A general, simple catalyst for enantiospecific cross couplings of benzylic ammonium triflates and boronic acids: No phosphine ligand required

Article abstract of DOI:10.1016/j.tet.2014.03.039

Highly improved conditions for the enantiospecific cross coupling of benzylic ammonium triflates with boronic acids are reported. This method relies on the use of Ni(cod)₂ without ancillary phosphine or N-heterocyclic carbene ligands as catalyst. These conditions enable the coupling of new classes of boronic acids and benzylic ammonium triflates. In particular, both heteroaromatic and vinyl boronic acids are well tolerated as coupling partners. In addition, these conditions enable the use of ammonium triflates with a variety of substituents at the benzylic stereocenter. Further, naphthyl-substitution is not required on the benzylic ammonium triflate; ammonium triflates with simple aromatic substituents also undergo this coupling. Good to high yields and levels of stereochemical fidelity are observed. This new catalyst system greatly expands the utility of enantiospecific cross couplings of these amine-derived substrates for the preparation of highly enantioenriched products.

Full text of DOI:10.1016/j.tet.2014.03.039

Tetrahedron 70 (2014) 4257e4263
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A general, simple catalyst for enantiospecific cross couplings of
benzylic ammonium triflates and boronic acids: no phosphine
ligand required
Danielle M. Shacklady-McAtee y, Kelsey M. Roberts y, Corey H. Basch, Ye-Geun Song,
*
Mary P. Watson
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly improved conditions for the enantiospecific cross coupling of benzylic ammonium triflates with
boronic acids are reported. This method relies on the use of Ni(cod)2 without ancillary phosphine or N-
heterocyclic carbene ligands as catalyst. These conditions enable the coupling of new classes of boronic
acids and benzylic ammonium triflates. In particular, both heteroaromatic and vinyl boronic acids are
well tolerated as coupling partners. In addition, these conditions enable the use of ammonium triflates
with a variety of substituents at the benzylic stereocenter. Further, naphthyl-substitution is not required
on the benzylic ammonium triflate; ammonium triflates with simple aromatic substituents also undergo
this coupling. Good to high yields and levels of stereochemical fidelity are observed. This new catalyst
system greatly expands the utility of enantiospecific cross couplings of these amine-derived substrates
for the preparation of highly enantioenriched products.
Received 15 January 2014
Received in revised form 10 March 2014
Accepted 12 March 2014
Available online 19 March 2014
Keywords:
Enantiospecific cross coupling
Nickel catalysis
Carbonenitrogen bond activation
Benzylic electrophiles
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
our reaction enabled the coupling of benzylic pivalates with aryl-
boroxines.11 Notably, this coupling relied on a simple nickel cata-
Diarylalkanes and triarylalkanes constitute important com-
pounds in organic synthesis and often possess exciting biological
activities.1 An efficient strategy for the preparation of these chiral
compounds is a cross coupling of a benzylic electrophile with an
organometallic reagent.2,3 However, until recently, both enantio-
selective and enantiospecific cross couplings of benzylic electro-
philes required the use of reactive, air-sensitive organometallic
coupling partners, such as Grignard or organozinc reagents.4e7 This
requirement limited the convenience and functional group toler-
ance of these reactions. To overcome this restriction, we developed
an enantiospecific, nickel-catalyzed cross coupling of benzylic
ammonium triflates with aryl boronic acids (Scheme 1A).8 This
method not only allows the use of commercially available, func-
tional group tolerant boronic acid coupling partners, but also en-
ables the use of amine-derived substrates. In our view, amines are
ideal starting materials for enantiospecific reactions due to their
lyst, bis(cyclooctadiene)nickel [Ni(cod)2], without the need for
ancillary phosphine or N-heterocyclic carbene (NHC) ligands.
Scheme 1. Prior art and our advances in enantiospecific cross couplings of benzylic
ammonium triflates.
wide availability in excellent enantiopurity via
a variety of
methods.9 Simultaneously with the Jarvo lab,10 we have also de-
veloped an enantiospecific, nickel-catalyzed cross coupling of
alcohol-derived substrates with organoborane coupling partners;
Although these new methods represent a significant advance by
enabling the use of commercially available aryl boronic coupling
partners, several limitations exist in the scope of substrates that can
be used. In particular, our previous investigations of the cross
couplings of benzylic ammonium triflates focused largely on the
* Corresponding author. E-mail address: mpwatson@udel.edu (M.P. Watson).
y
These authors contributed equally.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.039

4258
D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
Table 1
use of carbocyclic aryl boronic acids with only one example of
a vinyl boronic acid.8 Our attempts to use heteroaromatic boronic
acids resulted in modest yields and ee’s. In addition, substituents
other than methyl were not demonstrated at the benzylic stereo-
center (R1) in the enantiospecific cross couplings of ammonium
triflates. Further, enantiospecific couplings of benzylic electrophiles
were limited to those that possess an aromatic substituent with an
Scope of boronic acids and ammonium triflatesa
Entry
1
Product
mol % Ni(cod)2
3
Yield (%)b
80
ee (%)c
99
extended
p
system, such as 2-naphthyl or biphenyl.12,5b,c,6,13 For
example, under our previously reported conditions, the cross cou-
plings of benzylic ammonium salts 1 with naphthyl substituents
(Ar1¼2-Np) occurs with an average yield of 72%.8 However, the
cross coupling of benzylic ammonium triflates with substituted
phenyl substituents occurs with an average yield of only 45%. Given
the importance of heteroaromatic and substituted phenyl groups in
pharmaceutical agents and other biologically active compounds,14
we sought to develop conditions for the enantiospecific cross
coupling of benzylic ammonium triflates that would overcome
these limitations. We now report a general and simple catalyst
system for the cross coupling of benzylic ammonium triflates with
boronic acids (Scheme 1B). By using Ni(cod)2 as catalyst without
any ancillary phosphine or NHC ligands, we have achieved efficient
cross couplings with heteroaromatic boronic acids. These condi-
tions are also amenable to the use of vinyl boronic acids, as well as
carbocyclic aryl boronic acids. In addition, these conditions are ef-
fective for ammonium triflates with a variety of substituents at the
benzylic stereocenter (R1). Finally, under these conditions, we have
obtained promising results in the cross coupling of benzylic am-
monium triflates substituted with non-naphthyl aromatic groups.
This method greatly expands the utility of enantiospecific cross
couplings of these amine-derived starting materials, which are
available in exceptional enantiopurity.
3
3
(15e27)
97
98
2d
3
83
3
3
70
88
75
4
5
95e
6
3
3
3
81
98
7d
(79)
76
>99
99
8
9
2. Results and discussion
As stated above, our previous attempts to cross couple hetero-
aromatic boronic acids or ammonium triflates with non-naphthyl
aryl substituents resulted in modest yields and/or levels of ste-
reochemical fidelity. In an effort to overcome these limitations and
identify a simpler, more convenient, and less expensive catalyst, we
found that high yields and ee’s were possible in the absence of an
ancillary phosphine ligand. Simply using Ni(cod)2 as catalyst
resulted in a highly efficient catalyst system. This new ‘phosphine-
less’ catalyst system facilitates the convenience of this method,
lessens the cost of the catalyst, and simplifies purification of the
products by eliminating potential contamination by a phosphine
ligand. As described below, these conditions are amenable to the
use of new classes of boronic acids and benzylic ammonium triflate
substrates.
3
91
99
3
0
(92)
0
96
10d
11
n.d.f
12
13
14
3
10
3
50
96
82
>99
>99
(49)
Using this newly optimized, simple catalyst system, high yields
and levels of stereochemical fidelity were observed in the couplings
of a number of heteroaromatic boronic acids. In all cases, the re-
actions gave inversion of the absolute stereochemistry of the ben-
zylic stereocenter with high levels of stereochemical fidelity.
Oxygen-containing heteroaromatic groups can be coupled to de-
liver dibenzofuran 2 and benzofuran 3 in high yields and excellent
ee’s (Table 1, entries 1 and 3). Although some heteroaromatic bo-
ronic acids coupled in similar yields with either phosphine-
containing or phosphine-less catalysts,15 we observed dramatic
differences in yield with dibenzofuranyl boronic acid. The use of
Ni(cod)2/P(o-Tol)3 as catalyst resulted in only 15e27% yield of
product 3 (entry 2). Under the phosphine-less reaction conditions,
pyridyl boronic acids also underwent efficient coupling to give
products 4 and 5 in 70 and 88% yield, respectively (entries 4 and 5).
Although product 4 was formed in 75% ee (entry 4), pyridine 5 was
formed in 95% ee (entry 5).16
15g
16g
17
10
5
55
58
75
86
52
92
10
18h
19i
20
10
10
0
(29)
(39)
(0.3)
92
88
n.d.f
21
10
71
83

D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
4259
Table 1 (continued )
respectively (entries 17 and 21). With these non-naphthyl-
substituted electrophiles, the phosphine-less catalyst proved cru-
cial. The addition of t-Bu-XantPhos or P(o-Tol)3 to these reactions
resulted in significantly lower yields of 29% and 39%, respectively
(entries 18 and 19). In addition, control experiments demonstrated
that this cross coupling does not occur to any appreciable extent in
the absence of Ni(cod)2 (entry 20). Even electron-rich p-methox-
yphenyl product 16 could be formed under these conditions in 53%
yield. To our knowledge, these are the highest yields achieved to
date for benzylic electrophiles with simple phenyl substituents (not
naphthyl or biphenyl) in enantiospecific couplings with an orga-
noborane partner.
Entry
Product
mol % Ni(cod)2
10
Yield (%)b
53
ee (%)c
80
22
a
Conditions: ammonium triflate
1 (0.20 mmol, 1.0 equiv), boronic acid
(0.3 mmol, 1.5 equiv), Ni(cod)2, K3PO4 (1.5 equiv), dioxane (0.33 M), 80 ꢀC, 6 h.
Starting materials were ꢁ99% ee, unless noted otherwise.
b
Isolated yields. Yields in parentheses determined by 1H NMR analysis using an
internal standard.
Although detailed mechanistic experiments are required to
elucidate the nature of the active catalyst under our phosphine-less
conditions, we hypothesize that this reaction occurs via oxidative
addition of a nickel(0) species to the benzylic ammonium triflate,
likely with inversion of configuration of the benzylic stereocenter,
c
Determined by HPLC analysis using a chiral stationary phase, unless noted
otherwise.
d
P(o-Tol)3 (7 mol %) was added to this reaction.
Determined by SFC analysis using a chiral stationary phase.
e
f
n.d.¼not determined.
g
Amine precursor prepared via Grignard addition to N-tert-butanesulfinyl aldi-
to form either an h h
1- or 3-bound nickel complex (17, Scheme 2).18
mine as a single diastereomer. Starting material assumed to be >95% ee.
h
Subsequent transmetallation and reductive elimination, both with
retention of configuration,19 then result in the observed diary-
lalkane product with net inversion of configuration at the benzylic
stereocenter.
t-Bu-XantPhos (12 mol %) was added to this reaction.
P(o-Tol)3 (22 mol %) was added to this reaction.
i
In addition to heteroaromatic boronic acid coupling partners,
these reaction conditions are amenable to the use of vinyl boronic
acids. Under our previous conditions, Ni(cod)2/P(o-Tol)3, we had
found that (E)-2-phenylvinylboronic acid was an excellent coupling
partner.8 We were pleased to observe that these new, simpler
conditions also enable the use of vinyl boronic acids. The use of
both electron-rich and electron-poor phenylvinylboronic acids re-
sults in high yields and exceptional levels of stereochemical fidelity
(Table 1, entries 6, 8 and 9). Notably, an aryl chloride functional
group is tolerated under these reaction conditions (entry 8). With
vinyl boronic acids, the use of Ni(cod)2/P(o-Tol)3 as catalyst resulted
in similar yields and ee’s as the phosphine-less catalyst (entries 7
and 10). Thus, in this case, the main advantage of the phosphine-
less catalyst system is the ease of purification of the products by
eliminating potential contamination by a phosphine ligand. Nota-
bly, these cross couplings do not occur without the Ni(cod)2 catalyst
(entry 11). The coupling of the more sterically demanding 1-
phenylvinylboronic acid also proceeded with excellent stereo-
chemical fidelity, albeit in reduced yield (entry 12). We also in-
vestigated the use of alkyl-substituted vinyl boronic acids;
however, their use resulted in complex product mixtures, likely due
to olefin isomerization.
Having established a broadened scope with respect to the
boronic acid coupling partner, we turned our attention to the
ammonium triflate substrate. We were pleased to observe that
our new conditions provided high yields and exceptional levels
of stereochemical fidelity with carbocyclic aryl boronic acids,
such as p-tolyl boronic acid (Table 1, entry 13).8 The coupling
was also successful with electron-poor aryl boronic acids, such
as p-cyanophenylboronic acid, albeit in reduced yields (entry
14).17 In addition, the coupling of benzylic ammonium triflates
with the bulkier i-propyl substituent also underwent coupling
under these conditions to give diarylalkane 12 in 55% yield and
86% ee (entry 15). These conditions are also amenable to the
formation of triarylmethane 13, although in diminished ee
(entry 16).
Scheme 2. Proposed reaction mechanism.
3. Conclusion
As described above, we have identified new, general conditions
for the enantiospecific cross coupling of benzylic ammonium tri-
flates with aryl and vinyl boronic acids. These conditions rely on the
use of Ni(cod)2 as catalyst without ancillary phosphine or N-het-
erocyclic carbene ligands. This simple catalyst system facilitates the
convenience and lowers the cost of these cross couplings. Even
more importantly, these conditions enable the efficient cross cou-
pling of heteroaromatic and vinyl boronic acids, as well as benzylic
ammonium triflates with various substituents at the benzylic
stereocenter. Benzylic ammonium triflates with simple, non-
naphthyl aryl substituents also underwent couplings under these
conditions in good yields. We are now focused on understanding
the nature of the active catalyst formed under these conditions, as
well as the continued development of the scope of this enantio-
specific conversion of widely available amine-derived substrates
into valuable, highly enantioenriched di- and tri-arylalkanes and
1,3-diaryl allylic products.
4. Experimental section
4.1. General
Emboldened by these results, we examined our new conditions
for the coupling of simple, non-naphthyl-substituted benzylic
ammonium triflates (Table 1, entries 17, 21 and 22). Although the
stereochemical fidelity of these couplings is slightly diminished
(80e92% ee), moderate to good yields are achieved with these
highly challenging substrates.13 In particular, electron-poor sub-
strates efficiently undergo coupling to give p-fluorophenyl and m-
methoxyphenyl products 14 and 15 in 75 and 71% yield,
Reactions were performed either in a N2-atmosphere glovebox
in oven-dried 1-dram vials with Teflon-lined caps or in oven-dried
round-bottomed flasks unless otherwise noted. Flasks were fitted
with rubber septa, and reactions were conducted under a positive
pressure of N2. Stainless steel syringes or cannulae were used to
transfer air- and moisture-sensitive liquids. Flash chromatography
ꢀ
was performed on silica gel 60 (40e63
m
m, 60 A). Thin layer

4260
D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
chromatography (TLC) was performed on glass plates coated with
silica gel 60 with F254 indicator. Commercial reagents were pur-
chased from Sigma Aldrich, Acros, Fisher, Strem, TCI, Combi Blocks,
Alfa Aesar, or Cambridge Isotopes Laboratories and used as received
with the following exceptions: toluene, CH2Cl2, dioxane, and Et2O
were dried by passing through drying columns.20 Toluene and di-
oxane were then degassed by sparging with N2 and stored over
þ124.5 (c 1.11, CHCl3): 1H NMR (400 MHz, CDCl3)
d 7.94 (d,
J¼7.7 Hz, 2H), 7.85e7.71 (m, 5H), 7.58 (d, J¼8.2 Hz, 1H), 7.49e7.38
(m, 4H), 7.33 (t, J¼7.5 Hz, 1H), 7.28 (d, J¼4.5 Hz, 1H), 5.01 (q,
J¼7.2 Hz, 1H), 1.90 (d, J¼7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
156.1, 154.3, 142.7, 133.6, 132.3, 130.5, 128.0, 127.9, 127.7, 127.1,
127.0, 126.0, 125.7, 125.6, 125.5, 124.6, 124.2, 123.0, 122.7, 120.8,
118.7, 111.9, 39.0, 20.9; FTIR (NaCl/thin film) 3054, 2968, 1451, 1421,
1184, 751 cmꢂ1; HRMS (EIþ) [M]þ calculated for C24H18O: 322.1358,
found: 322.1342.
ꢀ
activated 4 A MS in a N2-atmosphere glovebox. Anhydrous K3PO4
was purchased from Acros and stored in an N2-atmosphere glo-
vebox. MeOTf was purchased from TCI, America, and used as re-
ceived. CDCl3 was stored over oven-dried potassium carbonate.
Proton nuclear magnetic resonance (1H NMR), carbon nuclear
magnetic resonance (13C NMR), and fluorine nuclear magnetic
resonance (19F NMR) spectra were recorded on 400 MHz spec-
trometers. Chemical shifts for protons are reported in parts per
million downfield from tetramethylsilane and are referenced to
4.2.2. (R)-2-(1-(Naphthalen-2-yl)ethyl)benzofuran
(3). General
procedure was followed using 3 mol % Ni(cod)2 and benzylic
ammonium triflate 1a prepared in 99.6% ee. The crude material
was purified by silica gel chromatography (100% hexanes) to give
compound 3 (45.0 mg, 83%) as a white solid (mp 97e100 ꢀC). The
enantiomeric excess was determined to be 98% ee by chiral HPLC
residual protium in the NMR solvent (CHCl3¼
d
7.28; (CD3)2CO¼
d
analysis (CHIRALPAK IC, 1.0 mL/min, 0.2% i-PrOH/hexane,
24
2.07). Chemical shifts for carbon are reported in parts per
l
¼254 nm); tR (minor)¼6.26 min, tR (major)¼6.84 min. [
a]
D
million downfield from tetramethylsilane and are referenced to
ꢂ38.3 (c 1.46, CHCl3): 1H NMR (400 MHz, CDCl3)
d 7.94e7.91 (m,
the carbon resonances of the solvent (CDCl3¼
d
77.07; (CD3)2CO¼
d
3H), 7.86 (s, 1H), 7.67e7.46 (m, 5H), 7.38e7.25 (m, 2H), 6.61 (s,
28.94). Data are represented as follows: chemical shift, multiplicity
(br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet, p¼pentet,
m¼multiplet, dd¼doublet of doublets, h¼heptet), coupling con-
stants in Hertz (Hz), integration. Infrared (IR) spectra were obtained
using FTIR spectrophotometers with material loaded onto a NaCl
plate. The mass spectral data were obtained at the University of
Delaware mass spectrometry facility. Optical rotations were mea-
sured using a 2.5 mL cell with a 0.1 dm path length. Melting points
were taken on an uni-melt Thomas Hoover capillary melting point
apparatus.
1H), 4.55 (q, J¼7.2 Hz, 1H), 1.91 (d, J¼7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3)
d 162.1, 155.0, 140.8, 133.7, 132.6, 128.8, 128.4,
127.9, 127.8, 126.2, 126.1, 126.0, 125.8, 123.6, 122.6, 120.6, 111.1,
102.4, 39.9, 20.4; FTIR (NaCl/thin film) 3053, 2973, 1455,
1255 cmꢂ1; HRMS (EIþ) [M]þ calculated for C20H16O: 272.1201,
found: 272.1186.
4.2.3. (R)-2-Fluoro-3-methyl-5-(1-(naphthalen-2-yl)ethyl)pyridine
(4). General procedure was followed using 3 mol % Ni(cod)2 and
benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (5% EtOAc/1%
Et3N/hexanes) to give compound 4 (37 mg, 70%) as a pale yellow oil.
The enantiomeric excess was determined to be 75% ee by chiral
Dimethyl benzyl amines were prepared either from the benzyl
amines using EscheweilereClarke conditions21 or via reductive
amination of benzaldehyde or acetophenone derivatives.22 It has
been reported that epimerization does not occur under the
EscheweilereClarke conditions.23 The amine precursors for salts 1b
and 1c were prepared via Grignard addition to N-tert-butane-
sulfinyl aldimines, isolated as single diastereomers as determined
by 1H NMR analysis, and therefore assumed to be >95% ee.24 Pre-
cursors for racemic ammonium triflates were synthesized via re-
ductive amination of the corresponding acetophenone derivatives.
Ammonium triflates 1a, 1d, and 1e were prepared as previously
described.8
HPLC analysis (CHIRALPAK IB, 1.0 mL/min, 5.0% i-PrOH/hexane,
24
l
¼254 nm); tR (minor)¼5.99 min, tR (major)¼7.18 min. [
a]
D
ꢂ89.6 (c 0.73, CHCl3): 1H NMR (400 MHz, CDCl3)
d 8.30e8.11 (m,
1H), 7.86e7.70 (m, 3H), 7.61e7.51 (m, 1H), 7.52e7.37 (m, 2H),
7.33e7.22 (m, 1H), 6.79e6.67 (m, 1H), 4.39 (q, J¼7.1 Hz, 1H), 2.21 (s,
3H), 1.74 (d, J¼7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 162.7 (d,
JCeF¼238.4 Hz), 151.8 (d, JCeF¼8.1 Hz), 145.7 (d, JCeF¼15.15 Hz),
142.3, 136.9 (d, JCeF¼5.1 Hz), 133.6, 132.2, 128.5, 127.7 (d,
JCeF¼4.0 Hz), 126.3, 125.8, 125.6, 110.7, 110.4, 39.6, 22.0, 19.8 (d,
JCeF¼3.0 Hz); 13C NMR (101 MHz, (CD3)2CO)
d 162.6 (d,
4.2. General procedure for enantiospecific cross coupling
JCeF¼232.3 Hz), 151.9 (d, JCeF¼8.1 Hz), 145.6 (d, JCeF¼16.2 Hz), 142.6,
137.4 (d, JCeF¼4.0 Hz), 133.7, 132.3, 128.2, 127.7, 127.5, 126.4, 126.1,
125.6,125.5,109.9 (d, JCeF¼19.2 Hz), 39.0, 21.2,18.6 (d, JCeF¼3.0 Hz);
FTIR (NaCl/thin film) 3053, 2968,1608,1485, 1373, 962 cmꢂ1; HRMS
(EIþ) [M]þ calculated for C18H16FN: 265.1267, found:265.1252.
Please note: Although two 13C NMR peaks are coincident when
CDCl3 is used as solvent, all 18 13C NMR peaks are seen when
(CD3)2CO is used as solvent.
In
a N2-atmosphere glovebox, Ni(cod)2 (either 1.6 mg,
0.006 mmol, 3 mol % or 5.5 mg, 0.020 mmol, 10 mol %) and K3PO4
(64.0 mg, 0.30 mmol, 1.5 equiv) were weighed into a 1-dram vial.
Benzyl ammonium triflate 1 (0.20 mmol,1.0 equiv) and boronic acid
(0.30 mmol, 1.5 equiv) were added, followed by dioxane (0.6 mL,
0.33 M). The vial was capped with a Teflon-lined cap and removed
from the glovebox. The mixture was stirred for 6 h at 80 ꢀC. After
cooling to room temperature, the reaction mixture was then di-
luted with Et2O (1.5 mL) and filtered through a short plug of silica
gel, which was rinsed with Et2O (10 mL). The filtrate was concen-
trated and purified by silica gel chromatography to give the cross-
coupled product.
4.2.4. (R)-2-Methoxy-3-(1-(naphthalen-2-yl)ethyl)pyridine
(5). General procedure was followed using 3 mol % Ni(cod)2 and
benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (5% EtOAc/1%
EtN3/hexanes) to give compound 5 (47 mg, 88%) as an oil. The en-
antiomeric excess was determined to be 95% ee by chiral SFC
4.2.1. (R)-4-(1-(Naphthalen-2-yl)ethyl)dibenzo[b,d]furan
(2). General procedure was followed using 3 mol % Ni(cod)2 and
benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (100% hexanes)
to give compound 2 (51 mg, 80%) as a white solid (mp 98e101 ꢀC).
The enantiomeric excess was determined to be 99% ee by chiral
analysis (OJ-H, 3.0 mL/min, 40% i-PrOH(0.1% DEA)/CO2,
220 nm); tR (major)¼2.46 min, tR (minor)¼3.07 min. [
1.73, CHCl3): 1H NMR (400 MHz, CDCl3)
l
¼254 and
a
]
D
24 þ58.4 (c
d
8.09e8.02 (m, 1H),
7.85e7.74 (m, 3H), 7.73e7.67 (m, 1H), 7.52e7.31 (m, 4H), 6.88e6.78
(m,1H), 4.61 (q, J¼7.1, 6.0 Hz,1H), 3.95 (s, 3H), 1.68 (d, J¼7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3)
d 161.6, 144.4, 142.7, 136.1, 133.6, 132.2,
HPLC analysis (CHIRALPAK IB, 1.0 mL/min, 0.2% i-PrOH/hexane,
129.1, 127.9, 127.8, 127.7, 127.1, 126.0, 125.6, 125.5, 116.9, 53.5, 37.9,
20.5; FTIR (NaCl/thin film) 3055, 2969, 2948, 1589, 1507, 1463, 1409,
24
l
¼254 nm); tR (major)¼7.996 min, tR (minor)¼10.60 min. [
a
]
D

D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
4261
24
1321, 1253, 1020 cmꢂ1; HRMS (EIþ) [M]þ calculated for C18H17NO:
l
¼254 nm); tR (minor)¼6.33 min, tR (major)¼6.73 min. [
a
]
D
263.1310, found: 263.1297.
ꢂ64.0 (c 0.64, CHCl3): 1H NMR (400 MHz, CDCl3)
d 7.88e7.76 (m,
3H), 7.76e7.70 (m, 1H), 7.53e7.42 (m, 3H), 7.42e7.33 (m, 2H),
7.33e7.16 (m, 3H), 5.53 (s, 1H), 5.27 (t, J¼1.3 Hz, 1H), 4.24 (q,
J¼7.0 Hz, 1H), 1.60 (d, J¼7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)
4.2.5. (S,E)-2-(4-(4-(Trifluoromethyl)phenyl)but-3-en-2-yl)naphtha-
lene (6). General procedure was followed using 3 mol % Ni(cod)2
and benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (100% hexanes)
to give compound 6 (53.0 mg, 81%) as a white solid (mp 70e73 ꢀC).
The enantiomeric excess was determined to be 98% ee by chiral
d
152.5, 142.7, 142.2, 133.7, 132.3, 128.2, 128.2, 127.8, 127.7, 127.3,
126.8, 126.6, 125.9, 125.4, 113.5, 44.4, 21.8; 13C NMR (101 MHz,
(CD3)2CO) 152.6, 142.8, 142.1, 133.7, 132.2, 128.0, 127.9, 127.53,
d
127.46, 127.2, 126.6, 126.4, 125.82, 125.79, 125.3, 112.5, 43.7, 21.2;
FTIR (NaCl/thin film) 3053, 2967, 2930, 2361, 2337, 1624, 1599,
1506 cmꢂ1; HRMS (EIþ) [M]þ calculated for C20H18: 258.1409,
found: 258.1422. Please note: Although two 13C NMR peaks are
coincident when CDCl3 is used as solvent, all 18 13C NMR peaks are
seen when (CD3)2CO is used as solvent.
HPLC analysis (CHIRALPAK IB, 0.8 mL/min, 100% hexane,
24
l
¼254 nm); tR (major)¼24.21 min, tR (minor)¼30.68 min. [
a]
D
ꢂ30.5 (c 1.18, CHCl3): 1H NMR (400 MHz, CDCl3)
d 7.90e7.76 (m,
3H), 7.76e7.64 (m, 1H), 7.54 (d, J¼8.2 Hz, 2H), 7.51e7.37 (m, 5H),
6.63e6.43 (m, 2H), 3.99e3.69 (m, 1H), 1.58 (d, J¼7.0 Hz, 3H); 13C
NMR (101 MHz, CDCl3)
d 142.5, 141.13, 141.11, 138.0, 133.8, 132.4,
129.0 (q, JCeF¼32.3 Hz), 128.3, 127.78, 127.76, 126.4, 126.3, 126.2,
125.64, 125.57 (q, JCeF¼4.0 Hz),125.5,124.4 (q, JCeF¼272.7 Hz), 42.8,
21.1; FTIR (NaCl/thin film) 3053, 2967, 1615, 1325, 1164, 1121,
1067 cmꢂ1; HRMS (EIþ) [M]þ calculated for C21H17F3: 326.1282,
found: 326.1284.
4.2.9. (S)-2-(1-p-Tolylethyl)naphthalene (10). General procedure
was followed using 10 mol % Ni(cod)2 and benzylic ammonium
triflate 1a prepared in 99.6% ee. The crude material was purified by
silica gel chromatography (100% hexanes) to give compound 10
(40 mg, 82%) as a white solid. The enantiomeric excess was de-
termined to be >99% ee by chiral HPLC analysis (CHIRALPAK IB,
4.2.6. (S,E)-2-(4-(4-Chlorophenyl)but-3-en-2-yl)naphthalene
(7). General procedure was followed using 3 mol % Ni(cod)2 and
benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (100% hexanes)
to give 7 (44.0 mg, 76%) as a white solid (mp 68e71 ꢀC). The en-
antiomeric excess was determined to be 99% ee by chiral HPLC
0.4 mL/min, 100% hexane,
(400 MHz, CDCl3)
l
¼254 nm); tR (major)¼21.65: 1H NMR
d
7.86e7.66 (m, 4H), 7.52e7.36 (m, 2H), 7.31 (dd,
J¼8.4, 1.8 Hz, 1H), 7.21e7.06 (m, 4H), 4.29 (q, J¼7.2 Hz, 1H), 2.32 (s,
3H), 1.72 (d, J¼7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 144.0, 143.3,
135.6,133.5,132.1,129.1,128.0,127.8,127.7,127.6,126.9,126.0,125.4,
125.3, 44.5, 21.9, 21.1. The spectral data for this compound matches
that reported in the literature.8 Comparison of the HPLC spectrum
of this product to that previously obtained in our laboratory con-
firmed that the absolute configuration of this product is S.8
analysis (CHIRALPAK IB, 1.0 mL/min, 100% hexane,
l
¼254 nm); tR
24
(major)¼22.47 min, tR (minor)¼28.85 min. [
a]
ꢂ40.8 (c 1.42,
D
CHCl3): 1H NMR (400 MHz, CDCl3)
d
7.98e7.82 (m, 3H), 7.77 (s, 1H),
7.63e7.43 (m, 3H), 7.43e7.25 (m, 4H), 6.59e6.38 (m, 2H), 3.98e3.80
(m, 1H), 1.63 (d, J¼7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
13C NMR
4.2.10. (S)-2-(2-Methyl-1-p-tolylpropyl)naphthalene (12). General
procedure was followed using 10 mol % Ni(cod)2 and benzylic
ammonium triflate 1b prepared in >95% ee. The crude material was
purified by silica gel chromatography (100% hexanes) to give
compound 12 (30 mg, 55%) as a white solid (mp 77e78 ꢀC). The
enantiomeric excess was determined to be 86% ee by chiral HPLC
(101 MHz, CDCl3)
d 142.4, 141.0, 141.0, 137.9, 133.7, 132.3, 128.2,
127.69, 127.66, 126.3, 126.2, 126.1, 125.6, 125.4, 42.7, 21.0; 13C NMR
(101 MHz, (CD3)2CO) 143.8, 137.2, 136.8, 134.5, 133.1, 132.7, 129.2,
d
128.7, 128.4, 128.3, 128.2, 128.1, 126.9, 126.6, 126.1, 125.8, 43.4, 21.4;
FTIR (NaCl/thin film) 3052, 2965, 1490, 1091, 966 cmꢂ1; HRMS (EIþ)
[M]þ calculated for C20H17Cl: 292.1019, found: 292.0993. Please
note: Although two 13C NMR peaks are coincident when CDCl3 is
used as solvent, all 18 13C NMR peaks are seen when (CD3)2CO is
used as solvent.
analysis (CHIRALPAK IB, 0.8 mL/min, 100% hexane,
l
¼254 nm); tR
ꢂ33.5 (c 0.864,
7.85e7.61 (m, 4H), 7.49e7.31
24
(major)¼8.24 min, tR (minor)¼8.93 min. [
a]
D
CHCl3): 1H NMR (400 MHz, CDCl3)
d
(m, 3H), 7.31e7.16 (m, 2H), 7.05 (d, J¼7.8 Hz, 2H), 3.53 (d, J¼10.8 Hz,
1H), 2.67e2.47 (m, 1H), 2.25 (s, 3H), 0.91 (d, J¼6.4 Hz, 3H), 0.87 (d,
4.2.7. (S,E)-2-(4-(4-Methoxyphenyl)but-3-en-2-yl)naphthalene
(8). General procedure was followed using 3 mol % Ni(cod)2 and
benzylic ammonium triflate 1a prepared in 99.6% ee. The crude
material was purified by silica gel chromatography (100% hexanes)
to give compound 8 (53.0 mg, 91%) as a white solid (mp 78e80 ꢀC).
The enantiomeric excess was determined to be 99% ee by chiral
J¼6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 142.7, 141.7, 135.5, 133.6,
132.1, 129.1, 128.0, 127.9, 127.6, 127.5, 126.5, 126.2, 125.8, 125.1, 60.5,
31.6, 22.0, 21.9, 21.0; FTIR (NaCl/thin film) 3053, 3019, 2955, 2922,
2868, 1508, 1457, 1385, 813, 760, 741 cmꢂ1; HRMS (EIþ) [M]þ cal-
culated for C21H22: 274.1722, found: 274.1724.
HPLC analysis (CHIRALPAK IA, 0.6 mL/min, 1% EtOAc/hexane,
4.2.11. (S)-2-(Phenyl(p-tolyl)methyl)naphthalene (13). General pro-
cedure was followed using 10 mol % Ni(cod)2 and benzylic am-
monium triflate 1c prepared in >95% ee. The crude material was
purified by silica gel chromatography (100% hexanes) to give
compound 13 (36 mg, 58%) as an oil. The enantiomeric excess was
determined to be 52% ee by chiral HPLC analysis (CHIRALCEL OD-H,
24
l
¼254 nm); tR (major)¼27.88 min, tR (minor)¼30.19 min. [
a]
D
ꢂ35.7 (c 1.43, CHCl3): 1H NMR (400 MHz, CDCl3)
d 7.86e7.77 (m,
3H), 7.72e7.68 (m, 1H), 7.50e7.38 (m, 3H), 7.34e7.28 (m, 2H),
6.90e6.80 (m, 2H), 6.48e6.26 (m, 2H), 3.81e3.78 (m, 4H), 1.55 (d,
J¼7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 158.9, 143.4, 133.7, 133.1,
132.3, 130.4, 128.3, 128.1, 127.8, 127.7, 127.4, 126.5, 126.0, 125.4,
125.3, 114.0, 55.4, 42.7, 21.4; FTIR (NaCl/thin film) 2962, 1607, 1511,
1250, 1175, 1034 cmꢂ1; HRMS (EIþ) [M]þ calculated for C21H20O:
288.1514, found: 288.1517.
0.3 mL/min, 0.2% i-PrOH/pentane,
l
¼254 nm); tR (major)¼
24
38.59 min, tR (minor)¼40.72 min. [
a
]
D
þ37.6 (c 1.88, CHCl3): 1H
NMR (400 MHz, CDCl3)
d
7.95e7.71 (m, 3H), 7.54 (s, 1H), 7.49 (dt,
J¼6.1, 3.5 Hz, 2H), 7.40e7.33 (m, 3H), 7.33e7.26 (m, 1H), 7.26e7.20
(m, 2H), 7.20e7.09 (m, 4H), 5.74 (s, 1H), 2.40 (s, 3H); 13C NMR
4.2.8. (R)-2-(3-Phenylbut-3-en-2-yl)naphthalene (9). General pro-
cedure was followed using 3 mol % Ni(cod)2 and benzylic ammo-
nium triflate 1a prepared in 99.6% ee. The crude material was
purified by silica gel chromatography (100% hexane) to give com-
pound 9 (26 mg, 50%) as a white solid (mp 64e65 ꢀC). The enan-
tiomeric excess was determined to be 96% ee by chiral HPLC
analysis (CHIRALCEL OD-H, 0.8 mL/min, 1% i-PrOH/hexane,
(101 MHz, CDCl3) d 143.9, 141.7, 140.7, 135.9, 133.4, 132.1, 129.5,
129.4,129.1,128.3,128.1,127.9, 127.8, 127.7,127.5,126.3,125.9,125.6,
56.5, 21.1. The spectral data for this compound matches that re-
ported in the literature.5c
4.2.12. (R)-2-(1-(4-Fluorophenyl)ethyl)naphthalene (14). General
procedure was followed using 10 mol % Ni(cod)2 and benzylic

4262
D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
ammonium triflate 1d prepared in 99% ee. The crude material was
purified by silica gel chromatography (100% petroleum ether) to
give compound 14 (38 mg, 75%) as an oil. The enantiomeric excess
was determined to be 92% ee by chiral HPLC analysis (CHIRALCEL
of 1b was complex due to the presence of rotamers. Please see the
spectrum in the Supplementary data.
4 . 3 . 2 . ( S ) - N , N , N -T r i m e t h y l - 1 - ( n a p h t h a l e n - 2 - y l ) - 1 -
phenylmethanaminiumtrifluoromethane sulfonate (1c). The dime-
thylbenzylamine (245 mg, 0.94 mmol, 1.0 equiv) was dissolved in
Et2O (0.24 mL, 4.0 M). MeOTf (0.13 mL, 1.2 mmol, 1.3 equiv) was
added dropwise at 0 ꢀC. The formation of two layers was observed.
After complete addition the reaction mixture was stirred for an
additional 15 min at 0 ꢀC. The top layer was decanted off. The
bottom layer was washed with washed with Et2O (5 mLꢃ3) and
then hexanes (5 mLꢃ3). Residual solvent was removed from the
resulting oil in vacuo to give salt 1c (225 mg, 57%) as a white fluffy
OD-H, 0.8 mL/min, 100% hexane,
l
¼254 nm); tR (minor)¼
24.62 min, tR (major)¼31.78 min: 1H NMR (400 MHz, CDCl3)
d
7.81e7.76 (m, 2H), 7.74 (d, J¼8.5 Hz, 1H), 7.68e7.64 (m, 1H),
7.49e7.37 (m, 2H), 7.29e7.23 (m, 1H), 7.23e7.16 (m, 2H), 7.01e6.91
(m, 2H), 4.29 (q, J¼7.2 Hz, 1H), 1.70 (d, J¼7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3)
d
161.3 (d, JCeF¼245.4 Hz), 143.6, 141.9 (d,
JCeF¼4.0 Hz), 133.5, 132.1, 129.1 (d, JCeF¼7.1 Hz), 128.1, 127.7, 127.6,
126.7, 126.1, 125.5, 125.3, 115.1 (d, JCeF¼21.2 Hz), 44.1, 21.9. The
spectral data for this compound matches that reported in the lit-
erature.8 Comparison of the HPLC spectrum of this product to that
previously obtained in our laboratory confirmed that the absolute
configuration of this product is R.8
solid (mp 61e63 ꢀC): 1H NMR (400 MHz, CDCl3)
7.98e7.76 (m, 6H), 7.58e7.39 (m, 5H), 6.12 (s, 1H), 3.25 (s, 9H); FTIR
d 8.32 (s, 1H),
(NaCl/thin film) 3042, 1489, 1262, 1225, 1158, 1030, 735 cmꢂ1 19F
;
NMR (565 MHz, CDCl3)
d
ꢂ78.3; LRMS (ESI) [MꢂOTf]þ calculated
4.2.13. (S)-1-Methoxy-3-(1-p-tolylethyl)benzene (15). General pro-
cedure was followed using 10 mol % Ni(cod)2 and benzylic am-
monium triflate 1e prepared in >99% ee. The crude material was
purified by silica gel chromatography (0e1% Et2O/hexanes) to give
compound 15 (32 mg, 71%) as an oil. The enantiomeric excess was
determined to be 83% ee by chiral HPLC analysis (CHIRALPAK IA,
for [C20H22N]þ: 276.2, found: 276. The 13C NMR spectrum of 1b was
complex due to the presence of rotamers. Please see the spectrum
in the Supplementary data.
4.3.3. (S)-1-(4-Methoxyphenyl)-N,N,N-trimethylethanaminium tri-
fluoromethanesulfonate (1f). The dimethylbenzylamine (426 mg,
2.4 mmol, 1.0 equiv) was dissolved in Et2O (0.6 mL, 4.0 M). MeOTf
(0.30 mL, 3.1 mmol, 1.3 equiv) was added dropwise at 0 ꢀC. White
precipitate formed immediately. After complete addition the re-
action mixture was stirred for an additional 15 min at 0 ꢀC. The
precipitate was isolated by filtration and washed with Et2O
(2ꢃ5 mL). The resulting solid was dried under vacuum to give salt
1f (783 mg, 73%) as a white solid (mp 94e95 ꢀC): 1H NMR
10.8 mL/min, 1% i-PrOH/hexane,
l
¼254 nm); tR (minor)¼5.55 min,
tR (major)¼5.81 min: 1H NMR (400 MHz, CDCl3)
d 7.32e7.21 (m,
1H), 7.20e7.08 (m, 4H), 6.92e6.82 (m, 2H), 6.77 (ddt, J¼8.1, 2.4,
1.4 Hz, 1H), 4.14 (q, J¼7.1 Hz, 1H), 3.82 (s, 3H), 2.36 (s, 3H), 1.66 (d,
J¼7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 159.7,148.4, 143.3,135.6,
129.4, 129.2, 127.5, 120.2, 113.8, 110.9, 55.2, 44.5, 22.0, 21.1. The
spectral data for this compound matches that reported in the lit-
erature.8 Comparison of the HPLC spectrum of this product to that
previously obtained in our laboratory confirmed that the absolute
configuration of this product is S.8
(400 MHz, CDCl3)
d 7.52e7.36 (m, 2H), 7.06e6.81 (m, 2H), 4.79 (q,
J¼13.7, 6.8 Hz, 1H), 3.81 (s, 3H), 3.09 (s, 9H), 1.77 (d, J¼6.7 Hz, 3H);
13C NMR (101 MHz, CDCl3)
d 161.3, 131.8, 124.0, 120.7 (q,
JCeF¼321.2 Hz), 114.6, 73.8, 55.5, 50.8, 15.0; 19F NMR (565 MHz,
4.2.14. (S)-1-Methoxy-4-(1-p-tolylethyl)benzene (16). General pro-
cedure was followed using 10 mol % Ni(cod)2 and benzylic am-
monium triflate 1f prepared in 99.5% ee. The crude material was
purified by silica gel chromatography (0e1% Et2O/hexane) to give
compound 16 (24 mg, 53%) as an oil. The enantiomeric excess was
determined to be 81% ee by chiral HPLC analysis (CHIRALCEL OJ-H,
CDCl3)
d
ꢂ78.5; FTIR (NaCl/thin film) 2967, 1611, 1518, 1258, 1157,
1029, 838 cmꢂ1; LRMS (ESI) [MꢂOTf]þ calculated for [C12H30NO]þ:
194.2, found: 194.
Acknowledgements
0.8 mL/min, 100% hexane,
l
¼254 nm); tR (major)¼45.54 min, tR
NIH, United States (COBRE P20 GM103541) is gratefully ac-
knowledged for partial support of this research. D.M.S.M. thanks
the University of Delaware for a University Graduate Fellowship.
We thank AstraZeneca for donated boronic acids and Lotus Sepa-
rations, LLC, for assistance in determining ee’s. Data were acquired
at UD on instruments obtained with the assistance of NSF, United
States and NIH, United States funding (NSF CHE 0421224, CHE
1229234, and CHE 0840401; NIH P20 GM103541 and S10
RR026962).
(minor)¼55.21 min. [
a
]
24 ꢂ23.0 (c 1.02, CHCl3): 1H NMR (400 MHz,
D
CDCl3)
d
7.21e7.07 (m, 6H), 6.90e6.79 (m, 2H), 4.09 (q, J¼7.2 Hz,
1H), 3.79 (s, 3H), 2.33 (s, 3H), 1.62 (d, J¼7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3)
d 157.9, 143.9, 138.9, 135.5, 129.2, 128.6, 127.5,
113.8, 55.4, 43.6, 22.3, 21.1. The spectral data for this compound
matches that reported in the literature.25
4.3. Procedure for benzyl ammonium triflates
Supplementary data
4.3.1. (S)-N,N,N,2-Tetramethyl-1-(naphthalen-2-yl)propan-1-
aminiumtrifluoromethane sulfonate (1b). The dimethylbenzylamine
(179 mg, 0.79 mmol, 1.0 equiv) was dissolved in Et2O (0.17 mL,
4.0 M). MeOTf (0.17 mL, 1.0 mmol, 1.3 equiv) was added dropwise at
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.039.
0
ꢀC. The formation of two layers was observed. After complete
References and notes
addition the reaction mixture was stirred for an additional
15 min at 0 ꢀC. The top layer was decanted off. The bottom layer was
then washed with Et2O (5 mLꢃ3) and then hexanes (5 mLꢃ3).
Residual solvent was removed from the resulting oil in vacuo to
1. (a) Cheltsov, A. V.; Aoyagi, M.; Aleshin, A.; Yu, E. C.-W.; Gilliland, T.; Zhai, D.;
Bobkov, A. A.; Reed, J. C.; Liddington, R. C.; Abagyan, R. J. Med. Chem. 2010, 53,
3899; (b) Huang, Z.; Ducharme, Y.; Macdonald, D.; Robichaud, A. Curr. Opin.
Chem. Biol. 2001, 5, 432; (c) Alami, M.; Messauoudi, S.; Hamze, A.; Provot, O.;
Brion, J.-D.; Liu, J.-M.; Bignon, J.; Bakala, J. Dihydro-Iso-Ca-4 and Analogues:
Potent Cytotoxics, Inhibitors of Tubulin Polymerization, WO2009/147217, 2009.
give 1b (298 mg, 97%) as an oil: 1H NMR (400 MHz, CDCl3)
d 7.97 (s,
1H), 7.96e7.86 (m, 2H), 7.86e7.80 (m, 1H), 7.58e7.44 (m, 3H), 4.61
(d, J¼5.2 Hz, 1H), 3.20 (s, 9H), 2.89e2.70 (m, 1H), 1.15e0.99 (m, 6H);
ꢁ
(d) Messaoudi, S.; Hamze, A.; Provot, O.; Treguier, B.; Rodrigo De Losada, J.;
19F NMR (565 MHz, CDCl3)
d
ꢂ78.4; FTIR (NaCl/thin film) 2975,
Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.;
Alami, M. ChemMedChem 2011, 6, 488; (e) Moree, W. J.; Li, B.-F.; Jovic, F.; Coon,
T.; Yu, J.; Gross, R. S.; Tucci, F.; Marinkovic, D.; Zamani-Kord, S.; Malany, S.;
Bradbury, M. J.; Hernandez, L. M.; O’Brien, Z.; Wen, J.; Wang, H.; Hoare, S. R. J.;
1490, 1278, 1166, 1030, 828, 638 cmꢂ1; LRMS (ESI) [MꢂOTf]þ cal-
culated for [C17H24 N]þ: 242.2, found: 242. The 13C NMR spectrum

D.M. Shacklady-McAtee et al. / Tetrahedron 70 (2014) 4257e4263
4263
Petroski, R. E.; Sacaan, A.; Madan, A.; Crowe, P. D.; Beaton, G. J. Med. Chem. 2009,
52, 5307; (f) Beaton, G.; Moree, W. J.; Jovic, F.; Coon, T.; Yu, J. Sleep Inducing
Compound and Methods Relating Thereto, US2006/14797, 2006.
Echten, E.; Koek, J.; ten Hoeve, W.; Kellogg, R. M.; Broxterman, Q. B.; Minnaard,
A.; Kaptein, B.; van der Sluis, S.; Hulshof, L.; Kooistra, J. Angew. Chem., Int. Ed.
1998, 37, 2349.
2. For other methods, see: (a) Zhang, J.; Bellomo, A.; Creamer, A. D.; Dreher, S. D.;
Walsh, P. J. J. Am. Chem. Soc. 2012, 134, 13765; (b) Luan, Y.; Schaus, S. E. J. Am.
Chem. Soc. 2012, 134, 19965; (c) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 9331; (d) Lewis, C. A.; Chiu, A.;
Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen,
K. B.; Miller, S. J. J. Am. Chem. Soc. 2006, 128, 16454; (e) Pathak, T. P.; Gligorich,
K. M.; Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870; (f) Nave, S.;
Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 17096;
(g) Roesner, S.; Casatejada, J. M.; Elford, T. G.; Sonawane, R. P.; Aggarwal, V. K.
Org. Lett. 2011, 13, 5740; (h) Bolshan, Y.; Chen, C.; Chilenski, J. R.; Gosselin, F.;
Mathre, D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D. Org. Lett. 2004, 6, 111.
10. Harris, M. R.; Hanna, L. E.; Greene, M. A.; Moore, C.; Jarvo, E. R. J. Am. Chem. Soc.
2013, 135, 3303.
11. Zhou, Q.; Srinivas, H. D.; Dasgupta, S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135,
3307.
12. Biphenyl-substituted benzylic electrophiles are coupled in high yields only
under Jarvo’s conditions using a Ni/NHC catalyst system to deliver triaryl-
methanes. See Ref. 10.
13. For examples of the use of chelating groups to accelerate reactions of phenyl-
substituted systems, see: (a) Correa, A.; Leon, T.; Martin, R. J. Am. Chem. Soc.
2014, 136, 1062; (b) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem.
Soc. 1999, 121, 9449; (c) Refs. 5b,c,6,10.
3. For examples of the opposite approach (enantiospecific couplings of alkyl nu-
celophiles with aryl halides), see: (a) Imao, D.; Glasspoole, B. W.; Laberge, V. S.;
Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024; (b) Ohmura, T.; Awano, T.;
Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191; (c) Awano, T.; Ohmura, T.;
Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738; (d) Sandrock, D. L.; Jean-
14. (a) Ghose, A.; Viswanadhan, V.; Wendoloski, J. J. Comb. Chem. 1999, 1, 55; (b) Xu,
J.; Stevenson, J. J. Chem. Inf. Comput. Sci. 2000, 40, 1177.
15. Benzofuran 2 was formed in 87% yield, as determined by 1H NMR analysis,
when Ni(cod)2/P(o-Tol)3 was used as catalyst [Conditions: 10 mol % Ni(cod)2,
22 mol % P(o-Tol)3, benzofuranyl boronic acid (1.2 equiv), K3PO4 (1.3 equiv),
dioxane, 80 ꢀC, 6 h].
ꢁ
Gerard, L.; Chen, C.-Y.; Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc. 2010, 132,
17108; (e) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894; (f) Li, L.;
Wang, C.-Y.; Huang, R.; Biscoe, M. R. Nat. Chem. 2013, 5, 607.
16. The reason for the difference in stereochemical fidelity in the formation of 4
and 5 is currently unclear and the subject of active investigation.
17. With Ni(cod)2/P(o-Tol)3) as catalyst, product 11 was formed in 76% yield and
95% ee. See Ref. 8.
4. For enantioselective couplings of benzylic electrophiles with organozinc re-
agents, see: (a) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482; (b) Binder,
J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 17003; (c) Do, H.-Q.;
Chandrashekar, E. R. R.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 16288.
18. Both the h h
1 and 3 forms of benzyl nickel(II) intermediates have been observed.
See: Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem. Soc. 2011, 133,
19020.
ꢁ
5. For enantiospecific cross couplings of with Grignard reagents, see: (a) Lopez-
ꢁ
Perez, A.; Adrio, J.; Carretero, J. C. Org. Lett. 2009, 11, 5514; (b) Greene, M. A. M.;
19. Retention of configuration is well precedented in reductive elimination. See: (a)
Stille, J. K. Oxidative Addition and Reductive Elimination InHartley, F. R., Patai, S.,
Eds.. The Chemistry of the MetaleCarbon Bond; John Wiley & Sons, Ltd: New
York, NY, 1985; Vol. 2, p 625; (b) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 3910.
Yonova, I. M. I.; Williams, F. J. F.; Jarvo, E. R. E. Org. Lett. 2012, 14, 4293; (c) Taylor,
B. L. H.; Harris, M. R.; Jarvo, E. R. Angew. Chem., Int. Ed. 2012, 51, 7790; (d) Taylor,
B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389; (e)
Li, M.-B.; Tang, X.-L.; Tian, S.-K. Adv. Synth. Catal. 2011, 353, 1980.
6. For enantiospecific cross couplings with organozinc reagents, see: Wisniewska,
H. M.; Swift, E. C.; Jarvo, E. R. J. Am. Chem. Soc. 2013, 135, 9083.
20. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
7. For an enantiospecific coupling of an
acid, see: He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132, 2524.
8. Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J.
Am. Chem. Soc. 2013, 135, 280.
a
-cyanohydrin meslate with a boronic
21. Icke, R. N.; Wisegarver, B. B.; Alles, G. A. Org. Synth, 1945, 25, 89.
22. Reductive aminations were carried out according to literature procedure, ex-
cept that Me2NH was formed in situ from Me2NH$HCl and Et3N. See: Bhatta-
charyya, S. Synth. Commun. 2000, 30, 2001.
9. (a) Nugent, T. C. Chiral Amine Synthesis; Wiley-VCH GmbH & KGaA: Weinheim,
Germany, 2010; (b) Mereyala, H. B.; Pola, P. Tetrahedron: Asymmetry 2003, 14,
2683; (c) Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis,
W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman,
G. W.; Hughes, G. J. Science 2010, 329, 305; (d) Vries, T.; Wynberg, H.; van
23. Sunman, C. J.; Farkas, E. J. Org. Chem. 1985, 50, 1110.
24. (a) Procopiou, G.; Lewis, W.; Harbottle, G.; Stockman, R. A. Org. Lett. 2013, 15,
2030; (b) Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.;
Suarez, R.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482.
25. Teranishi, S.; Kurahashi, T.; Matsubara, S. Synlett 2013, 2148.