Mild metal-free intramolecular oxidative alkylation of a Csp3-H bond adjacent to a nitrogen atom: A versatile approach to ring-fused tetrahydroquinolines

Article abstract of DOI:10.1002/adsc.201200731

A metal-free intramolecular oxidative cross-coupling reaction for the constructing C_sp3-C_sp3 bonds mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) under mild conditions was realized for the first time. This novel strategy prov

Full text of DOI:10.1002/adsc.201200731

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DOI: 10.1002/adsc.201200731
À
Mild Metal-Free Intramolecular Oxidative Alkylation of a Csp3
Bond Adjacent to a Nitrogen Atom: AVersatile Approach to
Ring-Fused Tetrahydroquinolines
H
Gen Zhang,a Shoulei Wang,a Yunxia Ma,a Weidong Kong,a and Rui Wanga,b,*
a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Life Sciences, State Key Laboratory of
Applied Organic Chemistry and Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000,
Peopleꢀs Republic of China
E-mail: wangrui@lzu.edu.cn
b
State Key Laboratory of Chiroscience, Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Kowloon, Hong Kong, Peopleꢀs Republic of China
Received: August 15, 2012; Published online: February 27, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200731.
Abstract: A metal-free intramolecular oxidative
cross-coupling reaction for the constructing Csp3
Csp3 bonds mediated by 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) under mild conditions was
realized for the first time. This novel strategy pro-
such as its high cost, air- and moisture-sensitivity, and
the possibility of toxic trace metal contaminants. For
À
À
À
these reasons, C C or C hetero atom bonds should
be formed with the same levels of efficiency and se-
lectivity as in transition metal-catalyzed reactions but
without the addition of any transition metal, which is
called the metal-free cross-coupling and indeed has
attracted increasing attention in recent years.[5]
Herein, we describe our first contribution on the in-
tramolecular metal-free oxidative coupling of amines
under mild conditions [Eq. (2)].
vides
a simple, efficient, and environmentally
friendly access to diverse ring-fused tetrahydroqui-
noline derivatives.
Keywords: intramolecular reaction; metal-free con-
ditions; oxidative cross-coupling; tetrahydroquino-
lines
The oxidative coupling reaction has been developed
to become one of the most efficient and atom-eco-
nomical strategies for forging new bonds through
À
À
direct coupling of two C H or heteroatom H
bonds.[1] The prospect of concise synthesis of complex
molecules from simple starting materials under mild
conditions makes this reaction particularly attractive.
Amongst such reactions, the oxidative coupling of
amines with various nucleophiles catalyzed by transi-
Ring-fused tetrahydroquinoline derivatives are
tion metals has received considerable attention,[2] and widely used in organic synthesis and pharmaceutical
tremendous progress has been made in this fascinat- chemistry owing to their significant applications as
ing field since the pioneering works of Murahashi and building blocks and for their intriguing biological ac-
Li.[3] Despite the remarkable achievements document- tivities.[6] Traditional methodologies for the formation
ed, the majority of them focused on intermolecular of these privileged heterocycles mainly include the
reactions [Eq. (1)], with a few examples reported on Povarov reaction,[7] reduction of quinolines[8] and
the intramolecular reactions.[4] On the other hand, a 1,5-hydride transfer/cyclization process.[9] However,
À
these reactions usually require the use of a transition the intramolecular oxidative Csp3 H alkylation of
metal, such as Cu, Fe, Pd, Pt, V, Au and Ru. How- amines, an alternative straightforward approach that
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Mild Metal-Free Intramolecular Oxidative Alkylation of a Csp3 H Bond Adjacent to a Nitrogen Atom
Table 1. Optimization of the reaction conditions.[a]
a better solvent with regard to the yield (Table 1, en-
tries 16 and 17).
With the best reaction conditions established, the
scope of substrates for the metal-free intramolecular
oxidative coupling reactions for the synthesis of
varous ring-fused tetrahydroquinoline derivatives was
then studied. In general, the reaction proceeded well
to afford the desired products in good to excllent
yields. The protocol was found to be tolerant to both
electron-withdrawing and electron-donating substitu-
ents in R1 and R2. When R1 was an electron-donating
substituent, a worse result was obtained (Table 2, en-
tries 1 and 4, the yield declined from 73% to 48%),
while R2 as a electron-donating group could greatly
improve the yield (compare entries 4 and 5, the yield
improved from 48% to 95%). This might be due to
the fact that the electron-donating substituent in R1
reduces the activity of ketone, but the electron-donat-
ing group on R2 enhances the activity of the tetrahy-
droisoquinoline to form an iminium cation. The same
result could be seen from entries 1 and 2, while an
electron-withdrawing group slightly hindered the re-
action (entry 3, yield reduced from 73% to 62%), al-
though a good yield could be obtained when the reac-
tion was carried out at 508C. This might be due to the
fact that the electron-donating substituent in R2 en-
hances the reactivity of tetrahydroisoquinoline, while
an electron-withdrawing group plays an opposite role.
The electrically neutral methyl substituent on the
[a]
[b]
Unless otherwise specified, the reaction was carried out
with 1a (0.2 mmol) in the presence of oxidant
(0.22 mmol) in DCM (1.0 mL) at room temperature for
12 h.
Isolated yield
terest in the functionalization of amines,[10] we recent- meta position gave a better yield of desired product
ly reported the first example of copper-catalyzed oxi- than a methyl substituent on the para position
dative cross-coupling reactions of amines with activat- (Table 2, entries 6 and 8), although this could be
À
ed methylenes and olefins for Csp3 H alkylation and avoided by introducing a methoxy group to the aro-
Csp3 H olefination of tertiary amines for the synthesis matic ring of tetrahydroisoquinoline (Table 2, en-
À
of C-1 alkyled and C-1 alkenylated tetrahydroisoqui- tries 7 and 9). When R was methyl, a better yield was
nolines.[10a,b] Encouraged by these successful efforts achieved than with H, and excellent diastereoselecti-
and aiming to develop other unprecedented transfor- vitycould be achieved (Table 2, entries 10 and 11, dr
mations, herein we describe our recent contribution up to 20/1). Finally, 4-[3,4-dihydroisoquinolin-2(1H)-
on intramolecular oxidative couplings of tertiary yl]butan-2-one could react under this system to yield
amines for the synthesis of ring-fused tetrahydroqui- the desirable product in 58% yield when the reaction
noline derivatives.
was carried at 508C (Table 2, entry 12).
As 2,3-dichloro-5,6-dicyanoquinone (DDQ) has
The possible pathways of this novel intramolecular
been widely used as an efficient oxidant in several oxidative coupling reaction is assumed to involve
recent oxidative coupling reactions,[11] we started our a single-electron transfer (SET) radical mechanism.[12]
study on the DDQ-mediated intramolecular oxidative Under DDQ, a hydrogen atom could be abstracted
coupling reaction of 1-{2-[3,4-dihydroisoquinolin- from the C-1 position of 1a to afford the radical
2(1H)-yl]phenyl}ethanone (1a) in the present of Cu- cation 4, which was subsequently transferred to imini-
ACHTUNGTRENNUNG(OTf)2 in DCM at room temperature. The reaction um cation 5 as a key intermediate (Scheme 1). To
gave a moderate yield (66%) when using a 1.1 equiv. check the intermediacy of a radical cation, TEMPO
amount of DDQ (Table 1, entry 1), while using DDQ (2,2,6,6-tetramethyl-piperidin-1-oxyl), a radical inhibi-
alone gave the same yield (entry 2, 67%). Other oxi- tor, was added to this reaction system; there was no
dants including organic oxidants (Table 1, entries 3– significant change in the yield of the intramolecular
10) and metal oxidants (Table 1, entries 11–15) were coupling product and the addition product of 1a with
also used to improve the activity of this reaction. TEMPO was not formed. These results indicate that
However, neither the organic oxidants nor the metal a radical cation might be involved but that the irre-
oxidants could give the desired product in good yield. versible hydrogen transfer could be so rapid that
Solvent optimization results showed that THF was TEMPO cannot capture this radical cation, however,
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Gen Zhang et al.
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Table 2. Investigating the scope of the procedure.[a]
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Adv. Synth. Catal. 2013, 355, 874 – 879

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Mild Metal-Free Intramolecular Oxidative Alkylation of a Csp3 H Bond Adjacent to a Nitrogen Atom
mild conditions with good to excellent yields (48–
95%). This method provides an alternative approach
to current transition metal-catalyzed oxidative cross-
coupling, and provides an efficient and environmen-
tally friendly way to access diverse ring-fused tetrahy-
droquinoline derivatives in one step from basic start-
ing materials and under a direct, efficient, mild and
atom-economical process. The development of this
novel metal-free system in other oxidative coupling
reactions is being pursued.
Experimental Section
For detailed experimental procedures, spectral data and
characterization see the Supporting Information.
Typical Experimental Procedure for the Preparation
of Ring-Fused Tetrahydroquinolines
Scheme 1. Proposed mechanism for metal-free intramolecu-
lar oxidative coupling.
A
solution
2,3-dichloro-5,6-dicyanoquinone
(DDQ,
0.22 mmol) in anhydrous THF (0.6 mL) was slowly added
dropwise to the solution of N-aryltetrahydroisoquinolin
1 (0.2 mmol) in anhydrous THF (0.4 mL) at room tempera-
ture for 0.5 h, and then the resultant reaction mixture was
stirred at room temperature for the appropriate time. After
the reaction was completed (monitored by TLC), the result-
ing mixture was concentrated under reduced pressure and
the residue was purified through column chromatography
on silica gel (eluent, ethyl acetate/hexane 1:10). After filtra-
tion the solvent was removed at reduced pressure to give
the pure products.
Scheme 2. Asymmetric induction in the metal-free intramo-
lecular oxidative coupling.
a little amount of this radical cation can be captured
by 2,6-di-tert-butyl-4-methylphenol (BHT; about 30%,
the yield of 3a decreased from 73 to 41%). After for-
mation of the iminium intermediate 5, the intramole-
cula electrophilic addition to enol occurs to give the
final product 3a.
For the development of an asymmetric intramolec-
ular oxidative coupling reaction mediated by DDQ
under mild conditions for the synthesis of chiral ring-
fused tetrahydroquinolines, we examined various
chiral organocatalysts (for the detail, see the Support-
ing Information). The coupling product 3j was ob-
tained with 14% ee when the chiral phosphoric acid
6a was used (Scheme 2).
Acknowledgements
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (nos. 20932003, 91213302, and
21272101) and the Key National S&T Program “Major New
Drug Development” of the Ministry of Science and Technol-
ogy of China (2012ZX09504-001-003).
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