Ru(II)-Catalyzed Oxidative Heck-Type Olefination of Aromatic Carboxylic Acids with Styrenes through Carboxylate-Assisted C-H Bond Activation

Article abstract of DOI:10.1021/acs.orglett.7b03852

A straightforward synthesis of 2-styrylbenzoic acids from aryl carboxylic acids is disclosed through a carboxylate-assisted coupling under Ru(II) catalysis. This protocol is simple and exhibits broad scope with high tolerance of common organic functional

Full text of DOI:10.1021/acs.orglett.7b03852

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ru(II)-Catalyzed Oxidative Heck-Type Olefination of Aromatic
Carboxylic Acids with Styrenes through Carboxylate-Assisted C−H
Bond Activation
Suman Dana, Anup Mandal, Harekrishna Sahoo, Sumitava Mallik, Gowri Sankar Grandhi,
and Mahiuddin Baidya*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: A straightforward synthesis of 2-styrylbenzoic acids from aryl carboxylic
acids is disclosed through a carboxylate-assisted coupling under Ru(II) catalysis. This
protocol is simple and exhibits broad scope with high tolerance of common organic
functional groups, providing good to excellent yields of diverse olefinated products. The
efficacy of this protocol has been showcased through sequential syntheses of isochromanone, isocoumarin, and formal synthesis
of anacardic acid derivative in good yields.
lkenyl aromatic carboxylic acids, such as 2-styrylbenzoic
acid and derivatives thereof, have profound synthetic
importance in light of their existence in many natural products,
agrochemicals, pharmaceuticals, and functional materials (Figure
1).1 They are also high-value synthons for the production of a
developed by exploiting the complex-induced proximity effect
with weakly coordinating and synthetically valuable common
organic functional groups.6b,c While significant advancements on
Ru(II)-catalyzed oxidative Heck-type coupling have been
accomplished using aromatic amides, esters, anilides, carbamates,
and phenol derivatives,7,8 similar examples with aromatic
carboxylic acids are limited (Scheme 1).9 Furthermore, in a
A
Scheme 1. Ru-Catalyzed Direct Styrenylation of Benzoic
Acids
Figure 1. Biologically important 2-styrylbenzoic acid derivatives.
large number of commodity chemicals and complex molecular
architectures including clinical drug candidates.2 Consequently,
devising synthetic protocols toward these scaffolds has remained
the focus of general interest. Traditionally, they have been
accessed through multistep Wittig and Peterson olefination
processes.2j−l Although hydroarylation of alkynes3 and Mizor-
oki−Heck coupling1b of aryl halides are predominant for the
synthesis of vinyl arenes, the requirement of prefunctionalized
starting materials limits their scope toward this pivotal
framework. A straightforward route would be the direct coupling
of styrenes with benzoic acids. This approach is advantageous
because benzoic acids are inexpensive chemicals with diverse
substitution patterns, and styrenes are easily accessible reaction
partners. Further, the carboxylic acid functionality can be easily
manipulated into various functional groups and also tracelessly
removed through protodecarboxylation.4
majority of the cases, the choice of coupling partners is largely
limited to activated acrylates and only a handful of examples are
known with styrene derivatives.7 There are no reports for the
synthesis of 2-styrylbenzoic acids using Ru(II) catalysis.
In our program on the development of ruthenium-catalyzed
C−H bond activation protocols with the aid of weakly
In the past two decades, synthetic chemists have witnessed a
radical shift beyond the conventional synthesis toward direct use
of otherwise unactivated C−H bonds for the functionalization of
organic molecules.5 In this context, Ru(II)-catalyzed reactions
turned out to be very promising.6 A series of new trans-
formations, particularly oxidative Heck-type coupling, have been
Received: December 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03852
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coordinating groups,10 we envisaged a strategic coupling of
styrenes with arene carboxylic acids for the synthesis of 2-
styrylbenzoic acids (Scheme 1). Aromatic carboxylic acid, on
exposure to Ru(II) catalyst, can form ruthenacycle A, which can
subsequently undergo facile migratory insertion with styrenes
followed by β-hydride elimination to forge the desired product.
However, an appropriate reaction condition is necessary to
nullify competitive heterocyclization,11a hydroarylation,11b and
decarboxylation11c processes.
a
Scheme 2. Ru-Catalyzed Mono-olefination of Benzoic Acids
We instigated our investigation employing commercially
available 2-toluic acid (1a) and styrene (2a) as model substrates.
Gratifyingly, when 1a was reacted to styrene 2a in the presence of
[Ru(p-cymene)Cl2]2 (5 mol %), K2HPO4 (1.0 equiv), and CuO
(2.0 equiv) in MeOH solvent at 85 οC for 24 h, oxidative Heck-
coupling proceeded smoothly, and the desired product 3a was
obtained in 84% isolated yield after esterification (Table 1, entry
a
Table 1. Optimization of Reaction Conditions
entry
deviation from final catalytic conditions
yield of 3a
1
none
84%
2
without Ru(II)
3
without CuO
18%
trace
73%
4
without K2HPO4
5
NaOAc instead of K2HPO4
NaOOCMes instead of K2HPO4
Cu(OAc)2 instead of CuO
DMF instead of MeOH
H2O instead of MeOH
1,4-dioxane instead of MeOH
at 75 οC
b
6
mixture
7
31%
trace
trace
trace
76%
85%
8
9
10
11
12
styrene (4.0 equiv)
a
Reaction conditions: 1 (0.15 mmol), styrene (2.0 equiv), [Ru(p-
cymene)Cl2]2 (5 mol %), K2HPO4 (1.0 equiv), CuO (2.0 equiv),
MeOH (0.5 mL) at 85 οC for 24 h; then K2CO3(2.0 equiv), MeI (3.0
equiv), MeCN (1.0 mL) at room temperature for 4 h; olefination
reactions were performed under aerial atmosphere in a screw cap
reaction tube, and esterification was performed for the ease of
b
purification via column chromatography. Complex mixture of
uncharacterized compounds.
a
1). It is worth noting that products of other competitive
processes depicted in Scheme 1 were not detected under the
reaction conditions. Control experiments indicated that all the
reagents are necessary for efficient product formation, and
ruthenium−copper synergy plays a key role in the transformation
(entries 2−4). Alteration of bases provided inferior results
(entries 5−6). When CuO was replaced with Cu(OAc)2, yield
decreased from 84% to 31% (entry 7). Screening of various
organic solvents revealed MeOH as the optimal solvent (entries
8−10). Deterioration in reaction yield was observed when the
reaction was performed at lower temperature (entry 11). Further
increase of styrene stoichiometry resulted in a negligible
improvement in reaction yield (Table 1, entry 12).
Reaction conditions: 1 (0.15 mmol), styrene (2.0 equiv), [Ru(p-
cymene)Cl2]2 (5 mol %), K2HPO4 (1.0 equiv), CuO (2.0 equiv),
MeOH (0.5 mL) at 85 οC for 24 h; then K2CO3 (2.0 equiv), MeI (3.0
equiv), MeCN (1.0 mL) at room temperature for 4 h; olefination
reactions were performed under aerial atmosphere in a screw cap
b
reaction tube. Reactions were performed using 1.5 equiv of styrene,
where bis-olefination products were also obtained in 15% and 11%
c
yields for 3h and 3i, respectively. Allylation of carboxylic acid and
hydroxyl functionalities were performed using allyl bromide (3.0
d
equiv) instead of MeI. Esterification was performed using NaH (1.2
equiv), MeI (3.0 equiv), THF, 0 °C−rt under N2 atmosphere.
good yields of desired products (3a−i, 44−84%). Disubstituted
benzoic acids also underwent smooth transformation, producing
3j−l in 61−91% yields. Reactions of α- and β-naphthoic acids
proceeded regioselectively at the less sterically hindered site,
rendering monostyrylated products 3m and 3n in 84% and 87%
yields, respectively. Olefination was also successful with 4-
Having established the suitable conditions, we next explored
the scope of the reaction (Scheme 2). The reaction is quite
general, and a series of benzoic acids having electron donating or
withdrawing substitutions at ortho-, meta-, and para-positions
effectively participated in this reaction, affording moderate to
B
DOI: 10.1021/acs.orglett.7b03852
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bromostyrene producing 3o in 53% yield. Interestingly, benzoic
acid bearing acetyl group at 3-position offered 63% yield of
olefinated product 3p. To our delight, salicylic acid possessing
free hydroxy group was also a good substrate for this process,
furnishing 3q in 65% yield. Notably, the presence of 4-acetamido
functionality (3r), a known weakly coordinating directing group
in C−H bond activation reactions, did not inhibit the reactivity
and selectively furnished the mono-olefination at the ortho-
position of the carboxylic acid group.12
Scheme 4. Sequential Synthesis of Isochromanone and
Isocoumarin
The importance of 2-styrylbenzoic acids was showcased
through the isolation of 2-styrylated free carboxylic acid
derivatives 3aa and 3ma in 85% and 92% yields, respectively.
Reactions were also fruitful with other styrene derivatives; 1-
naphthtyl (3ab), 3-phenoxy (3ac), and 3-methoxy (3ad)
derivatives of styrene gave synthetically useful yields of desired
carboxylic acids. However, catalytic conditions were ineffective
for strongly electron withdrawing nitro- (3sa) and cyano-
substituted (3ta) benzoic acids.
crude 3aa with catalytic amount of diphenyl diselenide in the
presence of bis(trifluoroacetoxy)iodobenzene (PIFA) in 58%
yield (Scheme 4).15c
To extend the applicability of the Ru(II)-catalyzed Heck-type
olefination methodology, formal synthesis of anacardic acid
derivative was accomplished (Scheme 5).16 Thus, reaction of
While the catalytic conditions are generally suitable for mono-
olefination process, minor bis-olefinated products were also
detected specifically in case of benzoic acids having electron-
donating substitution at the para-position (Scheme 2, 3h,i).
Intrigued by the importance of conjugated vinyl arenes in
chemical and material sciences,13 we reinvestigated the protocol
toward the synthesis of bis-olefinated benzoic acids. Pleasingly,
when para-substituted benzoic acids were treated with excess
styrene (3.5 equiv) under standard conditions, bis-styrylated
products 4a−d were obtained in 53−69% yields (Scheme 3).
Scheme 5. Formal Synthesis of Anacardic Acids
Scheme 3. Ruthenium-Catalyzed Diolefination of Benzoic
a
Acids
commercially available salicylic acid with alkene 2b rendered the
key intermediate 3pb, a ginkgolic acid analogue, in 62% isolated
yield. The reduction of 3pb to anacardic acid derivative was a
procedure reported in the literature.16
In conclusion, we have developed a straightforward Heck-type
styrylation of aromatic carboxylic acids based on Ru(II)-
catalyzed weak coordination assisted coupling. The catalytic
reaction is operationally simple, highly regioselective, and
provides direct access to versatile 2-styrylbenzoic acids in good
to excellent yields. The present protocol is also viable toward
functionalization of salicylic acid derivatives. It is also interesting
to note that the weak coordination of the acid group is effective in
the presence of acetamido functionality under the catalytic
conditions.
a
Reaction conditions: 1 (0.15 mmol), styrene (3.5 equiv), [Ru(p-
ASSOCIATED CONTENT
■
cymene)Cl2]2 (5 mol %), K2HPO4 (1.0 equiv), CuO (2.0 equiv),
MeOH (0.5 mL) at 85 οC for 24 h; then K2CO3 (2.0 equiv), MeI (3.0
equiv), MeCN (1.0 mL) at room temperature for 4 h; olefination
reactions were performed under aerial atmosphere in a screw cap
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03852.
b
reaction tube. Allyl bromide (3.0 equiv) was used instead of MeI.
Experimental details and NMR spectra (PDF)
Substitutions such as bromo (4d) and free-hydroxy (4e) were
well-tolerated in the reaction. Reactions with heteroaromatic
carboxylic acid such as thiophene-3-carboxylic acid gave the
product 4f in 33% yield.14
Synthetic utility of the process was highlighted through the
functionalization of styrylated benzoic acids. Accordingly, the
crude product 3aa, obtained from the reaction of 1a with 2a
under optimized conditions, was exposed to conc. H2SO4, and
the isochromanone15a 5 was obtained in 70% yield (Scheme 4).
Similarly, isocoumarin15b 6 was prepared by the treatment of
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mbaidya@iitm.ac.in.
ORCID
Mahiuddin Baidya: 0000-0001-9415-7137
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b03852
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) (a) Nandi, D.; Ghosh, D.; Chen, S.; Kuo, B.; Wang, N. M.; Lee, H.
M. J. Org. Chem. 2013, 78, 3445. (b) Li, J.; Ackermann, L. Org. Chem.
Front. 2015, 2, 1035. (c) Kumar, N. Y. P.; Bechtoldt, A.; Raghuvanshi,
K.; Ackermann, L. Angew. Chem., Int. Ed. 2016, 55, 6929.
(12) Reactions of acetophenone and acetanilide under the optimized
conditions were not productive with the recovery of respective starting
materials.
ACKNOWLEDGMENTS
■
We gratefully acknowledge CSIR New Delhi for the financial
support (02(0212)/14/EMR-II). S.D., H.S., and S.M. acknowl-
edge IIT-Madras for providing HTRA Fellowship. A.M. and
G.S.G. acknowledge UGC for SRF. We also thank the
Department of Chemistry, IIT-Madras for instrumental facilities.
(13) Cheng, Y.; Yang, S.; Hsu, C. Chem. Rev. 2009, 109, 5868.
(14) Reactions of indole-2-carboxyic acid and benzofuran-2-carboxylic
acid were very sluggish, and reaction outcomes did not improve even
after prolonged reaction time.
(15) (a) Kuang, C.; Yan, S. J.; Luo, L. S. Nat. Prod. Bioprospect. 2016, 6,
155. (b) Kornsakulkarn, J.; Thongpanchang, C.; Lapanun, S.;
Srichomthong, K. J. Nat. Prod. 2009, 72, 1341. (c) Shahzad, S. A.;
Venin, C.; Wirth, T. Eur. J. Org. Chem. 2010, 2010, 3465.
(16) Mamidyala, S. K.; Ramu, S.; Huang, J. X.; Robertson, A. A. B.;
Cooper, M. A. Bioorg. Med. Chem. Lett. 2013, 23, 1667.
REFERENCES
■
(1) (a) Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey,
J. E. J. Org. Chem. 2009, 74, 2271. (b) Guiso, M.; Marra, C.; Farina, A.
Tetrahedron Lett. 2002, 43, 597. (c) Kumar, V.; Shaw, A. K. J. Org. Chem.
2008, 73, 7526. (d) Laclef, S.; Anderson, K.; White, A. J. P.; Barrett, A. G.
M. Tetrahedron Lett. 2012, 53, 225. (e) Aslam, S. N.; Stevenson, P. C.;
Kokubun, T.; Hall, D. R. Microbiol. Res. 2009, 164, 191. (f) Odell, L. R.;
Savmarker, J.; Lindh, J.; Nilsson, P.; Larhed, M. In Comprehensive
Organic Synthesis, 2nd ed.; Molander, G. A., Knochel, P., Eds.; Elsevier:
̈
Oxford, U.K., 2014; Vol. 7, 492−537.
(2) (a) Martz, K. E.; Dorn, A.; Baur, B.; Schattel, V.; Goettert, M. I.;
Mayer-Wrangowski, S. C.; Rauh, D.; Laufer, S. A. J. Med. Chem. 2012, 55,
̂
7862. (b) Cherry, K.; Duchene, A.; Thibonnet, J.; Parrain, J.-L.; Anselmi,
E.; Abarbri, M. Synthesis 2009, 2009, 257. (c) Ioset, J. R.; Marston, A.;
Gupta, M. P.; Hostettmann, K. J. Nat. Prod. 2001, 64, 710. (d) Zhang, P.;
Pan, J.; Duan, W.; Li, X.; Zhang, Y.; Zhou, Y.; Jiang, Q.; Mao, Z.; Yu, P.
Molecules 2011, 16, 4059. (e) Khan, Z. A.; Iwaoka, M.; Wirth, T.
Tetrahedron 2010, 66, 6639. (f) Wu, N.; Messinis, A.; Batsanov, A. S.;
Yang, Z.; Whiting, A.; Marder, T. B. Chem. Commun. 2012, 48, 9986.
(g) Kagiyama, M.; Hirano, Y.; Mori, T.; Kim, S. Y.; Kyozuka, J.; Seto, Y.;
Yamaguchi, S.; Hakoshima, T. Genes to Cells 2013, 18, 147. (h) Rivaud,
M.; Mendoza, A.; Sauvain, M.; Valentin, A.; Jullian, V. Bioorg. Med.
Chem. 2012, 20, 4856. (i) Gillespie, J. P.; Amoros, L. G.; Stermitz, F. R. J.
Org. Chem. 1974, 39, 3239. (j) Aidhen, I. S.; Mukkamala, R.; Weidner,
C.; Sauer, S. Org. Lett. 2015, 17, 194. (k) Mitra, P.; Shome, B.; Ranjan
De, S.; Sarkar, A.; Mal, D. Org. Biomol. Chem. 2012, 10, 2742.
(l) Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis, 4th
ed.; Cambridge University Press: Cambridge, U.K., 2004; pp 105−155.
(3) (a) Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.
(b) Shibata, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 1781.
(4) Gooßen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P.; Fromm, A.
Chem. Commun. 2009, 7173.
(5) For C−H bond activation reviews: (a) Ackermann, L. Acc. Chem.
Res. 2014, 47, 281. (b) Davies, H. M. L.; Morton, D. J. Org. Chem. 2016,
81, 343. (c) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
̈
Rev. 2011, 40, 4740.
(6) For ruthenium catalysis reviews: (a) Ackermann, L. Org. Process
Res. Dev. 2015, 19, 260. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281.
(c) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv. Synth.
Catal. 2014, 356, 1461. (d) Dana, S.; Yadav, M. R.; Sahoo, A. K. Top.
Organomet. Chem. 2015, 55, 189.
(7) For ruthenium-catalyzed olefination reviews: (a) Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2013, 4, 886. (b) Manikandan, R.;
Jeganmohan, M. Chem. Commun. 2017, 53, 8931.
(8) (a) Yadav, M. R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. J. Org. Chem.
2014, 79, 6123. (b) Singh, K. S.; Dixneuf, P. H. Organometallics 2012,
31, 7320. (c) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Org.
Lett. 2012, 14, 728. (d) Suzuki, C.; Morimoto, K.; Hirano, K.; Satoh, T.;
Miura, M. Adv. Synth. Catal. 2014, 2, 1521. (e) Morioka, R.; Satoh, T.
Chem. Lett. 2016, 45, 682. (f) Padala, K.; Jeganmohan, M. Org. Lett.
2011, 13, 6144. (g) Manikandan, R.; Madasamy, P.; Jeganmohan, M.
ACS Catal. 2016, 6, 230. (h) Graczyk, K.; Ma, W.; Ackermann, L. Org.
Lett. 2012, 14, 4110. (i) Zhao, P.; Niu, R.; Wang, F.; Han, K.; Li, X. Org.
Lett. 2012, 14, 4166. (j) Padala, K.; Jeganmohan, M. Org. Lett. 2012, 14,
1134.
(9) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011,
76, 3024.
(10) (a) Dana, S.; Mandal, A.; Sahoo, H.; Baidya, M. Org. Lett. 2017,
19, 1902. (b) Mandal, A.; Dana, S.; Sahoo, H.; Grandhi, G. S.; Baidya, M.
Org. Lett. 2017, 19, 2430. (c) Mandal, A.; Sahoo, H.; Dana, S.; Baidya, M.
Org. Lett. 2017, 19, 4138.
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DOI: 10.1021/acs.orglett.7b03852
Org. Lett. XXXX, XXX, XXX−XXX