Buchwald-Hartwig amination of (hetero)aryl chlorides by employing Mor-DalPhos under aqueous and solvent-free conditions

Article abstract of DOI:10.1002/ejoc.201200510

We report on the application of the [Pd(cinnamyl)Cl]₂/Mor- DalPhos catalyst system in the Buchwald-Hartwig amination of (hetero)aryl chlorides with primary or secondary amines conducted either under aqueous conditions without the use of co-solvents and/or surfactants or under solvent-free conditions (52 examples). We have established that reactions of this type can be conducted without the rigorous exclusion of air, and in the case of the solvent-free reactions, we have demonstrated that appropriately selected liquid and solid reagents can be employed successfully.

Full text of DOI:10.1002/ejoc.201200510

Job/Unit: O20510
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FULL PAPER
DOI: 10.1002/ejoc.201200510
Buchwald–Hartwig Amination of (Hetero)aryl Chlorides by Employing Mor-
DalPhos under Aqueous and Solvent-Free Conditions
Bennett J. Tardiff[a] and Mark Stradiotto*[a]
Keywords: Amination / Cross-coupling / Palladium / Ligand design
We report on the application of the [Pd(cinnamyl)Cl]2/Mor-
DalPhos catalyst system in the Buchwald–Hartwig amination
of (hetero)aryl chlorides with primary or secondary amines
conducted either under aqueous conditions without the use
of co-solvents and/or surfactants or under solvent-free condi-
tions (52 examples). We have established that reactions of
this type can be conducted without the rigorous exclusion of
air, and in the case of the solvent-free reactions, we have
demonstrated that appropriately selected liquid and solid
reagents can be employed successfully.
though the advancement of aqueous BHA protocols has
benefited from the use of supported catalysts[7] as well as
the application of additives including co-solvents and sur-
factants,[8] the demonstrated substrate scope exhibited by
such catalyst systems is often limited in terms of the diver-
sity of the amine substrates employed, as well as the dearth
of examples involving (hetero)aryl chlorides. It is worth not-
ing that the modification of established ancillary ligands
with hydrophilic substituents that render the resultant metal
catalyst soluble in water has been employed successfully in
the pursuit of increasingly effective catalysts for use in aque-
ous media.[4a,4c,4d] Although the application of such hydro-
philic ligands in BHA chemistry has received scant atten-
tion, one could envision the potential benefits of employing
such ligands in terms of enabling catalyst recovery and re-
cycling under biphasic conditions. However, this approach
is not without drawbacks in that the appending of hydro-
philic addenda onto a ligand, the structure of which has
been optimized so as to offer desirable catalytic perform-
ance, can alter the behavior of the resulting catalyst often
in ways that cannot easily be predicted.[4a,4c,4d,9] Moreover,
the preparation of tailor-made ligands for use in water can
represent a practical impediment to the broader implemen-
tation of environmentally more friendly aqueous protocols,
including in BHA chemistry. In this regard, the investiga-
tion of BHA chemistry conducted under strictly aqueous
conditions without the use of additives by employing un-
modified and commercially available catalyst systems that
have an established track record of desirable catalytic per-
formance under nonaqueous conditions represents an im-
portant avenue of inquiry in the quest to advance green
chemistry concepts in BHA.
Introduction
The palladium-catalyzed cross-coupling of (hetero)aryl
(pseudo)halides and N–H-containing substrates (i.e., the
Buchwald–Hartwig amination, BHA) is a versatile C–N
bond-forming methodology that is widely employed on
both bench-top and industrial scales.[1] Following the initial
reports of such reactivity in 1995,[2] this class of transforma-
tions has attracted intense research interest, leading to a
rapid advancement of the state of the art. In particular, sig-
nificant attention has been directed towards evaluating how
the choice of base, palladium precursor, and ancillary co-
ligand influences the outcome of BHA reactions. As a re-
sult, a number of extremely effective classes of catalysts for
BHA have been identified that offer broad substrate scope
and excellent functional-group tolerance at relatively low
catalyst loadings, including for the cross-coupling of the
more abundant, but less reactive, (hetero)aryl chloride sub-
strates.[1,3]
Given the established reactivity benefits that can be de-
rived from conducting metal-catalyzed reactions in or on
water,[4] and in light of the increased emphasis that has been
placed on performing synthetic chemistry in environmen-
tally more benign media,[5] it is surprising that little atten-
tion has been given to the study of BHA reactions con-
ducted under strictly aqueous conditions. A breakthrough
in this area was disclosed by Buchwald and co-workers in
2003,[6] who reported the use of Cy-XPhos/Pd mixtures for
the cross-coupling of (hetero)aryl (pseudo)halides, albeit
with a somewhat limited substrate scope (nine examples,
1 mol-% Pd and 1–2.5 mol-% Cy-XPhos, 84–96%). Al-
[a] Department of Chemistry, Dalhousie University,
6274 Coburg Road, P. O. Box 15000, Halifax, Nova Scotia, B3H
4R2, Canada
We have recently developed a new class of phenylene P,N
“DalPhos” ligands[10] that have proven useful in metal-cata-
lyzed C–N[11] and C–C[12] cross-coupling reactions con-
ducted in organic media. In the context of the considera-
tions outlined above, and having demonstrated that the
Fax: +1-902-494-1310
E-mail: mark.stradiotto@dal.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200510.
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B. J. Tardiff, M. Stradiotto
FULL PAPER
[Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system offers ex- cused on the arylation of aniline by using the unhindered
cellent performance in BHA chemistry with a broad array and modestly deactivated substrate 4-chlorotoluene. Under
of amine and (hetero)aryl chloride coupling partners,[11] we reasonable catalyst loadings (3 mol-% Pd, unoptimized) the
became interested in exploring the behavior of this commer- desired cross-coupling product 1a (Scheme 1) was obtained
cially available catalyst system under strictly aqueous condi- in 91% isolated yield. Although for convenience we nor-
tions as well as under solvent-free (neat) conditions. We re- mally chose to prepare our catalytic reaction mixtures for
port herein on the results of these studies, including our the studies reported herein within a dinitrogen-filled
observation that the desirable catalytic performance exhib- glovebox[13] followed by the addition of nondegassed dis-
ited by the [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system tilled water to the sealed (dinitrogen-filled) reaction vessel,
for the cross-coupling of primary or secondary amines with we were pleased to find that the preparation of 1a could
(hetero)aryl chlorides is retained in aqueous media and also alternatively be conducted under air with negligible impact
under solvent-free conditions. Notably, we establish that re- on catalytic performance. No conversion to 1a was achieved
actions of this type can be conducted without the rigorous in control experiments in which either [Pd(cinnamyl)Cl]2 or
exclusion of air, and in the case of solvent-free reactions Mor-DalPhos was excluded from the reaction mixture.
we demonstrate that appropriately selected liquid and solid
reagents can be employed successfully.
With this promising result in hand, we sought to explore
the scope of this chemistry with both primary and second-
ary amines; broad substrate scope was determined
(Scheme 1). Electronically activated and deactivated unhin-
dered aryl chlorides proved to be suitable coupling partners
when paired with anilines (1a–e, 81–95%); this trend also
Results and Discussion
Our initial efforts to survey the utility of the [Pd(cinn- held for benzylamine (1g, 70%; 1h, 73%). ortho-Substituted
amyl)Cl]2/Mor-DalPhos catalyst system in BHA chemistry aryl chlorides were also found to be suitable reaction part-
conducted under strictly aqueous conditions (i.e., in the ab- ners, including with aniline (1f, 89%), octylamine (1j, 82%),
sence of additives such as co-solvents or surfactants) fo- and cyclohexylamine (1k, 73%). With the same protocol,
Scheme 1. Arylation of primary and secondary amines under aqueous conditions. Reagents and conditions: ArCl/amine/KOH = 1:1.1:1.2,
8 mol-% NaOtBu (for use in catalyst activation), 3 mol-% Pd, Pd/Mor-DalPhos = 1:2, H2O, 110 °C, nominal [ArCl] = 2.0 m. All reactions
were performed on a 0.5 mmol scale with reaction times of 12–36 h (unoptimized); the yields are of isolated material.
2
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
benzophenone imine was found to be a good amine cou- wave heating for the preparation of a series of substituted
pling partner (1l, 88%), and 2-chloropyridine, 3-chloropyr- N-arylindolines by employing aryl bromides, chlorides, and
idine, and 2-chloropyrazine successfully underwent cross- iodides.
coupling with anilines (1m, 1p–s), octylamine (1n, 1t), cy-
The results of our experimentation directed towards
clohexylamine (1o), and benzylamine (1u) in good to excel- using the [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system
lent yields (70–94%). The presence of an alkene functional for BHA reactions conducted under solvent-free conditions
group was also tolerated under these reaction conditions, are collected in Scheme 2. Notably, a range of amine and
enabling the isolation of 1v in high yield (89%).
aryl chloride coupling partners can be employed, including
Previous work by our group established the utility of the examples featured above in our investigation into aqueous
[Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system in chemo- reactivity (Scheme 1) as well as substrate pairings that we
selective Buchwald–Hartwig amination reactions conducted found to be incompatible with our aqueous conditions. Pri-
under nonaqueous conditions (1–2 mol-% Pd, toluene, mary amines were coupled with hindered and unhindered
NaOtBu) in which primary amines were preferentially aryl- tolyl chlorides in excellent yields (3a–c, 90–97%). In ad-
ated in the presence of competitor secondary amine frag- dition, 3-chloropyridine proved to be a suitable reaction
ments.[11d] Although this trend holds under the aqueous partner with aniline (3d, 92%), affording the product in a
conditions surveyed herein (3 mol-% Pd, water, KOH), al- high yield that is comparable to that obtained under the
lowing for the isolation of the primary amine monoaryl- aqueous protocol (Scheme 1). The successful cross-coupling
ation products 1w (88%), 1x (81%), and 1y (75%), it is of 2-aminopyridine and 1-chloro-4-(trifluoromethyl)benz-
evident that the use of aqueous reaction conditions results ene to give 3e in 83% isolated yield demonstrates that
in a lower yield of the target complex, despite the use of
higher catalyst loading.
Despite the preference of the [Pd(cinnamyl)Cl]2/Mor-
DalPhos catalyst system for primary amine substrates,[11d]
in turning our attention to secondary amines we found N-
methylaniline to be a suitable cross-coupling substrate un-
der aqueous conditions when paired with electronically ac-
tivated or deactivated unhindered aryl chlorides (2a–c, 62–
86%), 2-chloropyrazine (2d, 71%), or 2-chlorotoluene (2e,
68%). Morpholine, piperidine, and N-methylbenzylamine
also proved to be suitable cross-coupling substrates in com-
bination with electronically activated and deactivated un-
hindered aryl chlorides as well as with heteroaryl chlorides
(2f–l, 65–83%).[14] The capacity of the [Pd(cinnamyl)Cl]2/
Mor-DalPhos catalyst system to accommodate both pri-
mary and secondary amines under aqueous conditions is
attractive from a practical perspective, given the current
interest in establishing BHA catalyst systems that can oper-
ate across both amine substrate classes.[15] Furthermore, the
viability of conducting such catalytic transformations under
benchtop conditions was established in the aforementioned
preparation of the representative substrates 1h, 1j, 1x, 1y,
and 2k in which the reactions were conducted under air
rather than dry dinitrogen.
Despite the considerable interest in carrying out syn-
thetic organic transformations in the absence of added sol-
vent,[16] little attention has been paid to the development of
synthetically useful solvent-free (neat) BHA protocols. Such
protocols are attractive, not only in terms of advancing
green chemistry concepts, but also in terms of allowing for
the possible application of a wider range of bases in such
Scheme 2. Arylation of primary and secondary amines under sol-
catalytic chemistry compared with reactions conducted un-
vent-free conditions. Reagents and conditions: Unless stated other-
wise, ArCl/amine/NaOtBu = 1:1.1:1.4, 3 mol-% Pd, Pd/Mor-
DalPhos = 1:2, 110 °C. [a] ArCl/amine/K2CO3 = 1:1.1:1.2, 8 mol-
der aqueous conditions. Noteworthy reports in this area in-
clude the work of Yoshifuji and co-workers,[17] who de-
% NaOtBu (for use in catalyst activation), 3 mol-% Pd, Pd/Mor-
DalPhos = 1:2, 110 °C. [b] ArCl/amine/LiHMDS = 1:1.1:2.1,
8 mol-% NaOtBu (for use in catalyst activation), 3 mol-% Pd, Pd/
Mor-DalPhos = 1:2, 110 °C. All reactions were performed on a
0.5 mmol scale with reaction times of 12–36 h (unoptimized); the
scribed the application of a Pd precatalyst featuring a di-
phosphanylidenecyclobutene ancillary ligand for use in the
solvent-free amination of aryl bromides at room tempera-
ture, as well as the work of Beccalli and co-workers,[18] who
reported the use of solvent-free BHA methods with micro- yields are of isolated material.
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B. J. Tardiff, M. Stradiotto
FULL PAPER
room-temperature solids can successfully be employed as chemoselectivity observed parallels that achieved in organic
substrates under our solvent-free protocol. Secondary media. Encouraged by the ability of the Mor-DalPhos li-
amines are also viable substrates in this chemistry, as dem- gand to engender desirable catalytic behavior under aque-
onstrated in the case of morpholine (3f, 88%), N-methyl- ous and solvent-free conditions without the need for further
benzylamine (3g, 85%), and diphenylamine (3h, 90%). The structural modification, we are exploring more broadly the
ability to employ alternative bases such as K2CO3 or use of this and related ligands in the development of more
LiHMDS under these solvent-free conditions allowed for green metal-catalyzed transformations. Our progress will be
aryl chloride substrates containing base-sensitive functional disclosed in future reports.
groups (esters, amides) to be employed, as demonstrated by
the high-yielding formation of 3i (90%) and 3j (88%). In
keeping with reactions conducted in organic and aqueous
media, the presence of an alkene functional group within
the aryl chloride was tolerated under solvent-free condi-
tions, affording 3k (90%). Benzophenone hydrazone was
unsuccessfully employed as a substrate under aqueous con-
dard benchtop conditions. Deuteriated solvents (Cambridge Iso-
ditions, with negligible product formation observed by GC.
However, under solvent-free conditions this proved to be a
viable BHA substrate in combination with 4-chlorotoluene,
Experimental Section
General: Unless otherwise noted, all reactions were performed in-
side a dinitrogen-filled glovebox, whereas the organic products of
the catalytic reactions were isolated following workup under stan-
topes) were used as received. Mor-DalPhos[11a] and [Pd(cinnamyl)-
[19]
Cl]2 were prepared according to literature procedures. All other
reagents, solvents (including those used on the benchtop), and ma-
giving 3l (83%) and thereby further demonstrating the util- terials were used as received from commercial sources. Flash col-
umn chromatography was performed on silica gel (SiliaFlash P60,
Silicycle). GC was performed with a Shimadzu GC-2014 instru-
ment equipped with an SGE BP-5 column (30 m, 0.25 mm i.d.).
Stated yields correspond to isolated products. 1H and 13C NMR
data were collected at 300 K with a Bruker AV-500 spectrometer
operating at 500.1 and 125.8 Hz, respectively, with chemical shifts
reported in ppm downfield of the SiMe4 signal. Characterization
data for all new compounds are provided below, whereas those for
previously reported compounds, as well as 1H and 13C NMR spec-
tra for all reaction products, are given in the Supporting Infor-
ity of this solvent-free procedure. Benzophenone imine was
also successfully arylated under solvent-free conditions with
4-chlorobenzotrifluoride, affording the target product in
high yield (3m, 92%). The propensity of the [Pd(cinnamyl)-
Cl]2/Mor-DalPhos catalyst system to promote chemoselec-
tive BHA reactions at primary amine sites within diamine
substrates in organic and aqueous (see above) media is
maintained under these solvent-free conditions (3n, 85%).
Moreover, 3-chloro-N-methylaniline was successfully amin-
ated chemoselectively by using morpholine (3o, 88%), in mation.
keeping with the propensity of the [Pd(cinnamyl)-
General Procedure A. Aqueous Catalytic Reactions: In a dinitrogen-
Cl]2/Mor-DalPhos catalyst system for uptake of the more
electron-rich amine substrate that binds more efficiently
when two sterically comparable secondary amine species
are in competition. As was noted above for reactions con-
ducted under aqueous conditions, the viability of using
benchtop reaction protocols was confirmed in the afore-
mentioned preparation of the substrates 3d and 3f, with the
reactions being conducted under air.
filled glovebox, a vial was charged with [Pd(cinnamyl)Cl]2 (3 mol-
% Pd), Mor-DalPhos (6 mol-%), KOH (34 mg, 0.60 mmol), and
NaOtBu (8 mol-%) as well as a stirring bar. Although selected con-
trol experiments confirmed that the reactions can be conducted
successfully without added NaOtBu, we opted to include a catalytic
amount of NaOtBu (despite the short lifetime associated with the
butoxide anion in water) in the event that this might assist in cata-
lyst activation very early in the reaction for given substrate pairings.
The vial was sealed with a cap containing a PTFE septum and
removed from the glovebox; reagents were added in the glovebox
for convenience or on the benchtop (for 1h, 1j, 1x, 1y, and 2k)
through a microliter syringe (as needed) as was distilled water
(0.25 mL). Reaction mixtures were heated at 110 °C for 12–36 h
(times not optimized), and the consumption of the aryl chloride
was confirmed by GC. The reaction mixtures were then cooled,
opened to the air, and diethyl ether (5 mL) was added. The reaction
mixture was then filtered through a layer of neutral alumina, which
was then washed with dichloromethane (5 mL) and MeOH (5 mL).
Following removal of the solvent, the crude products were purified
Conclusions
The results presented herein establish the commercially
available [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system
as being effective for the cross-coupling of (hetero)aryl
chlorides and primary or secondary amines under aqueous
conditions without the use of additives (e.g., co-solvents or
surfactants) as well as under solvent-free (neat) conditions.
To the best of our knowledge, this study represents the most
extensive compilation of such reactivity to be reported thus
far in the literature. An array of activated and deactivated
(hetero)aryl chlorides can be employed as substrates in
combination with aryl and aliphatic amines (both primary
and secondary) by employing reasonable catalyst loadings
and without the rigorous exclusion of air. Included in the
substrate scope are examples of functionalized and base-
sensitive substrates as well as chemoselective transforma-
1
by column chromatography on silica and characterized by H and
13C NMR methods, as well as HR mass spectrometry (for new
compounds).
General Procedure B. Solvent-Free Catalytic Reactions: In a dinitro-
gen-filled glovebox, a vial was charged with [Pd(cinnamyl)Cl]2
(3 mol-% Pd), Mor-DalPhos (6 mol-%), and NaOtBu (67 mg,
0.7 mmol) as well as a stirring bar. The vial was sealed with a cap
containing a PTFE septum and removed from the glovebox; rea-
gents were added in the glovebox for convenience or on the
benchtop (for 3d and 3f) through a microliter syringe (as needed).
tions leading to arylated diamine products in which the Reaction mixtures were heated at 110 °C for 12–36 h (times not
4
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
optimized), and the consumption of the aryl chloride was con-
firmed by GC. The reaction mixtures were then cooled, opened to
the air, and dichloromethane (5 mL) was added to the vial. The
reaction mixtures were then filtered through a layer of neutral alu-
mina, which was then washed with dichloromethane (5 mL) and
MeOH (5 mL). Following removal of the solvent, the crude product
was purified by column chromatography on silica and charac-
terized by 1H and 13C NMR spectroscopy, as well as HR mass
spectrometry (for new compounds).
H), 6.80 (m, 1 H, ArH) ppm. 13C{1H} NMR (CDCl3): δ = 155.6,
148.6, 141.6, 138.3, 131.9 (q, JCF = 31.5 Hz), 130.0, 124.4 (q, JCF
=
272.9 Hz), 122.8, 119.0, 116.2 (q, JCF = 3.8 Hz), 116.2, 109.5 ppm.
HRMS (ESI): calcd. for C12H10F3N2 [M + H]+ 239.0791; found
239.0795.
N-Benzylpyrazin-2-amine (1u): General Procedure A was applied
with 2-chloropyrazine (45 μL, 0.50 mmol) and benzylamine (60 μL,
0.55 mmol) added through a microliter syringe. The reaction was
allowed to proceed for 36 h, and following workup and removal of
the solvent, the product was purified by silica gel column
chromatography (DCM/MeOH/NH4OH = 200:10:1) and isolated
as an orange oil in 86% yield (80 mg, 0.43 mmol). 1H NMR
(CDCl3): δ = 7.99 (m, 1 H, ArH), 7.88 (d, J = 1.5 Hz, 1 H, ArH),
7.81 (d, J = 3 Hz, 1 H, ArH), 7.35–7.34 (m, 4 H, ArH), 7.29 (m, 1
H, ArH), 5.04 (br. s, 1 H NH), 4.56 (d, J = 5.5 Hz, 2 H, CH2)
ppm. 13C{1H} NMR (CDCl3): δ = 154.8, 142.3, 138.8, 133.4, 132.4
129.1, 127.9, 45.9 ppm. HRMS (ESI): calcd. for C11H12N3 [M +
H]+ 186.1026; found 186.1032.
N-(p-Tolyl)-3-(trifluoromethyl)aniline (1b): General Procedure A
was applied with 4-chlorotoluene (59 μL, 0.50 mmol) and 3-CF3-
aniline (69 μL, 0.55 mmol) added through a microliter syringe. The
reaction was allowed to proceed for 19 h, and following workup
and removal of the solvent, the product was purified by silica gel
column chromatography (DCM) and isolated as an off-white solid
1
in 81% yield (102 mg, 0.41 mmol). H NMR (CDCl3): δ = 7.33 (t,
J = 8 Hz, 1 H, ArH), 7.22 (s, 1 H, ArH), 7.17 (d, J = 8.5 Hz, 2 H,
ArH), 7.15–7.11 (m, 2 H, ArH), 7.07–7.05 (m, 2 H, ArH), 5.73 (br.
s, 1 H, NH), 2.37 (s, 3 H, CH3) ppm. 13C{1H} NMR (CDCl3): δ =
145.2, 139.3, 132.7, 132.0 (q, JCF = 32.7 Hz), 130.4, 130.1, 124.5
(q, JCF = 271.7 Hz), 120.5, 119.2, 116.5 (q, JCF = 3.8 Hz), 112.6
(q, JCF = 3.8 Hz), 21.1 ppm. HRMS (ESI): calcd. for C14H13F3N
[M + H]+ 252.0995; found 252.1000.
N-Phenyl-4-(prop-1-en-2-yl)aniline (1v/3k): General Procedure A/B
was applied with 4-chloro-α-methylstyrene (71 μL, 0.50 mmol) and
aniline (50 μL, 0.55 mmol) added through a microliter syringe. The
reaction was allowed to proceed for 24 h, and following workup
and removal of the solvent, the product was purified by silica gel
column chromatography (DCM/MeOH/NH4OH 1000:10:1) and
isolated as a yellow solid in 89/90% yield (1v/3k, 94/95 mg, 0.45/
0.45 mmol). 1H NMR (CDCl3): δ = 7.41–7.39 (m, 2 H, ArH), 7.29–
7.26 (m, 2 H, ArH), 7.09–7.08 (m, 2 H, ArH), 7.05–7.03 (m, 2 H,
ArH), 6.94 (tt, J = 7, 1 Hz, 1 H, ArH), 5.74 (br. s, 1 H, NH), 5.31
(d, J = 1 Hz, 1 H, CH), 4.99 (d, J = 1 Hz, 1 H, CH), 2.14 (s, 3 H,
CH3) ppm. 13C{1H} NMR (CDCl3): δ = 143.2, 142.9, 142.8, 134.1,
129.7, 126.8, 121.5, 118.3, 117.6, 110.7, 22.2 ppm. HRMS (ESI):
calcd. for C15H15N [M + H]+ 210.1277; found 210.1272.
N-Octyl-4-(trifluoromethyl)aniline (1i): General Procedure A was
applied with 4-chlorobenzotrifluoride (62 μL, 0.50 mmol) and oc-
tylamine (91 μL, 0.55 mmol) added through a microliter syringe.
The reaction was allowed to proceed for 36 h, and following
workup and removal of solvent, the product was purified by silica
gel column chromatography (DCM/MeOH/NH4OH = 1000:10:1)
1
and isolated as a yellow oil in 87% yield (119 mg, 0.44 mmol). H
NMR (CDCl3): δ = 7.42 (d, J = 8.5 Hz, 2 H, ArH), 6.60 (d, J =
8.5 Hz, 2 H, ArH), 3.97 (br. s, 1 H, NH), 3.15 (t, J = 7 Hz, 2 H,
CH2), 1.67–1.62 (m, 2 H, CH2), 1.48–1.31 (m, 10 H, CH2), 0.94 (t,
J = 7 Hz, 3 H, CH3) ppm. 13C{1H} NMR (CDCl3): δ = 151.2,
126.8 (app. d, JCF = 3.8 Hz), 125.5 (q, JCF = 270.5 Hz), 118.6 (q,
JCF = 32.7 Hz), 111.9, 43.8, 32.2, 29.7, 29.6, 29.5, 27.4, 23.0,
14.4 ppm. HRMS (ESI): calcd. for C15H23F3N [M + H]+ 274.1777;
found 274.1771.
N-Methyl-3-morpholinoaniline (3o): General Procedure B was ap-
plied with 3-chloro-N-methylaniline (61 μL, 0.50 mmol) and
morpholine (49 μL, 0.55 mmol) added through a microliter syringe.
The reaction was allowed to proceed for 22 h, and following
workup and removal of solvent, the product was purified by silica
gel column chromatography (DCM/MeOH/NH4OH = 200:10:1)
and isolated as a red oil in 88% yield (84 mg, 0.44 mmol). 1H NMR
(CDCl3): δ = 7.10 (t, J = 8 Hz, 1 H, ArH), 6.32 (ddd, J = 8, 2.5,
1 Hz, 1 H, ArH), 6.20 (ddd, J = 8, 2.5, 1 Hz, 1 H, ArH), 6.16 (t, J
= 2.5 Hz, 1 H, ArH), 3.87–3.85 (m, 4 H, CH2), 3.69 (br. s, 1 H,
NH), 3.16–3.14 (m, 4 H, CH2), 2.83 (s, 3 H, CH3) ppm. 13C{1H}
NMR (CDCl3): δ = 152.9, 150.7, 130.1, 105.7, 105.2, 100.3, 67.3,
49.9, 31.1 ppm. HRMS (ESI): calcd. for C11H17N2O [M + H]+
193.1335; found 193.1338.
N-(Diphenylmethylene)-4-(trifluoromethyl)aniline (1l/3m): General
Procedure A/B was applied, with 4-chlorobenzotrifluoride (62 μL,
0.50 mmol) and benzophenone imine (92 μL, 0.55 mmol) added
through a microliter syringe. The reaction was allowed to proceed
for 36 h, and following workup and removal of the solvent, the
product was purified by silica gel column chromatography (DCM/
MeOH/NH4OH = 1000:10:1) and isolated as a yellow oil in 88/
92% yield (1l/3n, 143/150 mg, 0.44/0.46 mmol). 1H NMR (CDCl3):
δ = 7.78–7.76 (m, 2 H, ArH), 7.51 (m, 1 H, ArH), 7.45–7.39 (m, 4
H, ArH), 7.31–7.25 (m, 3 H, ArH), 7.13–7.11 (m, 2 H, ArH), 6.81–
6.79 (m, 2 H, ArH) ppm. 13C{1H} NMR (CDCl3): δ = 169.6, 154.7,
139.4, 135.9, 131.5, 130.4–128.5, 126.1 (q, JCF = 3.8 Hz), 125.3 (q,
JCF = 32.7 Hz), 124.7 (q, JCF = 270.5 Hz), 121.2 ppm. HRMS
(ESI): calcd. for C20H15F3N [M + H]+ 326.1151; found 326.1138.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR characterization data.
Acknowledgments
N-[3-(Trifluoromethyl)phenyl]pyridin-2-amine (1q): General Pro-
cedure A was applied with 2-chloropyridine (47 μL, 0.50 mmol)
and 3-CF3-aniline (69 μL, 0.55 mmol) added through a microliter
syringe. The reaction was allowed to proceed for 19 h, and follow-
ing workup and removal of the solvent, the product was purified by
silica gel column chromatography (DCM/MeOH/NH4OH gradient
from 100:0:0 to 100:5:0.5) and isolated as an off-white solid in 80%
We thank the Natural Sciences and Engineering Research Council
(NSERC) of Canada (including a Discovery Grant for M. S. and a
Canada Graduate Scholarship for B. J. T.), Innovacorp, the Killam
Trusts, and Dalhousie University for their generous support of this
work. Dr. Michael Lumsden (NMR-3, Dalhousie) is thanked for
technical assistance in the acquisition of NMR spectroscopic data,
and Mr. Xiao Feng (Maritime Mass Spectrometry Laboratories,
Dalhousie) is thanked for technical assistance in the acquisition
1
yield (95 mg, 0.40 mmol). H NMR (CDCl3): δ = 8.25 (dd, J = 5,
1 Hz, 1 H, ArH), 7.67 (s, 1 H, ArH), 7.57–7.52 (m, 2 H, ArH), of mass spectrometric data. Prof. Alison Thompson (Dalhousie) is
7.41 (t, J = 8 Hz, 1 H), 7.24 (s, 1 H, ArH), 6.86 (d, J = 8.5 Hz, 1 thanked for helpful discussions.
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O20510
/KAP1
Date: 05-06-12 15:32:12
Pages: 7
B. J. Tardiff, M. Stradiotto
FULL PAPER
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We have yet to detect the degradation of Mor-DalPhos when
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aqueous reaction described herein (e.g., homogeneous vs.
heterogeneous; in vs. on water). However, a preliminary assess-
ment of the solubility of Mor-DalPhos, in which 50 mg of the
ligand was stirred in 1 mL of distilled water for 48 h at ambient
temperature followed by filtration and removal of the water
in vacuo, revealed negligible quantities of the dissolved Mor-
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Received: April 19, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20510
/KAP1
Date: 05-06-12 15:32:12
Pages: 7
Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
Buchwald–Hartwig Amination
B. J. Tardiff, M. Stradiotto* ............. 1–7
Buchwald–Hartwig Amination of (Hetero)-
aryl Chlorides by Employing Mor-DalPhos
under Aqueous and Solvent-Free Con-
ditions
We report on the use of [Pd(cinnamyl)-
Cl]2/Mor-DalPhos in the Buchwald–Hart-
wig amination of (hetero)aryl chlorides
with primary or secondary amines under
aqueous or solvent-free conditions (52
examples).
Keywords: Amination / Cross-coupling /
Palladium / Ligand design
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