 1148 (s), 1096 (s), 1031 (m), 1008 (s) cm−1.
HRMS (CI): m/z calcd for C20H28N2 [M + H]+ 297.2331, found
297.2331.
N-(3-Chlorophenyl)-2-(piperidin-1-ylmethyl)aniline (24a). Follow-
ing representative procedure A, without base, using substrate 2669
(0.100 g, 0.332 mmol) and 3-chloroaniline (0.070 mL, 0.664 mmol),
the crude mixture (ratio45 24a/15b 72:28) was purified by silica gel
column chromatography (99:1 to 90:10 dichloromethane/EtOAc) to
1
afford product 24a as an orange oil (0.0545 g, 0.181 mmol, 55%). H
NMR (500 MHz, CDCl3) δ 9.16 (br s, 1H), 7.36 (d, J = 8.1 Hz, 1H),
7.20 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.4 Hz,
1H), 7.07 (br s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.84−6.82 (m, 2H),
3.51 (s, 2H), 2.51−2.29 (m, 4H), 1.62 (qn, J = 5.4 Hz, 4H), 1.55−1.45
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 142.8, 134.8,
130.6, 130.2, 128.0, 125.6, 119.9, 119.7, 116.7, 115.3, 115.2, 62.8, 53.8,
1,1′-(4,4′-Dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethyl-
methanamine) (10b). Following representative procedure B using
substrate 2969 (0.100 g, 0.343 mmol), the crude mixture was purified
by column chromatography on basic alumina (90:10 dichloro-
methane/ethyl acetate to 99:1 ethyl acetate/triethylamine) to afford
product 10b as a colorless solid (0.0257 g, 0.0783 mmol, 46%): mp
I
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1
84.6−85.5 °C; H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 2.2 Hz,
4H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.0, 137.1, 129.7, 128.7,
126.9, 125.8, 60.6, 54.6, 26.0, 24.4; IR (thin film, CDCl3) 3057 (m),
3021 (m), 2932 (s), 2851 (s), 2794 (s), 2754 (s), 2721 (m), 2683
(m), 1467 (m), 1442 (m), 1390 (m), 1367 (m), 1344 (m), 1325 (m),
1301 (m) cm−1. HRMS (ESI): m/z calcd for C24H32N2Na [M + Na]+
371.2463, found 371.2459.
1-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-
piperidine (26). Following the published procedure, benzyl bromide
and piperidine were used to synthesize 1-benzylpiperidine, which
matched previously reported data.71 To a solvent flask in a nitrogen-
filled glovebox was added [Ir(OMe)COD]2 (0.0597 g, 0.090 mmol),
bis(pinacolato)diboron (1.27 g, 5.01 mmol), picolylamine (0.0186 g,
0.180 mmol), followed by 1-benzylpiperidine (1.05 g, 6.00 mmol), and
methylcyclohexane (12 mL). The flask was sealed and heated at 90 °C
for 33 h. Upon cooling to room temperature, the reaction was
concentrated in vacuo and was found to have proceeded in 77%
conversion and 87:13 mono-ortho/bis-ortho ratio of boronate esters by
1H NMR spectroscopy. The crude brown oil (2.19 g) was purified by
basic alumina column chromatography (98:1:1 dichloromethane/
MeOH/triethylamine). The resulting product residue was further
purified by Kugelrohr distillation (0.5 mmHg, 70 °C, 20 min, trap
residue discarded; then 0.5 mmHg, 120 °C 1.5 h, trap residue
discarded; then 0.5 mmHg, 120 °C, 1.5 h, trap residue was product) to
afford 26 as a colorless oil (0.507 g, 1.68 mmol, 28%). 1H NMR (500
MHz, CDCl3) δ 7.61 (d, J = 7.1 Hz, 1H), 7.26−7.23 (m, 1H), 7.20 (t,
J = 6.7 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 3.79 (s, 2H), 2.60−2.58 (m,
4H), 1.60−1.56 (m, 4H), 1.52−1.49 (m, 2H), 1.34 (s, 12H); 13C{1H}
NMR (100 MHz, CDCl3) δ 142.4, 133.1, 128.5, 126.6, 126.2, 81.7,
60.2, 52.8, 25.5, 23.8, 23.5; IR (thin film, CDCl3) 2977 (s), 2934 (s),
2854 (m), 2800 (m), 1570 (m), 1601 (m), 1490 (m), 1443 (s), 1381
(s), 1371 (s), 1350 (s), 1310 (s) cm−1. HRMS (ESI): m/z calcd for
C18H28BNO2Na [M + Na]+ 324.2114, found 324.2114.
2H), 6.96 (d, J = 6.7, 2H), 6.79 (dd, J = 6.6, 2.2 Hz, 2H), 3.86 (s, 6H),
3.11 (d, J = 11.1 Hz, 2H), 3.05 (d, J = 11.1 Hz, 2H), 2.11 (s, 12H);
13C{1H} NMR (400 MHz, CDCl3) δ 158.8, 139.0, 132.8, 131.1, 113.5,
112.1, 61.0, 55.3, 45.6; IR (thin film, CH2Cl2) 2971 (br), 2941 (m),
2906 (br), 2854 (s), 2816 (m), 2767 (m), 1605 (s), 1570 (s), 1482
(s), 1466 (br), 1362 (s), 1276 (br), 1228 (s), 1174 (s), 1159 (s), 1146
(s), 1118 (s), 1097 (s), 1053 (m), 1030 (m), 1002 (s) cm−1. HRMS
(CI): m/z calcd for C20H28N2O2 [M + H]+ 329.2229, found 329.2243.
1,1′-(4,4′-Dichloro-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethylme-
thanamine) (11b). Following representative procedure B using
substrate 3069 (0.050 g, 0.169 mmol) without base, the crude mixture
was purified by column chromatography on basic alumina (90:10
dichloromethane/ethyl acetate to 99:1 ethyl acetate/triethylamine) to
afford product 11b as a colorless solid (0.0125 g, 0.0371 mmol, 44%):
1
mp 107.6−109.9 °C; H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 2.3
Hz, 2H), 7.24 (dd, J = 8.1, 2.2 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 3.08
(d, J = 14.0 Hz, 2H), 3.00 (d, J = 14.0 Hz, 2H), 2.10 (s, 12H);
13C{1H} NMR (400 MHz, CDCl3) δ 139.5, 137.9, 133.6, 130.8, 128.7,
126.5, 60.6, 45.5; IR (thin film, CH2Cl2) 2973 (m), 2942 (m), 2856
(s), 2817 (m), 2769 (m), 1589 (s), 1455 (m), 1395 (br), 1360 (s),
1295 (br), 1263 (br), 1244 (br), 1185 (br), 1148 (br), 1094 (m), 1033
(m), 1006 (s) cm−1. HRMS (CI): m/z calcd for C18H22Cl2N2 [M +
H]+ 337.1238, found 337.1245.
Diethyl 6,6′-bis((dimethylamino)methyl)-[1,1′-biphenyl]-3,3′-di-
carboxylate (12b). Following representative procedure B using
substrate 3169 (0.100 g, 0.300 mmol), the crude mixture was purified
by basica alumina column chromatography (90:10 dichloromethane/
ethyl acetate to 99:1 ethyl acetate/triethylamine) to afford product
12b as a colorless solid (0.0156 g, 0.0378 mmol, 25%): mp 97.0−99.0
°C; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.76 (s,
2H), 7.67 (d, J = 8.1 Hz, 2H), 4.37 (q, J = 7.08, 4H), 3.18 (d, J = 14.3
Hz, 2H), 3.09 (d, J = 14.3 Hz, 2H), 2.10 (s, 12H), 1.38 (t, J = 7.04,
6H); 13C{1H} NMR (400 MHz, CDCl3) δ 166.5, 142.7, 139.8, 130.6,
128.8, 128.7, 128.6, 60.95, 60.90, 45.5, 14.3; IR (thin film, CH2Cl2)
2977 (m), 2941 (m), 2903 (br), 2856 (br), 2817 (m), 2769 (m), 1719
(m), 1606 (s), 1572 (br), 1456 (br), 1391 (m), 1365 (s), 1307 (s),
1278 (br), 1249 (br), 1227 (s), 1173 (s), 1148 (s), 1108 (m), 1028
(m) cm−1. HRMS (ESI): m/z calcd for C24H32N2O4Na [M + Na]+
435.2260, found 435.2259.
ASSOCIATED CONTENT
■
S
* Supporting Information
Molecular structures and the preparation of boronate ester
1
substrates and H and 13C{1H} NMR spectra. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b01074.
1,1′-(5,5′-Dibromo-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethylme-
AUTHOR INFORMATION
Corresponding Author
*E-mail: clarkt@sandiego.edu.
Notes
thanamine) (13b). This byproduct of the amination reaction was not
■
1
isolated in pure form. Diagnostic spectral data: H NMR (500 MHz,
CDCl3) δ 7.49 (dd, J = 8.4, 1.8 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.24
(d, J = 1.8 Hz, 2H), 3.11 (d, J = 13.9 Hz, 2H), 3.00 (d, J = 13.9 Hz,
2H), 2.11 (s, 12H).
The authors declare no competing financial interest.
1,1′-(5,5′-Dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis(N,N-dimethylme-
thanamine) (14b). Following representative procedure B using
substrate 3369 (0.100 g, 0.363 mmol), the crude mixture was purified
by column chromatography on basic alumina (90:10 dichloro-
methane/ethyl acetate to 99:1 ethyl acetate/triethylamine) to afford
product 14b as a colorless solid (0.0224 g, 0.0756 mmol, 42%): mp
ACKNOWLEDGMENTS
■
We acknowledge the UCI Mass Spectrometry facility, National
Science Foundation (CHE-1151092 and CHE-1339149),
University of San Diego, and Research Corporation for Science
Advancement Department Development Award.
1
90.4−90.8 °C; H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz,
2H), 7.16 (d, J = 8.8 Hz, 2H), 6.89 (s, 2H), 3.14 (d, J = 13.6 Hz, 2H),
3.03 (d, J = 13.6 Hz, 2H) 2.34 (s, 6H), 2.10 (s, 12H); 13C{1H} NMR
(100 MHz, CDCl3) δ 140.7, 135.5, 134.1, 130.3, 128.5, 127.9, 60.6,
45.47, 21.03; IR (thin film, CH2Cl2) 3014 (br), 2972 (br), 2940 (br),
2853 (m), 2814 (m), 2764 (m), 1609 (m), 1454 (br), 1361 (s), 1298
(br), 1260 (br), 1174 (s), 1148 (s), 1130 (s), 1096 (s), 1030 (m)
cm−1. HRMS (ESI): m/z calcd for C20H28N2Na [M + Na]+ 319.2150
found 319.2153.
REFERENCES
■
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2,2′-Bis(piperidin-1-ylmethyl)-1,1′-biphenyl (15b). Following rep-
resentative procedure B using substrate 2669 (0.100 g, 0.332 mmol),
the crude mixture was purified by column chromatography on basic
alumina (90:10 dichloromethane/EtOAc then switching to 99:1
EtOAc/triethylamine) to afford product 15b as a colorless oil
(0.0322 g, 0.0924 mmol, 56%). 1H NMR (500 MHz, CDCl3) δ
7.57 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.0 Hz, 2H), 7.23 (t, J = 7.0 Hz,
2H), 7.08 (d, J = 7.5 Hz, 2H), 3.18 (d, J = 14.0 Hz, 2H), 3.09 (d, J =
14.5 Hz, 2H), 2.29−2.14 (m, 8H), 1.50−1.48 (m, 8H), 1.41−1.31 (m,
J
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