Activation of aryl thiocyanates followed by aryne insertion: Access to 1,2-thiobenzonitriles

Article abstract of DOI:10.1021/acs.orglett.5b00494

Palladium-catalyzed activation of carbon-sulfur bonds allows aryne insertion into aryl thiocyanates to generate new C-SAr and C-CN bonds in one step. The readily available starting materials make this method efficient in generating a variety of 1,2-thiobenzonitriles. By choosing an oxygen atmosphere the yields are increased and side reactions are minimized.

Full text of DOI:10.1021/acs.orglett.5b00494

Letter
pubs.acs.org/OrgLett
Activation of Aryl Thiocyanates Followed by Aryne Insertion: Access
to 1,2-Thiobenzonitriles
Martin Pawliczek,†,‡ Lennart K. B. Garve,† and Daniel B. Werz*,†
†Technische Universitat Braunschweig, Institut fur Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany
̈
̈
‡Georg-August-Universitat Gottingen, Institut fur Organische und Biomolekulare Chemie, Tammannstraße 2, 37077 Gottingen,
Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Palladium-catalyzed activation of carbon−sulfur
bonds allows aryne insertion into aryl thiocyanates to generate
new C−SAr and C−CN bonds in one step. The readily
available starting materials make this method efficient in
generating a variety of 1,2-thiobenzonitriles. By choosing an oxygen atmosphere the yields are increased and side reactions are
minimized.
he development of novel methodologies to form carbon−
simple reaction, we asked ourselves whether other Het−CN
Tsulfur bonds is crucial for the synthesis and derivatization bonds such as S−CN are able to undergo a similar
of target molecules in pharmaceutical and material science.1
transformation. In contrast to the reactivity of Het−CN
bonds with alkenes or alkynes the strained triple bond of an
aryne possesses a much higher reactivity; thus, numerous side
reactions such as triphenylene formation7 have to be sup-
pressed using this special kind of triple bond as a reaction
partner.
Important classes of sulfur-containing compounds are biaryl
sulfides and their higher oxidized homologues. For that
purpose, several methods have been described utilizing
transition metal2 or transition-metal-free3 conditions to prepare
the biaryl thioether moiety. Most of these approaches
predominantly tackle the problem to generate the carbon−
sulfur bond (e.g., by nucleophilic aromatic substitution),
generating one bond in one step. However, it is desirable to
find novel synthetic methods to install additional functionalities
concomitant with the formation of the carbon−sulfur bond.
Recently, transition-metal catalyzed intramolecular oxycyana-
tion and aminocyanation4 reactions of alkenes and intermo-
lecular cyanothiolation5 of terminal alkynes were reported.
After the cleavage of the Het−CN bond, new C−Het and C−
CN bonds were formed.
A major difference between cyanamides and thiocyanates is
the philicity of the two heteroatoms. The facile loss of the acidic
hydrogen of cyanamides renders the internal nitrogen highly
nucleophilic and enables attack to the electrophilic aryne
without further activation (Scheme 1).8 Contrary to nitrogen in
cyanamides, the sulfur in thiocyanates is rather positively
polarized9 and is not able to undergo a nucleophilic attack on
the aryne without further activation. Therefore, we tried to
combine aryne chemistry10 with a Pd-catalyzed activation of
aryl thiocyanates.
At the outset of our studies phenyl thiocyanate (1a) and
aryne precursor 2a were reacted under standard conditions
commonly employed in aryne chemistry using CsF and
acetonitrile at 40 °C (Table 1, entry 1). As expected, even
after heating up to 80 °C, the desired coupling product could
not be detected, but complete consumption of 2a was observed.
Application of Pd(PPh3)4 as a catalyst yielded traces of product
3aa with concomitant formation of diphenylthioether as the
major product (Table 1, entry 2). Therefore, Pd(OAc)2 in
combination with Xantphos was applied affording 3aa in yields
varying between 10% and 30% (Table 1, entry 3). Surprisingly,
oxidative reaction conditions using an oxygen atmosphere
dramatically increased the yield to 81% (Table 1, entry 4). In
addition, the formation of diphenylthioether was suppressed
(<10%) and the time for full substrate consumption could be
lowered from 54 to 18 h. Further attempts to improve the
In 2014, Rao and Zeng were able to convert arynes with
cyanamides resulting in a simultaneous C−N and C−CN bond
formation in one step (Scheme 1).6 No activation of the N−
CN bond by a transition metal was required. Intrigued by this
Scheme 1. Insertion of Arynes into Het−CN Bonds
Received: February 16, 2015
Published: March 16, 2015
© 2015 American Chemical Society
1716
DOI: 10.1021/acs.orglett.5b00494
Org. Lett. 2015, 17, 1716−1719

Organic Letters
Letter
a
a
Table 1. Screening of Reaction Conditions
Scheme 2. Scope with Respect to ArSCN
entry catalyst (10 mol %) ligand (mol %)
atmosphere
yield (%)
b
1
2
3
5
6
7
8
9
−
−
−
Ar or O2
Ar
0
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
traces
c
Xantphos (20)
Xantphos (20)
Xantphos (15)
PPh3 (20)
dppf (20)
dppp (20)
−
Ar
10−30
O2
81
42
0
O2
O2
O2
0
O2
traces
0
10
11
12
O2
Xantphos (20)
O2
0
Pd(OAc)2
Xantphos (20)
air
41
a
Reaction conditions: 1a (13.2 mg, 100 μmol, 1.0 equiv), 2a (34.0 μL,
140 μmol, 1.4 equiv), CsF (50.0 mg, 330 μmol, 3.3 equiv), MeCN (4
b
c
mL) at 40 °C for 18 h. Reaction temperature 40 and 80 °C. Reaction
time 54 h.
reaction conditions by applying a lesser amount of Xantphos or
different ligand systems significantly decreased the yield or
proved to be completely unsuccessful (Table 1, entries 6−9).
Utilizing either Pd(OAc)2 or Xantphos yielded 0% of 3aa,
respectively (Table 1, entries 10 and 11). The use of air instead
of an oxygen atmosphere was less successful and afforded the
product in only 41% yield (Table 1, entry 12). Moreover, to
prevent triphenylene formation the slow or stepwise addition of
2a was not necessary. The catalytic system in combination with
phenyl thiocyanate bypasses this undesired reaction pathway.
Other common oxidants such as benzoquinone, silver
carbonate, and copper(II) acetate entirely suppressed the
product formation. Application of oxone and ammonium
persulfate had no influence on the reaction and afforded the
product in similar yields as when under an argon atmosphere.
With the optimized reaction conditions in hand we started to
examine the scope of this transformation (Scheme 2). Various
electron-donating and -withdrawing aryl thiocyanates were
exposed to the reaction. Methyl substituents in ortho-, meta-,
and para-positions yielded the corresponding thiobenzonitriles
in similar yields ranging from 71% to 78% (3ba−3da).
Application of the electron-donating but inductively electron-
withdrawing anisole derivative delivered the corresponding
product 3ea in 51% yield. The electron-poor phenyl
thiocyanate containing the electron-withdrawing CF3 group
was converted to the desired product 3fa in only 17% yield.
Decreasing the reaction temperature to 25 °C increased the
yield up to 25%. Different halogens at the benzene ring revealed
only a small influence on the reactivity. The desired products
could be obtained in moderate yields ranging from 50% to 61%
(3ga−3ja). However, these examples represent products which
show difficulties in several other biaryl thioether syntheses.
Finally, thiocyanates with extended π-systems were employed
affording naphthalene derivative 3ka in 61% yield and indole
derivative 3la in 52% yield, respectively. In contrast to previous
examples trimerization of the aryne was a noteworthy side
reaction. Because of the formation of a large amount of
triphenylene side product, 4.5 equiv of 2a were required to
achieve a satisfactory conversion in the latter case.
a
Reaction conditions: 1 (13.2 mg, 100 μmol, 1.0 equiv), 2a (34.0 μL,
140 μmol, 1.4 equiv), Pd(OAc)2 (2.2 mg, 10.0 μmol, 10 mol %),
Xantphos (11.6 mg, 20.0 μmol, 20 mol %), CsF (50.0 mg, 330 μmol,
3.3 equiv), MeCN (4 mL) at 40 °C for 18 h under O2 atmosphere.
b
c
Reaction temperature 25 °C. 4.5 equiv of 2a were applied.
Afterward, we extended the scope of the 1,2-functionalization
with respect to the aryne (Table 2). Gratefully, electron-rich,
inductively electron-withdrawing arynes and those with
expanded π-systems could be converted to the corresponding
1,2-difunctionalized products in 42−78% yield (Table 2, entries
1−3). Unfortunately, when using 2e bearing two fluorine
substituents, the desired thiobenzonitrile 3ae was only observed
by GC-MS in less than 5% yield (Table 2, entry 4), although 2e
was entirely consumed concomitant with mostly untouched
phenyl thiocyanate. In addition, when unsymmetrical aryne
precursors were employed, regioisomeric mixtures were
obtained in 45% up to 79% yield (Table 2, entries 5−7).
Noteworthy, in the cases of 2g and 2h the major isomers
contain the small nitrile residue next to the sterically
encumbered position as unequivocally shown by 2D-NMR
spectroscopic investigations.
To elucidate the mechanistic scenario we tried to capture
reaction intermediates. Therefore, phenylacetylene or styrene,
respectively, were added to trap the reactive species after the
first bond forming step has occurred through either carbo- or
thiopalladation. Unfortunately, exclusively thiobenzonitrile 3aa
1717
DOI: 10.1021/acs.orglett.5b00494
Org. Lett. 2015, 17, 1716−1719

Organic Letters
Letter
a
Table 2. Scope with Respect to Aryne
Scheme 3. Proposed Reaction Mechanism
we assume a stabilizing effect for an intermediate which is
formed during the catalytic cycle rather than the occurrence of
Pd(IV). Commonly, Pd(II)/Pd(IV) chemistry would require
stronger oxidizing agents than oxygen.11 Regarding the role of
Xantphos we speculate that the large bite angle of this ligand
facilitates the coordination of the aryne.
In conclusion, we developed a novel access to 1,2-
thiobenzonitriles. Starting from aryne precursors and aryl
thiocyanates the desired products were obtained in moderate to
good yield. In consequence of its electronic properties the S−
CN bond had to be activated for aryne insertion, wherefore
palladium catalysis was employed. Choosing an oxygen
atmosphere dramatically increased the yield, minimized the
formation of side products, and significantly reduced the
reaction time. This protocol provides a straightforward access
to 1,2-thiobenzonitriles starting from readily available aryl
thiocyanates and aryne precursors and serves as an alternative
for the synthesis of biaryl thioethers.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Detailed experimental procedures, analytical data, and H and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
Reaction conditions: 1a (13.2 mg, 100 μmol, 1.0 equiv), 2 (34.0 μL,
140 μmol, 1.4 equiv), Pd(OAc)2 (2.2 mg, 10.0 μmol, 10 mol %),
Xantphos (11.6 mg, 20.0 μmol, 20 mol %), CsF (50.0 mg, 330 μmol,
3.3 equiv), MeCN (4 mL) at 40 °C for 18 h under O2 atmosphere.
Ratio 3fa-1/3fa-2 = 1:1. Ratio 3ga-1/3ga-2 = 3:1. Minor isomer
could not be isolated, ratio >20:1.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: d.werz@tu-braunschweig.de.
Notes
b
c
d
The authors declare no competing financial interest.
was observed as the coupling product without incorporation of
phenylacetylene or styrene (for details see Supporting
Information).
ACKNOWLEDGMENTS
■
This research was supported by the German Research
Foundation (DFG, Emmy Noether and Heisenberg Fellow-
ships to D.B.W.) and by the Fonds der Chemischen Industrie
(Ph.D. Fellowship to M.P. and Dozentenstipendium to
D.B.W.). L.K.B.G. thanks the Studienstiftung des deutschen
Volkes for a Ph.D. Fellowship.
Based on our experimental results and literature evidence,4,5,7
a plausible reaction mechanism is proposed in Scheme 3. The
combination of Pd(OAc)2 and Xantphos generates the active
[Pd(0)] catalyst which undergoes oxidative addition into the
PhS−CN bond to form intermediate B. Afterward, the aryne
generated from 2a and CsF is coordinated by the Pd center to
afford species C. Finally, two bond forming steps of unknown
order, consisting of a carbo- or thiometalation and reductive
elimination, generate the desired 1,2-thiobenzonitrile 3aa.
During the last step the active [Pd(0)] species is regenerated.
The role of the oxygen atmosphere is not really clear; however,
REFERENCES
■
(1) (a) Bagley, M. C.; Davis, T.; Dix, M. C.; Fusillo, V.; Pigeaux, M.;
Rokicki, M. J.; Kipling, D. J. Org. Chem. 2009, 74, 8336. (b) De
Martino, G.; Edler, M. C.; La Regina, G.; Coluccia, A.; Barbera, M. C.;
Barrow, D.; Nicholson, R. I.; Chiosis, G.; Brancale, A.; Hamel, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49, 947. (c) Popoff, I. C.;
1718
DOI: 10.1021/acs.orglett.5b00494
Org. Lett. 2015, 17, 1716−1719

Organic Letters
Letter
Engle, A. R.; Whitaker, R. L.; Shinghal, G. H. J. Med. Chem. 1971, 14,
1166.
(2) (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(b) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem.Eur. J. 2011,
17, 5652. (c) Anbarasan, P.; Neumann, H.; Beller, M. Chem. Commun.
2011, 47, 3233. (d) Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X.
Org. Lett. 2011, 13, 454. (e) Li, Y.; Li, X.; Wang, H.; Chen, T.; Xie, Y.
Synthesis 2010, 3602. (f) Xu, H.-J.; Zhao, X.-Y.; Deng, J.; Feng, Y.-S.
Tetrahedron Lett. 2009, 50, 434. (g) Huang, F.; Batey, R. A.
́
Tetrahedron 2007, 63, 7667. (h) Fernandez-Rodríguez, M. A.; Shen,
Q.; Hartwig, J. F. Chem.Eur. J. 2006, 12, 7782.
(3) (a) Yang, Y.; Chen, Z.; Rao, Y. Chem. Commun. 2014, 50, 15037.
(b) Qui, J.-K.; Hao, W.-J.; Wang, D.-C.; Wei, P.; Sun, J.; Jiang, B.; Tu,
S.-J. Chem. Commun. 2014, 50, 14782. (c) Yang, F.-L.; Tian, S.-K.
Angew. Chem., Int. Ed. 2013, 52, 4929. (d) Umiersky, N.; Manolikakes,
G. Org. Lett. 2013, 15, 188. (e) Liang, S.; Zhang, R.; Xi, L.; Chen, S.;
Yu, X. J. Org, Chem. 2013, 78, 5652.
(4) (a) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc.
2014, 136, 3732. (b) Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C.
J. Angew. Chem., Int. Ed. 2014, 53, 5170. (c) Koester, D. C.; Kobayashi,
M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134, 6544.
(5) (a) Ozaki, T.; Nomoto, A.; Kamiya, I.; Kawakami, J.-I.; Ogawa, A.
Bull. Chem. Soc. Jpn. 2011, 84, 155. (b) Zheng, W.; Ariafard, A.; Lin, Z.
Organometallics 2008, 27, 246. (c) Tak, Y.; Choi, S. Y.; Chung, Y. K.
Tetrahedron Lett. 2007, 48, 5673. (d) Kamiya, I.; Kawakami, J.-I.; Yano,
S.; Nomoto, A.; Ogawa, A. Organometallics 2006, 25, 3562.
(6) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314.
́
(7) Gracía-Lopez, J.-A.; Greaney, M. F. Org. Lett. 2014, 16, 2338.
(8) (a) Luo, K.; Meng, L.; Zhang, Y.; Zhang, X.; Wang, L. Adv. Synth.
Catal. 2013, 355, 765. (b) Liu, X.; Wang, X.; Li, Q.; Kozar, M. P.;
Melendez, V.; O’Neil, M. T.; Lin, A. J. J. Med. Chem. 2011, 54, 4523.
(c) Devan, B.; Rajagopalan, K. Synth. Commun. 1994, 24, 1691.
(9) (a) Melzig, L.; Rauhut, C. B.; Naredi-Rainer, N.; Knochel, P.
Chem.Eur. J. 2011, 17, 5362. (b) Werz, D. B.; Fischer, F. R.;
Kornmayer, S. C.; Rominger, R.; Gleiter, R. J. Org. Chem. 2008, 73,
8021. (c) Werz, D. B.; Gleiter, R.; Rominger, F. J. Org. Chem. 2004, 69,
2945. (d) Werz, D. B.; Gleiter, R. J. Org. Chem. 2003, 68, 9400.
(e) Schulte, J. H.; Werz, D. B.; Rominger, F.; Gleiter, R. Org. Biomol.
Chem. 2003, 1, 2788. (f) Rausch, B. J.; Werz, D. B.; Rittinger, S.;
Gleiter, R.; Oeser, T.; Rominger, F. J. Chem. Soc., Perkin Trans. 2 2002,
72. (g) Benisch, C.; Bethke, S.; Gleiter, R.; Oeser, T.; Pritzkow, H.;
Rominger, F. Eur. J. Org. Chem. 2000, 2479. (h) Toste, D. F.; Still, I.
W. J. Tetrahedron Lett. 1995, 36, 4361.
(10) (a) Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 596.
(b) Dong, Y.; Liu, B.; Chen, P.; Liu, Q.; Wang, M. Angew. Chem., Int.
Ed. 2014, 53, 3442. (c) Ye, W.; Zhang, L.; Ni, C.; Rong, J.; Hu, J.
Chem. Commun. 2014, 50, 10596. (d) Lui, F.-L.; Chen, J.-R.; Zou, Y.-
Q.; Wie, Q.; Xiao, W.-J. Org. Lett. 2014, 16, 3768. (e) Bhunia, A.; Roy,
T.; Pachfule, P.; Rajamohanan, P.; Biju, A. T. Angew. Chem., Int. Ed.
2013, 52, 10040. (f) Dubrovskiy, A.; Larock, R. C. J. Org. Chem. 2012,
77, 11232. (g) Kim, J.; Stoltz, B. M. Tetrahedron Lett. 2012, 53, 4994.
(h) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
(i) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B.
M. Org. Lett. 2010, 12, 1224. (j) Ebner, D. C.; Tambar, U. K.; Stoltz,
B. M. Org. Synth. 2009, 86, 161. (k) Tambar, U. K.; Stoltz, B. M. J. Am.
Chem. Soc. 2005, 127, 5340.
(11) (a) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010,
39, 712. (b) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412.
̃
1719
DOI: 10.1021/acs.orglett.5b00494
Org. Lett. 2015, 17, 1716−1719