Palladium-catalyzed oxidative coupling of trialkylamines with aryl iodides leading to alkyl aryl ketones

Article abstract of DOI:10.1021/ol200404z

Chemical equations presented. A new, simple method for selectively synthesizing alkyl aryl ketones has been developed by palladium-catalyzed oxidative coupling of trialkylamines with aryl iodides. In the presence of PdCl₂(MeCN)₂, TBAB, and ZnO, a variety of aryl iodides underwent an oxidative coupling reaction with tertiary amines and water to afford the corresponding alkyl aryl ketones in moderate to excellent yields. It is noteworthy that this method is the first example of using trialkylamines as the carbonyl sources for constructing alkyl aryl ketone skeletons.

Full text of DOI:10.1021/ol200404z

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2184–2187
Palladium-Catalyzed Oxidative Coupling
of Trialkylamines with Aryl Iodides
Leading to Alkyl Aryl Ketones
Yan Liu,† Bo Yao,† Chen-Liang Deng,*,† Ri-Yuan Tang,† Xing-Guo Zhang,† and
Jin-Heng Li*,‡
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035,
China, and College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
jhli@hunnu.edu.cn; dengchenliang78@tom.com
Received February 14, 2011
ABSTRACT
A new, simple method for selectively synthesizing alkyl aryl ketones has been developed by palladium-catalyzed oxidative coupling of
trialkylamines with aryl iodides. In the presence of PdCl2(MeCN)2, TBAB, and ZnO, a variety of aryl iodides underwent an oxidative coupling
reaction with tertiary amines and water to afford the corresponding alkyl aryl ketones in moderate to excellent yields. It is noteworthy that this
method is the first example of using trialkylamines as the carbonyl sources for constructing alkyl aryl ketone skeletons.
Alkyl aryl ketones are a valuable class of compounds in
chemistry and biology that have been widely used in the
pharmaceutical, fragrance, dye, agrochemical, and func-
tional material industries as well as in organic synthesis.1
For these reasons, considerable effort has been made on
the development of efficient methods for alkyl aryl
ketone synthesis.1À6 Among these methods, palladium-
catalyzed coupling reactions are particularly attractive
because they can avoid the use of both hazardous reagents
and excess stoichiometric catalysts by comparison with the
traditional FriedelÀCrafts acylation,2 as well as chelation
assistance by comparison with hydroacylation of olefins
and acylation of arenes.3,4 However, the carbonyl sources
for palladium-catalyzed coupling reactions with aryl ha-
lides are restricted with N-pyrazyl aldimines, N-tert-
butylhydrazones,5 or aldehydes.6 Moreover, aldehydes
often require a chelating auxiliary on them or the in
situ generation of the enamine intermediates with
pyrrolidine.6 Here, we report a novel method for the
synthesis of alkyl aryl ketones from palladium-cata-
lyzed oxidative coupling of aryl iodides with trialkyl-
amines (eq 1). To the best of our knowledge, it is the
first example of using trialkylamines as carbonyl
† Wenzhou University.
‡ Hunan University.
(1) (a) Franck, H. G.; Stadelhofer, J. W. Industrial Aromatic Chem-
istry; Springer-Verlag: Berlin, 1988. (b) Surburg, H.; Panten, J. Common
Fragrance and Flavor Materials, 5th ed.; Wiley-VCH: Weinheim, 2006.
(2) Olah, G. A. FriedelÀCrafts Chemistry; Wiley: New York, 1973.
(3) (a) Negishi, E.-i. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: New York, 2002. (b) Culkin, D. A.;
Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c) Park, Y. J.; Park, J.-W.;
Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (c) Willis, M. C. Chem. Rev.
2010, 110, 725.
(4) (a) Basle, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv. Synth. Catal.
2010, 352, 1145. (b) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org.
Lett. 2009, 11, 3120. (c) Barluenga, J.; Trincado, M.; Rubio, E.;
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Gonzalez, J. M. Angew. Chem., Int. Ed. 2006, 45, 3140. (d) Jia, X.;
Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120. (e)
Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Liu, Y.; Zhou, M.-B.; Wei, W.-T.;
Deng, G.-B.; Yin, D.-L.; Li, J.-H. J. Am. Chem. Soc. 2010, 132, 8900.
(5) (a) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996,
823. (b) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem.
2002, 67, 1682. (c) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed.
2005, 44, 455. (d) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem.
Soc. 2004, 126, 15356. (e) Ishiyama, T.; Hartwig, J. F. J. Am. Chem. Soc.
2000, 122, 12043. (f) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 14800. (g) Vo, G. D.; Hartwig, J. E. Angew. Chem., Int. Ed.
2008, 47, 2127.
(6) (a) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc.
2008, 130, 10510. (b) Colbon, P.; Ruan, J.; Purdie, M.; Xiao, J. Org. Lett.
2010, 12, 3670. (c) Zanardi, A.; Mata, J. A.; Peris, E. Organometallics
2009, 28, 1480. (d) Alvarez-Bercedo, P.; Flores-Gaspar, A.; Correa, A.;
Martin, R. J. Am. Chem. Soc. 2010, 132, 466. (e) Adak, L.; Bhadra, S.;
Ranu, B. C. Tetrahedron Lett. 2010, 51, 3811 and references cited
therein.
r
10.1021/ol200404z
Published on Web 04/07/2011
2011 American Chemical Society

sources through an oxidative deaminization/hydroly-
zation/oxidation process.
Table 1. Palladium-Catalyzed Oxidative Coupling of
Triethylamine (1a) with 4-Iodoansole (2a)a
The reaction of triethylamine (1a) with4-iodoansole(2a)
was carried out to determine the optimal reaction condi-
tions, and the results are summarized in Table 1.7 To our
delight, treatment of triethylamine (1a) with iodide 2a and
PdCl2(MeCN)2 (5 mol %) in DMSO at 100 °C for 16 h
afforded the desired 1-(4-methoxyphenyl)ethanone (3) in
23% yield (entry 1).8 Screening revealed that TBAB
(n-Bu4NBr) could improve the reaction: the yield was
enhanced to 33% in the presence of 1.5 equiv of TBAB
(entry 2). Prompted by the results, three other Pd catalysts,
such as PdCl2, Pd(OAc)2, and Pd(dba)2, were examined,
and they were less effective than PdCl2(MeCN)2 (entries
3À5). Interestingly, ZnO was found to facilitate the reac-
tion (entry 6). In light of these results, a mixture of
additives was tested to enhance the yield of 3 (entries
7À17). As expected, the reaction displayed high activity
in the presence of both TBAB and ZnO: the yield of 3 was
increased sharply to 70% (entry 7). Subsequently, a series
of other solvents, MeCN, DMF, and dioxane, were in-
vestigated, and they lowered the activity (entries 8À10)
The results demonstrated that the amount of both TBAB
and ZnO affected the reaction, and the reaction gave the
best results using 1.5 equiv of TBAB and 1.3 equiv of ZnO
(entries 11À14). Other additives, including ZnBr2, ZnCl2,
ZnF, MgO, and KF, were used to replace ZnO (entries
15À19); however, the efficacy of these additives were
lowered to some extent.7 In particular, the reaction could
not take place in the presence of KF.7 Another controlled
experiment showed that the reaction was also inert when
both ZnO and KF were added (entry 20). These imply that
ZnO is not used as a base to improve the reaction.7 Among
the amounts of PdCl2(MeCN)2 examined, it turned out
that the reaction gave the best results at a loading of
5 mol % of PdCl2(MeCN)2 (entries 7, 21, and 22). It is
noteworthy that the yield is reduced to 37% under argon
atmosphere (entry 23). Surprisingly, the yield was lowered
to 29% using 1 atm of O2 instead of air, and the GCÀMS
analysis results showed that many byproducts were gener-
ated (entry 24). Gratifyingly, the optimal conditions were
consistent with a 0.8 mmol scale of 1a (entry 25).
entry
[Pd] (mol %)
additive (equiv)
solvent yieldb (%)
1
2
3
4
5
6
7
8
9
PdCl2(MeCN)2 (5)
PdCl2(MeCN)2 (5) TBAB (1.5)
PdCl2 (5)
Pd(OAc)2 (5)
Pd(dba)2 (5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
23
33
11
21
9
TBAB (1.5)
TBAB (1.5)
TBAB (1.5)
PdCl2(MeCN)2 (5) ZnO (1.3)
39
70
42
43
28
41
32
45
68
49
52
50
45
trace
trace
64
39
37
29
71
PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) DMSO
PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) MeCN
PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) DMF
10 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) dioxane
11 PdCl2(MeCN)2 (5) TBAB (0.5)/ZnO (1.3) DMSO
12 PdCl2(MeCN)2 (5) TBAB (3)/ZnO (1.3)
13 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (0.5) DMSO
14 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (2) DMSO
15 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnBr2 (1.3) DMSO
16 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnCl2 (1.3) DMSO
17 PdCl2(MeCN)2 (5) TBAB (1.5)/ZnF2 (1.3) DMSO
18 PdCl2(MeCN)2 (5) TBAB (1.5)/MgO (1.3) DMSO
DMSO
19 PdCl2(MeCN)2 (5) TBAB (1.5)/KF (1.3)
DMSO
20c PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO2 (1.3) DMSO
21 PdCl2(MeCN)2 (10) TBAB (1.5)/ZnO (1.3) DMSO
22 PdCl2(MeCN)2 (2) TBAB (1.5)/ZnO (1.3) DMSO
23d PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) DMSO
24e PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) DMSO
25f PdCl2(MeCN)2 (5) TBAB (1.5)/ZnO (1.3) DMSO
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), [Pd], additive,
and solvent (2 mL) at 100 °C for 16 h under air atmosphere. b Isolated
yield. c In the presence of KF (1 equiv). d Under argon atmosphere.
e Under O2 (1 atm). f Substrate 1a (0.8 mmol) and 2a (2.0 mmol) for 32 h.
N-other unsymmetric tertiary amines, such as ethyl-N-
isopropylpropan-2-amine (1d), N,N-diethylbut-3-en-1-
amine (1e), and 2-(diethylamino)ethanol (1f), selectively
furnished 1-(4-methoxyphenyl)ethanone (3) in moderate
yields (entries 3À5). It was interesting to find that another
twice-coupled product 6, 1,2-bis(4-methoxyphenyl)etha-
none, was isolated from the reaction between 2-(diethyl-
amino)ethanol (1f) and iodide 2a (entry 5). However,
1-butylpyrrolidine (1g) was not a suitable substrate for
the reaction under the optimal conditions (entry 6). For
N-benzyl-N-butylbutan-1-amine (1h), only 1-(4-methoxy-
phenyl)ethanone (3) was isolated in 50% yield (entry 7).
Subsequently, the scope of aryl iodides was investigated
in the presence of PdCl2(MeCN)2, TBAB, and ZnO
(Table 3). The results disclosed that a variety of aryl halides
2bÀe and 2gÀk were suitable for the reaction (entries 1À5
and 7À11), but a bulky iodide 2f (entry 6) and aryl
bromides were inert. 4-Iodoaniline, for instance, was
reacted with triethylamine (1a) or tributylamine (1b)
smoothly to afford the corresponding products 7 and 8
in 96% and 87% yields, respectively (entries 1 and 2).
Other iodides, bearing p-Me, m-Me, NHAc, Cl, or CO2Et
groups on the aryl ring, were compatible with the optimal
conditions (entries 4, 5 and 7À10). However, substrate 1f
with an o-Me group was not suitable only providing a trace
of the desiredproduct 12 (entry 6). It is noteworthy that the
With the optimal conditions in hand, the scope of both
trialkylamines and aryl iodides was explored for the oxi-
dative coupling reaction (Tables 2 and 3). As shown in
Table 2, a number of trialkylamines 1 were first examined
by reacting with 4-iodoansole (2a) in the presence of
PdCl2(MeCN)2, TBAB, and ZnO. The results indicated
that tributylamine (1b) and triheptylamine (1c) success-
fully underwent the oxidative coupling reaction with 4-
iodoansole (2a) in good yield (entries 1 and 2). Notably,
(7) Detailed data is available in Table S1 of the Supporting
Information.
(8) Diethylamine was determined by GCÀMS analysis.
Org. Lett., Vol. 13, No. 9, 2011
2185

Table 2. Palladium-Catalyzed Oxidative Coupling of
Trialkylamines (1) with 4-Iodoanisole (2a)a
Table 3. Palladium-Catalyzed Oxidative Coupling of
Trialkylamines (1) with Aryl Iodides (2)a
a Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), PdCl2(MeCN)2
(5 mol %), TBAB (1.5 equiv), ZnO (1.3 equiv), and DMSO (2 mL) at
100 °C under air atmosphere. b 1,2-Bis(4-methoxyphenyl)ethanone (6)
was obtained in 12% yield.
amino group favors the reaction: while 1-chloro-4-iodo-
benzene (2h) provided the desired product 14 in 31% yield
(entry 8), substrate 2j bearing both a chloro group and a
amino group furnished the corresponding target product
16 in 72% yield (entry 10). It was noted that the reaction of
heteroaryl iodide 2k with amine 1b was also successful to
afford the desired product 17 in moderate yield (entry 11).
The 18O-labeled experiment was carried out to under-
stand the mechanism (Scheme 1, eq 2). Treatment of amine
1bwithiodide 2b, H218O (0.1 mL), PdCl2(MeCN)2, TBAB,
and ZnO in anhydrous DMSO afforded a 18O-contained
product 8-O-18, suggesting that the oxygen atom of
products is from water. However, treatment iodide 2a with
butyraldehyde (18) afforded the desired product 3 in a low
yield (Scheme 1, eq 3). Interestingly, product 3 was
obtained in 58% yield from the reaction between iodide
2a with butyraldehyde (18) in the presence of dibutylamine
(Scheme 1, eq 4). It is noteworthy that no butyraldehyde is
observed by GCÀMS analysis without aryl iodides
(Scheme 1, eq 5). These results suggest that imine inter-
mediates are generated in situ, which requires the aid of
aryl iodides.
a Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), PdCl2(MeCN)2
(5 mol %), TBAB (1.5 equiv), ZnO (1.3 equiv), and DMSO (2 mL) at
100 °C under air atmosphere.
Scheme 1. 18O-Labeled Experiment and Controlled
Experiments
Therefore, a possible mechanism as outlinedin Scheme 2
was proposed on the basis of the present results7 and the
reported mechanism.3À6,9 Intermediate A can be generated
(9) For selected reviews and paper on enamine catalysis, see: (a)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471. (b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004,
37, 580. (c) Kim, J. W.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int.
Ed. 2008, 47, 9249. (d) Murahashi, S. I.; Zhang, D. Z. Chem. Soc. Rev.
2008, 37, 1490. (e) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010,
110, 681.
with the aid of Pd, air, and ZnO.9 Intermediate A reacted
with ArPdI, which forms from the oxidative addition of
2186
Org. Lett., Vol. 13, No. 9, 2011

In summary, we have described a new and simple
protocol for the synthesis of alkyl aryl ketones by palla-
dium-catalyzed oxidative coupling of trialkylamines with
aryl iodides. Importantly, this method uses commercial
available tertiary amines as the carbonyl sources, which
makes it more attractive for organic synthesis and indus-
try. However, the catalytic system is inert to 1-iodo-2-
methylbenzene and aryl bromides. Thus, work to develop
new efficient catalytic system extending this protocol in
organic synthesis and study the detailed mechanism is
currently underway.
Scheme 2. Possible Mechanism
Acknowledgment. We thank the Program of Science
and Technology of Wenzhou (Nos. Y20090243 and
G20090080), National Natural Science Foundation of
China (Nos. 20872112 and 21002070), and Zhejiang Pro-
vincial Natural Science Foundation of China (Nos.
Y407116 and Y4080169) for financial support. Y.L. also
thanks Wenzhou University (No. 3160601010943) for
financial support.
Pd(0) to ArI, to afford intermediate B and regenerate the
active Pd(0) species through an eductive elimination
process.5 Intermediate B undergoes the reaction with Pd,
air and ZnO leading to intermediate C,9 followed by
hydrolyzation/oxidation reaction of intermediate C fur-
nish the desired product.5 We deduce that TBAB may play
as a ligand to stabilize the active Pd intermediates. The
occurrence of the reductive elimination of intermediateB is
difficultin the case of bulky arylgroups, which results in no
reaction for the bulky substrate 1f.
Supporting Information Available. Analytical data and
spectra (1H and 13C NMR) for all products; typical
procedure. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
2187