Copper-catalyzed nondecarboxylative cross coupling of alkenyltrifluoroborate salts with carboxylic acids or carboxylates: Synthesis of enol esters

Article abstract of DOI:10.1021/ol4013712

A mild copper-catalyzed Chan-Lam-Evans type cross-coupling reaction for the regioselective and stereospecific preparation of (E)- or (Z)-enol esters is described. The method couples carboxylate salts or carboxylic acids with potassium alkenyltrifluoroborate salts in the presence of catalytic CuBr and DMAP with 4 A molecular sieves under O₂ at 60 C. Overall, this method demonstrates carboxylic acids as suitable reaction partners for nondecarboxylative copper-catalyzed cross-couplings to form C-O bonds in an Ullmann-like reaction.

Full text of DOI:10.1021/ol4013712

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Nondecarboxylative
Cross Coupling of Alkenyltrifluoroborate
Salts with Carboxylic Acids or
Carboxylates: Synthesis of Enol Esters
Fang Huang, Tan D. Quach, and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received May 16, 2013
ABSTRACT
A mild copper-catalyzed ChanÀLamÀEvans type cross-coupling reaction for the regioselective and stereospecific preparation of (E)- or (Z)-enol
esters is described. The method couples carboxylate salts or carboxylic acids with potassium alkenyltrifluoroborate salts in the presence of
˚
catalytic CuBr and DMAP with 4 A molecular sieves under O2 at 60 °C. Overall, this method demonstrates carboxylic acids as suitable reaction
partners for nondecarboxylative copper-catalyzed cross-couplings to form CÀO bonds in an Ullmann-like reaction.
Transition metal catalyzed cross-couplings to form
CÀO, CÀN, and CÀS bonds have emerged as powerful
methods in organic synthesis. The formation of CÀO
bonds, for example, can be accomplished by Pd-based
cross-coupling of halides,1 or through Cu-based cross-
coupling of organometalloids under oxidative conditions
(Figure 1a).2 While such methods employing alcohols or
phenols as cross-coupling partners are routinely used,
the use of other oxygen-based nucleophiles is unusual.
In particular carboxylic acids constitute a general class of
oxygen-based nucleophile that is rarely encountered for
metal-catalyzed CÀO bond formation. Instead, carboxylic
acids3 are primarily utilized as nucleophilic cross-coupling
partners for CÀC bond formation under decarboxylative
conditions (Figure 1b),4À7 and as ortho- directing groups
for CÀH functionalizations.8,9 Isolated examples of CÀO
bond formation from carboxylic acids using alkenyl or aryl
halides,10 or with organometalloid derivatives,11,12 often
suffer from problems such as low yields, the use of
stoichiometric metals, high catalyst or reagent loadings,
and high reaction temperatures (Figure 1c). During the
(4) See for example: (a) Myers, A. G.; Tanaka, D.; Mannion, M. R.
J. Am. Chem. Soc. 2002, 124, 11250–11251. (b) Forgione, P.; Brochu,
M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am.
Chem. Soc. 2006, 128, 11350–11351. (c) Gooßen, L. J.; Deng, G.; Levy,
L. M. Science 2006, 313, 662–664. (d) Gooßen, L. J.; Rodrıguez, N.;
Linder, C. J. Am. Chem. Soc. 2008, 130, 15248–15249. (e) Wang, C.; Piel,
I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194–4195. (f) Gooßen, L. J.;
Rodriguez, N.; Lange, P.; Linder, C. Angew. Chem., Int. Ed. 2010, 49,
1111–1114. (g) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010,
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Y.; Liu, L. Angew. Chem., Int. Ed. 2011, 50, 4470–4474. (j) Rodriguez,
N.; Gooßen, L. J. Chem. Soc. Rev. 2011, 40, 5030–5048.
(5) One reason that couplings of carboxylic acids have not been
extensively studied is that the conditions and temperatures typically
required for CÀO bond formation using cross-coupling methods, as for
example in BuchwaldÀHartwig chemistry, could lead to competing
decarboxylation or protonation.
(6) For recent examples of CÀN bond formation via copper-
catalyzed decarboxylative cross-coupling of carboxylic acids, see: (a)
Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000–2003. (b) Zhang, Y.; Patel, S.;
Mainolfi, N. Chem. Sci. 2012, 3, 3196–3199.
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Organic Synthesis; Negishi, E.-i., Ed.; J. Wiley & Sons Inc.: New York,
2002; pp 1097À1106.
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CÀO, CÀN and CÀS bond formation, see: (a) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. Engl. 2009, 48, 6954–6971. (b) Dehli, J. R.;
Legros, J.; Bolm, C. Chem. Commun. 2005, 973–986. (c) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–2364. (d) Nelson,
T. D.; Crouch, R. D. Org. React. 2004, 63, 265–555. (e) Thomas, A. W.;
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Gooßen, L. J.; Rodrıguez, N.; Gooßen, K. Angew. Chem., Int. Ed. 2008,
47, 3100–3120.
r
10.1021/ol4013712
XXXX American Chemical Society

nondecarboxylative cross-coupling of carboxylic acids with
alkenylboron derivatives to give enol esters under mild
conditions that does not require the use of stoichiometric
metal additives (Figure 1c).
Enol derivatives such as enol esters serve as key synthetic
building blocks in organic, medicinal, and polymer chem-
istry, and are found in many target molecules including
many diverse natural products.15 The classical approach to
enolester synthesisinvolvesenolorenolatetrapping. More
recent approaches to their synthesis include metal cata-
lyzed (e.g., Ru, Ir, and Re) additions of carboxylic acids to
alkynes,16 isomerizations of allylic esters,17 and car-
bonylative arylations of aryl ketones.18 Control of enol
ester regiochemistry (i.e., Markovnikov versus anti-
Markovnikov products) and E/Z diastereoselectivity can
be an issue with such reactions. We envisaged that the use
of a carboxylic acid-based cross-coupling strategy could
potentially provide a solution to these issues, using stereo-
defined potassium alkenyltrifluoroborate salts. Organo-
boron compounds serve as valuable cross-coupling partners
for CÀO/N/S bond formation.19,20 Chan and Evans ori-
ginally reported the use of boronic acids as cross-coupling
partners with phenols under copper-catalyzed conditions
to form CÀO bonds.21 Potassium organotrifluoroborate
salts22 were subsequently revealed to be suitable partners
for copper-catalyzed cross-couplings with phenols and
aliphatic alcohols,23,24 aswell as with amines and amides.25
Potassium alkenyltrifluoroborate salts are readily formed
from the corresponding boronic acids with KHF2,26 but
are more stable and readily handled.
Figure 1. Cross-coupling reactions leading to CÀO or CÀC
bond formation.
course of our studies, Cheng has reported the reaction of
aryl carboxylic acids with arylboronic acids,13 and Liu and
co-workers demonstrated the use of a mixed copper/silver
promoted arylation of aryl carboxylic acids with arylboro-
nic acids.14 This reaction required the use of Cu(OTf)2
(20 mol %) and Ag2CO3 (2 equiv) at 120 °C and was
also applied to three examples using styrylboronic acid.
We now report the development of a stereospecific cata-
lytic copper(II)-based cross-coupling method for the
(7) For an example of CÀO bond formation via copper-catalyzed
decarboxylative cross-coupling of carboxylic acids, see: Bhadra, S.;
Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc. 2012, 134, 9938–9941.
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50, 9429–9432.
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mediated coupling of aryl and vinyl halides with copper carboxylates
only occurs at high reaction temperatures under stoichiometric condi-
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3810. (b) Kurata, Y.; Yamamoto, T. Can. J. Chem. 1983, 61, 86–91. (c)
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J. Org. Chem. 1987, 52, 2230–2239. (c) Gooßen, L. J.; Paetzold, J.;
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(17) Mamone, P.; Grunberg, M. F.; Fromm, A.; Khan, B. A.;
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(18) Schranck, J.; Tlili, A.; Neumann, H.; Alsabeh, P. G.; Stradiotto,
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and Applications in Organic Synthesis and Medicine; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; pp 205À240. (b) Qiao, J. X.; Lam,
P. Y. S. In Boronic Acids: Preparation and Applications in Organic
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B
Org. Lett., Vol. XX, No. XX, XXXX

potassium carboxylate salts afforded enol esters 1in excellent
yields exclusively as the trans isomers (g98:2 by NMR)
(Table 1). Reaction optimization revealed that solvent choice
plays a crucial role in the success of the reaction,27 with polar
solvents such as MeCN giving highest yields. The use of
DMAP was found to be critical for the success of the
reaction, since reaction in the absence of a ligand or the
use of other ligands such as TMEDA, 1,10-phenanthroline,
did not improve reactivity. However, the use of a
MeCN/DMSO (4:1) solvent mixture (Table 2, Protocol
B), led to dramatically improved yields, perhaps due to the
increased solubility of the reagents under these conditions.
Protocol A could also be applied with other potassium
(E)-alkenylborate salts, yielding (E)-enol esters 2 in good
yields and diastereoselectivities (g98:2 by NMR) (Figure 2).
€
pyridine, imidazole, triethylamine, or Hunig’s base resulted
in only trace amounts of product being observed.
Table 1. Copper-Catalyzed Cross-Coupling of Potassium
Carboxylates with Potassium (E)-Trifluorohexenylboratea
Figure 2. Formation of other enol acetates 2 from potassium
(E)-alkenylborate salts using Protocol A.
The enol esters 1 and 2 obtained from the cross-coupling
reactions of carboxylic acids were obtained as the trans
isomers (g98:2 by NMR). Of particular interest from a
mechanistic standpoint is whether the coupling reaction is
stereospecific. To establish the stereoselectivity of the reac-
tion, potassium (Z)-trifluoropropenylborate was used as a
coupling partner (cis/trans ratio =18:1).28 Reaction with
both electron-rich and electron-deficient benzoic acids or
carboxylate salts led to the products 3aÀd with high
a Reaction conditions: RCOOK (1.0 equiv), C6H11BF3K (2.0 equiv).
b Isolated yields after column chromatography.
1
cis-selectivity as determined by H NMR (Table 3). Since
alkene geometry is maintained in the reaction it supports a
mechanism involving transmetalation to copper followed by
a reductive elimination, similar to those previously proposed
in related cross-coupling reactions of organoboron com-
pounds (Figure 3).19,21,23À25 The stereospecific nature of the
coupling is not consistent with reactions involving free-
radical intermediates. In addition, there was no evidence
for the formation of any products resulting from decarboxyla-
tion of the carboxylic acids, as could have occurred, for
example, through conversion of intermediate 4 into 5. The
lack of such products presumably reflects the lower tempera-
ture employed for the cross coupling than is typically used for
decarboxylative cross-couplings.3À7 Interestingly, the observa-
tion of retention of stereochemistry contrasts with Masuda’s
observations of inversion of stereochemistry in the acet-
oxylation of alkenylboronic esters by PhI(OAc)2/NaI.29
In conclusion, a general stereoselective and regioselective
approach to enol ester synthesis has been developed using a
copper-catalyzed cross-coupling of alkenyltrifluoroborate
salts with carboxylate salts or carboxylic acids. The reaction
occurs in a stereospecific manner, is operationally straight-
forward and avoids the use of other additives such as Ag(I)
salts. The method is complementary to metal-catalyzed
additions of carboxylic acids to alkynes, and contrasts with
the widespread use of carboxylic acids in decarboxylative
While encouraged by the successful cross-coupling of
carboxylate salts, a more direct protocol utilizing car-
boxylic acids would be operationally more convenient,
since it would obviate the need for the prior formation of
the carboxylate salts. An excellent yield of 1a was obtained
in the coupling of benzoic acid under identical conditions
to those employed using carboxylate salts (Table 2, entry 1).
Addition of external bases to the reaction led to decreased
product yields. Other carboxylic acids could also be used in
the reaction under identical reaction conditions using
MeCN as the reaction solvent in generally good to
excellent yields (Table 2, Protocol A). In the case of sterically
hindered aromatic carboxylic acids, the products 1k, 1l,
and 1m were isolated in moderate yields. 4-Hydroxybenzoic
acid underwent coupling to give not only the desired enol
ester 1n, but also a byproduct resulting from cross-
coupling of both the carboxylic acid oxygen and phenolic
hydroxyl group. The product distribution obtained in this
case is noteworthy, since although phenols have previously
been used in cross-couplings with organoboron com-
pounds,21,23 it suggests that the carboxylic acid functional
group is more reactive toward cross-coupling under the
current reaction conditions. In some cases, yields of 1 were
poor. Further optimization studies revealed that increased
reaction temperature or the presence of additional bases
(28) Prepared from commercially available (Z)-propenylboronic
acid.
(29) Murata, M.; Satoh, K.; Watanabe, S.; Masuda, Y. J. Chem.
Soc., Perkin Trans. I 1998, 1465–1466.
(27) Optimization experiments included the effect of the copper
catalyst, ligand, solvent, reaction temperature, and ratio of coupling
partners.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Copper-Catalyzed Cross-Coupling of Carboxylic
Acids with Potassium (E)-Trifluorohexenylborate Using
Protocols A and Ba
Table 3. Formation of Enol Acetates 3 from Potassium
(Z)- Trifluoropropenylborate Using Protocols A and Ba
a Reaction conditions: RCOOH (1.0 equiv), C3H5BF3K (2.0 equiv),
using MeCN solvent (Protocol A) or MeCN/DMSO (4:1) solvent
(Protocol B). b Isolated yields after column chromatography. c dr
determined by 1H NMR analysis.
Figure 3. Mechanistic overview of enol acetate formation.
cross-coupling reactions. Further studies on cross-coupling
reactions and applications of potassium organotrifluorobo-
rate salts will be reported in due course.
Acknowledgment. The authors thank the Natural
Science and Engineering Research Council of Canada
(NSERC) for financial support.
Supporting Information Available. Full experimental
details and characterization data for all compounds
a Reaction conditions: RCOOH (1.0 equiv), C6H11BF3K (2.0 equiv),
using MeCN solvent (Protocol A) or MeCN/DMSO (4:1) solvent
(Protocol B). b Isolated yields after column chromatography. c dr g
98:2 as determined by 1H NMR analysis.
1
including H and 13C NMR. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX