Palladium-catalyzed β-arylation of silyl ketene acetals and application to the synthesis of benzo-fused δ-lactones

Article abstract of DOI:10.1021/ol402398s

Silyl ketene acetals are shown to be competent nucleophiles in Pd-catalyzed migrative C(sp³)-H arylations. Compared to the parent ester lithium enolates, they possess decreased reactivity but enhanced chemoselectivity. This behavior was exploited through the synthesis of valuable benzo-fused δ-lactones such as 1-isochromanones and dihydrocoumarins.

Full text of DOI:10.1021/ol402398s

ORGANIC
LETTERS
2013
Vol. 15, No. 19
5056–5059
Palladium-Catalyzed β‑Arylation of Silyl
Ketene Acetals and Application to the
Synthesis of Benzo-Fused δ‑Lactones
ꢀ
ꢀ
Sam Aspin, Laura Lopez-Suarez, Paolo Larini, Anne-Sophie Goutierre,
Rodolphe Jazzar, and Olivier Baudoin*
ꢀ
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, CNRS UMR 5246,
Universite Claude Bernard Lyon 1, CPE Lyon, 43 Boulevard du 11 Novembre 1918,
ꢀ
ꢀ
69622 Villeurbanne, France
olivier.baudoin@univ-lyon1.fr
Received August 20, 2013
ABSTRACT
Silyl ketene acetals are shown to be competent nucleophiles in Pd-catalyzed migrative C(sp3)ÀH arylations. Compared to the parent ester lithium
enolates, they possess decreased reactivity but enhanced chemoselectivity. This behavior was exploited through the synthesis of valuable benzo-
fused δ-lactones such as 1-isochromanones and dihydrocoumarins.
The metal-catalyzed functionalization of nonacidic
C(sp3)ÀH bonds in alkane fragments of organic molecules
is both a topic of current great interest and a very challen-
ging problem.1 In this context, a number of methods re-
lying on the introduction of a powerful directing group
have been successfully introduced for the intermolecular
arylation of unactivated C(sp3)ÀH bonds.2 We recently
reported the intermolecular palladium(0)-catalyzed mi-
grative CÀH arylation of ester lithium enolates as a
mechanistically distinct alternative to directed C(sp3)ÀH
arylations (Scheme 1a).3 This reaction was shown to occur
via initial formation of a palladium enolate, rearrangement
to the less hindered Pd homoenolate (via β-H elimination,
rotation, and insertion), and reductive elimination.3b,4
Although this method offers a number of advantages com-
pared to directed arylations, including the use of simple
esters, mild reaction temperatures, and the absence of
polyarylated products, we were aware that the generation
of a relatively basic and nucleophilic lithium enolate was
(4) For closely related migrative arylations: (a) Seel, S.; Thaler, T.;
Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P.
J. Am. Chem. Soc. 2011, 133, 4774. (b) Leskinen, M. V.; Yip, K.-T.;
Valkonen, A.; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750. (c) Yip,
K.-T.; Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Chem.;Eur. J. 2012,
18, 12590. (d) Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chem. Sci.
2013, 4, 2241.
(5) (a) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T.
J. Org. Chem. 1991, 56, 261. (b) Galarini, R.; Musco, A.; Pontellini, R.;
Santi, R. J. Mol. Catal. 1992, 72, L11. See also: (c) Sakamoto, T.;
Kondo, Y.; Masumoto, K.; Yamanaka, H. Heterocycles 1993, 36, 2509.
(d) Sakamoto, T.; Kondo, Y.; Masumoto, K.; Yamanaka, H. J. Chem.
Soc., Perkin Trans. 1 1994, 235. (e) Agnelli, F.; Sulikowski, G. A.
Tetrahedron Lett. 1998, 39, 8807. (f) Hama, T.; Liu, X.; Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 11176. (g) Liu, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2004, 126, 5182. (h) Huang, Z.; Liu, Z.; Zhou, J.
J. Am. Chem. Soc. 2011, 133, 15882.
(1) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (b) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902.
(2) Selected papers: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2005, 127, 13154. (b) Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (c) Wang, D.-H.; Wasa,
M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (d) Wasa, M.;
Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886. (e)
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. (f)
Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.; Miura, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2012, 134, 18570.
ꢀ
(3) (a) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.; Kefalidis, C. E.;
Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261. (b) Larini,
P.; Kefalidis, C. E.; Jazzar, R.; Renaudat, A.; Clot, E.; Baudoin, O.
Chem.;Eur. J. 2012, 18, 1932. (c) Aspin, S.; Goutierre, A.-S.; Larini, P.;
Jazzar, R.; Baudoin, O. Angew. Chem., Int. Ed. 2012, 51, 10808.
r
10.1021/ol402398s
Published on Web 09/18/2013
2013 American Chemical Society

detrimental to chemoselectivity with sensitive aryl halides.
To tackle this issue, we turned our attention to silyl ke-
tene acetals (SKAs), initially employed in Pd-catalyzed
R-arylations by Musco, Santi, and co-workers, as milder
surrogates for ester enolates (Scheme 1b).5 Herein, we
report that SKAs show diminished reactivity but enhanced
chemoselectivity compared to lithium enolates in the
β-arylation of esters. The newly developed method was
applied to the synthesis of valuable heterocycles such as
1-isochromanones and dihydrocoumarins.
Table 1. Optimization of the β-Arylation of Amino SKA 1a
entry ligand promoter (equiv) solvent temp (°C) NMR yield (%)a
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
CsF (0.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
NMP
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
100
120
80
0
Scheme 1. β-Arylation of Ester Lithium Enolates and SKAs
0
3
56
0
4
5
24
48
41
17
26
16
0
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CuF2 (0.5)
ZnCl2 (0.5)
LiOAc (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (1.0)
14
6
0
We started to investigate the β-arylation of (E) R-amino
SKA 1a obtained from bis-benzyl-protected alanine
methyl ester,6 with 2-fluorobromobenzene by extension
of our work on the corresponding lithium enolate.3c Reac-
tion parameters were screened extensively, and some re-
presentative examples are presented in Table 1. We first
used conditions adapted from Hartwig and co-workers
with ZnF2 as a promoter in DMF5f,g and tested ligands
L1ÀL3, which previously gave comparable results with
lithium enolates (with a slightly enhanced reactivity for
L3), in combination with PdMe2(TMEDA) (5 mol %) as
the Pdsource (entries 1À3).3c Inthe present case, the ligand
effect was much more pronounced since only ligand L3
showed significant reactivity. In light of this result, we
synthesizednovel analogues ofphosphine L3 (L4ÀL9)7 and
studied the effect of substituents at key positions on their
reactivity(entries 4À9). Wefound thatslight modifications
of the imidazole ring (L4ÀL5, entries 4 and 5), phosphorus
substituents R1 (L6, entry 6), and ortho substituent R2
(L7ÀL9) were detrimental to the reaction efficiency to
variable extents, and thus the initial imidazolylphosphine
L3 could not be outperformed.
0
44
50
48
58 (59)b
100
130
120
a Determined by 1H NMR analysis of the crude mixture using
3-fluorophenylacetonitrile as a standard. b With 10 mol % of L3. Yield
of the isolated product in parentheses.
Next, the effect of other promoters, which have been
previously employed in R-arylations of SKAs,5 was ana-
lyzed (entries 10À13). Zinc fluoride turned out to be by far
the most efficient promoter, and both its zinc and fluoride
components were found to be important (entries 10À12).
DMF was found to be the best solvent (entries 14 and 15),
and the optimal temperature was found to be 120 °C
(entries 16À18). Finally, increasing the amount of ZnF2
to 1 equiv and the ligand loading to 10 mol % slightly
improved the yield, which reached an optimal value of
59% for the isolated product 2a (entry 19). The hydrolyzed
SKA and the unreacted aryl bromide constituted most of
the remaining mass balance. No trace of R-arylated pro-
duct was observed with SKA 1a, similar to the correspond-
ing lithium enolate.3c
(6) Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C. Tetrahedron
1988, 44, 3671.
(7) See the Supporting Information for details. Ligand L7 has been
recently described: Wu, L.; Fleischer, I.; Jackstell, R.; Beller, M. J. Am.
Chem. Soc. 2013, 135, 3989.
(8) Ma, J. S. Chem. Today 2003, 21, 65.
(9) Kunz, H.; Mohr, J. J. Chem. Soc., Chem. Commun. 1988, 1315.
Org. Lett., Vol. 15, No. 19, 2013
5057

Next, the β-arylation of commercially available SKA 1b
(R = Me) was examined, by extension of previous work
with the corresponding lithium enolate (Scheme 2b).3a,b
We deliberately chose to employ aryl bromides with an
ortho electronegative group like in previous studies since
unproductive mixtures of β- and R-arylated products are
obtained in other cases. It was found that the use of SKA
1b greatly expanded the scope of the reaction compared to
the corresponding lithium enolate. Indeed, more sensitive
ortho substituents such as a nitrile (3b), methyl ester (3c),
acetate (3d), and nitro group (3e) can now be employed
with satisfying results, in addition to more inert substitu-
ents like F (3a) which were previously used with the lithium
enolate.3a,b Aryl bromides with multiple substituents also
underwent β-arylation successfully and in a completely
β-selective manner (3fÀi), in addition to a naphthyl bro-
mide (3j). SKA 1b was found to be more reactive than the
more hindered SKA 1a. This allowed the reaction to be run
at 80 °C and to increase functional group tolerance. In-
deed, acetate and nitrogroupswerefound tobe compatible
under these milder conditions. SKA 1b showed enhanced
chemoselectivity but lower reactivity than the correspond-
ing lithium enolate which reacts with 2-fluorobromo-
benzene as low as 30 °C. This is a further indication that
transmetalation is the rate-limiting step of the current
process.
Scheme 2. Scope of the β-Arylation of SKAs
The reaction of TES-protected SKA 1c (mixture of E
and Z isomers), readily available from methyl lactate, was
next studied (Scheme 2c). Of note, the reaction of the
corresponding lithium enolate would be compromised by
the known propensity of such species to decompose at
room temperature.5g,9 Compound 1c successfully under-
went β-arylation; however, similarly as above for SKA 1b
(and contrary to R-amino SKA 1a), an ortho electronega-
tive group on the aryl bromide was required to achieve a
complete β-selectivity. The reaction was again performed
at 120 °C similar to 1a, presumably due to the bulkiness of
SKA 1c. In addition to inert ortho substituents (4aÀc), the
reaction was successfully performed with an ortho cyano
group (4d), furnishing aryllactates 4aÀd in moderate to
good yields. It is noteworthy that the triethylsilyl group
was not cleaved under these reaction conditions. This
method was also applied successfully to differently sub-
stituted o-bromobenzonitriles (4eÀj), which were subse-
quently converted to 1-isochromanones (vide infra).
Some of the above β-arylated products contain reactive
ortho substituents which can be utilized to build original
heterocyclic compounds. As a first application, we were
able to convert aryllactates 4dÀi (Scheme 2c) to 1-isochro-
manones 5dÀi in good yields upon standard treatment
with concentrated sulfuric acid in methanol (Scheme 3).
Overall, this method represents a straightforward and
efficient access to this important class of heterocycles
a At 120 °C. b TES = triethylsilyl.
The optimal conditions were applied to other aryl
bromides, giving rise to valuable precursors of phenyl-
alanine analogues (Scheme 2a).8 Moderate to good yields
were obtained with a variety of electron-withdrawing sub-
stituents, including methyl esters (2d, 2i) and triflates (2e,
2j) which were previously found to be incompatible with
lithium enolates.3c Sensitive acetophenone 2f was also
obtained, albeit in lower yield. More sensitive functional
groups such as OH, NO2, and CHO were found to be
incompatible with these reaction conditions. In addition,
aryl bromides containing electron-donating substituents
such as OMe, NMe2, and OSi(iPr)3 were found to be
essentially unreactive. This behavior indicates that, with
bulky SKA 1a, transmetalation to form the intermediate
Pd enolate is rate-limiting and requires a very reactive
organopalladium ArPd(L)X species with an electron-defi-
cient Ar group to proceed. In addition, the conversion
dropped dramatically at temperatures lower than 80 °C,
whereas the reaction of the corresponding lithium enolate
performed efficiently at 70 °C, thereby pointing also at a
rate-limiting transmetalation with SKA 1a.
(10) (a) Heinrich, M. R.; Wetzel, A.; Kirschstein, M. Org. Lett. 2007,
9, 3833. (b) Venkatesh, C.; Reissig, H.-U. Synthesis 2008, 3605. (c)
Lakshminarayana, N.; Prasad, Y. R.; Gharat, L.; Thomas, A.; Ravikumar,
P.; Narayanan, S.; Srinivasan, C. V.; Gopalan, B. Eur. J. Med. Chem. 2009,
44, 3147. (d) Obushak, M. D.; Matiychuk, V. S.; Turytsya, V. V. Tetra-
hedron Lett. 2009, 50, 6112.
5058
Org. Lett., Vol. 15, No. 19, 2013

Scheme 3. Application to the Synthesis of 1-Isochromanones
Scheme 4. Application to the Synthesis of Dihydrocoumarins
and a Dihydroquinolinone
relevant to medicinal chemistry and natural product
synthesis.10
show decreased reactivity but enhanced chemoselectivity.
This behavior was exploited through the synthesis of
valuable benzo-fused lactones (and one lactam) such as
1-isochromanones and dihydrocoumarins.
In addition, we envisioned that o-acetoxylated β-arylated
products obtained as shown in Scheme 2b might lead to
valuable dihydrocoumarins upon basic hydrolysis of the
acetate and cyclization of the corresponding phenol onto
the methyl ester (Scheme 4a). After a short optimization of
this protocol, dihydrocoumarins 6d, 6i, and 6j were indeed
obtained efficiently.11 Dihydroquinolinones are similarly
interesting compounds for drug discovery.12 From o-nitro-
substituted β-arylated product 3e, a standard hydrogena-
tion in the presence of Pd/C directly afforded dihydroqui-
nolinone 6e in good yield (Scheme 4b).
ꢀ
Acknowledgment. We thank Region Rhone-Alpes
(programme CIBLE), Agence Nationale de la Recherche
^
ꢁ
(programme blanc “EnolFun”), Ministere de l’Enseigne-
ment Superieur et de la Recherche, Institut Universitaire
ꢀ
de France, and Johnson Matthey PLC (loan of palladium
ꢀ
salts). We are also grateful to E. Jeanneau (Universite
Claude Bernard Lyon 1) for X-ray diffraction analyses.
Supporting Information Available. Full characteriza-
tion of all new compounds, detailed experimental proce-
dures, copies of NMR spectra for target molecules, and
X-ray crystal structure data (CIF) for compound 5e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have shown that SKAs are competent
nucleophiles in Pd-catalyzed migrative C(sp3)ÀH aryla-
tions. Compared to the parent ester lithium enolates, they
(11) Posakony, J.; Hirao, M.; Stevens, S.; Simon, J. A.; Bedalov, A.
J. Med. Chem. 2004, 47, 2635.
(12) (a) Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron 2009, 65, 1982. (b)
Felpin, F.-X.; Coste, J.; Zakri, C.; Fouquet, E. Chem.;Eur. J. 2009, 15,
7238.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 19, 2013
5059