I2-CF3SO3H synergistic promoted sp 3 C-H bond diarylation of aromatic ketones

Article abstract of DOI:10.1021/ol302613q

An I₂-CF₃SO₃H synergistic promoted sp ³ C-H bond diarylation protocol was developed for the synthesis of 2,2-bis(4-(dimethylamino)phenyl)-1-aryl ethanones. The reaction performed well in the absence of any metal and ligand. It integrated three reactions with different mechanisms (iodination, Kornblum oxidation, and hydroarylation) in a single reactor.

Full text of DOI:10.1021/ol302613q

ORGANIC
LETTERS
I2ÀCF3SO3H Synergistic Promoted sp3
CÀH Bond Diarylation of Aromatic Ketones
XXXX
Vol. XX, No. XX
000–000
Yan-ping Zhu, Feng-cheng Jia, Mei-cai Liu, Liu-ming Wu, Qun Cai, Yang Gao, and
An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received September 23, 2012
ABSTRACT
An I2ÀCF3SO3H synergistic promoted sp3 CÀH bond diarylation protocol was developed for the synthesis of 2,2-bis(4-(dimethylamino)phenyl)-1-
aryl ethanones. The reaction performed well in the absence of any metal and ligand. It integrated three reactions with different mechanisms
(iodination, Kornblum oxidation, and hydroarylation) in a single reactor.
Diarylmethane derivatives are important substructures
and widely exist in natural products, dye precursors, histo-
logical stain agents, and materials science.1 Many com-
pounds containing a diarylmethane motif exhibit potent
biological activities and medicinal significance in anti-
tubercular, anticancer, and antiproliferative agents.2 Con-
sequently, many synthetic methods have been reported for
the synthesis of diarylmethane derivatives. The most com-
mon methods involve condensation of electron-rich arenes
with aldehydes/ketones or imines.3 Transition-metal cata-
lyzed coupling methods have also been developed.4
CÀC bonds. Many impressive results have been achieved
through this method.5 However, few methods have been
developed for diarylation of the CÀH bond in ketones
and esters. Recently, Myrboh and co-workers proposed a
graceful regioselective diarylation of aromatic ketones
in the presence of SeO2 and BF3ÀEt2O (Scheme 1, (a)).6
SabMartin and Domıguez also demonstrated an interesting
regioselective diarylation of ketone enolates by a homo-
geneous and heterogeneous catalysis strategy (Scheme 1,
(b)),7 whereas, Goossen developed an elegant palladium/
copper cocatalyzed strategy for diarylation of acetic acid
esters (Scheme 1, (c)).8
Direct arylation of the CÀH bond has been considered
as one of the most fundamental strategies to construct
(1) (a) Ryss, P.; Zollinger, H. Fundamentals of the Chemistry and
Application of Dyes; Wiley-Interscience: New York, 1972. (b) Hsin, L. W.;
Dersch, C. M.; Baumann, M. H.; Stafford, D.; Glowa, J. R.; Rothman, R. B.;
Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2002, 45, 1321. (c) Xu, Y. Q.;
Lu, J. M.; Li, N. J.; Yan, F.; Xia, X. W.; Xu, Q. F. Eur. Polym. J. 2008,
44, 2404. (d) Irie, M. J. Am. Chem. Soc. 1983, 105, 2078.
Scheme 1. Protocols for sp3 CÀH Bond Arylation
(2) (a) Parai, M. K.; Panda, G.; Chaturvedi, V.; Manju, Y. K.; Sinha, S.
Bioorg. Med. Chem. Lett. 2008, 18, 289. (b) Palchaudhuri, R.; Nesterenko,
V.; Hergenrother, P. J. J. Am. Chem. Soc. 2008, 130, 10274. (c) Shchepinov,
M. S.; Korshun, V. A. Chem. Soc. Rev. 2003, 32, 170.
(3) (a) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A.
J. Org. Chem. 1998, 63, 4481. (b) Prakash, G. K. S.; Panja, C.; Shakhmin,
A.; Shah, E.; Mathew, T.; Olah, G. A. J. Org. Chem. 2009, 74, 8659. (c)
Liu, C. R.; Li, M. B.; Yang, C. F.; Tian, S. K. Chem. Commun. 2008, 1249.
(d) Li, H. F.; Yang, J. Y.; Liu, Y. H.; Li, Y. Z. J. Org. Chem. 2009, 74,
6797. (e) Thirupathi, P.; Kim, S. S. J. Org. Chem. 2010, 75, 5240.
(4) (a) Werner, E. W.; Urkalan, K. B.; Sigman, M. S. Org. Lett. 2010,
12, 2848. (b) Endo, K.; Ishioka, T.; Ohkubo, T.; Shibata, T. J. Org.
€
Chem. 2012, 77, 7223. (c) Blumke, T. D.; Gross, K.; Karaghiosoff, K.;
Knochel, P. Org. Lett. 2011, 13, 6440. (d) Srimani, D.; Bej, A.; Sarkar, A.
J. Org. Chem. 2010, 75, 4296.
r
10.1021/ol302613q
XXXX American Chemical Society

Recently, metal-free CÀH coupling has attracted much
attention.9 However, the development of a metal-free proto-
col for diarylation of aromatic ketones remains very desir-
able. In a recent project, we developed a molecular iodide
promoted di(hetero)arylation of aromatic ketones with
indoles.10 However, the electron-rich arenes were not toler-
ant for this method. Following up on this work, we herein
reported an I2ÀCF3SO3H synergistic promoted protocol
for the diarylation of aromatic ketones with electron-rich
arenes such as N,N-dialkylanilines, N-methylpyrrole, and
anisole derivatives (Scheme 1, (2)).
Table 1. Optimization Studies for the Synthesis of 3aaa,b
I2
temp
time
(h)
yield
(%)c
entry
(mmol)
cat.
(°C)
1a
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
À
Ti(i-PrO)4
AlCl3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
12
12
12
12
12
12
12
4
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
55
Initially, the reaction of aryl methyl ketone (1a) and
N,N-dimethylaniline (2a) was selected as a model reaction for
optimization of the conditions. First, we screened a series of
Lewis acids, such as Ti(i-PrO)4, AlCl3, ZnCl2, FeCl3, InCl3,
and NbCl5, for this reaction, but none of the desired product
3aa was obtained (Table 1, entries 1À5). We then screened
various Brønsted acids and found MeSO3H and CF3SO3H
were particularly effective catalysts (Table 1, entries 8 and 9).
But, other Brønsted acids, such as H2SO4, HOAc, PTSA,
and TFA, could not promote the reaction. In addition, the
reaction could not perform without I2 (Table 1, entry 13).
After several experimental optimizations, we found that 1a
(1.0 mmol) reacted with I2 (1.5 mmol) in DMSO at 100 °Cfor
1À2 h, which was followed by the addition of 2a (2.0 mmol)
and CF3SO3H (50 mol %) for another 1 h. The desired
product was afforded in 68% yield (Table 1, entry 14).
Under the optimal conditions, the scope of aryl methyl
ketones was investigated. As shown in Scheme 2, the
reaction demonstrated good compatibility with various
aromatic ketones; both electron-donating and -withdraw-
ing groups attached to the phenyl group of 1 could afford
the corresponding products with moderate to good yields,
such as Me, OMe, 2,4-(OMe)2, Cl, Br, and NO2 groups.
And the electronic properties of aromatic ketones (2eÀ2i)
had little influence on the efficiency of the reaction.
Furthermore, the heteroaryl methyl ketones, such as fur-
anyl (1i), thiophenyl (1j, 1k), benzofuryl (1l), and morpho-
linyl (1o), were investigated under the optimal conditions.
To our delight, the corresponding products 3iaÀ3la and
2a
3a
FeCl3
4a
InCl3
5a
NbCl5
6a
H2SO4
7a
HOAc
8a
MeSO3H
CF3SO3H
PTSA
9a
4
58
10a
11a
12b
13a
14b
15b
16b
6
n.r.
n.r.
62
TFA
10
2
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
12
2
n.r.
68
I2 (1.5)
I2 (2.0)
I2 (1.5)
3
67
3
62
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), I2 (1.0 mmol)
catalyst (0.5 mmol, 50 mol %), heated in 3 mL of DMSO. b Reaction
conditions: 1a (1.0 mmol) and I2 in DMSO at 100 °C for 1À2 h. To this
reaction mixture were added 2a (2.0 mmol) and CF3SO3H (0.5 mmol) at
100 °C, until the disappearance of 2a, monitored by TLC. c Isolated yield.
3oa were also afforded in moderate yields (50%À63%).
Meanwhile, 2-naphthyl and 1-naphthyl methyl ketones
(1m and 1n) also reacted with N,N-dimethylaniline 2a to
give satisfying results (75% and 71% yields). Furthermore,
the target compounds 3ca were further determined by
X-ray crystallographic analysis (Figure 1).
Scheme 2. Scope of Aryl Methyl Ketones
(5) (a) Engle, K. M.; Mei, T. S.; Wasa, M.; Yu, J. Q. Acc. Chem. Res.
2012, 45, 788. (b) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074. (c) Ali, S.; Li, Y. X.; Anwar, S.; Yang, F.; Chen,
Z. S.; Liang, Y. M. J. Org. Chem. 2012, 77, 424. (d) Zhao, Y. S.; Chen, G.
Org. Lett. 2011, 13, 4850. (e) Hamann, B. C.; Hartwig, J. F. J. Am. Soc.
Chem. 1997, 119, 12382. (f) Moradi, W. A.; Buchwald, S. L. J. Am. Soc.
Chem. 2001, 123, 7996.
(6) Laloo, B. M.; Mecadon, H.; Rohman, Md. R.; Kharbangar, I.;
Kharkongor, I.; Rajbangshi, M.; Nongkhlaw, R.; Myrboh, B. J. Org.
Chem. 2012, 77, 707.
(7) Churruca, F.; SanMartin, R.; Tellitu, I.; Domıngues, E. Tetra-
hedron Lett. 2003, 44, 5925.
(8) Song, B.; Himmler, T.; Goossen, L. J. Adv. Synth. Catal. 2011,
353, 1688.
(9) (a) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010,
328, 1376. (b) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem.,
Int. Ed. 2011, 50, 5331. (c) Wei, W.; Zhang, C.; Xu, Y.; Wan, X. B. Chem.
Commun. 2011,47, 10827. (d) Chen, L.; Shi, E. B.; Liu, Z. J.; Chen, S. L.; Wei,
W.; Li, H.; Xu, K.; Wan, X. B. Chem.;Eur. J. 2011, 17, 4085. (e) Liu, Z. J.;
Zhang, J.; Chen, S. L.; Shi, E. B.; Xu, Y.; Wan, X. B. Angew. Chem., Int. Ed.
2012, 51, 3231. (f) Shi, E. B.; Shao, Y.; Chen, S. L.; Hu, H. Y.; Liu, Z. J.;
Zhang, J.; Wan, X. B. Org. Lett. 2012, 14, 3384. (g) Xie, J.; Jiang, H. L.;
Cheng, Y. X.; Zhu, C. J. Chem. Commun. 2012, 48, 979.
(10) Zhu, Y. P.; Liu, M. C.; Jia, F. C.; Yuan, J. J.; Gao, Q. H.; Lian,
M.; Wu, A. X. Org. Lett. 2012, 14, 3392.
B
Org. Lett., Vol. XX, No. XX, XXXX

1H NMR spectroscopic studies (Figure 2). Through com-
parison with anauthentic sample(see FigureS1), the signal
at 4.6 ppm was assigned to the ÀCH2À group of R-iodo
aryl methyl ketone 1aa at 5À15 min.11 In addition, the
signals at 9.54 and 5.70 ppm were assigned to the phenyl-
glyoxal aldehyde group (1ac) and the hemiacetal group
(1ab).12 With the addition of 2a and CF3SO3H, the char-
acteristic peaks of 1ac and 1ab were seen to disappear
immediately. Meanwhile, the characteristic peaks of 3aa were
seen to appear (Ha, Hb, and ÀN(Me)2 at δ = 8.08, 6.45, and
3.08 ppm). As shown in Figure 2, the reaction was achieved in
80 min with high conversion. These results demonstrated that
phenacyl iodine (1aa) and phenylglyoxal (1ac) were impor-
tant intermediates in the whole transformation.
Figure 1. X-ray crystal structure of compound 3ca.
To further expand the scope of the substrates, the
diversity of electron-rich arenes was examined. Gratify-
ingly, N,N-diethylaniline 2b and N,N-dipropylaniline 2c
could react smoothly with aryl methyl ketones to afford
the corresponding products in moderate yields (Scheme 3,
3abÀ3fc). Moreover, the electronic properties of sub-
strates 1 did not affect the reaction efficiency. However,
when the substrate 2d was used, the desired product 3ad
was only obtained in a very low yield, possibly due to the
strong steric hindrance involved (<15%). The N-methyl-
pyrrole 2e could also perform smoothly to afford the cor-
responding product under the conditions (Scheme 3, 3ae,
66%). The reaction of pyrrole 2f with acetophenone 1a
only gave a trace amount of the desired product. To our
disappointment, the electron-rich arenes, such as anisole
(2g), 1,2-dimethoxybenzene (2h), 1,4-dimethoxybenzene
(2i), and phenol (2j), could not react with acetophenone
1a to afford the desired products.
Figure 2. The reaction process of 1a (0.1 mmol), 2a (0.2 mmol),
and I2 (0.12 mmol) with CF3SO3H (50 mol %) at 100 °C was
monitored by 1H NMR spectroscopy (400 MHz, DMSO-d6).
Scheme 3. Scope of Aryl Methyl Ketones and Electron-Rich
Arenes
When the reaction of R-iodo ketone 1aa (1.0 mmol) with
dimethylaniline 2a (2.0 mmol) in the presence of CF3SO3H
(50 mol %) was performed in DMSO, the target product
3aa was obtained in 69% yield (Scheme 4, (a)). The
reaction of 1ab and 2a was treated with CF3SO3H (50
mol %) in DMSO at 100 °C, and the product 3aa was
subsequently obtained in good yield (82%). A competition
experiment was also conducted, where acetophenone 1a
was treated with I2 (1.2 mmol) in DMSO for 2 h and then
2a (1.0 mmol), 2b (1.0 mmol), and CF3SO3H (50 mol %)
were added to the mixture for 1 h. The corresponding
products 3aa and 3ab were obtained in 25% and 22%
yields, respectively, and the crossed product 3aab was
afforded in 18% yield.
On the basis of the above results, a possible mechanism
of the present reaction is depicted in Scheme 5. Initially,
(11) (a) Zhu, Y. P.; Gao, Q. H.; Lian, M.; Yuan, J. J.; Liu, M. C.;
Zhao, Q.; Yang, Y.; Wu, A. X. Chem. Commun. 2011, 47, 12700. (b) Zhu,
Y. P.; Jia, F. C.; Liu, M. C.; Wu, A. X. Org. Lett. 2012, 14, 4414.
(12) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao,
Q. H.; Wu, A. X. Chem. Commun. 2012, 48, 9086.
To further probe the reaction process, we monitored the
reaction of 1a (0.1 mmol) with 2a (0.2 mmol) in the
presence of I2 (0.12 mmol) and CF3SO3H (50 mol %) by
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Control Experiments
Scheme 5. Proposed Mechanism
molecular iodide promoted acetophenone 1a to afford the
intermediate R-iodo ketone 1aa, which was subsequently
converted into phenylglyoxal (1ac) by way of Kornblum
oxidation in the presence of DMSO.10 The aldehyde group
of phenylglyoxal (1ac) was then activated by CF3SO3H
to obtain activated intermediate A. Electron-rich N,N-
dimethylaniline 2a subsequently attacked the activated alde-
hyde group of phenylglyoxal (1ac) to give the intermediate
B,11 which underwent isomerization to afford the cation C.
Finally, another N,N-dimethylaniline 2a further trapped
cation C to give the desired product 3aa.
It therefore proved to be an efficient method for the
diarylation of aromatic ketones. Further studies on the
applications of this strategy will be reported in due course.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Grants
21032001 and 21272085) and PCSIRT (No. IRT0953).
We also thank Dr. Chuanqi Zhou, Hebei University, for
analytical support.
In conclusion, we developed an I2ÀCF3SO3H synergis-
tic promoted sp3 CÀH bond diarylation protocol for the
synthesisof 2,2-bis(4-(dimethylamino)phenyl)-1-aryl etha-
nones from simple and readily available aryl methyl ketones
and N,N-dialkylanilines. It is notable that the reaction
performed well in the absence of any metal and ligand.
Supporting Information Available. Spectrascopic data
and general procedure. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX