Transition-Metal-Free Decarboxylative Photoredox Coupling of Carboxylic Acids and Alcohols with Aromatic Nitriles

Article abstract of DOI:10.1021/acs.joc.6b01215

A transition-metal-free protocol for the redox-neutral light-induced decarboxylative coupling of carboxylic acids with (hetero)aromatic nitriles at ambient temperature is presented. A broad scope of acids and nitriles is accepted, and alcohols can be coupled in a similar fashion through their oxalate half esters. Various inexpensive sources of UV light and even sunlight can be used to achieve this C-C bond formation proceeding through a free radical mechanism.

Full text of DOI:10.1021/acs.joc.6b01215

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Note
Transition Metal-free Decarboxylative Photoredox Coupling
of Carboxylic Acids and Alcohols with Aromatic Nitriles
Benjamin Lipp, Alexander Matthias Nauth, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01215 • Publication Date (Web): 11 Jul 2016
Downloaded from http://pubs.acs.org on July 19, 2016
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Transition Metal-free Decarboxylative Photoredox
Coupling of Carboxylic Acids and Alcohols with
Aromatic Nitriles
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Benjamin Lipp, Alexander M. Nauth, and Till Opatz*
Address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128
Mainz, Germany
Email: opatz@uni-mainz.de
Table of Contents/ Abstract Graphic
Abstract
A transition metal-free protocol for the redox-neutral light-induced decarboxylative coupling of
carboxylic acids with (hetero)aromatic nitriles at ambient temperature is presented. A broad
scope of acids and nitriles is accepted and alcohols can be coupled in a similar fashion through
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their oxalate esters. Various inexpensive sources of UV light and even sunlight can be used to
achieve this C–C bond formation proceeding through a free radical mechanism.
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The homolytic substitution of heteroaromatic bases, mostly in their protonated form, by
nucleophilic carbon-centered radicals is commonly referred to as the Minisci reaction.1-4 A range
of radical precursors has been used, including alcohols, ethers, alkyl halides, aldehydes, olefins
and carboxylic acids.2 In particular the latter substrates are inexpensive and readily available
sources of C-centered radicals.5-7 The desire to use light as a sustainable energy source for C–C-
bond forming reactions has led to the emergence of photoredox catalysis which is currently in the
focus of interest of a steadily growing research community.5,8-12 Recent work has combined
photoredox catalysis with the traditional Minisci reaction and used radical additions to aromatic
heterocycles as a synthetically appealing way of trapping the radicals generated in the course of
photoredox-catalyzed transformations.13-16 A particular advantage of photoredox catalysis is the
feasibility to perform net redox-neutral reactions8 and by incorporating an anionic leaving group
into electron-deficient aromatics, Minisci-type reactions with carboxylic acids can proceed
without stoichiometric oxidants.17 MacMillan et al. reported the photoredox-catalyzed coupling
of various α-amino and α-oxy acids with a variety of aromatic nitriles at ambient temperature.18
However, an expensive, tailored iridium complex served as the photocatalyst. The search for
metal-free, cheaper alternatives like Eosin Y19, Rose Bengal20 or Fukuzumi-acridinium21 is
particularly challenging in this case since the catalyst has to be both a strong reductant and a
strong oxidant to reduce the (hetero)arene and to oxidize the carboxylate.18
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Phenanthrene proved to have suitable characteristics as its excited state offers remarkable redox-
properties (vide infra). Therefore, it has been used since the late 1970s as catalyst in
photochemical electron transfer reactions, most noteworthy by Sakurai et al..22-26 The
decarboxylative coupling of carboxylic acids with 1,4-dicyanobenzene was occasionally
observed when using this nitrile as oxidative quencher or electron shuttle in combination with
phenanthrene as photocatalyst.27-30 The alkylated cyanobenzenes were obtained in very low to
moderate yields as undesired side products or in the absence of a suitable radical trap.27-30 In
2009, Yoshimi et al. reported the phenanthrene-catalyzed substitution of a nitrile group in 1,2-,
1,3- and 1,4-dicyanobenzene by radicals generated from oxidative decarboxylation of carboxylic
acids.17 However, moderate yields were mostly obtained using exclusively unfunctionalized,
aliphatic carboxylic acids and the scope of aromatic nitriles was limited to dicyanobenzenes.17
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Herein, we report a detailed study of the coupling of carboxylic acids with various aromatic and
heteroaromatic nitriles at ambient temperature using phenanthrene as a cheap and recyclable
photoredox catalyst. An extensive reaction optimization was conducted including base-, solvent-
and concentration-screens as well as studies concerning the catalyst loading (see Supporting
Information). In addition, the first transition metal-free deoxygenative photoredox coupling of
alcohols with aromatic nitriles could be achieved through their readily accessible oxalate half
esters. Finally, the range of suitable light sources for this coupling reaction is extended to energy-
saving CFL bulbs and even to sunlight.
We first investigated the phenanthrene-catalyzed coupling of Boc-L-valine with 4-cyanopyridine
in the presence of various bases in mixtures of acetonitrile and water (Supporting Information,
Tables S1–S3). Even though a loading of 5 mol% of phenanthrene was found to be sufficient (up
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to 27% yield within 24 h), the best results were obtained with a catalyst loading of 75 mol% (up
to 77% yield within 24 h, Supporting Information, Table S4). Since phenanthrene is inexpensive
(< 1 USD/g), readily available and can be recovered almost quantitatively (90–96% recovery in 7
randomly chosen experiments from Scheme 1), the use of stoichiometric amounts of this catalyst
appears justified and is common practice.17,27-30 Using the optimized conditions, the scope of this
transition metal-free coupling was investigated (Scheme 1).
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Scheme 1: Scope of the phenanthrene-catalyzed coupling of carboxylic acids and alcohols with
aromatic nitriles. Method A: A solution of the aromatic nitrile (1.20 mmol, 1.00 equiv.), the
carboxylic acid (3.60 mmol, 3.00 equiv.), CsF (3.60 mmol, 3.00 equiv.) and phenanthrene
(0.90 mmol, 0.75 equiv.) in acetonitrile (54 mL) and water (6 mL) was irradiated according to the
general procedure A. Method B: A solution of the aromatic nitrile (0.90 mmol, 1.00 equiv.), the
cesium oxalate (2.70 mmol, 3.00 equiv.) and phenanthrene (1.13 mmol, 1.25 equiv.) in a mixture
of DMF (34 mL) and DMSO (34 mL) was irradiated according to the general procedure B.
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a
Unless stated otherwise, all yields are those of isolated products. Performed on a multigram-
scale using 26 mmol of 4-cyanopyridine. bProduct not isolated.
Gratifyingly, a set of proteinogenic α-amino acids furnished the desired products 1–5 in high
yields and the usual carbamate protecting groups (Boc, Cbz and Fmoc) were well tolerated.31
Since esters are not decarboxylated under the reaction conditions, the coupling of amino acids
bearing carboxylate side chains is feasible (compound 4). The first photoredox-catalyzed
coupling of a dipeptide with an aromatic nitrile could be effected in 55% yield (compound 5).
The reaction protocol could be successfully applied to α-oxy acids, and even the presence of an
unprotected α-hydroxy group was tolerated (compounds 6 and 7). Arylacetic acids afforded the
desired products 7–9 in good to excellent yields while an α-quaternary aliphatic acid gave a yield
of only 33% (compound 10). The presented coupling reaction proved to be scalable and a 5 g
batch of compound 9 could be prepared in 96% yield. 1,4-Dicyanobenzene afforded coupling
product 11 in a yield of 79% and the second nitrile function could be replaced by a
methoxycarbonyl moiety (compound 12). At this point, we questioned how photoredox catalysis
may be used to overcome difficulties associated with the traditional Minisci reaction. The
regioselectivity of the latter is determined by the LUMO-coefficient which is largest in γ-position
of the pyridine core.3 Thus, the alkylation of pyridine under traditional Minisci conditions affords
mixtures in which the 2-alkylpyridine isomer usually is the minor product.2,32 When the nitrile
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group was introduced in 2-position, the desired 2-alkylated pyridines 13, 14 and 15 could be
isolated in 54%,66%, and 37% yield, respectively and no 4-substitution product could be found.
In contrast to the traditional Minisci reaction, no polyalkylation was observed even when 1,4-
dicyanobenzene was used as the coupling component.2,32,33 It is noteworthy that halides do not
represent suitable leaving groups for the coupling reported herein (Supporting Information,
Scheme S1) and thus, the selective substitution of a nitrile group in the presence of a halide is
feasible (compound 15, no double-alkylated product could be found). This opens up the
possibility of combining this transition metal-free decarboxylative photoredox coupling with
traditional cross-coupling reactions for the construction of complex molecules. To test the
suitability of the C–C-coupling reported herein for the synthesis of alkaloid-like structures,
homoveratric acid was coupled to 1-cyanoisoquinoline to furnish compound 17 in 80% yield. The
alkylation of 3-cyanopyridine was unsuccessful (compound 18), as was the use of sp2-centered
radicals for the acylation or arylation of aromatic nitriles (compounds 19 and 20).
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Finally, the scope of radical precursors for this coupling reaction should be extended to alcohols
which are another readily available source for structurally diverse carbon-centred radicals.2,34,35
Recently, the groups of MacMillan and Overman have shown that cesium oxalates of secondary
and tertiary alcohols can be used as easily accessible and bench-stable precursors of alkyl radicals
in photoredox reactions.34 Thus, coupling of such oxalate salts with 4-cyanopyridine was
investigated. Again, a detailed optimization study was conducted (Supporting Information,
Tables S6–S10) and the scope of this unprecedented coupling reaction was investigated (Scheme
1). The cesium oxalates were obtained in high yields and without chromatographic work-up by
treating the corresponding alcohols with either methyl 2-chloro-2-oxoacetate or oxalyl chloride,
followed by hydrolysis of the resulting oxalic esters or chlorides.34 Oxalates of tertiary alcohols
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could be coupled with 4-cyanopyridine in yields of 56–58% (compounds 10, and 21). Thus, they
appear to be better suited as precursors of sterically demanding tertiary radicals for the coupling
with aromatic nitriles than the corresponding carboxylic acids (compare yields of 10 in Scheme
1). However, except for tertiary alcohols, only secondary benzylic alcohols appear to undergo the
coupling reported herein (compound 23), as the oxalates of cyclohexanol and veratryl alcohol
both afforded only traces of the desired products 22 and 9.
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A plausible mechanism for the transition metal-free coupling reported herein is presented in
Scheme 2.
Scheme 2: Plausible reaction mechanism for the phenanthrene-catalyzed coupling of carboxylic
acids and oxalates with aromatic nitriles.
Irradiation with UV-light produces an excited state of phenanthrene (24) (for absorption spectra
see Supporting Information, Figure S1). Fluorescence quenching experiments strongly indicate
that an oxidative quenching cycle is operating, starting with an electron transfer from excited
phenanthrene to the nitrile (E1/2(Phen·+/1[Phen]*) = –2.1 V vs SCE36, for 1,4-dicyanobenzene:
(E1/2(DCB/DCB·–) = –1.61 V vs SCE18).17,25 The resulting radical cation of phenanthrene is a
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strong oxidant (E1/2(Phen·+/Phen) = +1.50 V vs SCE)37 and it is well established that this species
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red
causes decarboxylation of carboxylates 26 (for Boc-Pro-OCs: E1/2 = +0.95 V vs SCE)18 by
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single-electron oxidation.17,27-30,38,39 Decarboxylation of cesium oxalates of type 27 (for
tBuOCOCO2Cs: E1/2red = +1.28 V vs SCE)34 should also be feasible. Combination of the nitrile´s
radical anion 25a with the alkyl radical 28 formed by decarboxylation affords anion 29 which is
stabilized by the elimination of cyanide.18 The absence of noteworthy amounts of homocoupled
products could be explained by the so-called persistent radical effect.40 The radical anions 25a do
not combine and have a much longer lifetime than the alkyl radicals 28 obtained from
decarboxylation. This causes a significant excess of the radical anions 25a after short reaction
times, strongly favoring the desired cross coupling reaction.40 The mechanistic proposal is in
accordance with literature reports17,18 and is supported by control experiments (Supporting
Information, Tables S5 and S11). Regardless of the radical source, the coupling reaction afforded
the unchanged starting materials when performed in the dark and only traces of the desired
product were obtained upon irradiation of the samples in the absence of phenanthrene.
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A drawback of phenanthrene is the necessity for using UV-light , which represents only about 3%
of the solar spectrum, for its excitation.41 Since it appeared questionable whether this justifies the
use of extremely expensive iridium complexes as visible-light absorbing catalysts (especially on
a preparative scale), we examined various readily available sources of UV-light for the
exemplary coupling of Boc-
L-valine (31) with 4-cyanopyridine (32) (Table 1).
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Table 1: Screening for light sources.
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Entry
Light Source
Yield (%)
79a
400 W medium pressure
metal halide lamp
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UV/Vis-CFL bulb
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Sunlightb
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27c
400 W UV-A spotlight
25 W energy-saving
UV-A lamp
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25 W energy-saving
UV-A lampd
70c
Unless stated otherwise, all reactions were performed
according to the general procedure A. aIsolated Yields.
b30 h irradiation time. cYields determined by 1H-NMR
spectroscopy using 1,4-bis(trimethylsilyl)benzene as
internal standard. Reaction performed in an NMR-
tube.
d
Detailed information about all lamps and the reaction set ups for the irradiations are included in
the Supporting Information. We were delighted to find that the strong mercury lamps typically
used for phenanthrene-catalyzed photoreactions17,27-30,38,39 could be replaced by an inexpensive
and widely available 25 W energy-saving UV/Vis-CFL bulb for application in terrariums (82%
yield within 24 h, entries 1 and 2). Even more remarkable is the finding that sunlight is well
suited to promote the coupling reported herein (61% yield within 30 h of discontinuous
irradiation, April, 50° N, entry 3). Since the used glassware shows no significant transmission of
light with wavelengths of less than about 300 nm and given the absorption spectra of
phenanthrene in both solvents used (Supporting Information, Figure S1), excitation of this arene
in the course of the coupling reactions should mainly be attributed to 300–350 nm light (See the
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Supporting Information for a more detailed discussion). Thus, black light (UV-A) sources whose
emission maximum lies above 350 nm afford significantly reduced yields (entries 4 and 5), while
much better results can be obtained when the reaction is performed in an NMR-tube (entry 6).
This is probably due to the larger surface-to-volume-ratio and improved penetration by light.
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In summary, the phenanthrene-catalyzed, net redox-neutral coupling of carboxylic acids with
aromatic nitriles reported by Yoshimi et al. in 200917 was substantially optimized and the scope
of acids as well as nitriles was significantly extended. For the first time, the photochemical,
deoxygenative coupling of alcohols, activated as oxalates, with aromatic nitriles is reported.
Studies concerning suitable light sources revealed that these coupling reactions are not only
devoid of any expensive reagents or catalysts, but can even be performed with natural sunlight,
the most sustainable energy source imaginable.
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Experimental Section
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Unless stated otherwise, all solvents and reagents were obtained from commercial suppliers and
used without prior purification. Phenanthrene had a purity of ˃ 96% (HPLC). Reaction solvents
were degassed in an ultrasonic bath by argon sparging for 20 minutes. Anhydrous tetrahydrofuran
and diethyl ether were distilled from potassium or sodium and benzophenone. Reactions
requiring anhydrous conditions were performed in dried glassware under an atmosphere of argon.
Chromatographic purification of products was performed as flash column chromatography on
silica gel (35–70 µm, Acros Organics) according to the procedure of Still.42 NMR spectra were
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1
13
recorded on a 300 MHz (300 MHz H-NMR, 75.5 MHz C-NMR) or a 400 MHz (400 MHz 1H-
NMR, 100.6 MHz 13C-NMR) spectrometer. All 13C-NMR spectra were broadband 1H-decoupled.
Chemical shifts are referenced to residual solvent signals (CDCl3: 7.26 ppm and 77.16 ppm,
1
DMSO-d6: 2.50 ppm and 39.52 ppm for H-NMR and 13C-NMR respectively) and reported in
parts per million (ppm) relative to tetramethylsilane (TMS). Coupling constants (J) are given in
Hz using the conventional abbreviations (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet and combinations thereof). Infrared (IR-) spectra were recorded on a FTIR-
spectrometer equipped with a diamond ATR unit and are reported in terms of frequency of
absorption ν [cm–1]. Melting points were determined in open capillary tubes using a digital
electrothermal apparatus. Electron spray ionization (ESI) mass spectra were recorded on a HPLC-
system with binary pump and integrated diode array detector coupled to an ion trap mass
spectrometer or a on an ESI/QTOF-instrument. High-resolution masses were recorded on an
ESI/QTOF-instrument with a suitable external calibrant.
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General procedure A: Coupling of carboxylic acids with aromatic nitriles (Scheme 1):
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A 100 mL-round bottom flask equipped with a stir bar and a septum was flushed with argon and
charged with acetonitrile (54 mL) and deionized water (6 mL). Both solvents were previously
degassed by ultrasonication (see above). The aromatic nitrile (1.20 mmol, 1.00 equiv.), the
carboxylic acid (3.60 mmol, 3.00 equiv.), CsF (3.60 mmol, 3.00 equiv.) and phenanthrene
(0.90 mmol, 0.75 equiv.) were added, followed by argon sparging for 1 min. The mixture was
irradiated with a 400 W-medium pressure Hg-metal halide lamp from a distance of 50 cm for
24 h. Saturated aqueous NaHCO3 solution (30 mL) was added, followed by extraction with
EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. Phenanthrene was recovered by filtration through a short pad of silica
using cyclohexane. The remaining components of the reaction mixture were collected by washing
with methanol and the solvent was removed in vacuo. Flash column chromatography afforded the
desired product.
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General procedure B: Coupling of oxalates with aromatic nitriles (Scheme 1):
The procedure was similar to the carboxylic acid-coupling, but a mixture of DMF and DMSO
(34 mL each, both degassed) was used as the solvent. The aromatic nitrile (0.90 mmol,
1.00 equiv.), the cesium oxalate (2.70 mmol, 3.00 equiv.) and phenanthrene (1.13 mmol,
1.25 equiv.) were irradiated under identical conditions. The combined organic layers were
washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo. Phenanthrene was
recovered and the products isolated as described for the use of carboxylic acids. The required
cesium oxalates were prepared according to a one-pot procedure by Overman et al..34 Briefly, the
alcohol was reacted with methyl chlorooxoacetate in the presence of DMAP and triethylamine in
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dry THF followed by hydrolysis of the mixed oxalate ester with CsOH, extractive workup and
lyophilization.
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tert-Butyl (2-methyl-1-(pyridin-4-yl)propyl)carbamate (1). Prepared according to the general
procedure A using 4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and Boc-L-Val-OH (782
mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column chromatography
c
(SiO2, Hex/EtOAc/NEt3 40:10:1) afforded the title compound (236 mg, 943 µmol, 79%) as a
c
slightly yellow foam. Rf = 0.13 (SiO2, Hex/EtOAc/NEt3 40:10:1). IR (ATR): ꢀ
̅
[cm–1] = 3243,
1
2972, 2875, 1695, 1601, 1525, 1456, 1390, 1365, 1246. H NMR, COSY (400 MHz, CDCl3):
δ/ppm = 8.55–8.52 (m, 2H, H-2´,6´), 7.15–7.13 (m, 2H, H-3´,5´), 5.01 (d, J = 8.2 Hz, 1H, NH),
4.44/4.22 (s, 1H, H-1), 2.05–1.89 (m, 1H, H-2), 1.41 (s, 9H, C(CH3)3), 0.88 (app t, J = 7.0 Hz,
6H, CH(CH3)2). 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 155.5 (CO), 151.3 (C-
4´), 149.9 (2C, C-2´,6´), 122.1 (2C, C-3´,5´), 79.9 (OC(CH3)3), 59.6 (C-1), 33.2 (C-2), 28.5
(C(CH3)3), 19.7 (CH(CH3)(CH3)), 18.1 (CH(CH3)(CH3)). ESI-MS (pos.): m/z = 251.1 (100%,
[M+H]+), 195.2 (8%, [M–tBu+H]+). ESI-HRMS (pos.): calculated for [C14H23N2O2]+: m/z =
251.1754, found: 251.1752. Hydrogen H-1 gives two signals in the 1H NMR spectrum, due to the
hindered rotation around the CO–N-bond.
tert-Butyl 2-(pyridin-4-yl)pyrrolidine-1-carboxylate (2). Prepared according to the general
procedure A using 4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and Boc-L-Pro-OH
(775 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
c
chromatography (SiO2, Hex/EtOAc 1:1) afforded the title compound (224 mg, 902 µmol, 75%)
as a colorless solid. Rf = 0.14 (SiO2, cHex/EtOAc 1:1). Mp: 71.5–72.3 °C. IR (ATR): ꢀ [cm–1] =
̅
2975, 2932, 2879, 1693, 1599, 1391, 1161, 1115, 993, 904. 1H NMR, COSY (400 MHz, CDCl3):
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A, δ/ppm = 8.51 (d, J = 5.5 Hz, 2H, H-2´,6´), 7.09–7.07 (m, 2H, H-3´,5´), 4.91–4.86 (m, 1H, H-
2), 3.66–3.46 (m, 2H, H-5), 2.40–2.25 (m, 1H, H-3a), 1.90–1.83 (m, 2H, H-4), 1.82–1.73 (m, 1H,
H-3b), 1.44 (s, 9H, C(CH3)3); B, δ/ppm = 8.51 (d, J = 5.5 Hz, 2H, H-2´,6´), 7.09–7.07 (m, 2H, H-
3´,5´), 4.74–4.69 (m, 1H, H-2), 3.66–3.46 (m, 2H, H-5), 2.40–2.25 (m, 1H, H-3a), 1.90–1.83 (m,
2H, H-4), 1.82–1.73 (m, 1H, H-3b), 1.18 (s, 9H, C(CH3)3). 13C NMR, HSQC, HMBC (100.6
MHz, CDCl3): A, δ/ppm = 154.3 (Cq), 154.2 (Cq), 149.8 (2C, C-2´,6´), 120.8 (2C, C-3´,5´), 79.9
(C(CH3)3), 60.0 (C-2), 47.4 (C-5), 34.4 (C-3), 28.6 (C(CH3)3), 23.7 (C-4); B, δ/ppm = 154.3 (Cq),
154.2 (Cq), 149.8 (2C, C-2´,6´), 120.8 (2C, C-3´,5´), 79.9 (C(CH3)3), 60.6 (C-2), 47.2 (C-5), 35.6
(C-3), 28.2 (C(CH3)3), 23.3 (C-4). ESI-MS (pos.): m/z = 249.1 (100%, [M+H]+), 193.1 (6%, [M–
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tBu+H]+). ESI-HRMS (pos.): calculated for [C14H21N2O2]+: m/z = 249.1603, found: 249.1608.
The product gives two sets of NMR signals, due to the presence of rotamers (A/B = 0.36/0.64).
The spectral data are consistent with those reported in the literature.18
tert-Butyl (2-phenyl-1-(pyridin-4-yl)ethyl)carbamate (3). Prepared according to the general
procedure A using 4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and Boc-L-Phe-OH
(955 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
c
chromatography (SiO2, Hex/EtOAc 2:1) afforded the title compound (281 mg, 942 µmol, 78%)
as a colorless solid. Rf = 0.10 (SiO2, cHex/EtOAc 2:1). Mp: 117.2–118.4 °C. IR (ATR): ꢀ [cm–1]
̅
1
= 3236, 3029, 2977, 1707, 1601, 1525, 1497, 1366, 1251, 1169. H NMR, COSY (400 MHz,
CDCl3): δ/ppm = 8.55 (br s, 2H, H-2´´,6´´), 7.28–7.19 (m, 3H, H-3´,4´,5´), 7.12 (br s, 2H, H-
3´´,5´´), 7.03–7.01 (m, 2H, H-2´,6´), 4.95 (br s, 2H, NH, H-1), 3.05–2.98 (m, 2H, H-2), 1.37 (s,
9H, C(CH3)3).13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 155.1 (CO), 150.0 (2C,
C-2´´,6´´), 149.9 (C-4´´), 136.3 (C-1´), 129.4 (C-3´,5´), 128.7 (C-2´,6´), 127.1 (C-4´), 121.7 (2C,
C-3´´,5´´), 80.2 (C(CH3)3), 55.1 (C-1), 42.7 (C-2), 28.4 (C(CH3)3). ESI-MS (pos.): m/z = 299.2
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(100%, [M+H]+), 243.1 (4%, [M–tBu+H]+). ESI-HRMS (pos.): calculated for [C18H23N2O2]+: m/z
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= 299.1760, found: 299.1757.
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tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-(pyridin-4-yl)butanoate (4). Prepared according
to the general procedure A using 4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and
Cbz-L
-Glu(O-tBu)-OH (1.22 g, 3.60 mmol, 3.00 equiv.). Purification of the crude product by
flash column chromatography (SiO2, cHex/EtOAc 1:1) afforded the title compound (305 mg, 823
c
µmol, 69%) as a colorless oil. Rf = 0.19 (SiO2, Hex/EtOAc 1:1). IR (ATR): ꢀ
̅
/ [cm–1] = 3324,
1
3032, 2978, 1720, 1601, 1530, 1454, 1367, 1251, 1150. H-NMR, COSY (400 MHz, CDCl3):
δ/ppm = 8.55 (d, J ≈ 5.4 Hz, 2H, H-2´,6´), 7.33 (br s, 5H, Ph-H), 7.20 (d, J ≈ 5.4 Hz, 2H, H-
3´,5´), 5.61 (d, J = 7.7 Hz, 1H, NH), 5.12–5.00 (m, 2H, Ph-CH2O), 4.70 (app q, J = 7.1 Hz, 2H,
H-4), 2.30 (t, J = 7.0 Hz, 2H, H-2), 2.01 (app q, J = 7.0 Hz, 2H, H-3), 1.43 (s, 9H, OC(CH3)3).
13C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 172.6 (C-1), 155.9 (NCO), 151.4 (C-
4´), 150.1 (2C, C-2´,6´), 136.3 (C-1´´), 128.6/128.3 (5C, CH of phenyl group), 121.4 (2C, C-
3´,5´), 81.2 (OC(CH3)3), 67.1 (CH2O), 54.6 (C-4), 32.2 (C-2), 30.8 (C-3), 28.2 (OC(CH3)3). ESI-
MS (pos.): m/z = 393.2 (6%, [M+Na]+), 371.2 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C21H27N2O4]+: m/z = 371.1971, found: 371.1967.
tert-Butyl ((((9H-fluoren-9-yl)methoxy)carbonyl)-l-alanyl)(2-methyl-1-(pyridin-4-yl)propyl)
carbamate (5). Prepared according to the general procedure A using 4-cyanopyridine (125 mg,
1.20 mmol, 1.00 equiv.) and Fmoc-
L-Ala-
L-Val-OH (1.45 g, 3.60 mmol, 3.00 equiv.).
c
Purification of the crude product by flash column chromatography (SiO2, Hex/EtOAc 1:3)
afforded the title compound (291 mg, 656 µmol, 55%) as a colorless solid. Rf = 0.14 (SiO2,
cHex/EtOAc 1:3). Mp: 84.6–85.2 °C. IR (ATR): ꢀ [cm–1] = 3305, 3040, 2965, 2935, 1662, 1601,
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1537, 1450, 1255, 737. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.52–8.50/8.44–8.42 (m,
1H/ m, 1H, H-2´´,6´´), 7.76 (d, J = 7.5 Hz, 2H, H-4´,5´), 7.55 (app t, J = 7.3 Hz, 2H, H-1´,8´),
7.39 (app t, J = 7.5 Hz, 2H, H-3´,6´), 7.31–7.26 (m, 2H, H-2´,7´), 7.12/7.08–7.06 (d, J = 5.5 Hz,
1H/m, 1H, H-3´´,5´´), 6.99–6.93 (m, 1H, NHCH(pyridin-4-yl)), 5.56 (s, 1H, NHCH(CH3)), 4.73–
4.66 (m, 1H, CH(pyridin-4-yl)), 4.43–4.37 (m, 2H, CH2O), 4.37–4.26 (m, 1H, NHCH(CH3)),
4.23–4.16 (m, 1H, H-9´), 2.05–1.90 (m, 1H, CH(CH3)2), 1.40/1.35 (d, J = 6.8 Hz, 1H/d, J = 6.8
Hz, 2H, NHCH(CH3)), 0.84 (td, J = 15.7, 6.8 Hz, 6H, CH(CH3)2). 13C-NMR, HSQC, HMBC
(100.6 MHz, CDCl3): δ/ppm = 172.0 (N(CO)C), 156.6 (N(CO)O), 150.4 (C-4´´), 150.0/149.9
(2C, C-2´´,6´´), 143.7 (2C, C-8´a,9´a), 141.4 (2C, C-4´a,4´b), 128.0 (2C, C-3´,6´), 127.2 (2C, C-
2´,7´), 125.0 (2C, C-1´,8´), 122.1 (2C, C-3´´,5´´), 120.2 (2C, C-4´,5´), 67.4 (CH2O), 58.4
(CH(pyridin-4-yl)), 50.6 (NHCH(CH3)), 47.1 (C-9´), 33.0 (CH(CH3)2), 19.8/19.7 (1C,
CH(CH3)2), 18.4/18.2/18.1 (2C, CH(CH3)2, NHCH(CH3)). ESI-MS (pos.): m/z = 466.2 (5%,
[M+Na]+), 444.3 (100%, [M+H]+). ESI-HRMS (pos.): calculated for [C27H30N3O3]+: m/z =
444.2287, found: 444.2296.
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4-(Tetrahydrofuran-2-yl)pyridine (6). Prepared according to the general procedure A using
4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and tetrahydrofuran-2-carboxylic acid
(418 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
chromatography (SiO2, cHex/EtOAc 1:1) afforded the title compound (98 mg, 657 µmol, 55%) as
c
a colorless liquid. Rf = 0.17 (SiO2, Hex/EtOAc 1:1). IR (ATR): ꢀ
̅
[cm–1] = 3027, 2976, 2871,
1
1600, 1559, 1412, 1364, 1320, 1062, 924. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.54–
8.52 (m, 2H, H-2,6), 7.23–7.21 (m, 2H, H-3,5), 4.88 (t, J = 7.1 Hz, 1H, H-2´), 4.10–4.04 (m, 1H,
H-5´a), 3.97–3.91 (m, 1H, H-5´b), 2.41–2.32 (m, 1H, H-3´a), 2.03–1.92 (m, 2H, H-4´), 1.79–1.70
(m, 1H, H-3´b). 13C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 152.9 (C-4), 149.9 (C-
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2,6), 120.6 (C-3,5), 79.2 (C-2´), 69.1 (C-5´), 34.4 (C-3´), 26.0 (C-4´). ESI-MS (pos.): m/z =
150.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for [C9H12NO]+: m/z = 150.0919, found:
150.0916.
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Phenyl(pyridin-4-yl)methanol (7). Prepared according to the general procedure A using
4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and (S)-(+)-mandelic acid (548 mg,
3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column chromatography
c
(SiO2, Hex/EtOAc 1:2) afforded the title compound (171 mg, 923 µmol, 77%) as a colorless
c
solid. Rf = 0.19 (SiO2, Hex/EtOAc 1:2). Mp: 122.1–123.8 °C, lit.43: 120–122 °C. IR (ATR):
1
ꢀ̅
[cm–1] = 3358, 3192, 2986, 1600, 1494, 1453, 1415, 1189, 1051, 1004. H-NMR, COSY (400
MHz, CDCl3): δ/ppm = 8.29–8.26 (m, 2H, H-2´,6´), 7.32–7.27 (m, 7H, Ph-H, H-3´,5´), 5.72 (s,
13
1H, H-1), 5.43 (br s, 1H, OH). C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 153.7
(C-4´), 149.1 (2C, C-2´,6´), 143.2 (C-1´´), 128.8 (2C, CH of phenyl group), 128.1 (CH of phenyl
group), 126.9 (2C, CH of phenyl group), 121.5 (2C, C-3´,5´), 74.7 (C-1). ESI-MS (pos.): m/z =
186.0 (100%, [M+H]+). ESI-HRMS (pos.): calculated for [C12H12NO]+: m/z = 186.0919, found:
186.0948. The spectral data are consistent with those reported in the literature.43
4-Benzylpyridine (8) was prepared according to the general procedure A using 4-cyanopyridine
(125 mg, 1.20 mmol, 1.00 equiv.) and phenylacetic acid (490 mg, 3.60 mmol, 3.00 equiv.).
c
Purification of the crude product by flash column chromatography (SiO2, Hex/EtOAc 2:1)
afforded the title compound (107 mg, 632 µmol, 53%) as a yellow oil. Rf = 0.24 (SiO2,
cHex/EtOAc 2:1). IR (ATR): ꢀ [cm–1] = 3065, 3027, 2921, 1596, 1559, 1495, 1415, 1219, 1071,
̅
1
994. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.49 (d, J = 5.7 Hz, 2H, H-2,6), 7.34–7.29
(m, 2H, H-3´,5´), 7.27–7.22 (m, 1H, H-4´), 7.19–7.16 (m, 2H, H-2´,6´), 7.11–7.08 (m, 2H, H-
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3,5), 3.96 (s, 2H, CH2). C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 150.0 (C-4),
149.9 (2C, C-2,6), 138.9 (C-1´), 129.1 (2C, C-2´,6´), 128.8 (2C, C-3´,5´), 126.8 (C-4´), 124.3
(2C, C-3,5), 41.3 (CH2).
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ESI-MS (pos.): m/z = 170.0 (100%, [M+H]+). The spectral data are consistent with those reported
in the literature.44
4-(3,4-dimethoxybenzyl)pyridine (9). Prepared according to the general procedure A using
4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and homoveratric acid (706 mg, 3.60 mmol,
3.00 equiv.). Since no non-volatile byproducts are formed, the title compound (254 mg, 1.11
mmol, 93%) can be isolated without column chromatography as a yellow oil. Rf = 0.20 (SiO2,
cHex/EtOAc 1:2). IR (ATR): ꢀ [cm–1] = 2998, 2935, 2835, 1597, 1513, 1463, 1415, 1260, 1237,
̅
1
1139. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.46 (br s, 2H, H-2,6), 7.07 (d, J = 5.0 Hz,
2H, H-3,5), 6.79 (d, J = 8.2 Hz, 1H, H-5´), 6.69 (dd, J = 8.2, 1.8 Hz, 1H, H-6´), 6.64 (d, J = 1.8
13
Hz, 1H, H-2´), 3.88 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3). C-NMR, HSQC,
HMBC (100.6 MHz, CDCl3): δ/ppm = 150.4 (C-4), 149.8 (C-2,6), 149.1 (C-3´), 147.8 (C-4´),
131.3 (C-1´), 124.1 (2C, C-3,5), 121.1 (C-6´), 112.2 (C-2´), 111.3 (C-5´), 55.9/55.8 (2C, OCH3),
40.8 (CH2). ESI-MS (pos.): m/z = 230.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C14H16NO2]+: m/z = 230.1181, found: 230.1180.
4-(1-Methylcyclohexyl)pyridine (10). Prepared according to the general procedure A using
4-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and 1-methylcyclohexane-1-carboxylic acid
(512 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
chromatography (SiO2, cHex/EtOAc 3:1) afforded the title compound (69 mg, 394 µmol, 33%) as
a slightly yellow oil. Rf = 0.15 (SiO2, cHex/EtOAc 3:1). IR (ATR): ꢀ [cm–1] = 2928, 2858, 1595,
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1549, 1454, 1409, 1303, 1225, 996, 818. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.52–
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6
8.50 (m, 2H, H-2,6), 7.27–7.25 (m, 2H, H-3,5), 2.02–1.93 (m, 2H), 1.60–1.52 (m, 4H), 1.48–1.32
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(m, 4H), 1.17 (s, 3H, CH3). C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 159.2 (C-
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4), 149.9 (2C, C-2,6), 121.6 (2C, C-3,5), 38.2 (C-1´), 37.3 (2C, CH2), 30.1 (CH3), 26.3 (CH2),
22.6 (2C, CH2). ESI-MS (pos.): m/z = 176.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C12H18N]+: m/z = 176.1439, found: 176.1443.
This compound was also obtained from 1-methylcyclohexan-1-ol which was first converted to
cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate according to a procedure by Overman et al..34
This oxalate (859 mg, 2.70 mmol, 3.00 equiv.) was then reacted with 4-cyanopyridine (94.0 mg,
900 µmol, 1.00 equiv.) according to the general procedure B. Purification of the crude product by
c
flash column chromatography (SiO2, Hex/EtOAc 5:1) afforded the title compound (88.0 mg,
502 µmol, 56%) as a slightly yellow oil. Analytical data as reported above.
tert-Butyl (1-(4-cyanophenyl)-2-methylpropyl)carbamate (11). Prepared according to the
general procedure A using 1,4-dicyanobenzene (154 mg, 1.20 mmol, 1.00 equiv.) and
Boc-
L-Val-OH (782 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash
c
column chromatography (SiO2, Hex/EtOAc 10:1) afforded the title compound (261 mg, 951
c
µmol, 79%) as a colorless solid. Rf = 0.17 (SiO2, Hex/EtOAc 10:1). Mp: 132.3–133.5 °C, lit.27:
135–136 °C. IR (ATR): ꢀ̅
[cm–1] = 3356, 2972, 2933, 2875, 2229, 1696, 1609, 1505, 1390, 1366.
1H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 7.62–7.59 (m, 2H, H-2´,6´), 7.32 (d, J = 8.2 Hz,
2H, H-3´,5´), 4.96 (s, 1H, NH), 4.46/4.25 (s, 1H, H-1), 2.01–1.90 (m, 1H, H-2), 1.40 (s, 9H,
C(CH3)3), 0.91 (d, J = 6.7 Hz, 3H, CH(CH3)(CH3)), 0.84 (d, J = 6.7 Hz, 3H, CH(CH3)(CH3)).
13C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 155.5 (CO), 148.0 (C-1´), 132.3 (2C,
C-2´,6´), 127.6 (2C, C-3´,5´), 119.0 (CN), 110.9 (C-4´), 80.0 (C(CH3)3), 60.5 (C-1), 33.6 (C-2),
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28.4 (C(CH3)3), 19.7 ((CH(CH3)(CH3)), 18.3 ((CH(CH3)(CH3)). ESI-MS (pos.): m/z = 297.1
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(13%, [M+Na]+), 275.1 (9%, [M+H]+), 219.1 (100%, [M–tBu+H]+). ESI-HRMS (pos.):
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calculated for [C16H22N2O2Na]+: m/z = 297.1579, found: 297.1591. H-1 gives two resonances in
the 1H NMR spectrum due to the hindered rotation around the CO–N-bond. The spectral data are
consistent with those reported in the literature.18
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Methyl 4-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)benzoate (12). Prepared according
to the general procedure A using methyl 4-cyanobenzoate (193 mg, 1.20 mmol, 1.00 equiv.) and
Boc-
L-Val-OH (782 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash
c
column chromatography (SiO2, Hex/EtOAc 7:1) afforded the title compound (199 mg, 647
c
µmol, 54%) as a colorless foam. Rf = 0.21 (SiO2, Hex/EtOAc 7:1). IR (ATR): ꢀ
̅
[cm–1] = 3370,
1
2965, 2932, 2874, 1700, 1518, 1366, 1280, 1170, 1113. H-NMR, COSY (400 MHz, CDCl3):
δ/ppm = 8.01–7.97 (m, 2H, H-2,6), 7.28 (d, J = 8.3 Hz, 2H, H-3,5), 4.91 (br s, 1H, NH),
4.48/4.31 (br s, 1H, H-1´), 3.90 (s, 3H, CO2CH3), 2.05–1.88 (m, 1H, H-2´), 1.40 (br s, 9H,
C(CH3)3), 0.92 (d, J = 6.7 Hz, 3H, CH(CH3)(CH3)), 0.84 (d, J = 6.7 Hz, 3H, CH(CH3)(CH3)).
13C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 167.1 (CO2CH3), 155.6 (COC(CH3)3),
147.7 (C-4), 129.8 (2C, C-2,6), 129.0 (C-1), 126.9 (2C, C-3,5), 79.8 (C(CH3)3), 60.5 (C-1´), 52.2
(CO2CH3), 33.8 (C-2´), 28.5 (3C, C(CH3)3), 19.8/18.5 (2C, CH(CH3)2). ESI-MS (pos.): m/z =
330.2 (33%, [M+Na]+), 252.1 (100%, [M–tBu+H]+). ESI-HRMS (pos.): calculated for
1
[C17H25NO4Na]+: m/z = 330.1681, found: 330.1678. H-1 gives two resonances in the H-NMR
spectrum due to the hindered rotation around the CO–N-bond.
2-(3,4-dimethoxybenzyl)pyridine (13). Prepared according to the general procedure A using
2-cyanopyridine (125 mg, 1.20 mmol, 1.00 equiv.) and homoveratric acid (706 mg, 3.60 mmol,
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3.00 equiv.). Purification of the crude product by flash column chromatography (SiO2,
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6
cHex/EtOAc 1:1) afforded the title compound (149 mg, 650 µmol, 54%), as a slightly yellow oil.
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8
9
c
Rf = 0.21 (SiO2, Hex/EtOAc 1:1). IR (ATR): ꢀ
̅
[cm–1] = 3062, 3003, 2935, 2834, 1590, 1512,
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1464, 1259, 1236, 1139. 1H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.55–8.53 (m, 1H, H-6),
7.57 (app td, J = 7.7, 1.9 Hz, 1H, H-4), 7.12–7.09 (m, 2H, H-3,5), 6.81–6.79 (m, 3H, H-2´,5´,6´),
4.09 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3). 13C-NMR, HSQC, HMBC (100.6
MHz, CDCl3): δ/ppm = 161.4 (C-2), 149.4 (C-6), 149.1/147.7 (2C, C-3´,4´), 136.7 (C-4), 132.2
(C-1´), 123.1/121.3 (2C, C-3,5), 121.2/112.4/111.4 (3C, C-2´,5´6´), 56.0/55.9 (2C, OCH3), 44.4
(CH2). ESI-MS (pos.): m/z = 230.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C14H16NO2]+: m/z = 230.1181, found: 230.1190.
2-(3,4-dimethoxybenzyl)-3-methylpyridine (14). Prepared according to the general procedure A
using 2-cyano-3-methylpyridine (142 mg, 1.20 mmol, 1.00 equiv.) and homoveratric acid
(706 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
c
chromatography (SiO2, Hex/EtOAc 1:1) afforded the title compound (194 mg, 797 µmol, 66%)
c
as a slightly yellow oil. Rf = 0.19 (SiO2, Hex/EtOAc 1:1). IR (ATR): ꢀ
̅
[cm–1] = 2998, 2953,
1
2834, 1589, 1514, 1464, 1448, 1260, 1140, 1028. H-NMR, COSY (400 MHz, CDCl3): δ/ppm =
8.42–8.40 (m, 1H, H-6), 7.42–7.39 (m, 1H, H-4), 7.07 (dd, J = 7.6, 4.9 Hz, 1H, H-5), 6.76–6.73
(m, 2H, Ph-H), 6.70–6.68 (m, 1H, Ph-H), 4.11 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 2.25 (s, 3H, CH3). 13C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 159.1 (C-2),
148.9/147.5 (2C, C-3´,4´), 146.8 (C-6), 138.1 (C-4), 131.8/131.6 (2C, C-3,1´), 121.8 (C-5), 120.7
(CH of phenyl group), 112.1/111.1 (2C, CH of phenyl group), 55.9 (2C, OCH3), 41.9 (CH2), 19.1
(CH3). ESI-MS (pos.): m/z = 244.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C15H18NO2]+: m/z = 244.1338, found: 244.1337.
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5-chloro-2-(3,4-dimethoxybenzyl)pyridine (15). Prepared according to the general procedure A
using 5-chloro-2-picolinonitrile (166 mg, 1.20 mmol, 1.00 equiv.) and homoveratric acid
(706 mg, 3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column
c
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chromatography (SiO2, Hex/EtOAc 5:1) afforded the title compound (116 mg, 440 µmol, 37%)
c
as a colorless oil. Rf = 0.15 (SiO2, Hex/EtOAc 5:1). IR (ATR): ꢀ
̅
[cm–1] = 3000, 2934, 2835,
1
1514, 1466, 1261, 1238, 1139, 1029, 804. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.46 (d,
J = 2.5 Hz, 1H, H-6), 7.50 (dd, J = 8.3, 2.5 Hz, 1H, H-4), 7.02 (d, J = 8.3 Hz, 1H, H-3), 6.81–
6.72 (m, 3H, Ph-H), 4.03 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 3.80 (s, 3H, OCH3). 13C-NMR,
HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 159.5 (C-2), 149.0 (C3´ or C-4´), 148.0 (C-6),
147.7 (C3´ or C-4´), 136.2 (C-4), 131.5 (C-1´), 129.6 (C-5), 123.7 (C-3), 121.0 (CH of phenyl
group), 112.2 (CH of phenyl group), 111.3 (CH of phenyl group), 55.9/55.8 (2C, OCH3), 43.6
(CH2). ESI-MS (pos.): m/z = 264.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C14H15NO2Cl]+: m/z = 264.0791, found: 264.0788.
2-(3,4-dimethoxybenzyl)pyrimidine (16). Prepared according to the general procedure A using
2-cyanopyrimidine (126 mg, 1.20 mmol, 1.0 equiv.) and homoveratric acid (706 mg, 3.60 mmol,
3.0 equiv.). Purification of the crude product by flash column chromatography (SiO2,
cHex/EtOAc 1:4) afforded the title compound (93 mg, 404 µmol, 34%) as a colorless foam. Rf =
c
0.19 (SiO2, Hex/EtOAc 1:4). IR (ATR): ꢀ
̅
[cm–1] = 2999, 2936, 2834, 1561, 1515, 1417, 1261,
1234, 1140, 1028. 1H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.66 (d, J = 4.9 Hz, 2H, H-4,6),
7.10 (t, J = 4.9 Hz, 1H, H-5), 6.90–6.87 (m, 2H, Ph-H), 6.81–6.77 (m, 1H, Ph-H), 4.21 (s, 2H,
13
CH2), 3.83 (s, 3H, OCH3), 3.82 (s, 3H, OCH3). C-NMR, HSQC, HMBC (100.6 MHz, CDCl3):
δ/ppm = 170.3 (C-2), 157.4 (2C, C-4,6), 148.9/147.8 (2C, C-3´,4´), 130.8 (C-1´), 121.2 (CH of
phenyl group), 118.7 (C-5), 112.3 (CH of phenyl group), 111.3 (CH of phenyl group), 55.9 (2C,
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OCH3), 45.7 (CH2). ESI-MS (pos.): m/z = 253.0 (2%, [M+Na]+), 231.1 (100%, [M+H]+). ESI-
HRMS (pos.): calculated for [C13H15N2O2]+: m/z = 231.1134, found: 231.1136.
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1-(3,4-dimethoxybenzyl)isoquinoline (17). Prepared according to the general procedure using
1-cyanoisoquinoline (185 mg, 1.20 mmol, 1.00 equiv.) and homoveratric acid (706 mg,
3.60 mmol, 3.00 equiv.). Purification of the crude product by flash column chromatography
(SiO2, cHex/EtOAc 2:1) afforded the title compound (263 mg, 962 µmol, 80%) as a brown foam.
c
Rf = 0.12 (SiO2, Hex/EtOAc 2:1). IR (ATR): ꢀ
̅
[cm–1] = 3052, 2999, 2934, 2834, 1514, 1463,
1
1259, 1234, 1141, 1028. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.50 (d, J = 5.8 Hz, 1H,
H-3), 8.19–8.16 (m, 1H, H-8), 7.81 (d, J = 8.2 Hz, H-5), 7.63 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H, H-6),
7.57–7.51 (m, 2H, H-4,7), 6.84 (d, J = 1.9 Hz, 1H, H-2´), 6.80 (dd, J = 8.2, 1.9 Hz, 1H, H-6´),
13
6.75 (d, J = 8.2 Hz, 1H, H-5´), 4.61 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3). C-
NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 160.4 (C-1), 149.0 (C-4´), 147.6 (C-3´),
142.1 (C-3), 136.7 (2C, C-4a,8a), 132.1 (C-1´), 130.0 (C-6), 127.5 (C-5), 127.3 (C-7), 125.9 (C-
8), 120.7 (C-6´), 119.9 (C-4), 112.0 (C-2´), 111.3 (C-5´), 55.9 (2C, OCH3), 41.8 (CH2). ESI-MS
(pos.): m/z = 302.1 (2%, [M+Na]+), 280.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for
[C18H18NO2]+: m/z = 280.1338, found: 280.1345. The spectral data are consistent with those
reported in the literature.45
4-(1-methylcyclopentyl)pyridine (21). 1-Methylcyclopentan-1-ol was first converted to
cesium 2-((1-methylcyclopentyl)oxy)-2-oxoacetate according to a procedure by Overman et al..34
This oxalate (821 mg, 2.70 mmol, 3.00 equiv.) was then reacted with 4-cyanopyridine (94.0 mg,
900 µmol, 1.00 equiv.) according to the general procedure B. Purification of the crude product by
c
flash column chromatography (SiO2, Hex/EtOAc 5:1) afforded the title compound (84.0 mg,
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521 µmol, 58%) as a slightly yellow oil. Rf = 0.16 (SiO2, cHex/EtOAc 5:1). IR (ATR): ꢀ [cm–1] =
̅
5
6
1
3023, 2958, 2872, 1597, 1550, 1450, 1410, 1330, 1223, 821. H-NMR, COSY (400 MHz,
7
8
9
CDCl3): δ/ppm = 8.49–8.46 (m, 2H, H-2,6), 7.22–7.19 (m, 2H, H-3,5), 1.90–1.68 (m, 8H), 1.23
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13
(s, 3H, CH3). C-NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm = 160.2 (C-4), 149.7 (2C,
C-2,6), 121.6 (2C, C-3,5), 47.0 (C-1´), 39.3 (2C, CH2), 28.8 (CH3), 23.8 (2C, CH2). ESI-MS
(pos.): m/z = 162.1 (100%, [M+H]+). ESI-HRMS (pos.): calculated for [C11H16N]+: m/z =
162.1283, found: 162.1281.
4-(1-phenylethyl)pyridine (23). 1-phenylethanol was first converted to cesium 2-oxo-2-(1-
phenylethoxy)acetate according to a procedure by Overman et al..34 This oxalate (880 mg,
2.70 mmol, 3.00 equiv.) was then reacted with 4-cyanopyridine (94.0 mg, 900 µmol, 1.00 equiv.)
according to the general procedure B. Purification of the crude product by flash column
chromatography (SiO2, cHex/EtOAc 3:1) afforded the title compound (82.0 mg, 447 µmol, 50%)
as a yellow oil. Rf = 0.19 (SiO2, cHex/EtOAc 3:1). IR (ATR): ꢀ [cm–1] = 3062, 3027, 2971, 2933,
̅
1
2876, 1595, 1494, 1452, 1413, 1220. H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 8.51–8.48
(m, 2H, H-2,6), 7.34–7.28 (m, 2H, Ph-H), 7.26–7.17 (m, 3H, Ph-H), 7.14–7.12 (m, 2H, H-3,5),
13
4.11 (q, J = 7.2 Hz, 1H, HC(CH3)), 1.64 (d, J = 7.2 Hz, 3H, CH3). C-NMR, HSQC, HMBC
(100.6 MHz, CDCl3): δ/ppm = 155.1 (C-4), 149.9 (2C, C-2,6), 144.5 (C-1´), 128.7 (2C, CH of
phenyl group), 127.7 (2C, CH of phenyl group), 126.7 (CH of phenyl group), 123.1 (2, C-3,5),
44.3 (HC(CH3)), 21.2 (CH3). ESI-MS (pos.): m/z = 184.1 (100%, [M+H]+). ESI-HRMS (pos.):
calculated for [C13H14N]+: m/z = 184.1126, found: 184.1124. The spectral data are consistent with
those reported in the literature.46
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Acknowledgements
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We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy and Dr. N. Hanold (Mainz) for
mass spectrometry. This work was supported by the Carl Zeiss foundation.
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Supporting Information
Detailed optimization studies for the coupling reactions reported herein, precise descriptions of
the used light sources, absorption spectra of phenanthrene in both reaction solvents, experiments
concerning halides as potential leaving groups and the recovery of excess radical precursor as
well as NMR spectra of all compounds including the cesium oxalates. This material is available
free of charge via the Internet at http://pubs.acs.org.
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