Ruthenium-catalyzed C-h oxygenation on aryl Weinreb amides

Article abstract of DOI:10.1021/ol303520h

Versatile ruthenium catalysts enabled unprecedented C-H bond oxygenations of aryl Weinreb amides with ample scope under exceedingly mild reaction conditions, thereby also giving access to valuable ortho-hydroxylated aldehydes. Mechanistic studies provided strong support for a kinetically relevant C-H bond activation.

Full text of DOI:10.1021/ol303520h

ORGANIC
LETTERS
2013
Vol. 15, No. 3
718–720
Ruthenium-Catalyzed CꢀH Oxygenation
on Aryl Weinreb Amides
Fanzhi Yang and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received December 22, 2012
ABSTRACT
Versatile ruthenium catalysts enabled unprecedented CꢀH bond oxygenations of aryl Weinreb amides with ample scope under exceedingly mild
reaction conditions, thereby also giving access to valuable ortho-hydroxylated aldehydes. Mechanistic studies provided strong support for a
kinetically relevant CꢀH bond activation.
N-Methoxy-N-methylamides;Weinreb amides;
represent functional groups of key importance in synthetic
organic chemistry, because they are easily accessible, and
because they can be chemoselectively transformed into
the corresponding ketones and aldehydes.1 Thus, these
amides have found numerous applications in organic
synthesis,1 as, for instance, illustrated by the preparation
of naturally occurring bioactive compounds.2 In contrast,
Weinreb amides have unfortunately been less explored for
metal-catalyzed CꢀH bond functionalizations,3 and direct
oxygenations4,5 of aryl Weinreb amides have, to the best of
our knowledge, thus far proven elusive. Within our re-
search program on sustainable ruthenium-catalyzed CꢀH
bond functionalization,6 we developed site selective C(sp2)ꢀH
bond oxygenations on aryl Weinreb amides under remark-
ably mild reaction conditions, on which we report herein.
At the outset of our studies, we tested different terminal
oxidants for the envisioned CꢀH bond oxygenation of
Weinreb amide 1a (Table 1). The transformation failed to
proceed in the absence of a stoichiometric oxidant or of a
ruthenium complex (entries 1 and 2). Likewise, copper(II)
or silver(I) oxidants were found to be ineffective (entries 3
and 4). In contrast, m-CPBA, K2S2O8, or PhI(OAc)2
proved to be viable alternatives (entries 5ꢀ7), with optimal
results being accomplished with the hypervalent iodine(III)
reagent PhI(OAc)2 at a reaction temperature of 50 °C
(1) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–
3818. Reviews: (b) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008,
3707–3738. (c) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997,
339, 517–524.
(2) Sected representative examples: (a) Paek, S.-M.; Seo, S.-Y.; Kim,
S.-H.; Jung, J.-W.; Lee, Y.-S.; Jung, J.-K.; Suh, Y.-G. Org. Lett. 2005, 7,
3159–3162. (b) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2008,
10, 4489–4492. (c) Shimizu, T.; Satoh, T.; Murakoshi, K.; Sodeoka, M.
Org. Lett. 2005, 7, 5573–5576. See also refs 1b, 1c.
(3) Illustrative recent reviews: (a) Arockiam, A. P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879–5918. (b) Hirano, K.; Miura,
M. Chem. Commun. 2012, 48, 10704–10714. (c) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (d) Ackermann,
L. Chem. Rev. 2011, 111, 1315–1345. (e) Satoh, T.; Miura, M. Chem.;
Eur. J. 2010, 16, 11212–11222. (f) Ackermann, L.; Vicente, R.; Kapdi, A.
Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (g) Thansandote, P.;
Lautens, M. Chem.;Eur. J. 2009, 15, 5874–5883 and references cited
therein. For a representative example, see: (h) Wang, D.-H.; Wasa, M.;
Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190–7191.
(4) Recent reviews on C(sp2)ꢀO bond forming reactions: (a) Enthaler,
S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912–4924. (b) Alonso, D. A.;
Najera, C.; Pastor, I. M.; Yus, M. Chem.;Eur. J. 2010, 16, 5274–5284. (c)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169 and
references cited therein.
(5) Representative examples of metal-catalyzed direct oxygenations:
(a) Mo, F.; Trzepkowski, L. J.; Dong, G. Angew. Chem., Int. Ed. 2012,
51, 13075–13079. (b) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem.,
Int. Ed. 2012, 51, 13070–13074. (c) Thirunavukkarasu, V. S.; Ackermann,
L. Org. Lett. 2012, 14, 6206–6209. (d) Yang, Y.; Lin, Y.; Rao, Y. Org.
Lett. 2012, 14, 2874–2877. (e) Thirunavukkarasu, V. S.; Hubrich, J.;
Ackermann, L. Org. Lett. 2012, 14, 4210–4213. (f) Jiang, T.-S.; Wang,
G.-W. J. Org. Chem. 2012, 77, 9504–9509. (g) McNeill, E.; Du Bois, J.
Chem. Sci. 2012, 3, 1810–1813. (h) McMurtrey, K. B.; Racowski, J. M.;
Sanford, M. S. Org. Lett. 2012, 14, 4094–4097. (i) Li, W.; Sun, P. J. Org.
Chem. 2012, 77, 8362–8366. (j) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2012, 134, 134–137. (k) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem.;
Eur. J. 2012, 18, 5541–5545. (l) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 14654–14655. (m) Dick, A. R.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301. (n) Liang, J.-L.; Yuan,
S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002,
41, 3465–3468. (o) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996,
108, 35–40 and references cited therein.
r
10.1021/ol303520h
Published on Web 01/22/2013
2013 American Chemical Society

(entries 7ꢀ10). It is important to note that this consti-
tutes the lowest reaction temperature reported thus far
for ruthenium-catalyzed C(sp2)ꢀH bond oxygenations.
[RuCl2(PPh3)3] could be employed as the catalyst as well
but furnished the desired product 2a in a diminished yield
(entry 11). However, the well-defined ruthenium(II) bis-
carboxylate complex [Ru(O2CMes)2(p-cymene)]7,8 com-
pared favorably with [RuCl2(p-cymene)]2 (entries 12 and
13). Generally, the ruthenium catalysts were found to be
highly robust, as showcased by all catalytic reactions being
performed without strict exclusion of moisture under an
atmosphere of air. Yet, the CꢀH bond oxygenation also
occurred readily under an inert N2 atmosphere (entry 14).
Scheme 1. Variation of the Amide Substitution Pattern
Table 1. Optimization of CꢀH Bond Oxygenationa
entry
oxidant
temp (°C)
yield
1
ꢀ
50
50
50
50
50
50
30
50
80
100
50
50
50
50
ꢀ
important electrophilic functional groups, including chloro,
bromo, or iodo substituents as well as a benzyl chloride.
Intramolecular competition experiments with meta-sub-
stituted arenes 1 highlighted steric effects to primarily
influence the site selectivity of the CꢀH bond functiona-
lization with methyl-substituted substrate 1p (Scheme 3).
Contrarily, meta-fluoro-substituted arene 1q led to signifi-
cant amounts of product 2q00.
Given the high catalytic activity of our ruthenium complex,
we became interested in performing mechanistic studies to
rationalize its working mode. To this end, intermolecular
competition experiments with arenes 1 showed electron-rich
substrates to be preferentially functionalized (Scheme 4).
b
2
K2S2O8
ꢀ
3
Cu(OAc)2 H2O
ꢀ
3
4
AgOAc
<5%c
39%
57%
30%
84%
60%
54%
57%d
80%e
76%f
79%g
5
m-CPBA
6
K2S2O8
7
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
8
9
10
11
12
13
14
a Reaction conditions: 1a (0.5 mmol), [RuCl2(p-cymene)]2 (2.5 mol %),
oxidant (0.5 mmol), TFA/TFAA (2.0 mL; 3/1); isolated yields. b No
catalyst. c GC conversion. d [RuCl2(PPh3)3] (5.0 mol %). e [Ru(O2CMes)2-
(p-cymene)] (2.5 mol %). f [RuCl2(p-cymene)]2 (1.3 mol %). g Under N2.
(8) Selected recent examples of carboxylate assistance in oxidative
ruthenium-catalyzed CꢀH bond functionalizations: (a) Ma, W.; Graczyk,
K.; Ackermann, L. Org. Lett. 2012, 14, 6318–6321. (b) Singh, K. S.;
Dixneuf, P. H. Organometallics 2012, 31, 7320–7323. (c) Zhao, P.; Wang,
F.; Han, K.; Li, X. Org. Lett. 2012, 14, 5506–5509. (d) Parthasarathy, K.;
Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14,
3478–3481. (e) Li, J.; Kornhaass, C.; Ackermann, L. Chem. Commun.
2012, 48, 11343–11345. (f) Kornhaass, C.; Li, J.; Ackermann, L. J. Org.
Chem. 2012, 77, 9190–9198. (g) Li, B.; Devaraj, K.; Darcel, C.; Dixneuf,
P. H. Green Chem. 2012, 14, 2706–2709. (h) Thirunavukkarasu, V. S.;
Donati, M.; Ackermann, L. Org. Lett. 2012, 14, 3416–3419. (i) Kishor,
P.; Jeganmohan, M. Org. Lett. 2012, 14, 1134–1137. (j) Li, B.; Ma, J.;
Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14, 736–739. (k)
Hashimoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.; Miura, M.
Chem. Lett. 2012, 41, 151–153. (l) Chinnagolla, R. K.; Jeganmohan, M.
Chem. Commun. 2012, 48, 2030–2032. (m) Ackermann, L.; Pospech, J.;
Graczyk, K.; Rauch, K. Org. Lett. 2012, 14, 930–933. (n) Ackermann,
L.; Lygin, A. V. Org. Lett. 2012, 14, 764–767. (o) Ackermann, L.; Wang,
L.; Lygin, A. V. Chem. Sci. 2012, 3, 177–180. (p) Hashimoto, Y.;
Ueyama, T.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1165–1166. (q) Ackermann, L.; Fenner, S. Org. Lett.
2011, 13, 6548–6551. (r) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13,
4153–4155. (s) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett.
2011, 13, 3278–3281. (t) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–708. (u) Ackermann,
L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379–6382.
Withan effective catalytic system in hand, westudied the
influence of the amide N-substitution pattern on the
efficacy of the CꢀH bond oxygenation (Scheme 1). No-
tably, a variety of groups on the amides was well tolerated
by the catalytic system to furnish the corresponding pro-
ducts 2bꢀ2h, even when being sterically hindered.
Subsequently, we evaluated the versatility of the CꢀH bond
oxygenation with Weinreb amides 1 bearing substituents
on the aromatic moiety (Scheme 2). The catalytic system
showed high chemoselectivity, in that it fully tolerated
(6) Recent reviews: (a) Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann,
L. Catal. Sci. Technol. 2013, 3, DOI:10.1039/C2CY20505J. (b) Ackermann,
L. Isr. J. Chem. 2010, 50, 652–663. (c) Ackermann, L.; Potukuchi, H. K. Org.
Biomol. Chem. 2010, 8, 4503–4513. (d) Ackermann, L. Pure Appl. Chem.
2010, 82, 1403–1413.
(7) For the use of [Ru(O2CMes)2(p-cymene)] in direct alkylations or
arylations, see: (a) Ackermann, L.; Pospech, J.; Potukuchi, H. K. Org. Lett.
2012, 14, 2146–2149. (b) Ackermann, L.; Vicente, R.; Potukuchi, H. K.;
ꢀ
(v) Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K.
ꢀ
Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (c) Ackermann, L.; Novak, P.;
Vicente, R.; Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045–6048.
Synthesis 2010, 2245–2253. (w) A review: Kozhushkov, S. I.; Ackermann,
L. Chem. Sci. 2013, 4, DOI:10.1039/C2SC21524A.
Org. Lett., Vol. 15, No. 3, 2013
719

Scheme 2. Scope of CꢀH Oxygenation of Weinreb Amides 1
Scheme 4. Intermolecular Competition Experiment
Scheme 5. CꢀH Oxygenation with Labled Substrate [D5]-1a
Scheme 3. Reactions of meta-Substituted Weinreb Amides 1
Scheme 6. CꢀH Fuctionalization with Substrates 1a and [D5]-1a
Scheme 7. Synthesis of ortho-Hydroxybenzaldehyde 3a
Catalytic oxygenations of labeled Weinreb amide [D5]-
1a were suggestive of an irreversible CꢀH bond metalation
event (Scheme 5).
Additionally, more detailed studies with substrate [D5]-
1a provided strong support for a kinetically relevant CꢀH
bond metalation with a kinetic isotope effect (KIE) of kH/
kD ≈ 3.0 (Scheme 6).
Acknowledgment. Support by the Chinese Scholarship
Council (fellowship to F.Y.), the CaSuS PhD program,
AstraZeneca, and the European Research Council under
the European Community’s Seventh Framework Program
(FP7 2007ꢀ2013)/ERC Grant Agreement No. 307535 is
gratefully acknowledged.
Finally, the practical importance of CꢀH bond oxygena-
tions on aryl Weinreb amides 1 was illustrated by the high
yielding preparation of the corresponding ortho-hydroxy-
benzaldehydes (Scheme 7), which are as of yet not accessible
via direct CꢀH bond oxygenation methods.4,5
In summary, we have reported on the first CꢀH bond
oxygenation of aryl Weinreb amides. Thus, a versatile
ruthenium catalyst allowed for the step- and atom-
economical synthesis of ortho-hydroxylated Weinreb amides
with a broad scope, occurring under exceedingly mild
reaction conditions. Mechanistic studies were suggestive
of an irreversible kinetically relevant CꢀH bond activation.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
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.
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Org. Lett., Vol. 15, No. 3, 2013