Reductive cross-coupling of nonaromatic, heterocyclic bromides with aryl and heteroaryl bromides

Article abstract of DOI:10.1021/jo500905m

Reductive cross-coupling allows the direct C-C bond formation between two organic halides without the need for preformation of an organometallic reagent. A method has been developed for the reductive cross-coupling of nonaromatic, heterocyclic bromides with aryl or heteroaryl bromides. The developed conditions use an air-stable Ni(II) source in the presence of a diamine ligand and a metal reductant to allow late-stage incorporation of saturated heterocyclic rings onto aryl halides in a functional-group tolerant manner.

Full text of DOI:10.1021/jo500905m

Article
pubs.acs.org/joc
Reductive Cross-Coupling of Nonaromatic, Heterocyclic Bromides
with Aryl and Heteroaryl Bromides
Gary A. Molander,*,† Kaitlin M. Traister,† and Brian T. O’Neill‡
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Reductive cross-coupling allows the direct C−C bond formation between
two organic halides without the need for preformation of an organometallic reagent. A
method has been developed for the reductive cross-coupling of nonaromatic,
heterocyclic bromides with aryl or heteroaryl bromides. The developed conditions use
an air-stable Ni(II) source in the presence of a diamine ligand and a metal reductant to
allow late-stage incorporation of saturated heterocyclic rings onto aryl halides in a
functional-group tolerant manner.
five-, and six-membered saturated heterocycles.1b Although
such methods have shown success, they have not been thus far
INTRODUCTION
■
There is a clear need in organic chemistry for versatile synthetic
methods that can couple an array of shelf-stable, nonaromatic
heterocycles in a high throughput fashion with certain
adapted to parallel medicinal chemistry strategies.
A second approach to the desired sp3−sp2 cross-coupling
involves the formation of an alkylmetallic reagent that can be
templates from medicinal chemistry programs. Because of the
coupled with an aryl halide (Scheme 2, route 2). This pathway
dramatic advances in sp2−sp2 couplings over the past decade,
allows addition of the saturated heterocyclic structures directly
onto larger structures containing an aryl halide. However,
drug target molecules have shown increasing trends toward flat,
planar structures.1 Incorporation of saturated, heteroatom-
existing methods pose additional limitations. Many of the
containing ring systems onto complex structures is desirable, as
alkylmetallic materials are not stable and must be formed either
it allows a larger amount of three-dimensional space to be
immediately prior to or during the reaction.6 One valuable
occupied in comparison to planar aromatic heterocycles,
method makes use of air-stable alkylstannanes to achieve similar
potentially permitting greater selectivity toward a druggable
transformations,7 but the necessity of a large protecting group
target while maintaining acceptable physical properties for good
on tin makes this method less than ideal for large scale
absorption and selectivity. Although methods exist to prepare
synthesis.
saturated heteroaromatic structures, many are multistep
processes that require cyclization2 or hydrogenation3 reactions
Our initial efforts toward developing a method that would
allow direct C−C bond formation between a nonaromatic
heterocycle and an aryl halide focused on creating an atom-
economical, air-stable, alkylmetallic species capable of such a
transformation. We directed our attention toward the cross-
coupling of nonaromatic heterocyclic alkyltrifluoroborate salts
to access the target structures (Scheme 1).
A great deal of interest has recently emerged, therefore, in
the formation of sp3−sp2 bonds involving nonaromatic
heterocyclic structures. Interestingly, while sp3−sp2 coupling
methods are known, many of the existing methods are either
(Scheme 3), which were prepared through a nickel-catalyzed
ineffective or extremely low-yielding on secondary alkyl
borylation of the corresponding halides.8 High throughput
substrates containing heteroatoms, e.g., piperidines, pyrroli-
experimentation was utilized to determine conditions that
dines, azetidines, tetrahydropyrans, tetrahydrofurans, or
oxetanes.1b Several C−H arylation methods exist to access
would allow the desired transformations to take place, but thus
aryl- and heteroaryl-substituted nonaromatic heterocycles,4 but
far extensive screening of Pd-, Ni,- and Cu-catalyzed conditions
has failed to lead to a generally applicable, high-yielding
these methods are limited by their lack of applicability to the
process.
entire class of desired structures.
One current approach to this desired sp3−sp2 bond
A method for late-stage incorporation of nonaromatic
heterocycles onto an aryl ring without having to metalate
either of the partners would clearly be more efficient and
formation includes the cross-coupling of an arylmetallic species
(M = Mg, Si, Zn, B) with a nonaromatic, heterocyclic halide
(Scheme 2, route 1).5 The coupling of arylboronic acids with
versatile (Scheme 2, route 3). Therefore, direct coupling of a
nonaromatic heterocycle with an aryl halide under conditions
nonaromatic heterocycles can also be achieved using coupling
partners other than the corresponding halides. Recently, a
cross-coupling of saturated heterocyclic sulfonylhydrazones
with boronic acids has allowed functionalization of four-,
Received: April 23, 2014
© XXXX American Chemical Society
A
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Scheme 1. Methods for Preparation of Saturated Heteroaromatic Structures
Scheme 2. Methods for sp3−sp2 Cross-Coupling Involving
has succeeded at developing methods that allow the reductive
cross-coupling of N-tosyl-4-bromopiperidine with alkyl and aryl
bromides and iodides.9e−g These methods, however, have not
been extended to other nonaromatic heterocyclic systems, and
only limited examples of heteroaryl bromide coupling partners
were demonstrated. A reductive cross-coupling pathway was
therefore pursued as a general method that would allow the
direct installation of a variety of commercially available,
saturated heterocyclic halides with aryl halides in a manner
that improves atom economy, cost, and efficiency compared to
traditional cross-coupling approaches.
Saturated Heterocyclic Structures
Scheme 3. Cross-Coupling of Nonaromatic Heterocyclic
Trifluoroborate Salts with Aryl Halides
RESULTS AND DISCUSSION
■
Optimization was initially approached using high throughput
experimentation (∼200 reactions), which allowed quick
screening of many combinations of nickel sources, ligands,
additives, and solvents on a small scale (10 μmol). The
reactions of 1-Boc-4-bromopiperidine with 4-chloro-, 4-bromo-,
and 4-iodoanisole were screened (eq 1), and the bromide
coupling partner proved preferable for the desired trans-
formation.
that possessed general functional group tolerance was sought.
Inspired by the extensive work that has been carried out in the
field of reductive cross-coupling within the past decade,9 we
considered a reductive pathway for the cross-coupling of aryl
halides with nonaromatic heterocyclic halides. A number of
notable reductive cross-coupling examples have been demon-
strated by Weix et al. in the reactions of primary and secondary
alkyl bromides and iodides with aryl iodides, bromides, and
chlorides under conditions that are remarkably functional-
group tolerant.9a−d Application of a similar method was
envisioned that would allow the saturated heterocyclic alkyl
bromides to be employed directly in the cross-coupling,
without a separate metalation step (Scheme 4). Gong et al.
Initial screening was conducted to examine the nickel source
and ligands in the presence of Zn dust, pyridine, NaI, and DMF
based on conditions developed by Weix et al.9a−d In the
presence of Ni(cod)2, numerous ligands were tested,11 and
while several bipyridine and phenanthroline derivatives led to
the formation of the desired product, 1,10-phenanthroline was
determined to be the most suitable ligand for the reaction. It
was confirmed empirically that both a pyridine derivative as
well as an inorganic salt additive were necessary for the success
of the reaction. Screening of further nickel sources12 led to the
discovery that NiCl2·glyme, an air-stable Ni(II) source, could
be used to promote the cross-coupling. Various pyridine
derivatives13 were tested for activity as additives in the reaction
system (Table 1), and the use of 50 mol % of 4-ethylpyridine
Scheme 4. Reductive Coupling Approach9 Compared to
Trifluoroborate Preparation10 and Coupling
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led to a lower amounts of protodehalogenation of the alkyl
bromide (Alk-H) and elimination of biaryl homocoupling (Ar−
Ar).
N-Cbz-4-bromopiperidine reacted with 4-bromoanisole under
the developed conditions; likewise, under conditions reported
by Gong et al. for the reductive coupling of N-Ts-4-
bromopiperidine,9g the desired coupling with 1-Boc-4-bromo-
piperidine did not proceed.
With satisfactory conditions in hand for the cross-coupling of
1-Boc-4-bromopiperidine with 4-bromoanisole, the substrate
scope was explored with various aryl bromides (Table 3). The
Table 1. Optimization of Pyridine Additive in the Reaction
of 1-Boc-4-Bromopiperidine with 4-Bromoanisole
Table 3. Cross-Coupling of 1-Boc-4-Bromopiperidine with
Aryl Bromides
entry
amine
product/Alk-H/Ar−Ar
1
2
3
4
5
pyridine
1:1.14:0.09
1:1.70:0.04
1:2.76:0.04
1:0.84:0
3,5-lutidine
4-N,N-dimethylaminopyridine
4-ethylpyridine
4-benzylpyridine
1:2.20:0.04
Other polar solvents14 were explored, leading to improved
conditions using MeOH as a reaction solvent. Some of the
continued optimization results are shown in Table 2, with
Table 2. Optimization of the Reaction of 1-Boc-4-
Bromopiperidine with 4-Bromoanisole
entry
variation to conditions
product/Alk-H/Ar−Ar
1
2
3
4
5
6
7
none
1:0.10:0.12
CsI instead of NaBF4
KBF4 instead of NaBF4
3 equiv of Mn
1:0.12:0.09
1:0.10:0.13
1:0.37:0.07
reaction run under air
no product formation
1:0.29:0.06
temp = rt
M0 = Zn instead of Mn
1:0.74:0.32
product formation shown relative to the amounts of
protodehalogenated alkyl bromide (Alk-H) and biaryl homo-
coupling (Ar−Ar), which were the two major side products
observed in the reaction. The use of Mn powder instead of Zn
dust not only led to less protodehalogenated material but also
did not require activation prior to use.15 Numerous inorganic
salts16 were tested as additives in the cross-coupling, and 1
equiv of NaBF4 was found to improve conversion to the desired
product compared to the iodide additives tested. The beneficial
effect of NaBF4 on the cross-coupling was somewhat surprising,
given that one of the presumed roles of the NaI additive under
established reductive coupling conditions was alkyl iodide
formation from the corresponding alkyl bromide.9b Other
proposed mechanistic roles for the halide additives often found
necessary in reductive coupling protocols include aiding
reductive elimination from the Ni center or acting as bridging
ligands,17 neither of which would appear to apply to a
a
6.0 mmol scale, modification to general conditions: 5 mol % NiCl2·
glyme, 10 mol % phenanthroline.
reaction conditions tolerated ortho-substitution (entry 3), as
well as amide (entry 5) and ketone (entry 6) functional groups.
The scalable nature of the reaction was demonstrated by the
application of the optimized method to a 6.0 mmol reaction
(entry 1), in which the catalyst loading could be reduced to 5
mol % (from 10 mol %) without diminished yield.
The cross-coupling of 1-Boc-4-bromopiperidine was next
explored with heteroaryl bromides under the same conditions
(Table 4). Although limitations on the substrate scope were
noted, the method could be extended to 5-bromobenzofuran
(entry 1) as well as a variety of pyridyl bromides. The cross-
coupling was successfully achieved at the 2-, 3-, and 4-positions
of pyridine systems and proceeded even in the presence of
ortho-substitution (entry 3). In all cases of cross-couplings of
−
noncoordinating ligand such as BF4 .
A 2:1 ratio of 1,10-phenanthroline to NiCl2·glyme was
determined to be ideal, and the use of anhydrous and/or
degassed MeOH was unnecessary, as it did not improve the
reaction. It was noted that neither N-Ts-4-bromopiperidine nor
C
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Table 4. Cross-coupling of 1-Boc-4-Bromopiperidine with
Heteroaryl Bromides
Table 5. Cross-Coupling of 4-Bromotetrahydropyran with
Aryl Bromides
pyridine substructures, significant amounts of protodehalo-
genated alkyl bromide were observed.
The cross-coupling conditions were next applied to 4-
bromotetrahydropyran (Table 5), and although the optimized
conditions led to significant product formation, the reactions
actually proceeded to a greater extent with reduced amounts of
Ni and 1,10-phenanthroline. Lowering the catalyst loading to
2.5 mol % (from 10 mol %) and the ligand to 5 mol % (from 20
mol %) allowed the successful cross-coupling of 4-bromote-
trahydropyran with a variety of aryl bromides. Comparable
yields of couplings with 2-, 3-, and 4-bromoanisole were
achieved with both 4-bromotetrahydropyran and 1-Boc-4-
bromopiperidine, suggesting that comparable reactivity be-
tween the systems can be expected. The method was shown to
tolerate the presence of a ketone (entry 4), a trifluoromethyl
group (entry 6), as well as an aryl sulfonamide (entry 7).
With conditions in place for the cross-coupling of aryl
bromides with both 1-Boc-4-bromopiperidine and 4-bromote-
trahydropyran, we sought to expand the scope of nonaromatic
heterocyclic bromides under the developed conditions (Table
6). A variety of saturated heterocyclic bromides were
successfully cross-coupled with 4-bromoanisole, and we were
delighted to see the robustness of the process upon application
to four-, five-, and six-membered ring systems. As with the 4-
bromotetrahydropyran couplings, the oxygen-containing alkyl
bromides could be coupled with reduced catalyst loading of 2.5
mol % (compared to 10 mol % needed to cross-couple the N-
Boc substrates).
The 3-bromotetrahydrofuran system showed isomerization
to the 2-substituted product in a ratio of approximately 8:1 (2-
substituted product/3-substituted product) when coupled
under the developed conditions. However, increasing the
catalyst loading with this substrate (from 2.5 mol % to 20 mol
% Ni) allowed the desired 3-substituted product to be isolated
as the major isomer (entry 7). The observation that increased
catalyst loading leads to a lower level of isomerized product is
difficult to reconcile with the mechanism of this process, by
which isomerization presumably occurs by a β-hydride
elimination/hydrometalation process that would not appear
to be dependent on catalyst concentration.
Interestingly, the reductive cross-coupling of 3-bromotetra-
hydrofuran with 4-bromoacetophenone resulted in minimal
(<5%) isomerization under the standard conditions (eq 2).
Increasing the catalyst loading in this case did not further
reduce the observed isomerization. Furthermore, isomerization
was not observed with any other alkyl bromide under the
developed reductive coupling conditions.
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As limitations had been recognized upon extension of the
developed method to heteroaryl bromides beyond pyridyl
systems, we sought to develop a set of conditions to allow
cross-coupling of desired saturated heterocyclic bromides with
a wide array of heteroaryl bromides. The reaction of 1-Boc-4-
bromopiperidine with 3-bromoquinoline was chosen as a model
system for establishment of a new set of reaction conditions.
Various nickel sources were tested, along with numerous
amine-based ligands in the presence of various solvents and
additives. The use of NiI2 in the presence of DMA as a reaction
solvent allowed formation of the desired product. Further
improvements to reaction conditions were achieved through
the use of 4,4′-di-tert-butyl-2,2′-bipyridine as a ligand and the
use of MgCl2 as an additive, as had previously been reported by
Gong et al. for a similar reductive coupling.9g With these
changes to the previously described conditions, the cross-
coupling of 1-Boc-4-bromopiperidine with 3-bromoquinoline
was achieved in 60% yield (Table 7, entry 1). These conditions
were next applied to a variety of heteroaryl bromides, including
both free and protected indoles (Table 7, entry 2 and Table 8).
The scope was further extended to include 4-bromotetrahy-
dropyran as a coupling partner under the developed set of
conditions (Table 7, entries 7−9).
Table 6. Cross-Coupling of 4-Bromoanisole with Various
Non-Aromatic, Heterocyclic Bromides
a
The applicability of this method to other alkyl bromides of
interest was demonstrated by carrying out the cross-coupling of
N-Boc-5-bromoindole with other nonaromatic, heterocyclic
bromides of interest (Table 8). Isomerization was not observed
with any of the alkyl bromides under the conditions employed.
In conclusion, by applying modifications to existing methods
for reductive cross-coupling protocols, two methods have been
developed for the direct coupling of saturated heterocyclic
bromides to aryl and heteroaryl bromides. These methods
allow the direct installation of nonaromatic heterocyclic
structures to molecules bearing an aryl bromide under
conditions that employ air-stable components and are func-
tional group tolerant.
EXPERIMENTAL SECTION
■
General Considerations. MeOH was used as received and was
neither dried nor degassed prior to use. Mn powder (∼325 mesh) was
purchased and used directly. 4-Ethylpyridine was distilled under a
vacuum. Solids were weighed out in air and were stored on a
laboratory bench without special considerations. H and 13C NMR
1
spectra were recorded at 500 and 125.8 MHz, respectively. Melting
points (°C) were determined using a Thomas-Hoover capillary
melting point apparatus and are uncorrected. HRMS data were
obtained using a TOF mass spectrometer using ESI or CI, as specified.
Method A: Procedure for the Reductive Cross-Coupling of
Nonaromatic Heterocyclic Bromides with Aryl Bromides. An
oven-dried Biotage 10 mL microwave vial equipped with a magnetic
stirbar was charged with alkyl bromide (1.0 mmol), NiCl2·glyme (0.1
mmol, 22.0 mg), 1,10-phenanthroline (0.2 mmol, 36.0 mg), NaBF4
(0.5 mmol, 54.9 mg), and Mn powder (2.0 mmol, 109.9 mg). The vial
was sealed with a disposable Teflon septum cap and was evacuated and
purged with Ar three times. MeOH (5 mL) and 4-ethylpyridine (0.5
mmol, 54 mg) were added via syringe, followed by the aryl bromide
(1.0 mmol). In cases where the aryl bromide was a solid, it was added
to the vial along with the other solids. The reaction was stirred under
Ar with conventional heating at 60 °C for 18 h, after which the
solution was cooled and diluted with 5 mL of EtOAc. The resulting
mixture was filtered through Celite, which was rinsed with EtOAc
(∼10 mL). The solution was concentrated, and the product was
isolated by column chromatography, eluting with a gradient of EtOAc
in hexanes (0 to 20% EtOAc). Note: For tetrahydropyranyl,
tetrahydrofuranyl, and oxetanyl substrates, the amount of NiCl2·
a
General conditions: Entries 1−4: NiCl2·glyme (10 mol %),
phenanthroline (20 mol %), 4-ethylpyridine (50 mol %), NaBF4 (50
mol %), Mn (2 equiv), MeOH (0.2 M), 60 °C, 18 h; Entries 5−8:
NiCl2·glyme (2.5 mol %), phenanthroline (5 mol %), 4-ethylpyridine
(50 mol %), NaBF4 (50 mol %), Mn (2 equiv), MeOH (0.2 M), 60
°C, 18 h. 20 mol % NiCl2·glyme and 10 mol % phenanthroline was
used; product was isolated as an 8:1 mixture of isomers (3-substituted
product/2-substituted product).
b
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Table 7. Cross-Coupling of Bromoheteroaromatics with
Various Non-Aromatic, Heterocyclic Bromides
Table 8. Cross-Coupling of N-Boc-5-Bromoindole with
Various Non-Aromatic, Heterocyclic Bromides
mides. An oven-dried Biotage 10 mL microwave vial equipped with
a magnetic stirbar was charged with the alkyl bromide (1.0 mmol),
NiI2 (0.1 mmol, 31.3 mg), 4,4′-di-tert-butyl-2,2′-bipyridine (0.1 mmol,
26.8 mg), MgCl2 (1 mmol, 95.2 mg), and Mn powder (2.0 mmol,
109.9 mg). The vial was sealed with a disposable Teflon septum cap
and was evacuated and purged with Ar three times. Dimethylacetamide
(5 mL) and 4-ethylpyridine (1.0 mmol, 108 mg) were added via
syringe, followed by the heteroaryl bromide (1.1 mmol). In cases
where the aryl bromide was a solid, it was added to the vial along with
the other solids. The reaction was stirred under Ar with conventional
heating at 60 °C for 18 h, after which the solution was cooled and
diluted with 25 mL of distilled H2O. The resulting mixture was
glyme was reduced to 0.025 mmol (5.5 mg), and the amount of 1,10-
phenanthroline was reduced to 0.05 mmol (9.0 mg).
Method B: Procedure for the Reductive Cross-Coupling of
Nonaromatic Heterocyclic Bromides with Heteroaryl Bro-
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extracted (3 × 10 mL) with EtOAc, and the combined organic
portions were washed (2 × 10 mL) with H2O. The organic layer was
dried (NaSO4), after which it was filtered and concentrated. The
product was isolated by column chromatography eluting with a
gradient of EtOAc in hexanes (10−60% EtOAc).
tert-Butyl 4-(Pyridin-3-yl)piperidine-1-carboxylate (2b).1b The
title compound was obtained as an orange oil in 43% yield (113
mg) according to method A. Spectral data were in accordance with
those published. 1H NMR (500 MHz, CDCl3): δ 8.48−8.47 (m, 2H),
7.50−7.48 (m, 1H), 7.25−7.22 (m, 1H), 4.25 (br, 2H), 2.82−2.78 (m,
2H), 2.68−2.66 (m, 1H), 1.83−1.80 (m, 2H), 1.65−1.60 (m, 2H),
1.47 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 154.9, 148.9, 148.0,
140.9, 134.2, 123.6, 79.7, 44.2 (br), 40.3, 33.0, 28.6.
tert-Butyl 4-(4-Methoxyphenyl)piperidine-1-carboxylate (1a).6c
The title compound was obtained as a colorless oil in 65% yield
(189 mg) according to method A. Spectral data were in accordance
1
with those published. H NMR (500 MHz, CDCl3): δ 7.13−7.11 (m,
tert-Butyl 4-(2-Methylpyridin-3-yl)piperidine-1-carboxylate (2c).
The title compound was obtained as an orange oil in 24% yield (66
2H), 6.86−6.84 (m, 2H), 4.23 (br, 2H), 3.79 (s, 3H), 2.80−2.77 (m,
2H), 2.59 (tt, J = 12.2, 3.5 Hz, 1H), 1.81−1.78 (m, 2H), 1.60−1.57
(m, 2H), 1.48 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 158.2,
155.0, 138.1, 127.8, 114.0, 79.5, 55.4, 44.8 (br), 42.0, 33.6, 28.6.
tert-Butyl 4-(3-Methoxyphenyl)piperidine-1-carboxylate (1b).
The title compound was obtained as a colorless oil in 64% yield
1
mg) according to method A. H NMR (500 MHz, CDCl3): δ 8.34−
8.33 (m, 1H), 7.45−7.43 (m, 1H), 7.11−7.09 (m, 1H), 4.27 (br, 2H),
2.85−2.80 (m, 3H), 2.58 (s, 3H), 1.77−1.74 (m, 2H), 1.60−1.55 (m,
2H), 1.47 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 155.9, 154.9,
146.7, 138.8, 133.4, 121.7, 79.7, 44.4 (br), 38.2, 32.2, 28.6, 22.2; FT-IR
(neat): 2975, 1690, 1422, 1161 cm−1; HRMS (ES+) m/z calcd. for
C16H25N2O2 (M+H)+ 277.1916, found 277.1920.
1
(186 mg) according to method A. H NMR (500 MHz, CDCl3): δ
7.25−7.21 (m, 1H), 6.81−6.75 (m, 3H), 4.24 (br, 2H), 3.80 (s, 3H),
2.81−2.74 (m, 2H), 2.64−2.59 (m, 1H), 1.83−1.81 (m, 2H), 1.63−
1.61 (m, 2H), 1.48 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 159.9,
155.0, 147.7, 129.6, 119.3, 112.9, 111.5, 79.6, 55.3, 44.2 (br), 42.9,
33.3, 28.6; FT-IR (neat): 2974, 1690, 1423, 1166 cm−1; HRMS (ES+)
m/z calcd. for C17H25NO3Na (M + Na)+ 314.1732, found 314.1737.
tert-Butyl 4-(2-Methoxyphenyl)piperidine-1-carboxylate (1c).3c
The title compound was obtained as a white solid in 58% yield
(169 mg) according to method A. mp: 63−65 °C; Spectral data were
tert-Butyl 4-(5-Methylpyridin-2-yl)piperidine-1-carboxylate (2d).
The title compound was obtained as a red-orange oil in 22% yield (61
mg) according to method A. 1H NMR (500 MHz, CDCl3): δ 8.35 (s,
1H), 7.43−7.41 (m, 1H), 7.03−7.02 (m, 1H), 4.24 (br, 2H), 2.82−
2.79 (m, 3H), 2.29 (s, 3H), 1.89−1.87 (m, 2H), 1.69−1.66 (m, 2H),
1.46 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 161.6, 154.9, 149.6,
137.3, 130.9, 120.4, 79.4, 44.2, 44.1 (br), 31.9, 28.6, 18.1; FT-IR
(neat): 2973, 1690, 1422, 1167 cm−1; HRMS (ES+) m/z calcd. for
C16H25N2O2 (M+H)+ 277.1916, found 277.1915.
1
in accordance with those published. H NMR (500 MHz, CDCl3): δ
7.24−7.12 (m, 2H), 6.92−6.89 (m, 1H), 6.85−6.83 (m, 1H), 4.21 (br,
2H), 3.81 (s, 3H), 3.09−3.04 (m, 1H), 2.81−2.80 (m, 2H), 1.77−1.75
(m, 2H), 1.58−1.54 (m, 2H), 1.46 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 156.9, 155.1, 134.0, 127.2, 126.6, 120.1, 110.5, 79.4, 55.4,
45.2 (br), 35.5, 32.0, 28.7.
tert-Butyl 4-(2-Methylpyridin-4-yl)piperidine-1-carboxylate (2e).
The title compound was obtained as a yellow oil in 40% yield (111
1
mg) according to method A. H NMR (500 MHz, CDCl3): δ 8.40−
8.39 (m, 1H), 6.97 (s, 1H), 6.91−6.90 (m, 1H), 4.24 (br, 2H), 2.80−
2.76 (m, 2H), 2.61−2.58 (m, 1H), 2.55 (s, 3H), 1.81−1.78 (m, 2H),
1.62−1.57 (m, 2H), 1.47 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ
158.6, 154.8, 154.8, 149.4, 121.8, 119.4, 79.7, 44.3 (br), 42.1, 32.4,
28.6, 24.5; FT-IR (neat): 1690, 1422, 1165 cm−1; HRMS (ES+) m/z
calcd. for C16H25N2O2 (M + H)+ 277.1916, found 277.1917.
tert-Butyl 4-(4-Fluorophenyl)piperidine-1-carboxylate (1d).3c The
title compound was obtained as a colorless oil in 70% yield (195 mg)
according to method A. Spectral data were in accordance with those
published. 1H NMR (500 MHz, CDCl3): δ 7.15−7.12 (m, 2H), 6.99−
6.96 (m, 2H), 4.23 (br, 2H), 2.82−2.74 (m, 2H), 2.64−2.59 (m, 1H),
1.80−1.77 (m, 2H), 1.59−1.55 (m, 2H), 1.47 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 161.5 (d, J = 244.1 Hz), 154.9, 141.6 (d, J =
3.7 Hz), 128.2 (d, J = 7.8 Hz), 115.3 (d, J = 21.0 Hz), 79.6, 44.1 (br),
42.1, 33.5, 28.6.
tert-Butyl 4-(5-Methoxypyridin-3-yl)piperidine-1-carboxylate (2f).
The title compound was obtained as a yellow solid in 35% yield (102
1
mg) according to method A. mp: 79−80 °C. H NMR (500 MHz,
CDCl3): δ 8.19 (m, 2H), 6.99 (s, 1H), 4.25 (br, 2H), 3.84 (s, 3H),
2.85−2.74 (m, 2H), 2.69−2.65 (m, 1H), 1.83−1.80 (m, 2H), 1.62−
1.60 (m, 2H), 1.47 (s, 9H); 13C NMR (125.8 MHz, CD3OD): δ 156.6,
155.2, 142.9, 139.9, 134.6, 119.8, 79.8, 55.0, 44.0 (br), 39.9, 32.6, 27.5;
FT-IR (neat): 1681, 1421, 1166 cm−1; HRMS (ES+) m/z calcd. for
C16H25N2O3 (M + H)+ 293.1865, found 293.1866.
tert-Butyl 4-(4-Acetamidophenyl)piperidine-1-carboxylate (1e).
The title compound was obtained as a white solid in 53% yield
1
(169 mg) according to method A. mp: 165−168 °C. H NMR (500
MHz, CDCl3): δ 7.57 (br, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.11−7.10
(m, 2H), 4.20 (br, 2H), 2.80−2.72 (m, 2H), 2.60−2.55 (m, 1H), 2.12
(s, 3H), 1.77−1.74 (m, 2H), 1.58−1.53 (m, 2H), 1.45 (s, 9H); 13C
NMR (125.8 MHz, CDCl3): δ 168.9, 155.1, 141.8, 136.5, 127.3, 120.4,
79.7, 44.4 (br), 42.2, 33.4, 28.6, 24.5; FT-IR (neat): 3312, 1700, 1661,
1427, 1170 cm−1; HRMS (ES+) m/z calcd. for C18H26N2O3Na (M +
Na)+ 341.1841, found 341.1851.
4-(4-Methoxyphenyl)tetrahydro-2H-pyran (3a).1b The title com-
pound was obtained as a colorless oil in 62% yield (119 mg) according
to method A. Spectral data were in accordance with those published.
1H NMR (500 MHz, CDCl3): δ 7.14 (d, J = 8.7 Hz, 2H), 6.86 (d, J =
8.2 Hz, 2H), 4.06 (dd, J = 10.6, 3.3 Hz, 2H), 3.79 (s, 3H), 3.51(td, J =
11.3, 2.8 Hz, 2H), 2.73−2.66 (m, 1H), 1.82−1.72 (m, 4H); 13C NMR
(125.8 MHz, CDCl3): δ 158.2, 138.3, 127.7, 114.0, 68.6, 55.4, 40.9,
34.6.
tert-Butyl 4-(4-Acetylphenyl)piperidine-1-carboxylate (1f). The
title compound was obtained as a yellow solid in 62% yield (188 mg)
according to method A. mp: 81−82 °C. 1H NMR (500 MHz, CDCl3):
δ 7.88 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 4.24 (br, 2H),
2.79−2.72 (m, 2H), 2.69−2.67 (m, 1H), 2.56 (s, 3H), 1.80 (d, J = 12.8
Hz, 2H), 1.63−1.60 (m, 2H), 1.46 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 197.8, 154.9, 151.4, 135.7, 128.8, 127.2, 79.7, 44.3 (br),
42.9, 33.0, 28.6, 26.7; FT-IR (neat): 2980, 1678, 1425, 1173 cm−1;
HRMS (ES+) m/z calcd. for C18H25NO3Na (M + Na)+ 326.1732,
found 326.1729.
tert-Butyl 4-(Benzofuran-5-yl)piperidine-1-carboxylate (2a). The
title compound was obtained as a white solid in 58% yield (175 mg)
according to method A. mp: 104−106 °C. 1H NMR (500 MHz,
CDCl3): δ 7.60−7.59 (m, 1H), 7.44−7.42 (m, 2H), 7.14−7.13 (m,
1H), 6.72 (s, 1H), 4.26 (br, 2H), 2.82−2.76 (m, 2H), 2.75−2.71 (m,
1H), 1.86−1.84 (m, 2H), 1.68−1.65 (m, 2H), 1.50 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 155.0, 153.9, 145.4, 140.6, 127.7, 123.6, 118.9,
111.4, 106.6, 79.6, 44.5 (br), 42.9, 33.9, 28.7; FT-IR (neat): 2974,
1678, 1428, 1164 cm−1; HRMS (ES+) m/z calcd. for C18H23NO3Na
(M + Na)+ 324.1576, found 324.1588.
4-(3-Methoxyphenyl)tetrahydro-2H-pyran (3b). The title com-
pound was obtained as a colorless oil in 59% yield (113 mg) according
1
to method A. H NMR (500 MHz, CDCl3): δ 7.26−7.23 (m, 1H),
6.84−6.76 (m, 3H), 4.09−4.07 (m, 2H), 3.81 (s, 3H), 3.55−3.50 (m,
2H), 2.75−2.71 (m, 1H), 1.84−1.76 (m, 4H); 13C NMR (125.8 MHz,
CDCl3): δ 159.9, 147.7, 129.6, 119.3, 113.0, 111.4, 68.5, 55.3, 41.8,
34.0; FT-IR (neat): 2980, 1601, 1270, 1130 cm−1; HRMS (ES+) m/z
calcd. for C12H17O2 (M + H)+ 193.1229, found 193.1221.
4-(2-Methoxyphenyl)tetrahydro-2H-pyran (3c). The title com-
pound was obtained as a white solid in 58% yield (111 mg) according
1
to method A. mp: 79−80 °C. H NMR (500 MHz, CDCl3): δ 7.18−
7.17 (m, 2H), 6.94−6.93 (m, 1H), 6.86−6.85 (m, 1H), 4.05 (d, J =
11.3 Hz, 2H), 3.81 (s, 3H), 3.56 (t, J = 11.6 Hz, 2H), 3.22−3.17 (m,
1H), 1.80−1.71 (m, 4H); 13C NMR (125.8 MHz, CDCl3): δ 157.0,
134.1, 127.2, 126.7, 120.8, 110.5, 68.8, 55.4, 34.6, 32.8; FT-IR (neat):
2940, 1494, 1234 cm−1; HRMS (ES+) m/z calcd. for C12H17O2 (M +
H)+ 193.1229, found 193.1233.
G
dx.doi.org/10.1021/jo500905m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-(4-(Tetrahydro-2H-pyran-4-yl)phenyl)ethan-1-one (3d). The
3-(4-Methoxyphenyl)tetrahydrofuran (4e).1b The title compound
was obtained as a colorless oil in 41% yield (39 mg) according to
method A. Compound was isolated as a mixture of isomers
(approximately 17% 2-(4-methoxyphenyl)tetrahydrofuran4a)). Spec-
tral data were in accordance with those published for the major isomer.
1H NMR (500 MHz, CDCl3): 7.18−7.16 (m, 2H), 6.88−6.85 (m,
2H), 4.13−4.10 (m, 1H), 4.08−4.03 (m, 1H), 3.93−3.89 (m, 1H),
3.80 (s, 3H), 3.70−3.66 (m, 1H), 3.37−3.34 (m, 1H), 2.35−2.32 (m,
1H), 2.01−1.95 (m, 1H); 13C NMR (125.8 MHz, CDCl3): δ 158.4,
134.7, 128.3, 114.1, 74.9, 68.6, 55.4, 44.4, 34.9.
title compound was obtained as a white solid in 50% yield (102
1
mg) according to method A. mp: 75−76 °C. H NMR (500 MHz,
CDCl3): δ 7.91 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.10−
4.07 (m, 2H), 3.56−3.51 (m, 2H), 2.85−2.84 (m, 1H), 2.58 (s, 3H),
1.84−1.75 (m, 4H); 13C NMR (125.8 MHz, CDCl3): δ 197.9, 151.5,
135.6, 128.9, 127.1, 68.3, 41.8, 33.7, 26.7; FT-IR (neat): 2940, 1681,
1268, 1118 cm−1; HRMS (CI+) m/z calcd. for C13H16O2 (M)+
204.1150, found 204.1144.
4-(o-Tolyl)tetrahydro-2H-pyran (3e). The title compound was
obtained as a colorless oil in 43% yield (76 mg) according to method
A. 1H NMR (500 MHz, CDCl3): δ 7.24−7.17 (m, 4H), 4.14−4.11 (m,
2H), 3.61−3.58 (m, 2H), 3.07−2.99 (m, 1H), 2.40 (s, 3H), 1.93−1.82
(m, 2H), 1.75−1.68 (m, 2H); 13C NMR (125.8 MHz, CDCl3): δ
143.6, 135.0, 130.0, 126.3, 125.9, 125.4, 68.6, 37.3, 33.1, 19.2; FT-IR
(neat): 2951, 1386, 1133, 1122 cm−1; HRMS (CI+) m/z calcd. for
C12H16O (M)+ 176.1201, found 176.1209.
3-(4-Methoxyphenyl)oxetane (4f).1b The title compound was
obtained as a colorless oil in 43% yield (71 mg) according to method
1
A. Spectral data were in accordance with those published. H NMR
(500 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.2 Hz,
2H), 5.05 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.4 Hz, 2H), 4.20−4.17 (m,
1H), 3.81 (s, 3H); 13C NMR (125.8 MHz, CDCl3): δ 158.8, 133.8,
128.0, 114.3, 79.4, 55.4, 39.8.
4-(4-(Trifluoromethyl)phenyl)tetrahydro-2H-pyran (3f).1b The
title compound was obtained as a white solid in 53% yield (122
mg) according to method A. mp: 30−31 °C. Spectral data were in
accordance with those published. 1H NMR (500 MHz, CDCl3): δ 7.57
(d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 4.11−4.08 (m, 2H),
3.57−3.51 (m, 2H), 2.83−2.81 (m, 1H), 1.84−1.76 (m, 4H); 13C
NMR (125.8 MHz, CDCl3): δ 149.9, 128.8 (q, J = 32 Hz), 127.3,
125.6 (q, J = 4 Hz), 125.5 (q, J = 272 Hz), 68.3, 41.6, 33.8.
4-(Tetrahydro-2H-pyran-4-yl)benzenesulfonamide (3g). The title
compound was obtained as a white solid in 41% yield (99 mg)
according to method A. mp: 186−188 °C. 1H NMR (500 MHz,
acetone-d6): δ 7.82 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.51
(s, 2H), 3.97 (d, J = 11.1 Hz, 2H), 3.50−3.45 (m, 2H), 2.91−2.88 (m,
1H), 1.74−1.72 (m, 4H); 13C NMR (125.8 MHz, acetone-d6): δ
150.7, 142.3, 127.4, 126.4, 67.7, 41.4, 33.7; FT-IR (neat): 3306, 1339,
1156 cm−1; HRMS (ES+) m/z calcd. for C11H14NO3S (M − H)−
240.0694, found 240.0702.
1-(4-(Tetrahydrofuran-3-yl)phenyl)ethan-1-one (4g). The title
compound was obtained as a colorless oil in 54% yield (102 mg)
according to method A. Compound was isolated as a mixture of
isomers (approximately 3.5% 1-(4-(tetrahydrofuran-2-yl)phenyl)-
1
ethan-1-one). H NMR (500 MHz, CDCl3): δ 8.05 (d, J = 7.9 Hz,
2H), 7.34 (d, J = 8.0 Hz, 2H), 4.15−4.06 (m, 2H), 3.94−3.90 (m,
1H), 3.77−3.74 (m, 1H), 3.49−3.44 (m, 1H), 2.58 (s, 3H), 2.43−2.38
(m, 1H), 2.04−1.99 (m, 1H); 13C NMR (125.8 MHz, CDCl3): δ
197.7, 148.9, 135.8, 128.9, 127.6, 74.5, 68.6, 45.1, 34.7, 26.7; FT-IR
(neat): 2925, 1681, 1606, 1269 cm−1; HRMS (ES+) m/z calcd. for
C12H15O2 (M + H)+ 191.1072, found 191.1066.
tert-Butyl 4-(Quinolin-3-yl)piperidine-1-carboxylate (5a). The
title compound was obtained as a yellow oil in 60% yield (187 mg)
1
according to method B. H NMR (500 MHz, CDCl3): δ 8.81−8.80
(m, 1H), 8.08−8.06 (m, 1H), 7.91−7.90 (m, 1H), 7.77−7.76 (m, 1H),
7.68−7.64 (m, 1H), 7.53−7.50 (m, 1H), 4.30 (br, 2H), 2.89−2.84 (m,
3H), 1.94−1.92 (m, 2H), 1.74−1.72 (m, 2H), 1.48 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 154.9, 151.0, 147.2, 138.3, 132.6, 129.2, 129.0,
128.2, 127.6, 126.8, 79.7, 44.5 (br), 40.3, 33.0, 28.6; FT-IR (neat):
1687, 1424, 1233, 1167 cm−1; HRMS (ES+) m/z calcd. for
C19H25N2O2 (M + H)+ 313.1916, found 313.1914.
tert-Butyl 3-(4-Methoxyphenyl)piperidine-1-carboxylate (4a).1b
The title compound was obtained as a colorless oil in 50% yield
(146 mg) according to method A. Spectral data were in accordance
with those published. 1H NMR (500 MHz, CDCl3): δ 7.14 (d, J = 8.7
Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.15 (br, 2H), 3.77 (s, 3H), 2.71−
2.63 (m, 3H), 1.99−1.97 (m, 1H), 1.81−1.72 (m, 1H), 1.59−1.57 (m,
2H), 1.46 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 158.4, 155.0,
135.8, 128.1, 114.0, 79.5, 55.3, 51.4 (br), 43.9 (br), 41.9, 32.1, 28.6,
25.7.
tert-Butyl 4-(1H-Indol-5-yl)piperidine-1-carboxylate (5b). The
title compound was obtained as a yellow oil in 27% yield (81 mg)
1
according to method B. H NMR (500 MHz, CDCl3): δ 8.23 (br,
1H), 7.46 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.19−7.18 (m, 1H), 7.05
(dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.51−6.50 (m, 1H), 4.26 (br, 2H), 2.84−
2.82 (m, 2H), 2.76−2.70 (m, 1H), 1.88−1.86 (m, 2H), 1.73−1.68 (m,
2H), 1.50 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 155.2, 137.4,
134.9, 128.2, 124.8, 121.5, 118.2, 111.2, 102.4, 79.6, 44.8 (br), 43.0,
34.1, 28.7; FT-IR (neat): 1669, 1428, 1166 cm−1; HRMS (ES+) m/z
calcd. for C18H24N2O2Na (M + Na)+ 323.1735, found 323.1738.
tert-Butyl 4-(Isoquinolin-4-yl)piperidine-1-carboxylate (5c).1b The
title compound was obtained as a yellow oil in 38% yield (204 mg)
according to method B. Spectral data were in accordance with those
tert-Butyl 3-(4-Methoxyphenyl)pyrrolidine-1-carboxylate (4b).1b
The title compound was obtained as a colorless oil in 40% yield (111
mg) according to method A. Spectral data were in accordance with
1
those published. H NMR (500 MHz, CDCl3): δ 7.15 (d, J = 8.6 Hz,
2H), 6.86 (d, J = 8.6 Hz, 2H), 3.82−3.73 (m, 4H), 3.65−3.52 (m,
1H), 3.40−3.19 (m, 3H), 2.22−2.21 (m, 1H), 1.98−1.92 (m, 1H),
1.47 (s, 9H) ; 13C NMR (125.8 MHz, CDCl3): δ 158.5, 154.7, 133.6,
128.1, 114.1, 79.3, 55.4, 52.9 and 52.1, 46.1 and 45.8, 43.7 and 42.8,
33.7 and 32.8, 28.7
1
published. H NMR (500 MHz, CDCl3): δ 9.13 (s, 1H), 8.41−8.40
(m, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.75−7.71
(m, 1H), 7.61−7.58 (m, 1H), 4.33 (br, 2H), 3.40−3.35 (m, 1H),
2.94−2.92 (m, 2H), 2.00−1.97 (m, 2H), 1.85−1.80 (m, 2H), 1.49 (s,
9H); 13C NMR (125.8 MHz, CDCl3): δ 155.0, 151.6, 140.2, 134.2,
134.0, 130.5, 128.8, 128.5, 126.9, 122.1, 79.8, 44.8 (br), 36.5, 32.6,
28.6.
tert-Butyl 3-(4-Methoxyphenyl)azetidine-1-carboxylate (4c).1b
The title compound was obtained as a colorless oil in 48% yield
(126 mg) according to method A. Spectral data were in accordance
with those published. 1H NMR (500 MHz, CDCl3): δ 7.23 (d, J = 6.9
Hz, 2H), 6.88 (d, J = 7.2 Hz, 2H), 4.31−4.28 (m, 2H), 3.93−3.92 (m,
2H), 3.80 (s, 3H), 3.69−3.68 (m, 1H), 1.46 (s, 9H); 13C NMR (125.8
MHz, CDCl3): δ 158.7, 156.6, 134.5, 127.9, 114.2, 79.6, 57.0 (br),
55.4, 33.0, 28.6.
tert-Butyl 4-(Quinoxalin-6-yl)piperidine-1-carboxylate (5d). The
title compound was obtained as a yellow solid in 29% yield (91 mg)
according to method B. mp: 108−110 °C. 1H NMR (500 MHz,
CDCl3): δ 8.82−8.81 (m, 2H), 8.07−8.05 (m, 1H), 7.91 (s, 1H),
7.68−7.66 (m, 1H), 4.31 (br, 2H), 2.93−2.88 (m, 3H), 1.97−1.94 (m,
2H), 1.79−1.73 (m, 2H), 1.50 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 154.9, 148.2, 145.2, 144.6, 143.3, 142.1, 130.2, 129.6, 126.4,
79.7, 44.7 (br), 42.9, 33.0, 28.6; FT-IR (neat): 1689, 1423, 1164 cm−1;
HRMS (ES+) m/z calcd. for C18H23N3O2Na (M + Na)+ 336.1688,
found 336.1686.
3-(4-Methoxyphenyl)tetrahydro-2H-pyran (4d). The title com-
pound was obtained as a light yellow solid in 43% yield (83 mg)
according to method A. mp: 38−39 °C. 1H NMR (500 MHz, CDCl3):
δ 7.14 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 4.00−3.94 (m,
2H), 3.79 (s, 3H), 3.46−3.42 (m, 1H), 3.36−3.31 (m, 1H), 2.81−2.80
(m, 1H), 2.03−2.01 (m, 1H), 1.79−1.69 (m, 3H); 13C NMR (125.8
MHz, CDCl3): δ 158.4, 134.9, 128.4, 114.0, 74.2, 68.3, 55.4, 42.3, 30.7,
26.4; FT-IR (neat): 2932, 1513, 1247, 1084 cm−1; HRMS (ES+) m/z
calcd. for C12H16O2 (M)+ 192.1150, found 192.1147.
tert-Butyl 4-(3-(1H-Pyrazol-5-yl)phenyl)piperidine-1-carboxylate
(5e). The title compound was obtained as a colorless oil in 65%
H
dx.doi.org/10.1021/jo500905m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
yield (214 mg) according to method B. 1H NMR (500 MHz, CDCl3):
δ 11.17 (br, 1H), 7.61−7.58 (m, 3H), 7.35−7.32 (m, 1H), 7.17−7.13
(m, 1H), 6.78−6.61 (m, 1H), 4.25 (br, 2H), 2.83−2.77 (m, 2H),
2.68−2.64 (m, 1H), 1.83−1.81 (m, 2H), 1.65−1.63 (m, 2H), 1.49 (s,
9H); 13C NMR (125.8 MHz, CDCl3): δ 155.1, 148.9, 146.4, 133.4,
132.5, 129.0, 126.4, 124.5, 124.1, 102.6, 79.7, 44.4 (br), 42.8, 33.2,
28.7; FT-IR (neat): 2930, 1687, 1427, 1169 cm−1; HRMS (ES+) m/z
calcd. for C19H26N3O2 (M + H)+ 328.2025, found 328.2016.
8.07−8.05 (m, 1H), 7.58−7.57 (m, 1H), 7.41 (s, 1H), 7.19−7.17 (m,
1H), 6.53−6.52 (m, 1H), 4.03−4.01 (m, 2H), 3.50−3.41 (m, 2H),
2.97−2.93 (m, 1H), 2.10−2.09 (m, 1H), 1.82−1.79 (m, 3H), 1.67 (s,
9H); 13C NMR (125.8 MHz, CDCl3): δ 149.9, 137.2, 134.2, 131.0,
126.3, 124.0, 119.4, 115.2, 107.3, 83.7, 74.4, 68.4, 43.0, 31.0, 28.3, 26.5;
FT-IR (neat): 2933, 1732, 1368, 1084 cm−1; HRMS (ES+) m/z calcd.
for C18H23NO3Na (M + Na)+ 324.1576, found 324.1582.
tert-Butyl 5-(Tetrahydrofuran-3-yl)-1H-indole-1-carboxylate (6c).
tert-Butyl 4-(4-(1,3,4-Oxadiazol-2-yl)phenyl)piperidine-1-carbox-
The title compound was obtained as a colorless oil in 44% yield (126
1
ylate (5f). The title compound was obtained as a white solid in 32%
mg) according to method B. H NMR (500 MHz, CDCl3): δ 8.08−
1
yield (105 mg) according to method B. mp: 146−147 °C. H NMR
8.07 (m, 1H), 7.59−7.58 (m, 1H), 7.44 (s, 1H), 7.22−7.21 (m, 1H),
6.53−6.52 (m, 1H), 4.20−4.16 (m, 1H), 4.12−4.08 (m, 1H), 3.97−
3.94 (m, 1H), 3.80−3.76 (m, 1H), 3.52−3.49 (m, 1H), 2.42−2.39 (m,
1H), 2.08−2.04 (m, 1H), 1.67 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 149.9, 137.2, 134.1, 131.0, 126.4, 123.8, 119.3, 115.3, 107.3,
83.8, 75.1, 68.7, 45.1, 35.1, 28.1; FT-IR (neat): 2979, 1731, 1471, 1134
cm−1; HRMS (ES+) m/z calcd. for C17H20NO3 (M − H)− 286.1443,
found 286.1444.
(500 MHz, CDCl3): δ 8.44 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.34 (d, J
= 7.4 Hz, 2H), 4.26 (br, 2H), 2.81−2.74 (m, 2H), 2.72−2.69 (m, 1H),
1.85−1.82 (m, 2H), 1.65−1.62 (m, 2H), 1.47 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 164.7, 154.8, 152.7, 150.2, 127.7, 127.4, 121.7,
79.6, 44.7 (br), 42.8, 33.0, 28.6; FT-IR (neat): 2924, 1670, 1428, 1167
cm−1; HRMS (ES+) m/z calcd. for C18H23N3O3Na (M + Na)+
352.1637, found 352.1637.
3-(Tetrahydro-2H-pyran-4-yl)quinoline (5g). The title compound
tert-Butyl 5-(Oxetan-3-yl)-1H-indole-1-carboxylate (6d). The title
was obtained as an orange solid in 41% yield (87 mg) according to
compound was obtained as a yellow oil in 70% yield (191 mg)
1
1
method B. mp: 97−99 °C. H NMR (500 MHz, CDCl3): δ 8.83 (s,
according to method B. H NMR (500 MHz, CDCl3): δ 8.14−8.13
1H), 8.07 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H),
7.68−7.65 (m, 1H), 7.54−7.51 (m, 1H), 4.14−4.12 (m, 2H), 3.61−
3.57 (m, 2H), 3.00−2.95 (m, 1H), 1.96−1.86 (m, 4H); 13C NMR
(125.8 MHz, CDCl3): δ 151.1, 147.3, 138.3, 132.5, 129.3, 129.0, 128.2,
127.7, 126.8, 68.3, 39.2, 33.7; FT-IR (neat): 2951, 2851, 1494, 1120
cm−1; HRMS (CI+) m/z calcd. for C14H16NO (M + H)+ 214.1232,
found 214.1237.
(m, 1H), 7.61−7.60 (m, 1H), 7.57 (s, 1H), 7.37−7.35 (m, 1H), 6.56−
6.55 (m, 1H), 5.13−5.10 (m, 2H), 4.84−4.82 (m, 2H), 4.33−4.30 (m,
1H), 1.68 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 149.8, 136.1,
134.5, 131.1, 126.6, 123.2, 119.0, 115.6, 107.3, 83.8, 79.4, 40.5, 28.3;
FT-IR (neat): 2973, 1731, 1368, 1162 cm−1; HRMS (ES+) m/z calcd.
for C16H18NO3 (M − H)− 272.1287, found 272.1280.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-indole-1-
carboxylate (6e). The title compound was obtained as a colorless
5-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine (5h).
1
The title compound was obtained as a white solid in 45% yield (91
oil in 51% yield (204 mg) according to method B. H NMR (500
1
mg) according to method B. mp: 165−167 °C. H NMR (500 MHz,
MHz, CDCl3): δ 8.06 (br, 1H), 7.58−7.57 (m, 1H), 7.38 (s, 1H),
7.17−7.16 (m, 1H), 6.53−6.52 (m, 1H), 4.21 (br, 2H), 2.87−2.82 (m,
2H), 2.76−2.71 (m, 1H), 1.87−1.85 (m, 2H), 1.67 (s, 9H), 1.50 (s,
9H), 1.49−1.46 (m, 2H); 13C NMR (125.8 MHz, CDCl3): δ 155.0,
149.9, 140.5, 134.0, 130.9, 126.3, 123.5, 118.7, 115.2, 107.4, 83.7, 79.5,
44.4 (br), 42.8, 33.8, 28.6, 28.3; FT-IR (neat): 1733, 1691, 1365, 1163
cm−1; HRMS (ES+) m/z calcd. for C23H32N2O4Na (M + Na)+
423.2260, found 423.2257.
CDCl3): δ 11.12 (br, 1H), 8.26−8.25 (m, 1H), 7.83−7.82 (m, 1H),
7.38−7.37 (m, 1H), 6.48−6.47 (m, 1H), 4.12 (dt, J = 11.8, 6.2 Hz,
2H), 3.60−3.56 (m, 2H), 2.93−2.88 (m, 1H), 1.95−1.82 (m, 4H); 13C
NMR (125.8 MHz, CDCl3): δ 148.2, 142.0, 133.2, 126.9, 126.1, 120.7,
100.3, 68.6, 39.5, 34.7; FT-IR (neat): 2954, 1587, 1354, 1086 cm−1;
HRMS (CI+) m/z calcd. for C12H14N2O (M)+ 202.1106, found
202.1110.
5-(Tetrahydro-2H-pyran-4-yl)benzofuran (5i). The title compound
was obtained as a colorless oil in 49% yield (99 mg) according to
method B. 1H NMR (500 MHz, CDCl3): δ 7.62−7.61 (m, 1H), 7.47−
7.45 (m, 2H), 7.19−7.17 (m, 1H), 6.75−6.74 (m, 1H), 4.13−4.10 (m,
2H), 3.60−3.55 (m, 2H), 2.89−2.84 (m, 1H), 1.90−1.81 (m, 4H); 13C
NMR (125.8 MHz, CDCl3): δ 153.9, 145.4, 140.8, 127.8, 123.6, 118.9,
111.4, 106.7, 68.7, 41.7, 34.7; FT-IR (neat): 2936, 2360, 1469, 1128
cm−1; HRMS (ES+) m/z calcd. for C13H14O2 (M)+ 202.0994, found
202.0995.
tert-Butyl 3-(Quinolin-3-yl)azetidine-1-carboxylate (5j). The title
compound was obtained as a yellow oil in 30% yield (85 mg)
according to method B. 1H NMR (500 MHz, CDCl3): δ 8.85 (s, 1H),
8.10−8.08 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.70−7.67 (m, 1H),
7.56−7.53 (m, 1H), 4.45−4.42 (m, 2H), 4.09−4.06 (m, 2H), 3.95−
3.90 (m, 1H), 1.48 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 156.5,
150.3, 147.5, 135.0, 133.1, 129.4, 129.4, 128.0, 127.7, 127.1, 80.0, 56.7
(br), 31.4, 28.5; FT-IR (neat): 2972, 1698, 1400, 1140 cm−1; HRMS
(ES+) m/z calcd. for C17H21N2O2 (M + H)+ 285.1603, found
285.1613.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-1H-indole-1-
carboxylate (6f). The title compound was obtained as a colorless
1
oil in 48% yield (192 mg) according to method B. H NMR (500
MHz, CDCl3): δ 8.07−8.06 (m, 1H), 7.58−7.57 (m, 1H), 7.41 (s,
1H), 7.20−7.18 (m, 1H), 6.53−6.52 (m, 1H), 4.17 (br, 2H), 2.78−
2.76 (m, 3H), 2.07−2.04 (m, 1H), 1.79−1.77 (m, 1H), 1.70−1.59 (m,
11H), 1.48 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 155.0, 149.9,
138.2, 134.2, 130.9, 126.3, 123.8, 119.1, 115.2, 107.3, 83.7, 79.5, 51.2
(br), 44.3 (br), 42.7, 32.3, 28.6, 28.3, 25.8; FT-IR (neat): 2977, 1733,
1689, 1367 cm−1; HRMS (ES+) m/z calcd. for C23H32N2O4Na (M +
Na)+ 423.2260, found 423.2256.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1-
carboxylate (6g). The title compound was obtained as a colorless oil
1
in 38% yield (147 mg) according to method B. H NMR (500 MHz,
CDCl3): δ 8.08−8.06 (m, 1H), 7.58−7.57 (m, 1H), 7.42 (s, 1H),
7.20−7.18 (m, 1H), 6.53−6.52 (m, 1H), 3.89−3.80 (m, 1H), 3.67−
3.57 (m, 1H), 3.43−3.30 (m, 3H), 2.29−2.28 (m, 1H), 2.04−2.01 (m,
1H), 1.67 (s, 9H), 1.48 (s, 9H); 13C NMR (125.8 MHz, CD3OD): δ
155.1, 149.7, 135.8, 134.3, 131.0, 125.9, 123.2, 118.8, 114.8, 107.1,
83.6, 79.6, 52.8 and 52.3, 46.0 and 45.5, 44.0 and 43.3, 33.2 and 32.4,
27.6, 27.2; FT-IR (neat): 2976, 1732, 1693, 1367 cm−1; HRMS (ES+)
m/z calcd. for C22H30N2O4Na (M + Na)+ 409.2103, found 409.2106.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-1H-indole-1-
carboxylate (6h). The title compound was obtained as a colorless
tert-Butyl 5-(Tetrahydro-2H-pyran-4-yl)-1H-indole-1-carboxylate
(6a). The title compound was obtained as a white solid in 73% yield
1
(220 mg) according to method B. mp: 86−87 °C. H NMR (500
MHz, CDCl3): δ 8.06−8.05 (m, 1H), 7.58−7.57 (m, 1H), 7.40 (s,
1H), 7.20−7.18 (m, 1H), 6.54−6.53 (m, 1H), 4.11−4.08 (m, 2H),
3.58−3.53 (m, 2H), 2.87−2.82 (m, 1H), 1.89−1.79 (m, 4H), 1.67 (s,
9H); 13C NMR (125.8 MHz, CDCl3): δ 149.9, 140.6, 134.1, 131.0,
126.3, 123.6, 118.7, 115.3, 107.4, 83.6, 68.6, 41.6, 34.6, 28.3; FT-IR
(neat): 2951, 1724, 1364, 1132 cm−1; HRMS (ES+) m/z calcd. for
C18H24NO3 (M + H)+ 302.1756, found 302.1755.
1
oil in 36% yield (134 mg) according to method B. H NMR (500
MHz, CDCl3): δ 8.11−8.10 (m, 1H), 7.60−7.59 (m, 1H), 7.49 (s,
1H), 7.27−7.26 (m, 1H), 6.54−6.53 (m, 1H), 4.38−4.35 (m, 2H),
4.03−4.00 (m, 2H), 3.83−3.82 (m, 1H), 1.67 (s, 9H), 1.48 (s, 9H);
13C NMR (125.8 MHz, CDCl3): δ 155.6, 149.7, 136.8, 134.4, 131.0,
126.6, 123.1, 119.0, 115.5, 107.2, 83.8, 79.5, 57.2 (br), 33.7, 28.6, 28.3;
FT-IR (neat): 2676, 1733, 1699, 1368 cm−1; HRMS (ES+) m/z calcd.
for C21H28N2O4Na (M + Na)+ 395.1947, found 395.1938.
tert-Butyl 5-(Tetrahydro-2H-pyran-3-yl)-1H-indole-1-carboxylate
(6b). The title compound was obtained as a colorless oil in 37% yield
1
(112 mg) according to method B. H NMR (500 MHz, CDCl3): δ
I
dx.doi.org/10.1021/jo500905m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Org. Lett. 2012, 14, 3352. (h) Gomes, P.; Gosmini, C.; Perichon, J.
Org. Lett. 2013, 5, 1043. (i) Gosmini, C.; Bassene-Ernst, C.;
Durandetti, M. Tetrahedron 2009, 65, 6141. (j) Durandetti, M.;
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures of H and 13C NMR spectra. This material is available
́ ́ ́
Nedelec, J.-Y.; Perichon, J. J. Org. Chem. 1996, 61, 1748. (k) Cherney,
free of charge via the Internet at http://pubs.acs.org.
A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135,
7442. (l) Leon, T.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2013, 135,
1221. (m) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Chem.Eur. J.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
Notes
■
́
2012, 18, 6039. (n) Durandetti, M.; Gosmini, C.; Perichon, J.
Tetrahedron 2007, 63, 1146. (o) Everson, D. A.; Weix, D. J. J. Org.
Chem. 2014, DOI: 10.1012/jo500507s.
(10) Molander, G. A.; Cavalcanti, L. N.; Garcia-Garcia, C. J. Org.
Chem. 2013, 78, 6427.
The authors declare no competing financial interest.
(11) 4,4′-Dimethoxy-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2′-bipyridine,
4,4′-dimethyl-2,2′-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-
phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2,2′-biquinoline,
terpyridine, 1,3-diphenylurea, picolinic acid, 1,3-di-i-Pr-imidazolium
chloride
(12) NiI2, NiI2·H2O, NiBr2, NiBr2·glyme, NiCl2·glyme, Ni(II)
phthalocyanine, Ni(OTf)2, NiCl2·hexaamine, Ni(acac)2, NiCl·dppe,
Ni(II) dimethylglyoxime.
ACKNOWLEDGMENTS
■
We would like to thank Drs. Anabella Villalobos and
Christopher Helal for support and encouragement. This work
was funded by World Wide Medicinal Chemistry and External
R&D Innovation at Pfizer. We thank Dr. Simon Berritt
(University of Pennsylvania) for his assistance with high
throughput experimentation and Dr. Rakesh Kohli (University
of Pennsylvania) for acquisition of HRMS spectra.
(13) Pyridine, 2,3-dimethylpyridine, 2,6-dimethylpyridine, 4-ethyl-
pyridine, 2-dimethylaminopyridine, 4-dimethylaminopyridine, 4-ben-
zylpyridine.
(14) DMF, DMSO, sulfolane, THF, i-PrOH, MeOH, EtOH, t-
BuOH, s-BuOH, TFE, H2O, CH3CN, DMPU, NMP, DMA.
(15) In our hands, Zn dust required activation with aqueous HCl
prior to use, as has also been demonstrated by Weix, et al. (ref 9b);
different lengths and methods of storage led to inconsistent results
with Zn.
(16) NaI, KI, n-Bu4NI, NaBr, LiBr, LiCl, MnI2, CuI, MgI2, ZnI2, LiI,
CaI2, CsI, FeI3, NaBF4, KBF4, LiBF4, MgCl2, ZnCl2, ZnBr2, FeCl3.
(17) (a) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627.
(b) Zembayashi, M.; Tamao, K.; Yoshida, J.; Kumada, M. Tetrahedron
Lett. 1977, 18, 4089.
REFERENCES
■
(1) (a) Loverling, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752. (b) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V.
J. Org. Chem. 2014, 79, 328.
(2) (a) Aikawa, H.; Tago, S.; Umetsu, K.; Haginiwa, N.; Asao, N.
Tetrahedron 2009, 65, 1774. (b) Tsunoda, T.; Ozaki, F.; Shirakata, N.;
Tamaoka, Y.; Yamamoto, H.; Ito, S. Tetrahedron Lett. 1996, 37, 2463.
(c) Diba, A. K.; Begouin, J.-M.; Niggemann, M. Tetrahedron Lett.
2012, 53, 6629.
(3) (a) Schmidle, C. J.; Mansfield, R. C. J. Am. Chem. Soc. 1956, 78,
1702. (b) Li, G.; Zhou, H.; Jiang, Y.; Keim, H.; Topiol, S. W.; Poda, S.
B.; Ren, Y.; Chandrasena, G.; Doller, D. Bioorg. Med. Chem. Lett. 2011,
21, 1236. (c) Wang, X.; Kauppi, A. M.; Olsson, R.; Almqvist, F. Eur. J.
Org. Chem. 2003, 4586.
(4) (a) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52,
4453. (b) Gartia, Y.; Ramidi, P.; Jones, D. E.; Pulla, S.; Ghosh, A.
Catal. Lett. 2014, 144, 507. (c) Millet, A.; Larini, P.; Clot, E.; Baudoin,
O. Chem. Sci. 2013, 4, 2241. (d) Seel, S.; Thaler, T.; Takatsu, K.;
Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P. J. Am. Chem.
Soc. 2011, 133, 4774.
(5) (a) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131,
9756. (b) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett
2005, 11, 1794. (c) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew.
Chem., Int. Ed. 2007, 46, 3556. (d) Duncton, M. A. J.; Estiarte, M. A.;
Tan, D.; Kaub, C.; O’Mahony, D. J. R.; Johnson, R. J.; Cox, M.;
Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly, M. G. Org. Lett. 2008, 10,
3259.
(6) (a) Pompeo, M.; Froese, R. D. J.; Hadei, N.; Organ, M. G. Angew.
Chem., Int. Ed. 2012, 51, 11354. (b) Han, C.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 7532. (c) Corley, E. G.; Conrad, K.; Murry, J.
A.; Savarin, C.; Holko, J.; Boice, G. J. Org. Chem. 2004, 69, 5120.
(d) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009,
131, 15592. (e) Duplais, C.; Krasovskiy, A.; Lipshutz, B. H.
Organometallics 2011, 30, 6090. (f) Melzig, L.; Gavryushin, A.;
Knochel, P. Org. Lett. 2007, 9, 5529.
(7) Li, L.; Wang, C.-Y.; Huang, R.; Biscoe, M. R. Nat. Chem. 2013, 5,
607.
(8) Presset, M.; Fleury-Bregeot, N.; Oehlrich, D.; Rombouts, F.;
Molander, G. A. J. Org. Chem. 2013, 78, 4615.
(9) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc.
2010, 132, 920. (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am.
Chem. Soc. 2012, 134, 6146. (c) Biswas, S.; Weix, D. J. J. Am. Chem.
Soc. 2013, 135, 16192. (d) Everson, D. A.; Buonomo, J. A.; Weix, D. J.
Synlett 2014, 25, 233. (e) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H.
Org. Lett. 2011, 13, 2138. (f) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.;
Gong, H. Chem. Sci. 2013, 4, 4022. (g) Wang, S.; Qian, Q.; Gong, H.
J
dx.doi.org/10.1021/jo500905m | J. Org. Chem. XXXX, XXX, XXX−XXX