Chan–Evans–Lam Amination of Boronic Acid Pinacol

33 Pages·2016·0.57 MB·English

by  Allan Watson

Chan–Evans–Lam Amination of Boronic Acid Pinacol (BPin) Esters:
Overcoming the Aryl Amine Problem
Julien C. Vantourout,a Robert P. Law,b Albert Isidro-Llobet,b Stephen J. Atkinson,b and Allan
J. B. Watson*a
a Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde,
Glasgow, G1 1XL (UK). E-mail: [email protected]
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY
(UK).

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.

Transition metal–mediated C-N bond formation is an 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
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 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.

a) Previous work: Chan-Evans-Lam coupling of RBPin
Cu(OAc)2 (10 mol %)
(i) Hartwig (2006): Ar BPin R2NH Ar NR2
KF, 4 Å MS, MeCN
alkyl only O2, 80 °C 31-67% yield
(ii) Kuninobu (2013): R BPin alRky2lN, aHryl (Ct-Bu(uOOA)2c,) 2P (h5M me,o 5l %0 °)C 20R->99%N yRie2ld
(iii) Clark (2015): N(R')2 R2NH Cu(OAc)2 (10 mol %) N(R')2
KF, 3 Å MS, MeCN
BPin aryl only O2, 80 °C NR2
45-75% yield
b) This work: general conditions for Chan–Evans–Lam coupling of ArBPin
Cu(OAc)2, Et3N
Ar BPin R2NH Ar NR2
MeCN or MeCN/EtOH
alkyl, aryl 4 Å MS, 80 °C up to 91% yield
alkyl amine: 38 examples
aryl amine: 24 examples
Scheme 1. Approaches to Chan-Evans-Lam coupling of RBPin.

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 by-product of this reaction, phenol 4
(1%). Conversion to product almost doubled when heating under reflux in CH Cl (entry 2).
2 2
Table 1. Reaction optimization.a
NHPh OH
BPin Cu(OAc)2, Et3N Ph 3a Ph 4
PhNH2 conditions H OEt
Ph
1a 2a
Ph Ph
5 6
entry reaction conditions 3a:4:5:6 (%)b
1 CH Cl , 0.25 M, 25 °C 16:1:0:--
2 2
2 CH Cl , 0.25 M, 40 °C 31:2:5:--
2 2
3 MeCN, 0.25 M, 60 °C 39:8:6:--
4 MeCN, 0.25 M, 80 °C 44:14:11:--
5 MeCN, 0.25 M, 3 Å MS, 80 °C 58:6:3:--
6 MeCN, 1.0 M, 3 Å MS, 80 °C 71:2:0:--
7 EtOH, 0.25 M, 60 °C 43:12:15:38
8 MeCN:EtOH (20:1), 1.0 M, 3 Å MS, 80 °C 82:6:3:7
9 MeCN:EtOH (20:1), 1.0 M, 3 Å MS, O 80 °Cc 21:2:0:0
2,
a 1a (1.0 equiv, 0.3 mmol), 2a (2 equiv, 0.6 mmol), Cu(OAc) (1 equiv, 0.3 mmol), Et N (2
2 3
equiv, 0.6 mmol), solvent, air, 24 h. b Determined by HPLC analysis using an internal
standard. Mass balance is returned starting material. c Using 10 mol % Cu(OAc) .
2

A survey of reaction solvents was useful (a broad range of solvents was evaluated, see ESI).
Replacement of CH Cl with MeCN allowed access to higher reaction temperatures and
2 2
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 (entries 3 and 4). Addition of
molecular sieves reduced the levels of phenolic by-product 4 (entry 5) and increasing the
reaction concentration boosted the yield of 3a further, providing relatively good efficiency
(entry 6). In addition to lowering production of phenol by-product 4, removal of H O by
2
addition of molecular sieves was observed to decrease formation of protodeboronation by-
product 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 6 as expected;3a,b,4d,e,9 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 mono-nuclear Cu(OAc) from the paddlewheel dimer, [Cu(OAc) ] .10 To limit the
2 2 2
production of 6 while attempting to retain this increase in reactivity, mixtures of MeCN:EtOH
were evaluated (see ESI). 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) under
2
an O atmosphere led to only 21% conversion to 3a (entry 9).
2

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) under
2
an O atmosphere.11 In this regard, a series of control experiments using boronic acid 1b,
2
aniline 2a, and stoichiometric CEL reaction conditions were informative (Table 2).
Table 2. The inhibitory effect of pinacol on CEL reactions of boronic acid 1b.a
NHPh
B(OH)2 Cu(OAc)2 (1 equiv), Et3N (2 equiv)
PhNH2
Ph 3 Å MS, CH2Cl2, 20 °C Ph
pinacol (x equiv), time (h)
1b 2a 3a
entry pinacol time 3a (%)b
1 --- 6 h 41
2 --- 24 h 70
3 1 equiv added at 0 h 6 h 11
4 1 equiv added at 0 h 24 h 12
5 1 equiv added at 6 h 6 h 46
6 1 equiv added at 6 h 24 h 50
a 1b (1.0 equiv, 0.25 mmol), 2a (2 equiv, 0.5 mmol), Cu(OAc) (1 equiv, 0.25 mmol), Et N
2 3
(2 equiv, 0.5 mmol), CH Cl (1 mL), air, 20 °C. b Determined by HPLC analysis using an
2 2
internal standard.

The CEL reaction of 1b with 2a proceeds well in the absence of pinacol, as expected (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 by-product as the
reactions of BPin substrates progress, inhibits catalyst turnover and therefore reaction
efficiency. Accordingly, stoichiometric Cu(OAc) are required with BPin substrates.
2
Based on this, we proceeded to evaluate the generality of the optimum stoichiometric
conditions (entry 8). Application of the developed protocol to a range of ArBPin and aniline
substrates showed the conditions to be broadly applicable (Scheme 2).
R
Ar2 R Cu(OAc)2 (1 equiv), Et3N (2 equiv)
Ar1 BPin N N
H 3 Å MS, MeCN/EtOH (20:1), 80 °C, 24 h Ar1 Ar2
3a-x
ArBPin variation:
H H H H
N N N N
Ph Ph Ph Ph Ph
Ph MeO MeO2C
3a: 79% 3b: 74% 3c: 70% 3d: 78%
H H H H
N N NC N BocHN N
Ph Ph Ph Ph
Br Cl
3e: 81% 3f: 78% 3g: 84% 3h: 67%
F3C HN Ph Me HN Ph NC HN Ph HN Ph
F
3i: 74% 3j: 55% 3k: 58% 3l: 77%
Aryl amine variation:
Ph MNe MPhe N Me Ph HN Ph HN
CO2Me OMe
3m: 65% 3n: 24% 3o: 69% 3p: 87%
Ph HN Ph HN CO2H Ph HN NO2 Ph HN CO2H
Br Cl CF3
3q: 71% 3r: 83% 3s: 52% 3t: 43%
H H H
N N N N
Ph Ph N Ph
N
S
3u: 51% 3v: 40% 3w: 34%
HO2C 3x: 31%
Scheme 2. Scope of the developed CEL reaction conditions to a range of aryl BPin and aryl
amine substrates. Isolated yields.
The reaction conditions tolerated functionality on both the aryl BPin and aryl amine
components. Electron-rich (3c, 3h, 3j), -neutral (3a, 3b, 3l), and –withdrawing groups (3d-g,
3i, 3k) were tolerated on the ArBPin. 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 reaction 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.
R1 R2 Cu(OAc)2 (1 equiv), Et3N (2 equiv) R1
Ar BPin N
H 3 Å MS, MeCN, 80 °C, 24 h Ar N R2
7a-al
ArBPin variation:
N N N N
Ph
Ph MeO MeO2C
7a: 74% 7b: 71% 7c: 78% 7d: 73%
N N NC N N
Br Cl F3CO
7e: 85% 7f: 84% 7g: 64% 7h: 71%
O O Me
N N N N
MeHN Me2N
N
7i: 62% 7j: 82% 7k: 40% 7l: 22%
BocHN N N N
O
N N
Boc
7m: 76% 7n: 73% 7o: 65%
Alkyl amine variation: H H
N Me NC N
Nn-Bu2
Ph Me
7p: 10% 7q: 73% 7r: 56%
Me O
HN NMe2 SO2
OMe
N N
N Ph Ph
Ph
7s: 71% 7t: 62% 7u: 69% 7v: 54%
O Me SO2Me H
Ph N Ph N Me Ph N Me Ph N Me
7w: 71% 7x: 43% 7y: 42% 7z: 70%
O
H H
N Me N
Ph Ph
NH NBoc
Me Ph NH
Ph
7aa: 52% 7ab: 82% 7ac: 74% 7ad: 86%
H OMe O
N H
Ph HN Ph N CF3 H NH
Ph N
Ph
7ae: 86% 7af: 84% 7ag: 69% 7ah: 32%
Me
H Ph
H H N O N
Ph N OMe Ph N NHBoc Ph H N Me
O N
Me
7ai: 76% 7aj: 70% 7ak: 78% 7al: 91%
Scheme 3. Scope of the developed CEL reaction conditions to a range of aryl BPin and alkyl
amine substrates. Isolated yields.
Conclusions
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,
Scheme 2, and Scheme 3). Glassware was oven-dried (150 °C) and purged with N before use.
2
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
hotplate/stirrer. 3 Å molecular sieves were purchased from Aldrich Chemical Company in
powdered form, and activated and stored in a oven at 150 °C until their use.
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 MHz and 101 MHz, respectively.
Chemical shifts are reported in ppm and coupling constants are reported in Hz with CDCl
3
referenced at 7.27 ppm (1H) and 77.36 ppm (13C) and DMSO-d referenced at 2.50 ppm (1H)
6
and 39.52 ppm (13C). High-resolution mass spectra were obtained using a quadropole 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/H O over 16 minutes at a flow rate of 2 mL/min. Samples for HPLC analysis
2
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 MeCN and 500 µL H O for HPLC analysis against established
2
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) (1 equiv, 0.30 mmol, 54 mg), Et N (2 equiv, 0.60 mmol, 61 mg,
2 3
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, filtered through Celite, and the filtrate was evaporated to give a
residue that was purified by silica chromatography (EtOAc/petroleum ether with 1% Et N
3
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) (1 equiv, 0.20 mmol, 36 mg), Et N (2 equiv, 0.40 mmol, 41
2 3
mg, 56` µL), and powdered activated 3 Å molecular sieves in MeCN (400 µL) was sealed in
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, filtered through Celite, and the filtrate was evaporated to give a residue that was
purified by silica chromatography (EtOAc/petroleum ether with 1% Et N modifier).
3
Appropriate fractions were evaporated to afford the desired product.
N-Phenyl-[1,1'-biphenyl]-4-amine (3a).13 Orange solid (57 mg, 79% yield). Purification:
silica chromatography, 0-3% (EtOAc + 1% Et N)/petroleum ether. M.pt.: 110-111 °C. 1H
3
NMR (400 MHz; DMSO-d ): δ 6.86 (t, J = 7.3 Hz, 1H), 7.12-7.17 (m, 4H), 7.27-7.28 (m, 3H),
6
7.42 (t, J = 7.6 Hz, 2H), 7.55-7.63 (m, 4H), 8.30 (br. s., 1H). 13C NMR (101 MHz, DMSO-
d ): 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.
6
LCMS (ESI): t = 1.43 min, [M+H]+ 246.2. HRMS (ESI): (C H N) [M+H]+ requires
R 18 16