Palladium-Catalyzed Carbonylative α-Arylation of tert -Butyl Cyanoacetate with (Hetero)aryl Bromides

Article abstract of DOI:10.1021/acs.joc.5b02897

A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl₂ and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of ¹³C-labeled carbon monoxide generated from ¹³COgen, the corresponding ¹³C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific ¹³C-isotope labeling. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02897

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pubs.acs.org/joc
Palladium-Catalyzed Carbonylative α‑Arylation of tert-Butyl
Cyanoacetate with (Hetero)aryl Bromides
Mikkel T. Jensen,† Martin Juhl,† Dennis U. Nielsen,† Mikkel F. Jacobsen,§ Anders T. Lindhardt,*,‡,⊥
and Troels Skrydstrup*,†
†Carbon Dioxide Activation Center (CADIAC), Department of Chemistry and the Interdisciplinary Nanoscience Center (iNANO),
Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
‡Interdisciplinary Nanoscience Center (iNANO), Department of Engineering, Aarhus University, Finlandsgade 22, 8200 Aarhus N,
Denmark
§Process Research, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
S
* Supporting Information
ABSTRACT: A three-component coupling protocol has been
developed for the generation of 3-oxo-3-(hetero)-
arylpropanenitriles via a carbonylative palladium-catalyzed α-
arylation of tert-butyl 2-cyanoacetates with (hetero)aryl
bromides followed by an acid-mediated decarboxylation step.
Through the combination of only a stoichiometric loading of
carbon monoxide and mild basic reaction conditions such as
MgCl2 and dicyclohexylmethylamine for the deprotonation
step, an excellent functional group tolerance was ensured for
the methodology. Through the use of 13C-labeled carbon
monoxide generated from 13COgen, the corresponding 13C-
isotopically labeled β-ketonitriles were obtained, and these
products could subsequently be converted into cyanoalkynes
and 3-cyanobenzofurans with site specific 13C-isotope labeling.
target β-ketonitriles, they are confined to the use of aryl iodides,
and the former approach requires two additional metal
additives, namely ZnF2 and CuBr2, whereas the latter relies
on the addition of strong base, NaHMDS, to activate the
nucleophile. We therefore set out to expand the usefulness of
the carbonylative α-arylation route to β-ketonitriles by
identifying reaction conditions that can also include (hetero)-
aryl bromides as viable substrates for this three-component
coupling strategy, as well as the adaptation of mild basic
conditions for the deprotonation step.
In this paper, we demonstrate the usefulness of tert-butyl 2-
cyanoacetate as an appropriate nucleophile for the carbon-
ylative α-arylation of (hetero)aryl bromides with a trialkylamine
base for accessing the desired 3-oxo-3-(hetero)-
arylpropanenitriles after a simple acid-mediated decarboxylation
reaction. Importantly, our approach relies on the use of only
stoichiometric amounts of carbon monoxide generated from
COgen for effective coupling, which also allow us to easily
adapt the developed protocol for 13C-isotope labeling.
INTRODUCTION
■
3-Oxo-3-(hetero)arylpropanenitriles, more commonly referred
to as β-ketonitriles, are key precursors applied for the synthesis
of imidazo[1,2-a]pyridines,1 2-pyridones,2 furans,3 amino-
pyrazoles,4 thiophenes,5 and others (Scheme 1). Furthermore,
they have been employed for the synthesis of biological active
targets against HIV,6 toward NHE-1 inhibitors,7 or toward
antidepressants (e.g., Prozac).8 One of the earliest examples of
́
β-ketonitrile preparation was reported by Obregia in 1891 by
the direct displacement of an α-bromide with potassium
cyanide.9 This classical halogen displacement is still applied
today, most often with sodium cyanide as the cyanide donor
(Scheme 1).10 Alternatively, nucleophilic displacement of ethyl
esters with α-substituted acetonitriles,11 copper-catalyzed
oxidation of alcohols in the presence of acetonitrile,12
etc.13a−e all provide β-ketonitriles (Scheme 1). Nevertheless,
for accessing 3-oxo-3-(hetero)arylpropanenitriles, these ap-
proaches require advanced (hetero)aryl intermediates.
On the other hand, in 2012, Lee et al. reported the first
carbonylative coupling approach to β-ketonitriles from aryl
iodides with (trimethylsilyl)acetonitrile promoted by a Pd
catalyst.14 One year later, Beller and Skrydstrup reported β-
ketonitrile formation via Pd-catalyzed carbonylation of aryl
iodides with α,α-disubstituted acetonitrile derivatives (Scheme
1).15 Although both protocols proved effective for accessing the
Received: December 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02897
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depicted in Scheme 2. In general, all meta- and para-substituted
aryl bromides afforded the desired β-ketonitriles in yields
ranging from 63−89% (compounds 1−3, 4−13). Electron-
withdrawing groups did not affect the reactivity and provided
yields of up to 89% (6−9, 12, 13). Similar reactivity was
observed when aryl bromides were applied with electron-
donating functionalities (compounds 2, 3, 10, 14, and 15).
Even a free aniline successfully afforded the β-ketonitrile 17,
although in a lowered yield of 50%. β-Ketonitrile 4 could be
isolated in a near-quantitative yield using bromobenzene as the
electrophile. Unfortunately, ortho-substitution of the aryl
bromides resulted in a complete shut down of reactivity.
Next, a few alternative electrophiles were tested including
phenyl triflate, two 2-bromovinylbenzenes, and benzyl chloride,
all affording the target compounds in 95%, 54%, 66%, and 93%
yields (compounds 4 and 18−20, respectively). Finally, the
application of heteoaryl bromides as electrophiles was
investigated. 2-Bromothiophene, 2-bromo- and 6-bromobenzo-
thiophene, 5-bromobenzofuran, and N-Boc-5-bromoindole
were tested and in all cases provided the β-ketonitriles in
yields ranging from 40 to 68% (compounds 21−25). Not
surprisingly, in the case of N-Boc-5-bromoindole, the
carbamate protection group was removed during the acid-
promoted decarboxylative step. Performing the reaction on a
larger scale (2.5 or 3.0 mmol) allowed for a reduction of the
catalyst loading from 5 to 2 mol% without affecting the yields
(compounds 2, 4, 12, and 15). Finally, by substituting CO for
its 13C-isotopically labeled counterpart, compounds 4* and 15*
were successfully obtained in yields of 96% and 74%,
respectively, carrying a 13C-labeled carbonyl moiety in the β-
ketonitrile structure.
Scheme 1. Representative Methods for the Generation and
Synthetic Utility of β-Ketonitriles
RESULTS AND DISCUSSION
■
We have previously reported on the development of
intermolecular Pd-catalyzed carbonylative α-arylations with
iodo- and bromoarenes to 1,3-diketones,16 β-ketoesters,17a
and -amides,17b and (heteroaryl)methyl ketones.18 These
methods rely on 1,3-dicarbonyl-derived nucleophiles (or
analogues thereof), such as acetyl acetone, potassium
acetoacetates, acetoacetamides, and 2-heteroarylacetones, there-
by increasing the acidity toward mild α-deprotonation in the
activation step of the nucleophile. Subsequent to the carbon-
ylative transformation, the additional acyl functionality was
selectively removed upon acidic treatment. To investigate the
carbonylative transformations to 3-oxo-3-(hetero)-
arylpropanenitriles, a model system based on our previous
reports16−18 utilizing a palladium/Xantphos catalytic system
combined with a mixture of anhydrous magnesium chloride
(MgCl2, 1.2 equiv) and N,N-dicyclohexyl-N-methylamine
(Cy2NMe, 4.0 equiv) was initially tested. As the nucleophile,
potassium 2-cyanoacetate (1.1 equiv) was chosen in combina-
tion with bromoanisole as the electrophile. A slight excess of
carbon monoxide (1.5 equiv) was delivered by applying the
two-chamber technique previously developed in our laborato-
ries. Following an acidic treatment with formic acid this
provided a low NMR conversion of 14% to the desired β-
ketonitrile 1 (result not shown). Substituting the nucleophile
with tert-butyl 2-cyanoacetate (1.1 equiv), however, afforded
the desired β-ketonitrile 1 in a 69% NMR conversion after
acidic treatment. Speculating that the lack of a 1,3-dicarbonyl
moiety in tert-butyl 2-cyanoacetate could account for a reduced
efficiency of the added Lewis acid, we doubled the loading of
MgCl2 from 1.2 to 2.4 equiv. To our delight, this simple
alteration increased the NMR conversion of 1 to a good 78%
(70% yield) after treatment of the intermediately formed tert-
butyl 2-cyano-3-oxo-3-phenylpropanotate with formic acid at
100 °C. Performing the reaction without the addition of MgCl2
provided 1 in less than 10% yield.
A pressure measurement experiment was conducted during
the synthesis of 4 by adaptation of a manometer to the COware
setup (Figure 1). CO is released within the first few minutes
causing the internal pressure to reach a plateau of 3 bar.
The pressure profile then shows a continuous drop in
pressure over the next 18 h with the majority of the reaction
already completed within the first 6 hours.
Instead of treatment with warm formic acid, the direct
coupling product could also be easily isolated as exemplified
with compound 26 shown in Scheme 3. Ethyl 2-cyanoacetate
also coupled well with isolation of product 27 in an excellent
97% yield. Finally, the similar nitro derivative tert-butyl 2-
nitroacetate was tested as a nucleophile affording compound 28
in a 61% yield after acidic decarboxylation (Scheme 3).
In 1990, Leclercq et al. reported on the conversion of β-
ketosulfonamides into sulfonamide-substituted alkynes upon
treatment with triethylamine in combination with Mukaiyama’s
reagent followed by the addition of aqueous sodium
hydroxide.19 In a similar manner, we found that the β-
ketonitriles 4 and 15 could be transformed into the
corresponding cyanoalkynes in good yields under the same
mild conditions (Scheme 4A, compounds 29 and 30). Starting
with 4* and 15*, this afforded the equivalent specifically
monolabeled 13C-cyanoalkynes in practically identical yields of
71% and 74% (compounds 29* and 30*, respectively).20
In 2012, Zhou et al. reported a one-pot two-step procedure
for the preparation of 3-cyanobenzofurans through a C−H
activation step starting from cyanoalkynes.23 This same method
was applied to the preparation of the 3-cyanobenzofurans from
β-ketonitriles 29 and 30.
With these conditions in hand, the scope of this simple
transformation was undertaken, the results of which are
In this manner, compounds 31 and 32 could be secured by
column chromatography in 30% and 42% yields for the two
B
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a
Scheme 2. Scope of Aryl Bromides toward β-Ketonitriles
a
Full experimental details are described in the Experimental Procedures. Key: (a) Pd(cod)Cl2 (2 mol%), Xantphos (2 mol%), anhydrous MgCl2 (2.4
equiv), tert-butyl 2-cyanoacetate (1.1 equiv), aryl bromide (3.0 mmol), dioxane (15 mL) and Cy2NMe (4.0 equiv); (b) starting from phenyl
trifluoromethanesulfonate; (c) starting from compound 26 (Scheme 3) with HCOOH in dioxane at 100 °C; (d) Pd(cod)Cl2 (2 mol%), Xantphos (2
mol%), anhydrous MgCl2 (2.4 equiv), tert-butyl 2-cyanoacetate (1.1 equiv), aryl bromide (2.50 mmol), dioxane (15 mL) and Cy2NMe (4.0 equiv);
(e) starting from BnCl. * = 13C-labeled.
sequential steps (Scheme 4B).23 As before, applying the 13C-
(230−400 mesh), unless otherwise stated. Fine silica refers to silica gel
60 (0.015−0.040 mm). NMR was conducted at 400, 100, and 376
isotopically labeled cyanoalkynes 29* and 30*, it was possible
to incorporate the 13C-carbon label directly into the furan core
obtaining compounds 31* and 32* in 37% and 38% yields,
respectively.
1
MHz for H NMR, 13C{1H} NMR, and 19F{1H} NMR, respectively,
on a 400 MHz NMR apparatus. The NMR chemical shifts were
reported in parts per million (ppm) compared to the solvent residual
signal.21 Signals in NMR are reported as s = singlet, d = doublet, t =
triplet, q = quartet, and b = broad. In some cases, it was not possible to
fully separate the title compounds and a side product of 3-oxo-3-
phenylpropanenitrile 4 probably arising from aryl scrambling.22 The
yields in these examples are therefore corrected for the low amount of
4 and marked as (corrected) (compounds 8, 10, and 11). Melting
points were obtained on a melting point apparatus. HRMS spectra
were recorded on an LC-TOF (ES) apparatus. Pressure curves were
measured on a digital manometer with electronic data collection. With
the exception of MgCl2, all purchased chemicals were used without
any further purification. Anhydrous MgCl2 was prepared by drying the
commercial MgCl2 under high vacuum at 165 °C for a minimum of 5
days and thereafter storage in an argon filled glovebox at rt.
General Method A. 3-(4-Chlorophenyl)-3-oxopropanenitrile (9):
General Procedure for the Carbonylation of Aryl Bromides toward
β-Ketonitriles. Chamber 2. In a glovebox under argon, to chamber 2
of the two-chamber system (20 mL) were added Pd(cod)Cl2 (2.0 mg,
0.008 mmol), HBF4·P(tBu)3 (2.2 mg, 0.015 mmol), COgen (9-
methylfluorene-9-carbonyl chloride) (182 mg, 0.75 mmol), and
dioxane (3 mL) in that order. Chamber 1: In a glovebox under
argon, to chamber 1 of the two-chamber system (20 mL) were added
In conclusion, a mild method has been developed for
accessing 3-oxo-3-(hetero)arylpropanenitriles from the Pd-
catalyzed carbonylative α-arylation of tert-butyl 2-cyanoacetates
with aryl bromides and stoichiometric carbon monoxide.
Various β-ketonitriles were prepared in good to excellent
yields including their 13C-isotopically labeled versions as well.
The protocol displayed excellent functional group tolerance
and operated well when starting from hetereoaromatic
bromides. Selected β-ketonitriles were transformed into the
corresponding cyanoalkynes that could subsequently be applied
to the synthesis of 3-cyanobenzofurans. Two 13C-carbon-
labeled β-ketonitriles could also be adapted to this synthetic
route, in turn leading to the isolation of two functionalized and
13C-carbon labeled 3-cyanobenzofurans.
EXPERIMENTAL PROCEDURES
■
General Procedures. Standard procedures were applied for drying
solvents. Column chromatography was performed on silica gel 60
C
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a
Scheme 4. Synthetic Applications of β-Ketonitriles
Figure 1. Pressure measurement in the preparation of β-ketonitrile 4.
a
Yield in parentheses indicate average yields for first and second step.
Scheme 3. Isolation of Reaction Intermediate and Coupling
with Alternative Nucleophiles
* = 13C-labeled.
General Method B. 3-Oxo-3-phenylpropanenitrile (4). General
Procedure for Scale-Up Carbonylation of Aryl Bromides to β-
Ketonitriles. Chamber 2. In a glovebox under argon, to chamber 2 of
the two-chamber system (100 mL) were added Pd(cod)Cl2 (10 mg,
0.04 mmol), HBF4·P(tBu)3 (11.0 mg, 0.075 mmol), COgen (9-
methylfluorene-9-carbonyl chloride) (910 mg, 3.75 mmol), and
dioxane (15 mL) in that order. Chamber 1: In a glovebox under
argon, to chamber 1 of the two-chamber system (100 mL) were added
Pd(cod)Cl2 (14.2 mg, 0.05 mmol), Xantphos (29 mg, 0.05 mmol),
anhydrous MgCl2 (575 mg, 6.0 mmol), tert-butyl 2-cyanoacetate (393
μL, 2.75 mmol), bromobenzene (393 mg, 2.50 mmol), dioxane (15
mL), and Cy2NMe (2.13 mL, 10.0 mmol) in that order. To chamber 2
was added Cy2NMe (1.60 mL, 7.5 mmol), and both chambers were
sealed with a screwcap fitted with a PTFE/silicone seal. The loaded
two-chamber system was removed from the glovebox and heated to
100 °C for 18 h. The lid was removed, HCOOH (5.0 mL) was added,
and stirring was continued for 1 h before cooling to rt and
concentration under reduced pressure. Purification was performed
by column chromatography (pentane/Et2O/HCOOH 34/6/1−14/6/
1) to yield the title compound as a yellow solid (361 mg, 2.50 mmol,
a
b
E/Z ratio not determined. Treated with HCOOH for 1 h at 100 °C.
Pd(cod)Cl2 (7.1 mg, 0.025 mmol), Xantphos (14.5 mg, 0.050 mmol),
anhydrous MgCl2 (115 mg, 1.20 mmol), tert-butyl 2-cyanoacetate
(78.6 μL, 0.55 mmol), 1-bromo-4-chlorobenzene (96.0 mg, 0.50
mmol), dioxane (3 mL), and Cy2NMe (426 μL, 2.0 mmol) in that
order. To chamber 2 was added Cy2NMe (320 μL, 1.5 mmol), and
both chambers were sealed with a screwcap fitted with a PTFE/silicon
seal. The loaded two-chamber system was removed from the glovebox
and heated to 100 °C for 18 h. The lid was removed, and HCOOH
(1.0 mL) was added and stirring continued for 1 h before cooling to rt
and concentration under reduced pressure. Purification was performed
by column chromatography (pentane/Et2O/HCOOH 34/6/1−14/6/
1) to yield the title compound as a yellow solid (63.0 mg, 0.35 mmol,
1
quant). H NMR (400 MHz, CDCl3): δ H ppm 7.92 (d, J = 7.3 Hz,
2H), 7.68 (t, J = 7.3 Hz, 1H), 7.52 (m, 2H), 4.10 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ C ppm 187.3, 134.9, 134.4, 129.3 (2C),
128.6 (2C), 114.0, 29.5. HRMS C9H8ON [M + H+]: calcd 146.0600,
found 146.0596. Mp (uncorrected): 79.5−80.8 °C.13a
3-(4-Methoxyphenyl)-3-oxopropanenitrile (1). Reaction with 1-
bromo-4-methoxybenzene (62.6 μL, 0.50 mmol) using general
method A was followed by workup by addition to satd NaHCO3(aq)
(30 mL) and extraction with dichloromethane (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtrated and
concentrated under reduced pressure. Purification was performed by
column chromatography (Pentane/Et2O/HCOOH 14/6/1) resulting
in the title compound as a yellow solid (61.4 mg, 0.35 mmol, 70%). 1H
NMR (400 MHz, CDCl3): δ H ppm 7.92−7.89 (m, 2H), 7.00−6.96
1
70%). H NMR (400 MHz, CDCl3): δ H ppm 7.86 (d, J = 8.6 Hz,
2H), 7.50 (d, J = 8.6 Hz, 2H), 4.07 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 186.2, 141.6, 132.7, 130.0 (2C), 129.7 (2C), 113.7,
29.6. HRMS C9ClH6ONNa [M + Na+]: calcd 202.0030, found
202.0030. Mp (uncorrected): 110.8−113.6 °C.13a
D
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(m, 2H), 4.01 (s, 2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 185.5, 164.9, 131.1 (2C), 127.4, 114.5 (2C), 114.2,
55.8, 29.2. HRMS C10H9NNaO2 [M + Na+]: calculated 198.0525,
found 198.0527. Mp (uncorrected): 129.2−131.1 °C.13a
(pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the title
1
compound as a yellow solid (351 mg, 2.40 mmol, 96%). H NMR
(400 MHz, CDCl3): δ H ppm 7.94−7.84 (m, 2H), 7.63 (t, J = 7.4 Hz,
1H), 7.50 (t, J = 7.4 Hz, 2H), 4.12 (d, J = 6.2 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ C ppm 187.5 (13C enriched), 134.7, 134.3 (d, J
= 57.8 Hz), 129.1 (d, J = 4.3 Hz, 2C), 128.5 (d, J = 2.9 Hz, 2C), 114.1
(d, J = 3.5 Hz), 29.5 (d, J = 40.1 Hz). HRMS C813CH8NO [M + H+]:
calcd 147.0634, found 147.0635. Mp (uncorrected): 82.1−84.0 °C.
4-(2-Cyanoacetyl)phenyl 4-methylbenzenesulfonate (5). Reaction
with 4-bromophenyl 4-methylbenzenesulfonate (164 mg, 0.50 mmol)
using general method A was followed by workup by addition to satd
NaHCO3(aq) (30 mL) and extraction with dichloromethane (3 × 30
mL). The combined organic phases were dried over Na2SO4, filtrated,
and concentrated under reduced pressure. Purification was performed
by column chromatography (pentane/Et2O/HCOOH 12/8/1)
resulting in the title compound as a yellow solid (99.2 mg, 0.31
mmol, 63%). 1H NMR (400 MHz, CDCl3): δ H ppm 7.87 (d, J = 8.8,
2H), 7.71 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.8
Hz, 2H), 4.05 (s, 2H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 186.0, 154.2, 146.2, 132.9, 132.0, 130.5 (2C), 130.2
(2C), 128.6 (2C), 123.2 (2C), 113.5, 29.6, 21.9. HRMS
C16H13NO4SNa [M + Na+]: calcd 338.0457, found 338.0457. Mp
(uncorrected): 125.3−126.4 °C.
3-Oxo-3-(p-tolyl)propanenitrile (2). Reaction with 1-bromo-4-
methylbenzene (85.5 mg, 0.50 mmol) using general method A was
followed by workup by addition to satd NaHCO3(aq) (30 mL) and
extraction with dichloromethane (3 × 30 mL). The combined organic
phases were dried over Na2SO4, filtrated, and concentrated under
reduced pressure. Purification was performed by column chromatog-
raphy (pentane/Et2O/HCOOH 16/4/1−15/5/1) resulting in the title
1
compound as a yellow solid (69.2 mg, 0.43 mmol, 76%). H NMR
(400 MHz, CDCl3): δ H ppm 7.81 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3
Hz, 2H), 4.04 (s, 2H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 186.7, 146.1, 132.0, 130.0 (2C), 128.8 (2C), 114.0,
29.4, 22.0. HRMS C10H9NONa [M + Na+]: calcd 182.0576, found
182.0576. Mp (uncorrected): 100.5−102.4 °C.13a
3-Oxo-3-(p-tolyl)propanenitrile (2). Reaction with 1-bromo-4-
methylbenzene (513 mg, 3.0 mmol) using general method B was
followed by workup by addition to satd NaHCO3(aq) (30 mL) and
extraction with dichloromethane (3 × 30 mL). The combined organic
phases were dried over Na2SO4, filtrated, and concentrated under
reduced pressure. Purification was performed by column chromatog-
raphy (pentane/EtOAc 1/10−3/10) resulting in the title compound
as a yellow solid (376 mg, 2.4 mmol, 79%). The physical and
spectroscopic data were in accordance with those reported for the
same compound using method A.
4-(2-Cyanoacetyl)benzonitrile (6). Reaction with 4-bromobenzoni-
trile (91.0 mg, 0.50 mmol) using general method A was followed by
workup by addition to satd NaHCO3(aq) (30 mL) and extraction with
dichloromethane (3 × 30 mL). The combined organic phases were
dried over Na2SO4, filtrated, and concentrated under reduced pressure.
Purification was performed by column chromatography (pentane/
Et2O/HCOOH 14/6/1) resulting in the title compound as a yellow
3-([1,1′-Biphenyl]-4-yl)-3-oxopropanenitrile (3). Reaction with 4-
bromo-1,1′-biphenyl (117 mg, 0.50 mmol) using general method A
was followed by workup by addition to satd NaHCO3(aq) (30 mL) and
extraction with dichloromethane (3 × 30 mL). The combined organic
phases were dried over Na2SO4, filtrated, and concentrated under
reduced pressure. Purification was performed by column chromatog-
raphy (pentane/Et2O/HCOOH 18/2/1−14/6/1). A second column
using fine silica (pentane/acetone 10/1) resulted in the title
1
solid (66.4 mg, 0.39 mmol, 78%). H NMR (400 MHz, CDCl3): δ H
ppm 8.03 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 4.12 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ C ppm 186.3, 137.2, 133.1
(2C), 129.0 (2C), 118.1, 117.5, 113.1, 29.9. HRMS C10H7N2O [M +
H+]: 171.0553, found 171.0549. Mp (uncorrected): 128.4−130.2 °C.14
3-(4-Acetylphenyl)-3-oxopropanenitrile (7). Reaction with 1-(4-
bromophenyl)ethan-1-one (99.5 mg, 0.50 mmol) using general
method A was followed by workup by addition to satd NaHCO3(aq)
(30 mL) and extraction with dichloromethane (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtrated, and
concentrated under reduced pressure. Purification was performed by
column chromatography (pentane/Et2O/HCOOH12/8/1−8/12/1)
resulting in the title compound as a yellow solid (68.5 mg, 0.36 mmol,
1
compound as a yellow solid (78.5 mg, 0.36 mmol, 71%). H NMR
(400 MHz, CDCl3): δ H ppm 8.00 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4
Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J =
7.2 Hz, 1H), 4.11 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ C
ppm 186.7, 147.5, 139.4, 133.1, 129.2 (4C), 128.9 (2C), 127.9 (2C),
127.5, 113.9, 29.5. HRMS C15H12NO [M + H+]: calcd 222.0913,
found 222.0915. Mp (uncorrected): 112.1−113.3 °C.25
3-Oxo-3-phenylpropanenitrile (4). Reaction with bromobenzene
(52.5 μL, 0.50 mmol) using general method A was followed by
workup by addition to satd NaHCO3(aq) (30 mL) and extraction with
dichloromethane (3 × 30 mL). The combined organic phases were
dried over Na2SO4, filtrated, and concentrated under reduced pressure.
Purification was performed by column chromatography (pentane/
Et2O/HCOOH 15/4/1) resulting in the title compound as a yellow
solid (71.0 mg, 0.49 mmol, 98%). The physical and spectroscopic data
were in accordance with that reported for the same compound under
method B.
3-Oxo-3-phenylpropanenitrile (4). Reaction with phenyl trifluor-
omethanesulfonate (113 mg, 0.50 mmol) using general method A
followed by column chromatography (pentane/Et2O/HCOOH 34/6/
1−14/6/1) resulted in the title compound as a yellow solid (69.8 mg,
0.48 mmol, 96%). The physical and spectroscopic data were in
accordance with that reported for the same compound under method
B.
1
73%). H NMR (400 MHz, CDCl3): δ H ppm 8.08 (d, J = 8.3 Hz,
2H) 8.01 (d, J = 8.3 Hz, 2H), 4.12 (s, 2H), 2.66 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ C ppm 197.1, 186.8, 141.5, 137.3, 129.0
(2C), 128.9 (2C), 113.4, 29.9, 27.1. HRMS C11H9NNaO2 [M + Na+]:
calcd 210.0525, found 210.0524. Mp (uncorrected): 121.7−122.8
°C.14
3-(4-Fluorophenyl)-3-oxopropanenitrile (8). Reaction with 1-
bromo-4-fluorobenzene (88.0 mg, 0.50 mmol) using general method
A was followed by column chromatography (pentane/Et2O/HCOOH
34/6/1−14/6/1). A second column using fine silica (pentane/Et2O/
HCOOH 34/6/1−14/6/1) resulted in the title compound as a yellow
1
solid (60.4 mg, 0.37 mmol, 74% (corrected)). H NMR (400 MHz,
CDCl3): δ H ppm 8−00−7−93 (m, 2H), 7.23−7.15 (m, 2H), 4.08 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 185.8, 166.7 (d, J =
258 Hz), 131.4 (d, J = 9.7 Hz, 2C), 130.9 (d, J = 3.0 Hz), 116.6 (d, J =
22.2 Hz, 2C), 113.8, 29.5. 19F{1H} NMR (376 MHz, CDCl3): δ F
ppm −101.6. HRMS C9H6FNNaO [M + Na+]: calcd 186.0326, found
186.0329. Mp (uncorrected): 88.5−92.0 °C.13a
3-Oxo-3-(m-tolyl)propanenitrile (10). Reaction with 1-bromo-3-
methylbenzene (86.0 mg, 0.50 mmol) using general method A was
followed by column chromatography (pentane/Et2O/HCOOH 34/6/
1). A second column using fine silica (pentane/Et2O/HCOOH 34/6/
1−14/6/1) resulted in the title compound as a yellow solid (62.1 mg,
0.39 mmol, 78% (corrected). 1H NMR (400 MHz, CDCl3): δ H ppm
7.73 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.40 (t,
J = 7.6 Hz, 1H), 4.07 (s, 2H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 187.4, 139.3, 135.7, 134.5, 129.1, 129.1, 125.8,
3-Oxo-3-phenylpropanenitrile (4). To tert-butyl (E/Z)-2-cyano-3-
hydroxy-3-phenyl acrylate (26) (116 mg, 0.47 mmol) in anhydrous
dioxane (3.0 mL) was added HCOOH (1.0 mL) and the reaction
heated to 100 °C for 1 h. Purification by column chromatography
(pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the title
compound as a yellow solid (58.7 mg, 0.40 mmol, 86%). The physical
and spectroscopic data were in accordance with those reported for the
same compound under method B.
[3-13C]-3-Oxo-3-phenylpropanenitrile (4*). Reaction with bromo-
benzene (393 mg, 2.50 mmol) using general method B (with
13COgen, 914 mg, 3.50 mmol) followed by column chromatography
E
DOI: 10.1021/acs.joc.5b02897
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The Journal of Organic Chemistry
Featured Article
114.0, 29.5, 21.4. HRMS C10H10NO [M + H+]: calcd 160.0757, found
160.0754. Mp (uncorrected): 73.4−75.0 °C.13a
C11H12NO3 [M + H+]: 206.0814, found 206.0817. Mp (uncorrected):
123.2−124.4 °C.
3-(3-Methoxyphenyl)-3-oxopropanenitrile (11). Reaction with 1-
bromo-3-methoxybenzene (94.0 mg, 0.50 mmol) using general
method A was followed by column chromatography (pentane/Et2O/
HCOOH 34/6/1 to 14/6/1). A second column using fine silica
(pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the title
compound as a yellow solid (64.8 mg, 0.37 mmol, 74% (corrected)).
1H NMR (400 MHz, CDCl3): δ H ppm 7.47−7.38 (m, 3H), 7.20−
7.16 (m, 1H), 4.09 (s, 2H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 187.2, 160.2, 135.6, 130.2, 121.3, 121.1, 114.0,
112.8, 55.7, 29.6. HRMS C10H9NNaO2 [M + Na+]: calcd 198.0525,
found 198.0527. Mp (uncorrected): 80.9−83.3 °C.14
[3-13C]-3-(3,5-Dimethoxyphenyl)-3-oxopropanenitrile (15*). Re-
action with 1-bromo-3,5-dimethoxybenzene (108 mg, 0.50 mmol)
using general method A (with 13COgen, 184 mg, 0.75 mmol) followed
by column chromatography (pentane/Et2O/HCOOH 34/6/1−14/6/
1) resulted in the title compound as a yellow solid (76.0 mg, 0.37
mmol, 74%). 1H NMR (400 MHz, CDCl3): δ H ppm 7.00 (dd, J = 4.4
Hz, J = 2.2 Hz, 2H), 6.72−6.69 (m, 1H), 4.05 (d, J = 6.3 Hz, 2H), 3.83
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 187.0 (13C
enriched), 169.3 (Unkwon 13C impurity), 161.3 (d, J = 6.2 Hz, 2C),
136.2 (d, J = 57.5 Hz), 113.9 (d, J = 3.5 Hz), 106.8, 106.4 (d, J = 3.2
Hz, 2C), 55.8, 29.6 (d, J = 40.5 Hz, 2C). HRMS C1013CH12NO3 [M +
H+]: calcd 207.0846, found 207.0845. Mp (uncorrected): 122.4−123.6
°C.
3-Oxo-3-(3-(trifluoromethyl)phenyl)propanenitrile (12). Reaction
with 1-bromo-3-(trifluoromethyl)benzene (69.7 μL, 0.50 mmol) using
general method A was followed by workup by addition to satd
NaHCO3(aq) (30 mL) and extraction with dichloromethane (3 × 30
mL). The combined organic phases were dried over Na2SO4, filtrated,
and concentrated under reduced pressure. Purification was performed
by column chromatography (pentane/Et2O/HCOOH 15/5/1)
resulting in the title compound as a yellow solid (95.3 mg, 0.45
3-(4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3,5-difluorophenyl)-3-oxopro-
panenitrile (16). Reaction with 1-(4-bromo-2,6-difluorophenyl)-2,5-
dimethyl-1H-pyrrole (143 mg, 0.50 mmol) using general method A
followed by column chromatography (pentane/Et2O/HCOOH 68/3/
1−34/6/1−14/6/1) resulted in the title compound as a yellow solid
1
(56.8 mg, 0.21 mmol, 41%). H NMR (400 MHz, CDCl3): δ H ppm
1
7.65 (d, J = 7.0 Hz, 2H), 5.99 (s, 2H), 4.10 (s, 2H), 2.02 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3): δ C ppm 184.5, 159.5 (dd, J = 256
Hz, J = 3.8 Hz, 2C), 135.1 (t, J = 7.6 Hz), 129.4 (2C), 122.4 (t, J =
16.8 Hz), 112.9, 112.6−112.3 (m, 2C), 107.9 (s, 2C), 29.7, 12.2 (2C).
19F{1H} NMR (376 MHz, CDCl3): δ F ppm −113.7. HRMS
C15H13F2N2O [M + H+]: calcd 275.0990, found 275.0991. Mp
(uncorrected): 113.7−117.0 °C.
mmol, 89%). H NMR (400 MHz, CDCl3): δ H ppm 8.17 (s, 1H),
8.12 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.9 Hz,
1H), 4.13 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
186.0, 134.8, 131.9 (q, J = 33.4 Hz), 132.6−131.4 (m), 131.4 (q, J =
3.51 Hz), 130.0, 125.3 (q, J = 3.80 Hz), 123.3 (q, J = 272 Hz), 113.1,
29.6. 19F{1H} NMR (376 MHz, CDCl3): δ F ppm −63.0. HRMS
C10H6F3NNaO [M + Na+]: calcd 236.0294, found 236.0296. Mp
(uncorrected): 56.8−58.0 °C.26
3-Oxo-3-(3-(trifluoromethyl)phenyl)propanenitrile (12). Reaction
with 1-bromo-3-(trifluoromethyl)benzene (563 mg, 2.50 mmol) using
general method B followed by column chromatography (pentane/
Et2O/HCOOH 34/6/1−14/6/1) resulted in the title compound as a
yellow solid (436 mg, 2.05 mmol, 82%). The physical and
spectroscopic data were in accordance with that reported for the
same compound using method A.
3-(4-Amino-3,5-dichlorophenyl)-3-oxopropanenitrile (17). Reac-
tion with 4-bromo-2,6-dichloroaniline (120 mg, 0.50 mmol) using
general method A followed by column chromatography (pentane/
Et2O/HCOOH 34/6/1−14/6/1) resulted in the title compound as a
yellow solid (57.2 mg, 0.25 mmol, 50%). 1H NMR (400 MHz,
CDCl3): δ H ppm 7.78 (s, 2H), 5.14 (bs, 2H), 3.95 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ C ppm 183.5, 145.7, 128.9 (2C), 124.4,
119.2 (2C), 113.8, 28.9. HRMS C9H7Cl2N2O [M + H+]: calcd
228.9930, found 228.9930. Mp (uncorrected): 125.8−129.7 °C.
(E)-4-(4-Cyano-3-oxobut-1-en-1-yl)benzonitrile (18). Reaction
with (E)-4-(2-bromovinyl)benzonitrile (104 mg, 0.50 mmol) using
general method A was followed by column chromatography (pentane/
Et2O/HCOOH 34/6/1−14/6/1). A second column using fine silica
(pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the title
S-Cyclohexyl 3-(2-Cyanoacetyl)benzothioate (13). Reaction with
S-cyclohexyl 3-bromobenzothioate (150 mg, 0.50 mmol) using general
method A followed by column chromatography (pentane/Et2O/
HCOOH 34/6/1−14/6/1) resulted in the title compound as a yellow
1
solid (100 mg, 0.35 mmol, 70%). H NMR (400 MHz, CDCl3): δ H
ppm 8.41 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H),
7.62 (t, J = 7.7 Hz, 1H), 4.14 (s, 2H), 3.82−3.71 (m, 1H), 2.09−1.96
(m, 2H), 1.82−1.71 (m, 2H), 1.69−1.59 (m, 1H), 1.58−1.45 (m, 4H),
1.40−1.26 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
190.8, 186.5, 138.5, 134.7, 133.1, 132.6, 129.8, 127.0, 113.5, 43.3, 33.2
(2C), 29.7, 26.1 (2C), 25.7. HRMS C16H18NO2S [M + H+]: calcd
288.1053, found 288.1055. Mp (uncorrected): 81.7−84.3 °C.
1
compound as a yellow solid (53.2 mg, 0.27 mmol, 54%). H NMR
(400 MHz, CDCl3): δ H ppm 7.76−7.63 (m, 5H), 6.95 (d, J = 16.0
Hz, 1H), 3.72 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
186.0, 144.0, 137.7, 133.0 (2C), 129.2 (2C), 125.1, 118.2, 114.8, 113.7,
31.4. HRMS C12H9N2O [M + H+]: calcd 197.0709, found 197.0713.
Mp (uncorrected): 143.9−145.9 °C.
3-(3,4-Dimethoxyphenyl)-3-oxopropanenitrile (14). Reaction with
4-bromo-1,2-dimethoxybenzene (72.2 μL, 0.50 mmol) using general
method A was followed by workup by addition to satd NaHCO3(aq)
(30 mL) and extraction with dichloromethane (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtrated, and
concentrated under reduced pressure. Purification was performed by
column chromatography (pentane/Et2O/HCOOH 12/8/1) resulting
in the title compound as a yellow solid (61.6 mg, 0.30 mmol, 60%). 1H
NMR (400 MHz, CDCl3): δ H ppm 7.52−7.48 (m, 2H), 6.92 (d, J =
8.8 Hz, 1H), 4.03 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ C ppm 185.6, 154.8, 149.7, 127.6, 123.6, 114.2,
110.5, 110.4, 56.4, 56.3, 29.1. HRMS C11H11NNaO3 [M + Na+]: calcd
228.0631, found 228.0634. Mp (uncorrected): 134.4−135.7 °C.27
3-(3,5-Dimethoxyphenyl)-3-oxopropanenitrile (15). Reaction with
1-bromo-3,5-dimethoxybenzene (542 mg, 2.50 mmol) using general
method B followed by column chromatography (pentane/Et2O/
HCOOH 34/6/1−14/6/1) resulted in the title compound as a yellow
(E)-5-(4-Methoxyphenyl)-3-oxopent-4-enenitrile (19). Reaction
with (E)-1-(2-bromovinyl)-4-methoxybenzene (107 mg, 0.50 mmol)
using general method A was followed by column chromatography
(pentane/Et2O/HCOOH 14/6/1−14/14/1). A second column using
fine silica (pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the
title compound as a yellow solid (66.4 mg, 0.33 mmol, 66%). 1H NMR
(400 MHz, CDCl3): δ H ppm 7.64 (d, J = 15.9 Hz, 1H), 7.54 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 15.9 Hz, 1H), 3.86
(s, 3H), 3.68 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
186.3, 162.7, 146.5, 131.0 (2C), 126.2, 121.1, 114.8 (2C), 114.4, 55.6,
30.8. HRMS C12H12NO2 [M + H+]: calcd 202.0863, found 202.0865.
Mp (uncorrected): 132.9−134.0 °C.
3-Oxo-4-phenylbutanenitrile (20). Reaction with benzyl chloride
(63.0 mg, 0.50 mmol) using general method A followed by column
chromatography (pentane/Et2O/HCOOH 38/3/1−34/6/1−14/6/1)
resulted in the title compound as a yellow oil (74.2 mg, 0.47 mmol,
1
93%). H NMR (400 MHz, CDCl3): δ H ppm 7.41−7.28 (m, 3H),
1
solid (395 mg, 1.93 mmol, 77%). H NMR (400 MHz, CDCl3): δ H
7.21 (d, J = 6.7 Hz, 2H), 3.84 (s, 2H), 3.46 (s, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ C ppm 195.5, 132.1, 129.5 (2C), 129.3 (2C),
128.0, 113.8, 49.2, 31.3. HRMS C10H10NO [M + H+]: calcd 160.0757,
found 160.0756.25
ppm 7.01 (d, J = 2.2 Hz, 2H), 6.71 (t, J = 2.2 Hz, 1H), 4.04 (s, 2H),
3.84 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 187.0,
161.3 (2C), 136.2, 113.8, 106.8, 106.4 (2C), 55.9, 29.6 (2C). HRMS
F
DOI: 10.1021/acs.joc.5b02897
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The Journal of Organic Chemistry
Featured Article
3-Oxo-3-(thiophene-2-yl)propanenitrile (21). Reaction with 2-
bromothiophene (82.0 mg, 0.50 mmol) using general method A was
followed by column chromatography (pentane/Et2O/HCOOH 14/6/
1). A second column using fine silica (pentane/Et2O/HCOOH 34/6/
1−14/6/1) resulted in the title compound as a yellow solid (40.1 mg,
0.27 mmol, 53%). 1H NMR (400 MHz, CDCl3): δ H ppm 7.82−7.76
(m, 2H), 7.23−7.16 (m, 1H), 3.99 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ C ppm 179.6, 141.1, 136.4, 133.8, 128.9, 113.5, 29.7.
HRMS C7H5NNaOS [M + Na+]: calcd 173.9984, found 173.9983. Mp
(uncorrected): 136.3−138.3 °C.25
3-(Benzo[b]thiophene-2-yl)-3-oxopropanenitrile (22). Reaction
with 2-bromobenzo[b]thiophene (107 mg, 0.50 mmol) using general
method A followed by column chromatography with fine silica
(pentane/Et2O/HCOOH 34/6/1) resulted in the title compound as a
yellow solid (40.6 mg, 0.20 mmol, 40%). 1H NMR (400 MHz,
CDCl3): δ H ppm 8.05 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.90 (d, J =
8.0 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 4.11 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 181.2, 143.1, 140.3,
138.8, 131.3, 128.7, 126.6, 125.8, 123.2, 114.1, 29.7. HRMS
C11H8NOS [M + H+]: calcd 202.0321, found 202.0326. Mp
(uncorrected): 118.4−125.6 °C.
Ethyl (E/Z)-2-Cyano-3-hydroxy-3-phenylacrylate (27). Reaction
with bromobenzene (79.0 mg, 0.50 mmol) using general method A
(without treatment with HCOOH at 100 °C) followed by column
chromatography (pentane/Et2O/HCOOH 68/3/1−34/6/1−14/6/1)
resulted in the title compound as a yellow solid (107 mg, 0.49 mmol,
1
98%). H NMR (400 MHz, CDCl3): δ H ppm 14.25 (s, 1H), 8.04−
7.95 (m, 2H), 7.65−7.53 (m, 1H), 7.53−7.44 (m, 2H), 4.41 (q, J = 7.1
Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ C ppm 183.1, 171.5, 133.4, 131.6, 128.8 (2C), 128.7 (2C), 116.0,
79.0, 63.0, 14.2. HRMS C12H12NO3 [M + H+]: calcd 218.0812, found
218.0814. Mp (uncorrected): 40.4−40.8 °C.28
4-(2-Nitroacetyl)phenyl 4-Methylbenzenesulfonate (28). Reaction
with 4-bromophenyl 4-methylbenzenesulfonate (79.0 mg, 0.50 mmol)
using general method A followed by column chromatography
(pentane/Et2O/HCOOH 34/6/1−14/6/1) resulted in the title
1
compound as a yellow solid (102.3 mg, 0.31 mmol, 61%). H NMR
(400 MHz, CDCl3): δ H ppm 13.74 (s, 0.13H, enol (minor isomer)),
7.83 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz,
2H), 7.18 (d, J = 8.7 Hz, 2H), 5.84 (s, 1.61H, ketone (major isomer)),
2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 184.6,
154.5, 146.3, 132.0, 132.0, 130.3 (2C), 130.2 (2C), 128.6 (2C), 123.4
(2C), 81.2, 21.9. HRMS C15H14NO6S [M + H+]: calcd 336.0536,
found 336.0540. Mp (uncorrected): 128.4−130.2 °C.29
3-(Benzo[b]thiophene-6-yl)-3-oxopropanenitrile (23). Reaction
with 6-bromobenzo[b]thiophene (107 mg, 0.50 mmol) using general
method A was followed by workup by addition to satd NaHCO3(aq)
(30 mL) and extraction with dichloromethane (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtrated, and
concentrated under reduced pressure. Purification was performed by
column chromatography (pentane/EtOAc 10/2) resulting in the title
3-(3,5-Dimethoxyphenyl)propiolonitrile (29). 3-(3,5-Dimethoxy-
phenyl)-3-oxopropanenitrile (15) (65.4 mg, 0.32 mmol), 2-chloro-1-
methylpyridin-1-ium iodide (246 mg, 0.95 mmol), anhydrous
dichloromethane (3 mL), and triethylamine (1.58 mL, 11 mmol)
was added to a 8 mL vial in that order at 0 °C under an argon
atmosphere. The mixture was vigorously stirred for 30 min before
stirring at rt overnight. NaOH (1 M, 3 mL) was added, and the
mixture was stirred for an additional 10 min before dilution with
dichloromethane and water. The reaction was extracted with
dichloromethane (3 × 30 mL), and the combined organic phases
were washed with 1 × 1 M NaOH (30 mL) and 1 × 1 M HCl (30
mL) and concentrated under reduced pressure. The crude product was
purified by column chromatography (pentane/Et2O/HCOOH 7/3/
0−7/3/1) resulting in the title compound as a clear solid (43.0 mg,
0.23 mmol, 72%). 1H NMR (400 MHz, CDCl3): δ H ppm 6.72 (d, J =
2.1 Hz, 2H), 6.61 (t, J = 2.1 Hz, 1H), 3.79 (s, 6H). 13C{1H} NMR
(100 MHz, CDCl3): δ C ppm 160.9, 118.7, 111.2 (2C), 105.5, 105.5
(2C), 83.1, 62.5, 55.7 (2C). HRMS C11H10NO2 [M + H+]: calcd
188.0706, found 188.0706. Mp (uncorrected): 110.7−112.3 °C.
[3-13C]-3-(3,5-Dimethoxyphenyl)propiolonitrile (29*). [3-13C]-3-
(3,5-Dimethoxyphenyl)-3-oxopropanenitrile (15*) (64.2 mg, 0.31
mmol)), 2-chloro-1-methylpyridin-1-ium iodide (244 mg, 0.93
mmol), anhydrous dichloromethane (3 mL), and triethylamine (1.43
mL, 10 mmol) were added to a 8 mL vial in that order at 0 °C under
an argon atmosphere. The mixture was vigorously stirred for 30 min
before being stirred at rt overnight. NaOH (1 M, 3 mL) was added,
and the mixture was stirred for an additional 10 min before dilution
with dichloromethane and water. The reaction was extracted with
dichloromethane (3 × 30 mL), and the combined organic phases were
washed with 1 × 1 M NaOH (30 mL) and 1 × 1 M HCl (30 mL) and
concentrated under reduced pressure. The crude product was purified
by column chromatography (pentane/Et2O/HCOOH 7/3/0−7/3/1)
resulting in the title compound as a clear solid (41.5 mg, 0.22 mmol,
71%). 1H NMR (400 MHz, CDCl3): δ H ppm 6.73 (dd, J = 6.0 Hz, J
= 2.2 Hz, 2H), 6.63−6.60 (m, 1H), 3.80 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ C ppm 160.9 (d, J = 8.1 Hz), 118.8 (d, J = 89.8 Hz),
111.2 (d, J = 2.1 Hz, 2C), 105.7, 105.5 (2C), 83.1 (13C enriched), 63.5,
55.7 (2C). HRMS C1013CH10NO2 [M + H+]: calcd 189.0740, found
189.0739. Mp (uncorrected): 110.8−112.5 °C.
1
compound as a yellow solid (67.3 mg, 0.33 mmol, 67%). H NMR
(400 MHz, CDCl3): δ H ppm 8.49 (s, 1H), 7.95−7.88 (m, 2H), 7.77
(d, J = 5.4 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 4.16 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ C ppm 186.7, 144.2, 140.1, 132.6, 130.4,
124.3, 124.1, 124.1, 123.9, 114.0, 29.7. HRMS C11H7NNaOS [M +
Na+]: calcd 224.0141, found 224.0140. Mp (uncorrected): 111.2−
112.8 °C.
3-(Benzofuran-5-yl)-3-oxopropanenitrile (24). Reaction with 5-
bromobenzofuran (99.0 mg, 0.50 mmol) using general method A
followed by column chromatography (pentane/Et2O/HCOOH 34/6/
1) resulted in the title compound as a yellow solid (63.2 mg, 0.34
mmol, 68%). 1H NMR (400 MHz, CDCl3): δ H ppm 8.22 (d, J = 1.5
Hz, 1H), 7.91 (dd, J = 8.7 Hz, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz,
1H), 7.60 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 4.16 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ C ppm 186.8, 158.3, 148.3,
129.9, 128.2, 125.2, 123.1, 114.1, 112.3, 107.4, 29.6. HRMS C11H8NO2
[M + H+]: calcd 186.0550, found 186.0550. Mp (uncorrected):
129.0−130.1 °C.
3-(1H-Indol-5-yl)-3-oxopropanenitrile (25). Reaction with tert-
butyl 5-bromoindole-1-carboxylate (123 mg, 0.43 mmol) using general
method A followed by column chromatography (pentane/Et2O/
HCOOH 34/6/1−14/6/1−14/14/1−0/29/1) resulted in the title
1
compound as a yellow solid (45.9 mg, 0.24 mmol, 58%). H NMR
(400 MHz, CDCl3): δ H ppm 8.49 (bs, 1H), 8.26 (s, 1H), 7.83 (dd, J
= 8.6 Hz, J = 1.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.34 (m, 1H), 6.71
(s, 1H), 4.15 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
186.9, 139.3, 127.8, 127.2, 126.5, 123.5, 122.5, 114.6, 111.8., 104.8,
29.4. HRMS C11H9N2O [M + H+]: calcd 185.0709, found 185.0711.
Mp (uncorrected): 95.9−96.2 °C.
tert-Butyl (E/Z)-2-Cyano-3-hydroxy-3-phenylacrylate (26). Reac-
tion with bromobenzene (79.0 mg, 0.50 mmol) using general method
A (without treatment with HCOOH at 100 °C) followed by column
chromatography (pentane/Et2O/HCOOH 68/3/1−34/6/1) resulted
in the title compound as a yellow solid (116 mg, 0.47 mmol, 95%).
Leaving the title compound on the column or in solution after column
for an extended time period result in degradation into 3-oxo-3-
3-Phenylpropiolonitrile (30). 3-Oxo-3-phenylpropanenitrile (1)
(182 mg, 1.25 mmol), 2-chloro-1-methylpyridin-1-ium iodide (958
mg, 3.75 mmol), anhydrous dichloromethane (11 mL), and
triethylamine (5.6 mL, 40 mmol) were added to a round-bottom
bottle in that order at 0 °C under an argon atmosphere. The mixture
was vigorously stirred for 30 min before stirring at rt overnight. NaOH
(1 M, 11 mL) was added, and the mixture was stirred for an additional
10 min before dilution with dichloromethane and water. The reaction
1
phenylpropanenitrile (1). H NMR (400 MHz, CDCl3): δ H ppm
14.43 (s, 1H), 8.04−7.93 (m, 2H), 7.62−7.54 (m, 1H), 7.54−7.44 (m,
2H), 1.61 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm
183.0, 171.1, 133.2, 132.0, 128.8 (2C), 128.7 (2C), 116.3, 85.6, 80.2,
28.2 (3C). HRMS C14H16NO3 [M + H+]: calcd 246.1125, found
246.1130. Mp (uncorrected): 103.5−105.5 °C.
G
DOI: 10.1021/acs.joc.5b02897
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Featured Article
was extracted with dichloromethane (3 × 30 mL), and the combined
organic phases were washed with 1 × 1 M NaOH (30 mL) and 1 × 1
M HCl (30 mL) and concentrated under reduced pressure (the title
compound was found to be volatile and the pressure during
concentration was therefore never lower than 600 mbar at 30 °C).
The crude product was purified by column chromatography (pentane/
Et2O 1/0−40/1) resulting in the title compound as a clear solid (115
mg, 0.90 mmol, 72%). 1H NMR (400 MHz, CDCl3): δ H ppm 7.66−
7.58 (m, 2H), 7.57−7.50 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 5.29
(Dichloromethane impurity). 13C{1H} NMR (100 MHz, CDCl3): δ C
ppm 133.6 (2C), 132.0, 129.0 (2C), 117.6, 105.6, 83.1, 63.2. HRMS
C9H6N [M + H+]: calcd 128.0495, found 128.0495. Mp
(uncorrected): 37.8−38.4 °C.30
added in the order listed. The vial was sealed and removed from the
glovebox before heating to 130 °C and stirred for 24 h. The mixture
was cooled to rt and filtered over a small plug of silica (EtOAc).
Purification by column chromatography using general method F
followed by column chromatography (pentane/Et2O 40/1−30/1−20/
1) resulted in the title compound as a clear solid (47.8 mg, 0.16 mmol,
37%). 1H NMR (400 MHz, CDCl3): δ H ppm 7.31 (dd, J = 4.8 Hz, J
= 2.2 Hz, 2H), 7.18 (s, 1H), 6.92 (s, 1H), 6.61−6.54 (m, 1H), 3.88 (s,
6H), 2.70 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
C ppm 161.3 (2C), 161.2 (13C enriched), 153.9 (d, J = 2.2 Hz), 137.1,
131.4 (d, J = 4.1 Hz), 129.8 (d, J = 69.6 Hz), 127.4, 123.1, 116.1 (d, J
= 6.7 Hz), 109.5 (d, J = 2.8 Hz), 104.3 (d, J = 2.4 Hz, 2C), 103.7, 87.9
(d, J = 82.2 Hz), 55.7 (2C), 21.8, 18.0. HRMS C1813CH18NO3 [M +
H+]: calcd 309.1315, found 309.1316. Mp (uncorrected): 174.7−175.8
°C.
[3-13C]-3-Phenylpropiolonitrile (30*). [3-13C]-3-Oxo-3-phenylpro-
panenitrile (1*) (146 mg, 1.00 mmol), 2-chloro-1-methylpyridin-1-
ium iodide (764 mg, 3.00 mmol), anhydrous dichloromethane (8.7
mL), and triethylamine (4.5 mL, 32 mmol) were added to a round-
bottom bottle in that order at 0 °C under an argon atmosphere. The
mixture was vigorously stirred for 30 min before stirring at rt
overnight. NaOH (1 M, 8.7 mL) was added, and the mixture was
stirred for an additional 10 min before dilution with dichloromethane
and water. The reaction was extracted with dichloromethane (3 × 30
mL), and the combined organic phases were washed with 1 × 1 M
NaOH (30 mL) and 1 × 1 M HCl (30 mL) and concentrated under
reduced pressure (the title compound was found to be volatile and the
pressure during concentration therefore never lower than 600 mbar at
30 °C). The crude product was purified by column chromatography
(pentane/Et2O 1/0−40/1) resulted in the title compound as a pale
yellow solid (94.8 mg, 0.74 mmol, 74%). 1H NMR (400 MHz,
CDCl3): δ H ppm 7.65−7.58 (m, 2H), 7.54 (t, J = 7.1 Hz, 1H), 7.42
(t, J = 7.7 Hz, 2H), 5.29 (dichloromethane impurity). 13C{1H} NMR
(100 MHz, CDCl3): δ C ppm 133.6 (d, J = 1.8 Hz, 2C), 132.0 (d, J =
1.7 Hz), 129.0 (d, J = 5.7 Hz, 2C), 117.6 (d, J = 89.8 Hz), 105.6 (d, J =
20.1 Hz), 83.1 (s, 13C enriched), 63.2 (d, J = 203 Hz). HRMS
C813CH6N [M + H+]: calcd 129.0528, found 129.0523. Mp
(uncorrected): 37.7−39.5 °C.
4,6-Dimethyl-2-phenylbenzofuran-3-carbonitrile (32).23 To an 8
mL vial were added 3-phenylpropiolonitrile-3 (30) (63.6 mg, 0.50
mmol), 3,5-dimethylphenol (67.2 mg, 0.55 mmol), DABCO (56.1 mg,
0.50 mmol), and 1,2-dichloroethane (1.0 mL). The vial was sealed
with a lid, heated to 45 °C, and stirred overnight before addition of 1
M HCl (1 mL) and extraction with 1,2-dichloroethane (3 × 1.0 mL).
The organic phases were transferred to a 10 mL vial and concentrated
under reduced pressure. The vial was transferred to an argon-filled
glovebox, and Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.050
mmol), Cu(OAc)2 (182 mg, 1.00 mmol), and dioxane (1.0 mL) were
added in the order listed. The vial was sealed and removed from the
glovebox before heating to 130 °C and stirred for 24 h. The mixture
was cooled to rt and filtered over a small plug of silica (EtOAc).
Purification by column chromatography (pentane/Et2O 40/1)
resulted in the title compound as a clear solid (51.7 mg, 0.21 mmol,
1
42%). H NMR (400 MHz, CDCl3): δ H ppm 8.17 (d, J = 6.7 Hz,
2H), 7.58−7.46 (m, 3H), 7.19 (s, 1H), 6.94 (s, 1H), 2.71 (s, 3H), 2.45
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 161.4, 154.0,
137.0, 131.4, 130.9, 129.2 (2C), 128.4, 127.4, 126.5 (2C), 123.2, 116.2,
109.5, 87.6, 21.8, 18.0. HRMS C17H14NO [M + H+]: calcd 248.1070,
found 248.1072. Mp (uncorrected): 110.5−111.8 °C.23
[2-13C]-4,6-Dimethyl-2-phenylbenzofuran-3-carbonitrile (32*).23
To a 8 mL vial were added [3-13C]-3-phenylpropiolonitrile (30*)
(51.8 mg, 0.40 mmol), 3,5-dimethylphenol (53.8 mg, 0.44 mmol),
DABCO (44.9 mg, 0.40 mmol), and 1,2-dichloroethane (0.80 mL).
The vial was sealed with a lid, heated to 45 °C, and stirred overnight
before addition of 1 M HCl (0.80 mL) and extraction with 1,2-
dichloroethane (3 × 0.80 mL). The organic phases were transferred to
a 10 mL vial and concentrated under reduced pressure. The vial was
transferred to an argon-filled glovebox, and Pd(OAc)2 (4.5 mg, 0.020
mmol), PPh3 (10.5 mg, 0.040 mmol), Cu(OAc)2 (146 mg, 0.80
mmol), and dioxane (0.80 mL) were added in the order listed. The vial
was sealed and removed from the glovebox before heating to 130 °C
and stirred for 24 h. The mixture was cooled to rt and filtered over a
small plug of silica (EtOAc). Purification by column chromatography
(pentane/Et2O 40/1) resulted in the title compound as a clear solid
2-(3,5-Dimethoxyphenyl)-4,6-dimethylbenzofuran-3-carbonitrile
(31).23 To an 8 mL vial were added 3-(3,5-dimethoxyphenyl)-
propiolonitrile-3 (29) (93.5 mg, 0.50 mmol), 3,5-dimethylphenol
(67.2 mg, 0.55 mmol), DABCO (56.1 mg, 0.50 mmol), and 1,2-
dichloroethane (1.0 mL). The vial was sealed with a lid, heated to 45
°C, and stirred overnight before addition of 1 M HCl (1 mL) and
extraction with 1,2-dichloroethane (3 × 1.0 mL). The organic phases
were transferred to a 10 mL vial and concentrated under reduced
pressure. The vial was transferred to an argon-filled glovebox, and
Pd(OAc)2 (5.61 mg, 0.025 mmol), PPh3 (13.1 mg, 0.050 mmol),
Cu(OAc)2 (182 mg, 1.00 mmol), and dioxane (1.0 mL) were added in
the order listed. The vial was sealed and removed from the glovebox
before heating to 130 °C and stirred for 24 h. The mixture was cooled
to rt and filtered over a small plug of silica (EtOAc). Purification by
column chromatography (pentane/Et2O 40/1−30/1−20/1) resulted
1
1
(37.5 mg, 0.15 mmol, 38%). H NMR (400 MHz, CDCl3): δ H ppm
in the title compound as a clear solid (46.6 mg, 0.15 mmol, 30%). H
8.22−8.12 (m, 2H), 7.57−7.45 (m, 3H), 7.19 (s, 1H), 6.93 (s, 1H),
2.71 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ C
ppm 161.4 (13C enriched), 154.0 (d, J = 2.2 Hz), 137.0, 131.4 (d, J =
4.1 Hz), 130.9 (d, J = 1.4 Hz), 129.2 (d, J = 4.8 Hz, 2C), 128.3 (d, J =
69.5 Hz), 127.3, 126.5 (d, J = 2.1 Hz, 2C), 123.2, 116.2 (d, J = 6.7 Hz),
109.5 (d, J = 2.8 Hz), 87.5 (d, J = 82.0 Hz), 21.8, 18.0. HRMS
C1613CH14NO [M + H+]: calcd 249.1103, found 249.1105. Mp
(uncorrected): 118.6−121.2 °C.
NMR (400 MHz, CDCl3): δ H ppm 7.31 (d, J = 2.1 Hz, 2H), 7.17 (s,
1H), 6.92 (s, 1H), 6.61−6.55 (m, 1H), 3.88 (s, 6H), 2.69 (s, 3H), 2.44
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 161.3 (2C),
161.2, 153.9, 137.1, 131.4, 129.8, 127.3, 123.1, 116.1, 110.3, 104.2
(2C), 103.7, 87.9, 55.7 (2C), 21.8, 18.0. HRMS C19H18NO3 [M +
H+]: calcd 308.1281, found 308.1284. Mp (uncorrected): 172.4−173.7
°C.
[2-13C]-2-(3,5-Dimethoxyphenyl)-4,6-dimethylbenzofuran-3-car-
bonitrile (31*).23 To an 8 mL vial were added [3-13C]-3-(3,5-
dimethoxyphenyl)propiolonitrile (29*) (79.4 mg, 0.42 mmol), 3,5-
dimethyl phenol (56.4 mg, 0.46 mmol), DABCO (47.1 mg, 0.42
mmol), and 1,2-dichloroethane (0.84 mL). The vial was sealed with a
lid, heated to 45 °C, and stirred overnight before addition of 1 M HCl
(0.84 mL) and extraction with 1,2-dichloroethane (3 × 1.0 mL). The
organic phases were transferred to a 10 mL vial and concentrated
under reduced pressure. The vial was transferred to an argon-filled
glovebox, and Pd(OAc)2 (4.7 mg, 0.021 mmol), PPh3 (11.0 mg, 0.042
mmol), Cu(OAc)2 (153 mg, 0.84 mmol), and dioxane (0.84 mL) were
tert-Butyl 2-Nitroacetate.24 Nitrite supported on a polymer (Fluka,
4 mmol/g resin, Amberlyst A26, batch 72580, 10 g) was dried on a
vacuum line overnight. The polymer−nitrite (5 g (wet weight),
approximately 20 mmol) was added to anhydrous acetonitrile (50 mL)
at −15 °C and stirred under an argon atmosphere for 30 min before
addition of tert-butyl 2-bromoacetate (1.95 g, 10 mmol). The reaction
was followed by GC analysis and quenched upon completion (18 h)
by filtration. The polymer was washed with 5× dichloromethane, and
the combined organic phases concentrated under reduced pressure.
The resulting oil was purified by column chromatography (pentane/
H
DOI: 10.1021/acs.joc.5b02897
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The Journal of Organic Chemistry
Featured Article
Et2O 97/3) resulting in the title compound as a clear oil (676 mg, 4.20
(17) (a) Korsager, S.; Nielsen, D. U.; Taaning, R. H. Angew. Chem.,
Int. Ed. 2013, 52, 9763. (b) Nielsen, D. U.; Korsager, S.; Lindhardt, A.
T.; Skrydstrup, T. Adv. Synth. Catal. 2014, 356, 3519.
(18) Makarov, I. S.; Kuwahara, T.; Jusseau, X.; Ryu, I.; Lindhardt, A.
T.; Skrydstrup, T. J. Am. Chem. Soc. 2015, 137, 14043.
(19) Leclercq, M.; Brienne, M.-J. Tetrahedron Lett. 1990, 31, 3875.
(20) Liu, Y.; Shen, B.; Kotora, M.; Takahashi, T. Angew. Chem. Int.
Ed. 1999, 38, 949.
1
mmol, 42%). H NMR (400 MHz, CDCl3): δ H ppm 5.07 (s, 2H),
1.51 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ C ppm 160.8,
85.4, 28.0 (3C). HRMS C6H11NNaO4 [M + Na+]: 184.0580, found
184.0582.24
ASSOCIATED CONTENT
■
S
* Supporting Information
(21) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I.
Organometallics 2010, 29, 2176.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02897.
1H, 13C{1H}, and 19F{1H} NMR spectra for all produced
compounds (PDF)
(22) Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991, 113, 6313.
(23) Zhou, W.; Zhang, Y.; Li, P.; Wang, L. Org. Biomol. Chem. 2012,
10, 7184.
(24) Scardovi, N.; Casalini, A.; Peri, F.; Righi, P. Org. Lett. 2002, 4,
965.
(25) Mamuye, A. D.; Castoldi, L.; Azzena, U.; Holzer, W.; Pace, V.
Org. Biomol. Chem. 2015, 13, 1969.
(26) Seneci, P.; Nicola, M.; Inglesi, M.; Vanotti, E.; Resnati, G. Synth.
Commun. 1999, 29, 311.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: lindhardt@eng.au.dk.
*E-mail: ts@chem.au.dk.
(27) Fang, Z.; Song, Y.; Sarkar, T.; Hamel, E.; Fogler, W. E.; Agoston,
G. E.; Fanwick, P. E.; Cushman, M. J. Org. Chem. 2008, 73, 4241.
(28) Tanaka, T.; Maezaki, N.; Furusawa, A.; Uchida, S. Heterocycles
2003, 59, 161.
(29) Lian, Z.; Friis, S. D.; Skrydstrup, T. Chem. Commun. 2015, 51,
3600.
Notes
The authors declare the following competing financial interest:
Anders T. Lindhardt and Troels Skrydstrup are co-owners of
SyTracks Aps, which commercializes the two-chamber
technology.
⊥Member of CADIAC.
(30) Rong, G.; Mao, J.; Zheng, Y.; Yao, R.; Xu, X. Chem. Commun.
2015, 51, 13822.
ACKNOWLEDGMENTS
■
We are deeply appreciative of generous financial support of this
work from the Danish National Research Foundation (Grant
No. DNRF118), the Villum Foundation, the Danish Council
for Independent Research: Technology and Production
Sciences, the Lundbeck Foundation, Lundbeck A/S, and
Aarhus University.
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DOI: 10.1021/acs.joc.5b02897
J. Org. Chem. XXXX, XXX, XXX−XXX