Expedient synthesis of gem-dialkylbenzyl heterocycles through olefinic hydroarylation

Article abstract of DOI:10.1016/j.tet.2015.10.006

A robust approach to gem-dialkylbenzyl heterocycles has been developed through a triflic acid-catalyzed hydroarylation of olefinic heterocycles. A broad range of substrates containing pyridine, quinoline, pyrazole, triazole and imidazole moieties are shown to be highly compatible with this method. This rapid construction of gem-dialkyl groups should be useful in the synthesis of drug-like molecules containing heterocyclic diversity and in the study of the gem-dialkyl effect.

Full text of DOI:10.1016/j.tet.2015.10.006

Accepted Manuscript
Expedient Synthesis of gem-Dialkylbenzyl Heterocycles through Olefinic
Hydroarylation
Yajing Lian, Kristen Burford, Allyn T. Londregan
PII:
S0040-4020(15)30107-1
10.1016/j.tet.2015.10.006
TET 27178
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 June 2015
Revised Date: 30 September 2015
Accepted Date: 1 October 2015
Please cite this article as: Lian Y, Burford K, Londregan AT, Expedient Synthesis of gem-Dialkylbenzyl
Heterocycles through Olefinic Hydroarylation, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.006.
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ACCEPTED MANUSCRIPT
Expedient Synthesis of gem-Dialkylbenzyl
Leave this area blank for abstract info.
Heterocycles through Olefinic
Hydroarylation
Yajing Lian *, Kristen Burford, Allyn T. Londregan
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Expedient Synthesis of gem-Dialkylbenzyl Heterocycles through Olefinic
Hydroarylation
Yajing Lian *, Kristen Burford, Allyn T. Londregan
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A robust approach to gem-dialkylbenzyl heterocycles has been developed through a triflic acid-
catalyzed hydroarylation of olefinic heterocycles. A broad range of substrates containing
pyridine, quinoline, pyrazole, triazole and imidazole moieties are shown to be highly compatible
with this method. This rapid construction of gem-dialkyl groups should be useful in the synthesis
of drug-like molecules containing heterocyclic diversity and in the study of the gem-dialkyl
effect.
Available online
Keywords:
gem-Dialkyl
2009 Elsevier Ltd. All rights reserved
.
Hydroarylation
Heterocycle
Triflic acid
Friedel-Crafts reaction
1. Introduction
CF3
N
Me
N
Me
Me
Heterocycles, such as pyridine, pyrazole, imidazole and other
nitrogen-rich arenes are important pharmacophores, present in
numerous approved drugs and drug candidates.1 As a result, the
functionalization of heterocycles has attracted tremendous
attention and numerous methods have been developed that allow
rapid access to a diverse scope of functionalized heterocycles.2
Introduction of cyclopropyl or gem-dialkyl groups to the benzylic
position of heterocycles is of considerable interest in medicinal
chemistry and has been shown for instance, to improve the
physicochemical and pharmacokinetic properties of drug-like
molecules (Figure 1).3 Specifically, These groups can be
incorporated to block the sites of metabolism on benzylic
methylenes that are often considered metabolic liabilities. These
substituents can also enforce unique conformational biases which
can lead to improved binding and increased potency, qualities
often sought in medicinal chemistry. In addition, gem-dialkyl
substituents have been shown to accelerate certain intramolecular
cyclization reactions through the Thorpe-Ingold effect. Substrates
containing this moiety are therefore of interest in the study and
development of synthetic methodologies.4
N
Me Me
O
N
Me
Me
N
FLAP inhibitor (AstraZeneca)
OH
LXR inhibitor (Wyeth)
CO2H
CO2H
OH
N
N
S
N
N
Me Me
Me Me
F
CF3
S1 P inhibitor (Amgen)
P-Selectin Inhibitor (Wyeth)
Figure 1. Selected examples of gem-dialkylbenzylic heterocycles
found in biologically active compounds.
in the synthesis of mono-substituted benzylic arenes (Scheme
1a), it has seldom been applied towards geminal-substitution.
Moreover, all reported examples of such hydroarylations are
performed on simple styrenes which are devoid of heterocyclic
diversity.5 Another approach to gem-dialkylbenzylic arenes is
base-mediated direct alkylation. For example, the gem-dimethyl
containing S1 P inhibitor (Figure 1)3b was synthesized via a
double alkylation reaction3b with iodomethane under harsh base
conditions. This strategy was presumably facilitated by the
enhanced acidity of the benzylic position adjacent to pyridine.
Recently, Klumpp and co-workers developed a hydroarylation
reaction of olefinic pyrazines and quinoxalines to generate anti-
Markovnikov addition products using benzene and triflic acid as
a co-solvent (Scheme 1b).6 To our knowledge, no general method
exists for the direct synthesis of gem-dialkylbenzyl heterocycles
Gem-dialkyl substituents are typically found adjacent to
carbonyl groups and often are installed through α-alkylation
reactions.4 In contrast, the introduction of gem-dialkyl groups at
the benzylic position of arenes, in particular hetero-arenes,
remains a challenge and merits further investigation. The
hydroarylation reaction of olefinic benzenes under
Lewis/Brønsted acidic or transition-metal catalysis is a potential
approach to this challenge. Although this strategy has been used
* Corresponding author. e-mail address: yajing.lian@pfizer.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
using olefinic hydroarylation. In our efforts to improve the
With these conditions in hand, we proceeded to explore the
potency and physicochemical properties of a lead series in one of
our drug discovery projects, we required a robust method for the
introduction of gem-dialkylbenzyl heterocycles. Herein, we
report an effective triflic acid-catalyzed hydroarylation reaction
of olefinic heterocycles for the synthesis of gem-dialkylbenzyl
heterocycles.
substrate scope of this methodology (Table 2). The reaction is
compatible with olefinic pyridines substituted at the 2, 3, or 4
positions, leading to products 3-5 in good yields. However, the
reaction with 2-substituted pyridine (5) was sluggish and to
improve the yield, benzene was used as the solvent. The slow
reaction rate is presumably due to the stronger electron
withdrawing induced effect by the protonated nitrogen when
olefinic pyridine substituted at 2 position over 3 or 4 positions.
Pyridines substituted with electron-neutral or rich groups were
well tolerated. Both the 4-MeO- and 2-Br-substituted methyl-
vinylpyridines generated the corresponding products 6 and 7 in
good yields. Electron-deficient pyridines failed to provide the
desired products. The steric and electronic effects of nucleophilic
arenes on the reaction outcome were then screened. With toluene
the product 8 was isolated in excellent yield as a mixture of para-
and ortho-substituted isomers in 8:1 selectivity, favoring the
para-substituted product. A similar result was observed with
chlorobenzene. In both cases the isomers could be separated
carefully by column chromatography affording the para-
isomeric products of 8 and 9. The reaction with m-xylene
exclusively afforded 10 as a single isomer. This result is
somewhat surprising as electrophilic aromatic substitution of m-
xylene typically favors addition adjacent to one of the methyl
substituents. In this case the high selectivity for this regioisomer
may arise due to the steric effect of the gem-dimethyl substituent.
With more nucleophilic arenes the reaction could be conducted at
room temperature, and good yields were observed. Products 11
and 12 were isolated in 72 and 76% yield, respectively. Electron
deficient arenes were unreactive under the reaction conditions.
Scheme 1. Examples of Olefin Hydroarylation
2. Results and discussion
As a model substrate, we chose 3-(prop-1-en-2-yl)pyridine 1a
and examined direct hydroarylation with benzene 2. Various
conditions were evaluated and summarized in Table 1. Initial
attempts using either Lewis acids or a mild Brønsted acid with
benzene as the solvent all failed to provide any expected product
(entries 1-3). Of interests, the use of 1.0 equiv of triflic acid
afforded the product 3 in 20% yield (entry 4). Increasing the acid
loading to 5 equiv dramatically improved the yield to 96% (entry
5). To enhance the utility of this reaction and allow the
economical addition of more valuable arenes, we decided to
explore reaction conditions that avoided the use of benzene as the
solvent. Conducting the reaction with 5 equiv of benzene in DCE
as the solvent afforded 3 in 78% yield (entry 6), with some
unreacted pyridine 1a. Increasing the temperature slightly to 100
oC led to complete consumption of starting material and
enhanced the yield to 94% (entry 7). Further decreasing the
benzene loading to 2.0 equiv and even 1.0 equiv still provided
the product, albeit with lower yields (entries 8 and 9). Using
nitromethane, a solvent which is commonly employed in Friedel-
Crafts-type reactions, decreased the yield to less than 10%.
Table 2. Substrate Scope with Olefinic Pyridinesa
o
Conducting the reaction in DCE at 100 C with 5 equiv of triflic
acid and arenes proved to be the optimal condition.
Table 1. Reaction Optimization
To further demonstrate the efficacy of this transformation, we
next explored the possibility of expanding this methodology to
different alkyl groups and other heterocycles as summarized in
Table 3. The reaction with 3-(but-1-en-2-yl)pyridine led to
product 13 in 66% yield. Meanwhile, the hydroarylation of
cyclohexenyl pyridine smoothly afforded product 14 in 70%
yield, demonstrating that this approach is applicable to other
alkyl groups. To broaden the synthetic utility of this method, this
approach was then extended to other heterocycles. As expected,
the reaction with an olefinic quinoline went smoothly and
afforded product 15 in excellent yield. We were delighted to see
that this transformation was also applicable to five-membered
heterocycles, such as pyrazole, triazole, and imidazole. All of
these led to the corresponding products 16-18 in good yields. The

3
typical approach to construct such structures necessitates a de
novo synthesis of the corresponding heterocycle through a multi-
step sequence.7 Unlike the hydroarylation of olefinic pyrazines
and quinoxalines, leading to anti-Markovnikov addition
products,6c the reaction with nitrogen-rich heterocycles generated
Markovnikov products 16-18 exclusively.
triazole and imidazole are all highly compatible with this
ACCEPTED MANUSCRIPT
method. In view of the robust nature of the transformation
together with the ability to use readily available reactants make
this transformation of interest to any field where rapid access to
gem-dialkyl heterocycles is needed.
4. Experimental section
4.1. General remarks
Table 3. Substrate Scope with other heterocyclesa
All reagents were obtained from commercial suppliers and
used without further purification, unless otherwise noted. Vinyl
heterocycles were synthesized according to published procedures.
All solvents used were purchased anhydrous in a DriSolv bottle.
Silica gel chromatography was performed using medium pressure
CombiFlashRf systems employing Redi Sep Rf Gold silica
column, with heptane/EtOAc as eluent. The solvent was
evaporated using rotary evaporator at room temperature and 10
mBar. 1H and 13C{1H} NMR characterization data were
collected at 300 K on a Bruker AV-500 spectrometer operating at
500.1 and 125.8 MHz (respectively) with chemical shifts
reported in parts per million relative to CHCl3 (1H NMR; 7.26
ppm, 13C{1H} NMR; 77.23 ppm). Melting point was recorded on
Buchi B-545 melting point apparatus. IR spectra were recorded
on a Nicolet Avatar 360 FT-IR spectrometer and only partial data
are provided. High resolution mass spectroscopy (HRMS) was
performed on an Agilent (6220) LC-MS TOF using a Xbridge
C18 2.5 ꢀm 3.0 X 5.0 mm at 60 oC; ammonium formate: water as
mobile phase A1 and 50:50 Methanol:Acetonitrile as mobile
Phase B1
Another useful feature of this methodology is that it
capitalizes on a broad set of readily available reactants. Indeed,
the olefinic aromatic heterocycles employed in this report can be
readily synthesized through conventional approaches as listed in
Scheme 2. The Wittig reaction, for instance, is a powerful
method to synthesize olefinic pyridines,8 where pyridyl ketones
are commercially available. Halogenated heterocycles are widely
available and transition-metal catalyzed coupling reactions such
as the Suzuki,9 Negishi10 and Barluenga-like11 coupling reactions
can also provide fast entry into an assortment of olefinic six- and
five-membered heterocycles. Each of these methods was
successfully utilized to prepare the substrates found in this work.
4.2 General Procedure for the Preparation of Vinyl
Heterocycles
In table 2, products 3, 8, 9, 10, 11 and 12 were synthesized
from starting material 1a and products 4, 5, 6 and 7 were made
from starting materials 1b, 1c, 1d and 1e correspondingly. In
table 3, products 13, 14, 15, 16, 17 and 18 were made from 1f,
1g, 1h, 1i, 1j and 1k correspondingly.
4.2.1 1b, 1c, 1d, 1f were prepared by the Wittig reaction
To a 200 mL round bottle flash was added sodium tert-
butoxide (1.3 equiv), followed by the addition of 50 mL
anhydrous THF, the mixture was stirred until all base was
dissolved. Methyltriphenylphosphonium iodide (1.2 equiv) was
added in one port and the heterogeneous solution was stirred at rt
for 30 mins. Pyridyl ketones (1.0 equiv) were added slowly and
the mixture was stirred at rt overnight. The mixture was
quenched with water and extracted with ether twice. The
combined organic layer was dried (MgSO4) and filtered,
concentrated to provide some oil mixed with powder. The crude
material was then distilled by Kugelrohr apparatus at 10 mBar
with temperature ranging from 50-100 oC to afford the product as
colorless liquid. Characterization of unreported 1d, 1f is listed
below:
Scheme 2. Different approaches to olefinic heterocycles
3. Conclusion
4.2.1.1 2-bromo-3-(prop-1-en-2-yl)pyridine (1d): Colorless oil
(0.331 g, 67% yield). H NMR (CDCl3): δ 8.27 (dd, J = 4.8, 2.0
Hz, 1H), 7.47 (dd, J = 7.5, 2.0 Hz, 1H), 7.23 (dd, J = 7.5, 4.7 Hz,
1H), 5.27-5.30 (m, 1H), 5.00 (s, 1H), 2.11 (s, 3H); 13C NMR
(CDCl3): δ 148.6, 143.8, 141.9, 141.4, 137.9, 122.8, 117.7, 23.2;
1
In conclusion, we have developed an expedient approach to
gem—dialkylbenzyl aromatic heterocycles through the
hydroarylation reaction of olefinic heterocycles. A broad range of
aromatic heterocycles, including pyridine, quinoline, pyrazole,

4
Tetrahedron
IR(film): 1551, 1380, 1047, 904, 806, 747, 650 cm-1; HRMS
4.2.3 3-(prop-1-en-2-yl)quinoline 1h was prepared by the
ACCEPTED MANUSCRIPT
(ESI/[M+H]+) calcd. For C8H9BrN: 197.9913 Found: 197.9942.
Negeshi reaction
In a 50 mL oven-dried round bottle flask with ZnCl2 (3.2 mL
of 1.9 M in methyltetrahydrofuran, 6.2 mmol, 3.0 equiv) was
added isopropenylmagnesium bromide solution (12.0 mL of 0.5
4.2.1.2 3-(but-1-en-2-yl)pyridine (1f): Colorless oil (0.39g, 79%
yield). 1H NMR (CDCl3): δ 8.66 (s, 1H), 8.49 (d, J = 4.5 Hz, 1H),
7.67 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.9, 4.7 Hz, 1H), 5.31 (s,
1H), 5.15 (s, 1H), 2.50 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.4 Hz,
3H); 13C NMR (CDCl3): δ 148.5, 147.6, 147.2, 137.0, 133.4,
123.2, 112.8, 28.0, 12.8; IR(film): 2968, 1629, 1410, 1022, 897,
814, 717, 623 cm-1; HRMS (ESI/[M+H]+) calcd. For C9H12N:
134.0964 Found: 134.0961.
o
M in THF, 6.2 mmol, 3.0 equiv) at 0 C slowly. The reaction
mixture was warmed up to room temperature and was stirred for
additional 30 mins. In another 100 mL oven-dried round bottle
flask was added 3-bromoquinoline (416 mg, 2.0 mmol, 1.0
equiv) and Pd(PPh3)4 (119 mg, 0.05 equiv) in 4 mL THF. After
degassed with N2 for 5 mins, the mixture was then heated to 60
oC. The zincate solution was transferred into the bromide solution
slowly through cannula. The reaction was kept at 60 oC for
addition 2h. After cooling down to rt, the reaction was quenched
with NH4Cl solution, extracted by EtOAc (15 mL three times).
The organic layers were combined, dried over MgSO4 and
filtered. The organic solution was then concentrated under
reduced pressure and the residue mixture was loaded into combi
flush for purification ) to afford the product as colorless oil (286
mg, 85% yield). The analytical data was consistent with the
reported literature.12
4.2.2 1e, 1i, 1j, 1k were prepared by the Suzuki reaction
To
a 50 mL round bottle flask was added 1,1'-
Bis(diphenylphosphino)ferrocenedichloro Palladium(II) (0.1
equiv), bromide (1.0 equiv) and vinylboronic acid pinacol ester
(2.0 equiv) in 20 mL dioxane. The mixture was degassed for 5
mins, and sodium carbonate aqueous solution (2.0 M, 10 equiv)
o
was added. The mixture was then heated to 85 C for 14h. After
cooled to rt, the reaction mixture was filtered through a short
celite pad and washed with EtOAc. The organic solution was
concentrated under reduced pressure and the residue was loaded
into combi flush for purification to afford the product as oil.
4.2.4 3-(cyclohex-1-en-2-yl)pyridine 1g was prepared by the
Barluenga-like reaction
To a 100 ml oven-dried round bottle flask was added N'-
cyclohexylidene-4-methylbenzenesulfonohydrazide (3.79 g, 14.2
4.2.2.1 4-methoxy-2-(prop-1-en-2-yl)pyridine (1e): Colorless oil
(139 mg, 47% yield). H NMR (CDCl3): δ 8.41 (d, J = 5.7 Hz,
mmol,
1.0
equiv)
and
1,1'-
1
bis(diphenylphosphino)ferrocenedichloro palladium(II) (388 mg,
0.475 mmol, 0.05 equiv) in 50 ml dioxane. The reactions were
evacuated and purged with N2 three times lithium tert-butoxide
(1.71 g, 20.9 mmol, 2.2 equiv) was added followed by the
addition of 3-bromopyridine (1.5 g, 9.49 mmol, 1.0 equiv). The
reactions were evacuated and purged with N2 for additional twice
1H), 6.97 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 5.85
(s, 1H), 5.28 (s, 1H), 3.85 (s, 3H), 2.19 (s, 3H); 13C NMR
(CDCl3): δ 166.3, 160.1, 150.3, 143.2, 115.9, 108.1, 106.4, 55.2,
20.7; IR(film): 2972, 1586, 1563, 1300, 1233, 1038, 868, 815 cm-
1; HRMS (ESI/[M+H]+) calcd. For C9H12NO: 150.0913. Found:
150.0912.
o
and was heated at 90 C overnight. After cooling down to rt, the
reaction mixture was filtered through celite and washed with
ethyl acetate. The solvent was evaporated under reduced pressure
and the residue was loaded into combi flush for purification by
hexane/EtOAC to afford the product as yellowish oil (712 mg,
47%). The analytical data was consistent with the reported
literature.13
4.2.2.2 1-methyl-4-(prop-1-en-2-yl)-1H-pyrazole (1i): Colorless
oil (543 mg, 90% yield). 1H NMR (CDCl3): δ 7.56 (d, J = 2.8 Hz,
1H), 7.34 (d, J = 2.8 Hz, 1H), 5.17 (s, 1H), 4.82 (s, 1H), 3.85 (s,
3H), 2.00 (s, 3H); 13C NMR (CDCl3): δ 136.6, 135.0, 126.9,
124.3, 108.7, 39.0, 21.9; IR(film): 2975, 2941, 1635, 1451, 1377,
1240, 1147, 984, 874, 850, 716 cm-1; HRMS (ESI/[M+H]+)
calcd. For C7H11N2: 123.0917. Found: 123.0915.
4.3 General Procedure for the Synthesis of gem-Dialkylbenzyl
Heterocycles
To a one draw vial with olefin (1.0 equiv), arenes (5.0 equiv)
in dichloroethane (1.0 mL, c = 0.42 M) was added triflic acid
(315 mg, 2.1 mmol, 5.0 equiv). The mixture was then heated to
4.2.2.3
1-methyl-4-(prop-1-en-2-yl)-1H-1,2,3-triazole
(1j):
1
Colorless oil (390 mg, 94% yield). H NMR (CDCl3): δ 7.48 (s,
1H), 5.70 (d, J = 0.7 Hz, 1H), 5.10 (t, J = 1.6 Hz, 1H), 4.09 (s,
3H), 2.14 (d, J = 1.1 Hz, 3H); 13C NMR (CDCl3): δ 149.1, 133.7,
120.7, 112.5, 36.7, 20.8; IR(film): 3132, 2919, 1641, 1454, 1221,
1056, 1037, 893, 809, 717 cm-1; HRMS (ESI/[M+H]+) calcd. For
C6H10N3: 124.0869. Found: 124.0869.
o
100 C for 20h. After cooling down to rt, the reaction mixture
o
was quenched with 4N NaOH solution at 0 C. The mixture was
extracted by ether for four times. The organic layers were
combined and then evaporated by flushing with N2. The residue
was then loaded into combi flush for purification by
heptane/EtOAc to generate the product as an oil.
4.2.2.4
1-methyl-4-(prop-1-en-2-yl)-1H-imidazole
(1k):
4.3.1 3-(2-phenylpropan-2-yl)pyridine (3): Colorless oil (77.8
mg, 94% yield). H NMR (CDCl3): δ 8.47 (d, J = 2.5 Hz, 1H),
1
1
Colorless oil (136 mg, 22% yield). H NMR (CDCl3): δ 7.36 (s,
1H), 6.82 (s, 1H), 5.64 (s, 1H), 4.89 (s, 1H), 3.64 (s, 3H), 2.02 (s,
3H); 13C NMR (CDCl3): δ 143.6, 137.8, 136.2, 116.5, 109.4,
33.4, 20.4; IR(film): 2943, 1635, 1493, 1232, 1130, 977, 884,
828, 618 cm-1; HRMS (ESI/[M+H]+) calcd. For C7H11N2:
123.0917. Found: 123.0918.
8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.41 (ddd, J = 8.0, 2.5, 1.6 Hz,
1H), 7.17-7.23 (m, 2H), 7.07-7.16 (m, 4H), 1.63 (s, 6H); 13C
NMR (CDCl3) δ 149.4, 148.6, 147.2, 145.9, 134.6, 128.4, 126.8,
126.2, 123.0, 41.9, 30.5; IR(film): 2969, 1476, 1413, 1023, 763,
698 cm-1; HRMS (ESI/[M+H]+) calcd. For C14H16N: 198.1277.
Found: 198.1273.

5
4.3.2 4-(2-phenylpropan-2-yl)pyridine (4): Colorless oil (70.4
mg, 85% yield). 1H NMR (CDCl3): δ 8.49-8.52 (m, 2H), 7.28-
7.35 (m, 2H), 7.21-7.26 (m, 3H), 7.14-7.17 (m, 2H), 1.70 (s, 6H);
13C NMR (CDCl3) δ 159.7, 149.8, 148.8, 128.4, 126.8, 126.3,
122.2, 43.0, 30.1; IR(film): 2971, 1595, 1409, 1071, 822, 764,
732, 698, 579 cm-1; HRMS (ESI/[M+H]+) calcd. For C14H16N:
198.1277. Found: 198.1271.
4.3.8 3-(2-(3,5-dimethylphenyl)propan-2-yl)pyridine (10):
1
ACCEPTED MANUSCRIPT
Colorless oil (68.3 mg, 72% yield). H NMR (CDCl3): δ 8.55 (d,
J = 2.4 Hz, 1H), 8.43 (dd, J = 4.8, 1.6 Hz, 1H), 7.50 (ddd, J =
8.0, 2.4, 1.6 Hz, 1H), 7.18 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 6.85 (s,
1H), 6.83 (s, 2H), 2.27 (s, 6H), 1.69 (s, 6H); 13C NMR (CDCl3) δ
149.3, 148.6, 147.1, 146.1, 137.7, 134.5, 127.8, 124.7, 123.0,
41.6, 30.6, 21.6; IR(film): 1404, 914, 843, 733, 703 cm-1; HRMS
(ESI/[M+Na]+) calcd. For C16H19NNa: 248.141, found 248.1421.
4.3.3 2-(2-phenylpropan-2-yl)pyridine (5): Colorless oil (74.6
1
mg, 90% yield). H NMR (CDCl3): δ 8.61 (dd, J = 5.1, 2.2 Hz,
4.3.9
3-(2-(4-methoxyphenyl)propan-2-yl)pyridine
(11):
1H), 7.56 (td, J = 7.9, 1.9 Hz, 1H), 7.27-7.34 (m, 4H), 7.19-7.24
(m, 1H), 7.08-7.13 (m, 2H), 1.79 (s, 6H); 13C NMR (CDCl3) δ
168.8, 149.7, 148.6, 136.1, 128.3, 126.8, 125.9, 121.8, 120.9,
45.7, 29.7; IR(film): 2970, 1585, 1427, 992, 787, 747, 698, 573
cm-1; HRMS (ESI/[M+H]+) calcd. For C14H16N: 198.1277.
Found: 198.1279.
Colorless oil (68.9 mg, 72% yield). 1H NMR indicated the
regiomeric ratio was 1.2:1 favored the para-isomer. 1H NMR
(CDCl3): δ 8.54 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H),
8.42 (dd, J = 4.8, 1.5 Hz, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.43-7.51
(m, 3H), 7.25 (t, J = 7.7 Hz, 1H), 7.11-7.20 (m, 4H), 7.00 (t, J =
7.5 Hz, 1H), 6.77-6.85 (m, 3H), 3.79 (s, 3H), 3.36 (s, 3H), 1.69
(12H); 13C NMR (CDCl3) δ 157.9, 157.5, 148.6, 147.5, 147.1,
146.2, 146.1, 141.6, 136.9, 134.6, 133.3, 129.6, 128.2, 127.8,
126.6, 123.0, 122.8, 120.6, 113.7, 112.5, 55.4, 55.1, 41.3, 40.7,
30.7, 29.3; IR(film): 2966, 1510, 1413, 1242, 1182, 1024, 807,
753, 714 cm-1; HRMS (ESI/[M+H]+) calcd. For C15H18NO:
228.1383. Found: 228.1377.
4.3.4 2-bromo-3-(2-phenylpropan-2-yl)pyridine (6): Colorless oil
(97.6 mg, 84% yield). 1H NMR (CDCl3): δ 8.29 (dd, J = 4.6, 1.9
Hz, 1H), 7.97 (dd, J = 7.8, 1.9 Hz, 1H), 7.34 (dd, J = 7.8, 4.6 Hz,
1H), 7.27-7.31 (m, 2H), 7.19-7.24 (m, 1H), 7.11-7.16 (m, 2H),
1.81 (s, 6H); 13C NMR (CDCl3) δ 148.4, 147.6, 145.3, 144.0,
136.6, 128.4, 126.3, 125.9, 122.6, 44.0, 30.1; IR(film): 2970,
1555, 1381, 1114, 1039, 908, 727, 697 cm-1; HRMS
(ESI/[M+H]+) calcd. For C14H15BrN: 276.0382. Found:
276.0379.
4.3.10 3-(2-(3,4-dimethoxyphenyl)propan-2-yl)pyridine (12):
Colorless oil (82.1 mg, 76% yield). 1H NMR (CDCl3): δ 8.55 (d,
J = 2.4 Hz, 1H), 8.43 (dd, J = 4.7, 1.5 Hz, 1H), 7.49 (d, J = 8.0
Hz, 1H), 7.18 (dd, J = 8.1, 4.7 Hz, 1H), 6.80 (s, 2H), 6.65 (s, 1H),
3.86 (s, 3H), 3.77 (s, 3H), 1.69 (s, 6H); 13C NMR (CDCl3) δ
148.8, 148.3, 147.5, 147.1, 146.1, 142.0, 134.7, 123.1, 118.7,
110.9, 110.8, 56.01, 55.99, 41.6, 30.7; IR(film): 2966, 1588,
1509, 1463, 1411, 1253, 1153, 1024, 807, 715, 652 cm-1; HRMS
(ESI/[M+H]+) calcd. For C16H10NO2: 258.1489. Found:
258.1488.
4.3.5 4-methoxy-2-(2-phenylpropan-2-yl)pyridine (7): Colorless
1
oil (80.0 mg, 84% yield). H NMR (CDCl3): δ 8.41 (d, J = 5.6
Hz, 1H), 7.25-7.30 (m, 4H), 7.18 (td, J = 6.7, 1.9 Hz, 1H), 6.61-
6.65 (m, 2H), 3.75 (s, 3H), 1.73 (s, 6H); 13C NMR (CDCl3) δ
170.5, 166.0, 150.0, 149.5, 128.3, 126.7, 126.0, 108.2, 106.8,
55.1, 45.7, 29.6; IR(film): 2968, 1589, 1566, 1475, 1301, 1039,
698 cm-1; HRMS (ESI/[M+H]+) calcd. For C15H18NO: 228.1383.
Found: 228.1377.
4.3.11 3-(2-phenylbutan-2-yl)pyridine (13): Colorless oil (58.5
1
mg, 66% yield). H NMR (CDCl3): δ 8.53 (d, J = 2.5 Hz, 1H),
8.45 (dd, J = 4.7, 1.6 Hz, 1H), 7.48 (ddd, J = 8.0, 2.4, 1.6 Hz,
1H), 2.28-2.33 (m, 2H), 7.18-7.24 (m, 4H), 2.19 (q, J = 7.4 Hz,
2H), 1.67 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ
149.2, 148.3, 147.1, 145.0, 135.2, 128.3, 127.5, 126.1, 123.0,
45.5, 33.9, 26.8, 9.2; IR(film): 2969, 1476, 1413, 1022, 760, 697
cm-1; HRMS (ESI/[M+H]+) calcd. For C15H18N: 212.1434.
Found: 212.1427.
4.3.6 3-(2-(p-tolyl)propan-2-yl)pyridine (8): Colorless oil (85.0
mg, 96% yield). H NMR indicated the regiomeric ratio was 8:1
1
favored the para-isomer. Partial separation was achieved by
using DCM/EtOAc as eluent. 1H NMR (CDCl3): δ 8.55 (d, J =
2.4 Hz, 1H), 8.43 (dd, J = 4.7, 1.6 Hz, 1H), 7.49 (ddd, J = 8.0,
2.5, 1.6 Hz, 1H), 7.17 (ddd, J = 8.1, 4.7, 0.8 Hz, 1H), 7.10 (s,
4H), 2.32 (s, 3H), 1.70 (s, 6H); 13C NMR (CDCl3) δ 148.6, 147.2,
146.5, 146.1, 135.7, 134.6, 129.1, 126.7, 123.0, 41.6, 30.6, 21.0;
IR(film): 2963, 1510, 1466, 1243, 1029, 753, 636 cm-1; HRMS
(ESI/[M+H]+) calcd. For C15H18N: 212.1434. Found: 212.1428.
4.3.12 3-(1-phenylcyclohexyl)pyridine (14): White powder (69.8
mg, 70 % yield), (mp: 148-150 oC)1H NMR (CDCl3): δ 8.56 (d, J
= 2.2 Hz, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.59 (dt, J = 7.9,
2.0 Hz, 1H), 7.32-7.38 (m, 2H), 7.21-7.30 (m, 4H), 2.60-2.71 (m,
2H), 2.02-2.14 (m, 4H), 1.62-1.75 (m, 4H); 13C NMR (CDCl3) δ
149.0, 147.6, 147.2, 142.5, 134.3, 128.5, 126.9, 126.2, 123.5,
44.0, 41.7, 34.43, 34.36; IR(film): 2924, 2851, 1423, 1265, 735,
700 cm-1; HRMS (ESI/[M+H]+) calcd. For C17H20N: 238.1590.
Found: 238.1592.
4.3.7 3-(2-(4-chlorophenyl)propan-2-yl)pyridine (9): Colorless
1
oil (90.2 mg, 93% yield). H NMR indicated the regiomeric ratio
was 5:1 favored the para-isomer. Partial separation was achieved
by reverse phase chromatography with CH3CN/water as eluent.
1H NMR (CDCl3): δ 8.54 (s, 1H), 8.44 (d, J = 4.7 Hz, 1H), 7.48
(dt, J = 8.1, 1.7 Hz, 1H), 7.22-7.27 (m, 2H), 7.19 (dd, J = 8.0, 4.7
Hz, 1H), 7.11-7.16 (m, 2H), 1.68 (s, 6H); 13C NMR (CDCl3) δ
147.7, 147.6, 146.6, 146.0, 135.5, 132.2, 128.6, 128.3, 123.5,
41.8, 30.5; IR(film): 2969, 2926, 1490, 1414, 1096, 1012, 828,
714 cm-1; HRMS (ESI/[M+H]+) calcd. For C14H15ClN: 232.0888.
Found: 232.0893.
4.3.13 3-(2-phenylpropan-2-yl)quinolone (15): Colorless oil
1
(100.4 mg, 97% yield). H NMR (CDCl3): δ 8.72 (d, J = 2.3 Hz,
1H), 8.07-8.11 (m, 2H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.70 (ddd,
J = 8.5, 6.9, 1.5 Hz, 1H), 7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H),
7.21-7.35 (m, 5H), 1.84 (s, 6H); 13C NMR (CDCl3) δ 151.7,
149.0, 146.4, 143.2, 131.7, 129.1, 128.9, 128.4, 127.82, 127.79,

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Tetrahedron
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4. Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735-1766.
126.8, 126.7, 126.2, 42.0, 30.5; IR(film): 2968, 1493, 1370,
1236, 1084, 905, 750, 698, 557 cm-1; HRMS (ESI/[M+H]+)
calcd. For C18H18N: 248.1434. Found: 248.1429.
5. For some selected recent examples, see: (a) Sha, S.; Zhang, J.; Carroll, P.
J.; Walsh, P. J. J. Am. Chem. Soc. 2013, 135, 1760217609. (b) Sun H.; Li,
B.; Hua, R.; Yin, Y. Eur. J. Org. Chem. 2006, 4231-4236. (c) Hu, X.;
Martin, D.; Melaimi, M.; Bertrand, G. J. Am. Chem. Soc. 2014, 136,
13594-13597. (d) Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M.
Org. Lett. 2006, 8, 19-22. (e) Rueping, M.; Nachtsheim, B. J.; Scheidt, T.
Org. Lett. 2006, 8, 3717-3719. (f) Beaud, R.; Guillot, R.; Kouklovsky,
C.; Vincent, G. Angew. Chem. Int. Ed. 2012, 51, 12546-12550. (g)
Mohan, D. C.; Patil, R. D.; Adimurthy, S. Eur. J. Org. Chem. 2012,
3520-3525. (h) Niggemann, M.; Bisek, N. Chem. Eur. J. 2010, 16,
11246-11249. (i) Sun, G.; Sun, H.; Wang, Z.; Zhou, M. Synlett. 2008, 7,
1096-1100. (j) Chu, C.; Huang, W.; Liu, J.; Yao, C. Tetrahedron Lett.
2007, 48, 6881-6884. For reviews, see: (k) Boorman, T. C.; Larrosa, I.
Chem. Soc. Rev. 2011, 40, 1910-1925. (l) Andreatta, J. R.; Mckeown, B.
A.; Gunnoe, T. B. J. Organomet. Chem. 2011, 696, 305-315. (m) de
Mendoza, P.; Echavarren, A. M. Pure. Appl. Chem. 2010, 82, 801-820.
6. (a) Zhang, Y.; Sheets, M. R., Raja, E. K.; Boblak, K. N.; Klumpp, D. A.
J. Am. Chem. Soc. 2011, 133, 8467-8469. (b) Klumpp, D. A.; Garza, M.;
Sanchez, G. V.; Lau, S.; Leon, S. J. Org. Chem. 2000, 65, 8997-9000. (c)
Zhang, Y.; Briski, J.; Zhang, Y.; Rendy, R.; Klumpp, D. A. Org. Lett.
2005, 7, 2505-2508. (d) Boblak, K. N.; Klumpp, D. A. J. Org. Chem.
2014, 79, 5852-5858. (e) Zhang, Y.; McElrea, A.; Sanchez, G. V. Jr.; Do,
D.; Gomez, A.; Aguirre, S. L.; Rendy, R.; Klumpp, D. A. J. Org. Chem.
2003, 68, 5119-5122.
4.3.14 1-methyl-4-(2-phenylpropan-2-yl)-1H-pyrazole (16):
Colorless oil (50.5 mg, 60 % yield). H NMR (CDCl3): δ 7.25-
1
7.34 (m, 5H), 7.15-7.20 (m, 1H), 7.07 (s, 1H), 3.86 (s, 3H), 1.64
(s, 6H); 13C NMR (CDCl3) δ 150.2, 137.4, 132.7, 128.2, 127.8,
126.3, 125.9, 39.0, 37.1, 31.4; IR(film): 2966, 1442, 1203, 986,
761, 699, 681 cm-1; HRMS (ESI/[M+H]+) calcd. For C13H17N2:
201.1386. Found: 201.1386.
4.3.15 1-methyl-4-(2-phenylpropan-2-yl)-1H-1,2,3-triazole (17):
Colorless oil (76.8 mg, 91 % yield). 1H NMR (CDCl3): δ 7.34 (d,
J = 7.3 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H),
7.10 (s, 1H), 4.02 (s, 3H), 1.76 (s, 6H); 13C NMR (CDCl3) δ
157.3, 148.7, 128.3, 126.3, 126.2, 121.4, 38.3, 36.6, 29.9;
IR(film): 2969, 1444, 1196, 763, 698 cm-1; HRMS (ESI/[M+H]+)
calcd. For C12H16N3: 202.1339. Found: 202.1345.
7. For some selected examples, see: (a) Puthiyapurayil, P.; Poojary, B.;
Kumar, S.; Hunnur, R. J. Heterocyclic Chem. 2011, 48, 998-1005. (b)
Hirai, K.; Watanabe, B.; Kobayashi, O.; Arakura, N.; Kawauchi, S.
P2010-180194A(JP).
8. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
9. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
10. Nigishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233-257.
11. Barluenga, J.; Valdes, C. Angew. Chem. Int. Ed. 2011, 50, 7486-7500.
12. Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem.
2004, 1075-1082.
4.3.16 1-methyl-4-(2-phenylpropan-2-yl)-1H-imidazole (18):
Colorless oil (57.8 mg, 69 % yield). H NMR (CDCl3): δ 7.34-
1
7.39 (m, 3H), 7.24-.28 (m, 2H), 7.14-7.18 (m, 1H), 6.51 (d, J =
1.4 Hz, 1H), 3.60 (s, 3H), 1.69 (s, 6H); 13C NMR (CDCl3) δ
151.9, 149.6, 137.2, 128.0, 126.4, 125.7, 115.7, 39.4, 33.3 29.6;
IR(film): 2966, 1499, 1225, 1200, 970, 762, 697, 623 cm-1;
HRMS (ESI/[M+H]+) calcd. For C13H17N2: 201.1386. Found:
201.1383.
13. Ojha, D. P.; Prabhu, K. R. J. Org. Chem. 2012, 77, 11027-11033.
Supplementary Material
1
Supplementary data (Supplementary data comprising H and
Acknowledgments
13C NMR for all new compounds was given and it can be found
in the online version) related to this article can be found.
We thank Dr. Vincent Mascitti for reviewing this manuscript and
Justin Stroh for high resolution mass spectrometry determination.
All colleagues acknowledged are affliated with Pfizer, Inc.,
Groton, CT USA.
References and notes
1. For some selected reviews, see: (a) Vitaku, E.; Smith, D. T.; Njardarson,
J. T. J. Med. Chem. 2014, 57, 10257-10274. (b) Taylor, R. D.; Maccoss,
M.; Lawson, A. D. J. Med. Chem. 2014, 57, 5845-5859. (c) Li, J. J.
Heterocyclic Chemistry in Drug Discovery Jon. Wiley 2013.
2. For some selected reviews, see: (a) Guo X.; Gu, D.; Wu, Z.; Zhang, W.
Chem. Rev. 2015, 115, 1622-1651. (b) Duncton, M. A. J.
MedChemComm 2011, 2, 113-118. (c) Schnuerch, M.; Dastbara-vardeh,
N.; Ghobrial, M.; Mrozek, B.; Mihovilovic, M. D. Curr. Org. Chem.
2011, 15, 2694-2730. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev.
2007, 36, 1173-1193. (e) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2008, 41, 1013-1025.
3. (a) Lemurell, M.; Ulander, J.; Winiwarter, S.; Dahlen, A.; Da-vidsson,
O.; Emtenas, H.; Broddefalk, J.; Swanson, M.; Houdal, D.; Plowright, A.
T.; Pettersen, A.; Ryden-Landergren, M.; Barlind, J.; Llinas, A.; Herslof,
M.; Drmota, T.; Sigfridsson, K.; Moses, S.; Whatling, C. J. Med. Chem.
2015, 58, 897-911. (b) Cee, V. J.; Frohn, M.; Lanman, B. A.; Golden, J.;
Muller, K.; Neira, S.; Pickrell, A.; Arnett, H.; Buys, J.; Gore, A.; Fiorino,
M.; Horner, M.; Itano, A.; Lee, M. R.; McElvain, M.; Middleton, S.;
Schrag, M.; Rivenzon-Segal, D.; Vargas, H. M.; Xu, H.; Xu, Y.; Zhang,
X.; Siu, J.; Wong, M.; Burli, R. W. ACS Med. Chem. Lett. 2011, 2, 107-
112. (c) Huang, A.; Moretto, A.; Janz, K.; Lowe, M.; Bedard, P. W.;
Tam, S.; Di, L.; Clerin, V.; Sushkova, N.; Tchernychev, B.; Tsao, D. H.
H.; Keith, J. C.; Shaw. G. D.; Schaub, R. G.; Wang, Q.; Kaila, N. J. Med.
Chem. 2010, 53, 6003-6017. (d) Collini, M. D.; Singhaus, R. R.; Hu, B.;
Jetter, J. W.; Morris, R. L.; Kaufman, D. H.; Miller, C. P.; Ullrich, J. W.;
Unwalla, R. J.; Wrobel, J. E.; Quinet, E.; Nambi, P.; Bernotas, R. C.;
Elloso, M. US-20050131014 A1, 2005.

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Supporting Information for:
Expedient Synthesis of gem-Dialkylbenzyl Heterocycles through Olefinic
Hydroarylation
Yajing Lian,* Kristein Burford, and Allyn T. Londregan
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, CT, 06340 USA
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