Pd-catalyzed thiocarbonylation with stoichiometric carbon monoxide: Scope and applications

Article abstract of DOI:10.1021/ol400138m

A general protocol for the Pd-catalyzed thiocarbonylation of aryl iodides with stoichiometric carbon monoxide has been established employing a catalytic system composed of Pd(OAc)₂ and DPEphos with low catalyst loading (1 mol %). Both electron-rich and -deficient aryl iodides proved effective for these couplings with aryl and alkyl thiols. The choice of the metal ligands and the solvent system was crucial for the efficiency and chemoselectivity of these transformations.

Full text of DOI:10.1021/ol400138m

ORGANIC
LETTERS
2013
Vol. 15, No. 4
948–951
Pd-Catalyzed Thiocarbonylation with
Stoichiometric Carbon Monoxide:
Scope and Applications
Mia N. Burhardt, Rolf H. Taaning, and Troels Skrydstrup*
Center for Insoluble Protein Structure (inSPIN), Department of Chemistry,
Interdisciplinary Nanoscience Center, Aarhus University, Gustavs Wieds Vej 14,
8000 Aarhus C, Denmark
ts@chem.au.dk
Received January 16, 2013
ABSTRACT
A general protocol for the Pd-catalyzed thiocarbonylation of aryl iodides with stoichiometric carbon monoxide has been established employing a
catalytic system composed of Pd(OAc)2 and DPEphos with low catalyst loading (1 mol %). Both electron-rich and -deficient aryl iodides proved
effective for these couplings with aryl and alkyl thiols. The choice of the metal ligands and the solvent system was crucial for the efficiency and
chemoselectivity of these transformations.
Thioesters are important structural entities widespread
in biochemistry but which have also found extensive applica-
tions as activated esters for the synthesis of amides, esters,
aldehydes, and ketones.1 Protocols such as native chemical
ligation invoking peptidyl thioesters have revolutionized
synthetic approaches for accessing proteins.2 Thioesters also
have the advantage of being generally more stable than acyl
halides, thereby simplifying purification and storage of these
activated esters. Although procedures for the synthesis of
thioesters from carboxylic acids or derivatives thereof are
well-known, they nevertheless require the use of stoichio-
metric dehydration reagents.3 Transition-metal-catalyzed
carbonylation chemistry represents an alternative approach
for the synthesis of unsaturated thioesters.
carbonyl-containing functional groups.4 Nevertheless,
Pd-catalyzed thiocarbonylations of aryl halides are less
well-known. Only two previous reports in the literature
have demonstrated the feasibility of this transformation
with aryl iodides. In 2008, Alper and co-workers reported
the first Pd-catalyzed thiocarbonylation of aryl iodides
using a phosphonium salt-based ionic liquid solvent in
combination with 14 atm of CO pressure.5,6 Later, Lei
et al. in mechanistic studies on Pd-catalyzed carbonylation
(4) For some recent reviews, see: (a) Wu, X.-F.; Beller Neumann, H.;
Beller, M. Chem. Rev. 2013, 113, 1. (b) Odell, L. R.; Russo, F.; Larhed, M.
Synlett 2012, 685. (c) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev.
2011, 40, 4986. (d) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2009, 48, 4114. (e) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111,
2177. (f) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515.
(5) Cao, H.; McNamee, L.; Alper, H. J. Org. Chem. 2008, 73, 3530.
(6) Alper’s group has developed a number of other Pd-catalyzed
thiocarbonylation reactions; see: (a) Xiao, W. J.; Alper, H. J. Org. Chem.
1997, 62, 3422. (b) Xiao, W.-J.; Vasapollo, G.; Alper, H. J. Org. Chem.
1998, 63, 2609. (c) Xiao, W. J.; Alper, H. J. Org. Chem. 1998, 63, 7939.
(d) Xiao, W.-J.; Vasapollo, G.; Alper, H. J. Org. Chem. 1999, 64, 2080.
(e) Xiao, W. J.; Alper, H. J. Org. Chem. 1999, 64, 9646. (f) Xiao, W.-J.;
Vasapollo, G.; Alper, H. J. Org. Chem. 2000, 65, 4138. (g) Xiao, W.-J.;
Alper, H. J. Org. Chem. 2001, 66, 6229. (h) Xiao, W.-J.; Alper, H. J. Org.
Chem. 2005, 70, 1802. (i) Cao, H.; Xiao, W.-J.; Alper, H. Adv. Synth.
Catal. 2006, 348, 1807. (j) Li, C.-F.; Xiao, W.-J.; Alper, H. J. Org. Chem.
2008, 74, 888.
Carbonylation reactions promoted by Pd catalysis are
now recognized as a key approach for the installment of
(1) (a) Nambu, H.; Hata, K.; Matsugi, M.; Kita, Y. Chem.;Eur. J.
2005, 11, 719. (b) Fuwa, H.; Mizunuma, K.; Matsukida, S.; Sasaki, M.
Tetrahedron 2011, 67, 4995. (c) Fuwa, H.; Ichinokawa, N.; Noto, K.;
Sasaki, M. J. Org. Chem. 2011, 77, 2588. (d) Liebeskind, L. S.; Srogl, J.
J. Am. Chem. Soc. 2000, 122, 11260.
(2) Dawson, P.;Muir, T.;Clark-Lewis, I.;Kent, S.Science 1994, 266, 776.
€
(3) (a) Zeiler, E.; Korotkov, V. S.; Lorenz-Baath, K.; Bottcher, T.;
Sieber, S. A. Bioorg. Med. Chem. 2012, 20, 583. (b) Neises, B.; Steglich,
W. Angew. Chem., Int. Ed. 1978, 17, 522.
r
10.1021/ol400138m
Published on Web 02/05/2013
2013 American Chemical Society

reactions demonstrated that the same transformation
could be carried out using a sodium thiolate in a thiol/
THF solvent mixture and a CO pressure of 10 atm.7,8
Recently, we reported a simple setup for running Pd-
catalyzed alkoxy- and aminocarbonylations employing
stoichiometric carbon monoxide generated from an acid
chloride precursor.9 This procedure provided a convenient
access to amides without concerns about handling this
toxic gas. The optimization of the catalytic system withlow
CO loadings was the key to success for such transforma-
tions. Furthermore, the method proved to be easily adapt-
able for 13C- and 14C-isotope labeling of pharmaceutically
relevant small molecules.10 In this paper, we demonstrate
that through optimization of the catalytic system and the
reaction conditions a diverse array of aromatic thioesters
can be obtained from the reaction of thiols with both
electron-rich and electron-deficient aryl iodides using a
simple procedure with only stoichiometric amounts of
carbon monoxide. The method also lends itself as an ideal
technique for isotope labeling of the carbonyl group.
In order to identify effective conditions for promoting
the Pd-thiocarbonylation, we initially relied on the catalyt-
ic system developed by Hartwig and co-workers in their
efficient synthesis of aryl thioethers using the combination
of Pd(OAc)2/Josiphos (PhPF-t-Bu) as the catalytic sys-
tem and sodium tert-butoxide as the base in DME.11 All
reactions were carried out applying a two-chamber system
with the ex situ production of CO as earlier reported.9
However, coupling of thiophenol with p-iodoanisole under
these conditions gave the direct coupling product 2 in a
91% yield with only traces of the desired thioester 1
(Scheme 1). A ligand and base screening revealed that
DPEphos in combination with sodium acetate as the base
Scheme 1. Results from Optimization Studies
a Ex situ generated CO from 9-methylfluorene-9-carbonyl chloride
(COgen).
afforded a complete reversal in chemoselectivity leading to
compound 1 in a gratifying yield of 93% (see the Support-
ing Information for the optimization table). A few other
bidentate ligands also proved effective for this conver-
sion including DPPF and Xantphos. However, the yields
of thioester 1 were generally approximately 10À20% lower
than for DPEphos. The catalytic loading could also be
reduced from 5 to only 1 mol % without a significant dete-
rioration in the thioester yield (89% isolated yield of 1).
Significantly, only 1.5 equivalents of carbon monoxide
were necessary for this reaction to run effectively.
The generality of the reaction conditions was next tested
on a variety of aryl iodides and thiols as illustrated in
Scheme 2. Coupling of thiophenol to a number of differ-
ently functionalized aryl iodides provided the thioesters in
good yields (1À16). Even heteroaromatic iodides proved
effective for these carbonylative couplings as depicted with
the indole and thiophene ring system leading to products
14/15 and 16, respectively, in over 80% yield. With the
former, partial deprotection of the indole nitrogen took
place under the reaction conditions, but the combined
thioester yield still attained 90%. A few other aromatic
thiols were also successfully tested as represented by com-
pounds 17À19. Finally, three alkyl thiols were run, provid-
ing the functionalized esters (20À22) in approximately
70% yield. In particular, compounds 21 and 22 are gener-
ated from two cysteine derivatives. No epimerization was
noted on the 1H NMR spectra of compound 22 attesting to
the mildness of the reactionconditionsemployingthe weak
base, sodium acetate. Applying the reaction conditions to
electron-deficient aryl iodides proved to be somewhat
problematic. In general, the thioethers were obtained as
the major product. Increasing the number of equivalents of
CO and, hence, the overall pressure of the reaction system,
provided a partial solution, but not one which was satis-
factory. This observation on the reactivity of such sub-
strates corresponds well with a mechanism whereby the
CO-insertion step into the PdÀaryl bond is slow compared to
the other steps of the catalytic cycle.12 A solvent screening was
undertaken to investigate its effect on the chemoselectivity in
(7) Hu, Y. H.; Liu, J.; Lu, Z. X.; Luo, X. C.; Zhang, H.; Lan, Y.; Lei,
A. W. J. Am. Chem. Soc. 2010, 132, 3153.
(8) Recently, Oshima and co-workers showed the possibility of using
the iron carbonyl complex [CpFe(CO)2]2 as a CO precursor for Pd-
catalyzed thioarylation of a few simple aryl iodides in varying yields.
Although the method also makes use of stoichiometric carbonylation, it
nevertheless requires the presence of a toxic transition-metal carbonyl
complex. Nakaya, R.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2011,
40, 904.
(9) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
(10) (a) Hermange, P.; Gøgsig, T. M.; Lindhardt, A. T.; Taaning,
R. H.; Skrydstrup, T. Org. Lett. 2011, 13, 2444. (b) Nielsen, D. U.;
Taaning, R. H.; Lindhardt, A. T.; Gøgsig, T. M.; Skrydstrup, T. Org.
Lett. 2011, 13, 4454. (c) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.;
Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 18114. (d) Xin, Z.; Gøgsig,
T. M.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2012, 14, 284. (e)
Bjerglund, K.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2012, 77,
3793. (f) Gøgsig, T. M.; Nielsen, D. U.; Lindhardt, A. T.; Skrydstrup, T.
Org. Lett. 2012, 14, 2536. (g) Burhardt, M. N.; Taaning, R.; Nielsen,
N. C.; Skrydstrup, T. J. Org. Chem. 2012, 77, 5357. (h) Gøgsig, T. M.;
Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. Angew. Chem., Int. Ed.
2012, 51, 798. (i) Nielsen, D. U.; Neumann, K.; Taaning, R. H.;
Lindhardt, A. T.; Modvig, A.; Skrydstrup, T. J. Org. Chem. 2012, 77,
6155. (j) Lindhardt, A. T.; Simonssen, R.; Taaning, R. H.; Gøgsig,
T. M.; Nilsson, G. N.; Stenhagen, G.; Elmore, C. S.; Skrydstrup, T.
J. Labelled Compd. Radiopharm. 2012, 55, 411.
(11) (a) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117,
2937. (b) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.;
ꢀ
Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205. (c) Fernandez-Rodrıguez,
(12) In this case, the product yields obtained with the electron-
deficient aryl halides are generally lower than those for the electron-rich
substrates. For examples, see: Wu, X.-F.; Neumann, H.; Spannenberg,
A.; Schulz, T.; Jiao, H.; Beller, M. J. Am. Chem. Soc. 2010, 132, 14596
and ref 10a,10f.
M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180. (d)
ꢀ
Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (e) Fernandez-Rodrıguez,
M. A.; Hartwig, J. F. J. Org. Chem. 2009, 74, 1663. (f) Alvaro, E.;
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7858.
Org. Lett., Vol. 15, No. 4, 2013
949

Scheme 2. Thiocarbonylation with Electron-Rich Aryl Iodides
Scheme 3. Thiocarbonylation with Electron-Deficient Aryl
Iodides
a Chamber 1: Thiophenol (0.25 mmol), iodide (0.25 mmol), Pd(OAc)2
(2.5 μmol), DPEphos (2.5 μmol), NaOAc (0.28 mmol), anisole (1.0 mL).
Chamber 2: Pd(dba)2 (13 μmol), PtBu3 (13 μmol), 9-methylfluorene-9-
carbonyl chloride (0.38 mmol, 1.5 equiv), Cy2NMe (0.56 mmol), anisole
(1.5 mL). b 3.0 equiv of CO was generated in chamber 2.
Pd-mediated carbonylative Suzuki reactions employing
ligandless conditions anisole proved tobe the only effective
solvent for these transformations.14
An interesting observation was made in the reaction of
the three regioisomeric diiodobenzenes with either thio-
phenol or its p-methoxy derivative (Scheme 4). In all cases,
the major products 33À36 resulted from a thiocarbonylation/
thioarylation sequence even though 3 equiv of CO was
applied. Although the reaction sequence order was not
determined, it is worth noting that the double thioarylation
product was obtained in better yields than the corresponding
dithioester. It is interesting to note that a switch of DME to
anisole as the solvent in the reaction with 1,4-diiodobenzene
led to the formation of the dithioester 37 as the major
product.
The value of the thioesters for amide library synthesis is
illustrated with a few examples in Scheme 5. All amides
(38À45) were prepared using simple coupling procedures
from the thioester and are nonoptimized. They provide a
good illustration of the diversity of compounds that can be
obtained from a simple and easily storable thioester.15
a Chamber 1: thiol (0.25 mmol), p-iodoanisole (0.25 mmol), Pd(OAc)2
(2.5 μmol), DPEphos (2.5 μmol), NaOAc (0.28 mmol), DME (1.0 mL).
Chamber 2: Pd(dba)2 (13 μmol), PtBu3:HBF4 (13 μmol), 9-methylfluor-
ene-9-carbonyl chloride (0.38 mmol, 1.5 equiv), Cy2NMe (0.56 mmol),
DME (1.5 mL). b Pd(OAc)2 (5.0 μmol) and DPEphos (5.0 μmol) were
used in this reaction. Partial deprotection was observed.
the reaction of p-trifluoromethylphenyl iodide with thio-
phenol (see the Supporting Information). Of the several
solvents tested (including toluene, proprionitrile, dioxane,
CPME, and trifluorotoluene), the use of anisole furnished
the thioester 23 in a good 79% yield (Scheme 3).
The scope of the thiocarbonylation procedure with the
electron-poor aryl iodides is shown in Scheme 3. In most
cases, good to excellent yields of the thioesters 23À32 were
obtained. Even in the case of the p-nitro derivative, the
desired compound 31 was formed.13 Although the exact
role of the solvent for promoting carbonylation is spec-
ulative, it is interesting to note that in the case of
(14) (a) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura,
N. J. Org. Chem. 1998, 63, 4726. (b) Khedkar, M. V.; Tambade, P. J.;
Qureshi, Z. S.; Bhanage, B. M. Eur. J. Org. Chem. 2010, 6981 and
references cited therein.
(13) For these substrates, the corresponding thioethers were obtained
as the byproduct arising from the direct coupling. Nevertheless, the
separation by column chromatography proved to be facile due to
the relatively large Rf difference between the two sulfur-containing
products.
(15) The amide, tert-butyl (3-(4-((4-methoxyphenyl)thio)benzamido)-
propyl)carbamate (46) (see the Supporting Information), was prepared
via a one-pot procedure from 1,4-diiodobenzene, p-methoxythiophenol,
and subsequent addition of tert-butyl (3-aminopropyl)carbamate under
basic conditions. The desired product was isolated in 34% yield.
950
Org. Lett., Vol. 15, No. 4, 2013

Scheme 4. Thiocarbonylation/Thioarylation with Diiodobenzene
Scheme 6. Synthesis and 13C-Labeling of an Amide Analogue of
Vortioxetine
a Chamber 1: thiol (0.50 mmol), iodide (0.25 mmol), Pd(OAc)2
(2.5 μmol), DPEphos (2.5 μmol), NaOAc (0.55 mmol), DME (1.0 mL).
Chamber 2: Pd(dba)2 (25 μmol), PtBu3 (25 μmol), 9-methylfluorene-9-
carbonyl chloride (0.76 mmol, 3.0 equiv), Cy2NMe (1.13 mmol), DME
(3.0 mL). b Reaction scaled up 5Â (see the Supporting Information).
c Anisole was used.
a Chamber 2: Pd(dba)2 (25 μmol), PtBu3 (25 μmol), 9-methylfluorene-
9-carbonyl chloride (0.76 mmol, 3.0 equiv), Cy2NMe (1.13 mmol), DME
(3.0 mL).
o-diiodobenzene and 2,4-dimethylthiophenol with only
1.5 equiv of CO generated in the two-chamber system.
This furnished a satisfactory 64% yield of 47 and a 65%
yield of 13C-47 from 13C-labeled CO. Subsequent amide
formation with N-Boc pyrazine and acid-promoted depro-
tection led to a 70% isolated yield for both 49 and 13C-49.
In conclusion, a catalytic system was developed for the
Pd-catalyzed thiocarbonylation of aryl iodides with thiols
exploiting a simple setup and reaction conditions, which
use only stoichiometric carbon monoxide. Both electron-
rich and electron-deficient aryl iodides could be applied
and the nature of the metal ligands and the solvent system
proved crucial for the chemoselectivity of these transfor-
mations. A protocol, which allows expansion of this
chemistry to other aromatic halides, is currently under
investigation and will be reported in due course.17
Scheme 5. Amide Formation from Thioesters 17 and 36
Acknowledgment. We are deeply appreciative of gener-
ous financial support from the Danish National Research
Foundation, the Danish Natural Science Research Coun-
cil, the Villum Foundation, the Carlsberg Foundation, the
Lundbeck Foundation, and Aarhus University.
a Thioester (0.37 mmol), amine nucleophile (0.55 mmol), triethyl-
amine (0.5 mL), pyridine (0.5 mL). b Thioester (0.11 mmol), amine
nucleophile (0.16 mmol), K2CO3 (0.21 mmol), DMF (1.0 mL).
Finally, we have exploited the thiocarbonylation/
thioarylation protocol to prepare an interesting amide
version of the new antidepressive agent, vortioxetine,16
including its 13C-isotope derivative (Scheme 6). The
sequential transformation could be carried out with
Supporting Information Available. Experimental de-
tails and copies of 1H NMR and 13C NMR spectra for all
coupling products. This material is available free of
charge via the Internet at http://pubs.acs.org
(17) Preliminary investigations in the coupling of bromoanisole with
thiophenol in anisole as the solvent applying the described catalytic
system provided a 55% conversion to a mixture of the thioester and the
thioether after a reaction time of 18 h and heating to 120 °C.
(16) (a) Bang-Andersen, B.; Ruhland, T.; Jørgensen, M.; Smith, G.;
Frederiksen, K.; Jensen, K. G.; Zhong, H.; Nielsen, S. M.; Hogg, S.;
Mørk, A.; Stensbøl, T. B. J. Med. Chem. 2011, 54, 3206. (b) Moore, N.;
Bang-Andersen, B.; Brennum, L.; Fredriksen, K.; Hogg, S.; Mørk, A.;
Stensbøl, T.; Zhong, H.; Sanchez, C.; Smith, D. Eur. Neuropsychopharm.
2008, 18, S321.
The authors declare no competing financial interest.
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