Steric effects in palladium-catalysed amination of aryl triflates and nonaflates with the primary amines PhCH(R)NH2 (R=H, Me)

Article abstract of DOI:10.1016/j.tet.2007.11.074

A systematic study of the effects of aryl triflate and nonaflate structure on the yield of amination with the primary amines PhCH(R)NH₂ (R=H, Me) under palladium catalysis has been carried out. High throughput screening indicated that a catalyst composed of X-Phos/Pd₂(dba)₃/1,4-dioxane was optimal based on a model reaction of Ar(OR_f) [R_f=Tf (SO₂CF₃), Nf (SO₂(CF₂)₃CF₃)] with PhCH₂NH₂. Comparisons of the reactivity of various ArOTf and ArONf [Ar=4-MePh, 2-naphthyl, 1-naphthyl, 2-PhC₆H₄] indicated that both ortho substitution in the aryl electrophile and at the α-position on the amine are detrimental to the coupling particularly when they occur in combination. Despite being formally a monodentate ligand use of X-Phos leads to only small degrees of racemisation when using (R)-PhCH(Me)NH₂ (typically resulting in a reduction from 97 to 86-94% ee for the amine stereocentre).

Full text of DOI:10.1016/j.tet.2007.11.074

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1218e1224
www.elsevier.com/locate/tet
Steric effects in palladium-catalysed amination of aryl triflates
and nonaflates with the primary amines PhCH(R)NH2 (R¼H, Me)
*
Rebecca E. Meadows, Simon Woodward
School of Chemistry, The University of Nottingham, University Park, Nottingham, United Kingdom
Received 24 September 2007; received in revised form 1 November 2007; accepted 22 November 2007
Available online 24 November 2007
Abstract
A systematic study of the effects of aryl triflate and nonaflate structure on the yield of amination with the primary amines PhCH(R)NH2
(R¼H, Me) under palladium catalysis has been carried out. High throughput screening indicated that a catalyst composed of XePhos/
Pd2(dba)3/1,4-dioxane was optimal based on a model reaction of Ar(ORf) [Rf¼Tf (SO2CF3), Nf (SO2(CF2)3CF3)] with PhCH2NH2. Comparisons
of the reactivity of various ArOTf and ArONf [Ar¼4-MePh, 2-naphthyl, 1-naphthyl, 2-PhC6H4] indicated that both ortho substitution in the aryl
electrophile and at the a-position on the amine are detrimental to the coupling particularly when they occur in combination. Despite being for-
mally a monodentate ligand use of XePhos leads to only small degrees of racemisation when using (R)-PhCH(Me)NH2 (typically resulting in
a reduction from 97 to 86e94% ee for the amine stereocentre).
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: BuchwaldeHartwig coupling; Phosphines; CeN coupling; Methodology
1. Introduction
with aniline, amide, imine and sec-amine nucleophiles are de-
lineated, see Ref. 1]. Steric factors are known to sometimes
cause problems in BuchwaldeHartwig couplings and such
factors are likely to be especially important in the use of
1,10-binaphthol/biphenyl based substrates. Due to the lack of
literature examples, we have conducted a small systematic
study on the effect of steric factors in the coupling of various
sulfonates 4 and 5 with R3R4CHNH2 leading to secondary
amines 6 (box in Scheme 1). Simple systems have been inves-
tigated to attempt to understand, which catalyst systems might
be applicable in applications using 1,10-biaryl based and other
hindered substrates.
In the last ten years palladium-catalysed amination of
halides has become a versatile weapon in preparation of
N-functionalised aryl and other species. However, such a super-
abundance of catalyst combinations now exists that even the
highly extensive reviews1 available sometimes struggle to
make clear predictions as to the optimal system for a given
C(sp2)-X/amine combination. Three of the more versatile sys-
tems from the primary literature are summarised in Scheme 1
together with some popular ‘tricks’ for their further promotion.
We have an interest in the preparation of functional 1,10-
biphenol and 1,10-binaphthol species for which amination via
triflates or nonaflates potentially offer an attractive strategy
for N-derivatisation. However, <5% of the present literature
covers this particular coupling and particularly the effect of
steric factors in such primary amine couplings has not been
described to the best of our knowledge [related processes
2. Results and discussion
As initial test substrates the o-phenyl triflate (4a, R1¼Ph,
R2¼H, Rf¼Tf) and nonaflate (5a, R1¼Ph, R2¼H, Rf¼C4F9)
were selected as representative moderately sterically hindered
substrates. Both 4a and 5a are readily synthesised from the
corresponding phenol 7. Extensive catalyst screening of the
coupling of 4a/5a with benzylamine was carried out and
* Corresponding author. Fax: þ44 115/9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.074

R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
1219
Notes
Aminating System
Ref
[2]
[3]
Pd/BINAP/Cs2CO3/toluene
* ArI activated in presence of ArCl
* Slowed by steric factors in ArX and amine
Pd/X-Phos 1a/Cs2CO3/toluene
[1a]
[4]
[5]
* K3PO4 as alternative base
* Can couple ArOTf and ArOTs
Pd/DPE-Phos 2/Cs2CO3/toluene
* Couples hindered ArX and ArOTf
* Xant-Phos 3 as alternative
* Amides and Ph2C=NH work best
[1a]
[1a]
PPh2
PPh2
PR2
PPh2
PPh2
O
Y
iPr
iPr
2 DPE-Phos, Y = 2 x H
3 Xant-Phos, Y = CMe2
iPr
BINAP
1a X-Phos, R = cC6H11
1b tBu-X-Phos, R = tBu
R1
Promotion 'tricks'
OSO2Rf
R2
4-5
* Excess (3-5 equiv.) powdered Cs2CO3 for Pd/BINAP
* Excess (3-5 equiv.) powdered K3PO4 for Pd/X-Phos 1
* Use of t-BuOH or amyl alcohol as solvent
* Use of 1,4-dioxane as solvent
R1
R3
R4
N
H
R2
* Can be faster with Pd(OAc)2 than Pd2(dba)3
6
Scheme 1. Popular system for aryl amination and the challenge of hindered aryl fluorosulfonates (4, Rf¼CF3; 5, Rf¼C4F9) with primary amines.1a,2e5
some of the more successful combinations are reported in
Table 1. To allow direct comparison all in situ screenings
were carried out under identical conditions (100 ꢀC for 16 h)
using catalysts prepared from ligand addition to palladium
acetate or Pd2(dba)3.
The superiority of XePhos 1a in the presence of K3PO4
and 1,4-dioxane (runs 7 and 8) was clearly evident; other
ligands from the ‘Buchwald ligand kit’6 performing poorly.
Attempted optimisation by both increasing (runs 9 and 10)
or decreasing the ligand’s steric profile (runs 11 and 12) had
a detrimental effect on the yield of 5a. The only high yield
by-product in all these reactions was competing loss of the
sulfonyl group; but this was eliminated by use of XePhos
1a/K3PO4. The mass balance of all reactions was accounted
for by unreacted starting material 4a/5a. As we were interested
in a comparative study the reaction conversions were not fol-
lowed after 16 h; all of the reactions were quenched at this
point to allow direct comparison of the yield data under iden-
tical conditions. The use of alternative strong or aqueous bases
or alcohol promoters (e.g., NaOtert-Bu, LiHDMS, KOH,
tert-BuOH) was not tolerated with electrophiles 4/5. Under
these conditions, SeO ester hydrolysis became the major reac-
tion. Hartwig’s approach of adding the triflate slowly to avoid
such behaviour was not investigated here because our reac-
tions were carried out on small scale.1b,7 However, we can
note that a slightly smaller degree of hydrolysis was always
encountered in the nonaflate series 5. In our investigations
Pd2(dba)3 proved a superior precatalyst than Pd(OAc)2, which
is in line with the work of both Fairlamb8 and Fu.9 The use of
a dioxane solvent combined with effective stirring is vital in
attaining high yields in the chemistry as shown in Table 1. In
particular, in scaleup to >5.0 mmol amounts the yield of 6a
fell to unacceptable levels if the suspended K3PO3 was not ef-
ficiently agitated. Having identified a suitably active catalyst
system we next compared a range of aryl triflates and nona-
flates in couplings with both benzylamine and a-methylbenzyl
Table 1
Catalytic amination of 4a/5a using PhCH2NH2 and various catalystsa
Ph
Ph
Ph
BnNH2
PCy2
+
5 mol%
Pd/Ligand
OH
N
H
Ph
ORf
Ph
John-Phos 8
6a
7
4a Rf = SO2CF3
5a Rf = SO2C4F9
Run Reagent
Ligand
Base
Solvent 6a/%b 7/%b
(Pd source)c
1
4a (OAc)
4a (OAc)
4a (dba)
4a (OAc)
4a (OAc)
5a (OAc)
4a (dba)
5a (dba)
4a (dba)
5a (dba)
4a (dba)
5a (dba)
BINAP
XePhos 1a
Cs2CO3 Toluene
Cs2CO3 Toluene
3
8
33
20
24
17
36
12
0
2
3
DPEePhos 2
XantePhos 3
XePhos 1a
XePhos 1a
XePhos 1a
XePhos 1a
Cs2CO3 Toluene <1
Cs2CO3 Toluene
4
3
5
Cs2CO3 Dioxane 21
Cs2CO3 Dioxane 25
K3PO4 Dioxane 66
K3PO4 Dioxane 76
6
7
8
0
9
tert-BueXePhos 1b K3PO4 Dioxane 12
tert-BueXePhos 1b K3PO4 Dioxane
48
29
33
19
10
11
12
a
8
John-Phos 8
John-Phos 8
K3PO4 Dioxane 17
K3PO4 Dioxane 13
Carried out on 0.5 mmol 4a/5a, the ratio 4a (or 5a)/PhCH2NH2/base/
Pd2(dba)3/ligand was 0.5:0.6:3.0:0.015:0.025; solvent volume 1 mL, 100 ꢀC,
16 h.
b
Determined by GC against a calibrated internal standard (phenyldecane)
the mass balance of the reaction was starting 4a and 4b.
c
‘OAc’ indicates Pd(OAc)2 was used; ‘dba’ that Pd2(dba)3 was employed.

1220
R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
amine using the optimal catalyst. The yields of coupled
products (6 from BnNH2 and 9 from the chiral amine) attained
in these studies are shown graphically in Scheme 2. Again, to
allow direct comparison of the results the reactions were all
carried out under identical conditions (dioxane, K3PO4
100 ꢀC, 16 h) using the same XePhos/Pd2(dba)3 catalyst.
OTf
OH
OTf
OPMB
10 [ex ref. 11]
11 [ex ref. 5]
< 1% coupling with BnNH2
< 1% coupling with BnNH2
OTf
OTf
OTf
~
OTf
Ph
Number is
% yield
from ArOTf
coupling
OTf
OTf
OTf
increasing
steric
4c
4d
4b
4a
OTs
profile
Ph
13 [ex ref. 12]
NH2
79% (6d)
80% (9d)
89% (6c)
60% (9c)
91% (6b)
49% (9b)
78% (6a)
8% (9a)
12 [ex ref. 11]
mixture containing ~15%
coupling product with
BnNH2
< 1% coupling with PhCH(Me)NH2
Ph
NH2
Scheme 3. Attempted amine couplings of 1,10-binaphthyl and 1,10-biphenyl
substrates.5,11,12
increasing
steric
profile
ONf
ONf
The isolated amines 9aed (all from 100 ꢀC, 16 h runs under
identical conditions) were subjected to chiral HPLC analysis.
Within experimental error (ꢁ2% on repeated runs) only modest
degradation of the parent amines’ enantiopurities was observed
(Scheme 4). The behaviour of the system is independent of the
electrophiledin those cases where the equivalent nonaflate
was used an equivalent level of racemisation was observed. It
is apparent from these studies that XePhos does not act as
a simple monodentate phosphine in these couplings [as was
proposed for P(o-Tol)3]. One likely explanation is that the
XePhos adopts a P,C]C chelate binding mode akin to that
in the crystallographically characterised 14.15 Occasional dis-
ruption of the semi-labile chelate would fashion the free site re-
quired for b-hydride eliminationdthe prerequisite for amine
racemisation. Alternatively, minor amounts of ligand-free
palladium species may be responsible.
ONf
~
ONf
Ph
Number is
% yield
from ArONf
coupling
increasing
steric
5c
5d
5b
5a
profile
Ph
Ph
NH2
NH2
84% (6d)
75% (9d)
70% (6c)
59% (9c)
98% (6b)
82% (9b)
77% (6a)
12% (9a)
increasing
steric
profile
Scheme 2. Isolated chemical yields of CeN coupling products resulting from
Pd/XePhos 1a/K3PO4 catalysis of aryl triflates and nonaflates (identical
conditions to Table 1; product shown in parentheses).
It can be clearly seen from Scheme 2 that the XePhos/Pd
CeN coupling reaction is less tolerant of steric requirements
in the amine than it is of those in the aryl triflate or nonaflate.
In the cases where both partners have large steric requirements
the reaction essentially shuts down. The nonaflates do not offer
any exceptional synthetic benefits for these problematic com-
binations. In accord with the findings of Scheme 2 attempted
couplings of triflates 10e13 (Scheme 3) were found to be
highly challengingdat best only traces of the desired coupling
products could be detected in the reaction mixtures of the pre-
cursor triflates and benzyl amine or (R)-PhCH(Me)NH2.10
In early work Buchwald had stated that monophosphanee
Pd catalysts had a tendency to racemise a-methylbenzylamine
when it was used in intermolecular couplings employing
P(o-Tol)3.13 We are aware of only two other chiral CeN cou-
pling studies. Ohta demonstrated partial kinetic resolutions of
(ꢁ)-a-methylbenzylamine when reacted with aryl halides un-
der Pd0eToleBINAP catalysis.14a Similarly, Ma could show
that L-valine could be coupled to PhBr without racemisation us-
ing PdCl2[P(o-Tol)3]2 in the presence CuI. In the absence of
CuI the reaction did not precede and the methodology failed
for L-glutamic acid and L-serine.14b It is therefore pertinent to
chek to see if extensive racemisation is encountered in the
use of the Pd/Xephos 1a/K3PO4 catalysis described here.
Finally, we can note that the (þ) antipode of 9d resulting
from Ohta’s kinetic resolution studies with (R)-ToleBINAP
corresponds to (R)-9d.14a
3. Conclusion
We have described an investigation of steric factors in the
couplings of primary amines with aryl triflates (nonaflates)
that makes it clear that the coupling of 1,1-binaphthol or
1,10-biphenyl systems will be extremely challenging when
the amine is a-branched. For less demanding electrophiles
the combination of XePhos/Pd2(dba)3/K3PO4 is a potent cata-
lyst that is somewhat protected from racemising chiral second-
ary amines by its potential ability to form a P,C]C chelate.
4. Experimental
4.1. General methods
Procedures involving air or moisture sensitive reagents/in-
termediates were performed under atmospheres of argon using
standard Schlenk techniques. Chromatography was performed

R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
1221
Ph
Ph
H
N
HN
Ph
9a
b
a
Ph
H
H
Ph
Pd
86% ee
Cy2
P
Ph
94% ee
9b
O
H2N
97% ee
Ph
c
d
HN
H
N
Ph
14
9d
92% ee
9c
93% ee
Scheme 4. Racemisation in CeN couplings promoted by Pd2(dba)3/XePhos/K3PO4 (100 ꢀC, 16 h). Reagents: (a) 1,2-C6H4Ph(OTf); (b) 2-C10H7OTf; (c)
1-C10H7OTf; (d) 4-MePhOTf or 4-MePhONf.
using forced flow (flash chromatography) with the solvent sys-
tems indicated in the relevant experimental procedures. The
stationary phase used was silica gel 60 (220e240 mesh) sup-
plied by Fluka. Thin layer chromatography (TLC) was per-
formed on pre-coated plates (0.25 mm) silica. The plates
were visualised by the use of a combination of ultraviolet light
(254 and 366 nm) and aqueous potassium permanganate or
phosphomolybdic acid (PMA) solution. 1H and 13C NMR
spectra were recorded on a Bruker (AV400) spectrometer.
All chemical shifts (d) were referenced to chloroform and
are reported in parts per million (ppm). Coupling constants
(J ) are given in hertz. The following abbreviations apply:
(br) broad, (s) singlet, (d) doublet, (t) triplet, (m) multiplet,
(dd) double doublet, etc. Mass spectra (MS) were recorded
at high resolution (HRMS) on a micromass LCT or VG
micromass 70E mass spectrometers using electrospray ionisa-
tion (ESI) or electron impact (EI). Optical rotations were
measured using a JASCO DIP370 Digital polarimeter at
ambient temperature (nominally 22 ꢀC) and are quoted
as 10ꢂ1 deg cm2 gꢂ1. Concentration (c) is given in units of
g/100 cm3. GC analysis was performed on a Varian 3380 gas
chromatograph using suitable cyclodextrin based stationary
phases, with phenyldecane as internal standard. Chiral
HPLC analysis was performed on a Hewlett Packard
1100LC chromatograph using Daicel Chiracel AD-H
(250 mm) stationary phase column. Light petroleum refers to
that fraction boiling at 40e60 ꢀC. Dioxane was dried over
HCl 2 M (2ꢃ100 mL) and water (100 mL), and the aqueous
layer was extracted with dichloromethane. The organic layer
was then dried over magnesium sulfate, filtered and the sol-
vent removed in vacuo. Purification by column chromato-
graphy (2:1 light petrol/dichloromethane) gave 5a as a
colourless oil (12.51 g, 27.7 mmol, 94% yield). Rf 0.91 (25%
dichloromethane in light petrol). 1H NMR (400.1 MHz,
CDCl3) dH¼7.50e7.38 (m, 8H, 8ꢃAreH ) ppm. 13C NMR
(100.6 MHz, CDCl3) dC¼147.1 (CeO), 135.8 (C), 135.7 (C),
132.0 (CH), 129.4 (2ꢃCH, Ph-o), 129.0 (CH), 128.5 (CH),
128.5 (2ꢃCH, Ph-m), 128.3 (CH), 122.0 (CH) ppm. HRMS
found (ESI) (MþH)þ 453.0201; C16H10O3F9S requires M
453.0207. Compound 5a has appeared in the literature4a but
no spectroscopic data was presented.
4.3. 1-Naphthyl perfluorobutanesulfonate (nonaflate) 5b
As 5a using 1-naphthol (0.721 g, 5.0 mmol), triethylamine
(2.09 mL, 15.0 mmol) and perfluoro-1-butane sulfonylfluoride
(1.08 mL, 6.0 mmol) in dichloromethane (15 mL). Purification
by column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless crystalline solid (2.06 g,
4.84 mmol, 97% yield). Rf 0.86 (25% dichloromethane in light
petrol). 1H NMR (400.1 MHz, CDCl3) dH¼8.12 (d, J¼8.4 Hz,
1H, 8-H), 7.92 (d, J¼8.0 Hz, 1H, 5-H), 7.87 (dd, J1¼6.0,
J2¼3.4 Hz, 1H, 3-H), 7.66 (ddd, J1¼8.2, J2¼6.9, J3¼1.3 Hz,
1H, 6 or 7-H), 7.60 (ddd, J1¼8.2, J2¼7.0, J3¼1.3 Hz, 1H, 6 or
7-H), 7.49 (d, J¼3.4 Hz, 1H, 2-H) overlapped with 7.49 (d,
J¼6.0 Hz, 1H, 4-H) ppm. 13C NMR (100.6 MHz, CDCl3)
dC¼145.8 (CeO), 134.9 (C), 128.5 (CH), 128.0 (CH), 127.9
(CH), 127.4 (CH), 126.5 (C), 125.1 (CH), 120.9 (CH), 117.8
(CH) ppm. HRMS found (EI) Mþ 425.9976; C14H7O3F9S
requires M 425.9972, found (EI) 143.0497. C10H7O requires
143.0497]. These data were in accord with an alternative
preparation.19
˚
4 A molecular sieves before use. Liquid starting materials
were dried by distillation of suitable drying agents and stored
˚
over 4 A molecular sieves under argon. The following triflates
were prepared by literature methods: 4a,16 4b,17 4c and 4d.18
4.2. Biphenyl perfluorobutanesulfonate (nonaflate) 5a
Solid 2-phenylphenol (5.0 g, 29.4 mmol) was dissolved in
dry dichloromethane (90 mL) and triethylamine (12.4 mL,
88.1 mmol) added. Perfluoro-1-butane sulfonylfluoride (Toxic!
6.86 mL, 38.2 mmol) in dichloromethane (90 mL) was then
added dropwise at ꢂ78 ꢀC and the reaction mixture was al-
lowed to come to room temperature overnight. After this
time, the reaction was quenched with HCl 2 M, washed with
4.4. 2-Naphthyl perfluorobutanesulfonate (nonaflate) 5c
As 5a using 2-naphthol (0.721 g, 5.0 mmol), triethylamine
(2.09 mL, 15.0 mmol) and perfluoro-1-butane sulfonylfluoride
(1.08 mL, 6.0 mmol) in dichloromethane (15 mL). Purification

1222
R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
by column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless oil (1.91 g, 4.47 mmol, 89%
yield). Rf 0.82 (25% dichloromethane in light petrol). 1H
NMR (400.1 MHz, CDCl3) dH¼7.93 (d, J¼9.0 Hz, 1H, 5-H),
7.90 (d, J¼6.5 Hz, 1H, 4-H), 7.88 (d, J¼6.4 Hz, 1H, 3-H),
7.77 (d, J¼2.4 Hz, 1H, 1-H), 7.58 (ddd, J1¼12.8, J2¼6.9,
J3¼2.0 Hz, 1H, 6 or 7-H) overlapped with 7.58 (ddd, J1¼
12.7, J2¼6.9, J3¼1.9 Hz, 1H, 6 or 7-H), 7.39 (dd, J1¼9.0,
J2¼2.5, 1H, 8-H) ppm. 13C NMR (100.6 MHz, CDCl3)
dC¼147.3 (CeO), 133.3 (C), 132.3 (C), 130.6 (CH), 128.1
(CH), 127.9 (CH), 127.6 (CH), 127.2 (CH), 119.6 (CH), 119.2
(CH) ppm. HRMS found (EI) Mþ 425.9986; C14H7O3F9S re-
quires M 425.9972. These data were in accord with an alterna-
tive preparation.19
over magnesium sulfate, filtered and the solvent removed in
vacuo. Column chromatography with the relevant solvent sys-
tem gave the aminated product.
4.8. Benzyl(biphenyl-2-yl)amine 6a
Column chromatography (2:1 light petrol/dichloromethane)
gave 6a as a colourless crystalline solid (0.101 g, 0.40 mmol,
78% yield). Mp 84e87 ꢀC. Rf 0.53 (25% dichloromethane in
1
light petrol). H NMR (400.1 MHz, CDCl3) dH¼7.49e7.42
(m, 4H, 4ꢃAreH ), 7.37e7.30 (m, 5H, 5ꢃAreH ), 7.20
(ddd, J1¼9.0, J2¼7.4, J3¼1.6 Hz, 1H, AreH ), 7.12 (dd,
J1¼7.4, J2¼1.6 Hz, 1H, AreH ), 6.79 (ddd, J1¼J2¼7.4,
J3¼1.1 Hz, 1H, AreH ), 6.68 (app. d, J¼8.2 Hz, 1H, AreH ),
4.53 (br s, 1H, NH ), 4.34 (s, 2H, CH2) ppm. 13C NMR
(100.6 MHz, CDCl3) dC¼144.8 (C), 139.4 (CH), 130.2
(CH), 129.3 (2ꢃCH, Ph-o), 128.9 (2ꢃCH, Ph-o), 128.6 (CH),
128.5 (2ꢃCH, Ph-m), 127.6 (C), 127.2 (CH), 126.9 (2ꢃC,
2ꢃCH, Ph-m), 117.1 (CH), 110.7 (CH), 48.0 (CH2) ppm.
HRMS found (ESI) (MþH)þ 260.1439; C19H18N requires
260.1439. These data were in accord with 6a produced by
an alternative route.23
4.5. 4-Tolyl perfluorobutanesulfonate (nonaflate) 5d
As 5a using p-cresol (0.541 g, 5.0 mmol), triethylamine
(2.09 mL, 15.0 mmol) and perfluoro-1-butane sulfonylfluoride
(1.08 mL, 6.0 mmol) in dichloromethane (15 mL). Purification
by column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless oil (1.85 g, 4.75 mmol, 95%
yield). Rf 0.9 (25% dichloromethane in light petrol). 1H
NMR (400.1 MHz, CDCl3) dH¼7.49 (app. d, J¼8.8 Hz, 2H,
Ts-o), 7.19 (app. d, J¼8.7 Hz, 2H, Ts-m), 2.40 (s, 3H,
Ts-CH3) ppm. 13C NMR (100.6 MHz, CDCl3) dC¼147.8 (C),
138.5 (C), 130.6 (2ꢃCH, Ts-o), 121.0 (2ꢃCH, Ts-m), 20.9
(CH3) ppm. HRMS found (EI) Mþ 389.9973; C11H7O3F9S
requires M 389.9972. Only limited data have appeared for
this compound.20
4.9. Benzyl(1-naphthyl)amine 6b
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless crystalline solid (0.114 g,
0.489 mmol, 98% yield). Mp 66e68 ꢀC. Rf 0.47 (25% di-
chloromethane in light petrol). 1H NMR (400.1 MHz,
CDCl3) dH¼7.85e7.82 (m, 2H, 8-H, 5-H), 7.50e7.33 (m,
8H, Ph-o, Ph-m, Ph-p, 3-H, 6-H, 7-H), 7.28 (d, J¼8.2 Hz,
1H, 4-H), 6.66 (d, J¼7.4 Hz, 1H, 2-H), 4.73 (br s, 1H, NH ),
4.52 (s, 2H, CH2) ppm. 13C NMR (100.6 MHz, CDCl3)
dC¼143.2 (CeN), 139.0 (C), 134.3 (C), 128.7 (2ꢃCH, Ph-o),
128.7 (CH), 127.7 (2ꢃCH, Ph-m), 127.4 (CH), 126.6 (CH),
125.7 (CH), 124.7 (CH), 123.3 (C), 119.9 (CH), 117.6 (CH),
104.7 (CH) 48.6 (CH2) ppm. HRMS found (ESI) (MþH)þ
234.1277; C17H16N requires MþH 124.1283. These
data were in accord with 6b produced by an alternative
route.24
4.6. Parallel catalyst screening procedure for amination
trials
In a flame-dried carousel tube in a Radleys reactor,21 Pd
catalyst (3 mol %), ligand (5 mol %) and base (300 mol %)
were dissolved in dry solvent (1 mL) and 4a/5a (100 mol %)
and benzylamine (120 mol %) were added. The carousel tubes
were heated to reflux (100 ꢀC) and left overnight. After this
time, the reactions were quenched with water or HCl (2 M),
and internal standard (phenyldecane, 25 mL) was added. The
reaction mixture was then extracted with diethyl ether, filtered
through a plug of silica and GC analysis of the crude reaction
mixture was carried out (50 min, 220 ꢀC isotherm) for yield
and conversion results, calibrated against the internal standard.
4.10. Benzyl(2-naphthyl)amine 6c
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a pale yellow crystalline solid (0.104 g,
0.446 mmol, 89% yield. Mp 60e62 ꢀC. Rf 0.26 (25% di-
chloromethane in light petrol). 1H NMR (400.1 MHz,
CDCl3) dH¼7.68 (d, J¼8.1 Hz, 1H, 4-H), 7.65 (d, J¼8.8 Hz,
1H, 5-H), 7.60 (d, J¼8.3 Hz, 1H, 3-H), 7.43 (app. d,
J¼7.2 Hz, 2H, Ph-o), 7.39e7.29 (m, 4H, Ph-m, Ph-p, 7-H),
7.20 (ddd, J1¼8.0, J2¼7.0, J3¼1.2 Hz, 1H, 6-H), 6.93 (dd,
J1¼8.8, J2¼2.4 Hz, 1H, 8-H), 6.86 (d, J¼2.1 Hz, 1H, 1-H),
4.45 (s, 2H, CH2), 4.32 (br s, 1H, NH ) ppm. 13C NMR
(100.6 MHz, CDCl3) dC¼145.7 (CeN), 139.1 (C), 135.1
(C), 128.9 (CH), 128.7 (2ꢃCH, Ts-o), 127.6 (2ꢃCH, Ts-m),
127.3 (CH), 126.3 (CH), 126.0 CH), 122.0 (CH), 117.8 (CH),
104.7 (CH) 43.4 (CH2) ppm. HRMS found (ESI) (MþH)þ
4.7. Optimised amination conditions
In
a flame-dried Schlenk tube, Pd2(dba)3 (0.014 g,
0.015 mmol), XePhos 1a (0.012 g, 0.025 mmol) and K3PO4
(0.318 g, 1.5 mmol) were dissolved in dry 1,4-dioxane
(1 mL) and substrate (0.5 mmol) and amine (0.6 mmol) were
added. The reaction mixture was then heated to 100 ꢀC and
left overnight. Efficient stirring was attained by use of a me-
dium cross shape PTFE magnetic stirring bar.22 After 16 h
the reaction mixture was cooled to room temperature, water
added, and the product extracted with diethyl ether, dried

R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
1223
234.1277; C17H16N requires MþH 234.1283. These data were
in accord with 6b produced by an alternative route.25
(CH), 126.5 (CH), 125.8 (2ꢃCH, Ph-m), 125.6 (CH),
124.6 (CH), 123.2 (C), 119.7 (CH), 117.2 (CH), 106.0 (C),
53.6 (CH), 25.2 (CH3) ppm. HRMS found (ESI) (MþH)þ
248.1434; C18H18N requires MþH 248.1439. HPLC Column
AD-H. Hexane/i-PrOH: 90:10, 0.5 mL/min; retention time of
enantiomer 1: 13.8 min (R), retention time of enantiomer 2:
16.8 min (S ). Literature values give only a low optical rotation
for this compound on a near racemate prepared by a different
route.27
4.11. Benzyl(4-tolyl)amine 6d
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a low melting point solid (0.082 g,
0.418 mmol, 82% yield). Rf 0.33 (25% dichloromethane in
1
light petrol). H NMR (400.1 MHz, CDCl3) dH¼7.34e7.33
(m, 4H, Ph-o, Ph-m), 7.28 (tt, J1¼6.9, J2¼1.7 Hz, 1H, Ph-p),
7.00 (app. d, J¼8.0 Hz, 2H, Ts-o), 6.58 (dt, J1¼8.4,
J2¼2.0 Hz, 2H, Ts-m), 4.32 (s, 2H, CH2), 3.92 (br s, 1H,
NH ), 2.25 (s, 3H, TseCH3) ppm. 13C NMR (100.6 MHz,
CDCl3) dC¼145.9 (C), 139.6 (C), 129.7 (2ꢃCH, Ts-o),
128.6 (2ꢃCH, Ph-o), 127.6 (2ꢃCH, Ts-m), 127.1 (Ph-p),
126.7 (C), 113.0 (2ꢃCH, Ph-m), 48.6 (CH2), 20.4 (CH3) ppm.
HRMS found (ESI) (MþH)þ 198.1277; C14H16N requires M
198.1283. These data were in accord with 6b produced by
an alternative route.26
4.14. (R)-(þ)-2-Naphthyl-(1-phenyl-ethyl)amine 9c
Column chromatography (1:1 light petrol/dichloromethane)
gave the product as a colourless crystalline solid (0.074 g,
0.299 mmol, 60% yield). Mp 68e70 ꢀC. Rf 0.41 (25% di-
chloromethane in light petrol). [a]D þ146 (c 0.9, CHCl3) for
1
93% ee material. H NMR (400.1 MHz, CDCl3) dH¼7.64 (d,
J¼8.0 Hz, 1H, 4-H), 7.60 (d, J¼8.8 Hz, 1H, 5-H), 7.48 (d,
J¼8.2 Hz, 1H, 3-H), 7.42 (app. d, J¼7.4 Hz, 2H, Ph-o), 7.34
(dd, J1¼J2¼7.3 Hz, 2H, Ph-m), 7.30 (ddd, J1¼8.2, J2¼6.9,
J3¼1.2 Hz, 1H, 6 or 7-H), 7.24 (tt, J1¼7.3, J2¼1.2 Hz, 1H,
Ph-p), 7.16 (ddd, J1¼8.0, J2¼6.9, J3¼1.1 Hz, 1H, 6 or 7-H),
6.90 (dd, J1¼8.8, J2¼2.4, 1H, 8-H), 6.64 (d, J¼2.2 Hz, 1H,
1-H), 4.64 (q, J¼6.7 Hz, 1H, CH ), 4.24 (br s, 1H, NH ), 1.59
(d, J¼6.7 Hz, 3H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3)
dC¼144.5 (C), 144.7 (C), 135.0 (C), 128.8 (CH), 128.7
(2ꢃCH, Ph-o), 127.5 (CH), 127.3 (C), 126.9 (CH), 126.1
(CH), 125.9 (CH), 125.8 (2ꢃCH, Ph-m), 121.9 (CH), 117.9
(CH), 53.4 (CH), 24.8 (CH3) ppm. HRMS found (ESI)
(MþH)þ 248.1434; C18H18N requires MþH 248.1439. HPLC
column: AD-H. Hexane/i-PrOH: 90:10, 0.5 mL/min; retention
time of enantiomer 1: 14.0 min (R), retention time of enantio-
mer 2: 17.4 min (S ). This compound has been prepared by
a different route but no spectroscopic or related data were
presented.28
4.12. (R)-(þ)-Biphenyl-2-yl-(1-phenyl-ethyl)amine 9a
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless solid (0.016 g, 0.059 mmol,
12% yield). Mp 49e51 ꢀC. Rf 0.47 (25% dichloromethane in
light petrol). [a]D 0.56 (c 1.07, CHCl3) for 86% ee material.
1H NMR (400.1 MHz, CDCl3) dH¼7.53e7.48 (m, 4H,
4ꢃAreH ), 7.41e7.22 (m, 6H, 6ꢃAreH ), 7.10e7.05 (m,
2H, 2ꢃAreH ), 6.72 (t, J¼7.3 Hz, 1H, Ph-p), 6.46 (d,
J¼8.0 Hz, 1H, AreH ), 4.49 (q, J¼6.7 Hz, 1H, CH ), 4.32
(br s, 1H, NH ), 1.41 (d, J¼6.7 Hz, 3H, CH3) ppm. 13C
NMR (100.6 MHz, CDCl3) dC¼145.2 (C), 144.0 (C), 139.6
(C), 130.1 (CH), 129.3 (2ꢃCH, Ph-o), 129.3 (2ꢃCH, Ph-o),
128.9 (2ꢃCH, Ph-m), 128.5 (CH), 127.5 (C), 127.2 (CH),
126.8 (CH), 125.7 (2ꢃCH, Ph-m), 116.9 (CH), 111.7 (CH),
53.5 (CH), 25.1 (CH3) ppm. HRMS found (ESI) (MþH)þ
274.1596; C20H19N requires MþH 274.1596. HPLC column:
AD-H. Hexane/i-PrOH: 90:10, 0.5 mL/min; retention time of
enantiomer 1: 15.2 min (S ), retention time of enantiomer 2:
17.0 min (R).
4.15. (R)-(þ)-4-Tolyl-(1-phenyl-ethyl)amine 9d
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless crystalline solid (0.084 g,
0.398 mmol, 80% yield). Mp 51e53 ꢀC. Rf 0.33 (25%
dichloromethane in light petrol). [a]D þ5 (c 0.86, CHCl3)
for 92% ee material. 1H NMR (400.1 MHz, CDCl3) dH¼
7.38e7.30 (m, 4H, Ph-o, Ph-m), 7.24e7.20 (m, 1H, Ph-p),
6.90 (d, J¼8.4 Hz, 2H, Ts-o), 6.44 (d, J¼8.4 Hz, 2H, Ts-m),
4.46 (q, J¼6.7 Hz, 1H, CH ), 3.90 (br s, 1H, NH ), 2.19 (s,
3H, TseCH3), 1.51 (d, J¼6.7 Hz, 3H, CHCH3) ppm. 13C
NMR (100.6 MHz, CDCl3) dC¼145.4 (C), 145.0 (C), 129.6
(2ꢃCH, Ph-o), 128.6 (2ꢃCH, Ph-m), 126.8 (Ph-p), 126.3
(C), 125.8 (2ꢃCH, Ts-o), 113.4 (2ꢃCH, Ts-m), 53.6 (CH),
25.0 (CH3), 20.3 (TseCH3) ppm. HRMS found (ESI) (MþH)þ
212.1434, C15H18N requires M 212.1439. HPLC column AD.
Hexane/i-PrOH: 95:5, 1.0 mL/min; retention time of enantio-
mer 1: 5.5 min (S ), retention time of enantiomer 2: 6.1 min
(R). Prepared by a different method 9d had [a]D þ27 (c 0.7,
EtOAc) for 91% ee material.29
4.13. (R)-(ꢂ)-1-Naphthyl-(1-phenyl-ethyl)amine 9b
Column chromatography (2:1 light petrol/dichloromethane)
gave the product as a colourless crystalline solid (0.114 g,
0.462 mmol, 92% yield). Mp 68e71 ꢀC. Rf 0.59 (25%
dichloromethane in light petrol). [a]D ꢂ239 (c 0.9, CHCl3)
for 94% ee material. 1H NMR (400.1 MHz, CDCl3)
dH¼7.97e7.94 (m, 1H, AreH ), 7.82e7.80 (m, 1H, AreH ),
7.50 (m, 2H, 6-H, 7-H), 7.45 (d, J¼7.16 Hz, 2H, Ph-o),
7.36e7.33 (m, 2H, 2ꢃAreH ), 7.28e7.24 (m, 1H, AreH ),
7.21 (d, J¼4.9 Hz, 2H, Ph-m) 6.43e6.40 (m, 1H, AreH ), 4.76
(br s, 1H, NH ), 4.70 (q, J¼6.7 Hz, 1H, CH ), 1.69 (d, J¼
6.7 Hz, 3H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3) dC¼
144.9 (C), 142.1 (C), 128.7 (CH), 128.7 (2ꢃCH, Ph-o), 126.9

1224
R.E. Meadows, S. Woodward / Tetrahedron 64 (2008) 1218e1224
11. Solinas, M.; Meadows, R. E.; Wilson, C.; Blake, A. J.; Woodward, S.
Eur. J. Org. Chem. 2007, 1613e1630.
Acknowledgements
12. Percec, V.; Okita, S. J. Polym. Sci., A 1993, 31, 877e884.
13. Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
8451e8458. See also Ref. 1b, p 144.
14. (a) Tagashira, J.; Imao, D.; Yamamoto, T.; Ohta, T.; Furukawa, I.; Ito, Y.
Tetrahedron: Asymmetry 2005, 16, 2307e2314; (b) Ma, D.; Yao, J.
Tetrahedron: Asymmetry 1996, 7, 3075e3078.
We thank the European Commission for support through
Project FP6-505267-1 (LIGBANK) and the EPSRC for partial
support of a studentship (R.M.).
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triflate cleavage.