Product Control using Substrate Design: Ruthenium-Catalysed Oxidative C?H Olefinations of Cyclic Weinreb Amides

Article abstract of DOI:10.1002/chem.201603126

A new class of Weinreb amides has been developed as directing groups for the ruthenium-catalysed regioselective oxidative C?H olefination. The new Weinreb amides successfully inhibit the N?O bond reductive cleavage usually associated with the cationic ruthenium system, thereby keeping intact the synthetic utility of Weinreb amides. Mechanistic studies reveal interesting aspects of the directing group capabilities of Weinreb amides when compared to simple amides of similar structures.

Full text of DOI:10.1002/chem.201603126

DOI: 10.1002/chem.201603126
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Organic Chemistry |Hot Paper|
Product Control using Substrate Design: Ruthenium-Catalysed
Oxidative CÀH Olefinations of Cyclic Weinreb Amides
Riki Das and Manmohan Kapur*[a]
Abstract: A new class of Weinreb amides has been devel-
oped as directing groups for the ruthenium-catalysed regio-
selective oxidative CÀH olefination. The new Weinreb
amides successfully inhibit the NÀO bond reductive cleavage
usually associated with the cationic ruthenium system,
thereby keeping intact the synthetic utility of Weinreb
amides. Mechanistic studies reveal interesting aspects of the
directing group capabilities of Weinreb amides when com-
pared to simple amides of similar structures.
Introduction
Often, various directing groups are employed in this reaction
to effect a site-selective CÀH activation.[7] Recently, Weinreb
amides have emerged as versatile directing groups, owing to
their inherent synthetic utility. Further, the use of external oxi-
dant could be avoided by utilising the sensitive NÀO bond of
the Weinreb amide as an internal oxidant.[8–10] However, the
synthetic identity of Weinreb amides is lost if the N-alkoxyl
group is missing and such a synthetic methodology may not
be useful if further utility of the Weinreb amide is desirable
after the CÀH functionalisation reaction. In this regard, Wang
and co-workers have reported a rhodium-catalysed oxidative-
Heck of aryl Weinreb amides in which they used activated ole-
fins like acrylates as coupling partners.[8c] Wang[9a] and
Huang[9b] both reported palladium-catalysed double functional-
isation in the synthesis of isoquinolines. In these reports as
well as some other transformations, the sensitive NÀO alkoxyl
group survived the reaction conditions.[9] In continuation to
our work in the area of CÀH functionalisation,[11] we disclose
herein, a new class of cyclic Weinreb amides which retain their
synthetic utility upon ruthenium-catalysed oxidative Heck reac-
tion. In a previously reported work, we had used simple Wein-
reb amides as substrates in the ruthenium-catalysed oxidative-
Heck reaction (Scheme 2).[11f]
Weinreb amides[1] are important building blocks in organic syn-
thesis. Their versatile utilities are well reported in literature.[2]
Nucleophilic addition to the Weinreb amides results in
a unique and stable five membered cyclic tetrahedral inter-
mediate which prevents the over-addition, leading to a selec-
tive transformation (Scheme 1).[3] The Mizoroki–Heck reaction[4]
is one of the most remarkable discoveries in the field of CÀC
bond forming processes. An attractive improvisation of this re-
action is the oxidative coupling of unactivated aryl CÀH bonds
with olefins, termed the Fujiwara–Moritani or the oxidative-
Heck reaction.[5] Not limited only to palladium, other transition
metals have been successfully incorporated to expand the syn-
thetic utility of this transformation.[6]
Scheme 1. Synthetic utility of Weinreb amides.
[a] R. Das, Dr. M. Kapur
Department of Chemistry
Indian Institute of Science Education and Research Bhopal
Bhopal Bypass Road, Bhauri, Bhopal 462066, MP (India)
E-mail: mk@iiserb.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603126.
Scheme 2. Product control using substrate structure design.
Chem. Eur. J. 2016, 22, 1 – 6
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Although we had obtained very good transformation in the
form of ortho-olefinated products, the Weinreb amide func-
tionality was lost, with the N-alkoxyl group being reductively
cleaved to result in products that were ordinary amides.
Table 2. Substrate scope for seven-membered cyclic Weinreb amides.[a]
Results and Discussion
Our ultimate aim was to develop a substrate system where the
Weinreb amide functionality would be unaffected at the end
of the ruthenium-catalysed Fujiwara–Moritani reaction. In our
previous work we had used five-membered cyclic Weinreb
amides, along with simple ones. In almost all cases, we had ob-
tained the ring-opened products. We postulated that the
reason for this was the facile insertion of the metal into the NÀ
O bond at the later stage of the reaction pathway. We there-
fore envisaged that inhibition of this insertion could lead us to
the products, in which the Weinreb amide functionality would
be retained at the end of the CÀH functionalisation. One way
to do this would be to make this insertion product relatively
higher in energy and this would need a change in the struc-
ture of the substrate. To our delight, under our previously opti-
mised reaction conditions,[11f] when the ring size was increased
from five-membered isoxazolidine to higher ring sizes (six-
membered oxazinane and seven membered oxazepane), it re-
sulted in a clean conversion to the CÀH olefination product
without the destruction of the Weinreb amide functionality
(Table 1 and Table 2).
[a] All yields are isolated yields.
fected by the reaction conditions. Notably, the reaction did not
work with electron-neutral olefins. It was not unexpected
though, given the reactivity trend usually observed either for
the Heck or the oxidative-Heck reactions. A plausible mecha-
nism for this transformation is depicted in Scheme 3. The first
step is usually the generation of the cationic ruthenium com-
plex. Complexation of the metal to the more Lewis-basic
amide carbonyl oxygen followed by the acetate-assisted CÀH
activation leads to the ruthenacycle. Interestingly, two different
pathways are possible, one involving a 5-membered ruthena-
cycle arising out of coordination to the carbonyl oxygen (B in
Scheme 3) and another pathway incorporating the 6-mem-
bered ruthenacycle arising out of coordination to the ring
oxygen (E in Scheme 3).
Table 1. Substrate scope for six-membered cyclic Weinreb amides.[a]
[a] All yields are isolated yields.
The substrate scope was excellent and in most cases good
to moderate yield was observed. The regioselectivity was ex-
clusive and unlike the previous case,[11f] no diolefinated prod-
uct was observed. Electronic effects on both the coupling part-
ners were well tolerated. The reaction worked well with styr-
enes and other activated olefins. Halogen functionalities on
both the substrates were very well tolerated and were unaf-
Scheme 3. Plausible mechanism and two different modes of coordination.
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The first pathway is expected to dominate, due to the
higher relative stability of the 5-membered ruthenacycle. This
is followed by the coordination of the olefin, subsequent mi-
gratory insertion and then the b-hydride elimination.
ring-size Weinreb amides resist the NÀO bond cleavage. In this
mechanism, upon insertion into the NÀO bond, the resulting
ruthenacycle (H, Scheme 4) would be destabilised in higher
ring systems and therefore this insertion would be disfavoured
for the 6- and 7-membered Weinreb amides.
Release of AcOH followed by the oxidation of Ru0 to RuII re-
generates the active catalyst. Although there could be various
postulated pathways for the NÀO bond cleavage,[13a,b] we feel
that three pathways could be proposed (Scheme 4). In the first
pathway,[9b] an aldehyde by-product would be expected. Since
we do not observe this product in our reactions, this pathway
can be excluded. The second pathway,[9b] involving hydride-
transfer, would be unlikely and is expected to be a rather high-
energy pathway. The third pathway[13c–f] seems likely and can
provide a plausible explanation for the fact that the higher
To check the effect of the ring oxygen on the rate of the re-
action, a study of relative rates was conducted with the 6- and
7-membered cyclic amides (5a, 5b). The rate of reaction (initial
rates) of the 6- and 7-membered cyclic Weinreb amides (1a,
3a) was found to be lower than the corresponding piperidine
and azepane amides (5a,b, Scheme 5).
It is postulated that the ring-oxygen draws the electron den-
sity of the nitrogen towards itself, thus reducing the Lewis-ba-
sicity of the carbonyl oxygen. This would probably lead to
Scheme 4. Plausible pathways for the NÀO bond cleavage.
Scheme 5. Study of relative rates of reactions for the cyclic Weinreb amide and corresponding cyclic amides.
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a slightly weaker coordination of the carbonyl oxygen to the
metal as against that for the substrate with azepane, in turn
lowering the rate of the reaction. This also indicates that the
carbonyl of the regular amides possess better coordinating
ability than those of the Weinreb amides.
carried out in the absence of the coupling partner, deuterium
incorporation was significant, clearly indicating that the next
steps in the catalytic cycle were much faster than the reverse
reaction. This also indicated that in both the cases, the metala-
tion step was reversible.
Study of the kinetic isotope effect provided a moderate KIE
of 1.85 for the oxazepane amide and a value of 4.42 was ob-
tained for the azepane amide (Scheme 6).[14]
The synthetic utility of the cyclic Weinreb amides was dem-
onstrated by converting the functionalised products to the cor-
responding aldehydes and ketones with reactions of excess
lithium aluminium hydride and Grignard reagents, respectively,
with high yields (Scheme 8). This indicated that the functional-
ised six- and seven-membered cyclic Weinreb amides possess
the same synthetic potential as original Weinreb amides.
Conclusions
In summary, we have developed a new class of Weinreb
amides which are not only excellent directing groups but also
inhibit ruthenium-catalysed NÀO bond reductive cleavage to
provide CÀH olefination products, retaining the important
Weinreb amide functionality. The transformation is highly site-
selective, provides good to moderate yields of monoolefinated
products with a broad substrate scope and is expected to
have important synthetic utility for organic chemists. The rela-
tive-rate studies as well as deuterium-incorporation studies
provide insight into the pathway of the reaction and indicate
that the ruthenacycle formation is reversible, with the subse-
quent steps being faster, thereby driving the reaction in the
forward direction.
Scheme 6. Kinetic isotope effect studies (parallel reactions).
The acyclic Weinreb amide also afforded a moderate value
of 2.08 for the KIE. This indicated that the CÀH activation step
was probably proceeding through a concerted metalation de-
protonation (CMD) process.[15] To check whether the metalation
step was reversible, we carried out the reaction in the pres-
ence of D2O (Scheme 7). In general, the reaction was retarded
to some extent due to the presence of D2O. When the reac-
tions were carried out in the presence of the coupling partner,
low levels of deuterium incorporation were observed in the re-
covered starting materials. The products were devoid of any
deuterium incorporation in them. When the reactions were
Acknowledgements
Funding from DST-India (SB/S1/OC-10/2014) and CSIR-India
(02(205)/14/EMR-II) is gratefully acknowledged. R.D. thanks
Scheme 7. Reactions in the presence of D2O.
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Scheme 8. Retention of the synthetic utility of the Weinreb amides.
c) W. Yang, J. Wang, Z. Wei, Q. Zhang, X. Xu, J. Org. Chem. 2016, 81,
1675; d) S. L. Yedage, B. M. Bhanage, J. Org. Chem. 2016, 81, 4103;
e) R. S. Phathake, P. Patel, C. V. Ramana, Org. Lett. 2016, 18, 2828.
[10] For early work in this area, see: a) N. Guimond, C. Gouliaras, K. Fagnou,
J. Am. Chem. Soc. 2010, 132, 6908; b) S. Rakshit, C. Grohumann, T.
Besset, F. Glorius, J. Am. Chem. Soc. 2011, 133, 2350; c) N. Guimond, S. I.
Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133, 6449; d) L. Ackermann,
S. Fenner, Org. Lett. 2011, 13, 6548; e) B. Li, H. Feng, S. Xu, B. Wang,
Chem. Eur. J. 2011, 17, 12573; f) J. Karthikeyan, C.-H. Cheng, Angew.
Chem. Int. Ed. 2011, 50, 9880; Angew. Chem. 2011, 123, 10054; g) H.
Wang, C. Grohmann, C. Nimphius, F. Glorius, J. Am. Chem. Soc. 2012,
134, 19592; h) H. Wang, F. Glouris, Angew. Chem. Int. Ed. 2012, 51, 7318;
Angew. Chem. 2012, 124, 7430; i) R. Zeng, C. Fu, S. Ma, J. Am. Chem. Soc.
2012, 134, 9597; j) B. Li, J. Ma, N. Wang, H. Feng, S. Xu, B. Wang, Org.
Lett. 2012, 14, 736; k) X. Xu, Y. Liu, C.-M. Park, Angew. Chem. Int. Ed.
2012, 51, 9372; Angew. Chem. 2012, 124, 9506; l) H. Zhong, D. Yang, S.
Wang, J. Wang, Chem. Commun. 2012, 48, 3236; m) M. Jithunsa, M.
Ueda, N. Aoi, S. Sugita, T. Miyoshi, O. Miyata, Synlett 2013, 24, 475; n) F.
Yang, L. Ackermann, Org. Lett. 2013, 15, 718; o) F. Yang, L. Ackermann, J.
Org. Chem. 2014, 79, 12070; p) Z.-W. Chen, Y.-Z. Zhu, J.-W. Ou, Y.-P.
Wang, J.-Y. Zheng, J. Org. Chem. 2014, 79, 10988; q) S. Warratz, C. Korn-
haanb, A. Cajaraville, B. Niepotter, D. Stalke, L. Ackermann, Angew.
Chem. Int. Ed. 2015, 54, 5513; Angew. Chem. 2015, 127, 5604; r) A. Bech-
toldt, C. Tirler, K. Raghuvanshi, S. Warratz, C. Kornhaab, L. Ackermann,
Angew. Chem. Int. Ed. 2016, 55, 264; Angew. Chem. 2016, 128, 272.
[11] For selected contributions from our group, see: a) G. G. Pawar, G. Singh,
V. K. Tiwari, M. Kapur, Adv. Synth. Catal. 2013, 355, 2185; b) V. K. Tiwari,
G. G. Pawar, R. Das, A. Adhikary, M. Kapur, Org. Lett. 2013, 15, 3310;
c) V. K. Tiwari, G. G. Pawar, M. Kapur, Chem. Commun. 2014, 50, 7322;
d) V. K. Tiwari, N. Kamal, M. Kapur, Org. Lett. 2015, 17, 1766; e) G. G.
Pawar, V. K. Tiwari, H. S. Jena, M. Kapur, Chem. Eur. J. 2015, 21, 9905; f) R.
Das, M. Kapur, Chem. Asian J. 2015, 10, 1505; g) G. G. Pawar, A. Brahma-
nandan, M. Kapur, Org. Lett. 2016, 18, 448; h) G. S. Kumar, M. Kapur, Org.
Lett. 2016, 18, 1112.
UGC-India for a Research Fellowship. We thank CIF, IISERB for
the analytical data and Ms. Anusha Upadhyay, IISERB, for the X-
ray data. We also thank the Director, IISERB, for funding and in-
frastructure facilities.
Keywords: CÀH activation · CÀH functionalization · oxidative-
Heck · ruthenium · Weinreb amides
[1] S. Nahm, M. S. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
[2] For selected reviews on Weinreb amides, see: a) M. P. Sibi, Org. Prep.
Proced. 1993, 25, 15; b) M. Mentzel, M. H. Hoffmann, J. Prakt. Chem.
1997, 339, 517; c) J. Singh, N. Satyamurthi, I. S. Aidhen, J. Prakt. Chem.
2000, 342, 340; d) S. Balsubramanium, I. S. Aidhen, Synthesis 2008,
3707.
[3] a) M. Adler, S. Adler, G. Bouche, J. Phys. Org. Chem. 2005, 18, 193; b) B.
Qu, D. B. Collum, J. Org. Chem. 2006, 71, 7117.
[4] Recent reviews: a) S. Brase, A. De Meijere, in Metal-Catalyzed Cross-Cou-
pling Reactions (Eds.: A. De Meijere, F. Diederich), Wiley-VCH, Weinheim,
2004; pp. 217–315; b) The Mizoroki-Heck Reaction (Ed.: M. Oestrtreich),
Wiley, Chichester, 2009.
[5] a) Y. Fujiwara, I. Moritani, S. Danno, R. Asano, S. Teranishi, J. Am. Chem.
Soc. 1969, 91, 7166; b) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1997,
38, 1119.
[6] For reviews on this topic see: a) C. Jia, T. Kitamura, Y. Fujiwara, Acc.
Chem. Res. 2001, 34, 633; b) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111,
1170; c) S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4, 886; d) Y.
Wu, J. Wang, F. Mao, F. Y. Kwong, Chem. Asian J. 2014, 9, 26; e) L. Zhou,
W. Lu, Chem. Eur. J. 2014, 20, 634.
[7] Some selected reviews on CÀH functionalisation and use of directing
groups, see: a) A. E. Shilov, G. B. Shul’pin, Chem. Rev. 1997, 97, 2879;
b) S. S. Stahl, J. A. Labinger, J. E. Bercaw, Angew. Chem. Int. Ed. 1998, 37,
2180; Angew. Chem. 1998, 110, 2298; c) J. A. Labinger, J. E. Bercaw,
Nature 2002, 417, 507; d) R. G. Bergman, Nature 2007, 446, 391; e) F. Ka-
kiuchi, T. Kochi, Synthesis 2008, 3013; f) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; Angew. Chem.
2009, 121, 5196; g) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev.
2010, 110, 624; h) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147;
i) J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40,
4740; j) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012,
45, 788; k) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369; l) M.
Moselage, L. Ackermann, ACS Catal. 2016, 6, 498.
[12] >CCDC 1043523 (4h) contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[13] a) W. Guo, Y. Xia, J. Org. Chem. 2015, 80, 8113; b) L. Du, Y. Xu, S. Yang, J.
Li, X. Fu, J. Org. Chem. 2016, 81, 1921; c) T. Zhou, W. Guo, Y. Xia, Chem.
Eur. J. 2015, 21, 9209; d) S. Wu, R. Zeng, C. Fu, Y. Yu, X. Zhang, S. Ma,
Chem. Sci. 2015, 6, 2275; e) S. R. Neufeldt, G. Jimenez-Oses, J. R. Huck-
ins, O. R. Thiel, K. N. Houk, J. Am. Chem. Soc. 2015, 137, 9843; f) Y.-F.
Yang, K. N. Houk, Y.-D. Wu, J. Am. Chem. Soc. 2016, 138, 6861.
[14] The deuterated Weinreb amides were synthesised from benzoic
[D5]acid, see the Supporting Information for details.
[15] a) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
10848; b) D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118, and refer-
ences therein.
[8] a) J. W. Wrigglesworth, B. Cox, G. C. Llyod-Jones, K. I. Brooker-Milburn,
Org. Lett. 2011, 13, 5326; b) D.-D. Li, T.-T. Yuan, G.-W. Wang, Chem.
Commun. 2011, 47, 12789; c) Y. Wang, C. Li, Y. Li, F. Yin, X.-S. Wang, Adv.
Synth. Catal. 2013, 355, 1724; d) S.-S. Zhang, J.-Q. Wu, Y.-X. Lao, X.-G.
Liu, Y. Liu, W.-X. Lv, D.-H. Tan, Y.-F. Zeng, H. Wang, Org. Lett. 2014, 16,
6412.
[9] a) G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem. Int. Ed. 2011, 50, 1380;
Angew. Chem. 2011, 123, 1416; Angew. Chem. 2011, 123, 1416; b) S. Lu,
Y. Lin, H. Zhong, K. Zhao, J. Huang, Tetrahedron Lett. 2013, 54, 2001;
Received: June 30, 2016
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FULL PAPER
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Organic Chemistry
R. Das, M. Kapur*
&& – &&
Product Control using Substrate
Design: Ruthenium-Catalysed
Oxidative CÀH Olefinations of Cyclic
Weinreb Amides
In the right direction: A new class of
Weinreb amides has been developed as
directing group for the ruthenium-cata-
lysed regioselective oxidative CÀH ole-
fination (see scheme). The new Weinreb
amides successfully inhibit the NÀO
bond reductive cleavage usually associ-
ated with the cationic ruthenium
system, thereby keeping intact the syn-
thetic utility of Weinreb amides. Mecha-
nistic studies reveal interesting aspects
of the directing group capabilities of
Weinreb amides when compared to
simple amides of similar structures.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!