An approach to heterodiarylmethanes via sp2-sp3 Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1016/j.tet.2016.02.030

The synthesis of a range of structurally diverse diarylmethanes via the Suzuki-Miyaura cross-coupling of aryl methane acetates and arylboronic acids is reported, including several challenging examples containing nitrogen, oxygen and sulfur heteroatoms in one or both coupling partners. A single set of optimized conditions was used to generate the diarylmethanes in 52-91% yield.

Full text of DOI:10.1016/j.tet.2016.02.030

Accepted Manuscript
2
3
An approach to heterodiarylmethanes via sp -sp Suzuki−Miyaura cross-coupling
Gavin W. Stewart, Peter E. Maligres, Carl A. Baxter, Ellyn M. Junker, Shane W.
Krska, Jeremy P. Scott
PII:
S0040-4020(16)30093-X
10.1016/j.tet.2016.02.030
TET 27500
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 December 2015
Revised Date: 5 February 2016
Accepted Date: 10 February 2016
Please cite this article as: Stewart GW, Maligres PE, Baxter CA, Junker EM, Krska SW, Scott JP, An
2
3
approach to heterodiarylmethanes via sp -sp Suzuki−Miyaura cross-coupling, Tetrahedron (2016), doi:
10.1016/j.tet.2016.02.030.
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ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
An approach to heterodiarylmethanes via sp2-sp3 Suzuki−Miyaura cross-coupling
Gavin W. Stewart, ,† Peter E. Maligres, ,‡ Carl A. Baxter,† Ellyn M. Junker,† Shane W. Krska‡ and Jeremy
P. Scott†
†Department of Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom
‡Department of Process Chemistry, Merck Research Laboratories, Rahway, NJ 07065, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of a range of structurally diverse diarylmethanes via the Suzuki−Miyaura cross-
coupling of aryl methane acetates and arylboronic acids is reported, including several challeng-
ing examples containing nitrogen, oxygen and sulfur heteroatoms in one or both coupling part-
ners. A single set of optimized conditions was used to generate the diarylmethanes in 52-91%
yield.
Available online
2016 Elsevier Ltd. All rights reserved
.
Keywords:
Diarylmethanes
Suzuki
Cross-Coupling
1. Introduction
Synthetic procedures for the construction of diarylmethanes,
especially those containing heterocyclic systems, are highly desir-
able as (aryl)(heteroaryl)methane skeletons feature in many bio-
logically active compounds. These include drugs with a range of
indications such as diabetes and HIV (Figure 1).1 Heterocyclic
compounds are of key importance to the pharmaceutical industry
due to their ability to interact with biological systems through
polar interactions. Unfortunately, it is these heterocycles that in-
hibit many of the very useful metal/ligand-catalyzed cross-
coupling reactions through their interactions with the catalyst2
and/or unfavorable electronic properties.3 The Suzuki−Miyaura
cross-coupling reaction has been used to construct diarylmethanes
in recent years, primarily using benzylic halides.4 Such electro-
philic partners, however, can be unstable in the presence of nucle-
ophilic heterocyclic systems. Moreover, the rates of oxidative
insertion of transition metals into alkyl halide bonds and subse-
quent reductive elimination to form the cross-coupled product
from the catalyst, are relatively slow. In light of these shortcom-
ings, alternative benzylic electrophiles such as phosphates,5 car-
bonates6 and acetates7 have received some attention. Arylmethane
acetates offer several advantages over other electrophiles. Firstly,
the compounds are stable both in solution and as isolated sol-
ids/oils at room temperature and are often commercially available.
Secondly, they are simple and inexpensive to prepare. Thirdly, as
synthetic intermediates for pharmaceuticals, they are likely to have
low potential for genotoxicity in contrast to ArCH2X (where X =
halide) which is a structurally-alerting functional group that is
known to be involved in reactions with DNA.8 Preliminary screen-
ing experiments in our laboratories identified benzylic acetates as
superior electrophiles over several others, reinforcing the signifi-
cance of earlier work by Kuwano and co-workers.7
NH2
Cl
OEt
OH
OMe
R
O
N
HO
HO
H2N
N
HO
Dapagliflozin (Bristol-Myers Squibb/AstraZeneca
type 2 diabetes, SGLT2 inhibitor
OMe
Brodimiprim R = Br
Trimethoprim R = OMe (GlaxoSmithKline)
bactereostatic dihydrofolate reductase
inhibitor
OH
O
HO
HO
Et
Me
OMe
HO
O
N
Tofogliflozin (Chugai Pharme/Kowa/Sanofi)
type 2 diabetes, SGLT2 inhibitor
H2N
N
N
F
O
OMe
Cl
COOH
OH
Piritrexim (PTX) (GlaxoSmithKline)
bactereostatic dihydrofolate reductase inhobitor
N
O
OH
MeO
O
N
N
NH
S-1360 (Shionogi/GSK) Phase III AIDS
F
Eviltegravir (GS-9137) (Gilead Sciences)
AIDS
Figure 1. Pharmacologically active examples of compounds con-
taining diarylmethane systems.
A one pot preparation of diaryl methanes via diborylmethane has
also been reported via an intermediate coupling of aryl bromides
with benzylic boronates.9 However, the structural diversity in the
products reported has been quite limited. Indeed, few examples of
Suzuki−Miyaura cross-couplings where both the arylmethane
1

ACCEPTED MANUSCRIPT
electrophile and arylboronic acid contain heteroatoms, have been
Having established the most effective ligands, attention
switched to determining the optimal solvent for the reaction.
Keeping all other variables constant, the coupling was per-
formed in DMAc, THF, toluene and iPrOH in the presence of
X-Phos, S-Phos, RuPhos, dppf, dippf and dppb (Table 1).
Gratifyingly, the use of iPrOH (the solvent used in the original
ligand screen) offered considerably higher assay yields (up to
98%) than the other three solvents for all six ligands for cou-
pling 1a with 2a. The highest assay yields (98%) resulted
from the use of both S-Phos and RuPhos. The latter was se-
lected for further study.
reported.10 Those that contain nitrogen-based heterocycles have
typically been electronically deactivated or N-protected, presuma-
bly due to the potent electrophilic nature of the benzylic chlorides
employed. Recently, a nickel-catalyzed direct C-H coupling of
heteroarenes to benzylic carbonates has appeared in the literature;
but these couplings are limited to the activated position of the
heterocycle.11 Herein, we report the synthesis of a range of dia-
rylmethanes via the Suzuki−Miyaura cross-coupling of acetates
and boronic acids, including several examples containing heteroa-
toms in one or both coupling partners.
2. Results and discussion
Reaction conditions were screened for the cross-coupling of
pyridin-3-ylmethyl acetate (1a) and naphthalen-1-ylboronic
acid (2a) (Figure 2). The choice of ligand and solvent was
varied whilst the catalyst [Pd(OAc)2], base (K2CO3), solvent
(10:1 iPrOH:H2O) and reaction temperature (80 °C) were kept
constant. The highest assay yields (85-98%) were obtained in
the presence of X-Phos, S-Phos, RuPhos, dppf, dippf and dppb.
Figure 2. Screen of ligands for the cross-coupling of pyridin-3-
ylmethyl acetate (1a, red, front) and benzyl acetate (1aa, purple,
rear) with naphthalen-1-ylboronic acid (2a). Reactions conditions:
0.02 mmol of 1a or 1aa, 0.02 mmol of 2a, 0.06 mmol of K2CO3, 5
mol % of Pd(OAc)2 and either 10.5 mol % monodentate ligand or
5.025 mol % bidentate ligand in 5.5 mL/mmol solvent (10:1
iPrOH:H2O for 1a and toluene for 1aa) at 80 °C for 48 h. Vertical
axis shows % assay yield.
97
46
18
4
98
7
98
68
34
7
85
15
4
92
20
23
44
94
0
iPrOH
DMAc
THF
6
51
35
3
64
Toluene
2

ACCEPTED MANUSCRIPT
Table 1. Screen of ligands and solvents for the cross-coupling of
leneboronic acid 2a. The original test substrates (1a and 2a)
were coupled and the product isolated in 91% yield. A more
modest yield (52%) was obtained from the coupling of (2-
methylpyrimidin-4-yl)methyl acetate (1b) and 2a whilst the
use of (1,3-dimethyl-1H-pyrazol-5-yl)methyl acetate (1c) led
to a 75% yield of cross-coupled product (entries 6,7). The tol-
erability of these reaction conditions to boronic acids contain-
ing heteroatoms other than nitrogen was investigated next us-
ing 4-(trifluoromethyl)benzyl acetate (1d) as the control sub-
strate. Pleasingly, the use of both thienyl (2f-h) and furanyl
(2i) boronic acids was successful with cross-coupled products
3h-k generated in 53-91% yield (Entries 8-11).
pyridin-3-ylmethyl acetate 1a and naphthalen-1-ylboronic acid 2a.
Reactions conditions: 1a and 2a (1 equiv each), K2CO3, (3 equiv),
Pd(OAc)2 (5 mol %), monodentate ligand (10.5 mol %) or biden-
tate ligand (5.025 mol %), solvent:H2O (10:1, 0.18 M), 80
h; % assay yield is indicated.
°C, 48
Interestingly, a screen for the cross-coupling of simple benzyl
acetate (1aa) with 2a showed good results with a wider range
of ligands and solvents (see Supporting Information), thus
verifying the increased difficulty encountered in the presence
of a heterocyclic system. In contrast to the coupling of 1a, this
screen revealed the best results for the coupling of 1aa were
obtained in toluene for the higher performing ligands while
only modest results were obtained in iPrOH. A further screen
of bases with several successful ligands at various catalyst
loadings showed good results for the coupling of 1a with 2a
can be obtained with RuPhos using a variety of bases at cata-
lyst loadings as low as 1 mol % (Table 2). Even weak bases
such as KF and KHCO3 gave excellent results, which would
allow coupling of base labile substrates under mild conditions.
Table 3. Cross coupling of various heteroaryl and ar-
yl(methyl) acetatesb with heteroaryl and arylboronic acids.c
entry
1
2
3
yield (%)
Table 2. Screen of bases at various catalyst loadings with sev-
eral ligands in cross coupling of 1a with 2a.a
mol%
Pd
RuPhos
RuPhos
RuPhos
S-Phos
S-Phos
S-Phos
dippf
5
2
1
5
2
1
5
2
1
98
98
98
98
98
91
92
83
70
98
98
98
98
98
91
93
83
66
98
98
98
98
98
92
93
83
71
98
98
98
98
98
96
93
83
74
98
98
98
98
98
86
93
82
71
98
98
90
98
95
61
90
70
51
dippf
dippf
a Reactions conditions: 0.02 mmol of 1a, 0.02 mmol of 2a, 0.06
mmol of base, 2.1 equiv monodentate ligand or 1.05 equiv mol %
bidentate ligand relative to Pd(OAc)2 in 10:1
iPrOH:H2O (5.5
mL/mmol) at 80 C for 48 h; % assay yield is indicated.
°
Having achieved success with a nitrogen heteroatom in the
methyl acetate portion, we decided to explore the feasibility of
coupling pyridinylmethyl acetate 1a with N-heteroarylboronic
acids 2b-e (Table 3). Couplings of 1a with 1H-indolylboronic
acids 2b, 2c and 2e were found to proceed in moderate to good
yield (67-81% isolated yields, entries 1-3) whilst a 64% yield
was obtained from coupling pyrimidinylboronic acid 2d with
1a (entry 4).
Next, the effect of varying the N-heteroaryl(methyl) acetate
coupling partner was explored in conjunction with naphtha-
3

ACCEPTED MANUSCRIPT
7
1d
4a
2a
4a
70 (3p)
72 (3q)
80 (3q)
bMethane acetate preparation: aryl methanol alcohol (1.0 equiv)
8
9
in dichloromethane (15 mL), triethylamine (1.3 equiv) and acetic
anhydride (1.1 equiv) at 0 °C for 16 h. Products were isolated as
oils after aqueous work-up. cCross-coupling conditions: substrate 1
(1.1 equiv), substrate 2 (1.0 equiv), Pd(OAc)2 (2 mol %), RuPhos
1h
1h
d Reactions conditions: substrate 1 (1.1 equiv), substrate 2a or
4a (1.2 equiv), Pd(OAc)2 (0.5 mol %), RuPhos (1 mol %), K2CO3
(4 mol %), K2CO3 (2.5 equiv), 10:1
iPrOH:H2O, 80 °C, under N2
atmosphere.
(3.5 equiv), 10:1 iPrOH:H2O, 80 °C, under N2 atmosphere; 0.02
The potential of the standard reaction conditions to generate
products with differing heteroatoms in each heterocycle was
assessed using thiophen-3-ylboronic acid 2g as the control
substrate. Furanyl(methyl) acetates 1e and 1f and pyridinyl
methane acetate 1a were selected as the coupling partners. All
three reactions were successful with 3l-n isolated in good to
excellent yield (entries 12-14).
mmol; % isolated yield is indicated. eAssay yield was 91%. fAssay
yield was 20%.
3. Conclusion
In conclusion, a single set of conditions has been developed
to facilitate the synthesis of a range of structurally diverse dia-
rylmethanes. Such compounds are highly desirable as many
To broaden the scope of this coupling to include boronic acid
esters, naphthaleneboronic acid pinacol ester 4a was coupled
with several benzylic esters (Table 4). Good results were ob-
tained in coupling 1a with 4a (91% assay yield, 86% isolated
yield); whereas, inferior results were obtained in coupling 1aa
with 2a (20% assay yield, 17% isolated yield). Further investi-
gation demonstrated that yields were considerably affected by
choice of boron species. Electron-rich benzylic acetates 1aa
and 1 g offered poor cross-coupling efficiency, presumably
due to slow oxidative addition, with both compounds still pre-
sent at the end of the reactions. However, this difference was
less pronounced in the case of electron-poor benzylic acetates
1d and 1h with diarylmethane products obtained in similar
yield for both. Therefore, as a practical recommendation, we
suggest exploring the use of boronic esters in addition to acids
when utilizing our coupling conditions.
biologically
active
substances
contain
(ar-
yl)(heteroaryl)methane skeletons. The Suzuki−Miyaura cross-
coupling of heteroaryl/arylmethane acetates and heteroar-
yl/arylboronic acids generated 14 heterocyclic products in 52-
91% yield. Notably, diarylmethanes bearing heteroatoms on
both coupling partners were successfully prepared, expanding
access to these valuable building blocks.
4. Experimental section
4.1 General remarks
All materials were purchased from commercial suppliers
and used without further purification. All reactions were con-
ducted under an atmosphere of nitrogen unless noted other-
wise. Reactions were monitored for completion by removing a
small sample from the reaction mixture and analyzing the
sample by HPLC. HPLC analyses were performed using an
Ascentis Express C18, 2.7 µm, 150 × 4.60 mm column, and a
mobile phase consisting of acetonitrile and 0.1% aqueous
phosphoric acid. Melting points were obtained using Stuart
Scientific Melting Point Apparatus SMP3. NMR spectra were
recorded on a Bruker AVANCE DPX or DRX 400 (1H NMR
Table 4. Boronic acid vs. pinacol boronate.d
at 400 MHz, 13C NMR at 100 MHz) spectrometer. H NMR
1
data are reported as follows: chemical shifts are reported in
ppm with the solvent resonance resulting from incomplete
deuteration as the internal standard (CDCl3: 7.26; CD2Cl2:
5.35), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, br = broad, m = multiplet or combinations thereof),
coupling constants, and integration. 13C NMR data are reported
as follows: chemical shifts are reported in ppm with the solvent
resonance as the internal standard (13CDCl3: 77.16; 13CD2Cl2:
53.43); and then where applicable the multiplicity (d = dou-
blet), coupling constant, and integration. High resolution mass
spectra were obtained by LCMS using a Waters QToF Premier
system, and a mobile phase consisting of 0.1% aqueous formic
acid and 0.1% formic acid in acetonitrile.
Benzylic ace-
tate
Coupling
partner
Entry
Yield, %
1
2
3
4
5
6
1a
1aa
1aa
1g
4a
2a
4a
2a
4a
2a
86e (3a)
17f (3aa)
55 (3aa)
13 (3o)
23 (3o)
66 (3p)
4.2 Acetate formation: General synthetic method
Aryl methanol alcohol (6 mmol) in dichloromethane (15
ml) was cooled to 0 °C. Triethylamine (7.8 mmol) and acetic
anhydride (6.6 mmol) were added dropwise sequentially, keep-
ing T < 1 °C. The solution was aged at room temperature for 1-
16 h, samples were taken at different time intervals and ana-
lysed by HPLC, and the reaction was quenched with 10%
1g
1d
4

ACCEPTED MANUSCRIPT
aqueous NH4Cl (4 ml) when HPLC indicated reaction comple-
tially with brine and saturated aqueous NH4Cl. The organics
were dried over Na2SO4 and the solvent was removed in vacuo.
Product was purified by column chromatography (hep-
tane/MTBE).
tion. The aqueous layer was discarded and the organics were
washed with water (4 ml) and then dried over Na2SO4. The
solvent was removed in vacuo, affording the product.
1
Pyridin-3-ylmethyl acetate (1a). Yellow oil; yield 99%; H
3-(Naphthalen-1-ylmethyl)pyridine (3a). Pink solid, yield
91%; mp 52-53 °C; H NMR (400 MHz, CDCl3): δ 8.60 (s,
1
NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.57 (d, J = 4.8 Hz,
1H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.30 (dd, J = 7.6, 4.8 Hz,
1H), 5.12 (s, 2H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 170.7, 149.6, 149.5, 136.1, 131.3, 123.5, 63.7, 20.9; HRMS
(ESI+) calculated for C8H9NO2 176.0534, found 176.0532.
Spectroscopic data consistent with literature.12
1H), 8.47 (d, J = 4.0 Hz, 1H), 7.92 (m, 2H), 7.82 (d, J = 8.4
Hz, 1H), 7.47 (m, 4H), 7.32 (d, J = 7.2 Hz, 1H), 7.19 (dd, J =
8.0, 5.2 Hz, 1H), 4.47 (s, 2H); 13C NMR (100 MHz, CDCl3): δ
150.0, 147.5, 136.2 (2C), 135.2, 134.0, 131.8, 128.9, 127.7,
127.4, 126.3, 125.8, 125.6, 123.9, 123.5, 36.2; HRMS (ESI+)
calculated for C16H13N 220.1126, found 220.1124. Spectro-
scopic data consistent with literature.18
1-Benzylnaphthalene (3aa). White solid, yield 55%; 1H
NMR (400 MHz, CDCl3): δ 8.03 (m, 1H), 7.90 (m, 1H), 7.80
(d, J = 8.0 Hz, 1H), 7.47 (m, 3H), 7.28 (m, 6H), 4.49 (s, 2H).
Spectroscopic data consistent with literature.19
2-Methylpyrimidin-4-yl)methyl acetate (1b). Amber colored
1
solid; yield 96%; mp 61-63 °C; H NMR (400 MHz, CDCl3): δ
8.64 (d, J = 5.1 Hz, 1H), 7.15 (dd, J = 5.1, 0.8 Hz, 1H), 5.16 (s,
2H), 2.74 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
170.3, 167.9, 164.9, 157.3, 114.9, 65.4, 25.9, 20.8; HRMS
(ESI+) calculated for C8H10N2O2 167.0821, found 167.0824.
(1,3-Dimethyl-1H-pyrazol-5-yl)methyl acetate (1c). Yellow
6-(Pyridin-3-ylmethyl)-1H-indole (3b). Off-white solid;
yield 80%; mp 87-90 °C; H NMR (400 MHz, CDCl3): δ 8.66
1
1
oil; yield 96%; H NMR (400 MHz, CDCl3): δ 6.07 (s, 1H),
5.05 (s, 2H), 3.81 (s, 3H), 2.23 (s, 3H), 2.08 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 170.4, 147.4, 137.2, 107.1, 56.0, 36.2,
20.8, 13.3; HRMS (ESI+) calculated for C8H12N2O2 169.0977,
found 169.0974. Spectroscopic data consistent with literature.13
(br s, 1H), 8.56 (m, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.6 (d,
J = 8.2 Hz, 1H), 7.52 (m, 1H), 7.19 (m, 3H), 6.99 (dd, J = 7.8,
1.6 Hz, 1H), 6.54 (m, 1H), 4.09 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 149.8, 147.1, 137.6, 136.8, 136.3, 133.6, 126.5,
124.4, 123.6, 121.2, 120.9, 111.2, 102.3, 39.3; HRMS (ESI+)
calculated for C14H12N2 209.1079, found 209.1073.
4-Trifluoromethanebenzyl acetate (1d). Colorless oil; yield
1
88%. H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.0 Hz, 2H),
7.59 (d, J = 8.0 Hz, 2H), 2.18 (s, 2H), 2.15 (d, 3H). Spectro-
5-(Pyridin-3-ylmethyl)-1H-indole (3c). Off-white solid;
yield 67%; mp 129-131 °C; H NMR (400 MHz, CDCl3): δ
1
scopic data consistent with literature.14
8.58 (m, 2H), 8.47 (dd, J = 4.7, 1.6 Hz, 1H), 7.53 (ddd, J = 7.8,
2.3, 1.6 Hz, 1H), 7.47 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.21
(m, 2H), 7.01 (dd, J = 8.2, 1.6 Hz, 1H), 6.52 (m, 1H), 4.10 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 149.7, 147.0, 138.0,
136.8, 134.7, 131.0, 128.2, 124.8, 123.5, 123.1, 120.6, 111.3,
102.3, 39.2; HRMS (ESI+) calculated for C14H12N2 209.1079,
found 209.1073.
Furan-3-ylmethyl acetate (1e). Dark yellow oil; yield
100%; H NMR (400 MHz, CDCl3): δ 7.47 (dd, J = 1.6, 0.8
Hz, 1H), 7.42 (m, 1H), 6.44 (m, 1H), 4.99 (s, 2H), 2.09 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 170.9, 143.4, 141.6, 120.4,
110.6, 57.7, 21.0. Spectroscopic data consistent with litera-
ture.15
1
1
4-Methoxybenzyl acetate (1g). Colorless oil; yield 97%; H
5-(Pyridin-3-ylmethyl)pyrimidine (3d). Colorless oil; yield
64%; 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 8.59 (s, 2H),
8.52 (d, J = 2.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.26 (dd, J =
8.0, 4.7 Hz, 1H), 3.99 (s, 2H); 13C NMR (100 MHz, CDCl3): δ
157.3, 157.0 (2C), 149.8, 148.4, 136.3, 122.9, 133.1, 123.8,
33.7; HRMS (ESI+) calculated for C10H9N3 172.0875, found
172.0868.
NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.6 Hz, 2H), 6.92 (d, J
= 8.6 Hz, 2H), 5.06 (s, 2H), 3.83 (s, 3H), 2.10 (s, 3H). Spectro-
scopic data consistent with literature.16
3-Cyanobenzyl acetate (1h). Colorless oil; yield 99%; 1H
NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.61 (m, 2H), 7.49
(m, 1H), 5.14 (s, 2H), 2.14 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 170.6, 137.6, 132.3, 131.8, 131.5, 129.4, 118.5,
112.8, 64.8, 20.9; HRMS (ESI+) calculated for C10H10O2N
176.0712, found 176.0711. Spectroscopic data consistent with
literature.17
4-(Pyridin-3-ylmethyl)-1H-indole (3e). Green solid; yield
1
81%; mp 138-140 °C; H NMR (400 MHz,CDCl3): δ 8.64 (br
s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 4.7, 1.6 Hz, 1H),
7.56 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.18 (m, 3H), 6.92 (dd,
J = 7.4, 0.8 Hz, 1H), 6.51 (m, 1H), 4.28 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 149.7, 147.0, 136.8, 136.7, 135.9, 131.5,
127.3, 124.2, 123.5, 122.1, 120.1, 109.9, 100.8, 36.7; HRMS
(ESI+) calculated for C14H12N2 209.1079, found 209.1070.
4.3 Suzuki reaction: General synthetic method
Boronic acid (6 mmol), acetate (7.2 mmol), Pd(OAc)2 (0.12
mmol) and RuPhos (0.24 mmol) in 2-propanol (10 ml) and
water (1 ml) were stirred for 5 minutes under N2 atmosphere.
K2CO3 (15 mmol) was added and the suspension was sparged
sub-surface with N2 for 5 minutes. The suspension was heated
to 80 °C for 1-48 h, samples were taken at different time inter-
vals and analysed by HPLC, and the reaction was cooled to
room temperature when HPLC indicated reaction completion.
Water (2.5 ml) and MTBE (2.5 ml) were added and the aque-
ous layer was removed. The organic layer was washed sequen-
2-Methyl-4-(naphthalen-1-ylmethyl)pyrimidine (3f). Color-
less oil; yield 52%; 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J =
5.1 Hz, 1H), 7.90 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.46 (m,
4H), 6.67 (d, J = 5.2 Hz, 1H), 4.56 (s, 2H), 2.80 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 169.7, 167.7, 156.8, 134.0, 133.2,
132.0, 128.8, 128.1 (2C), 126.4, 125.9, 125.6, 124.2, 117.1,
41.8, 26.0; HRMS (ESI+) calculated for C16H13N 235.1239,
found 235.1239.
5

ACCEPTED MANUSCRIPT
1,3-Dimethyl-5-(naphthalen-1-ylmethyl)-1H-pyrazole (3g).
126.2, 123.5, 121.7, 33.7; HRMS (ESI+) calculated for
C10H9NS 176.0534, found 176.0532.
Pink solid; yield 91%; mp 76-78 °C; 1H NMR (400 MHz,
CDCl3): δ 7.99 (m, 1H), 7.91 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H),
7.54 (m, 2H), 7.42 (m, 1H), 7.14 (d, J = 7.1 Hz, 1H), 5.70 (s,
1H). 4.37 (s, 2H), 3.76 (s, 3H), 2.23 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 147.3, 141.5, 122.9, 133.5, 131.7, 128.8,
127.6, 126.3, 126.2, 125.8, 125.6, 123.5, 106.0, 36.0, 29.2,
13.4; HRMS (ESI+) calculated for C16H16N2 237.1392, found
237.1382.
1-(4-Methoxybenzyl)naphthalene (3o). White solid; yield
23%; 1H NMR (400 MHz, CDCl3): 8.04 (m, 1H), 7.89 (m,
1H), 7.79 (d, J = 8.0 Hz, 1H), 7.46 (m, 3H), 7.30 (m, 1H), 7.15
(m, 2H), 6.85 (m, 2H), 4.42 (s, 2H), 3.80 (s, 3H). Spectroscop-
ic data consistent with literature.22
1-(4-Trifluoromethanebenzyl)naphthalene (3p). White sol-
1
id, yield 70%; H NMR (400 MHz, CDCl3): δ 7.92 (m, 2H),
2-(4-(Trifluoromethyl)benzyl)thiophene (3h). Colorless oil;
yield 60%; 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.0 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 5.1, 1.2 Hz, 1H),
6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.84 (ddd, J = 3.5, 2.0, 1.2 Hz,
1H), 4.24 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 144.4,
142.5, 128.89 (2C), 128.87 (d, J = 32 Hz, 2C), 127.0, 125.6,
125.5 (d, J = 3.8 Hz, 2C), 124.4, 124.3 (d, J = 270 Hz, 2C),
35.8; HRMS (ESI+) calculated for C12H9F3S 243.0455, found
243.0444.
7.82 (d, J = 8.2 Hz, 1H), 7.50 (m, 5H), 7.32 (m, 3H), 4.52 (s,
2H). Spectroscopic data consistent with literature.23
3-(Naphthalene-1-ylmethyl)benzonitrile (3q). Colorless oil;
1
yield 80%; H NMR (400 MHz, CDCl3): δ 7.93-7.84 (m, 3H),
7.53-7.45 (m, 6H), 7.39-7.32 (m, 2H), 4.49 (s, 2H); 13C NMR
(100 MHz, CDCl3): δ 142.3, 134.9, 134.1, 133.2, 132.1, 131.8,
130.0, 129.3, 128.9, 127.9, 127.7, 126.4, 125.9, 125.6, 123.9,
119.0, 112.5, 38.6; HRMS (ESI+) calculated for C18H13N
244.1126, found 244.1116.
3-(4-(Trifluoromethyl)benzyl)thiophene (3i). Colorless oil;
yield 82%; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz,
2H), 7.38-7.31 (m, 3H), 6.98 (s, 1H), 6.94 (d, J = 5.2 Hz, 1H),
4.08 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 144.7, 140.3,
129.1 (2C), 128.6 (d, J = 33 Hz, 2C), 127.2 (d, J = 220 Hz,
1C), 125.7, 125.4 (d, J = 4 Hz, 2C), 123.0, 121.7, 36.3; HRMS
(ESI+) calculated for C12H9F3S 243.0455, found 243.0446.
Naphthalene-1-boronic acid pinacol ester (4a). Naphtha-
lene-1-boronic acid (60 mmol) and pinacol (60 mmol) in THF
(50 ml) were aged for 3 days at room temperature. Solvent was
removed in vacuo. Purification by column chromatography
(hexane/EtOAc) afforded the desired product as a white solid;
yield 64%; 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 8.8 Hz,
1H), 8.10 (dd, J = 1.2, 6.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H),
7.85 (dd, J = 1.2, 8.8 Hz, 1H), 7.56 (ddd, J = 1.6, 6.8, 10.0 Hz,
1H), 7.49 (dd, J = 7.2, 8.0 Hz, 2H), 1.45 (s, 12H). Spectro-
scopic data consistent with literature.24
3-Methyl-4-(4-(trifluoromethyl)benzyl)thiophene (3j). Col-
orless oil; yield 91%; 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J
= 8.2 Hz, 2H), 7.30 (dd, J = 8.6, 0.8 Hz, 2H), 6.97 (m, 1H),
6.86 (d, J = 3.5 Hz, 1H), 3.97 (s, 2H), 2.13 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 144.1, 139.4, 136.8, 129.0 (2C), 128.5
(d, J = 32 Hz, 1C), 125.3 (d, J = 4 Hz, 2C), 124.3 (d, J = 270
Hz, 1C), 122.6, 121.8, 35.2, 14.5; HRMS (ESI+) calculated for
C13H11F3S 257.0612, found 257.0605.
Acknowledgments
The authors thank Alexia Bertrand and Brett O’Brien for
mass spectrometry work.
3-(4-(Trifluoromethyl)benzyl)furan (3k). Colorless oil; yield
53%; 1H NMR (400 MHz, CD2Cl2): δ 7.59 (d, J = 8.1 Hz, 2H),
7.40 (m, 3H), 7.29 (d, J = 1.5 Hz, 1H), 6.28 (s, 1H), 3.87 (s,
2H). Spectroscopic data was consistent with literature.20
References and notes
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3-(Thiophen-3-ylmethyl)furan (3l). Colorless oil; yield 81%;
1H NMR (400 MHz, CDCl3): δ 7.40 (m, 1H), 7.28 (m, 2H),
6.98 (m, 2H), 6.31 (d, J = 2.0 Hz, 1H), 3.81 (s, 2H); 13C NMR
(100 MHz, CDCl3): δ 143.0, 140.8, 139.5, 128.3, 125.6, 123.8,
121.0, 25.8; HRMS (ESI+) calculated for C9H8OS 165.0374,
found 165.0386.
2-(Thiophen-3-ylmethyl)furan (3m). Colorless oil; yield
83%; 1H NMR (400 MHz, CD2Cl2): δ 7.38 (dd, J = 2.0, 0.8 Hz,
1H), 7.31 (dd, J = 5.1, 3.1 Hz, 1H), 7.08 (m, 1H), 7.02 (dd, J =
5.1, 1.2 Hz, 1H), 6.35 (dd, J = 3.1, 2.0 Hz, 1H), 6.09 (m, 1H),
4.02 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 154.2, 141.4,
138.5, 128.3, 125.6, 121.5, 110.3, 105.9, 29.0; HRMS (ESI+)
calculated for C9H8OS 165.0374, found 165.0370. Spectro-
scopic data consistent with literature.21
3-(Thiophen-3-ylmethyl)pyridine (3n). Colorless oil; yield
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1
91%; H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 1.6 Hz, 1H),
8.49 (dd, J = 4.7, 1.6 Hz, 1H), 7.51 (m, 1H), 7.29 (dd, J = 4.9,
2.9 Hz, 1H), 7.24 (ddd, J = 7.8, 4.7, 0.8 Hz, 1H), 6.95 (m, 1H),
6.91 (dd, J = 4.9, 1.4 Hz, 1H), 4.00 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 150.1, 147.7, 140.1, 136.2, 136.0, 128.2,
6

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Supplementary material
Procedures for ligand, solvent and base screens. Detailed
screening results. NMR spectra for all new compounds.
7