Catalyst Efficacy of Homogeneous and Heterogeneous Palladium Catalysts in the Direct Arylation of Common Heterocycles

Article abstract of DOI:10.1055/s-0035-1561436

The direct arylation of several common heterocycles, using homogeneous and heterogeneous palladium (pre)catalysts, has been examined by initial rate analysis. The study reveals that apparently distinct palladium catalysts can display similar activities in such transformations, implying formation of a comparable active palladium catalyst phase. A substrate dependence was noted for the palladium catalysts examined.

Full text of DOI:10.1055/s-0035-1561436

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Catalyst Efficacy of Homogeneous and Heterogeneous Palladium
Catalysts in the Direct Arylation of Common Heterocycles
Alan J. Reay
Lydia K. Neumann1
Ian J. S. Fairlamb*
Department of Chemistry, University of York, Heslington, York,
YO10 5DD, UK
ian.fairlamb@york.ac.uk
Received: 18.03.2016
Accepted after revision: 04.04.2016
Published online: 18.04.2016
ubiquitous palladium (pre)catalysts often display heteroge-
neous-type catalytic behaviour, typically through specia-
tion to form higher-order palladium colloids or nanoparti-
cles (PdNPs) under commonly found experimental condi-
tions. This is evident in traditional palladium-mediated
cross-couplings6 and more recently in C–H bond function-
alisation reactions.7
DOI: 10.1055/s-0035-1561436; Art ID: st-2016-u0189-c
Abstract The direct arylation of several common heterocycles, using
homogeneous and heterogeneous palladium (pre)catalysts, has been
examined by initial rate analysis. The study reveals that apparently dis-
tinct palladium catalysts can display similar activities in such transfor-
mations, implying formation of a comparable active palladium catalyst
phase. A substrate dependence was noted for the palladium catalysts
examined.
Glorius and co-workers reported the regioselective di-
rect arylation of 2-n-butylthiophene and other simple het-
erocycles, using the heterogeneous catalyst Pd/C (Scheme
1).8 It was noted that Pd/C, obtained from different com-
mercial sources, demonstrated profoundly different activi-
ties. Several established tests for heterogeneous catalysis
were performed and revealed no evidence for active homo-
geneous palladium species, although poor catalyst recy-
clability was observed suggesting palladium leaching, or
palladium catalyst restructuring, could have occurred un-
der the oxidising conditions. Our group has previously in-
vestigated the nature of the active catalyst in similar direct
arylation reactions, where the activity of pre-formed ‘stabi-
lised’ PdNP catalysts can be compared to that of PdNPs
formed in situ from nominally homogeneous precursors
such as Pd(OAc)2.9 With these observations in mind, we
proposed that kinetic examination, using ex situ GC analy-
sis, would provide valuable insight into the behaviour of
these and similar reactions.10
To begin our studies, we identified four palladium cata-
lyst sources which provide a useful test of two ubiquitous
precatalysts, a supported catalyst and well-defined palladi-
um nanoparticulate catalyst, namely: Pd3(OAc)6 hereafter
Pd(OAc)2 (>99% purity), Pd2(dba)3·CHCl3 [dba = (E,E)-diben-
zylideneacetone], hereafter Pd2(dba)3 (91% purity, based on
Ananikov’s method),11 Pd/C (5 wt%, Sigma Aldrich, cata-
logue number 205680, lot number 06230AJ-298) and PVP–
Pd (PVP = polyvinylpyrrolidinone). The latter catalyst, PVP–
Pd, is an established polymer-supported PdNP catalyst, the
Key words catalysis, palladium, homogeneous, heterogeneous, aryla-
tion, heterocycles
The importance of palladium-mediated cross-coupling
reactions in organic synthesis is without question, as the
ability to selectively form C–C bonds in the presence of oth-
er molecular functionality is unparalleled in its utility.2
While highly useful from a synthetic viewpoint, a signifi-
cant drawback to traditional cross-coupling reactions is the
requirement for substrate pre-functionalisation with acti-
vating groups such as organoboronic acids or organos-
tannes, among others. Recent advances in direct C–H bond
functionalisation chemistry have addressed this issue, as
many mild and selective methods can now be used to cleave
and generate C–H bonds directly without pre-functional-
isation, significantly expanding the toolkit of the synthetic
chemist.3
One issue that remains is the elemental sustainability of
rare and precious metals, which increasingly leads to pro-
hibitive costs and issues surrounding the criticality of sup-
ply chains.4 One approach to obviate this concern is to de-
termine whether current palladium catalysts can be used
more effectively, by recycling the precious metal from each
reaction and preventing it from entering waste streams.5
Central to this approach is the understanding that many
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Under the conditions shown in Scheme 2, Pd2(dba)3 and
PVP–Pd proved the most active catalysts, with rapid con-
version of substrate 1 within the first five minutes of sub-
strate turnover (the first recorded data point). This implies
a similarity between the active catalytic species in these re-
actions, despite the apparently highly dissimilar starting
catalysts. Pd/C and Pd(OAc)2 exhibited markedly different
reactivity, although these two catalysts were broadly simi-
lar in their activity. These results suggest that if PdNPs are
catalysing this reaction, the nanoparticles produced from
Pd(OAc)2 and Pd/C are similar, yet distinct from the
nanoparticles produced by Pd2(dba)3 and PVP–Pd. It is also
interesting to note that of the catalysts tested, only PVP–Pd
led to complete consumption of substrate 1 after 24 hours.
Despite its relatively slow initial rate, Pd/C eventually pro-
vides conversion that parallels Pd2(dba)3, which is more ac-
tive in the early stages of the reaction. However, Pd(OAc)2
does not achieve these levels of conversion; the activity of
this catalyst eventually drops off, despite matching the ini-
tial turnover rates of Pd/C. This type of behaviour can be ra-
tionalised if the deactivating agglomeration of PdNPs is
more facile in the absence of a supporting matrix such as
activated carbon, even if the PdNPs originally formed from
Pd(OAc)2 and Pd/C are similar. Conversely, little difference is
seen in the reaction profiles when using either Pd2(dba)3 or
PVP–Pd as the catalyst.
H
R2
Ar1
R2
R1
R1
X–
S
S
I+
27 examples
<96% yield
Ar1
Ar2
X = BF4, OTf
Pd/C (5 mol%)
EtOH, 60 °C, 22 h
R
R
Ar1
X
X
6 examples
40–94% yield
X = NH, O, S
Scheme 1 Direct arylation using Pd/C of thiophenes and related het-
erocycles8
synthesis of which provides well-controlled, regular
nanoparticles typically between 2–4 nm in diameter (see
Supporting Information).12 These four catalysts were initial-
ly applied to the direct arylation of N-methylindole (1) un-
der the conditions shown in Scheme 1.13 Substrate 1
demonstrated high reactivity under these conditions, with
all four palladium catalysts rapidly producing the C-2 ary-
lated product 2.14 The reaction temperature was lowered to
50 °C to provide improved discrimination between the ac-
tivity of these catalysts, and reactions followed ex situ by
GC analysis (Scheme 2). During this process a novel method
of sample quenching by centrifugation with CeliteTM was
developed to give reliable data (see Supporting Information
for details).
The four palladium catalysts shown above were exam-
ined further in the reaction of benzofuran (3) at 60 °C; ki-
netic profiles are shown in Scheme 3. Overall, substrate 3
Scheme 3 Direct arylation of benzofuran at 60 °C over 24 h. Data is
fitted to a first-order exponential decay equation for Pd/C and PVP–Pd.
Detailed analysis over the initial 7 h shown, final conversions by GC after
24 h; Pd/C: 88%, PVP–Pd: 91%, Pd(OAc)2: 31%, Pd2(dba)3: 31%. X =
starting concentration of substrate at t = 0.
Scheme 2 Direct arylation of N-methylindole at 50 °C over 24 h. Data
is fitted to a first-order exponential decay equation. Detailed analysis
over the initial 7 h shown, final conversions by GC after 24 h; Pd/C: 83%,
PVP–Pd: 100%, Pd(OAc)2: 66%, Pd2(dba)3: 88%.
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demonstrated lower activity towards arylation than N-me-
thylindole (1). PVP–Pd proved to be the most active cata-
lyst, providing ca. 29% conversion to the C-2 arylated prod-
uct 4 within five minutes, and >90% after 24 hours.15 Inter-
estingly, Pd/C performed similarly to PVP–Pd, in stark
contrast to its poor initial activity when using N-methylin-
dole 1 as a substrate. Pd(OAc)2 and Pd2(dba)3 displayed poor
catalyst activity for this arylation. Comparing arylations 1 →
2 and 3 → 4 we can see that there is a substrate dependence
on the catalytic activity for this transformation; whether
this is due to variation in PdNP formation or behaviour, or
rather a difference in palladium leaching rates/catalyst re-
structuring, is unclear at this stage.
2-n-Butylthiophene (5), the key substrate in the previ-
ous study reported by Glorius and co-workers,8 was also ex-
amined under these conditions (Scheme 4). 2-n-Butylthio-
phene (5) demonstrated catalyst activity lower than that of
either N-methylindole (1) or benzofuran (3), as expected,
but did reach 86% conversion to the C-3 arylated product 6
after 24 hours, using PVP–Pd as a catalyst (which was again
the most reactive catalysts of those tested).15,16 Little differ-
ence between palladium catalysts was observed during ear-
ly substrate turnover, which had earlier provided a discrim-
ination between catalysts vide supra. However, the final
conversion varied significantly, that is, between worst-per-
forming catalyst, Pd2(dba)3 (42%), and best-performing cat-
alyst, PVP–Pd (86%).
The substrates tested thus far were all reported by Glo-
rius and co-workers to be active under their conditions,
when using Pd/C as the catalyst.8 We hypothesised that 2-
n-butylfuran (7) should also prove effective in this protocol,
but the original publication states that reaction of this sub-
strate with [Ph2I]BF4 using Pd/C leads to degradation of the
starting materials. Conversion to the desired arylated prod-
uct is feasible using a strongly electron-deficient diaryl-
iodonium salt.8
We pursued further studies with substrate 7 (Scheme
5). Reaction of 7 under the standard arylation conditions13
using the four palladium catalysts led to substrate turnover
of 7. Reactivity not dissimilar to that of benzofuran (3) was
realised, with PVP–Pd and Pd/C proving the most effective
catalysts; complete conversion was recorded after 24 hours
at 60 °C. Pd(OAc)2 and Pd2(dba)3 were less effective, with ca.
60–65% conversion after 24 hours.
Scheme 5 Direct arylation of 2-n-butylfuran at 60 °C over 24 h. Data is
fitted to a first-order exponential decay equation [with the exception of
Pd(OAc)2 which showed more complex behaviour under the reaction
conditions]. Final conversions by GC after 24 h; Pd/C: 100%, PVP–Pd:
95%, Pd(OAc)2, 62%, Pd2(dba)3: 65%. X = starting concentration of sub-
strate at t = 0.
The activity of these four palladium catalysts is similar
over the first hour of the reaction, but a distinction be-
tween the palladium catalysts tested is apparent after this
time point.
In order to gain a detailed picture of the reactivity of 7
under conditions catalysed by Pd/C, the reaction was re-
peated at a higher temperature (70 °C) and samples taken at
Scheme 4 Direct arylation of 2-n-butylthiophene at 60 °C over 24 h.
Data is fitted to a first-order exponential decay equation. Final conver-
sions by GC after 24 h; Pd/C: 66%, PVP–Pd: 86%, Pd(OAc)2: 75%,
Pd2(dba)3: 42%.
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regular intervals until reaction completion after ca. ten
hours. Loss of substrate 7 was concomitant with formation
of the C-2 arylated product 8, with no observable side prod-
ucts (Scheme 6).17
MS (EI), and 1H NMR spectroscopic analysis. Iodobenzene is
also present as a major byproduct of [Ph2I]BF4 (bp 188 °C),
which complicates the matter due to the relatively low boil-
ing point of 8 (95 °C).19 Purification of 8 by silica gel column
chromatography of a separate reaction, catalysed by PVP–
Pd, enabled its isolation in pure form in 45% yield, con-
1
firmed as the C2-arylated regioisomer 8 by H NMR analy-
sis.17 Degradation of ArIIIIX2 species to give ArI in similar re-
actions has been reported previously.20
The detailed analysis of the initial stages of reaction us-
ing these substrates allowed fitting of first-order exponen-
tial decay equations, as shown in the appropriate Schemes
2–6. Good fits were obtained in the majority of cases;
where line fitting could not be performed this is suspected
to be the result of rapid initial reactivity followed by loss of
catalytic activity, for example, the reaction of benzofuran
with Pd(OAc)2 as catalyst. These analyses allowed calcula-
tion of the initial rate of reaction (kobs) for the majority of
substrate and catalyst combinations; these are shown in Ta-
ble 1. Errors in these values are calculated from the stan-
dard deviation of a linear regression of the initial reaction
rates, (least-squares method). These rate constants are
broadly similar to one another, lying between ca. 1·10–6 and
1·10–5 s–1 for all the catalyst/substrate combinations tested.
By comparison, a pseudo-first-order rate constant of
3.5(2)·10–4 s–1 M–1 for the arylation of 2-methylthiophene
has been reported, measured directly with [PdAr(μ-
OAc)(PPh3)]2 in 1,4-dioxane at 90 °C.21
Scheme 6 Direct arylation of 2-n-butylfuran at 70 °C over 10 h. Data is
fitted to a first-order exponential decay (substrate) or logarithmic growth
(product) equation. X = starting concentration of substrate at t = 0.
In conclusion, the effects of four nominally distinct pal-
ladium catalysts in direct arylation reactions, mediated by
homogeneous and heterogeneous palladium, have been ex-
amined.8 Initial-rate kinetic analysis showed similarities in
catalytic behaviour between apparently distinct palladium
catalysts, implying that dissimilar catalyst structures can
function as precatalysts for the formation of a comparable
active catalyst phase; speciation to form PdNPs or clusters is
proposed as one possible mechanism for this process, under
the reaction conditions tested. It may be that PdNPs are not
actively catalysing these reactions (i.e., acting as a palladi-
um reservoir),22 the active species instead consisting of
It is not obvious why substrate 7 provides excellent re-
activity in our hands. It may be that the different sources of
Pd/C used provide unique forms of catalytically active palla-
dium. Alternatively, an impurity such as those reported for
other commercially available palladium catalysts may be
present,18 which manifests itself when using this substrate.
It was noted during our investigations that purification of
the arylated product 8 from the Pd/C-catalysed reactions
was challenging. Attempted purification of several reac-
tions catalysed by Pd/C afforded inseparable mixtures of
the desired product 8 and biphenyl, confirmed by TLC, GC–
a
Table 1 Observed Pseudo-First-Order Rate Constants (kobs) for Direct Arylation Reactions Mediated by Pd/C, PVP–Pd, Pd(OAc)2, and Pd2(dba)3
Pd/C
(9.2 ± 0.5)·10–6
PVP–Pd
Pd(OAc)2
Pd2(dba)3
N-methylindole (1)
(1.3 ± 0.1)·10–5
(2.1 ± 0.5)·10–6
(1.6 ± 0.2)·10–6
(4.8 ± 0.5)·10–6
N/A
(9.7 ± 0.4)·10–6
–
benzofuran (3)
(6.3 ± 0.8)·10–6
(6.1 ± 0.6)·10–6
(7.1 ± 0.6)·10–6
(9.3 ± 0.9)·10–6
(9.4 ± 1.6)·10–6
–
–
2-n-butylthiophene (5)
2-n-butylfuran (7)(at 60 °C)
2-n-butylfuran (7)(at 70 °C)
5-phenyl-2-n-butylfuran (8)(at 70 °C)b
(1.9 ± 0.3)·10–6
(1.6 ± 0.1)·10–6
N/A
(2.6 ± 0.3)·10–6
(3.3 ± 0.5)·10–6
N/A
N/A
N/A
N/A
a Rate constants calculated from initial rates using a fitted first-order decay, using at least five recorded data points with ≥90% correlation. All rates are shown in s–1
In many cases, rapid conversion occurs within ca. five minutes (the first recorded data point), which has not been considered in these data. Hyphens indicate
those reactions which cannot be fitted to a first-order exponential decay.
.
b Rate constant for product formation calculated from initial rates using a fitted first-order logarithmic growth (Scheme 6).
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leached mononuclear/lower-order palladium species. If this
is the case, then perhaps the parallels between catalyst
types manifest as a result of similar leaching rates. Notably,
following the initial stages of reactivity more pronounced
differences between catalysts were seen, which is indica-
tive of catalyst deactivation.10d It is important to recognize
that whether these results are due to variation in active pal-
ladium nanoparticle formation/behaviour, or a difference in
palladium leaching rates, is not clear at this stage. In-depth
mechanistic studies are required to address these ques-
tions.
References and Notes
(1) Leibniz Institute for Catalysis, Albert-Einstein-Str. 29a, 18059
Rostock, Germany. Email: lydia.neumann@catalysis.de
(2) (a) Nicolaou, K. C.; Bulger, P. J.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4442. (b) Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc.
Rev. 2011, 40, 4937.
(3) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed.
2009, 48, 9792. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K.
Angew. Chem. Int. Ed. 2012, 51, 8960.
(4) Hunt, A. J.; Farmer, T. J.; Clark, J. H. In Element Recovery and Sus-
tainability; Vol. 1; Hunt, A. J., Ed.; RSC Publishing: Cambridge,
2013, 1.
A pronounced substrate effect has been revealed in
these studies, which suggests that reaction conditions, in-
cluding substrate choice, could be as important as the par-
ticular palladium (pre)catalyst used. It is commonplace to
see reaction optimisation of a single benchmark reaction in
palladium-catalysed direct arylation chemistry, with cata-
lyst type and other reaction conditions varied. We suggest,
based on the observations detailed herein, that it is worth
also varying substrate type against several palladium cata-
lysts, before reaching a definite conclusion about which
particular palladium catalyst is best for subsequent ad-
vanced substrate-scoping studies.
2-n-Butylfuran (7), reported to be unstable under direct
arylation reaction conditions using Pd/C as the catalyst,8
has been shown to react effectively to provide the desired
direct arylation product 8 with four palladium catalysts in
~100% conversion. This example represents an illustration
of the dichotomy in outcomes that can be observed when
using Pd/C, which can be poorly defined. We suggest that
such an issue might manifest itself on the scale-up of direct
arylation processes using Pd/C. On a general note, our stud-
ies highlight the value of simple kinetic analysis of these
types of direct arylation reactions, as opposed to the more
common practice of evaluating catalyst performance as a
function of yield.23
(5) Blaser, H.-U.; Indolese, A.; Schnyder, A.; Steiner, H.; Studer, M.
J. Mol. Catal. A: Chem. 2001, 173, 3.
(6) (a) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133. (b) Molnár, Á.
Chem. Rev. 2011, 111, 2251. (c) Balanta, A.; Godard, C.; Claver, C.
Chem. Soc. Rev. 2011, 40, 4973.
(7) (a) Djakovitch, L.; Felpin, F.-X. ChemCatChem 2014, 6, 2175.
(b) Cano, R.; Schmidt, A. F.; McGlacken, G. P. Chem. Sci. 2015, 6,
5338.
(8) Tang, D.-T. D.; Collins, K. D.; Ernst, J. B.; Glorius, F. Angew. Chem.
Int. Ed. 2014, 53, 1809.
(9) (a) Baumann, C. G.; De Ornellas, S.; Reeds, J. P.; Storr, T. E.;
Williams, T. J.; Fairlamb, I. J. S. Tetrahedron 2014, 70, 6174.
(b) Reay, A. J.; Fairlamb, I. J. S. Chem. Commun. 2015, 51, 16289.
(10) (a) Widegren, J. A.; Bennett, M. A.; Finke, R. G. J. Am. Chem. Soc.
2003, 125, 10301. (b) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A:
Chem. 2003, 198, 317. (c) Crabtree, R. H. Chem. Rev. 2012, 112,
1536. (d) Crabtree, R. H. Chem. Rev. 2015, 115, 127. (e) Mower,
M. P.; Blackmond, D. G. J. Am. Chem. Soc. 2015, 137, 2386.
(11) (a) Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31,
2302. (b) Kapdi, A. R.; Whitwood, A. C.; Williamson, D. C.;
Lynam, J. M.; Burns, M. J.; Williams, T. J.; Reay, A. J.; Holmes, J.;
Fairlamb, I. J. S. J. Am. Chem. Soc. 2013, 135, 8388.
(12) (a) Ellis, P. J.; Fairlamb, I. J. S.; Hackett, S. F. J.; Wilson, K.; Lee, A.
F. Angew. Chem. Int. Ed. 2010, 49, 1820. (b) Lee, A. F.; Ellis, P. J.;
Fairlamb, I. J. S.; Wilson, K. Dalton Trans. 2010, 39, 10473. Other
supported PdNPs are available for direct arylation, e.g. Pd@PPy,
which are highly active and appear to operate as molecular/col-
loidal Pd species at higher reactions temperatures (150 °C), see:
(c) Zinovyeva, V. A.; Vorotyntsev, M. A.; Bezverkhyy, I.;
Chaumont, D.; Hierso, J.-C. Adv. Funct. Mater. 2011, 21, 1064. ;
also see ref. 9a High turnover numbers can be achieved in direct
arylations using Pd(OAc)2 at higher reaction temperatures, see:
(d) Požgan, F.; Roger, J.; Doucet, H. ChemSusChem 2008, 1, 404.
(13) General Conditions for Direct Arylation Reactions
To a microwave vial fitted with magnetic stirrer bar was added
[Ph2I]BF4 (309 mg, 0.84 mmol, 1.4 equiv), Pd catalyst (5 mol%),
and EtOH (3 mL). To initiate the reaction, substrate (0.6 mmol, 1
equiv) was added, the vial sealed with a septum, and the reac-
tion stirred at the given temperature for 24 h in a pre-heated
solid heating block. Under these conditions the isolated product
yields were: 2 [32 mg, 51%, using Pd(OAc)2], 4 [18 mg, 31%,
using Pd(OAc)2], 6 (45 mg, 69%, using PVP-Pd), and 8 (27 mg,
45%, using PVP-Pd) (nonoptimized).
Acknowledgment
The research leading to these results has received funding from the
Innovative Medicines Initiative Joint Undertaking project CHEM21
under grant agreement n°115360, resources of which are composed
of financial contribution from the European Union’s Seventh Frame-
work Programme (FP7/2007-2013) and EFPIA companies’ in kind con-
tribution (PhD studentship for A.J.R.). We gratefully acknowledge the
Chemiefonds-Stipendium des Verbands der Chemischen Industrie for
the secondment of L.K.N. for 3 months and Prof Matthias Beller for his
support of the exchange visit to our laboratories. We thank Josh Bray
for assistance with a 13C NMR experiment.
(14) 1-Methyl-2-phenylindole (2)
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.0 Hz, 1 H), 7.56–7.46
(m, 4 H), 7.45–7.36 (m, 2 H), 7.28–7.23 (m, 1 H), 7.18–7.12 (m, 1
H), 6.57 (s, 1 H), 3.76 (s, 1 H). 13C NMR (101 MHz, CDCl3): δ =
141.7, 138.5, 133.0, 129.5, 128.6, 128.1, 128.0, 121.8, 120.6,
120.0, 109.7, 101.8, 31.3.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561436.
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(15) 2-Phenylbenzofuran (4)
(17) 5-n-Butyl-2-phenylfuran (8)
1H NMR (400 MHz, CDCl3): δ = 7.92–7.87 (m, 2 H), 7.63–7.59 (m,
1 H), 7.57–7.53 (m, 1 H), 7.50–7.44 (m, 2 H), 7.40–7.35 (m, 1 H),
7.31 (ddd, J = 8.0, 7.0, 1.5 Hz, 1 H), 7.26 (ddd, J = 8.0, 7.0, 1.5 Hz,
1 H), 7.05 (d, J = 1.0 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ =
156.0, 155.0, 130.6, 129.3, 128.9, 128.7, 125.1, 124.4, 123.1,
121.0, 111.3, 101.4. GC–MS (EI): m/z (ion) = 194 [C14H10O]+;
HRMS (EI): m/z calcd for C14H10O: 194.0732; found: 194.0720
[C14H10O]+.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.63 (m, 2 H), 7.40–7.34 (m,
2 H), 7.23 (tt, J = 7.5, 1.0 Hz, 1 H), 6.56 (d, J = 3.0 Hz, 1 H), 6.08
(dt, J = 3.0, 1.0 Hz, 1 H), 2.70 (app t, J = 7.5 Hz, 2 H), 1.70 (tt, J =
7.5, 6.5 Hz, 2 H), 1.44 (app sext, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.5
Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 156.6, 152.2, 131.4,
128.7, 126.8, 123.4, 107.0, 105.8, 30.4, 28.0, 22.4, 14.0. GC–MS
(EI): m/z (ion) = 200 [C14H16O]+. HRMS (EI): m/z calcd for
C
14H16O: 200.1201; found: 200.1202 [C14H16O]+.
(16) 4-n-Butyl-2-phenylthiophene (6)
(18) Bajwa, S. E.; Storr, T. E.; Hatcher, L. E.; Williams, T. J.; Baumann,
C. G.; Whitwood, A. C.; Allan, D. R.; Teat, S. J.; Raithby, P. R.;
Fairlamb, I. J. S. Chem. Sci. 2012, 3, 1656.
(19) Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590.
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(21) Wakioka, M.; Nakamura, Y.; Wang, Q.; Ozawa, F. Organometal-
lics 2012, 31, 4810.
1H NMR (400 MHz, CDCl3): δ = 7.61–7.56 (m, 2 H), 7.42–7.36 (m,
2 H), 7.31–7.25 (m, 1 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.09 (dt, J = 1.5,
1.0 Hz, 1 H), 2.87 (t, J = 7.5 Hz, 2 H), 1.77–1.67 (m, 2 H), 1.50–
1.38 (m, 2 H), 0.97 (t, J = 7.5 Hz, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 146.8, 141.9, 136.4, 128.8, 127.0, 126.4, 123.5, 117.9,
33.9, 30.0, 22.4, 14.0. ESI-MS: m/z (ion) = 217 [C14H17S]+; ESI-
HRMS m/z calcd for
C
14H17S: 217.1045; found: 217.1024
(22) Fairlamb, I. J. S.; Lee, A. F. In C–H and C–X Bond Functionaliza-
tion: Transition Metal Mediation; Ribas, X., Ed.; RSC Publishing:
Cambridge, 2013, Chap. 3, 72.
[C14H17S]+.
(23) Kozuch, S.; Martin, J. M. L. ACS Catal. 2012, 2, 2787.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F