CDC reactions of N-aryl tetrahydroisoquinolines using catalytic amounts of DDQ: C-H activation under aerobic conditions

Article abstract of DOI:10.1002/chem.201200100

An oxidative cross-dehydrogenative coupling (CDC) reaction for the formation of C-C and C-P bonds is disclosed using a catalytic amount of DDQ (10 mol %) under aerobic conditions (see scheme). This unprecedented environmentally benign strategy of using AI

Full text of DOI:10.1002/chem.201200100

DOI: 10.1002/chem.201200100
CDC Reactions of N-Aryl Tetrahydroisoquinolines Using Catalytic Amounts
À
of DDQ: C H Activation under Aerobic Conditions**
Kaliyamoorthy Alagiri, Pradeep Devadig, and Kandikere R. Prabhu*[a]
Dedicated to Professor Sosale Chandrasekhar on the occasion of his 60th birthday
À
C C bond-forming reactions through oxidative cross-de-
hyrogenative coupling (CDC) reactions have been in the
limelight recently,[1] mainly because CDC methods do not
require pre-functionalized precursors prior to the coupling
reactions, and are atom economical and environmentally
benign.[1] Generally, CDC reactions are accomplished using
transition-metal catalysts with co-oxidants such as tert-butyl-
hydroperoxide (TBHP), H2O2, molecular oxygen, and so
on.[1] Metal-free reactions have evoked a great deal of atten-
tion from the synthetic community because metal impurities
can be detrimental in pharmaceutically important intermedi-
ates and final products.[2] Hence, there is a devoted effort to
Scheme 1. Reactions that use catalytic amounts of DDQ.
accomplish metal-free reaction. In this context, a considera-
ble attempt has been made to perform CDC reactions in the
absence of metal catalysts.[1e] As a result, there are number
À
of reports on C C bond formation using a stoichiometric
amount of oxidants either in the presence or in the absence
of metal catalysts (but in some cases metal catalysts are un-
avoidable).[3] DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none) is a well-known oxidant with a high oxidation poten-
tial;[4] it has been used in a stoichiometric amount in many
reactions such as deprotection of ethers,[5a] benzylic oxida-
ganic co-oxidants, which is one of the major setbacks due to
toxicity and environmental concerns. Furthermore, the use
of a catalytic amount of DDQ with a catalytic amount of
co-oxidant remains largely an unexplored area. One of the
practical ways to overcome such problem is to use DDQ in
a catalytic amount and employ molecular oxygen as a co-ox-
idant;[8] this strategy has significant environmental and eco-
nomic benefits due to the natural abundance of molecular
oxygen, lower cost, and the production of water as the sole
by-product in the reaction. To the best of our knowledge,
À
tion,[5b] oxidation of activated alcohols,[5c] and C C bond-
À
forming reactions.[3] However, when DDQ is employed in
a stoichiometric amount, the major difficulty is the removal
of the resultant by-product 2,3-dichloro-5,6-dicyanohydro-
quinone (DDQH2).[6] The additional impediments in using
DDQ are the high cost and high molecular weight of this
oxidant. Therefore, there are sustained efforts to address
these issues by attempting to employ DDQ in a catalytic
amount and regenerate DDQ from the resulting DDQH2 by
C C bond forming reactions mediated by
a catalytic
amount of DDQ is scarce.[7] Thus this is the first report of
regenerating DDQ by using catalytic amount of azobisisobu-
tyronitrile (AIBN) and molecular oxygen. Herein, we pres-
À
À
ent C C and C P bond forming reactions by CDC method
mediated by a catalytic amount of DDQ using molecular
oxygen as the co-oxidant and AIBN as an additive.
ACTHNUTRGNEUNG
using various co-oxidants such as FeCl3,[6a] Mn(OAc)3,[6b,c]
MnO2,[7], and so forth (Scheme 1). However, most of these
efforts resulted in using a large excess (3–6 equiv) of inor-
Mannich products such as b-amino ketones and aldehydes
are versatile synthetic intermediate for numerous pharma-
ceuticals and natural products. b-Amino ketones and alde-
hydes can be converted in to 1,3-amino alcohols by reduc-
tion or to Michael acceptors by elimination of amine func-
tionality.[9] Traditionally, the Mannich reaction involves the
addition of carbonyl compounds to imines or iminium ion.
Interestingly, similar Mannich products are synthesized by
employing a CDC reaction of tertiary amines with carbonyl
compounds, which proceed through the in situ activation of
[a] K. Alagiri, P. Devadig, Dr. K. R. Prabhu
Department of Organic Chemistry
Indian Institute of Science
Bangalore 560012, Karnataka (India)
Fax : (+91)80-23600529
E-mail: prabhu@orgchem.iisc.ernet.in
[**] DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; CDC=cross-de-
hydrogenative coupling.
À
C H bonds adjacent to the nitrogen to form an iminium
ion. These CDC reactions are accomplished by using a varie-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200100.
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Chem. Eur. J. 2012, 18, 5160 – 5164

COMMUNICATION
ty of reagents such as CuI/O2/AcOH (Guo et al.),[10a]
VO
(acac)2/TBHP/proline (Klussmann et al.),[10b] Ru/visible
radical initiator as the additive and follow the reaction. In-
terestingly, the addition of azobisisobutyronitrile (AIBN,
10 mol%) induced a striking change in the outcome of re-
sults and furnished the expected product 3a in 80% along
with the corresponding N-oxide 4 in a trace amount (6%,
Table 1, entry 6). However, performing the same reaction
under ambient temperature resulted in lower yields of the
product (25%, Table 1, entry 7). Increasing the oxidant
(DDQ) loading as well as varying the amount of AIBN has
brought out a marginal change in the yields of the products
(Table 1, entries 8–11). Although the use of benzoyl perox-
ide (BPO) as a radical initiator furnished 3a in 74%, it also
gave the by-product 4 (12%, Table 1, entry 12). The control
experiment of 1a with 2a in argon atmosphere (in the ab-
sence of molecular oxygen) furnished a trace amount of 3a
(9%, Table 1, entry 13), indicating that molecular oxygen is
crucial for the reaction. Similarly, the reaction of 1a with 2a
in the absence of DDQ furnished a trace amount of the
product 2a (Table 1, entry 14). These two control experi-
ments clearly indicate that the reaction requires DDQ,
AIBN, and molecular oxygen. Based on these optimization
studies, further reactions were performed at 608C using
THIQ (1 equiv), ketone (5 equiv), DDQ (10 mol%), and
AIBN (10 mol%) in molecular oxygen.
ACHTUNGTRENNUNG
light/proline (Rueping et al.),[10c] and others.[10d–f] In all these
cases, it is essential to activate ketones to their enolate form
because ketones are less reactive pronucleophiles. Addition-
ally, substituted ketones resulted in lower yields of the re-
quired product, and hence they are not studied in greater
À
detail. In continuation of our studies in C H functionaliza-
tion,[11] herein we report an unprecedented Mannich-type re-
action of THIQ (tetrahydroisoquinoline) with ketones by
employing a catalytic amount of DDQ (10 mol%) in the
presence of molecular oxygen and a catalytic amount AIBN
as an additive. The additional advantage of this method is
that it does not require the activation of ketones.
For the optimization studies, we chose N-phenyl tetrahy-
droisoquinoline (1a) and 2-butanone (2a) as model sub-
strates. As shown in Table 1, the reaction of 1a (1 equiv)
with 2a (5 equiv) in the presence of DDQ (10 mol%) as an
oxidant and molecular oxygen as a co-oxidant at 608C
under solvent-free conditions furnished the expected prod-
uct 3a in 48% yield (Table 1, entry 1). It is worth noting
Table 1. Optimization of reaction conditions.
The scope and generality of this method was investigated
using a variety of N-aryl tetrahydroisoquinolines and ke-
tones (Table 2). Ethyl methyl ketone underwent a facile
coupling with N-phenyl tetrahydroisoquinoline to furnish
the expected product 3a in good yield (80%, Table 2). Inter-
estingly, reaction of sterically hindered ketone such as isobu-
Entry
DDQ
[mol%]
Additive
[(mol%)]
T
[8C]
t
Yield [%][a]
3a
G
G
[h]
4
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
20
10
5
–
60
60
60
60
60
60
RT
60
60
60
60
60
60
60
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
56
52
56
80
80
25
86
82
70
32
74
9
–
–
–
–
–
6
–
4
4
6
7
12
–
–
Table 2. DDQ-catalyzed Mannich reaction of N-aryl tetrahydroisoquino-
lines.[a,b,c]
Fe powder (10)
MoO3(10)
Pd
E
V2O5(10)
AIBN (10)
AIBN (10)
AIBN (30)
AIBN (20)
AIBN (5)
AIBN (5)
BPO (5)
9
10
11
12
13[b]
14
10
10
–
AIBN (10)
AIBN (10)
trace
[a] Conversion of yields based on tertiary amine and determined by
NMR spectroscopy. [b] Reaction in the absence of O2. AIBN=Azobis-
isobutyronitrile. BPO=Benzoyl peroxide.
that ketone 2a underwent a facile coupling reaction with
THIQ (1a) in the absence of activating reagents such as
bases or acids.[10] Addition of metal catalysts (10 mol%)
such as iron powder, MoO3 and PdACHTNUTRGNEUNG(OAc)2 as additives did
not improve yields of the product (Table 1, entries 2–4).
However, addition of V2O5 (10 mol%) as additive improved
the yield of the product dramatically to 80% (Table 1,
entry 5). As the DDQ-mediated reaction follows a free radi-
cal pathway, we thought that it is appropriate to use free-
[a] Standard reaction conditions: 1a (1 mmol), 2a (5 mmol), DDQ
(0.1 mmol), AIBN (0.1 mmol), neat, 608C, 24 h. [b] Yields determined by
NMR spectroscopy based on tertiary amine. [c] Isolated product yields
are presented in parenthesis.
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K. R. Prabhu et al.
Table 3. DDQ-catalyzed CDC reaction of N-aryl tetrahydroisoquinolines
tyl methyl ketone with N-phenyl tetrahydroisoquinoline fur-
nished the expected product 3b in 88% yield (Table 2).
However, it is documented that the similar reaction using
with hydroxycoumarins.[a,b,c]
VOACHTUNGTRENNUNG(acac)2/TBHP/l-proline catalytic system furnished the
same product in lower yields and required an extended reac-
tion time.[10b] N-(p-Methyl)phenyl and N-(p-fluoro)phenyl
tetrahydroisoquinolines underwent facile CDC reactions
with ethyl methyl ketone (2a) and isobutyl methyl ketone
(2b) to afford the desired coupled products 3c, 3d, 3e, and
3 f in 80, 79, 83, and 86% yields, respectively (Table 2). In
addition, acetophenone (2c) with N-phenyl tetrahydroiso-
quinoline afforded the expected product in excellent yield
(92%, Table 2). As seen from these examples, the coupling
reaction of N-aryl tetrahydroisoquinoline with ketone oc-
curred at the less-hindered side of the ketone, which may be
due to steric hindrance.[12]
After successful oxidative Mannich reaction of THIQ
with ketones, we turned our attention to apply this method-
ology for the alkylation of 4-hydroxycoumarins (at position
3) with N-aryl tetrahydroisoquinolines. Hydroxycoumarin
derivatives are found to exhibit anti-HIV, anti-bacterial,
anti-tumor, anti-inflammatory, anti-viral effects, antioxidant,
anti-coagulant, antitubercular, and analgesic activities.[13]
Owing to their remarkable and broad-ranging pharmacolog-
ical activity, these compounds have aroused a great deal of
synthetic interest.[13] To the best of our knowledge, hitherto
there have been no reports on the utility of 4-hydroxycou-
marin derivatives as nucleophiles in CDC reactions. There-
fore, we document the first report of a DDQ-catalyzed
CDC reaction of N-aryl tetrahydroisoquinolines with 4-hy-
droxycoumarin derivatives in the presence of molecular
oxygen as the oxidant and AIBN as the additive (Table 3).
As can be seen in Table 3, N-phenyl and N-(p-fluoro)phenyl
tetrahydroisoquinolines underwent coupling reaction with 4-
hydroxycoumarin (5a) to furnish the desired coupled prod-
ucts 6a and 6b (Table 3). Interestingly, 6-methyl-4-hydroxy-
coumarin (5b) with various N-aryl tetrahydroisoquinolines
such as N-(p-methyl)phenyl tetrahydroisoquinoline, N-(p-
methoxy)phenyl tetrahydroisoquinoline, N-(p-fluoro)phenyl
tetrahydroisoquinoline, and N-(p-bromo)phenyl tetrahydro-
isoquinoline furnished the expected products 6c, 6d, 6e, and
6 f in good yields (Table 3).
[a] Standard reaction conditions: 1a (1 mmol), 5a (1 mmol), DDQ
(0.1 mmol), AIBN (0.1 mmol), MeOH, 608C, 24 h. [b] Yields based on
tertiary amine and determined by NMR spectroscopy. [c] Isolated prod-
uct yields are presented in parenthesis.
Table 4. DDQ-catalyzed a-phosphonation of N-aryl tetrahydroisoquino-
lines by a CDC method.[a,b]
After alkylation of 4-hydroxycoumarins, we continued our
investigation for the hydrophosphorylation of N-aryl tetra-
hydroisoquinolines using CDC reactions. a-Amino phospho-
nates are biologically active compounds and are a potential
alternative to an amino acid moiety.[14] a-Phosphonation of
tertiary amines through CDC methods are reported using
Cu, Ir, Fe and Eosin Y as the catalysts.[14] In continuation of
our pursuit on metal-free reactions,[15] herein, we report the
a-phosphonation of N-aryl tetrahydroisoquinolines using
same catalytic system (DDQ/O2/AIBN) in MeOH at 608C
and the results are depicted in Table 4. Diethyl phosphite
(7a) underwent a facile hydrophosphorylation reaction with
a variety of N-aryl tetrahydroisoquinolines such as N-phenyl
tetrahydroisoquinolines, N-(p-methoxy)phenyl tetrahydro-
isoquinoline, and N-phenyl-6,7-dimethoxy tetrahydroisoqui-
[a] Standard reaction condition: 1a (1 mmol), 5a (1.1 mmol), DDQ
(0.1 mmol), AIBN (0.1 mmol), MeOH, 608C, 24 h. [b] Isolated product
yields.
noline to furnish the corresponding phosphonated products
such as 8a, 8b, and 8c in good yields (Table 4). Interestingly,
dimethyl phosphite (7b) and sterically hindered diisopropyl
phosphite (7c) underwent smooth reaction with N-aryl tet-
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Chem. Eur. J. 2012, 18, 5160 – 5164

CDC Reactions of N-Aryl Tetrahydroisoquinolines
COMMUNICATION
rahydroisoquinolines to furnish the desired a-phosphonated
products 8d–8i, which were isolated in good yields
(Table 4).
The exact mechanism of the reaction is not clear at this
stage, however the reaction did not proceed in the presence
of radical scavenger BHT (2,6-bis(1,1-dimethylethyl)-4-
methylphenol), which indicates that the reaction proceeds
through the radical pathway (Scheme 2). We believe that in
maceuticals. Interestingly, the Mannich reaction does not re-
quire any extra reagent or co-catalyst to activate ketones to
enolates. In addition, a-phosphonation of N-aryl tetrahy-
droisoquinolines employs only a stoichiometric amount of
dialkyl H-phosphonates.
Experimental Section
A mixture of DDQ (10 mol%, 10.8 mg, 0.048 mmol), AIBN (7.8 mg,
0.048 mmol), N-phenyl tetrahydroisoquinoline (100 mg, 0.48 mmol) and
4-hydroxycoumarin (5a, 77.5 mg, 0.48 mmol) in MeOH (1 mL) were
heated at 608C under oxygen atmosphere (oxygen balloon) for 24 h. The
solvent was removed under vacuo, added water and extracted with
CH2Cl2. The combined organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. Then, the crude product was purified by
column chromatography on silica gel using ethyl acetate/hexane (1:4) to
afford the desired product 6a (72%) as a pale yellow solid in 72% yield.
M.p. 138–1408C; 1H NMR (400 MHz, CDCl3): d=7.65 (dd, J1 =1.2 Hz,
J2 =7.9 Hz, 1H), 7.45–7.38 (m, 4H), 7.34–7.30 (m, 2H), 7.25–7.12 (m,
6H), 6.16 (s, 1H), 3.69 (dd, J1 =4.9 Hz, J2 =11.9 Hz, 1H), 3.58–3.49 (m,
1H), 3.25 (td, J1 =2.8 Hz, J2 =12.2 Hz, J3 =24.2 Hz, 1H), 2.96 ppm (d, J=
16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=165.1, 164.0, 153.3, 148.5,
135.6, 132.7, 131.9, 129.6, 128.2, 127.4, 126.9, 126.2, 123.6, 123.2, 122.3,
116.4, 104.7, 58.2, 54.9, 30.3 ppm; IR (neat): n˜ =3712, 2923, 2866, 2846,
2629, 2066, 1633 cmÀ1
[M+Na]; found: 392.1261.
; HRMS: m/z: calcd for C24H19NO3: 392.1263
Acknowledgements
This work was supported by CSIR, New-Delhi (No 01ACHTNUTRGNEUNG(2415)/10/EMR-II),
Indian Institute of Science and the RL fine Chem. The authors thank Dr.
A. R. Ramesha and Prof. S. Chandrasekhar for useful discussion. K. A.
thanks CSIR, New-Delhi for a senior research fellowship.
Scheme 2. Plausible mechanism for the a-functionalization of N-aryl tet-
rahydroisoquinolines.
À
Keywords: CDC reaction
hydroxycoumarins · Mannich reaction · metal-free reaction
·
C H activation
·
DDQ
·
the presence of DDQ, N-aryl tetrahydroisoquinoline forms
an iminium ion intermediate, which undergoes further reac-
tion with various pronucleophiles to form the desired cou-
pled product. With respect to the Mannich reaction, the
DDQ anion abstracts the a proton from the ketones and
generates the corresponding enolates.[3b,16] Further work is
underway in our laboratory to exploit the utility of this new
catalytic system, DDQ/O2/AIBN in organic synthesis.
[1] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; b) C. J. Scheuermann,
Chem. Asian J. 2010, 5, 436; c) S.-I. Murahashi, D. Zhang, Chem.
Soc. Rev. 2008, 37, 1490; d) Z. Li, D. S. Bohle, C. J. Li, Proc. Natl.
Acad. Sci. USA 2006, 103, 8928; e) C. S. Yeung, V. M. Dong, Chem.
Rev. 2011, 111, 1215.
[2] a) S. Ahuja, Impurities Evaluation of Pharmaceuticals, Marcel
Dekker, New York, 1998; b) F. Qiu, D. L. Norwood, J. Liq. Chroma-
togr. Relat. Technol. 2007, 30, 877.
[3] a) Y. Zhang, C.-J. Li, Angew. Chem. 2006, 118, 1983; Angew. Chem.
Int. Ed. 2006, 45, 1949; b) Y. Zhang, C.-J. Li, J. Am. Chem. Soc.
2006, 128, 4242; c) A. S.-K. Tsang, M. H. Todd, Tetrahedron Lett.
2009, 50, 1199; d) W. Su, J. Yu, Z. Li, Z. Jiang, J. Org. Chem. 2011,
76, 9144; e) H. Mo, W. Bao, Adv. Synth. Catal. 2009, 351, 2845; f) Y.
Lia, W. Bao, Adv. Synth. Catal. 2009, 351, 865; g) J. Jin, Y. Li, Z.
Wang, W. Qian, W. Bao, Eur. J. Org. Chem. 2010, 1235; h) D.
Cheng, W. Bao, J. Org. Chem. 2008, 73, 6881; i) C. A. Correia, C.-J.
Li, Adv. Synth. Catal. 2010, 352, 1446; j) B.-P. Ying, B. G. Trogden,
D. T. Kohlman, S. X. Liang, Y.-C. Xu, Org. Lett. 2004, 6, 1523;
k) G. L. V. Damu, J. J. P. Selvam, C. V. Rao, Y. Venkateswarlu, Tetra-
hedron Lett. 2009, 50, 6154; l) H. Mitsudera, C.-J. Li, Tetrahedron
Lett. 2011, 52, 1898; m) B. Yu, T. Jiang, J. Li, Y. Su, X. Pan, X. She,
Org. Lett. 2009, 11, 3442.
In summary, we have exploited a catalytic amount of
À
DDQ (10 mol%) to accomplish C H functionalization of
N-aryl tetrahydroisoquinolines by CDC method to form
À
À
C C, and C P bonds. Furthermore, the catalytic use of
DDQ to accomplish the CDC reaction is unprecedented.
This CDC reaction is versatile and works well with a variety
of N-aryl tetrahydroisoquinolines in combination with pro-
nucleophiles. The highlight of the method is that it requires
only a catalytic amount AIBN (10 mol%) as additive under
aerobic conditions. Furthermore, for the first time 4-hy-
droxycoumarin is used as a pronucleophile in the CDC reac-
tion with N-aryl tetrahydroisoquinolines. As hydroxycou-
marin derivatives exhibit a broad-ranging pharmacological
activity,[13] 4-hydroxycoumarin-derived N-aryl tetrahydroiso-
quinoline derivatives may also find an application as phar-
[4] a) D. Walker, J. D. Hiebert, Chem. Rev. 1967, 67, 153; b) P. P. Fu,
R. G. Harvey, Chem. Rev. 1978, 78, 317.
Chem. Eur. J. 2012, 18, 5160 – 5164
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5163

K. R. Prabhu et al.
[5] a) K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu, Tet-
rahedron 1986, 42, 3021; b) H. Lee, R. G. Harvey, J. Org. Chem.
1988, 53, 4587; c) H.-D. Becker, A. Bjork, E. Adler, J. Org. Chem.
1980, 45, 1596.
[6] a) S. Chandrasekhar, G. Sumithra, J. S. Yadav, Tetrahedron Lett.
1996, 37, 1645; b) C. C. Cosner, P. J. Cabrera, K. M. Byrd, A. M. A.
Thomas, P. Helquist, Org. Lett. 2011, 13, 2071; c) G. V. M. Sharma,
B. Lavanya, A. K. Mahalingam, P. R. Krishna, Tetrahedron Lett.
2000, 41, 10323; d) K. Tanemura, T. Suzuki, T . Horaguch, J. Chem.
Soc. Chem. Commun. 1992, 979.
tion also is due to steric hindrance. Therefore, the coupling always
takes place at less-substituted side of the unsymmetrical ketones.
[13] a) Q. Shen, J. Shao, Q. Peng, W. Zhang, L. Ma, A. S. C. Chan, L.
Gu, J. Med. Chem. 2010, 53, 8252; b) N. Vukovic, S. Sukdolak, S.
Solujic, N. Niciforovic, Food Chem. 2010, 120, 1011; c) T. Devji, C.
Reddy, C. Woo, S. Awale, S. Kadota, D. Carrico-Moniz, Bioorg.
Med. Chem. Lett. 2011, 21, 5770; d) P. Theerthagiri, A. Lalitha, Tet-
rahedron Lett. 2010, 51, 5454.
[14] a) O. Baslꢁ, C.-J. Li, Chem. Commun. 2009, 4124; b) M. Rueping, S.
Zhu, R. M. Koenigs, Chem. Commun. 2011, 47, 8679; c) D. P. Hari,
B. Konig, Org. Lett. 2011, 13, 3852; d) W. Han, A. R. Ofial, Chem.
Commun. 2009, 6023; e) W. Han, P. Mayer, A. R. Ofial, Adv. Synth.
Catal. 2010, 352, 1667; f) While preparing this manuscript, a DDQ-
mediated a-phosphonation of THIQ appeared, which used a stoi-
chiometric amount of DDQ (1.1 equiv) and excess of dialkyl-H-
phosphonates (2 equiv), see: H. Wang, X. Li, F. Wu, B. Wan, Tetra-
hedron Lett. 2012, 53, 681.
[7] L. Liu, P. E. Floreancig, Org. Lett. 2010, 12, 4686.
[8] a) W. Zhang, H. Ma, L. Zhou, Z. Sun, Z. Du, H. Miao, J. Xu, Mole-
cules 2008, 13, 3236; b) Z. Shen, J. Dai, J. Xiong, X. He, W. Mo, B.
Hu, N. Sun, X. Hu, Adv. Synth. Catal. 2011, 353, 3031.
[9] M. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096;
Angew. Chem. Int. Ed. 1998, 37, 1044 and references therein.
[10] a) Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan. C. C. Guo, Chem.
Commun. 2009, 953; b) A. Sud, D. Sureshkumar, M. Klussmann,
Chem. Commun. 2009, 3169; c) M. Rueping, C. Vila, R. M. Koenigs,
K. Poscharny, D. C. Fabry, Chem. Commun. 2011, 47, 2360; d) D.
Sureshkumar, A. Sud, M. Klussmann, Synlett 2009, 1558; e) Y. Pan,
C. W. Kee, L. Chen, C.-H. Tan, Green Chem. 2011, 13, 2682; f) F.
Yang, J. Li, J. Xie, Z.-Z. Huang, Org. Lett. 2010, 12, 5214.
[15] a) K. Alagiri, K. R. Prabhu, Chem. Eur. J. 2011, 17, 6922; b) M. R.
Maddani, K. R. Prabhu, J. Org. Chem. 2010, 75, 2327.
[16] In a reaction of benzylic ethers with DDQ, a single electron transfer
from benzylic ethers to DDQ generates a radical cation and DDQ
radical anion. The radical oxygen of the DDQ radical anion thus
generated abstracts a hydrogen atom from the radical cation to gen-
erate a benzoxy cation. Further, the anionic oxygen of the DDQ
radical anion abstracts the a hydrogen from the ketone to generate
an enolate. Finally, the attack of the enolate on the benzoxy cation
generates the CDC product (see ref. [3b]). Based on this informa-
tion, we have shown that DDQ anion can abstract the a hydrogen
of the ketone to form the enolate. On the other hand, generally ke-
tones are in equilibrium with their enol form to a lesser extent.
Hence, we believe that the reaction may proceed through addition
of the enol to the iminium ion to form the Mannich products.
[11] a) K. Alagiri, G. S. R. Kumara, K. R. Prabhu, Chem. Commun. 2011,
47, 11787; b) K. Alagiri, K. R. Prabhu, Org. Biomol. Chem. 2012, 10,
835.
[12] The regioselectivity obtained in this reaction can be explained on
the basis of predictions of Mannich reactions with unsymmetrical
ketones, see: H. O. House, Modern Synthetic Methods, 2nd ed.,
W. A. Benjamin Inc., Berlin, 1972, p. 657. Additionally, Klussmann
(ref. [10b]) and Huang (ref. [10f]) in their work on CDC reactions
reported the sensitivity of Mannich reaction towards steric hin-
drance. Hence, the coupling generally occurs at the a carbon, which
is unsubstituted in the case of unsymmetrical ketones. We believe
that the regioselectivity observed in DDQ-catalyzed Mannich reac-
Received: January 10, 2012
Published online: March 19, 2012
5164
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Chem. Eur. J. 2012, 18, 5160 – 5164