Synthesis of alkyl aryl ketones by Pd/light induced carbonylative cross-coupling of alkyl iodides and arylboronic acids

Article abstract of DOI:10.1021/ol401363t

Alkyl aryl ketones were synthesized by the carbonylative cross-coupling reaction of alkyl iodides and arylboronic acids under combined Pd/light conditions. In this reaction, it is likely that an acylpalladium species would be formed via carbonylation of t

Full text of DOI:10.1021/ol401363t

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of Alkyl Aryl Ketones
by Pd/Light Induced Carbonylative
Cross-Coupling of Alkyl Iodides
and Arylboronic Acids
Shuhei Sumino, Takahito Ui, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received May 15, 2013
ABSTRACT
Alkyl aryl ketones were synthesized by the carbonylative cross-coupling reaction of alkyl iodides and arylboronic acids under combined Pd/light
conditions. In this reaction, it is likely that an acylpalladium species would be formed via carbonylation of the alkyl radical, which would then
undergo transmetalation of an arylboronic acid to give the corresponding acyl(aryl)palladium species, ready to undergo reductive elimination to
yield the alkyl aryl ketone.
Carbonylation reactions with carbon monoxide have
found magnificent applications in organic synthesis as a
means for the synthesis of a wide variety of carbonyl
compounds.1 Transition-metal catalyzed carbonylative
cross-coupling reaction of organo halides, such as aryl,
vinyl, and allyl halides,2À4 with organometallic species
provides useful access to unsymmetrical ketones.5 Alkyl
aryl ketones are generally synthesized via the Type 1
strategy shown in Scheme 1, which involves the oxidative
addition of aromatic halides to the metal center to give
arylmetal complexes, CO insertion, and alkylation to
form aroylalkylmetal species as a precursor to alkyl aryl
ketones.2 On the other hand, the Type 2 reaction based
on the oxidative addition of alkyl halides to the metal
center is relatively scarce in the literature.6 This is pre-
sumably due to the fact that the resulting alkylmetal
species would suffer from β-elimination and subsequent
isomerization.7,8
(6) For Pd catalysis, see: (a) Shimizu, R.; Fuchikami, T. Tetrahedron
Lett. 1996, 37, 8405. (b) Shimizu, R.; Fuchikami, T. Tetrahedron Lett.
2001, 42, 6891. (c) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc.
2010, 132, 12823. For Pt catalysis, see: (d) Kondo, T.; Tsuji, Y.;
Watanabe, Y. J. Organomet. Chem. 1988, 345, 397.
€
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(1) (a) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6, 1097.
€
(b) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2009, 48, 4114. (c) Tsuji, J. Palladium Reagents and Catalysis: Innova-
tions in Organic Synthesis; Wiley: Chichester, 1995. (d) Carbonylation:
Direct Synthesis of Carbonyl Compounds; Colquhoun, H. M., Thompson,
D. J., Twigg, M. V., Eds.; Plenum Press: New York, 1991. (e) Ryu, I.; Sonoda,
N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (f) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. Rev. 1996, 96, 177. (g) Ryu, I. Chem. Soc. Rev. 2001,
30, 16.
(2) For reviews on carbonylative cross-coupling reactions leading to
unsymmetrical ketones, see: Wu, X. F.; Neumann, H.; Beller, M. Chem.
Soc. Rev. 2011, 40, 4986.
(3) For earlier work on the synthesis of unsymmetrical ketones using
metal carbonyl complexes, see: (a) Hirota, Y.; Ryang, M.; Tsutsumi, S.
Tetrahedron Lett. 1971, 1531. (b) Rhee, I.; Ryang, M.; Watanabe, T.;
Omura, H.; Murai, S.; Sonoda, N. Synthesis 1977, 776. (c) Cooke, M. P.,
Jr.; Parlman, R. M. J. Am. Chem. Soc. 1979, 99, 5222. Also see ref 1b.
(4) For selected examples, see: (a) Tamaru, Y.; Ochiai, H.; Yamada,
Y.; Yoshida, Z. Tetrahedron Lett. 1983, 24, 3869. (b) Yasui, K.; Fugami,
K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 1365.
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(7) For efforts by ligand design, see: (a) Cardenas, D. J. Angew.
€
Chem., Int. Ed. 2003, 42, 384. (b) Netherton, M. R.; Dai, C.; Neuschutz,
K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (c) Neuschutz, M. R.;
€
Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945. (d) Kirchhoff,
J. H.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910. (e) Kirchhoff,
J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 13662. (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527.
(g) Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Commun.
2007, 825. (h) Hadei, N.; Kantchev, E. A. B.; O’Brie, C. J.; Organ, M. G.
J. Org. Chem. 2005, 70, 8503. (i) Hadei, N.; Kantchev, E. A. B.; O’Brie,
C. J.; Organ, M. G. Org. Lett. 2005, 7, 3805. Also see rewiews: (j) Luh,
T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev. 2000, 100, 3187. (k)
Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Adv. Synth. Catal. 2004,
346, 346. (l) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44,
674. (m) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545.
(n) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(o) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(p) Hu, X. Chem. Sci. 2011, 2, 1867.
(5) For radical-mediated synthesis of unsymmetrical ketones, see:
Kim, S. Adv. Synth. Catal. 2004, 346, 19. Also see refs 1e and 1f.
(8) Urata, H.; Maekawa, H.; Takahashi, S.; Fuchikami, T. J. Org.
Chem. 1991, 56, 4320.
r
10.1021/ol401363t
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sparingly soluble in benzene, and therefore we added water
to increase its solubility. The addition of 0.1 mL of water to
4 mL of benzene dramatically increased the yield of 3a up
to 57%.12 To our delight, when 2 mL of water were
added to 4 mL of benzene, 3a was obtained in 92% yield.
The reaction in the absence of the Pd catalyst did not take
place, and the use of thermal conditions (80 °C) in the dark
gave 3a in very low yield.
Scheme 1. Strategies for Alkyl Aryl Ketone Synthesis by
Transition-Metal Catalyzed Carbonylation
Scheme 2. Reaction of 1-Iodooctane (1a) and Phenylboronic
Acid (2a) To Give Nonanophenone (3a)
Thus far our group has focused on the potential of the
Pd/light-induced system for the carbonylation of alkyl
iodides and we have previously reported the synthesis of
aliphatic carboxylic acid derivatives9 and alkyl alkynyl
ketones.10 A key to the success of this approach may lie
in the employment of the free radical pathway9c which
favors formation of the key acylmetal species. In this
manner, the system can circumvent the problematic
formation of the alkylmetal species prior to CO insertion.
Webelievedthat a similar approach shouldenablea Type 2
strategy for the synthesis of alkyl aryl ketones starting
from alkyl halides as the substrate. We were pleased to
discover that, with arylboronic acids coupling partners,
alkyl aryl ketones could be synthesized effectively from
alkyl iodides and CO under Pd/light induced reaction
conditions.11
We then examined the generality of the carbonylative
coupling reaction using a variety of alkyl iodides and
arylboronic acids, whose results are summarized in Table 1.
Similarly as in the case of 1a, substituted primary alkyl
iodides 1b, 1c, and 1d gave the corresponding unsymme-
trical ketones 3b, 3c, and 3d in good yields (entries 2À4).
Both cyclic and linear secondary alkyl iodides 1e and 1f
gave the corresponding ketones 3e and 3f in good yields
(entries 5 and 6). We also examined the reactivity of tertiary
alkyliodides1gand 1h. The reaction of 1-adamantyl iodide
(1g) with CO and 2a gave adamantyl phenyl ketone (3g) in
78% yield, whereas the reaction of tert-butyl iodide (1h)
gave only a modest yield of ketone 3h (entries 7 and 8,
respectively). A variety of boronic acids 2bÀ2h were also
shown toparticipate inthe unsymmetrical ketone synthesis
(entries 9À15). For example, the reaction of 1a with
2-naphthylboronic acid (2b) and p-methoxyphenylboronic
acid (2c) gave 3i and 3j in 80 and 92% yields, respectively.
However, the reaction of p-trifluoromethyl-substituted
phenylboronic acid 2d gave the desired ketone 3k in
only 21% yield. In this reaction the anhydride of non-
anoic acid was formed as the major carbonyalted
product.13 The use of a 5-fold excess of 1a relative to 2d
resulted in an increase in the yield of 3k to 63% (entry 11).
F- and Br-substituted arylboronic acids 2f and 2g gave
the corresponding ketones with the halogen remaining
intact (entries 13 and 14). The reaction of cyclopropyl-
methyl iodide (1i) and 2a gave the ring-opened ketone 3p,
generated by the cyclopropylcarbinyl radical to
As a model reaction we chose the reaction of 1-iodooc-
tane (1a) and phenylboronic acid (2a) (Scheme 2). When a
mixture of 1a, 2a, K2CO3, and a catalytic amountofPdCl2-
(PPh3)2 (5 mol %) was irradiated under 45atm of COusing
a xenon lamp (500 W) through a Pyrex filter, nonanophe-
none (3a) was obtained in 6% yield. Phenylboronic acid is
(9) (a) Ryu, I.; Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi,
Y.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124, 3812. (b)
Fukuyama, T.; Nishitani, S.; Inouye, T.; Morimoto, K.; Ryu, I. Org.
Lett. 2006, 8, 1383. (c) Fukuyama, T.; Inouye, T.; Ryu, I. J. Organomet.
Chem. 2007, 692, 685. (d) Fusano, A.; Sumino, S.; Fukuyama, T.; Ryu, I.
Org. Lett. 2011, 13, 2114. (e) Fusano, A.; Sumino, S.; Nishitani, S.;
Inouye, T.; Morimoto, K.; Fukuyama, T.; Ryu, I. Chem.;Eur. J. 2012,
18, 9415.
(10) Fusano, A.; Fukuyama, T.; Nishitani, S.; Inouye, T.; Ryu, I.
Org. Lett. 2010, 12, 2410.
(11) For the synthesis of unsymmetrical ketones using 9-BBN derived
reagents, see: (a) Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron
Lett. 1991, 32, 6923. (b) Ishiyama, T.; Murata, M.; Suzuki, A.; Miyaura,
N. J. Chem. Soc., Chem. Commun. 1995, 295.
(12) While the SuzukiÀMiyaura coupling product was not formed,
nonanoic acid anhydride was formed as the byproduct.
(13) Acid anhydrides are formed as byproducts in the cases where the
yields of ketones are not high. For a similar observation, see ref 10.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Synthesis of Alkyl Aryl Ketones 3 by Carbonylative
Coupling of Alkyl Iodides 1 and Arylboronic Acids 2a
Scheme 3. Four-Component Cascade Carbonylation Reactions
We then examined four-component cascade reactions
(Scheme 3). When the reaction of 5-iodo-1-pentene (1j)
and 2a was carried out, double carbonylation accompa-
nied with cyclization took place to give aryl ketone 3q
bearing a cyclopentanone scaffold, in 57% yield. The four-
component reaction comprising ethyl iodoacetate (4),
1-octene (5), CO, and 2a also proceeded smoothly to give
the expected functionalized ketone 6 in 62% yield. These
results demonstrated that the present Pd/light-induced
carbonylative cross-coupling reactions can be readily com-
bined with radical cascade reactions.
Scheme 4. Radical/Metal Relay Mechanism
a Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), PdCl2(PPh3)2
(5.0 mol %), K2CO3 (1.0 mmol), C6H6 (4 mL), H2O (2 mL), hν (Xe lamp,
Pyrex), 16 h, rt. b Isolated yield. c 1a (2.5 mmol), 2d (0.5 mmol),
PdCl2(PPh3)2 (5.0 mol %), K2CO3 (1.0 mmol), C6H6 (4 mL), H2O
(2 mL), hν (Xe lamp, Pyrex), 40 h, rt.
(15) For examples of an electron transfer from low valent palladium
or platinum complexes to iodoalkanes, see: (a) Kramer, A. V.; Osborn,
J. A. J. Am. Chem. Soc. 1974, 96, 7832. (b) Kramer, A. V.; Labinger,
J. A.; Bradley, J. S.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7145.
(c) Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 205.
Also see ref 9e.
(16) For SET induced radical reactions of perfluoroalkyl iodides, see:
(a) Chen, Q. Y.; Yang, Z. Y.; Zhao, C. X.; Qiu, Z. M. J. Chem. Soc.,
Perkin Trans. 1 1988, 563. (b) Qiu, Z. M.; Burton, D. J. J. Org. Chem.
1995, 60, 5570. (c) Iizuka, M.; Yoshida, M. J. Fluorine Chem. 2009, 130,
926.
undergo a homoallyl radical ring-opening reaction
(entry 16).14
(14) (a) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113,
5699. (b) Newcomb, M. Tetrahedron 1993, 49, 1151.
Org. Lett., Vol. XX, No. XX, XXXX
C

The proposed mechanism for the Pd/light carbonylation
reaction is shown in Scheme 4, taking the conversion of 1j
to 3q as an example. In the first step, 1j would react with
Pd(0) under irradiation conditions toaffordalkyl radicalA
and Pd(I)I by a one-electron transfer.15,16 Under the
employed pressurized CO conditions, the resulting
alkyl radical A would be quickly converted to acyl
radical B17 which then undergoes 5-exo cyclization to
give alkyl radical C. Then, the alkyl radical C would
add to a second molecule of CO to form acyl radical D.
Acyl radical D would couple with Pd(I)I to form
acylpalladium intermediate E. Transmetalation of 2a
with E would give F, which undergoes reductive elimina-
tion to give the product 3q with accompanying libera-
tion of Pd(0).
In summary, we have demonstrated that the carbonyla-
tive coupling reaction of alkyl iodides, CO, and arylboro-
nic acids proceeds effectively in a combined Pd/light
reaction system to give good yields of alkyl aryl ketones.
Extension of this methodology to four-component coupl-
ing reactions is also possible. Unlike typical organo-
metallic reagents, arylboronic acids are readily available
and easily handled in air, and this presents an attractive
feature of the carbonylation method reported herein.
Acknowledgment. We thank JSPS and MEXT, Japan
for generous financial support of this work.
Supporting Information Available. Experimental pro-
cedure and compound characterization. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(17) The primary alkyl radical adds to CO at the rate constant of 2.1 Â
105 sÀ1 at 60 °C. See: Nagahara, K.; Ryu, I.; Kambe, N.; Komatsu, M.;
Sonoda, N. J. Org. Chem. 1995, 60, 7384 and references cited therein.
The authors declare no competing financial interest.
D
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