Domino cross dehydrogenative coupling of 2-aryl acetals with ketones using DDQ as oxidant and reactant precursor

Article abstract of DOI:10.1002/cjoc.201200302

A novel domino cross dehydrogenative coupling of 2-aryl acetals with unmodified ketones has been developed, using DDQ as both the oxidant and reactant precursor.

Full text of DOI:10.1002/cjoc.201200302

COMMUNICATION
DOI: 10.1002/cjoc.201200302
Domino Cross Dehydrogenative Coupling of 2-Aryl Acetals
with Ketones Using DDQ as Oxidant and Reactant Precursor
Li, Jiangsheng*(李江胜)
Cheng, Chao(程超)
Cai, Feifei†(蔡菲菲)
Liu, Weidong(刘卫东)
Li, Zhiwei*(李志伟)
Xue, Yuan(薛媛)
Cao, Zhong(曹忠)
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chem-
istry and Biological Engineering, Changsha University of Science & Technology, Changsha, Hunan 410114, China
A novel domino cross dehydrogenative coupling of 2-aryl acetals with unmodified ketones has been developed,
using DDQ as both the oxidant and reactant precursor.
Keywords acetals, C—H activation, DDQ, cross dehydrogenative coupling, ketones
Introduction
Herein, we report for the first time a novel domino
CDC reaction of acetals with methyl ketones by sp3 C—
H activation using DDQ as the oxidant and reactant
precursor. It allows the incorporation of DDQ as mo-
lecular moiety into the final product (Eq. 1).
Cross-coupling reactions involving C—H activation
have emerged as robust alternatives to conventional
transformations for the construction of new C—C and
C-hetero bonds.[1] Among these cross-coupling reac-
tions, considerable attention has been paid to cross-
dehydrogenative-coupling (CDC) reactions.[2] Owing to
avoiding the use of functionalized substrates, they have
been a more atom-economic and environmentally
friendly method and a very promising tool for the crea-
tion of new bonds.
O
O
CN
CN
O
R
O
Ar
O
DDQ
O
O
H
(1)
+
R
Cl
O
Ar
Cl
1
2
3
The CDC reactions of various sp3 C—H bonds, such
as α-C—H bonds of tertiary amines,[3] ethers[1c] and
π-systems including arenes,[4] alkenes[5] and alkynes,[6]
with a variety of electrophiles have been successfully
developed.[2]
Acetals are important compounds, and widely used
as protective groups for 1,2-/1,3-diols, and carbonyl
group.[7] In fact, acetals are geminal diethers and
somewhat similar to ethers, but are more susceptible to
oxidation than ethers. To the best of our knowledge,
however, no examples of CDC reactions of acetals are
available. The similarity to ethers and susceptibility to
oxidation inspired us to embark on an investigation of
CDC reactions of acetals with unmodified ketones, with
the aim of seeking procedures for oriented synthesis of
monoprotected β-dicarbonyl compounds.
Results and Discussion
Initially, we attempted to perform the coupling reac-
tion of 2-phenyl-1,3-dioxolane (1a) and acetophenone
(2a) using DDQ as oxidant under N2 atmosphere at 100
℃, hopefully achieving the coupled product by sp3 C—
H activation and subsequent C—C bond formation (Eq.
2, Ar＝R＝Ph). We were delighted to find that the reac-
tion gave one new main spot by TLC analysis. However,
1H NMR spectrum suggested that it was not the coupled
product as expected. Based on further 13C NMR, IR and
MS analysis, we postulated that this was probably de-
rived from DDQ as well as acetal and ketone and pos-
sessed the structure 3 as shown in Eq. 1 (Ar＝R＝Ph).
O
DDQ
X
O
O
O
O
O
(2)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
is a well-known oxidant in organic synthesis[8] and has
been utilized in efficient CDC reactions involving sp3
C—H activation.[5,6,9] In these transformations, DDQ
usually serves only as dehydrogenating reagent and is
not incorporated into the final product.[10]
R
Ar
H
Ar
R
To further identify the product structure, we at-
tempted to grow single crystals of adducts by natural
evaporation from a mixture of different solvents. Luck-
*
E-mail: js_li@yahoo.com.cn (Dr. J. S. Li) & lizwhn@126.com (Dr. Z. W. Li)
Equal contribution with the first author.
†
Received March 28, 2012; accepted April 16, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200302 or from the author.
Chin. J. Chem. 2012, 30, 1699—1701 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
COMMUNICATION
ily, the colorless block crystal of 3b was achieved from
Et2O/petroleum ether and its X-ray crystal analysis (see
SI section 3) confirmed the structure as postulated
above (Figure 1).
variety of substrates including cyclic acetals and ke-
tones were subjected to this transformation and the cor-
responding results were listed in Table 2. In general,
there is little difference in yield for the three dioxolanes
studied. Aryl methyl ketones were found to be excellent
substrates, providing the desired products in syntheti-
cally useful yields. Aliphatic ketones, however, yielded
no desired products. For example, when acetone or
cyclohexanone reacted with 2-phenyl-1,3-dioxolane
(1a), no desired product was detected. It is interesting to
note that alkyl groups and ethers sensitive to DDQ, in-
cluding methyl, ethyl, and ethoxyl groups, well survived
this reaction condition. Additionally, as for ketones
bearing electron-rich substituents (Entries 5 and 6),
prolonging reaction time resulted in a dramatic decrease
in the yield.
Figure 1 X-ray structure of the benzoate 3b.
Table 2 CDC reactions of 2-aryl acetals with simple ketonesa
This result encouraged us to further investigate this
novel CDC reaction. To begin with, we screened the
reaction parameters to improve the yield of the coupling
product on this model system. Various reaction tem-
peratures, solvents and molar ratios were examined
(Table 1). When 1.8 equiv. DDQ was used, the product
was obtained in 40% yield (Entry 1). Decrease in the
amount of DDQ to 1.2 equiv. reduced the yield to only
18% (Entry 2). Evidently, the ratio of DDQ to acetal
made a great difference to the yield. Thus, 2.4 and 3.0
equiv. DDQ were also tested. The use of 2.4 equiv.
DDQ gave 61% yield. With 3.0 equiv. DDQ being used,
the reaction mixture became too thick for efficient stir-
ring, leading to a slight decrease in yield (Entry 4, 58%).
Decrease in the equivalent of acetophenone led to a de-
cline in yield (Entry 3 vs. 5). Both increasing and low-
ering the reaction temperature resulted in a considerable
decrease in yield (Entries 6 and 7). The use of MeNO2
and DCE as solvents led to relatively low yields (Entries
8 and 9). From the results above, the optimal conditions
are using acetal/ketone/DDQ ratio 1∶5∶2.4 (molar
ratio) at 100 ℃ under N2 in neat condition, under
which the desired product was afforded in 61% yield.
With the optimized reaction conditions in hand, a
Entry Acetal (Ar)
Ketone (R)
Product Yieldb/%
1
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
3a
3b
3c
3d
3e
3f
61
64
63
58
43
40
60
62
37
59
60
2
4-MePh (2b)
4-EtPh (2c)
3
4
2,4-(Et)2Ph (2d)
1-naphthyl (2f)
2,4-(EtO)2Ph (2g)
5c
6c
7
4-MePh (1b) Ph (2a)
3g
3h
3i
8
4-MePh (1b) 4-MePh (2b)
4-MePh (1b) 4-ClPh (2h)
9
10
4-ClPh (1c)
4-ClPh (1c)
Ph (2a)
3j
11
4-MePh (2b)
3k
a
Reaction conditions: acetals (2 mmol), ketones (10 mmol),
DDQ (4.8 mmol), N2, 100 ℃, 1 h. b Isolated yield. c Stirred for
30 min.
On the basis of the above experiment results together
with the related reports,[10] a plausible mechanism is
proposed for the formation of the unusual coupling
product (Figure 2). Firstly, single electron transfer fol-
lowed by H-atom abstraction or direct hydride abstrac-
tion may generate an acetal cation, on which subsequent
nucleophilic attack at the C-4 rather than C-2 position
by a DDQH counterion provides DDQH ether. This
may be due to the steric hindrance of the cation and
thermodynamic stability of the intermediate ether. Then,
the DDQH ether coupling with ketone may be involved
in a free radical process, mediated by another DDQ
molecule.
Table 1 Optimization of the reaction conditionsa
Entry 1a/2a/DDQ
Temp.b/℃
Solventc Yieldd/%
1
2
3
4e
5
6
7
8
9
1∶5∶1.8
1∶5∶1.2
1∶5∶2.4
1∶5∶3.0
1∶3∶2.4
1∶5∶2.4
1∶5∶2.4
1∶5∶2.4
1∶5∶2.4
100
Neat
Neat
Neat
Neat
Neat
Neat
Neat
MeNO2
DCE
40
18
61
58
52
23
25
53
36
100
100
100
100
130
Conclusions
50
In summary, for the first time we present a novel
domino CDC reaction of acetals with simple aryl ke-
tones by using DDQ as a sole oxidant and a reactant
precursor. In this transformation, new C—O and C—C
bonds are successively formed. The scope and mecha-
nism of this method as well as the application of these
100
100
a 2-Phenyl-1,3-dioxolane (2 mmol) and acetophenone used as the
b
c
d
substrates. Oil bath. Not dried. Isolated yield. e Difficult to
stir.
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1699—1701

Domino Cross Dehydrogenative Coupling of 2-Aryl Acetals with Ketones
Program for New Century Excellent Talents in Univer-
sity (No. 10-0138), Hunan Provincial Science and
Technology Project (No. 2011WK3038), the Scientific
Research Fund of Hunan Provincial Education Depart-
ment (No. 10W017), Changsha Municipal Science and
Technology Project (No. K1104066-31), the Hunan
Provincial Key Laboratory of Materials Protection for
Electric Power and Transportation (No. 2012CL03),
Changsha University of Science & Technology, China.
O
Ar
O
DDQ
O
OH
CN
CN
Cl
Cl
O
O
O
H
Ar
Ar
DDQH
OH
DDQ
DDQH
O
O
O
CN
O
CN
Ar
Ar
Cl
O
References
3
Cl
O
[1] For books and representative reviews on C—H activation, see: (a)
Dyker, G. Handbook of C—H transformations, Wiley-VCH, Wein-
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York, 2010; (c) Zhang, S. Y.; Zhang, F. M.; Tu, Y. Q. Chem. Soc.
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Chem. Rev. 2009, 110, 1082.
H
CN
DDQH2
R
O
CN
O
O
Cl
Cl
Figure 2 Proposed mechanism for this domino CDC reaction.
coupled products are under further investigation.
[2] For reviews on CDC reactions, see: (a) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215; (b) Scheuermann, C. J. Chem. Asian J.
2010, 5, 436; (c) Yoo, W. J.; Li, C. J. Top. Curr. Chem. 2010, 292,
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[3] For selected examples, see: (a) Xu, Z; Yu, X.; Feng, X.; Bao, M. J.
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K. R. Chem. Commun. 2011, 47, 11787; (c) Su, W.; Yu, J.; Li, Z.;
Jiang, Z. J. Org. Chem. 2011, 76, 9144.
[4] For selected examples, see: (a) Xiong, T.; Li, Y.; Bi, X.; Lv, Y.;
Zhang, Q. Angew. Chem., Int. Ed. 2011, 50, 7140; (b) Xia, Q.; Chen,
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Prabhakar, P.; Venkateswarlu, Y. Tetrahedron Lett. 2010, 51, 4898;
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J. J. Am. Chem. Soc. 2006, 128, 56.
Experimental
To a mixture of DDQ (4.8 mmol) and ketone (10
mmol), acetal (2.0 mm) was added dropwise under ni-
trogen at room temperature. Then the reaction mixture
was stirred at 100 ℃ (oil bath) immediately. After 1 h,
the resulting mixture was diluted with ethyl acetate, to
which little silica gel was added. The solvent was re-
moved under the reduced pressure and the resulting
powder was added to the top of a short silica-gel column
and purified using petroleum ether/ethyl acetate in a
10∶1 ratio (volume ratio) as the eluent to afford the
desired product. The data for selected compound 3a: 1H
NMR (400 MHz, CDCl3) δ: 8.07 (dd, J＝8.4, 1.2 Hz,
2H), 7.88 (dd, J＝8.4, 1.2 Hz, 2H), 7.66 (t, J＝7.6 Hz,
1H), 7.58 (tt, J＝7.6, 1.2 Hz, 1H), 7.50 (t, J＝8.0 Hz,
2H), 7.45 (t, J＝8.0 Hz, 2H), 4.85—4.76 (m, 2H), 4.69
(t, J＝4.4 Hz, 2H), 4.50 (d, J＝18.0 Hz, 1H), 4.36 (d,
J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
193.18, 178.68, 166.10, 158.06, 144.61, 136.55, 135.04,
133.86, 133.41, 129.73 (2C), 129.63, 129.27, 129.12
(2C), 128.49 (4C), 113.56, 113.06, 93.29, 73.39, 62.42,
48.22, 45.02; IR (KBr) νmax: 2238.87 (CN), 2215.65
(CN), 1722.88 (ester C＝O), 1708.69 (ketone C＝O),
1680.31 (C＝O), 1272.04 (ester C—O) cm－ 1; MS
(APCI) m/z: 512.0 [M ＋ NH4] ＋ . Anal. calcd for
C25H16Cl2N2O5: C 60.62, H 3.26, N 5.66; found C 60.74,
H 3.45, N 5.53.
[6] Cheng, D.; Bao, W. J. Org. Chem. 2008, 73, 6881.
[7] Wuts, P. G. M.; Greene, T. W. Greene's Protective Groups in Or-
ganic Synthesis, John Wiley and Sons, Hoboken, 2007, p. 424 & p.
435.
[8] Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
[9] For selected examples using DDQ, see: (a) Xie, J.; Huang, Z. Z.
Angew. Chem., Int. Ed. 2010, 49, 10181; (b) Guo, C.; Song, J.; Luo,
S. W.; Gong, L. Z. Angew. Chem., Int. Ed. 2010, 49, 5558; (c) Jin, J.;
Li, Y.; Wang, Z. J.; Qian, W. X.; Bao, W. Eur. J. Org. Chem. 2010,
7, 1235; (d) Correia, C. A.; Li, C. J. Adv. Synth. Catal. 2010, 352,
1446; (e) Zhang, Y.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 4242.
[10] For exceptions, see: (a) Kucklaender, U.; Bollig, R.; Frank, W.;
Gratz, A.; Jose, J. Bioorg. Med. Chem. 2011, 19, 2666; (b)
Bhattacharya, A.; DiMichele, L. M.; Dolling, U. H. E.; Grabowski, J.
J.; Grenda, V. J. J. Org. Chem. 1989, 54, 6118; (c) Tanemura, K.;
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Iwamura, J. I.; Iwamoto, N.; Hirao, N. Nippon Kagaku Kaishi 1977,
7, 1009.
Acknowledgement
This work was financially supported by the National
Natural Science Foundation of China (No. 21075011),
(Cheng, F.)
Chin. J. Chem. 2012, 30, 1699—1701
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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