Pd-catalyzed cross-coupling of potassium alkenyltrifluoroborates with 2-chloroacetates and 2-chloroacetamides

Article abstract of DOI:10.1021/ol401377q

A protocol for the stereocontrolled synthesis of (E)- and (Z)-β,γ-unsaturated esters and amides is reported. 2-Chloroacetates as well as secondary and tertiary 2-chloroacetamides were successfully employed as electrophiles in the Suzuki-Miyaura cross-coupling reaction with potassium (E)- and (Z)-alkenyltrifluoroborates, affording the corresponding products in high yield.

Full text of DOI:10.1021/ol401377q

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Pd-Catalyzed Cross-Coupling
of Potassium Alkenyltrifluoroborates with
2‑Chloroacetates and 2‑Chloroacetamides
Gary A. Molander,* Thiago Barcellos, and Kaitlin M. Traister
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
gmolandr@sas.upenn.edu
Received May 16, 2013
ABSTRACT
A protocol for the stereocontrolled synthesis of (E)- and (Z)-β,γ-unsaturated esters and amides is reported. 2-Chloroacetates as well as secondary
and tertiary 2-chloroacetamides were successfully employed as electrophiles in the SuzukiÀMiyaura cross-coupling reaction with potassium
(E)- and (Z)-alkenyltrifluoroborates, affording the corresponding products in high yield.
(E)- and (Z)-β,γ-unsaturated esters and amides are
encountered in many natural products that exhibit biolo-
gical activity,1 and they are also important precursors for
the synthesis of biologically active compounds.2
The stereocontrolled synthesis of this significant class of
compounds has been considered quite difficult. The most
general method involves the palladium- or ruthenium-
catalyzed carbonylation of allylic substrates.3 Another
common method is the deprotonation/reprotonation of
R,β-unsaturated carbonyl compounds. Alternative ap-
proaches include the reaction of alkenyl-9-BBN com-
pounds with R-halo carbanions generated from ethyl
bromoacetate4 orethyl(dimethylsulfuranylidene) acetate,5
cross-metathesis of allyl halides with olefins bearing
amides,6 or a sequential eliminationÀreduction process
of R-halo-β-hydroxy-γ,δ-unsaturated esters promoted by
SmI2.7 Radical addition of alkenylindiums to R-halo car-
bonyl compounds8 and Ni-catalyzed enantioselective ad-
dition of alkenylzirconium reagents to R-bromo esters and
ketones9 have emerged as more recent advances in the
synthesis of β,γ-unsaturated carbonyl moieties.
Although numerous pathways toward accessing the
β,γ-unsaturated carbonyl motif have been studied, all
suffer from specific limitations. Carbonylation reactions
require the use of toxic CO gas, which is sometimes
required under high pressures.3a Isomerization reactions
afford a mixture of (E)- and (Z)-isomers.10 Both the cross-
metathesis reaction and the SmI2-catalyzed reactions
mentioned above require complex starting materials that
are not readily available. Reactions involving other orga-
nometallic species, such as alkenylindiums and alkenyl-9-
BBN compounds, have proven effective in the forma-
tion of β,γ-unsaturated carbonyl esters, but these require
(1) (a) Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. J. Org. Chem.
1983, 48, 4404. (b) Oehlschlager, A. C.; Wong, J. W.; Verigin, V. G.;
Pierced, H. D. J. Org. Chem. 1983, 48, 5009.
(2) (a) Fernandes, R. A.; Ingle, A. B. Synlett 2010, 158. (b) Eissler, S.;
Nahrwold, M.; Neumann, B.; Stammler, H. G.; Sewald, N. Org. Lett.
2007, 9, 817. (c) Mathew, J. J. Org. Chem. 1990, 55, 5294. (d) Hirao, T.;
Fujihata, Y.; Kurokawa, K.; Ohshiro, Y.; Agawa, T. J. Org. Chem.
1986, 51, 2830.
(3) For examples of the synthesis of β,γ-unsaturated esters, see: (a)
Mitsudo, T.-A.; Suzuki, N.; Kondo, T.; Watanabe, Y. J. Org. Chem.
1994, 59, 7759. For examples of the synthesis of β,γ-unsaturated amides,
see: (b) Murahashi, S.-I.; Imada, Y.; Nishimura, K. Tetrahedron 1994,
50, 453. (c) Murahashi, S.-I.; Imada, Y.; Nishimura, K. J. Chem Soc.,
Chem. Commun. 1988, 1578. (d) Loh, T. P.; Cao, G. Q.; Yin, Z.
Tetrahedron Lett. 1999, 40, 2649.
(4) Brown, H. C.; Cho, B. T.; Park, W. S. J. Org. Chem. 1986, 51,
3398.
(5) Deng, M. Z.; Li, N. S.; Huang, Y. Z. J. Org. Chem. 1992, 57, 4017.
(6) Yun, J. I.; Kim, H. R.; Kim, S. K.; Kim, D.; Lee, J. Tetrahedron
2012, 68, 1177.
(7) Concellon, J. M.; Bernad, P.; Rodriguez-Solla, H. Angew. Chem.,
Int. Ed. 2001, 40, 3897.
(8) Oshima, K.; Takami, K.; Yorimitsu, H. Org. Lett. 2004, 6, 4555.
(9) Fu, G. C.; Lou, S. J. Am. Chem. Soc. 2010, 132, 5010.
(10) (a) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron
1987, 43, 743. (b) Kende, A.; Toder, B. H. J. Org. Chem. 1982, 47, 163.
r
10.1021/ol401377q
XXXX American Chemical Society

Table 1. Cross-Coupling of 2-Chloroacetates with (E)- and
(Z)-Alkenyltrifluoroboratesa
Figure 1. Structures of XPhos ligand and XPhos-Pd-G2
precatalyst.
preformation of sensitive organometallic species and low
temperature reaction conditions. The use of alkenyl-TMS
substrates is effective in an asymmetric Hiyama cross-
coupling with R-bromoesters,11 but as is the case with
alkenylzirconium reagents, a large excess of the organome-
tallic reagent is required (30 and 100 mol %, respectively).
SuzukiÀMiyaura cross-coupling reactions have also
been applied as a strategy toward accessing this class of
compounds. In a recent study, (E)-β,γ-unsaturated amides
were obtained in moderate to good yields via the cross-
coupling of N,N-dimethyl-2-bromoacetamide with alke-
nylboranes, which were prepared in situ by hydroboration
with dicyclohexylborane in the presence of Pd(dba)2 and
tricyclohexylphosphine.12
Additionally, the cross-coupling of R-bromoacetates
with alkenylboronic acids has recently been investigated.13
Good yields were achieved in this study, but only
(E)-alkenylboronic acids were evaluated, none of which
provided any evidence of functional group compatibility.
Although alkenylboronic acids are efficient substrates and
solve many of the prevailing limitations in the synthesis of
β,γ-unsaturated carbonyl compounds, they suffer disad-
vantages related to the instability of alkenylboronic acids.
These compounds exhibit a tendency to polymerize read-
ily, which is especially prevalent in low molecular weight
examples such as vinyl and propenylboronic acids.14 Fur-
thermore, the use of a large excess (20 mol %) of the
boronic acid partner is usually necessary to obtain good
yields of desired product.13
Alkenyltrifluoroborates provide advantages over the
boronic acid counterparts and are excellent partners in
SuzukiÀMiyaura reactions wherein the double-bond geo-
metry is retained with a high degree of fidelity. Further-
more, alkenyltrifluoroborates can be prepared on large
scale and stored indefinitely at room temperature under
a Reaction conditions: chloroacetate (0.5 mmol), potassium alkenyl-
trifluoroborate (0.525 mmol, 1.05 equiv), K2CO3 (1.5 mmol, 3 equiv),
XPhos-Pd-G2 (2.5 μmol, 0.5 mol %), solvent (2 mL), 80 °C. b 5.0 mmol
scale, 0.25 mol % XPhos-Pd-G2, 18 h. c 1.0 mol % of Pd. d Product
contains >5% trans isomer.
(11) Fu, G. C.; Dai, X.; Strotman, N. A. J. Am. Chem. Soc. 2008, 130,
3302.
(12) Luo, F. T.; Lu, T. Y.; Xue, C. Tetrahedron Lett. 2003, 44, 7249.
(13) (a) Duan, Y.; Zhang, J.; Yang, J.; Deng, M. Chin. J. Chem. 2009,
27, 179. (b) Peng, Z.-Y.; Wang, J.-P.; Cheng, J.; Xie, X.-M.; Zang, Z.
Tetrahedron 2010, 66, 8238.
air.15 Because of their greater stability compared to alke-
nylboronic acids, a large excess of the trifluoroborate
coupling partner is not generally required.
Herein is reported an efficient and general protocol for
the synthesis of β,γ-unsaturated esters and amides through
(14) Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228.
(15) (a) Molander, G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71,
2493. (b) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950. (c)
Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424. (d)
Furstner, A.; Larionov, O.; Flugge, S. Angew. Chem., Int. Ed. 2007, 46,
5545. (e) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
(f) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
€
€
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Cross-Coupling of N-Benzyl-2-chloroacetamide with
(E)- and (Z)-Alkenyltrifluoroboratesa
Table 3. Expanded 2-Chloroacetamide Scope for
Cross-Coupling with (E)-Alkenyltrifluoroboratesa
a Reaction conditions: N-benzyl-2-chloroacetamide (0.5 mmol),
potassium alkenyltrifluoroborate (0.525 mmol, 1.05 equiv), K2CO3
(1.5 mmol, 3 equiv), XPhos-Pd-G2 (5 μmol, 1 mol %), solvent (2 mL),
80 °C. b Product contains >5% trans isomer.
SuzukiÀMiyaura cross-coupling of 2-chloroesters or amides
with potassium (E)- and (Z)-alkenyltrifluoroborates. Initi-
ally, a limited screening of Pd/ligand systems was carried out
with benzyl chloroacetate 1a and potassium (E)-styryltri-
fluoroborate as model substrates. Palladium(II) sources
such as Pd(OAc)2 and (η3-C3H5)Pd2Cl2 were evaluated with
a variety of electron-rich ligands. XPhos (Figure 1)
in combination with both Pd sources afforded good
conversion to the desired product. However, an in-
creased amount of homocoupling was detected in the
presence of Pd(OAc)2. The combination of K2CO3 and
THF/H2O (4:1) proved to be the most effective reaction
system, leading to high conversions to the β,γ-unsatu-
rated ester.
Subsequently, the second generation Buchwald precata-
lyst, XPhos-Pd-G2 (Figure 1)16 was evaluated in comparison
to the (η3-C3H5)Pd2Cl2/XPhos system. An increased reaction
rate was observed, and the catalyst loading could be reduced
to 0.5 mol % on a 0.5 mmol reaction scale. Additionally,
1.05 equiv of potassium trifluoroborate was sufficient to
obtain 3a in 96% yield after 8 h (Table 1, entry 1).
a Reaction conditions: 2-chloroacetamide (0.5 mmol), potassium
alkenyltrifluoroborate (0.525 mmol, 1.05 equiv), K2CO3 (1.5 mmol,
3 equiv), XPhos-Pd-G2 (5 μmol, 1 mol %), solvent (2 mL), 80 °C.
suitable substrates, leading to stereocontrolled β,γ-unsa-
turated ester products in high yield. The crude 1H NMR
spectra of the reactions reveal that none of the R,β-
unsaturated regioisomers of the desired products are
formed under the optimized conditions, and the (Z)-1-
decenyltrifluoroborate (entry 3) was transformed with
complete stereospecificity. However, some E/Z isomeriza-
tion was observed with cis-propenyl and cis-styrenyl sub-
strates (Table 1, entries 16 and 17, and Table 2, entry 6).
Thus, although the commercially obtained starting mate-
rials for these two contained∼5% of the corresponding(E)
isomers, the cross-coupled products contained about
10À12% of the diastereomer. The levels of the trans
isomers that appeared in the final product could not be
accounted for soley by preferential reaction of the (E)
isomeric starting material, and thus an isomerization event
Once the optimal conditions were determined, various
potassium (E)- and (Z)-alkenyltrifluoroborates were
evaluated in the cross-coupling reaction with benzyl
2-chloroacetate 1a as shown in Table 1. Unstabilized
(E)- and (Z)-alkenyltrifluoroborates were illustrated to be
(16) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (b)
Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
14073.
Org. Lett., Vol. XX, No. XX, XXXX
C

occurred either during the cross-coupling event or upon
formation of the final product.17
moderate yields were observed under the initial reaction
conditions. Increasing the catalyst loading of XPhos-Pd-
G2 to 1 mol % was sufficient for the cross-coupling of
N-benzyl-2-chloroacetamide 4a with various alkenyltri-
fluoroborates as shown in Table 2. An allylic amide that
has been demonstrated to be an important substrate in
domino hydrocarbonylation reactions18 and ring-closing
metathesis19 was obtained in good yields (Table 2, entry 4).
In addition to N-benzyl-2-chloroacetamide 3a, several
other R-chloroacetamides were successfully employed as
the electrophilic coupling partners (Table 3). Primary,
secondary, and tertiary amides were successfully cross-
coupled under the same reaction conditions. A cyclic,
fluorinated alkenyltrifluoroborate was shown to react in
good yield under the employed conditions (Table 3, entry 9).
In summary, a simple, scalable, and general protocol to
obtain stereoselective, functionalized (E)- and (Z)-β,γ-
unsaturated esters as well as primary, secondary, and
tertiary amides through mild cross-coupling conditions
with low catalyst loading is disclosed. All reaction compo-
nents are air-stable and are easily prepared or obtained
from commercial sources.
The reaction conditions were shown to be compatible
with a potassium alkenyltrifluoroborate containing a ni-
trile group, which afforded the desired product in high
yield (Table 1, entry 7). A cyclic substrate was also shown
tobe a viablenucleophilic partner in the employed reaction
conditions (Table 1, entry 6). The scalable nature of the
reaction conditions was illustrated by the ability to reduce
the Pd loading to 0.25 mol % on a 5.0 mmol scale without a
significant decrease in reaction yield (Table 1, entry 2).
Isopropyl and tert-butyl 2-chloroacetates (1c, 1b) were
also evaluated as electrophilic coupling partners in the
optimized reaction conditions. Both esters showed good
selectivity. However, only moderate yields of the desired
products were achieved (Table 1, entries 9À11). To illus-
trate the advantageous nature of these reaction conditions
in terms of functional group compatibility, benzyl chlor-
oacetatewascross-coupled withsubstratesbearinganalkyl
chloride (Table 1, entry 12), a tertiary amine (Table 1,
entry 13), and benzyl and THP-protected alcohols
(Table 1, entries 14À15).
The reactivity of 2-chloroacetamides in the cross-cou-
pling with potassium alkenyltrifluoroborates was subse-
quently investigated. Longer reaction times were necessary
to allow the reaction to proceed to completion, and
Acknowledgment. The NIH (NIGMS R01 GM035249)
and NSF (GOALI) are acknowledged for funding of this
research. The National Council for Scientific and Techno-
logical Development (CNPq-Brazil) is acknowledged for
funding the postdoctoral fellowship of Dr. Thiago Barcellos.
Dr. Rakesh Kohli (University of Pennsylvania) is acknowl-
edged for acquisition of HRMS spectra.
(17) (a) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67,
4627. (b) Lloyd-Jones, G. C.; Tan, E. H. P.; Harvey, J. N.; Lennox,
A. J. J.; Mills, B. M. Angew. Chem., Int. Ed. 2011, 50, 9602.
(18) (a) Cini, E.; Airiau, E.; Girard, N.; Mann, A.; Salvadori, J.;
Taddei, M. Synlett 2011, 2, 199. (b) Airiau, E.; Spangenberg, T.; Girard,
N.; Schoenfelder, A.; Salvadori, J.; Taddei, M.; Mann, A. Chem.;Eur.
J. 2008, 14, 10938. (c) Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem.
1991, 56, 2024.
Supporting Information Available. Complete experi-
mental procedures and characterization data (1H and 13
C
(19) (a) Yun, J. I.; Kim, H. R.; Kim, S. K.; Kim, D.; Llee, J.
ꢀ
NMR, IR, and HRMS). This material is available free of
charge via the Internet at http://pubs.acs.org.
Tetrahdron 2012, 68, 1177. (b) Baron, A.; Verdie, P.; Martinez, J.;
ꢀ
Lamaty, F. J. Org. Chem. 2011, 76, 766. (c) Arrayaz, R. G.; Alcudia,
A.; Liebeskind, L. S. Org. Lett. 2001, 3, 3381. (d) Fu, G. C.; Grubbs,
R. H. J. Am. Chem. Soc. 1992, 114, 7324.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX