Intramolecular PdII-catalyzed dehydrogenative C(sp 3)-C(sp2) coupling: An alternative to Pd 0-catalyzed C(sp3)-H arylation from aryl halides?

Article abstract of DOI:10.1016/j.tet.2012.11.060

The synthesis of fused thiophene-cyclopentanes by Pd^II-catalyzed dehydrogenative C(sp²)-H/C(sp³)-H coupling is described. This reaction shows interesting chemo- and diastereoselectivity, however a direct comparison showed that it is yet much less efficient than the two-step sequence composed of electrophilic halogenation and Pd⁰-catalyzed C(sp³)-H arylation.

Full text of DOI:10.1016/j.tet.2012.11.060

Tetrahedron 69 (2013) 4473e4478
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Tetrahedron
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Intramolecular PdII-catalyzed dehydrogenative C(sp3)eC(sp2)
coupling: an alternative to Pd0-catalyzed C(sp3)eH arylation
from aryl halides?
*
Cathleen Pierre, Olivier Baudoin
ꢀ
ꢀ
ꢀ
Universite Claude Bernard Lyon 1, CNRS UMR 5246, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, CPE Lyon,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
The synthesis of fused thiopheneecyclopentanes by PdII-catalyzed dehydrogenative C(sp2)eH/C(sp3)eH
coupling is described. This reaction shows interesting chemo- and diastereoselectivity, however a direct
comparison showed that it is yet much less efficient than the two-step sequence composed of
electrophilic halogenation and Pd0-catalyzed C(sp3)eH arylation.
Article history:
Received 5 October 2012
Received in revised form 12 November 2012
Accepted 16 November 2012
Available online 23 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Arylation
CeH activation
Dehydrogenative cross-coupling
1. Introduction
(Scheme 1b, right). A direct comparison with the Pd0-catalyzed
C(sp3)eH/C(sp2)eX coupling approach is also provided.
In recent years, palladium-catalyzed C(sp2)eH arylation has
emerged as an atom-economical alternative to conventional CeC
cross-couplings involving two prefunctionalized substrates.1 In
parallel, this approach has been extended to the somewhat more
challenging unactivated C(sp3)eH bonds.2 More recently, increasing
efforts have been devoted to the development of dehydrogenative
CeH/CeH couplings, which, in principle, are the ultimate atom-
economical CeC couplings involving two unfunctionalized sub-
3
ꢀ
strates. In 2008, Liegault and Fagnou reported the first, and to date
only, example of intramolecular dehydrogenative C(sp3)eH/C(sp2)e
H coupling involving unactivated (i.e., non-acidic) C(sp3)eH bonds
(Scheme 1a).4e6 This method, which showed moderate efficiency
and scope, employed a PdII catalyst and air as the stoichiometric
terminal oxidant. In comparison, the analogous Pd0-catalyzed
C(sp3)eH/C(sp2)eCl coupling seems to show less atom-economy,
but better efficiency and scope.7 However, a direct comparison of
C(sp3)eH/C(sp2)eH and C(sp3)eH/C(sp2)eX (X¼leaving group)
couplings would require substrates with identical scaffolds. We have
recently reported the efficient construction of fused thiophenes by
intramolecular Pd0-catalyzed C(sp3)eH/C(sp2)eCl coupling
(Scheme 1b, left).7,8 In this article, we disclose our efforts to perform
the corresponding PdII-catalyzed dehydrogenative coupling
Scheme 1. PdII-catalyzed dehydrogenative C(sp3)eC(sp2) coupling.
2. Results and discussion
2.1. Synthesis of precursors and Pd0-catalyzed C(sp3)eH/
C(sp2)eBr coupling
2-Arylthiophene 1a was first selected as substrate for the
dehydrogenative intramolecular C(sp3)eH/C(sp2)eH coupling
(Scheme 2). The C-2 aryl substituent was chosen to block the un-
desired C-2 palladation and subsequent dimerization that could
* Corresponding author. Tel.: þ33 4 72432961; fax: þ33 4 72432963; e-mail
address: olivier.baudoin@univ-lyon1.fr (O. Baudoin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.060

4474
C. Pierre, O. Baudoin / Tetrahedron 69 (2013) 4473e4478
enabling the challenging C(sp3)eH activation step, contrary to the
Pd0-catalyzed system. On the other hand, product 2a was isolated
in high diastereoisomeric purity from the dehydrogenative reaction
whereas an inseparable 4:1 mixture of cis/trans diastereoisomers
was obtained in the latter case.13
The scope of the dehydrogenative coupling was next evaluated
under the optimized conditions (Table 2). Thiophene, furan, and
thiazole-based substrates 1bek were obtained in the same manner
as above for thiophene 1a, by using direct CeH arylation to regio-
selectively introduce the aryl group in the C-5 position of the het-
eroarene (see the Experimental section).
Fused thiophenes 2aei and thiazole 2j were obtained with yields
in the 19e39% range and high (drꢁ19:1) diastereoselectivities. In
contrast, the formation of furan 2k was not observed under the
same conditions, indicating that the sulfur atom on the thiophene
and thiazole substrates is not responsible for the catalyst de-
activation and the observed yields. Interestingly, compounds 2feh
could not be obtained from the corresponding palladium(0)-
catalyzed reaction from aryl chlorides,8 and thus the current
method seems to tolerate a greater variety of substituents on the C-
5 arene. Finally, thiophene 6 (Scheme 2) did not provide fused
cyclopentane 2l under these conditions (Table 2) and the formation
of the corresponding C-5 dimer was observed by GC and NMR
analysis, as anticipated. Therefore, the C-5 position of the thiophene
ring has indeed to be blocked to prevent the more facile C-5 pal-
ladation and allow for the desired CeH functionalization at C-2.
A proposed mechanism is shown in Scheme 3.4 A first C(sp2)eH
palladation of thiophene 1 with a palladium(II) carboxylate (pre-
sumably pivalate) catalyst gives rise to organopalladium(II) in-
termediate A, which undergoes intramolecular C(sp3)eH activation
to give palladacycle B. Reductive elimination from B provides
product 2 and Pd0, which is reoxidized with silver(I) to regenerate
the active catalytic species.
Scheme 2. Synthesis of precursors and Pd0-catalyzed C(sp3)eH arylation.
occur easily under PdII catalysis.9 At the same time, 1a should
readily provide bromothiophene 3a, the substrate of the Pd0-cat-
alyzed C(sp3)eH/C(sp2)eX coupling. Compound 1a was synthe-
sized in four steps, 41% overall yield, from 3-methylthiophene 4
according to Scheme 2. The introduction of the o-tolyl group on the
C-5 position of thiophene 6 was performed efficiently and regio-
selectively by Pd-catalyzed C(sp2)eH arylation according to the
conditions developed by Fagnou et al.10
Bromothiophene 3a, which was quantitatively obtained from 1a
bystandardelectrophilicbromination, underwentC(sp3)eHarylation
under usual conditions with the Pd0/PCy3 catalytic system, to give
product 2a in 83% yield and with a diastereomeric ratio (dr) of 4:1 in
favor of the cis diastereoisomer, consistent with previous results.7,8
An experiment with deuterated pivalic acid (PivOD, 1 equiv) in-
stead of PivOH was conducted to assess the reversibility of the initial
palladation step (Scheme 4). No trace of deuterium incorporation on
the C-2 position of the thiophene ring was observed by 2D and 13
C
NMR of the mixture at 50% conversion, thereby indicating that the
C(sp2)eH palladation step is irreversible in the present case, con-
trary to previous findings on pyrrole-based substrates.4 We propose
that both the C(sp2)eH and C(sp3)eH activation steps occur through
the base-induced concerted metalationedeprotonation (CMD)
mechanism,7,14 in accordance with previous work of DeBoef et al. on
dehydrogenative C(sp2)eC(sp2) couplings.15
2.2. Study of the dehydrogenative coupling
A very extensive screening of reaction conditions was conducted
with substrate 1a, and only representative examples are shown in
Table 1 (see the Supplementary data for additional conditions
3. Conclusion
ꢀ
tested). We first tested the conditions reported by Liegault and
Fagnou without any success (entry 1),4 showing that these condi-
tions cannot be directly transposed to seemingly similar substrates.
The first significant result was obtained by using silver carbonate as
the stoichiometric oxidant and base in DMF at 100e140 ꢀC (entries
2e3). Then, we tested a number of additives (entries 4e7), solvents
(entries 8e11), silver salts (entries 12e13), ligands (entries 14e18),11
Pd sources (entries 19e21),12 and co-oxidants (entries 22e24), in-
spired by conditions reported in the literature for dehydrogenative
and related oxidative couplings.3,5 In spite of our efforts, only 33%
yield of reaction product 2a could be obtained by using 20 mol %
Pd(OAc)2, 3 equiv Ag2CO3 and 1 equiv PivOH in DMF (c¼0.3 M) at
100 ꢀC (entry 4). Varying the Pd loading from 1 to 50 mol % did not
improve the yield. However, 2a was obtained in high diastereomeric
purity (dr 30:1) with the cis relative configuration.
In conclusion, we have shown that the synthesis of fused thio-
pheneecyclopentanes by PdII-catalyzed dehydrogenative C(sp2)e
H/C(sp3)eH coupling is feasible. However, it is currently much less
efficient than the two-step sequence composed of electrophilic
halogenation and Pd0-catalyzed C(sp3)eH arylation, and thus it
cannot be considered as a synthetically competitive alternative yet.
However, this double CeH activation approach looks particularly
promising with regard to chemo- and diastereoselectivity. We be-
lieve that improvement of the reaction efficiency should arise from
a better mechanistic understanding and the development of new
specific ligands.
4. Experimental
Thus, the one-step dehydrogenative reaction of 1a to give
2a (33%) is much less efficient than the two-step procedure in-
volving electrophilic bromination and C(sp3)eH arylation (83%
overall, Scheme 2). We believe that the lack of efficiency of the
PdII-catalyzed reaction is related to the absence of a proper ligand
4.1. General information
Reactions involving air-sensitive compounds were performed
under an oxygen-free atmosphere of argon with rigid exclusion of
moisture from reagents and glassware using standard techniques.

C. Pierre, O. Baudoin / Tetrahedron 69 (2013) 4473e4478
4475
Table 1
Optimization of the dehydrogenative coupling
Entry
Pd source (mol %)
Ligand
Oxidant/basea
Additiveb
Solvent
Temp (ꢀC)
GC yield %c
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
d
d
d
d
d
d
d
d
d
d
d
d
d
Air/NaOt-Bue
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
d
PivOH
DMF
DMF
DMF
DMF
140
140
100
100
100
100
100
100
100
100
100
100
100
0
9
d
d
14
33d
22
17
9
20
31d
5
PivOH
PivOHf
CsOPiv
K3PO4
PivOH
PivOH
PivOH
PivOH
PivOH
d
DMF
DMF
DMA
NMP
Mesitylene
AcOH
DMF
9
10
11
12
13
0
10
23
AgOPiv
NMP
14
Pd(OAc)2 (20)
Ag2CO3
Ag2CO3
PivOH
DMF
DMF
100
5
15
Pd(OAc)2 (20)
PivOH
100
9
16
17
18
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Ag2CO3
Ag2CO3
Ag2CO3
PivOH
PivOH
PivOH
DMF
DMF
DMF
100
100
100
2
18
10
i-Pr2S
19
20
21
22
23
24
Pd(IPr)(
Pd(TFA)2 (20)
[Pd(MeCN)4][BF4]2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
h
3-allyl)Cl (20)
d
d
d
d
d
d
Ag2CO3
Ag2CO3
Ag2CO3
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
DMF
DMF
DMF
DMF
NMP
NMP
100
100
100
100
100
100
12
16
25
13
15
29
Ag2CO3/BQg
Ag2CO3/PhI(OAc)2
b
b
Pd(OAc)2 (20)
Ag2CO3/Cu(OAc)2
a
3 equiv.
1 equiv.
b
c
d
e
f
Determined using tetradecane as internal standard.
Yield of the isolated product.
0.2 equiv.
0.3 equiv.
2 equiv.
g
Commercially available chemicals were used without further puri-
fication unless otherwise specified. Anhydrous solvents were ob-
tained by distillation over CaH2 (CH3CN, CH2Cl2, pyridine) or by
distillation over sodium/benzophenone (THF, toluene, mesitylene).
DMF (99.8% extra dry) and DMSO (99.7% extra dry) were purchased
from Acros Organics. Analytical thin layer chromatography (TLC)
was performed using EM Reagent 0.25 mm silica gel 60-F plates.
Visualization of the developed chromatogram was performed by UV
absorbance (254 nm) or TLC stains (KMnO4). Flash chromatography
was performed using EM Silica Gel 60 (60e200 mesh) with the in-
dicated solvent system according to standard technique. GC analy-
ses were performed with a Shimadzu QP2010 GCeMS apparatus,
with injection on a SLB-5ms column lined with a mass (EI) detection
spectra were obtained with complete proton decoupling. Data are
reported in parts per million (ppm) as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, qn¼quin-
tet, sept¼septuplet, m¼multiplet, and br¼broad), coupling constant
in Hertz and integration. When ambiguous, proton and carbon
assignments were established using DEPT, COSY, HSQC, and HMBC
experiments. High-resolution mass spectra were measured under
electrospray ionization (ESI) or electronic impact (EI) mode.
4.2. General procedures
4.2.1. General procedure A: synthesis of precursors 1aek by
intermolecular C(sp2)eH arylation. In a glovebox, a Schlenk tube
€
system. Melting points were obtained on a Buchi melting point
containing a magnetic stir bar was charged with Pd(OAc)2
apparatus. Infrared spectra were taken on a Thermo Scientific
Nicolet iS10 FT-IR spectrometer and are reported in reciprocal cen-
timeters (cmꢂ1). Nuclear magnetic resonance spectra were recorded
either on a Bruker ALS 300, DRX 300 or DRX 400 spectrometer (300,
300, and 400 MHz, respectively) in deuterated chloroform (residual
(10 mol %), Cy3P$HBF4 (20 mol %), K2CO3 (1.5 equiv), and PivOH
(30 mol %). The flask was closed with a rubber septum and removed
from the glovebox. To this flask was added a solution of heterocycle
(1 equiv) and bromoarene if solid (1.1 equiv) in dry DMA (0.3 M).
Then the bromoarene (1.1 equiv) was added at this point if liquid.
After 5 min stirring at room temperature the reaction mixture was
peaks 1H
d C d 77.16 ppm) unless otherwise noted. All
7.26 ppm, 13

4476
C. Pierre, O. Baudoin / Tetrahedron 69 (2013) 4473e4478
Table 2
Scope of the dehydrogenative couplinga
Scheme 4. Deuterium incorporation experiment.
heated at 140 ꢀC (preheated oil bath) until total conversion of
starting material according to GC/MS analysis. After cooling, the
mixture was diluted with EtOAc, filtered through CeliteÒ and the
solvent evaporated under reduced pressure. Purification was per-
formed by preparative thin layer chromatography (5% EtOAc/cy-
clohexane) affording the desired products.
4.2.2. General procedure B: synthesis of fused carbocycles 2aej by
dehydrogenative C(sp3)eH/C(sp2)eH arylation. In
a glovebox,
a Schlenk tube containing a magnetic stir bar was charged with
Pd(OAc)2 (20 mol %), Ag2CO3 (3 equiv), and PivOH (1 equiv). The
flask was closed with a rubber septum and removed from the
glovebox. To this flask was added a solution of the heterocyclic
reactant (1 equiv) in dry DMF (0.3 M). The mixture was stirred for
5 min at room temperature and then for 18 h at 100 ꢀC (preheated
oil bath). After cooling down to room temperature, the mixture was
diluted with EtOAc and filtered through CeliteÒ. The solvent from
the filtrate was evaporated under reduced pressure and the residue
was purified by preparative TLC or flash chromatography to afford
the desired indane.
4.3. Synthesis and characterization of products 1e6
4.3.1. 2-(Thiophen-3-yl)acetonitrile (5). NBS (9.07 g, 50.9 mmol,
1 equiv) and AIBN (836 mg, 5.1 mmol, 0.1 equiv) were added to
a solution of 3-methylthiophene (5 g, 50.9 mmol, 1 equiv) in CCl4
(20 mL). The resulting mixture was refluxed for 1 h. After cooling,
the solvent was evaporated under reduced pressure and the residue
obtained was dissolved in dry acetonitrile (40 mL). To this solution,
TMSCN (20 mL, 153 mmol, 3 equiv) and TBAF (1 M in THF, 153 mL,
153 mmol, 3 equiv) were added dropwise at 0 ꢀC under argon at-
mosphere. After stirring overnight at room temperature, the sol-
vent was evaporated under reduced pressure. The residue was
purified by flash chromatography (5% EtOAc/cyclohexane) afford-
ing 5 as an orange oil (4.06 g, 33 mmol, 65% for the two steps). 1H
NMR (300 MHz, CDCl3):
d
7.22 (dd, J¼5.0, 3.0 Hz,1H), 7.10 (dd, J¼2.8,
1.1 Hz, 1H), 6.90 (dd, J¼5.0, 1.2 Hz, 1H), 3.58 (s, 2H) ppm. 13C NMR
(100 MHz, CDCl3):
d 129.4, 127.0, 126.9, 122.9, 117.7, 18.4 ppm. IR
(neat):
n .
3104, 2360, 2340, 2255, 1688, 1415, 832, 771, 692 cmꢂ1
GCeMS: m/z C6H5NS [Mþꢃ] 122.
4.3.2. 2-Isopropyl-3-methyl-2-(thiophen-3-yl)butanenitrile
(6). LiHMDS (1.06 M in THF, 149 mL, 159 mmol, 4 equiv) was added
dropwise at 0 ꢀC to a solution of compound 5 (4.9 g, 40 mmol,
1 equiv) in THF (15 mL). After stirring for 20 min, isopropyl iodide
(16 mL, 159 mmol, 4 equiv) was added. The resulting mixture was
stirred at room temperature overnight. A saturated solution of
NH4Cl was added and the aqueous layer was extracted twice with
EtOAc. The combined organic layers were dried over MgSO4. After
filtration and evaporation, the crude mixture was purified by flash
Scheme 3. Proposed simplified mechanism.

C. Pierre, O. Baudoin / Tetrahedron 69 (2013) 4473e4478
4477
chromatography (7% EtOAc/cyclohexane) affording 6 as an orange
oil (6.2 g, 30 mmol, 75%).1H NMR (300 MHz, CDCl3):
J¼6.6 Hz, 6H), 0.97 (d, J¼6.8 Hz, 6H) ppm. 13C NMR (100 MHz,
d
7.32 (dd, J¼5.1,
CDCl3): d 148.8, 141.7, 137.8, 135.7, 131.6, 130.1, 124.4, 124.2, 122.3,
3.0 Hz, 1H), 7.25 (dd, J¼3.0, 1.4 Hz, 1H), 6.99 (dd, J¼5.0, 1.4 Hz, 1H),
2.37 (sept, J¼6.8 Hz, 2H),1.04 (d, J¼6.7 Hz, 6H), 0.90 (d, J¼6.8 Hz, 6H)
121.7, 120.4, 55.3, 33.0 (2C), 18.9 (2C), 17.9 (2C) ppm. IR (neat):
2969, 2162, 1305, 1129, 1108, 766 cmꢂ1
HRMS (ESI): m/z
C18H21N2O2S [MHþ] calculated: 329.1318; found: 329.1320.
n
.
ppm. 13C NMR (100 MHz, CDCl3):
d 136.2, 126.7, 125.6, 123.4, 122.1,
55.0, 32.9 (2C),18.9 (2C),17.8 (2C) ppm. IR (neat): n 3102, 2255,1415,
833, 771, 691 cmꢂ1. GCeMS: m/z C12H17NS [Mþꢃ] 207.
4.3.8. 2-Isopropyl-3-methyl-2-(5-phenylthiophen-3-yl)butanenitrile
(1e). General procedure A starting from 6 (0.48 mmol) afforded 1e
as a colorless oil (114 mg, 0.40 mmol, 84%). 1H NMR (400 MHz,
4.3.3. 2-Isopropyl-3-methyl-2-(5-(o-tolyl)thiophen-3-yl)butaneni-
trile (1a). General procedure A starting from 6 (0.96 mmol) affor-
ded 1a as a yellow oil (240 mg, 0.81 mmol, 84%). 1H NMR (400 MHz,
CDCl3):
d
7.48 (d, J¼7.5 Hz, 2H), 7.39 (t, J¼7.3 Hz, 2H), 7.30 (t,
J¼7.4 Hz, 1H), 7.17 (s, 2H), 2.38 (sept, J¼6.7, 2H), 1.1 (d, J¼6.6 Hz, 6H),
CDCl3):
d
7.40 (dd, J¼6.9, 1.8 Hz, 1H), 7.29e7.23 (m, 4H), 6.93 (d,
0.95 (d, J¼6.8 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d 144.6,
J¼1.6 Hz, 1H), 2.42 (s, 3H), 2.39 (sept, J¼6.7, 2H), 1.1 (d, J¼6.7 Hz,
137.1, 134.1, 129.1 (2C), 128.0, 125.9 (2C), 122.8, 122.7, 122.0, 55.3,
6H), 0.97 (d, J¼6.8 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d
143.3,
33.0 (2C), 19.0 (2C), 18.0 (2C) ppm. IR (neat): n 2967, 1466, 1450,
136.1, 136.1, 133.9, 130.9, 130.4, 128.2, 126.1, 126.1, 123.2, 122.0, 55.3,
1389, 762, 689 cmꢂ1. HRMS (ESI): m/z C18H22NS [MHþ] calculated:
33.0 (2C), 21.2, 19.0 (2C), 17.9 (2C) ppm. IR (neat):
n
2968, 2876,
284.1467; found: 284.1473.
2233, 1463, 1389, 1170, 759, 724 cmꢂ1. HRMS (ESI): m/z C19H24NS
[MHþ] calculated: 298.1624; found: 298.1629.
4.3.9. 2-Isopropyl-2-(5-(3-methoxyphenyl)thiophen-3-yl)-3-methyl
butanenitrile (1f). General procedure A starting from 6 (0.48 mmol)
afforded 1f as a colorless oil (46 mg, 0.15 mmol, 31%). 1H NMR
4.3.4. 2-(2-Bromo-5-(o-tolyl)thiophen-3-yl)-2-isopropyl-3-
methylbutane nitrile (3a). NBS (67 mg, 0.37 mmol, 1.1 equiv) was
added in one portion to a solution of 1a (100 mg, 0.34 mmol,
1 equiv) in DMF (2 mL). The resulting mixture was stirred overnight
at 60 ꢀC. Water was added and the aqueous layer was extracted
twice with EtOAc. The combined organic layers were dried over
MgSO4. After filtration and evaporation, the crude mixture was
purified by flash chromatography (5% EtOAc/cyclohexane) afford-
ing 3a as a yellow solid (127 mg, 0.34 mmol, quant.). Mp 71e72 ꢀC.
(400 MHz, CDCl3): d 7.24e7.18 (m, 1H), 7.12e7.09 (m, 3H), 7.04e7.03
(m, 1H), 6.77 (ddd, J¼8.2, 2.5, 0.7 Hz, 1H), 3.77 (s, 3H), 2.29 (sept,
J¼6.7, 2H), 0.99 (d, J¼6.7 Hz, 6H), 0.87 (d, J¼6.8 Hz, 6H) ppm. 13C
NMR (100 MHz, CDCl3): d 160.1,144.4,137.0,135.4,130.1,123.0,122.7,
122.0,118.5,113.3,111.7, 55.5, 55.3, 33.0 (2C),19.0 (2C),17.9 (2C) ppm.
IR (neat): n
2967,1599,1579,1464,1288,1266,1048, 776 cmꢂ1. HRMS
(ESI): m/z C19H24NOS [MHþ] calculated: 314.1573; found: 314.1575.
1H NMR (400 MHz, CDCl3):
d
7.33 (d, J¼7.2 Hz, 1H), 7.27e7.20 (m,
4.3.10. 3-(4-(3-Cyano-2,4-dimethylpentan-3-yl)thiophen-2-yl)ben-
zonitrile (1g). General procedure A starting from 6 (0.48 mmol)
afforded 1g as awhite solid (93 mg, 0.3 mmol, 63%). Mp 86e88 ꢀC.1H
3H), 6.90 (s br, 1H), 2.71 (s br, 2H), 2.41 (s, 3H), 1.17 (d, J¼6.7 Hz, 6H),
1.02 (d, J¼6.8 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d 142.5,
136.0, 132.7, 132.3, 131.0, 130.1, 129.6, 128.6, 126.3, 120.8, 108.8, 55.6,
NMR (300 MHz, CDCl3):
d
7.87 (s, 1H), 7.81 (d, J¼7.7 Hz, 1H), 7.58 (d,
33.5 (2C), 21.1,19.1 (2C), 18.5 (2C) ppm. IR (neat):
n
2960, 2162, 1460,
J¼7.6 Hz,1H), 7.51 (t, J¼7.7 Hz,1H), 7.27 (s,1H), 7.24 (s,1H), 2.40 (sept,
1015, 761 cmꢂ1. HRMS (ESI): m/z C19H23BrNS [MHþ] calculated:
J¼6.7, 2H),1.08 (d, J¼6.6 Hz, 6H), 0.96 (d, J¼6.7 Hz, 6H) ppm.13C NMR
376.0729; found: 376.0734.
(75 MHz, CDCl3): d 141.8, 137.7, 135.3, 131.1, 130.0, 130.0, 129.2, 124.1,
124.1, 121.7, 118.5, 113.4, 55.3, 33.0 (2C), 18.9 (2C), 17.9 (2C) ppm. IR
4.3.5. 2-Isopropyl-3-methyl-2-(5-(2-(trifluoromethyl)phenyl)thio-
phen-3-yl)butanenitrile (1b). General procedure A starting from 6
(0.48 mmol) afforded 1b as a white solid (150 mg, 0.43 mmol, 89%).
(neat): n
2970, 2930, 2231, 1930, 1483, 1466, 733, 682 cmꢂ1. HRMS
(ESI): m/z C19H21N2S [MHþ] calculated: 309.1420; found: 309.1433.
Mp 110e111 ꢀC. 1H NMR (400 MHz, CDCl3):
d
7.76 (d, J¼7.8 Hz, 1H),
4.3.11. 2-Isopropyl-3-methyl-2-(5-(p-tolyl)thiophen-3-yl)butaneni-
trile (1h). General procedure A starting from 6 (0.48 mmol) affor-
ded 1h as a colorless oil (63 mg, 0.21 mmol, 44%). 1H NMR
7.58e7.46 (m, 3H), 7.33 (d, J¼1.1 Hz, 1H), 6.98 (s, 1H), 2.37 (sept,
J¼6.7 Hz, 2H), 1.07 (d, J¼6.6 Hz, 6H), 0.94 (d, J¼6.8 Hz, 6H) ppm. 13C
NMR (100 MHz, CDCl3):
d
139.9, 136.3, 133.4, 133.0, 131.6, 129.2 (q,
(300 MHz, CDCl3):
d
7.37 (d, J¼8.1 Hz, 1H), 7.08 (d, J¼8.0 Hz, 1H),
J¼29.8 Hz), 128.4, 127.2, 126.6 (q, J¼5.3 Hz), 124.4, 124.0 (q,
7.02 (s, 2H), 2.31e2.20 (m, 5H), 0.96 (d, J¼6.7 Hz, 6H), 0.84 (d,
J¼272.2 Hz), 120.0, 55.3, 33.0 (2C), 18.9 (2C), 17.7 (2C) ppm. 19F NMR
J¼6.8 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3):
d 144.7, 137.9, 137.0,
(376 MHz, CDCl3):
d
ꢂ58.0 ppm. IR (neat):
n
2969, 2162, 1305, 1129,
131.3, 129.7 (2C), 125.8 (2C), 122.3, 122.1, 122.0, 55.3, 33.0 (2C), 21.3,
1108, 766 cmꢂ1. HRMS (ESI): m/z C19H21F3NS [MHþ] calculated:
18.9 (2C), 17.9 (2C) ppm. IR (neat): n 2968, 1509, 1466, 1389, 1170,
352.1355; found: 352.1341.
813, 658 cmꢂ1. HRMS (ESI): m/z C19H22NS [MHþ] calculated:
298.1624; found: 298.1631.
4.3.6. 2-(4-(3-Cyano-2,4-dimethylpentan-3-yl)thiophen-2-yl)benzo-
nitrile (1c). General procedure A starting from 6 (0.48 mmol)
afforded 1c as a colorless oil (139 mg, 0.45 mmol, 94%). 1H NMR
4.3.12. 2-(5-(2-Fluorophenyl)thiophen-3-yl)-2-isopropyl-3-
methylbutane nitrile (1i). General procedure A starting from 6
(0.48 mmol) afforded 1i as a colorless oil (126 mg, 0.42 mmol, 87%).
(400 MHz, CDCl3):
d
7.75 (d, J¼7.7 Hz,1H), 7.64e7.63 (m, 2H), 7.48 (d,
J¼1.4 Hz,1H), 7.44 (t, J¼4.4 Hz,1H), 7.42 (d, J¼1.2 Hz,1H), 2.42 (sept,
1H NMR (300 MHz, CDCl3):
d 7.54e7.49 (m, 1H), 7.24 (s, 1H),
J¼6.7 Hz, 2H), 1.1 (d, J¼6.6 Hz, 6H), 0.98 (d, J¼6.8 Hz, 6H) ppm. 13C
7.20e7.13 (m, 2H), 7.09e7.00 (m, 2H), 2.29 (sept, J¼6.7 Hz, 2H), 0.97
NMR (100 MHz, CDCl3): d 139.7,137.5,137.0,134.3,133.1,129.6,128.0,
(d, J¼6.6 Hz, 6H), 0.85 (d, J¼6.7 Hz, 6H) ppm. 13C NMR (100 MHz,
126.6, 125.5, 121.6, 118.6, 110.1, 55.4, 32.9 (2C), 18.8 (2C), 17.7 (2C)
CDCl3):
d
159.1 (d, J¼248.6 Hz), 137.4 (d, J¼3.2 Hz), 136.8, 129.1 (d,
ppm. IR (neat):
n
2968, 2223,1484,1466,1167, 760 cmꢂ1. HRMS (ESI):
J¼8.5 Hz), 128.6 (d, J¼3.2 Hz), 125.8 (d, J¼6.7 Hz), 124.6 (d,
m/z C19H20N2NaS [MNaþ] calculated: 331.1239; found: 331.1245.
J¼3.5 Hz), 123.7 (d, J¼3.8 Hz), 121.9, 116.6, 116.3, 55.3, 32.9 (2C), 18.9
(2C), 17.8 (2C) ppm. 19F NMR (282 MHz, CDCl3):
d
ꢂ114.2 ppm. IR
4.3.7. 2-Isopropyl-3-methyl-2-(5-(3-nitrophenyl)thiophen-3-yl)bu-
tane nitrile (1d). General procedure A starting from 6 (0.48 mmol)
afforded 1d as a white solid (94 mg, 0.29 mmol, 60%). Mp
(neat): n
2969, 2233, 1492, 1454, 1102, 809, 755, 658 cmꢂ1. HRMS
(ESI): m/z C18H21FNS [MHþ] calculated: 302.1373; found: 302.1379.
100e102 ꢀC. 1H NMR (400 MHz, CDCl3):
8.14 (dd, J¼8.2, 1.4 Hz, 1H), 7.91 (d, J¼7.9 Hz, 1H), 7.58 (t, J¼8.0 Hz,
1H), 7.31 (s, 1H), 7.30 (s, 1H), 2.42 (sept, J¼6.7 Hz, 2H), 1.1 (d,
d
8.42 (t app, J¼1.9 Hz, 1H),
4.3.13. 2-Isopropyl-3-methyl-2-(2-phenylthiazol-4-yl)butanenitrile
(1j). General procedure A starting from 2-isopropyl-3-methyl-2-
(thiazol-4-yl)butanenitrile (0.38 mmol) afforded 1j as a white solid

4478
C. Pierre, O. Baudoin / Tetrahedron 69 (2013) 4473e4478
(64 mg, 0.21 mmol, 57%). Mp 63e65 ꢀC. 1H NMR (300 MHz, CDCl3):
7.71 (d, J¼7.2 Hz, 1H), 7.39 (s, 1H), 7.35e7.24 (m, 3H), 2.60 (sept,
J¼6.8 Hz, 2H), 2.56 (s, 3H), 1.08 (d, J¼6.8 Hz, 6H), 0.97 (d, J¼6.8 Hz,
6H) ppm. 13C NMR (100 MHz, CDCl3):
167.9, 152.1, 136.7, 132.8,
131.8, 129.9, 129.7, 126.3, 122.0, 117.7, 56.0, 32.8 (2C), 22.0, 19.0 (2C),
4.3.18. 4-Isopropyl-5-methyl-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta
[d]thiazole-4-carbonitrile (2j). General procedure B starting from 1j
(0.17 mmol) afforded 2j as a white solid (12 mg, 0.04 mmol, 24%).
d
d
Mp 70e72 ꢀC. 1H NMR (300 MHz, CDCl3):
d
7.66 (d, J¼7.3 Hz, 1H),
7.35e7.26 (m, 3H), 3.19 (dd, J¼7.6, 15.5 Hz, 1H), 3.05e2.97 (m, 1H),
2.67 (dd, J¼15.6, 6.5 Hz, 1H), 2.59 (s, 3H), 2.29 (sept, J¼6.8 Hz, 1H),
1.48 (d, J¼7.0 Hz, 3H), 1.21 (d, J¼6.8 Hz, 3H), 1.17 (d, J¼6.8 Hz, 3H)
18.1 (2C) ppm. IR (neat): n
3090, 2969, 1462, 1000, 758 cmꢂ1. HRMS
(ESI): m/z C18H23N2S [MHþ] calculated: 299.1576; found: 299.1584.
ppm. 13C NMR (100 MHz, CDCl3):
d 172.3, 158.1, 136.9, 135.9, 133.3,
4.3.14. 2-Isopropyl-3-methyl-2-(5-(o-tolyl)furan-3-yl)butanenitrile
(1k). General procedure A starting from (0.5 mmol) afforded 1k as
a colorless oil (82 mg, 0.29 mmol, 58%). 1H NMR (300 MHz, CDCl3):
131.7, 129.8, 129.6, 126.2, 119.6, 53.7, 44.0, 35.2, 34.0, 21.7, 19.6, 18.6,
18.3 ppm. IR (neat):
n 2964, 2876, 225, 1463, 1188, 1080, 969,
767 cmꢂ1. HRMS (ESI): m/z C18H21N2S [MHþ] calculated: 297.1420;
d
7.59 (d, J¼6.2 Hz, 1H), 7.41 (d, J¼0.9 Hz, 1H), 7.19e7.13 (m, 3H),
found: 297.1412.
6.32 (d, J¼0.9 Hz, 1H), 2.39 (s, 3H), 2.21 (sept, J¼6.7, 2H), 1.0 (d,
J¼6.7 Hz, 6H), 0.90 (d, J¼6.8 Hz, 6H) ppm. 13C NMR (100 MHz,
Acknowledgements
CDCl3):
d 154.2, 140.2, 134.7, 132.8, 131.3, 128.0, 127.2, 126.2, 122.4,
ꢁ
ꢀ
108.6, 50.9, 32.5 (2C), 22.0, 18.7 (2C), 17.9 (2C) ppm (CN undetect-
We thank Ministere de l’Enseignement Superieur et de la
Recherche (fellowship to C.P.), Agence Nationale de la Recherche
(programme blanc ‘AlCaCHA’), Institut Universitaire de France and
Johnson Matthey PLC (loan of palladium acetate).
able due to steric hindrance). IR (neat):
n 2971, 2936, 2253, 1766,
1464, 1017, 908, 728 cmꢂ1. HRMS (ESI): m/z C19H24NO [MHþ] cal-
culated: 282.1852; found: 282.1861.
Fused carbocycles 2a, 2b, 2c, 2d, 2e, and 2i were synthesized
following general procedure B. Characterization data were in
agreement with those previously reported.8
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.060.
4.3.15. 4-Isopropyl-2-(3-methoxyphenyl)-5-methyl-5,6-dihydro-4H-
cyclopenta[b]thiophene-4-carbonitrile (2f). General procedure
starting from 1f (0.13 mmol) afforded 2f as a yellow oil (12 mg,
0.04 mmol, 30%). 1H NMR (400 MHz, CDCl3):
B
References and notes
d
7.29 (d, J¼7.9 Hz,1H),
1. For reviews, see: (a) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253; (b)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173; (d) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (e) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447; (f) Bellina, F.; Rossi, R. Tetrahedron
2009, 65, 10269; (g) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792.
7.14 (d, J¼6.2 Hz, 1H), 7.11 (s, 1H), 7.08 (tap, J¼2.3 Hz, 1H), 6.83 (dd,
J¼8.2, 2.4 Hz, 1H), 3.85 (s, 3H), 3.19 (dd, J¼15.9, 7.8 Hz, 1H),
2.99e2.90 (m, 1H), 2.63 (dd, J¼15.9, 4.9 Hz, 1H), 2.11 (sept, J¼6.8 Hz,
1H), 1.41 (d, J¼7.1 Hz, 3H), 1.12 (d, J¼6.8 Hz, 3H), 1.10 (d, J¼6.8 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3):
d 160.1, 148.2, 143.5, 142.3,
136.1, 130.1, 120.5, 118.3, 118.0, 113.3, 111.3, 55.6, 55.5, 44.4, 36.7,
2. For reviews, see: (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.dEur. J. 2010, 16, 2654; (b) Baudoin, O. Chem. Soc. Rev. 2011,
40, 4902; (c) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191.
3. For reviews, see: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335; (b) You, S.-L.; Xia, J.-B.
In Topics in Current Chemistry; Yu, J.-Q., Shi, Z., Eds.; Springer: Heidelberg, 2010;
Vol. 292, pp 165e194; (c) Scheuermann, C. J. Chem.dAsian J. 2010, 5, 436; (d)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
35.6, 20.1, 18.8, 18.5 ppm. IR (neat):
n 2924, 1957, 1465, 1263, 1165,
1047, 775, 688 cmꢂ1. HRMS (ESI): m/z C19H22NOS [MHþ] calculated:
312.1417; found: 312.1421.
4.3.16. 2-(3-Cyanophenyl)-4-isopropyl-5-methyl-5,6-dihydro-4H-cy-
ꢀ
4. Liegault, B.; Fagnou, K. Organometallics 2008, 27, 4841.
5. For related dehydrogenative C(sp3)eO and C(sp3)eN couplings, see: (a) Dangel,
B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149; (b) Lee, J. M.;
clopenta[b]thiophene-4-carbonitrile (2g). General procedure
startingfrom1g(0.17 mmol) afforded 2gasa paleyellowsolid (10 mg,
0.032 mmol,19%). Mp 105e107 ꢀC. 1H NMR (400 MHz, CDCl3):
7.80
B
€
Chang, S. Tetrahedron Lett. 2006, 47, 1375; (c) Neumann, J. J.; Rakshit, S.; Droge,
T.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 6892; (d) Novak, P.; Correa, A.;
d
ꢀ
(s, 1H), 7.76 (dd, J¼7.8, 1.1 Hz, 1H), 7.55 (dd, J¼7.7, 1.1 Hz, 1H), 7.48 (t,
J¼7.8 Hz, 1H), 7.17 (s, 1H), 3.22 (dd, J¼16.1, 7.8 Hz, 1H), 3.01e2.93 (m,
1H), 2.65 (dd, J¼16.1, 5.0 Hz, 1H), 2.17e2.07 (m, 1H), 1.42 (d, J¼7.1 Hz,
Gallardo-Donaire, J.; Martin, R. Angew. Chem., Int. Ed. 2011, 50, 12236.
6. For intermolecular dehydrogenative arylations of unactivated C(sp3)eH bonds,
see: (a) Deng, G.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 6278; (b) Guo,
X.; Li, C.-J. Org. Lett. 2011, 13, 4977; (c) Leskinen, M. V.; Yip, K.-T.; Valkonen, A.;
Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750; (d) Yip, K.-T.; Nimje, R. Y.;
Leskinen, M. V.; Pihko, P. M. Chem.dEur. J. 2012, 18, 12590.
7. Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.; Clot, E.;
Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706.
8. Pierre, C.; Baudoin, O. Org. Lett. 2011, 13, 1816.
3H),1.12 (t ap, J¼5.8 Hz, 6H) ppm.13C NMR (100 MHz, CDCl3):
d 145.5,
144.1, 143.9, 136.0, 130.9, 129.9, 129.7, 128.9, 120.3, 119.3, 118.6, 113.4,
55.5, 44.5, 36.7, 35.6, 20.0, 18.8, 18.5 ppm. IR (neat):
n 2966, 2918,
2229, 1488, 1464, 794, 683 cmꢂ1. HRMS (ESI): m/z C19H18N2NaS
[MNaþ] calculated: 329.1083; found: 329.1085.
9. Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
ꢀ
10. Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009,
74, 1826.
4.3.17. 4-Isopropyl-5-methyl-2-(p-tolyl)-5,6-dihydro-4H-cyclopenta
[b]thiophene-4-carbonitrile (2h). General procedure B starting from
1h (0.17 mmol) afforded 2h as a yellow oil (18 mg, 0.06 mmol, 35%).
11. (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Shi, B.-F.; Maugel, N.;
Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882; (c) Yamaguchi, A. D.;
Mandal, D.; Yamaguchi, J.; Itami, K. Chem. Lett. 2011, 40, 555; (d) Kirchberg, S.;
Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011,
50, 2387; (e) Li, H.; Liu, J.; Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2011, 13, 276.
12. Nishikata, T.;Abela, A. R.;Huang, S.;Lipshutz, B. H. J. Am. Chem. Soc. 2010,132, 4978.
13. However, the diastereoisomeric ratio depends on the nature of the ligand in the
Pd0-catalyzed reaction: see Ref. 7 and: Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.;
Baudoin, O. Chem.dEur. J. 2012, 18, 4480.
14. For reviews: (a) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Baha-
monde, A. I. Dalton Trans. 2009, 5820; (b) Balcells, D.; Clot, E.; Eisenstein, O.
Chem. Rev. 2010, 110, 749; (c) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118;
(d) Ackermann, L. Chem. Rev. 2011, 111, 1315.
1H NMR (300 MHz, CDCl3):
d
7.44 (d, J¼8.2 Hz, 2H), 7.17 (d, J¼7.9 Hz,
2H), 7.06 (s, 1H), 3.18 (dd, J¼15.8, 7.8 Hz, 1H), 2.99e2.88 (m, 1H),
2.62 (dd, J¼15.8, 5.0 Hz, 1H), 2.36 (s, 3H), 2.11 (sept, J¼6.8 Hz, 1H),
1.40 (d, J¼7.1 Hz, 3H), 1.11 (d, J¼6.8 Hz, 3H), 1.10 (d, J¼6.8 Hz, 3H)
ppm.13C NMR (100 MHz, CDCl3):
d 148.6, 143.5, 141.6, 137.7, 132.0,
129.7 (2C), 125.6 (2C), 120.6, 117.3, 55.5, 44.4, 36.7, 35.6, 21.3, 20.1,
18.8, 18.5 ppm. IR (neat): y 2965, 2874, 2230, 1514, 1464, 1184, 1080,
963, 810, 732 cmꢂ1. HRMS (ESI): m/z C19H22NS [MHþ] calculated:
15. Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am.
296.1467; found: 296.1468.
Chem. Soc. 2010, 132, 14676.