Palladium-catalyzed formal hydroacylation of allenes employing acid chlorides and hydrosilanes

Article abstract of DOI:10.1021/ol400862k

The palladium-catalyzed formal hydroacylation of allenes employing acid chlorides and hydrosilanes has been achieved. The reactions proceed with commercially available Pd(OAc)₂ as a catalyst and HSi(iPr) ₃ as a reducing reagent, giving the corresponding α,β-unsaturated ketones regio- and stereoselectively.

Full text of DOI:10.1021/ol400862k

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2286–2289
Palladium-Catalyzed Formal
Hydroacylation of Allenes Employing Acid
Chlorides and Hydrosilanes
Tetsuaki Fujihara, Kenta Tatsumi, Jun Terao, and Yasushi Tsuji*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan
ytsuji@scl.kyoto-u.ac.jp
Received March 29, 2013
ABSTRACT
The palladium-catalyzed formal hydroacylation of allenes employing acid chlorides and hydrosilanes has been achieved. The reactions proceed
with commercially available Pd(OAc)2 as a catalyst and HSi(iPr)3 as a reducing reagent, giving the corresponding R,β-unsaturated ketones regio-
and stereoselectively.
The addition of aldehydes to carbonÀcarbon multiple
bonds, namely hydroacylation, is a useful synthetic method to
produce unsymmetrical ketones.1 However, intermolecular
additions of aldehydes to carbonÀcarbon multiple bonds
such as alkenes or alkynes often suffer from low selectivity
and low yields. To ensurehighefficiency, (i) intramolecular
addition,2 (ii) carbon monoxide pressure,3 (iii) substrates
having proper directing groups,1c,d,4 and (iv) oxidative or
reductive formal hydroacylation employing alcohols1b,5 or
anhydrides6 as acyl donors were often indispensable.
Meanwhile, oxidative addition of acid chlorides to a
metal center is a more facile step than that of aldehydes.7
Thus, acid chlorides were utilized as promising substrates
(1) For reviews, see: (a) Willis, M. C. Chem. Rev. 2010, 110, 725–748.
(b) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202–2209. (c) Park,
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G. C. In Modern Rhodium-Catalyzed Organic Reactions; Evans, A., Ed.;
Wiley-VCH: Weinheim, 2005; pp 79À91.
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Hoshimoto, Y.; Hayashi, Y.; Suzuki, H.; Ohashi, M.; Ogoshi, S. Angew.
Chem., Int. Ed. 2012, 51, 10812–10815. (b) Coulter, M. M.; Dornan,
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Chem. Soc. 2009, 131, 6916–6917. (b) Bower, J.; Skucas, E.; Patman,
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Chem. Soc. 2008, 130, 14120–14122. (e) Shibahara, F.; Bower, J. F.;
Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6338–6339. (f) Patman,
R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 2066–2067. (g) Omura, S.; Fukuyama, T.; Horiguchi, J.;
Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094–14095.
(h) Hatanaka, S.; Obora, Y.; Ishii, Y. Chem.;Eur. J. 2010, 16, 1883–
1888.
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2006, 45, 6885–6888.
(7) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G.
Principles and Applications of Organotransition Metal Chemistry; Uni-
versity Science Books: Mill Valley, CA, 1987; Chapter 5.
(8) (a) Yang, F.-Y.; Wu, M.-Y.; Cheng, C.-H. J. Am. Chem. Soc.
2000, 122, 7122–7123. (b) Yang, F.-Y.; Shanmugasundaram, M.;
Chuang, S.-Y.; Ku, P.-J.; Wu, M.-Y.; Cheng, C.-H. J. Am. Chem. Soc.
2003, 125, 12576–12583.
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Tetrahedron Lett. 1987, 28, 6229–6230.
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von Delius, M.; Le, C. M.; Dong, V. M. J. Am. Chem. Soc. 2012, 134,
15022–15032. (b) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong,
V. M. J. Am. Chem. Soc. 2010, 132, 16330–16333. (c) Murphy, S. K.;
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r
10.1021/ol400862k
Published on Web 04/22/2013
2013 American Chemical Society

in various reactions. Cheng and co-workers reported the
reactions of acid chlorides with allenes in the presence of a
diboron, a disilane, or a distannane.8 Recently, we found
that the iridium-catalyzed addition of acid chlorides to
terminal alkynes gives β-chloro-R,β-unsaturated ketones
regio- and stereoselectively.9 We also reported a palladium
complex catalyzed reduction of acid chlorides with hydro-
silanes to the corresponding aldehydes.10
and HSi(iPr)3, 3aa was not obtained at all. Under other-
wise the same conditions as those for entry 1, HSnBu3
instead of HSi(iPr)3 provided 3aa in 13% yield. Other
reducing reagents such as molecular hydrogen and pina-
colborane in place of the hydrosilane did not afford 3aa at
all. Thus, the combination of acid chlorides and easy-
to-handle hydrosilanes was most suitable to realize the
intermolecular hydroacylation reaction of allenes.
Herein, we report palladium-catalyzed reactions of acid
chlorides with hydrosilanes in the presence of allenes. The
present reaction is regarded as a formal intermolecular
hydroacylation of allenes. As for the hydroacylation of
allenes using aldehydes,11,12 there have been only two
precedents to date, in which the aldehydes must bear
hydroxyl11a or thioether11b functional groups as directing
groups.12 These reactions employing aldehydes as acyl
sources afforded β,γ-unsaturated ketones while R,β-unsa-
turated ketones were obtained regio- and stereoselectively
in the present reaction. Noteworthy is that no directing
groups are necessary in the present reaction.
Table 1. Effect of Hydrosilanes on the Palladium-Catalyzed
Formal Hydroacylation of Cyclohexylallene (1a) Employing
3-Phenylpropionyl Chloride (2a)a
total yield of
3aa (%)b
(E)-3aa/
isomersc
entry
hydrosilanes
First, a reaction of 3-phenylpropionyl chloride (1a) with
cyclohexylallene (2a) was carried out employing various
hydrosilanes in the presence of a catalytic amount of
Pd(OAc)2 at 50 °C (Table 1). Employing HSi(iPr)3 as a
hydrosilane, a mixture of R,β-unsaturated ketones (3aa)
was obtained in 96% total yield with high (E)-3aa selectiv-
ity ((E)-3aa/other isomers = 96/4, entry 1). Here, neither
the reduction of 1a to 3-phenylpropanal nor hydrosilyla-
tion of 2a proceeded at all. Furthermore, there was no
indication of styrene formation via decarbonylation of 1a
followed by the β-hydrogen elimination. By silica gel
column chromatography, pure (E)-3aa was isolated in
92% yield (entry 1). Employing HSiEt3, HSiPh3, HSi(OEt)3,
or polymethylhydrosiloxane (PMHS) as the hydrosi-
lane, the yield of 3aa decreased considerably (entries 2À5).
With H2SiPh2 or H3SiPh3 (entries 6 and 7), yields of 3aa
were low and the reduction of 1a to 3-phenylpropanal
occurred to some extent. Under the reaction conditions of
entry 1, other Pd catalysts such as PdCl2(PhCN)2 and
Pd(dba)2 similarly afforded 3aa in 96% yields. However,
with the addition of PPh3 orPCy3 tothe entry 1 conditions,
the reaction ceased completely (entries 8 and 9). 1,4-
Dioxane, 1,2-dichloroethane, and acetonitrile were as
effective as toluene as a solvent, and 3aa was afforded in
84%, 83%, and 93% yields, respectively, with high selec-
tivity ((E)-3aa/isomers = 96/4). DMF as a solvent gavethe
products only in 28% yield with low selectivity ((E)-3aa/
isomers = 70/30). When the corresponding aldehyde,
3-phenylpropanal, was used instead of a mixture of 1a
1
HSi(iPr)3
HSiEt3
96 (92)d
96/4
94/6
94/6
94/6
90/10
93/7
74/26
À
2
76
69
68
46
28
12
0
3
HSiPh3
4
HSi(OEt)3
PMHSe
5
6
H2SiPh2
H3SiPh
7
8f
9g
HSi(iPr)3
HSi(iPr)3
0
À
a Reaction conditions: 3-phenypropionyl chloride (1a, 0.20 mmol),
cyclohexylallene (2a, 0.22 mmol), hydrosilane (0.22 mmol), Pd(OAc)2
(0.0050 mmol, 2.5 mol %), in toluene (0.40 mL), at 50 °C, for 18 h. b Yield
by the GC internal standard method. c Selectivity of (E)-3aa. The
isomers consist of (Z)-3aa and another isomeric product (GCMS and
NMR). d Isolated yield of (E)-3aa with 0.40 mmol of 1a scale. e Poly-
methylhydrosiloxane. f A mixture of Pd(OAc)2 (0.0050 mmol) and
PPh3 (0.010 mmol) was used as the catalyst. g A mixture of Pd(OAc)2
(0.0050 mmol) and PCy3 (0.010 mmol) was used as the catalyst.
Under the optimum conditions of entry 1 in Table 1,
various acid chlorides (1bÀm) afforded the corresponding
(E)-R,β-unsaturatedketones ((E)-3baÀma) ingood tohigh
isolated yields (Table 2). The regio- and stereochemistry of
all the isolated products were unambiguously determined
utilizing 2D NMR. The structure of 3la was alsoconfirmed
by a single-crystal X-ray diffraction study (see Supporting
Information for details). Aliphatic acid chlorides (1bÀf)
gave the corresponding products (3baÀfa) in good to high
yields. Ester functional groups were tolerated in the reac-
tion (entry 3). With pivaroyl chloride (1e) as a substrate, an
E/Z mixture of 3ea was obtained in 82% crude yield with a
ratio of E/Z = 81/19. From the mixture, (E)-3ea was
isolated in 54% yield (entry 4). Phenylacetyl chloride (1f)
afforded the corresponding adduct in 84% yield (entry 5).
Various benzoyl chloride derivatives (1gÀk) having electron-
donating (1h) and electron-withdrawing substituents (1iÀk)
afforded 3gaÀka in good to high yields (entries 6À10).
Under the reaction conditions, bromo as well as chloro
functional groups on phenyl rings remained intact (entries 9
and 10). 2-Naphthoyl chloride (1l) and 2-thienoyl chloride
(9) (a) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc.
2012, 134, 1268–1274. (b) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y.
J. Am. Chem. Soc. 2009, 131, 6668–6669.
(10) Fujihara, T.; Cong, C.; Iwai, T.; Terao, J.; Tsuji, Y. Synlett 2012,
23, 2389–2392.
(11) (a) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303–311. (b) Osborne, J. D.;
Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am.
Chem. Soc. 2008, 130, 17232–17233.
(12) Recently, Murakami and co-workers reported the rhodium-
catalyzed 1:2 coupling of aldehydes and allenes: Toyoshima, T.; Miura,
T.; Murakami, M. Angew. Chem., Int. Ed. 2011, 50, 10436–10439.
Org. Lett., Vol. 15, No. 9, 2013
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Phenylallene derivatives (2eÀg) also gave the adducts
efficiently (entries 4À6). Boryl- and silyl-substituted allenes
(2h and 2i) afforded the corresponding R,β-unsaturated
ketones (3ah and 3ai) in good isolated yields (entries 7 and 8).
Table 2. Palladium-Catalyzed Formal Hydroacylation of 2a
Employing Various Acid Chlorides (1) and HSi(iPr)3
a
Table 3. Palladium-Catalyzed Formal Hydroacylation of
Various Allenes (2) Employing 1a and HSi(iPr)3
a
a Reaction conditions: 1a (0.50 mmol), allene (2, 0.55 mmol),
HSi(iPr)3 (0.55 mmol), Pd(OAc)2 (0.0125 mmol, 2.5 mol %), toluene
(1.0 mL) at 50 °C for 18 h. b Isolated yield of (E)-3abÀai. c At 60 °C.
Besides monosubstituted allenes, disubstituted allenes
afforded the corresponding R,β-unsaturated ketones
(Scheme 1). The reaction employing a symmetrical 1,1-
disubstituted allene (2j) afforded the corresponding adduct
(3aj) in high isolated yield (Scheme 1a). An unsymmetrical
1,1-disubstituted allene (2k) gave an E/Z mixture of the
adducts in 77% total yield (Scheme 1b). A 1,3-disubsti-
tuted allene (2l) reacted with 1a at 80 °C and gave the
products in moderate yield with poor stereoselectivity
(63:38) (Scheme 1c). Gratifyingly, norbornene (4) could
be employed in the reaction (Scheme 2). With 1a, 1g, and
1n, the reaction afforded 5a, 5g, and 5n in 78%, 72%, and
68% yields in a highly exo-selective manner.
a Reaction conditions: acid chloride (1, 0.50 mmol), 2a (0.55 mmol),
HSi(iPr)3 (0.55 mmol), Pd(OAc)2 (0.0125 mmol, 2.5 mol %), toluene
(1.0 mL) at 50 °C for 18 h. b Isolated yield of (E)-3baÀma.
(1m) gave the corresponding products (3la and 3ma) in
good yields (entries 11 and 12).
Various monosubstituted allenes (2bÀi) were smoothly
converted to the corresponding R,β-unsaturated ketones
(3abÀ3ai) in good to high yields with high (E)-selectivity
(entries 1À8, Table 3). An allene bearing a tertiary
alkyl moiety (2d) gave the product smoothly (entry 3).
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Org. Lett., Vol. 15, No. 9, 2013

Scheme 1. Reactions of 1a with 1,1- or 1,3-Disubstituted Allenes
Scheme 3. A Plausible Catalytic Cycle
Scheme 2. Reactions with Norbornene (4)
In conclusion, we have developed the palladium-catalyzed
formal hydroacylation of allenes employing acid chlorides
and hydrosilanes. The reactions afforded R,β-unsaturated
ketones regio- and stereoselectively without any directing
group on the acid chlorides. Further studies on applications
and the reaction mechanism are now in progress.
A possible catalytic cycle is shown in Scheme 3. First, the
oxidative addition of acid chlorides (1) to an active
palladium(0) species affords an acylpalladium species A
(step a). Successful insertion of an allene (2) before the
decarbonylation gives a π-allylpalladium intermediate B
(step b). Then, reaction of B with a hydrosilane gives a
hydridopalladium intermediate (C) (step c). Finally, re-
ductive elimination provides an R,β-unsaturated ketone
(3) and the palladium(0) species regenerates (step d).
Consistent with the mechanism, the reaction of 1a with
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovative Areas (“Organic
synthesis based on reaction integration” and “Molecular
activation directed toward straightforward synthesis”)
from MEXT, Japan.
13
Supporting Information Available. Experimental pro-
cedures and characterization of the products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
2e in the presence of DSi(iPr)3 afforded the adduct
(E)-3ae-d in 61% isolated yield with 99% D incorporation
at the methyl position (eq 1).
(13) Ogata, K.; Atsuumi, Y.; Fukuzawa, S. Org. Lett. 2010, 12, 4536–
4539.
The authors declare no competing financial interest.
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