Sustainable Alkylation of Nitriles with Alcohols by Manganese Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00792

A general and chemoselective catalytic alkylation of nitriles using a homogeneous nonprecious manganese catalyst is presented. This alkylation reaction uses naturally abundant alcohols and readily available nitriles as coupling partners. The reaction tolerates a wide range of functional groups and heterocyclic moieties, efficiently providing useful cyanoalkylated products with water as the only side product. Importantly, methanol can be used as a C1 source and the chemoselective C-methylation of nitriles is achieved. The mechanistic investigations support the multiple role of the metal-ligand manganese catalyst, the dehydrogenative activation of the alcohol, α-C-H activation of the nitrile, and hydrogenation of the in-situ-formed unsaturated intermediate.

Full text of DOI:10.1021/acs.joc.9b00792

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Article
Sustainable Alkylation of Nitriles with Alcohols by Manganese Catalysis
Jannik C. Borghs, Mai Anh Tran, Jan Sklyaruk, Magnus Rueping, and Osama El-Sepelgy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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The Journal of Organic Chemistry
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Jannik C. Borghs,† Mai Anh Tran,† Jan Sklyaruk,† Magnus Rueping,† * and Osama El-Sepelgy†*
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡ KAUST Catalysis Center (KCC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900,
Saudi Arabia
ABSTRACT: A general and chemoselective catalytic alkylation of nitriles using a homogenous non-precious manganese catalyst is
presented. This alkylation reaction uses naturally abundant alcohols and readily available nitriles as coupling partners. The reaction
tolerates a wide range of functional groups and heterocyclic moieties, efficiently providing useful cyanoalkylated products with
water as the only side product. Importantly, methanol can be used as a C1 source and the chemoselective C-methylation of nitriles
is achieved. The mechanistic investigations support the multiple role of the metal-ligand manganese catalyst; the dehydrogenative
activation of the alcohol; α-C-H activation of the nitrile; and hydrogenation of the in-situ formed unsaturated intermediate.
selective manganese catalysed alkylation of non-activated
nitriles with a broad range of alcohols (Scheme 1). A related
The construction of C−C bonds via the hydrogen autotransfer
strategy is of particular academic and industrial interest. The
key motivation for this strategy is the application of alcohol
feedstock as a benign alkylating reagent,1 while liberating
water as the sole by-product. Thus, the procedure eliminates
the need for mutagenic alkyl halides and avoids the production
of copious waste. To date the majority of appropriate catalytic
systems are based on noble metals including Ru, Rh, Ir, Pd
and Pt.2 The low availability of these precious metals has
triggered the development of alternative catalytic systems
based on earth abundant metals.3 In this context, progress has
been made in the alkylation of ketones,4 alcohols,5 esters,6 and
amides 6 using base metal catalysts. In contrast, the alkylation
of nitriles is more challenging due to the sensitivity of the
cyano group towards the activated hydrogen and the water
side product. In more detail, the metal catalyst can transfer
hydrogen from the alcohol to the nitriles to form primary
amines and aldehydes,7 and these can subsequently be con-
verted to secondary amines8 or amides.9 However, water might
result in the hydrolysis of the nitrile functionality to the corre-
sponding amide.10 In addition, the alkylation of nitriles with
alcohols often leads to a mixture of the alkylnitrile product
along with the corresponding olefin intermediate,11 giving rise
to critical selectivity issues. Thus, until recently, the direct
alkylation of nitriles with alcohols was only known with pre-
cious metal catalysis such as Ru,12 Ir,13 Rh,14 Os15 and Pd.16
study has also been reported by Maji et. al.23 In our study we
focused on a catalytic system that utilizes a bench stable cata-
lyst which can easily be prepared in one step from the com-
mercially available and air stable MACHO ligand and
Mn(CO)5Br. Interestingly, the presented catalytic system is not
limited to the long-chain alcohols as the more challenging C-
alkylation can also be achieved with methanol as C1-source.
Furthermore, the manganese catalyst does not require any
sensitive reagents for activation and is simply activated with
catalytic amounts of suitable base.
Scheme 1. Manganese Catalyzed Alkylation of Nitriles
with Alcohols
In order to develop the base metal catalyzed alkylation reac-
tion we started to investigate the reaction between
phenylacetonitrile (1a) and the n-butanol (2a) applying differ-
ent manganese catalysts (Table 1). Initially, we screened the
catalytic activity of the different manganese complexes Mn-1
to Mn-3 in toluene using t-BuOK as the catalyst activator. The
pyridyl-based PNP complex Mn-122j led to unsatisfactory
results providing only a trace amount of the product (Table 1,
entry 1). However, in the presence of the complex Mn-2,22k
bearing an aliphatic NH group, excellent conversion was ob-
served and 86% of the desired product 3a along with 11 % of
the unsaturated olefin 3a’(Table 1, entry 2) was obtained. Use
of the Mn-PNN pincer complex Mn-320b (Table 1, entry 3)
provided similar results. Due to the facile access of Mn-2 and
the availability of the ligand, we decided to further optimize
the model reaction using Mn-2 in combination with different
bases and solvents. Running the reaction using equimolar
amounts of the manganese and the base, resulted in 66% con-
Our interest in the development of an improved synthesis of
alkylnitriles is due to their great importance as valuable inter-
mediates in the fine chemical industry. Importantly, the
cyanoalkyl moiety is also ubiquitous in different natural prod-
ucts and pharmaceuticals.17 Very recently, Wang and co-
workers have reported an interesting iron catalysed alkylation
of nitriles with primary alcohols, by applying stoichiometric
amount of strong base (NaOH).18 Pursuant to our interest in
developing sustainable transformations based on nonprecious
metal catalysis,19 and inspired by the recent advances in man-
ganese catalysis,20-22 we herein report highly reactive and
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version and 47% combined yield of 3a and 3a’ (Table 1, entry
Scheme 2. Manganese Catalyzed Alkylation of Nitriles
with Different Alcohols.
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4). Using polar solvents such as t-amyl alcohol, 1,4-Dioxane
or 2-Me-THF, did not lead to improved results (Table 1, en-
tries 5-7). In addition, we tested various bases including KOH,
K2CO3 and Cs2CO3 (Table 1, entries 8-10). From these exper-
iments the best results were obtained using Cs2CO3 and the
desired product was obtained in 79% yield along with 8% of
the alkenyl nitrile 3a’. Pleasingly, slightly increasing the base
loading to 10 mol % led to quantitative yield with complete
chemoselectivity (Table 1, entry 11).
9
Table 1. Optimization of the Reaction Conditions.a
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base
(mol %)
conv.
(%)
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97
96
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78
>99
84
>99
>99
yield
3a/3a’(%)
>5/>5
86/11
70/09
35/12
77/12
25/06
60/10
96/04
67/12
79/08
99/00
entry
cat.
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3
Mn-1
Mn-2
Mn-3
Mn-2
Mn-2
Mn-2
Mn-2
Mn-2
Mn-2
Mn-2
Mn-2
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (1)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
KOH (3)
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5b
6c
7d
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11
K2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (10)
aReaction conditions: 1a (0.5 mmol), 2a (1 mmol), [Mn]
(0.005 mmol) and base in toluene (0.5 mL) at 135 °C in a
glass tube under an inert atmosphere for 18 h. Conversions
and yields were determined by GC analysis of the crude reac-
tion mixture using mesytilene as an internal standard.
bReaction in t-amyl alcohol. cReaction in 2-Me THF.
dReaction in 1,4-dioxane.
Having established the optimized reaction conditions, we next
investigated the generality of this protocol by exploring the
scope of the nitrile alkylation partner (Scheme 2A). To our
delight, in all cases the reaction was accomplished within 18 h
using 1 mol % of the bench stable catalyst Mn-2. Notably, a
diverse range of substituted benzyl cyanides can be used to
yield the C-alkylated nitriles derivatives 3b – 3g in very good
yields and with excellent chemoselectivity. It is important to
highlight that the benzonitrile moiety was tolerated to give the
desired product 3h. Importantly, heterocycle containing
benzylic nitriles, such as 3i and 3j can also be efficiently al-
kylated.
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), Mn-2 (0.005
We next decided to explore the scope of primary alcohols as
alkylating agents (Scheme 2B). Importantly, a large array of
benzyl alcohols bearing electron withdrawing and electron
donating groups in different positions could be applied to give
mmol), Cs2CO3 (0.05 mmol), toluene (0.5 mL), 135 °C (alu-
b
c
minum block), 18 h. Mn-2 (0.025 mmol). Reaction condi-
tions: 1 (0.5 mmol), methanol (1 mL), Mn-2 (0.025 mmol),
Cs2CO3 (0.05 mmol), 1,4-dioxane (1 mL), 24 h.
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the desired products 4a-4f in very good isolated yields. Fur-
the α-alkylated nitrile 3 via a metal-ligand cooperative mecha-
nism.
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thermore, a naphthyl-substituted product 4g was obtained in
83% yield. Similar to the scope of the nitrile, alcohols bearing
heterocyles (pyridine, thiophene, furane) could also be used to
access the corresponding products 4h-4k. Moreover, this
protocol is not limited to benzlic alcohols, as exemplified by
the rapid incorporation of different aliphatic alcohols under the
same reaction conditions (4l-4p), whereby unsaturated C=C
bonds remain intact (4o).
100
80
60
40
20
0
1a
3a
3a'
However, a higher activation energy barrier needs to be
overcome for the dehydrogenation of the methanol compared
with other alcohols, our catalytic system proved to be suitable
for the challenging α-methylation of nitriles. Slightly modified
reaction conditions have to be used to successfully accomplish
the C1-alkylation. Indeed, a broad series of differently substi-
tuted nitriles, including heterocycles, can be methylated to
deliver the products 5a–5h in moderate to good yields
(Scheme 2C). Interestingly, our base metal catalyzed proce-
dure shows superior catalytic activity to the recently disclosed
Ru-catalyzed protocol.12a
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0
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Time [h]
Figure 1. Monitoring of the reaction progress (reaction condi-
tions as in table 1, entry 11).
In order to gain more insight into the reaction mechanism we
monitored the reaction progress between phenylacetonitrile
(1a) and 1-butanol (2a) catalyzed by Mn-2 (Figure 1). After 1
hour, we observed 83% of conversion of the nitrile 1a and the
formation of 66% yield of 3a along with 15% of the unsaturat-
ed intermediate 3a’. After 3 hours, almost full conversion of
1a was obtained with 80% yield of the 3a, while the amount of
the remaining intermediate 3a’ was still constant (ca.15 %).
Complete conversion was observed after 18 hours. Subse-
quently, we decided to carry out several control NMR experi-
ments (Figure 2). The treatment of Mn-2 with one equivalent
of t-BuOK at room temperature for one hour in C6D6 led to the
formation of the soluble imido complex Mn-2a as confirmed
by the 31P-NMR spectrum (91.02 ppm). When one equivalent
of 4-flurophenylacetonitrile was added, we immediately ob-
served the formation of two new broad peaks at 73.65 and
78.82 ppm at 31P-NMR, indicating the coordination between
the manganese catalyst and the nitrile substrate.
Figure 2. 31P NMR spectra at RT. a) Mn-2 in CD2Cl2. b) Mn-
2 + 1 equiv. t-BuOK in C6D6. c) Mn-2 + 1 equiv. of t-
BuOK+1 equiv. of 4-flurophenylacetonitrile in C6D6.
Scheme 3. Proposed Reaction Mechanism
Based on the experimental background and the DFT studies, a
proposed reaction mechanism is shown in Scheme 3. Initially,
the manganese pre-catalyst reacts with the base to generate an
imido complex as the active catalytic species (Scheme 3a).
This imido complex activates the alcohol via dehydrogenation
with the simultaneous formation of the manganese species
H-Mn-N-H. Most likely, this reaction takes place via the for-
mation of a Mn-alkoxide intermediate. In addition to the role
of the manganese catalyst in the alcohol activation, the NMR
experiment indicates the role of the metal catalyst in the C-H
activation of the nitrile substrate. 24 The two new broad peaks
in figure 2c most likely correlate to the species A and B in
scheme 3b. The initial coordination of the nitrile substrate with
the 16e species lead to the formation of the molecule A. Then,
the ligand plays a crucial role for the hydrogen abstraction and
the generation of the highly nucleophilic species B.25 Thus, the
same metal catalyst simultaneously activates both of the sub-
strates to produce the electrophile (aldehyde) and nucleophile
B. the addition of the intermediate B to the in-situ generated
aldehyde delivers the intermediate C and one molecule of
water. This intermediate leads to the formation of the olefin
intermediate 3’ and regenerates the Mn-2a. Finally, the shut-
tled hydrogen on the H-Mn-N-H is transferred to 3’ to produce
In summary, manganese PNP pincer catalyzed alkylation of
nitriles with alcohols is reported. This environmentally benign,
hydrogen autotransfer reaction is characterized by the absence
of noble metals and stoichiometric reagents, generating water
as the only side product. A broad range of alcohols could be
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dichloromethane/diethylether to remove insoluble inorganic side
used as green alkylating reagents and, importantly, the chal-
lenging methylation reaction is feasible, resulting in the de-
sired C-methylated nitriles with excellent chemo-selectivity.
The experimental studies support the reaction mechanism in
which the manganese catalyst plays a multiple role in activat-
ing both the reaction partners as well as the subsequent hydro-
genation of the alkenyl nitrile to selectively produce the highly
value-added α-alkylated nitriles.
products. The solution was concentrated under reduced pressure and
dried to afford the complex Mn-2 as a yellow powder (410 mg, 65%).
1H NMR (600 MHz, CD2Cl2) δ 7.92 – 7.89 (m, 4H, CHAr), 7.60 –
7.57 (m, 4H, CHAr), 7.43 – 7.29 (m, 12H, CHAr), 3.74 – 3.59 (m, 2H,
NCH2CH2), 3.52 (br, 1H, NH), 3.32 – 3.23 (m, 2H, NCH2CH2), 2.78
– 2.73 (m, 2H, NCH2CH2), 2.44 – 2.40 (m, 2H, NCH2CH2); 31P{1H}
NMR (243 MHz, CD2Cl2) δ = 69.7 (s); 13C{1H} NMR (151 MHz,
CD2Cl2) δ =231.6 (br, CO), 226.0 (br, CO), 137.9 (vt, J = 19.1 Hz,
PCAr,ipso), 135.5 (vt, J = 19.1 Hz, PCAr, ipso), 133.8 (vt, J = 5.0 Hz,
CHAr), 130.6 (vt, J = 5.0 Hz, CHAr), 130.3 (s, CHAr), 129.6 (s, CHAr),
129.0 (vt, J = 4.3 Hz, CHAr), 128.7 (vt, J = 4.6 Hz, CHAr), 53.0 (vt, J
= 4.7 Hz, NCH2CH2), 28.4 (vt, J = 8.9 Hz, NCH2CH2); IR (ATR): ν–1
3189, 1910, 1826 cm-1; HRMS (ESI+): m/z [M – Br]+: calcd for
C30H29MnNO2P2, 552.1049; found, 552.1050.
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General Method
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All reactions were carried out under an argon atmosphere using oven-
dried glassware. Purified compounds were further dried under high
vacuum (0.01–0.05 Torr). Yields refer to purified compounds. Ana-
lytical thin-layer chromatography (TLC) was performed using silica
gel 60 pre-coated aluminium plates (Macherey-Nagel 0.20 mm thick-
ness) with a fluorescent indicator UV254. Visualization was per-
formed with standard phosphomolybdic acid stain (10g in 100 mL
EtOH) or UV light. Column chromatography was performed using
Macherey-Nagel Aluminium oxide 90 neutral (50–200 μm). 1H-
NMR, 13C-NMR and 31P-NMR spectra were recorded on VNMRS-
400, VNMRS-600 or Mercury 300 spectrometer in CDCl3. Chemical
shifts (δ) are reported in ppm and multiplicities are indicated: s (sin-
glet), d (doublet), dd (doublet of doublet, t (triplet), dt (doublet of
triplet), td (triplet of doublet), q, (quartet), quint (quintet) m
(multiplet); coupling constants (J) are in Hertz (Hz). The abbreviation
“vt” corresponds to a “virtual triplet” due to scalar coupling with two
magnetically nonequivalent phosphorus nuclei. Mass spectra were
acquired on a Finnigan SSQ7000 (EI/CI) spectrometer and high
resolution mass spectra on a Finnigan MAT 95 (EI/CI) or on a
ThermoFisher Scientific LTQOrbitrap XL (ESI) using ion trap as
analyzer type. IR spectra were recorded on a Perkin Elmer Spectrum
100 spectrometer and are reported in terms of frequency of absorption
(cm-1).
Synthesis of dicarbonyl(bis(2-(diphenylphosphaneyl)ethyl)amide)-
manganese(I) (Mn-2a).
In an argon filled glovebox complex Mn-2 (127 mg, 0.2 mmol) was
introduced into a 25 mL Schlenk tube and was dissolved in toluene (5
mL). After 2 min stirring, t-BuOK (34 mg, 0.3 mmol) was added
upon which the yellow solution turned deep red. The reaction mixture
was stirred for 1h at 50 °C (oil bath). Then the mixture was filtered
and the solution was concentrated under reduced pressure to give a
1
deep red powder (75 mg, 68%) that was stored in glovebox. H NMR
(600 MHz, C6D6) δ 7.73 – 7.71 (m, 8H, CHAr), 7.10 – 7.08 (m, 8H,
CHAr), 7.04 – 7.02 (m, 4H), 3.25 – 3.24 (m, 4H, NCH2CH2), 2.35 –
2.32 (m, 4H, NCH2CH2); 31P{1H} NMR (243 MHz, C6D6) δ 91.06 (s);
13C{1H} NMR (151 MHz, C6D6) δ = 233.5 (br, CO), 136.6 (vt, J =
18.0 Hz, PCAr,ipso), 132.7 (s, CHAr), 129.8 (s, CHAr), 128.8 (vt, J = 4.3
Hz, CHAr), 62.1 (NCH2CH2), 33.7 (NCH2CH2); IR (ATR): 1903,
1828 cm-1, (no NH band observed).
Synthesis of tricarbonyl(2-(diphenylphosphaneyl)-N-(pyridin-2-
ylmethyl)ethan-1-amine)manganese(I) bromide (Mn-3).20b
A flame dried Schlenk tube was charged with the PNN pincer ligand
(300 mg, 1.07 mmol, 1 eq.) and Mn(CO)5Br (293 mg, 1.07 mmol, 1.0
eq.). The Schlenk tube was evacuated and backfilled with argon for
several time. Afterwards, 15 mL of degassed THF was added and the
reaction mixture was stirred at 80 °C (oil bath) for 20 h. The suspen-
sion was allowed to cool to room temperature and the yellow precipi-
tate was filtered off and washed with diethyl ether and n-hexane. The
remaining solid was dried under vacuum to afford the complex Mn-3
as a yellow powder (0.49 g, 84%); 1H NMR (600 MHz, DMSO-d6): δ
7.93 – 7.92 (m, 1H), 7.87 – 7.84 (m, 2H), 7.81-7.78 (m, 1H), 7.58-
7.49 (m, 4H), 7.39 – 7.37 (m, 1H), 7.31 – 7.29 (m, 2H), 7.20 – 7.09
(m, 2H), 6.94 – 6.92 (m, 1H), 4.58 – 4.54 (m, 1H), 4.38 (m, 1H), 3.28
– 3.20 (m, 1H), 3.04 – 3.00 (m, 1H), 2.95-2.89 (m, 1H), 2.40 – 2.27
(m, 1H); 13C{1H} NMR (151 MHz, DMSO-d6) δ 221.2, 219.9, 215.3,
162.1, 153.0, 139.2, 132.4, 132.0, 131.1, 131.0, 130.9, 130.8, 129.9,
129.8, 129.6, 125.0, 122.4, 59.8, 53.8 (d, J = 8.8 Hz), 22.7 (d, J = 22.7
Hz); 31P{1H} NMR (242 MHz, DMSO-d6) δ 65.86; IR (ATR): 3045,
2891, 2024, 1914, 1843, 1477, 1434, 1099, 892, 752, 693 cm-1; HRMS
(ESI): m/z [M-Br]+ calcd for C23H21MnN2O3P, 459.0665; found,
459.0675.
Synthesis of tricarbonyl(2,6-bis((diphenylphosphaneyl)methyl)py-
ridine)manganese(I) bromide (Mn-1).22j
A flame dried Schlenk tube was charged with Mn(CO)5Br (420 mg,
1.53 mmol, 1.0 eq.) and the pincer PNP ligand (800 mg, 1.68 mmol,
1.1 eq.). The tube was evacuated and backfilled with argon for three
times. THF (25 mL) was added and the resulting orange suspension
was heated to 60 °C (oil bath) and stirred for 20 h. The solution was
allowed to cool to room temperature and THF was removed in vacuo.
The work-up was done under ambient atmosphere. The yellow solid
was washed three times with n-hexane (3 x 5 mL). The crude yellow
powder was taken into dichloromethane and transferred into a 50 mL
round bottom flask to remove insoluble inorganic side products. The
solution was concentrated under reduced pressure and the complex
1
Mn-1 was isolated as a yellow powder (1.02 g, 95%); H NMR (300
MHz, CD2Cl2) δ 8.09 (s, 2H), 7.81 – 7.26 (m, 21H), 4.65 (s, 4H);
31P{1H} NMR (243 MHz, CD2Cl2) δ 69.4. (s, 2P); IR (ATR) 1918,
1840, 1571, 1435, 1284, 1172, 1097, 964, 833, 696 cm–1; HRMS
(ESI+): m/z [M – Br]+ calcd for C34H27MnNO3P2, 614.0841; found,
614.0853.
General procedure of C-alkylation of nitriles using aliphatic and
benzylic alcohols
Synthesis of bromodicarbonyl(bis(2-(diphenylphosphaneyl)ethyl)-
amine)manganese(I) (Mn-2).22K
A glass pressure tube (10 mL) equipped with a magnetic stirrer was
charged with Mn-2 (3.2 mg, 0.005 mmol), Cs2CO3 (16.3 mg, 0.05
mmol). A rubber septum was attached to the tube and the reaction
vessel was evacuated and backfilled with argon for three times. Under
an inert atmosphere primary alcohol (1.0 mmol), nitrile (0.5 mmol)
and toluene (0.5 mL) were added and the tube was closed with a
screw cap. The resulting mixture was stirred at 135 °C (aluminum
block) for 18 h under argon atmosphere. Upon cooling down to room
temperature the residue was directly purified by flash column chroma-
tography on silica gel eluting with pentane: diethyl ether (20:1 (v/v))
to give the pure alkylated nitrile.
A flame dried Schlenk tube was charged with the HCl salt of the PNP
pincer ligand (478 mg, 1.0 mmol, 1.0 equiv.), toluene (8 mL), water
(2 mL) and NaOH (120 mg, 3.0 mmol, 3.0 equiv.). The reaction
mixture was stirred at 45 °C (oil bath) for 30 min. The two phases
were separated, and the organic layer was washed with water (5 × 5
mL). The pH-value was checked until the solution turned neutral. The
organic layer was concentrated under reduced pressure. Subsequently,
toluene (12 mL) and Mn(CO)5Br precursor were added to the Schlenk
tube. The reaction mixture was heated up to 110 °C (oil bath) and the
atmosphere was exchanged three times by evacuating and backfilled
with argon. After the mixture was stirred for 20 h at reflux tempera-
ture, it was cooled to room temperature and concentrated in vacuo.
The crude precipitate was washed with pentane and extracted with
2-phenylhexanenitrile (3a).12a Colorless oil; 78 mg (88%) 1H NMR
(400 MHz, CDCl3) δ 7.46 – 7.27 (m, 5H), 3.77 (dd, J = 8.5, 6.3 Hz,
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1H), 2.04 – 1.74 (m, 2H), 1.60 – 1.25 (m, 4H), 0.92 (t, J = 7.2 Hz,
2242, 1728, 1461, 1379, 1238, 1038, 836, 703 cm-1; HRMS (ESI+):
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.2, 129.1, 128.0, 127.3,
m/z [M + Na]+ calcd for C10H13N1NaS, 202.0661; found 202.0659.
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2,3-diphenylpropanenitrile (4a).10 Colorless oil; 89 mg (86%); 1H
NMR (600 MHz, CDCl3) δ 7.41 – 7.26 (m, 8H), 7.18 – 7.14 (m, 2H),
4.02 (dd, J = 8.5, 6.4 Hz, 1H), 3.21 (dd, J = 13.6, 8.4 Hz, 1H), 3.15
(dd, J = 13.7, 6.4 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 136.4,
135.3, 129.3, 129.1, 128.7, 128.3, 127.6, 127.5, 120.5, 42.3, 39.9.
121.0, 37.5, 35.7, 29.2, 22.2, 13.8.
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2-(p-tolyl)hexanenitrile (3b)13d Colorless oil; 81 mg (87%); H NMR
(600 MHz, CDCl3) δ 7.25 – 7.16 (m, 4H), 3.74 (dd, J = 8.6, 6.3 Hz,
1H), 2.36 (s, 3H), 1.99 – 1.77 (m, 2H), 1.55 – 1.29 (m, 4H), 0.92 (t, J
= 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 137.8, 133.1,
129.7, 127.2, 121.2, 37.0, 35.7, 29.2, 22.2, 21.1, 13.9.
2-(2-methoxyphenyl)hexanenitrile (3c).12a Colorless oil; 96 mg (94%);
eluent mixture: pentane: diethyl ether (10:1 (v/v)), 1H NMR (400
MHz, CDCl3) δ 7.42 – 7.40 (m, 1H), 7.30 – 7.27 (m, 1H), 7.00 – 6.96
(m, 1H), 6.91 – 6.82 (m, 1H), 4.19 (dd, J = 8.2, 6.3 Hz, 1H), 3.85 (s,
3H), 1.86 (m, 2H), 1.62 – 1.23 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 156.1, 129.3, 128.3, 124.5,
121.4, 120.9, 110.8, 55.5, 33.5, 31.4, 29.4, 22.1, 13.8.
3-phenyl-2-(pyridin-2-yl)propanenitrile (4b).13c Yellowish oil; 76 mg
1
(73%); eluent mixture: pentane: diethyl ether (10:1 (v/v)); H NMR
(600 MHz, CDCl3) δ 8.65 – 8.64 (m, 1H), 7.68 – 7.65 (m, 1H), 7.30 –
7.24 (m, 5H), 7.18 – 7.16 (m, 2H), 4.21 (dd, J = 8.7, 5.9 Hz, 1H), 3.37
(dd, J = 13.6, 5.9 Hz, 1H), 3.26 (dd, J = 13.6, 8.7 Hz, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 154.6, 150.1, 137.3, 136.4, 129.3, 128.8,
127.5, 123.2, 122.3, 119.8, 42.2, 40.2.
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2-phenyl-3-(p-tolyl)propanenitrile (4c).14 White solid; 101 mg (91%);
1H NMR (600 MHz, CDCl3) δ 7.39 – 7.33 (m, 3H), 7.29 – 7.28 (m,
2H), 7.13 – 7.11 (m, 2H), 7.06 – 7.04 (m, 2H), 3.99 (dd, J = 8.5, 6.3
Hz, 1H), 3.16 (dd, J = 13.7, 8.5 Hz, 1H), 3.11 (dd, J = 13.7, 6.4 Hz,
1H), 2.34 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 137.1, 135.4,
133.3, 129.4, 129.2, 129.1, 128.2, 127.6, 120.6, 41.9, 40.0, 21.2.
2-(3,4-dimethoxyphenyl)hexanenitrile (3d). Colorless oil; 103 mg
(88%); eluent mixture: pentane: diethyl ether (5:1 (v/v)); 1H NMR
(600 MHz, CDCl3) δ 6.85 – 6.76 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H),
3.68 (dd, J = 8.7, 6.3 Hz, 1H), 1.94 – 1.75 (m, 2H), 1.50 – 1.26 (m,
4H), 0.87 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ
149.3, 148.7, 128.4, 121.2, 119.5, 111.3, 110.2, 110.1, 56.0, 55.9,
36.9, 35.6, 29.1, 22.1, 13.8; IR: 2936, 2865, 2087, 1906, 1595, 1457,
1343, 1253, 1146, 1026, 913, 809, 759 cm-1. HRMS (ESI+): m/z [M]+
calcd for C14H19O2N, 233.1410; found 233.1413.
2-(benzo[d][1,3]dioxol-5-yl)hexanenitrile (3e).12a Colorless oil; 87
mg (80%); eluent mixture: pentane: diethyl ether (5:1 (v/v)); 1H NMR
(600 MHz, CDCl3) δ 6.81 – 6.73 (m, 3H), 5.96 (s, 2H), 3.67 (dd, J =
8.5, 6.4 Hz, 1H), 1.93 – 1.74 (m, 2H), 1.50 – 1.27 (m, 4H), 0.94 –
0.85 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 148.2, 147.4,
129.8, 121.1, 120.7, 108.6, 107.7, 107.7, 101.4, 37.1, 35.7, 29.1, 22.1,
13.8.
3-(3,4-dimethoxyphenyl)-2-phenylpropanenitrile (4d).13c Off-white
solid; 121 mg (91%); eluent mixture: pentane: diethyl ether (10:1
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(v/v)); H NMR (600 MHz, CDCl3) δ 7.38 – 7.30 (m, 3H), 7.26 –
7.22 (m, 2H), 6.78 – 6.79 (m, 1H), 6.71 – 6.69 (m, 1H), 6.52 – 6.51
(m, 1H), 3.98 (dd, J = 7.8, 6.4 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H),
3.14 (dd, J = 13.7, 7.9 Hz, 1H), 3.09 (dd, J = 13.7, 6.4 Hz, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 148.8, 148.4, 135.3, 129.1,
128.7, 128.3, 127.7, 121.5, 120.6, 112.5, 111.2, 56.0, 55.9, 41.9, 40.0.
3-(benzo[d][1,3]dioxol-4-yl)-2-phenylpropanenitrile (4e). Colorless
oil; 91 mg (72%); eluent mixture: pentane: diethyl ether (5:1 (v/v));
1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (m, 3H), 7.28 – 7.25 (m,
2H), 6.73 – 6.72 (m, 1H), 6.63 – 6.58 (m, 2H), 5.94 (s, 2H), 3.96 (dd,
J = 8.4, 6.4 Hz, 1H), 3.10 (dd, J = 13.7, 8.3 Hz, 1H), 3.05 (dd, J =
13.8, 6.5 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 147.8, 147.0,
135.2, 130.0, 129.1, 128.3, 127.6, 122.6, 120.5, 109.6, 108.5, 101.2,
42.0, 40.1; IR: 3064, 3031, 2899, 2241, 1685, 1605, 1495, 1446,
1249, 1194, 1100, 1039, 810, 751, 699 cm-1; HRMS (ESI+): m/z [M +
H]+ calcd for C16H14O2N, 252.1019; found 252.1017.
2-(4-chlorophenyl)hexanenitrile (3f).26a Colorless oil; 82 mg (79%);
1H NMR (600 MHz, CDCl3) δ 7.35 – 7.25 (m, 4H), 3.75 (dd, J = 8.6,
6.2 Hz, 1H), 1.97 – 1.77 (m, 2H), 1.51 – 1.28 (m, 4H), 0.90 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 134.6, 134.0, 129.3,
128.7, 120.6, 36.9, 35.6, 29.1, 22.1, 13.8.
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2-(2-chlorophenyl)hexanenitrile (3g). Colorless oil; 82 mg (79%); H
NMR (600 MHz, CDCl3) δ 7.56 – 7.55 (m, 1H), 7.42 – 7.36 (m, 1H),
7.32 – 7,31 (m, 1H), 7.28 – 7.25 (m, 1H), 4.28 (dd, J = 9.0, 5.6 Hz,
1H), 1.96 – 1.79 (m, 2H), 1.61 – 1.30 (m, 4H), 0.92 (t, J = 7.4 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 134.0, 132.6, 130.0, 129.5,
128.9, 127.7, 120.5, 34.7, 34.0, 29.3, 22.1, 13.9; IR: 3424, 2935,
2866, 2666, 2323, 2103, 1921, 1728, 1466, 1278, 1040, 754 cm-1;
HRMS (ESI+): m/z [M + Na]+ calcd for C12H14N1Cl1Na1 230.0707;
found, 230.0707.
2-phenyl-3-(3-(trifluoromethyl)phenyl)propanenitrile (4f). Colorless
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oil; 105 mg (76%); H NMR (600 MHz, CDCl3) δ 7.55 – 7.53 (m,
1H), 7.44 – 7.42 (m, 1H), 7.39 – 7.33 (m, 4H), 7.30 – 7.29 (m, 1H),
7.26 – 7.23 (m, 2H), 4.04 (dd, J = 8.1, 6.5 Hz, 1H), 3.25 (dd, J = 13.7,
8.1 Hz, 1H), 3.21 (dd, J = 13.7, 6.5 Hz, 1H); 13C{1H} NMR (151
MHz, CDCl3) δ 137.1, 134.6, 130.9 (q, J = 32.4 Hz), 129,3, 129,2,
128.6, 127.6, 126.2 (q, J = 3.8 Hz), 124.4 (q, J = 3.8 Hz), 123.9 (q, J
= 272.2 Hz), 41.9, 39.5; 19F NMR (282 MHz, CDCl3) δ - 62.73; IR:
3066, 3035, 2933, 2243, 1599, 1495, 1451, 1330, 1166, 1126, 1075,
911, 792, 754, 701 cm-1; HRMS (ESI+): m/z [M + Na]+ calcd for
C16H12NF3Na, 298.0814; found 298.0814.
3-(naphthalen-1-yl)-2-phenylpropanenitrile (4g).26b Colorless oil; 107
mg (83%);1H NMR (400 MHz, CDCl3) δ 7.97 – 7.89 (m, 2H), 7.82 –
7.80 (m, 1H), 7.59 – 7.50 (m, 2H), 7.43 – 7.29 (m, 7H), 4.18 (dd, J =
8.7, 6.7 Hz, 1H), 3.70 – 3.57 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 135.8, 134.1, 132.4, 131.4, 129.4, 129.3, 128.5, 128.4,
128.3, 127.5, 126.7, 125.9, 125.6, 122.7, 120.6, 39.7, 39.0 ppm.
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4-(1-cyanopentyl)benzonitrile (3h). Yellowish oil; 52 mg (53%); H
NMR (600 MHz, CDCl3) δ 7.70 – 7.68 (m, 2H), 7.47 – 7.46 (m, 2H),
3.85 (dd, J = 8.6, 6.1 Hz, 1H), 1.98 – 1.82 (m, 2H), 1.54 – 1.29 (m,
4H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ
141.3, 133.0, 128.2, 119.8, 118.3, 112.4, 37.6, 35.5, 29.1, 22.2, 13.9;
IR: 3470, 3064, 2958, 2867, 2231, 1610, 1506, 1462, 1414, 1381,
1115, 1021, 841 cm-1; HRMS (ESI+): m/z [M + H]+ calcd for
C13H15N2 199.1230 ; found 199.1230.
2-(pyridin-2-yl)hexanenitrile (3i). Colorless oil; 86 mg (99%); eluent
mixture: pentane: diethyl ether (10:1 (v/v)); 1H NMR (600 MHz,
CDCl3) δ 8.58 – 8.51 (m, 1H), 7.70 – 7.67 (m, 1H), 7.42 – 7.37 (m,
1H), 7.22 – 7.20 (m, 1H), 3.94 (dd, J = 8.3, 6.4 Hz, 1H), 1.99 – 1.95
(m, 2H), 1.53 – 1.25 (m, 4H), 0.86 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(151 MHz, CDCl3) δ 155.4, 149.9, 137.3, 122.9, 121.7, 120.2, 39.9,
33.9, 29.1, 22.1, 13.8; IR: 3180, 2933, 2867, 2322, 1920, 1738, 1586,
1467, 1437, 1301, 1206, 994, 755, 665 cm-1; HRMS (ESI+): m/z [M]+
calcd for C11H14N2, 174.1152; found 174.1145.
2-phenyl-3-(pyridin-4-yl)propanenitrile (4h).14 Yellowish oil; 73 mg
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(70%); H NMR (600 MHz, CDCl3) δ 8.62 – 8.60 (m, 1H), 7.65 –
7.62 (m, 1H), 7.37 – 7.36 (m, 4H), 7.34 – 7.30 (m, 1H), 7.23 – 7.20
(m, 1H), 7.15 – 7.14 (m, 1H), 4.50 (dd, J = 9.3, 6.6 Hz, 1H), 3.36 (dd,
J = 13.9, 9.3 Hz, 1H), 3.30 (dd, J = 13.9, 6.6 Hz, 1H); 13C{1H} NMR
(151 MHz, CDCl3) δ 156.1, 149.5, 136.9, 135.4, 129.1, 128.2, 127.4,
124.0, 120.5, 44.1, 37.3.
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2-(thiophen-2-yl)hexanenitrile (3j). Yellowish oil; 58 mg (65%), H
2-phenyl-3-(pyridin-2-yl)propanenitrile (4i).10 Yellowish oil; 49 mg
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NMR (600 MHz, CDCl3) δ 7.27 – 7.26 (m, 1H), 7.06 – 7.05 (d, J =
3.5 Hz, 1H), 6.98 – 6.97 (m, 1H), 4.06 (dd, J = 8.4, 6.3 Hz, 1H), 2.06
– 1.91 (m, 2H), 1.58 – 1.43 (m, 2H), 1.43 – 1.33 (m, 2H), 0.93 (t, J =
7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 138.2, 127.1, 126.1,
125.5, 120.1, 35.7, 32.6, 29.1, 22.1, 13.9; IR: 3468, 3109, 2957, 2865,
(47%); H NMR (600 MHz, CDCl3) δ 8.61 – 8.59 (m, 1H), 7.62 –
7.60 (m, 1H), 7.36 – 7.35 (m, 4H), 7.34 – 7.29 (m, 1H), 7.21 – 7.18
(m, 1H), 7.13 – 7.12 (m, 1H), 4.48 (dd, J = 9.3, 6.5 Hz, 1H), 3.35 (dd,
J = 13.9, 9.3 Hz, 1H), 3.28 (dd, J = 13.9, 6.5 Hz, 1H); 13C{1H} NMR
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(151 MHz, CDCl3) δ 156.3, 149.8, 136.9, 135.5, 129.2, 128.3, 127.5,
124.0, 122.5, 120.7, 44.3, 37.4.
2-(3-methoxyphenyl)propanenitrile (5c).26g Yellowish oil 56 mg
(70%); H NMR (600 MHz, CDCl3) δ 7.30 (m, 1H), 6.94-6.93 (m,
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3-(furan-2-yl)-2-phenylpropanenitrile (4j).26c Colorless oil; 62 mg
(63%); H NMR (600 MHz, CDCl3) δ 7.39 – 7.25 (m, 6H), 6.30 –
1H), 6.89 (m, 1H), 6.87-6.85 (m, 1H), 3.87 (q, J = 7.3 Hz, 1H), 3.83
(s, 3H), 1.64 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ
160.2, 138.6, 130.3, 121.7, 119.1, 113.5, 112.7, 55.5, 31.4, 21.5.
2-(4-methoxyphenyl)propanenitrile (5d).26e Yellowish oil 48 mg
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6.29 (m,1H), 6.12 – 6.11 (m, 1H), 4.15 (dd, J = 8.6, 6.5 Hz, 1H), 3.27
(dd, J = 15.0, 8.6 Hz, 1H), 3.19 – 3.13 (m, 1H); 13C{1H} NMR (151
MHz, CDCl3) δ 150.1, 142.3, 135.0, 129.2, 128.7, 128.5, 110.6,
108.4, 37.2, 34.8.
2-phenyl-3-(thiophen-2-yl)propanenitrile (4k).18 Colorless oil; 87 mg
(82%),; 1H NMR (600 MHz, CDCl3) δ 7.40 – 7.26 (m, 5H), 7.17 (m,
1H), 6.92 (m, 1H), 6.85 (m, 1H), 4.04 (dd, J = 8.1, 6.4 Hz, 1H), 3.43
(dd, J = 14.8, 8.2 Hz, 1H), 3.34 (dd, J = 14.8, 6.3 Hz, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 138.0, 134.8, 129.2, 128.5, 127.5, 127.2,
127.1, 125.0, 40.1, 36.2.
2-phenylbutanenitrile (4l).12a Colorless oil; 38 mg (52%); 1H NMR
(600 MHz, CDCl3) δ 7.41 – 7.29 (m, 5H), 3.74 (t, J = 7.2 Hz, 1H),
1.97 – 1.92 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 135.9, 129.1, 128.1, 127.4, 120.9, 39.0, 29.4, 11.6.
2-phenyloctanenitrile (4m).10 Colorless oil; 94 mg (93%); 1H NMR
(600 MHz, CDCl3) δ 7.39 – 7.37 (m, 2H), 7.34 – 7.31 (m, 3H), 3.77
(dd, J = 8.7, 6.2 Hz, 1H), 1.97 – 1.82 (m, 2H), 1.55 – 1.42 (m, 2H),
1.36 – 1.25 (m, 6H), 0.88 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 136.2, 129.1, 128.0, 127.3, 121.0, 37.5, 36.0, 31.6,
28.7, 27.0, 22.6, 14.1.
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(59%); H NMR (600 MHz, CDCl3) δ 7.30-7.28 (m, 2H), 6.94-6.91
(m, 2H), 3.87 (q, J = 7.4 Hz, 1H), 3.83 (s, 3H), 1.64 (d, J = 7.3 Hz,
3H); 13C{1H} NMR (151 MHz, CDCl3) δ 159.4, 129.2, 128.0, 122.0,
114.6, 55.5, 30.6, 21.7.
2-(2-chlorophenyl)propanenitrile (5e).26e Yellowish oil; 51 mg (61%);
1H NMR (600 MHz, CDCl3) δ 7.58 (m, 1H), 7.41-7.39 (m, 1H), 7.36-
7.32 (m, 1H), 7.30-7.27 (m, 1H), 4.36 (q, J = 7.1 Hz, 1H), 1.63 (d, J =
7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 134.9, 132.6, 130.2,
129.6 128.4, 127.9, 121.2, 29.0, 20.1.
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2-(4-chlorophenyl)propanenitrile (5f).26e Yellowish oil; 57 mg (69%);
1H NMR (600 MHz, CDCl3) δ 7.38-7.35 (m, 2H), 7.31-7.28 (m, 2H),
3.88 (q, J = 7.4 Hz, 1H), 1.63 (d, J = 7.3 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 135.6, 134.2, 129.5, 128.2, 121.3, 30.9, 21.5.
2-(pyridin-2-yl)propanenitrile (5g).26h
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36 mg (55%), yellowish oil; H NMR (600 MHz, CDCl3) δ 8.62-8.61
(m, 1H), 7.77-7.74 (m, 1H), 7.48-7.47 (m, 1H), 7.29-7.27 (m, 1H),
4.08 (q, J = 7.4 Hz, 1H), 1.73 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 156.2, 150.0, 137.6, 123.1, 121.2, 121.1, 33.9, 19.8.
2-(thiophen-2-yl)propanenitrile (5h).26i Yellowish oil; 42 mg (61%);
1H NMR (600 MHz, CDCl3) δ 7.28-7.27 (m, 1H), 7.08-7.07 (m, 1H),
6.99-6.98 (m, 1H), 4.18 (q, J = 7.4 Hz, 1H), 1.74 (d, J = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ 139.3, 127.2, 125.7, 125.5, 120.8,
26.7, 21.6.
4-methyl-2-phenylpentanenitrile (4n).13c Colorless oil; 71 mg (82%);
1H NMR (600 MHz, CDCl3) δ 7.40 – 7.30 (m, 5H), 3.81 (dd, J = 9.8,
6.4 Hz, 1H), 1.91 (ddd, J = 13.4, 9.8, 5.5 Hz, 1H), 1.88 – 1.80 (m,
1H), 1.64 (ddd, J = 13.3, 8.4, 6.3 Hz, 1H), 0.99 (dd, J = 8.0, 6.5 Hz,
6H); 13C{1H} NMR (151 MHz, CDCl3) δ 136.4, 129.2, 128.1, 127.3,
121.1, 45.1, 35.61, 26.2, 22.7, 21.7.
Representative procedure for gram-scale synthesis of 2-phenyl-3-
(p-tolyl)propanenitrile (4c)
2-phenylhept-6-enenitrile (4o).26d Colorless oil; 78 mg (78%); 1H
NMR (600 MHz, CDCl3) δ δ 7.41 – 7.30 (m, 5H), 5.76 (ddt, J = 17.0,
10.2, 6.7 Hz, 1H), 5.05 – 4.97 (m, 2H), 3.79 (dd, J = 8.6, 6.2 Hz, 1H),
2.13 – 2.08 (m, 2H), 1.98 – 1.84 (m, 2H), 1.67 – 1.52 (m, 2H);
13C{1H} NMR (151 MHz, CDCl3) δ 137.6, 136.0, 129.1, 128.1, 127.3,
120.9, 115.5, 37.3, 35.3, 33.0, 26.2.
A glass pressure tube (25 mL) equipped with a magnetic stirrer was
charged with Mn-2 (35.2 mg, 0.055 mmol), Cs2CO3 (179.3 mg, 0.55
mmol). A rubber septum was attached to the tube and the reaction
vessel was evacuated and backfilled with argon for three times. Under
an inert atmosphere p-tolylmethanol (1.34 g, 11.0 mmol), 2-
phenylacetonitrile (632 μL, 644 mg, 5.5 mmol) and toluene (5.5 mL)
were added and the tube was closed with a screw cap. The resulting
mixture was stirred at 135 °C (aluminum block) for 24 h under argon
atmosphere. Upon cooling down to room temperature the residue was
concentrated under reduced pressure and purified by flash column
chromatography on silica gel eluting with pentane: diethyl ether (20:1
(v/v)) to give the pure 4c (1022 mg, 84% yield).
3-cyclohexyl-2-phenylpropanenitrile (4p).14
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Colorless oil; 77 mg (72%); H NMR (600 MHz, CDCl3) δ 7.40 –
7.30 (m, 5H), 3.85 (dd, J = 10.1, 6.2 Hz, 1H), 1.92 – 1.81 (m, 2H),
1.78 – 1.62 (m, 5H), 1.57 – 1.49 (m, 1H), 1.31 – 1.13 (m, 3H), 1.01 -
0.92 (m, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 136.6, 129.2,
128.0, 127.3, 121.2, 43.8, 35.4, 34.9, 33.4, 32.4, 26.4, 26.0, 25.9.
General procedure of C-methylation of nitriles
A glass Ace pressure tube (22 mL) equipped with a magnetic stir bar
was charged with Mn-2 (8 mg, 0.025 mmol), Cs2CO3 (16.3 mg, 0.05
mmol). A rubber septum was attached to the tube and the reaction
vessel was evacuated and backfilled with argon for three times. Under
an inert atmosphere nitrile (0.5 mmol), methanol (1 mL) and 1,4-
dioxane (1 mL) were added and the tube was closed with a screw cap.
The resulting mixture was stirred at 135 °C (aluminum block) for 24 h
under argon atmosphere. Upon cooling down to room temperature the
residue was directly purified by flash column chromatography on
silica gel eluting with pentane:diethyl ether mixtures to give the pure
desired product.
The Supporting Information is available free of charge on the
ACS Publications website: copies of NMR spectra (PDF)
* Magnus.Rueping@rwth-aachen.de
* Osama.Elsepelgy@rwth-aachen.de
1
2-phenylpropanenitrile (5a).26e Yellowish oil; 46 mg (70%); H NMR
Magnus Rueping: 0000-0003-4580-5227
Osama El-Sepelgy: 0000-0003-3131-4988
(600 MHz, CDCl3) δ 7.41-7.31 (m, 5H), 3.90 (q, J = 7.3 Hz, 1H), 1.65
(d, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 137.2, 129.3,
128.2, 126.8, 121.7, 31.4, 21.6.
2-(2-methoxyphenyl)propanenitrile (5b).26f
The authors declare no competing financial interests.
Yellowish oil 52 mg (65%); eluent mixture: pentane: diethyl ether
(10:1 (v/v)); 1H NMR (600 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.32-
7.29 (m, 1H), 7.01-6.98 (m, 1H), 6.91-6.89 (m, 1H), 4.25 (q, J = 7.2
Hz, 1H), 3.87 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 156.2, 129.4, 127.7, 125.5, 122.1, 121.1, 110.9, 55.6,
25.7, 19.6.
J.C.B. acknowledges the German Federal Environmental Founda-
tion (DBU) for a doctoral fellowship. J.S. is grateful for a doctoral
fellowship provided by the Fonds der Chemischen Industrie.
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