Engaging nonaromatic, heterocyclic tosylates in reductive cross-coupling with aryl and heteroaryl bromides

Article abstract of DOI:10.1021/acs.joc.5b00135

A method has been developed for the introduction of nonaromatic heterocyclic structures onto aryl and heteroaryl bromides using alkyl tosylates in a reductive cross-coupling manifold. This protocol offers an improvement over previous methods by utilizing alkyl tosylate coupling partners that are bench-stable, crystalline solids that can be prepared from inexpensive, commercially available alcohols.

Full text of DOI:10.1021/acs.joc.5b00135

Note
pubs.acs.org/joc
Engaging Nonaromatic, Heterocyclic Tosylates in Reductive
Cross-Coupling 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 Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A method has been developed for the introduction of
nonaromatic heterocyclic structures onto aryl and heteroaryl bromides using
alkyl tosylates in a reductive cross-coupling manifold. This protocol offers an
improvement over previous methods by utilizing alkyl tosylate coupling
partners that are bench-stable, crystalline solids that can be prepared from
inexpensive, commercially available alcohols.
ecently, reductive cross-coupling protocols have garnered
Ra significant amount of attention as a means of forming
C−C bonds without the necessity for generation of an organo-
metallic reagent.1 Although several methods have been
developed for the introduction of nonaromatic heterocycles
onto arenes,2 a particularly attractive route involves the direct
reductive coupling between nonaromatic heterocyclic halides
and (hetero)aryl halides that forges the sp3−sp2 linkage.3
Unlike earlier methods, these reductive protocols allow the
desired transformation to be carried out in a single step and
tolerate a variety of functional groups (Scheme 1). As one
example of the importance of such efforts, medicinal
chemistry programs continue to struggle to incorporate
nonaromatic heterocycles during SAR investigations, and
new methods that enable more complex functional group
arrays will extend the scope of matter in attractive physical
property space.
aryl and alkyl bromides.7 An example was illustrated in which a
nonaromatic heterocyclic tosylate was coupled with cyclohexyl
bromide in good yield (eq 1).
Recent work by Gong et al. demonstrated the Ni-catalyzed
reductive methylation of alkyl halides with methyl tosylate.8
Among the substrates were select N-containing nonaromatic
heterocyclic bromides (eq 2).
Although the previously reported methods of Gong et al.3c
(Scheme 1A) and Molander et al.3d (Scheme 1B) increase the
efficiency in the installation of nonaromatic heterocycles onto
arenes by eliminating the need for a low-yielding metalation
step, the cost and availability of the nonaromatic, heterocyclic
halides may still be prohibitive in some cases. An improvement
of this protocol was envisioned in which less expensive alkyl
coupling partners could be used to effect the desired trans-
formation. Notably, the alcohols of nitrogen- and oxygen-
containing nonaromatic heterocycles are significantly less
expensive than the corresponding bromides and iodides.4 The
alcohols can be easily converted to the nonaromatic hetero-
cyclic tosylates,5 which are stable, colorless, crystalline solids at
room temperature, compared to the corresponding bromides,
many of which were liquids or gummy solids that became
discolored after a few weeks even when refrigerated.6
A general, functional group-tolerant method was therefore
pursued that would allow the reductive cross-coupling of a variety
of nonaromatic heterocyclic tosylates with aryl and heteroaryl
halides. A protocol was envisioned for this transformation based
on previous work in the area of Ni-catalyzed reductive cross-
coupling of saturated heterocyclic substructures.3d
Optimization of the targeted transformation was initiated on
the cross-coupling of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate
with N-Boc-5-bromoindole (eq 3).
A similar approach was developed by Liu et al., who developed
Received: January 19, 2015
a Cu-catalyzed cross-coupling of unactivated alkyl tosylates with
© XXXX American Chemical Society
A
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Scheme 1. Reductive Methods for sp3−sp2 Cross-Coupling Involving Saturated Heterocyclic Structures
Table 1. Cross-Coupling of Nonaromatic, Heterocyclic
Tosylates with N-Boc-5-Bromoindole
Under previously developed conditions, 1-Boc-4-bromo-
piperidine had been successfully cross-coupled with N-Boc-5-
bromoindole in the presence of catalytic NiI2 and MgCl2 as
an additive. Under this protocol, the reaction of tert-butyl
4-(tosyloxy)piperidine-1-carboxylate with N-Boc-5-bromoindole
led to the formation of the desired cross-coupled product in
addition to nearly equal amounts of biaryl homocoupling and
protodehalogenation of the indole substrate (eq 4). Unreacted
alkyl tosylate remained, but no Boc-cleavage was observed on
any of the reaction components. Upon application of these
conditions to several aryl and heteroaryl bromides, these major
side products were formed to a significant extent in every case.
The use of NiBr2·glyme in place of NiI2 and the elimination
of MgCl2 significantly reduced the formation of both the
protodehalogenated and homocoupled side products. Further
optimization revealed that addition of 1 equiv of KI significantly
improved conversion to the cross-coupled product, as did an
increase in reaction temperature from 60 to 80 °C. The amount
of Ni and ligand could be reduced from 10 to 5 mol % with-
out a decrease in yield. With these modifications to the orig-
inal reaction conditions, the cross-coupling of tert-butyl
4-(tosyloxy)piperidine-1-carboxylate with N-Boc-5-bromoindole
proceeded in 73% yield (Table 1, entry 1).
a
From the corresponding alkyl mesylate.
The developed conditions were applied to the reductive
cross-coupling of a variety of nonaromatic, heterocyclic
tosylates with N-Boc-5-bromoindole (Table 1). The method
was extended to other six-membered ring systems, including
a benzyl-protected piperidine system, tetrahydropyran, and
B
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tert-butyl 3-(tosyloxy)piperidine-1-carboxylate. Both pyrrolidinyl
and tetrahydrofuranyl tosylate systems participated in the cross-
coupling. It was observed that the corresponding mesylates
of the tetrahydrofuranyl and piperidinyl systems reacted under
the standard conditions, albeit in lower yields (Table 1, entries
1 and 3). Unfortunately, both azetidine and oxetane substrates
were unreactive under the standard protocol, and the use of aryl
chlorides instead of aryl bromides led to minimal product
formation. Interestingly, under the conditions developed for
nonaromatic, heterocyclic systems, cyclohexyl tosylate was
unreactive.
Table 2. Cross-Coupling of Nonaromatic, Heterocyclic
Tosylates with Heteroaryl Bromides
A variety of heteroaryl bromide substrates, including quin-
oline, pyridine, benzothiophene, and benzofuran substrates,
provided the desired cross-coupling products in moderate to
good yields. Additionally, aryl bromides reacted under the same
conditions, and the reaction tolerated amide and ketone func-
tional groups in addition to ortho-substitution. The scalable
nature of the method was demonstrated by the ability to
carry out a gram-scale reaction without a decrease in the yield
(Table 2, entry 1).
Although the mechanism of this reaction has not been
investigated, it is possible that KI serves to generate an alkyl
iodide in situ from the corresponding alkyl tosylate. Notably,
other metal halides, e.g. CsI, LiI, and KBr, served as suitable
additives for the given transformation, albeit leading to lower
product conversion. Based on a previously proposed mecha-
nistic pathway for reductive cross-coupling reactions,1c once
formed, the nonaromatic, heterocyclic halide could serve as a
source of alkyl radicals, which would then combine with an
Ar−Ni(II)−Br complex generated from the oxidative addition of
the aryl bromide to Ni(0). Reductive elimination from the newly
generated diorgano-Ni(III) species would provide the cross-
coupled product and a Ni(I) species that would be reduced to
Ni(0) by Mn.
The concept of in situ sulfonate/halogen exchange has been
proposed in the Ni-catalyzed reductive methylation of alkyl
halides with methyl tosylate8 and in Ni-catalyzed dimeriza-
tions of alkyl pseudohalides.9 Although the latter contribution
employs NaI as an additive, the former (eq 2) uses no obvious
source of nucleophilic halide and there is no speculation on
the proposed pathway for alkyl halide formation. It has been
suggested that in instances where reactive alkyl halides undergo
rapid dimerization in the presence of Ni catalysts, their slow
formation from a less reactive species, i.e., alkyl mesylate or
tosylate, may be advantageous.8,10 In our hands, N-Boc-4-
iodopiperidine was never observed in the analytical sampling of
the crude reaction mixture. Additionally, under the developed
reductive coupling conditions, N-Boc-4-iodopiperidine in place
of the corresponding tosylate was unreactive with or without
the KI additive.11 If the alkyl iodide is, in fact, only a capable
coupling partner when formed in low concentration and rapidly
consumed, these observations can be rationalized. However, the
use of alkyl iodides did not lead to formation of an alkyl−alkyl
dimer or radical disproportionation products, which would be
predicted if rapid radical formation were problematic. Fur-
thermore, the reaction also proceeds to some extent in the
absence of KI.12 These observations bring to question the
possibility of alkyl iodide formation as the sole function of KI
within the process and suggest that perhaps the iodide additive
plays a more complex role,1b,13 possibly in stabilization of a
transient nickel complex that facilitates reductive elimination
in the catalytic cycle or as a bridging ligand that facilitates
electron transfer.
a
Reaction carried out on 3.0 mmol scale.
In conclusion, a method has been developed for the
reductive cross-coupling of nonaromatic, heterocyclic tosylates
with aryl and heteroaryl bromides. Notably, low catalyst
loadings are used for these transformations, and stoichiometric
ratios of the coupling partners are also employed.1b This
method provides an extension to previously reported reductive
cross-coupling protocols between nonaromatic, heterocyclic
bromides and (hetero)aryl bromides by allowing use of
pseudohalide alkyl partners that can easily be accessed from
less expensive, commercially available alcohols.
EXPERIMENTAL SECTION
■
General Considerations. DMA 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
vacuum. Solids were weighed out in air and were stored on a labo-
ratory bench without special considerations. 1H and 13C NMR spectra
were recorded at 500 and 125.8 MHz, respectively. Melting points (°C)
C
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were determined using a Thomas-Hoover capillary melting point
apparatus and are uncorrected. HRMS data were obtained on a TOF
mass spectrometer using ESI.
1.48 (s, 9H); 13C NMR (125.8 MHz, CD3OD): δ 155.0, 149.7, 135.7,
134.2, 131.0, 125.9, 123.3, 118.9, 114.9, 107.1, 83.5, 79.5, 52.8 and
52.3, 46.0 and 45.6, 44.0 and 43.3, 33.2 and 32.4, 27.7, 27.2.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-1H-indole-
1-carboxylate (1f). The title compound was obtained as a colorless
oil in 24% yield (48 mg). The spectral data are in accordance with
those published.3d 1H NMR (500 MHz, CDCl3): δ 8.07−8.06 (m, 1H),
7.59−7.58 (m, 1H), 7.42 (s, 1H), 7.21−7.19 (m, 1H), 6.54−6.53 (d,
J = 3.6 Hz 1H), 4.18 (br, 2H), 2.77−2.76 (m, 3H), 2.09−2.05
(m, 1H), 1.80−1.77 (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, 32.4,
28.6, 28.3, 25.7.
tert-Butyl 4-(Quinolin-3-yl)piperidine-1-carboxylate (2a).
The title compound was obtained as a yellow oil in 74% yield
(116 mg). On a 3.0 mmol scale, the product was isolated in 81% yield
(759 mg). The spectral data are in accordance with those published.3d
1H NMR (500 MHz, CDCl3): δ 8.80−8.79 (d, J = 2.2 Hz 1H), 8.07−
8.06 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.77−7.75 (d, J = 8.3 Hz, 1H),
7.67−7.64 (m, 1H), 7.53−7.50 (m, 1H), 4.30 (br, 2H), 2.88−2.83
(m, 3H), 1.94−1.91 (m, 2H), 1.74−1.71 (m, 2H), 1.48 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 154.9, 151.0, 147.2, 138.3, 132.7, 129.2, 129.0,
128.2, 127.7, 126.8, 79.7, 44.6 (br), 40.3, 33.0, 28.6.
Experimental Procedure. An oven-dried Biotage 10 mL
microwave vial equipped with a magnetic stirbar was charged with
alkyl tosylate (0.5 mmol), NiBr2·glyme (0.025 mmol, 7.7 mg), 4,4′-di-
tert-butyl-2,2′-bipyridine (0.025 mmol, 6.7 mg), KI (0.5 mmol,
83.0 mg), and Mn powder (1.0 mmol, 55.0 mg). The vial was sealed
with a disposable Teflon septum cap and was evacuated and purged
with Ar three times. Dimethylacetamide (2.5 mL) and 4-ethylpyridine
(0.5 mmol, 54 mg) were added via syringe, followed by the (hetero)aryl
bromide (0.5 mmol). In cases where the (hetero)aryl bromide was a
solid, it was added to the vial along with the other solids. The reaction
was stirred under Ar at 80 °C for 18 h, after which the solution was
cooled and diluted with 5 mL of MeCN. The resulting mixture was
filtered through a pad of Celite, which was rinsed with MeCN
(∼10 mL), and the solution was concentrated. The resulting residue
was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL),
and the combined organic portions were washed with H2O (2 × 10 mL)
and brine (10 mL). 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 to
60% EtOAc).
tert-Butyl 4-(2-Methylpyridin-4-yl)piperidine-1-carboxylate
(2b). The title compound was obtained as a yellow oil in 60% yield
(83 mg). The spectral data are in accordance with those published.3d
1H NMR (500 MHz, CDCl3): δ 8.39−8.38 (d, J = 5.1 Hz, 1H), 6.97
tert-Butyl 5-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-indole-
1-carboxylate (1a). The spectral data are in accordance with those
published.3d The title compound was obtained as a colorless oil in 73%
yield (146 mg). 1H NMR (500 MHz, CDCl3): δ 8.06 (br, 1H), 7.58−
7.57 (m, 1H), 7.39 (s, 1H), 7.18−7.16 (m, 1H), 6.53−6.52 (d, J = 3.6
Hz, 1H), 4.27 (br, 2H), 2.86−2.82 (m, 2H), 2.76−2.71 (m, 1H),
1.87−1.85 (m, 2H), 1.69−1.67 (m, 11H), 1.50 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 155.0, 149.8, 140.5, 134.0, 130.9, 126.2, 123.6,
118.7, 115.3, 107.4, 83.6, 79.4, 44.3 (br), 42.8, 33.8, 28.7, 28.3
tert-Butyl 5-(Tetrahydro-2H-pyran-4-yl)-1H-indole-1-carbox-
ylate (1b). The title compound was obtained as a white solid in 69%
yield (104 mg). The spectral data are in accordance with those
(s, 1H), 6.92−6.91 (d, J = 5.2 Hz, 1H), 4.24 (br, 2H), 2.78−2.76
(m, 2H), 2.60−2.58 (m, 1H), 2.51 (s, 3H), 1.81−1.77 (m, 2H),
1.62−1.55 (m, 2H), 1.46 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 158.7,
154.9, 154.8, 149.4, 121.9, 119.5, 79.8, 44.3 (br), 42.1, 32.4, 28.6, 24.6.
tert-Butyl 4-(Benzo[b]thiophen-2-yl)piperidine-1-carbox-
ylate (2c). The title compound was obtained as a white solid in
1
42% yield (67 mg). Mp: 83−84 °C. H NMR (500 MHz, CDCl3): δ
7.77 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.32−7.26 (m, 2H),
7.03 (s, 1H), 4.23 (br, 2H), 3.03−3.00 (m, 1H), 2.88−2.82 (m, 2H),
2.07−2.04 (m, 2H), 1.72−1.66 (m, 2H), 1.49 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 154.9, 150.6, 140.0, 138.8, 124.3, 123.8, 123.1,
122.4, 119.0, 79.7, 44.3 (br), 38.4, 33.8, 28.6; FT-IR (neat): 1681,
1428, 1156 cm−1; HRMS (ES+) m/z calcd for C18H23NO2SNa
(M + Na)+ 340.1347, found 340.1346.
published.3d Mp: 82−84 °C (lit. 86−87 °C). H NMR (500 MHz,
1
CDCl3): δ 8.07−8.06 (m, 1H), 7.58−7.57 (m, 1H), 7.40 (s, 1H),
7.20−7.18 (m, 1H), 6.53−6.52 (d, J = 3.7 Hz, 1H), 4.11−4.08 (m, 2H),
3.58−3.53 (m, 2H), 2.86−2.83 (m, 1H), 1.92−1.79 (m, 4H), 1.66 (s,
9H); 13C NMR (125.8 MHz, CDCl3): δ 149.9, 140.6, 134.0, 131.0,
126.3, 123.5, 118.7, 115.3, 107.4, 83.7, 68.7, 41.7, 34.6, 28.3.
5-(Tetrahydro-2H-pyran-4-yl)benzofuran (2d). The title com-
pound was obtained as a colorless oil in 49% yield (50 mg). The
spectral data are in accordance with those published.3d 1H NMR (500
MHz, CDCl3): δ 7.62−7.61 (m, 1H), 7.47−7.45 (m, 2H), 7.19−7.17
(d, J = 8.6 Hz, 1H), 6.75−6.74 (m, 1H), 4.13−4.10 (m, 2H), 3.59−
3.54 (m, 2H), 2.88−2.83 (m, 1H), 1.92−1.80 (m, 4H); 13C NMR
(125.8 MHz, CDCl3): δ 153.9, 145.4, 140.8, 127.7, 123.6, 118.9, 111.4,
106.7, 68.7, 41.7, 34.7.
tert-Butyl 5-(Tetrahydrofuran-3-yl)-1H-indole-1-carboxylate
(1c). The title compound was obtained as a colorless oil in 36%
yield (52 mg). From the corresponding mesylate, the compound was
isolated in 28% yield (40 mg). The spectral data are in accordance with
those published.3d 1H NMR (500 MHz, CDCl3): δ 8.07−8.06
(m, 1H), 7.59−7.58 (m, 1H), 7.44 (s, 1H), 7.22−7.20 (d, J = 8.6 Hz,
1H), 6.53−6.52 (d, J = 3.6 Hz, 1H), 4.20−4.17 (m, 1H), 4.13−4.08
(m, 1H), 3.97−3.92 (m, 1H), 3.79−3.76 (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, 137.1, 134.1, 131.0, 126.4, 123.8, 119.3,
115.4, 107.3, 83.8, 75.1, 68.7, 45.0, 35.1, 28.3.
tert-Butyl 5-(1-Benzylpiperidin-4-yl)-1H-indole-1-carboxylate
(1d). The title compound was obtained as a colorless oil in 66% yield
(129 mg). 1H NMR (500 MHz, CDCl3): δ 8.09−8.07 (m, 1H), 7.60−
7.59 (d, J = 3.4 Hz, 1H), 7.42−7.38 (m, 5H), 7.36−7.34 (m, 1H),
7.18−7.16 (m, 1H), 6.54−6.53 (d, J = 3.7 Hz, 1H), 5.19 (s, 2H), 4.37
(br, 2H), 2.94−2.93 (m, 2H), 2.80−2.75 (m, 1H), 1.91−1.89 (m, 2H),
1.71−1.67 (m, 11H); 13C NMR (125.8 MHz, CDCl3): δ 155.3, 149.7,
140.0, 136.9, 130.7, 128.4, 127.9, 127.8, 126.1, 123.3, 118.5, 115.0,
107.1, 83.5, 67.0, 44.7, 42.5, 33.5 (br), 28.1; FT-IR (neat): 1732, 1698,
1366, 1223 cm−1; HRMS (ES+) m/z calcd for C25H31N2O2 (M + H)+
391.2386, found 391.2379.
2-(4-(Tetrahydro-2H-pyran-4-yl)phenyl)-1,3,4-oxadiazole (2e).
The title compound was obtained as a white solid in 62% yield
1
(77 mg). Mp: 110−112 °C. H NMR (500 MHz, CDCl3): δ 8.45 (s,
1H), 8.01 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 4.10−4.07
(m, 2H), 3.55−3.50 (m, 2H), 2.85−2.79 (m, 1H), 1.87−1.76 (m, 4H);
13C NMR (125.8 MHz, CDCl3): δ 164.8, 152.7, 150.3, 127.7, 127.5,
121.7, 68.3, 41.7, 33.7; FT-IR (neat): 1615, 1493, 1086 cm−1; HRMS
(ES+) m/z calcd for C13H15N2O2 (M + H)+ 231.1134, found 231.1134.
tert-Butyl 4-(4-Acetamidophenyl)piperidine-1-carboxylate
(2f). The title compound was obtained as a white solid in 38% yield
(61 mg). The spectral data are in accordance with those published.3d
Mp: 171−172 °C (lit. 165−168 °C). 1H NMR (500 MHz, CDCl3): δ
7.61 (br, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.21
(br, 2H), 2.79−2.74 (m, 2H), 2.61−2.56 (m, 1H), 2.14 (s, 3H), 1.78−
1.75 (m, 2H), 1.57−1.53 (m, 2H), 1.47 (s, 9H); 13C NMR (125.8
MHz, CDCl3): δ 168.6, 155.0, 141.9, 136.4, 127.3, 120.4, 79.7, 44.4
(br), 42.2, 33.4, 28.6, 24.6.
tert-Butyl 5-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-
1-carboxylate (1e). The title compound was obtained as a colorless
oil in 52% yield (100 mg). The spectral data are in accordance with
those published.3d 1H NMR (500 MHz, CDCl3): δ 8.08−8.07
(m, 1H), 7.59−7.58 (m, 1H), 7.42 (s, 1H), 7.20−7.19 (m, 1H), 6.54−6.53
(d, J = 3.5 Hz, 1H), 3.89−3.80 (m, 1H), 3.67−3.58 (m, 1H), 3.44−
3.30 (m, 3H), 2.29−2.28 (m, 1H), 2.06−2.02 (m, 1H), 1.67 (s, 9H),
tert-Butyl 4-(4-Fluorophenyl)piperidine-1-carboxylate (2g).
The title compound was obtained as a colorless oil in 65% yield
(91 mg). The spectral data are in accordance with those published.3d
1H NMR (500 MHz, CDCl3): δ 7.15−7.13 (m, 2H), 7.00−6.97 (m, 2H),
D
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4.24 (br, 2H), 2.81−2.74 (m, 2H), 2.64−2.59 (m, 1H), 1.81−1.78
(m, 2H), 1.62−1.55 (m, 2H), 1.47 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 161.5 (d, J = 244.1 Hz), 155.0, 141.6 (d, J = 3.4 Hz), 128.2
(d, J = 7.7 Hz), 115.3 (d, J = 20.9 Hz), 79.6, 44.4 (br), 42.1, 33.5, 28.6.
tert-Butyl 4-(2-Methoxyphenyl)piperidine-1-carboxylate
(2h). The title compound was obtained as a white solid in 60%
yield (87 mg). Mp: 65−66 °C (lit: 63−65 °C). The spectral data are in
accordance with those published.3d 1H NMR (500 MHz, CDCl3): δ
7.20−7.14 (m, 2H), 6.95−6.93 (m, 1H), 6.88−6.86 (m, 1H), 4.24 (br,
2H), 3.83 (s, 3H), 3.12−3.07 (m, 1H), 2.84−2.81 (m, 2H), 1.82−1.78
(m, 2H), 1.61−1.57 (m, 2H), 1.49 (s, 9H); 13C NMR (125.8 MHz,
CDCl3): δ 156.9, 155.1, 134.0, 127.2, 126.6, 120.8, 110.5, 79.4, 55.4,
44.4 (br), 35.5, 32.0, 28.7.
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R.; Biscoe, M. R. Nat. Chem. 2013, 5, 607.
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13, 2138. (b) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem.
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1-(4-(Tetrahydro-2H-pyran-4-yl)phenyl)ethan-1-one (2i).
The title compound was obtained as a white solid in 72% yield
(74 mg). Mp: 71−73 °C (lit: 75−76 °C). The spectral data are in
accordance with those published.3d 1H NMR (500 MHz, CDCl3): δ
7.90 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.08−4.05 (m, 2H),
3.54−3.49 (m, 2H), 2.83−2.78 (m, 1H), 2.56 (s, 3H), 1.85−1.73
(m, 4H); 13C NMR (125.8 MHz, CDCl3): δ 197.9, 151.5, 135.6,
128.9, 127.1, 68.3, 41.7, 33.7, 26.7.
(4) Based on price comparison of an online supplier.
(5) Katz, J. D.; Jewell, P.; Guerin, D. J.; Lim, J.; Dinsmore, C. J.;
Deshmukh, S. V.; Pan, B.-S.; Marshall, C. G.; Lu, W.; Altman, M. D.;
Dahlberg, W. K.; Davis, L.; Falcone, D.; Gabarda, A. E.; Hang, G.;
Hatch, H.; Holmes, R.; Kunii, K.; Lumb, K. J.; Lutterbach, B.;
Mathvink, R.; Nazef, N.; Patel, S. B.; Qu, X.; Reilly, J. F.; Rickert, K.
W.; Rosenstein, C.; Soisson, S. M.; Spencer, K. B.; Szewczak, A. A.;
Walker, D.; Wang, W.; Young, J.; Zeng, Q. J. Med. Chem. 2011, 54,
4092.
ASSOCIATED CONTENT
(6) Several vendors recommend storage of nonaromatic, heterocyclic
bromides at <7 °C.
■
S
* Supporting Information
1
Figures of H and 13C NMR spectra. This material is available
(7) Liu, J.-H.; Yang, C.-T.; Lu, X.-Y.; Zhang, Z.-Q.; Xu, L.; Cui, M.;
Lu, X.; Xioa, B.; Fu, Y.; Liu, L. Chem.Eur. J. 2014, 20, 15334.
(8) Liang, Z.; Xue, W.; Lin, K.; Gong, H. Org. Lett. 2014, 16, 5620.
(9) (a) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci.
2013, 4, 4022. (b) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Chem.
Commun. 2010, 46, 5743.
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
■
(10) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix,
D. J. Chem. Sci. 2015, 6, 1115.
Notes
(11) When N-Boc-4-bromopiperidine was used under the standard
conditions, product was isolated in 24% yield (0.5 mmol scale).
(12) With the use of NaBF4 as an additive in place of KI under the
standard conditions, the reaction of tert-butyl 4-(tosyloxy)piperidine-1-
carboxylate with N-Boc-5-bromoindole proceeded in 13% yield on a
1.0 mmol scale.
(13) For possible roles of halide additives in Ni catalyzed reactions
see: (a) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627.
(b) Zembayashi, M.; Yoshida, J.; Kumada, M. Tetrahedron Lett. 1977,
18, 4089. (c) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc.
2014, 136, 17645.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Drs. Anabella Villalobos and Chris-
topher Helal for support and encouragement. This work was
funded by World Wide Medicinal Chemistry and External R&D
Innovation at Pfizer. We thank Dr. Rakesh Kohli (University of
Pennsylvania) for acquisition of HRMS spectra.
REFERENCES
■
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DOI: 10.1021/acs.joc.5b00135
J. Org. Chem. XXXX, XXX, XXX−XXX