Rh(III)-catalyzed decarboxylative coupling of acrylic acids with unsaturated oxime esters: Carboxylic acids serve as traceless activators

Article abstract of DOI:10.1021/ja412444d

α,β-Unsaturated carboxylic acids undergo Rh(III)-catalyzed decarboxylative coupling with α,β-unsaturated O-pivaloyl oximes to provide substituted pyridines in good yield. The carboxylic acid, which is removed by decarboxylation, serves as a traceless activating group, giving 5-substituted pyridines with very high levels of regioselectivity. Mechanistic studies rule out a picolinic acid intermediate, and an isolable rhodium complex sheds further light on the reaction mechanism.

Full text of DOI:10.1021/ja412444d

Communication
pubs.acs.org/JACS
Rh(III)-Catalyzed Decarboxylative Coupling of Acrylic Acids with
Unsaturated Oxime Esters: Carboxylic Acids Serve as Traceless
Activators
Jamie M. Neely and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: α,β-Unsaturated carboxylic acids undergo
Rh(III)-catalyzed decarboxylative coupling with α,β-
unsaturated O-pivaloyl oximes to provide substituted
pyridines in good yield. The carboxylic acid, which is
removed by decarboxylation, serves as a traceless activating
group, giving 5-substituted pyridines with very high levels
of regioselectivity. Mechanistic studies rule out a picolinic
acid intermediate, and an isolable rhodium complex sheds
further light on the reaction mechanism.
ubstituted pyridines are among the most prevalent scaffolds
S
encountered in medicinal chemistry.1 For this reason, a
wealth of research has focused on the construction of these
heterocycles.2 Nonetheless, access to desired substitution
patterns often remains a challenge with traditional multi-
component approaches to pyridine synthesis.3 Classic con-
densation protocols rely on aldol and Michael-type steps, and
the position and identity of product substituents are dictated by
the activating groups required for reactivity.4 Intermolecular [2
+ 2 + 2] cycloadditions of nitriles and alkynes often afford
regioisomeric mixtures,5 an obstacle that is typically circum-
vented by tethering strategies.6 Novel approaches to diversely
substituted pyridines are highly desirable, and several
impressive reports highlight the recent advances in this field.7
Our efforts in the area of pyridine synthesis have exploited
rhodium-catalyzed coupling of α,β-unsaturated oxime esters8
and alkenes to access 6-substituted pyridines.9 During the
course of this study, we discovered that selectivity depends
crucially on the nature of the alkene substrate. Namely,
activated alkenes react with exquisite regioselectivity (eq 1)
while unactivated alkenes incorporate to give mixtures of
regioisomeric products (eq 2). This limitation prompted us to
investigate whether the carboxylic acid moiety of acrylic acid
derivatives could serve as a ‘traceless’ activating group.10
Indeed, this strategy has been utilized by a number of research
groups in the context of C−H functionalization (eq 3).11,12 In
these examples, carboxylate ligation imparts selectivity to the
C−H activation step, and the acid residue is ultimately cleaved
via in situ decarboxylation. In a similar manner, we envisioned
that the carboxylic acid moiety would direct regioselective
alkene incorporation and then be removed by decarboxylation
(eq 4).13 This work would complement our previously reported
rhodium-catalyzed pyridine synthesis, since 5-substituted
pyridines14 could be prepared with high selectivity without
the constraint of activating group incorporation in the products.
We evaluated the feasibility of the proposed approach in the
reaction of α,β-unsaturated O-pivaloyl oxime 1a and crotonic
acid (2a) (Table 1). An initial screen with catalytic
[RhCp*Cl2]2 and AgOAc as an oxidant identified hexafluoro-
isopropanol (HFIP) as the optimal solvent, furnishing the
desired 3aa in 60% yield (entry 1). Importantly, no 6-
substituted regioisomer (not shown) was observed. In an effort
to avoid superstoichiometric silver reagents, we conducted a
screen of other oxidants, which revealed potassium persulfate
(K2S2O8) to be modestly effective (entry 2). However, the
desired pyridine 3aa was formed in a 1:1 mixture with picolinic
acid 4aa, the nondecarboxylated product of the desired
coupling. Addition of a catalytic amount of silver p-toluene-
sulfonate (AgOTs) afforded a 10:1 mixture of products (entry
3), and increasing the amount of AgOTs gave full conversion to
3aa as a single product (entry 4). Changing to [RhCpCF Cl2]2
3
(CpCF = tetramethyl(trifluoromethyl)cyclopentadienyl) was
3
necessary for increasing reactivity with aryl acrylic acid
substrates such as 2k (Table 1, entries 5 and 6, and Supporting
Received: December 6, 2013
Published: February 10, 2014
© 2014 American Chemical Society
2735
dx.doi.org/10.1021/ja412444d | J. Am. Chem. Soc. 2014, 136, 2735−2738

Journal of the American Chemical Society
Communication
a
chloride and pivaloyl chloride. Knoevenagel condensation of
the appropriate aldehyde and malonic acid conveniently
accesses acrylic acid derivatives 2.15 The reaction of various
α,β-unsaturated O-pivaloyl oximes (1) and nonenoic acid (2b)
affords the 5-substituted pyridines in good yields.16 Both
primary and secondary alkyl acrylic acids undergo the desired
coupling efficiently; notably, alkyl chloride 2d is tolerated under
the Ag(I) conditions. The acrylic acid may also bear aryl or
heteroaryl substitution (2h−2m). While the alkene contains
two possible activating groups in these cases, 5-substituted
products are formed with complete regioselectivity. Finally,
acrylic acid (2n) also undergoes decarboxylative coupling to
furnish 2,3-disubstituted 3bn in good yield.
Table 1. Reaction Optimization
Several key experiments contributed to our current under-
standing of the reaction mechanism. We initially considered a
pathway involving decarboxylation of a picolinic acid
intermediate 4 (eq 5, Scheme 1a). Ag(I)-catalyzed decarbox-
a
b
c
1
1.2 equiv of 2, 0.3 M. Determined by H NMR. Without K2S2O8.
Scheme 1. Mechanistic Studies
Information (SI)), and we thus chose this catalyst for further
development.
We examined the scope of the reaction with these optimized
conditions (Chart 1). Oxime esters 1 are easily synthesized
from the corresponding enones with hydroxylamine hydro-
a
Chart 1. Reaction Scope
ylation is a well-known process17 and has been demonstrated
with aryl18 and heteroaryl19 carboxylic acids at elevated
temperatures. To test this hypothesis, we synthesized possible
intermediate 4ca and subjected it to the reaction conditions (eq
6). In the event, we observed no formation of decarboxylated
3ca, ruling out the intermediacy of picolinic acid 4ca.
a
b
c
Conditions: 1.2 equiv of 2, 0.3 M. 1 mmol scale. 0.5 equiv of
d
AgOTs. In TFE at 74 °C.
2736
dx.doi.org/10.1021/ja412444d | J. Am. Chem. Soc. 2014, 136, 2735−2738

Journal of the American Chemical Society
Communication
We gained further mechanistic insight from isotope and
stoichiometric experiments (Scheme 1b−d). Reaction of 1a and
2a in trifluoroethanol-d1 performed to ∼30% conversion results
in partial deuteration at the β-position of the remaining 1a, an
observation consistent with a reversible C−H activation step
(eq 7). After a mixture of 1a, 2a and a stoichiometric amount of
RhCp*(OAc)2 was heated for 90 min, the major products
observed are rhodium carboxylate complexes 5 and 6 (eq 8).
Importantly, in 5 and 6, C−N bond formation and N−O bond
cleavage have taken place but decarboxylation has not yet
occurred, clarifying the timing of the decarboxylation step.
Treatment of 5 and 6 with TMSCl affords chloride complex 7,
an orange solid that is isolated by filtration. The structure given
in Scheme 1c was confirmed by single crystal X-ray analysis of 7
(Figure 1). Acetate complex 5 is converted to a 1:1 mixture of
Scheme 2. Proposed Mechanism
substituted pyridines with complete regioselectivity. Mecha-
nistic studies suggest that decarboxylation does not occur via a
picolinic acid intermediate. We identified significant rhodacyclic
intermediates that clarify the order of C−N bond formation
and decarboxylation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 1. X-ray crystal structure of 7 with thermal ellipsoids drawn at
the 50% probability level.
Experimental procedures, compound characterization, addi-
tional experiments, and crystallographic data. This information
is available free of charge via the Internet at http://pubs.acs.org.
3aa and 4aa upon heating (eq 9), implicating 5 as a common
intermediate of both observed products. In agreement with
earlier observations, addition of AgOTs to the reaction leads to
exclusive formation of 3aa (eq 9). Interestingly, heating
chloride complex 7 results in a 1:3 mixture of 3aa and 4aa
(eq 10), suggesting that X ligand identity at this stage
influences the divergence of reaction pathways to the two
products.
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
■
Notes
The authors declare no competing financial interest.
Based on the described mechanistic observations, we propose
that pyridine and picolinic acid formation proceeds by the
mechanism depicted in Scheme 2. After generation of active
catalyst I, reversible C−H activation at the β-position of 1a and
ligand exchange provide cationic complex II. Migratory
insertion and deprotonation give rhodacycle III. C−N bond
formation and N−O bond cleavage afford intermediate IV that
is analogous to observable complexes 5 and 6. From IV, proton
assisted ionization may occur to liberate either of the two
carboxylate ligands, giving cationic complex V or VI.21
Deprotonation of V leads to metallacycle VII, which can
undergo a retro [2 + 2 + 1] cycloaddition to extrude CO2 and
provide pyridine 3aa and a Rh(I) species.22 Alternatively,
deprotonation of VI forms intermediate VIII from which β-
hydride elimination gives picolinic acid 4aa. Reductive
elimination of the resultant Rh(III) hydride gives a Rh(I)
complex that is oxidized to regenerate the active catalyst.
In conclusion, we have developed a rhodium-catalyzed
decarboxylative coupling of α,β-unsaturated O-pivaloyl oximes
and acrylic acid derivatives. This method takes advantage of a
carboxylic acid as a traceless activating group to produce 5-
ACKNOWLEDGMENTS
We thank NIGMS (GM80442) for support and Johnson
Matthey for a generous loan of rhodium salts.
■
REFERENCES
■
(1) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337.
(2) (a) Hill, M. D. Chem.Eur. J. 2010, 16, 12052. (b) Henry, G. D.
Tetrahedron 2004, 60, 6043. (c) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science: Malden, MA, 2000; pp 63−120.
(3) For reviews of pyridine synthesis by direct functionalization of
the heterocycle, see: (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.;
Charette, A. B. Chem. Rev. 2012, 112, 2642. (b) Nakao, Y. Synthesis
2011, 3209. (c) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36,
1161.
(4) (a) Allais, C.; Lieb
Eur. J. Org. Chem. 2013, 4131. (b) Allais, C.; Lieb
́
y-Muller, F.; Rodriguez, J.; Constantieux, T.
y-Muller, F.;
́
Constantieux, T.; Rodriguez, J. Adv. Synth. Catal. 2012, 354, 2537. For
reviews of pyridine syntheses by condensation methods, see: (c)
Reference 2c. (d) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269.
(e) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459.
2737
dx.doi.org/10.1021/ja412444d | J. Am. Chem. Soc. 2014, 136, 2735−2738

Journal of the American Chemical Society
Communication
(5) (a) Knoch, F.; Kremer, F.; Schmidt, U.; Zenneck, U.; Le Floch,
P.; Mathey, F. Organometallics 1996, 15, 2713. (b) Diversi, P.; Ermini,
L.; Ingrosso, G.; Lucherini, A. J. Organomet. Chem. 1993, 447, 291.
(6) For a review of pyridine syntheses by [2 + 2 + 2] cycloaddition,
(14) For recent approaches to 5-substituted pyridines by
derivatization of a pyridine core, see: (a) Ye, M.; Gao, G.-L.;
Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 19090. (b) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 6964. (c) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2,
488.
(15) (a) Reference 13c. (b) Szymanski, W.; Wu, B.; Weiner, B.; de
Wildeman, S.; Feringa, B. L.; Janssen, D. B. J. Org. Chem. 2009, 74,
9152.
(16) 1-Cyclohexene-1-carboxaldehyde O-pivaloyl oxime eliminates
PivOH under the reaction conditions, giving the corresponding nitrile
(50% yield). The reaction of 1-penten-3-one O-pivaloyl oxime results
in low conversion to the desired product (10% yield).
(17) For selected examples, see: (a) Liu, X.; Wang, Z.; Cheng, X.; Li,
C. J. Am. Chem. Soc. 2012, 134, 14330. (b) Citterio, A.; Minisci, F.;
Franchi, F. J. Org. Chem. 1980, 45, 4752. (c) Anderson, J. M.; Kochi, J.
K. J. Am. Chem. Soc. 1970, 92, 1651.
́
see: (a) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787. For selected
examples, see: (b) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew. Chem., Int.
Ed. 2011, 50, 7162. (c) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2007, 9, 505. (d) McCormick, M. M.; Duong, H. A.; Zuo,
G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030. For a transition metal-
free protocol, see: (e) Kral, K.; Hapke, M. Angew. Chem., Int. Ed. 2011,
50, 2434.
(7) For leading examples, see: (a) Stark, D. G.; Morrill, L. C.; Yeh, P.-
P.; Slawin, A. M. Z.; O’Riordan, T. J. C.; Smith, A. D. Angew. Chem.,
Int. Ed. 2013, 52, 11642. (b) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.;
Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 4708. (c) Wei, Y.; Yoshikai,
N. J. Am. Chem. Soc. 2013, 135, 3756. (d) Michlik, S.; Kempe, R.
Angew. Chem., Int. Ed. 2013, 52, 6326. (e) Loy, N. S. Y.; Singh, A.; Xu,
X.; Park, C.-M. Angew. Chem., Int. Ed. 2013, 52, 2212. (f) He, Z.;
Dobrovolsky, D.; Trinchera, P.; Yudin, A. K. Org. Lett. 2013, 15, 334.
(g) Yamamoto, S.-I.; Okamoto, K.; Murakoso, M.; Kuninobu, Y.;
Takai, K. Org. Lett. 2012, 14, 3182. (h) Gati, W.; Rammah, M. M.;
Rammah, M. B.; Couty, F.; Evano, G. J. Am. Chem. Soc. 2012, 134,
9078. (i) Chen, M. Z.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134,
1352. (j) Ohashi, M.; Takeda, I.; Ikawa, M.; Ogoshi, S. J. Am. Chem.
Soc. 2011, 133, 18018. (k) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba,
S. J. Am. Chem. Soc. 2011, 133, 6411. (l) Wang, Y.-F.; Chiba, S. J. Am.
Chem. Soc. 2009, 131, 12570. (m) Manning, J. R.; Davies, H. M. L. J.
Am. Chem. Soc. 2008, 130, 8602. (n) Liu, S.; Liebeskind, L. S. J. Am.
Chem. Soc. 2008, 130, 6918. (o) Movassaghi, M.; Hill, M. D.; Ahmad,
O. K. J. Am. Chem. Soc. 2007, 129, 10096. (p) Movassaghi, M.; Hill, M.
D. J. Am. Chem. Soc. 2006, 128, 4592.
(18) (a) Goossen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P.;
Fromm, A. Chem. Commun. 2009, 7173. (b) Cornella, J.; Sanchez, C.;
Banawa, D.; Larrosa, I. Chem. Commun. 2009, 7176. (c) References
11a−11e.
(19) (a) Lu, P.; Sanchez, C.; Cornella, J.; Larrosa, I. Org. Lett. 2009,
11, 5710. (b) References 11d,f.
(20) Partial deuteration of the 2-Me and 6-H of 3aa is also observed;
see SI.
(21) The exact role played by Ag+ in increasing selectivity for 3 is not
fully understood at this time.
(22) A stepwise process of CO2 extrusion and reductive elimination
is another possibility.
(8) α,β-Unsaturated oximes have been coupled to alkynes by Rh(III)
catalysis to form polysubstituted pyridines. See: (a) Martin, R. M.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012, 77, 2501. (b) Hyster,
T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846. (c) Too, P. C.; Noji,
T.; Lim, Y. J.; Li, X.; Chiba, S. Synlett 2011, 2789. (d) Parthasarathy,
K.; Cheng, C.-H. Synthesis 2009, 1400. (e) Parthasarathy, K.;
Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. For the
analogous reaction of α,β-unsaturated imines, see: (f) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645.
(9) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66.
(10) For a review of the use of removable directing groups, see:
Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.
(11) (a) Bhadra, S.; Dzik, W. I.; Goossen, L. J. Angew. Chem., Int. Ed.
2013, 52, 2959. (b) Morimoto, K.; Itoh, M.; Hirano, K.; Satoh, T.;
Shibata, Y.; Tanaka, K.; Miura, M. Angew. Chem., Int. Ed. 2012, 51,
5359. (c) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed.
2011, 50, 9429. (d) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J.
Org. Chem. 2011, 76, 3024. (e) Mochida, S.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2010, 12, 5776. (f) Maehara, A.; Tsurugi, H.;
Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159.
(12) Transition-metal-catalyzed decarboxylative coupling is also an
established method for ipso substitution. For selected recent examples,
see: (a) Haley, C. K.; Gilmore, C. D.; Stoltz, B. M. Tetrahedron 2013,
69, 5732. (b) Bhadra, S.; Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc.
2012, 134, 9938. (c) Goossen, L. J.; Lange, P. P.; Rodríguez, N.;
Linder, C. Chem.Eur. J. 2010, 16, 3906. (d) Goossen, L. J.;
Rodríguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248.
(e) Goossen, L. J.; Rodríguez, N.; Melzer, B.; Linder, C.; Deng, G.;
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (f) Becht, J.-M.; Catala,
C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781. (g) Forgione, P.;
Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F.
J. Am. Chem. Soc. 2006, 128, 11350. (h) Goossen, L. J.; Deng, G.; Levy,
L. M. Science 2006, 313, 662. For a review of decarboxylative coupling,
see: (i) Rodríguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030.
(13) (a) Yang, Y.; Yao, J.; Zhang, Y. Org. Lett. 2013, 15, 3206.
(b) Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Org. Lett. 2012, 14, 957.
̌
(c) Smejkal, T.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 3946.
2738
dx.doi.org/10.1021/ja412444d | J. Am. Chem. Soc. 2014, 136, 2735−2738