Palladium-catalyzed direct C-H bond alkynylations of heteroarenes using gem-dichloroalkenes

Article abstract of DOI:10.1021/ol300514d

Palladium-catalyzed direct alkynylations of heteroarenes were accomplished with inexpensive gem-dichloroalkenes as user-friendly electrophiles, which set the stage for a modular, step-economical synthesis of diversely decorated heteroaryl alkynes with amp

Full text of DOI:10.1021/ol300514d

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1824–1826
Palladium-Catalyzed Direct CꢀH Bond
Alkynylations of Heteroarenes Using
gem-Dichloroalkenes
Lutz Ackermann,* Christoph Kornhaass, and Yingjun Zhu
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received February 28, 2012
ABSTRACT
Palladium-catalyzed direct alkynylations of heteroarenes were accomplished with inexpensive gem-dichloroalkenes as user-friendly
electrophiles, which set the stage for a modular, step-economical synthesis of diversely decorated heteroaryl alkynes with ample scope.
Recent years have witnessed significant progress in the
direct functionalization of ubiquitous CꢀH bonds via their
use as latent functional groups.1 While a remarkable
advance has particularly been made in direct arylations
and alkenylations,2 CꢀH bond alkylations3 and alkynyla-
tions4 have unfortunately met thus far with rather limited
success. However, the direct alkynylation of heteroarenes
gained a considerable impetus by the recent use of 1-bro-
moalkynes as organic electrophiles (Scheme 1a).5 Unfor-
tunately, the required 1-haloalkynes are usually relatively
unstable, and a significantly more attractive strategy was
elegantly developed by Piguel and co-workers, exploiting
moisture-stable gem-dibromoalkenes6ꢀ8 as alkynylating
reagents (Scheme 1b).9 Yet, while versatile direct arylations
have been devised in recent years with aryl chlorides,10
inexpensive, but challenging, gem-dichloroalkenes11 have,
to the best of our knowledge, thus far not been utilized for
catalyzed direct alkynylations of unactivated CꢀH bonds,
(3) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877.
(4) Reviews: (a) Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org.
Chem. 2010, 6495–6516. (b) Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2096–2098.
(5) For recent examples, see: (a) Ano, Y.; Tobisu, M.; Chatani, N.
Org. Lett. 2012, 14, 354–357. (b) Ano, Y.; Tobisu, M.; Chatani, N.
J. Am. Chem. Soc. 2011, 133, 12984–12986. (c) Nicolai, S.; Waser, J. Org.
Lett. 2011, 13, 6324–6327. (d) Kim, S. H.; Chang, S. Org. Lett. 2010, 12,
1868–1871. (e) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am.
Chem. Soc. 2010, 132, 2522–2523. (f) Kawano, T.; Matsuyama, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 1764–1766. (g)
Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48,
9346–9349. (h) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2009, 11, 4156–4159. (i) Tobisu, M.; Ano, Y.; Chatani, N. Org.
Lett. 2009, 11, 3250–3252. (j) Besselievre, F.; Piguel, S. Angew. Chem.,
Int. Ed. 2009, 48, 9553–9556. (k) Seregin, I. V.; Ryabova, V.; Gevorgyan,
V. J. Am. Chem. Soc. 2007, 129, 7742–7743 and references cited therein.
For examples of cross-dehydrogenative alkynylations, see: (l) Kitahara,
M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.;Eur. J. 2010,
16, 1772–1775. (m) Yang, L.; Zhao, L.; Li, C.-J. Chem. Commun. 2010,
46, 4184–4186. (n) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2010, 12, 2358–2361.
(1) Recent representative reviews on CꢀH bond functionalizations:
(a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
DOI: 10.1021/ar200185g. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
111, 1215–1292. (c) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. (d)
Herrmann, P.; Bach, T. Chem. Soc. Rev. 2011, 40, 2022–2038. (e)
Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503–
4513. (f) Wasa, M.; Engle, K. M.; Yu, J.-Q. Isr. J. Chem. 2010, 50, 605–
616. (g) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (h) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. (i) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (j)
Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig,
J. F. Chem. Rev. 2010, 110, 890–931. (k) Fagnou, K. Top. Curr. Chem.
2010, 292, 35–56. (l) Willis, M. C. Chem. Rev. 2010, 110, 725–748. (m)
Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874–5883 and
references cited therein.
(6) Comprehensive reviews on applications of gem-dihaloalkenes:
(a) Chelucci, G. Chem. Rev. 2012, DOI: 10.1021/cr200165q. (b) Legrand,
F.; Jouvin, K.; Evano, G. Isr. J. Chem. 2010, 50, 588–604.
(7) For selected recent examples of transition-metal-catalyzed CꢀH
bond functionalizations involving gem-dihaloalkenes, see: (a) Ye, S.;
Liu, G.; Pu, S.; Wu, J. Org. Lett. 2012, 14, 70–73. (b) Qin, X.; Cong, X.;
Zhao, D.; You, J.; Lan, J. Chem. Commun. 2011, 47, 5611–5613. (c)
Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054–3061. (d) Fayol,
A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203–4206. See also: (e)
Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152–5160
and references cited therein.
(2) Selected reviews: (a) Hirano, K.; Miura, M. Synlett 2011, 294–
307. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792–9826. (c) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174–238.
r
10.1021/ol300514d
Published on Web 03/28/2012
2012 American Chemical Society

despite their reduced molecular weight as compared to the
corresponding gem-dibromoalkenes. Within our program
on sustainable metal-catalyzed direct CꢀH bond transfor-
mations for an overall streamlining of organic synthesis,12
we consequently became interested in devising a catalyst
for direct alkynylations of heteroarenes with user-friendly
gem-dichloroalkenes, on which we report herein. Notably, a
broadly applicable palladium catalyst furnished diversely
substituted (hetero)aryl acetylenes, key structural motifs
inter alia in chemical biology and material sciences.13
Table 1. Optimization of Direct Alkynylation of Benzoxazole
(1)a
entry
[TM]
CuI
L (mol %)15
base
yield (%)
1
XantPhos (5.0)
XantPhos (5.0)
DPEPhos (5.0)
XantPhos (5.0)
PPh3 (10)
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
KOt-Bu
K3PO4
13
13
17
46
38
20
40
40
19
39
56
62
68
ꢀ
2
CuBr•SMe2
CuBr•SMe2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
3
Scheme 1. Direct CꢀH Bond Alkynylations with Organic
4
Electrophiles
5
6
PCy3 (10)
7
JohnPhos (10)
DavePhos (10)
HIPrCl (10)
8
9
10
11
12
13
14
15
16
17
18
dppp (5.0)
dppf (5.0)
dppe (5.0)
DPEPhos (5.0)
DPEPhos (5.0)
DPEPhos (5.0)
DPEPhos (5.0)
DPEPhos (5.0)
DPEPhos (6.0)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
ꢀ
Cs2CO3
LiOt-Bu
ꢀ
75b
a Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol), [TM] (5.0 mol %),
L (5.0ꢀ10 mol %), base (2.50 mmol), 1,4-dioxane (2.0 mL), 100 °C, 16 h.
b 120 °C, 13 h; yields of isolated products.
We initiated our studies by probing various reaction
conditions for the direct alkynylation of benzoxazole (1)14
with easily accessible gem-dichloroalkene 2a (Table 1).
Copper(I) catalysts that were previously utilized for trans-
formations of gem-dibromoalkenes unfortunately led only
Scheme 2. Direct Alkynylation with Substituted gem-Dichloro-
alkenes 2
(8) For an example of vic-dihaloalkenes in catalyzed CꢀH bond
tranformations, see: Ackermann, L.; Althammer, A.; Mayer, P. Synth-
esis 2009, 3493–3503.
(9) Berciano, B. P.; Lebrequier, S.; Besselievre, F.; Piguel, S. Org.
Lett. 2010, 12, 4038–4041. (b) A more recent report: Reddy, G. C.;
Balasubramanyam, P. N. S.; Das, B. Eur. J. Org. Chem. 2012, 471–474.
(10) Representative examples of palladium-catalyzed direct CꢀH
bond arylations with aryl chlorides: (a) Nadres, E. T.; Lazareva, A.;
Daugulis, O. J. Org. Chem. 2011, 76, 471–483. (b) Roy, D.; Mom, S.;
Beauperin, M.; Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2010,
49, 6650–6654. (c) Ackermann, L.; Vicente, R.; Born, R. Adv. Synth.
Catal. 2008, 350, 741–748. (d) Chiong, H. A.; Daugulis, O. Org. Lett.
2007, 9, 1449–1451. (e) Ackermann, L.; Althammer, A. Angew. Chem.,
Int. Ed. 2007, 46, 1627–1629. (f) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–590 and references cited
therein.
(11) A recent environmentally benign synthesis of gem-dichloroal-
kenes: Newman, S. G.; Bryan, C. S.; Perez, D.; Lautens, M. Synthesis
2011, 342–346.
(12) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413. (b)
Ackermann, L. Isr. J. Chem. 2010, 50, 652–663. (c) Ackermann, L.
Synlett 2007, 507–526. (d) Ackermann, L.; Born, R.; Spatz, J. H.;
Althammer, A.; Gschrei, C. J. Pure Appl. Chem. 2006, 78, 209–214.
(13) Selected reviews: (a) Zucchero, A. J.; McGrier, P. L.; Bunz,
U. H. F. Acc. Chem. Res. 2010, 43, 397–408. (b) Acetylene Chemistry;
Diederich, F., Tykwiski, R. R., Stang, P., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (c) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew.
Chem., Int. Ed. 2000, 39, 2632–2657.
to unsatisfactory yields (entries 1ꢀ3). More promising
results were, on the contrary, achieved with palladium(II)
complexes. Among a variety of phosphine and N-hetero-
cyclic carbene (NHC) ligands, the most efficient catalysis
was ensured by bidentate DPEPhos as the ligand (entries
(14) For selected examples of palladium-catalyzed CꢀH bond trans-
formations with azoles from our laboratories, see: (a) Ackermann, L.;
€
Barfusser, S.; Kornhaass, C.; Kapdi, A. R. Org. Lett. 2011, 13, 3082–
(15) Acronyms and abbreviations of (pre)ligands: XantPhos = 4,5-
(diphenylphosphino)-9,9-dimethylxanthene; JohnPhos = 2-(dicyclohexyl-
phosphino)biphenyl; DavePhos = 2-dicyclohexylphosphino-20-(N,N-di-
methylamino)biphenyl; HIPr = N,N0-bis(2,6-diisopropylphenyl)imida-
zolium; DPEPhos = oxybis(2,1-phenylene)bis(diphenylphosphine).
€
3085. (b) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12,
724–726. (c) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem.,
Int. Ed. 2009, 48, 201–204. (d) Ackermann, L.; Vicente, R. Org. Lett.
2009, 11, 4922–4925.
Org. Lett., Vol. 14, No. 7, 2012
1825

Scheme 3. CꢀH Bond Alkynylation Using Oxazoles 4
Scheme 4. CꢀH Bond Alkynylation on Benzothiazole (6)
With an optimized catalytic system in hand, we explored
its scope in the direct alkynylation of benzoxazole (1) using
differently substituted gem-dichloroalkenes 2 (Scheme 2).
Thereby, substituted alkynes 3 were obtained bearing
electron-withdrawing or -donating substituents on the
arenes, even when employing sterically congested, ortho-
substituted starting materials 2.
The optimized palladium catalyst was not restricted to
benzoxazoles 1 as the substrates. Indeed, the direct func-
tionalization of oxazoles 4 occurred with remarkably high
catalytic efficacy as well, which allowed for the modular
assembly of different heteroaryl alkynes 5(Scheme3). Here, a
variety of useful functional groups was well tolerated, thereby
also setting the stage for the preparation of alkynes 5 being
decorated with valuable heteroarenes, such as pyridines
(5kꢀ5q), furans (5r and 5s), or thiophenes (5tꢀ5w).
Finally, the catalytic direct CꢀH bond alkynylation of
benzothiazole (6) with gem-dichloroalkenes 2 was found to
be possible as well, provided that cocatalytic amounts of
CuI were employed as an additive (Scheme 4).
In summary, we have reported on the first CꢀH bond
alkynylations with user-friendly, inexpensive gem-dichloro-
alkenes as electrophiles, which enabled step-economical,
thus environmentally benign, direct functionalizations of
various heteroarenes with ample scope.
€
Acknowledgment. We thank Dr. Sebastian Barfusser
(Georg-August-Universitat Gottingen) for preliminary ex-
€
€
€
periments and Mr. Kris Runge (Georg-August-Universitat
Gottingen) for the synthesis of substrates. Support by the
€
CaSuS PhD program (fellowship to C.K.) is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
4ꢀ13), while LiOt-Bu resulted in being the base of choice
(entries14ꢀ18). As to the solvent, 1,4-dioxane (75%, entry 18)
proved superior when being compared to DMA (<2%),
NMP (<2%), meta-xylene (39%), or toluene (62%) under
otherwise identical reaction conditions.
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
1826
Org. Lett., Vol. 14, No. 7, 2012