Ruthenium-Catalyzed Dehydrogenative β-Benzylation of 1,2,3,4-Tetrahydroquinolines with Aryl Aldehydes: Access to Functionalized Quinolines

Article abstract of DOI:10.1021/acs.orglett.6b01390

A new benzylation protocol, enabling straightforward access to β-benzylated quinolines, has been demonstrated. By employing readily available [RuCl₂(p-cymene)]₂ as a catalyst and O₂ as a sole green oxidant, various 1,2,3,4-tetrahydroquinolines were efficiently converted in combination with aryl aldehydes into desired products in a step- and atom-economic fashion together with the advantages of excellent functional group tolerance and chemoselectivity, offering an important basis for the transformation of saturated N-heterocycles into functionalized N-heteroaromatics via a dehydrogenative cross-coupling strategy. Mechanistic investigations support that the reaction undergoes a monodehydrogenation-triggered β-benzylation mode.

Full text of DOI:10.1021/acs.orglett.6b01390

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Dehydrogenative β‑Benzylation of 1,2,3,4-
Tetrahydroquinolines with Aryl Aldehydes: Access to Functionalized
Quinolines
Zhenda Tan, Huanfeng Jiang, and Min Zhang*
School of Chemistry & Chemical Engineering, South China University of Technology, Wushan Road - 381, Guangzhou 510641,
People’s Republic of China
*
S Supporting Information
ABSTRACT: A new benzylation protocol, enabling straightforward access to β-benzylated quinolines, has been demonstrated.
By employing readily available [RuCl (p-cymene)]2 as a catalyst and O2 as a sole green oxidant, various 1,2,3,4-
2
tetrahydroquinolines were efficiently converted in combination with aryl aldehydes into desired products in a step- and atom-
economic fashion together with the advantages of excellent functional group tolerance and chemoselectivity, offering an
important basis for the transformation of saturated N-heterocycles into functionalized N-heteroaromatics via a dehydrogenative
cross-coupling strategy. Mechanistic investigations support that the reaction undergoes a monodehydrogenation-triggered β-
benzylation mode.
ue to the extensive applications of alkylated N-
heteroaromatics in many fields including medicinal and
The above-described idea and our continuous efforts in the
11 12
D
transformation of alcohols and CO2 into value-added
products prompted us to test the reaction of 1,2,3,4-
tetrahydroquinoline 1a with 4-chlorobenzylic alcohol 2a′
material science, the development of efficient alkylation
methods to access such compounds has emerged as one of
the most attractive topics in organic chemistry. Pioneered by
using [RuCl (p-cymene)] as a catalyst. However, it failed to
2
2
1
yield any product (Scheme 1, eq 1) under a N or an O
the Friedel−Crafts reaction, much attention has been focused
2
2
on discovering alternative protocols to realize the related end in
recent years. Representative examples mainly involve the cross-
coupling reactions with alkyl halides via directing group-assisted
Scheme 1. New Observation on Dehydrogenative β-
Benzylation Reaction
2
3
C−H bond activation, hydroheteroarylation of alkenes, ring-
4
5
opening alkylation, radical alkylation including Minisci-type
6
7
reactions, carbene insertion, and Catellani-Lauten-type
8
coupling reactions. Despite these important advances, many
of the existed methods require the use of prefunctionalized or
less environmentally benign halogenated reagents, which could
easily result in preparation difficulties and a detrimental
influence on environment. Hence, the search for green
alkylation shortcuts still remains a challenge.
atmosphere, whereas replacing alcohol 2a′ with 4-chloroben-
zaldehyde 2a under N protection produced a β-benzylated
2
quinoline 3a in 11% yield (Scheme 1, eq 2). Upon thorough
investigation of this new observation, we wish herein to report a
rutheniun-catalyzed dehydrogenative β-benzylation of 1,2,3,4-
tetrahydroquinolines with aryl aldehydes, leading to β-function-
alized quinolines in a step- and atom-economic fashion.
Initially, we tried to formulate an effective reaction system.
The coupling of 1a and 2a was chosen as a model reaction to
evaluate different parameters. First, the reaction was performed
In recent years, the direct dehydrogenation of saturated N-
heterocycles to N-heteroaromatics has been elegantly achieved
9
,10
by employing improved catalyst systems.
However, the
strategy that combines dehydrogenation of saturated N-
heterocycles and coupling processes in one operation, leading
to functionalized N-heteroaromatics, has been scarcely ex-
plored. To realize such a goal, at least two challenging issues
have to be addressed: (i) The in situ formed metal hydride
species should not reduce the coupling reagents. (ii) There
should be a compatible catalyst system to ensure that the
coupling process is much faster than the second dehydroar-
omatization step, thus suppressing the formation of non-
coupling N-heteroaromatics.
in p-xylene at 120 °C for 16 h under an O atmosphere.
2
Gratifyingly, the product (3aa) yield increased to 36% (Table 1,
entry 1), and the addition of benzoic acid significantly
Received: May 12, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01390
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Variation of Aldehydes
ones (3af−3aj), presumably because benzaldehydes possessing
an electron-withdrawing group could enhance the electro-
philicity of the carbonyl group, thus favoring the coupling
process. Gratifyingly, (E)-2-methyl-3-phenylacrylaldehyde
could undergo a smooth dehydrogenative cross-coupling
reaction to give product 3ak bearing an allylic group, albeit
the yield was somewhat low. Heteroaryl aldehydes (2l, 2m)
were also proven to be effective coupling partners, affording the
corresponding products 3al and 3am in 83% and 40% yields,
respectively.
Next, we turned our attention to the variation of 1,2,3,4-
tetrahydroquinolines 1. Thus, various combinations of 1 with
aldehydes 2 were tested. Similar to the results described in
Scheme 2, all the reactions afforded the desired products in
moderate to excellent isolated yields (Scheme 3). In
comparison with aryl aldehydes, the electronic property of
substituents of 1 significantly affected the product formation.
Specifically, an electron-donating group containing 1,2,3,4-
tetrahydroquinolines 1 afforded the products in much higher
yields (see 3dd, 3da, 3ec, and 3el) than those of electron-
deficient ones (see 3ca and 3fa), which is ascribed to electron-
a
Unless otherwise stated, the reaction was performed with 1a (1.5
mmol), 2a (0.5 mmol), cat. (1 mol %), additive (50 mol %), in p-
xylene (1.5 mL) at 120 °C for 16 h using O balloon. Yields are with
respect to DMF, DMSO, and chlorobenzene used as the solvents,
respectively. Yields are with respect to at 110 and 130 °C,
b
2
c
d
respectively. GC yields (%).
improved the reaction efficiency to afford a 75% yield (entry 2).
However, the absence of a ruthenium complex failed to give
any product (entry 3), indicating that the ruthenium catalyst is
essential in affording the product. Next, we tested several other
organic acids (entries 4−7); 4-nitrobenzoic acid was proven to
be the best choice (90% yield). Lewis acid FeCl and base
K CO were totally ineffective for the transformation (entry 8).
3
Scheme 3. Variation of 1,2,3,4-Tetrahydroquinolines
2
3
Several polar and less-polar solvents were less effective than p-
xylene (entry 9). Further, another five ruthenium catalyst
precursors were examined, but the results indicated that they
were inferior to [RuCl (p-cymene)] (entries 10−14). Finally, a
2
2
decrease or an increase of reaction temperature led to a
diminished product yield (entry 15). Thus, the optimized
reaction conditions are as described in entry 4 of Table 1.
With the optimal reaction conditions in hand, we then
examined the generality and the limitation of the synthetic
protocol. First, 1a in combination with various benzaldehydes 2
were tested. As shown in Scheme 2, all the reactions proceeded
smoothly and furnished the desired products in good to
excellent yields upon isolation (see 3aa−3aj). The results
indicated that the electronic property of substituents on the aryl
ring of benzaldehydes slightly affected the product yields.
Generally, electron-deficient substituents afforded the products
(3aa−3ac) in relatively higher yields than those of electron-rich
B
DOI: 10.1021/acs.orglett.6b01390
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Organic Letters
Letter
rich 1,2,3,4-tetrahydroquinolines enabling enhancement of the
nucleophilicity of the in situ formed intermediates, which is in
favor of the cross-coupling process with aldehydes. Finally, we
tested the dehydrogenative cross-coupling reaction of 1,2,3,4-
tetrahydroquinoline 1a with heptanal 2n. Interestingly, a β-
alkenylated product 3an′ was obtained in 9% yield (eq 3).
(BHT) and ethene-1,1-diyldibenzene to the model reaction had
little influence on product yields (Scheme 4, eq 4), showing
Scheme 4. Verification Experiments
It is worth mentioning that various function groups (i.e.,
−
OH, −Cl, −Br, −NO , and ester group) are well tolerated in
2
the synthetic protocol (Schemes 1 and 2), which offers the
potential for elaboration of complex molecules via further
chemical transformations. Moreover, the N-alkylation, which is
generally believed to be a favorable reaction, was not observed
in all tested reactions. More importantly, all the dehydrogen-
ative cross-coupling products did not undergo further benzylic
oxidation to form the ketones, whereas such a oxidation
occurred efficiently in Bert’s catalyst system. The excellent
chemoselectivity demonstrated in our synthetic protocol affords
the potential for further preparation of functional products.
To gain insight into the reaction mechanism, a time−
concentration profile of the dehydrogenative β-benzylation of
that the reaction undergoing a radical pathway is less likely.
Then, the reaction of 3aa′ with aldehyde 2a or alcohol 2a′ was
not able to afford 3aa (eq 5), indicating that quinoline 3aa′
serving as a reaction intermediate can be ruled out. Finally,
enamine C-1a could efficiently couple with aldehyde 2a to yield
product 3aa in almost quantative yield in the presence of of 4-
nitrobenzoic acid, showing 2a is a key reaction intermediate (eq
14
6
), and the cross−coupling step occurs prior to the second
dehydrogenation of 1a to 3aa′.
Based on the above-observed findings, a monodehydrogena-
tion-triggered benzylation mode was proposed in Scheme 5.
1
,2,3,4-tetrahydroquinoline 1a with aldehyde 2a under the
optimized conditions was performed. As shown in Figure 1, 1a
Scheme 5. Possible Reaction Pathway
The reaction initiates with the activation of 1,2,3,4-tetrahy-
droquinoline 1 via N atom coordination to ruthenium, which
15
results in an ortho-C−H bond activation. Then, a slow α-
hydride disassociation (B) followed by a deprotonation process
gives a cyclic enamine C and [RuH ], and the catalytic species
2
is regenerated in the presence of O . Further, a fast trap of C by
2
Figure 1. Representative time course of the model reaction.
aryl aldehyde, via successive nucleophilic addition and
dehydration steps assisted by 4-nitrobenzoic acid, generates
an alkenyl imine E. Finally, the tautomerization of E yields the
β-benzylated product 3. Differentially, the dehydration of D
occurs on the outside alkyl chain while employing an alkyl
aldehyde, and a diene E′ is afforded via a tautomerization step,
which would result in the β-alkenylated product 3′ via further
dehydroaromatization.
with aldehyde 2a was converted into 3aa in a maximum yield
(
90%) within 16 h. The growth rate of 3aa and the descending
speed of 2a were very fast within the first 8 h and then became
slow. Because 1a was excessive, the reaction inevitably gave
quinoline 3aa′, and it reached the highest concentration (65%
in terms of the original 1a) within 16 h. 3aa′ was not observed
in the first 1 h, whereas 3aa was detected in 10% yield, which
indicates, after the first dehydrogeantion of 1a, the subsequent
coupling step with aldehyde 2a is much faster than the second
dehydrogenation to form quinoline 3aa′.
In summary, by employing readily available [RuCl (p-
2
cymene)] as the catalyst and molecular O as the sole green
2
2
oxidant, we have demonstrated a new benzylation approach,
enabling straightforward access to various β-benzylated quino-
lines. A variety of 1,2,3,4-tetrahydroquinolines were efficiently
converted in combination with aryl aldehydes into desired
products in a step- and atom-economic fashion together with
To gain more product-forming information, several ver-
ification experiments were performed. First, addition of excess
radical scanvengers such as 2,6-di-tert-butyl-4-methylphenol
C
DOI: 10.1021/acs.orglett.6b01390
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Letter
the advantages of excellent functional group tolerance and
chemoselectivity, offering an important basis for the trans-
formation of saturated N-heterocycles into functionalized N-
heteroaromatics. Mechanistic studies support the reaction
proceeding in a monodehydrogenation-triggered benzylation
mode. Further investigations applying the dehydrogenative
cross-coupling strategy in creation of other functionalized
heterocycles are ongoing in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
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glett.6b01390.
(11) (a) Xiong, B.; Zhang, S. D.; Jiang, H. F.; Zhang, M. Org. Lett.
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Experimental procedures and spectral data (PDF)
2
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AUTHOR INFORMATION
Corresponding Author
■
*
1
6, 6028−6031. (f) Chen, M. M.; Zhang, M.; Xie, F.; Wang, X. T.;
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M.; Wang, X. T.; Jiang, H. F.; Zhang, M. Org. Biomol. Chem. 2014, 12,
minzhang@scut.edu.cn
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(
761−2768.
12) (a) Xiong, W. F.; Qi, C. R.; He, H. T.; Ouyang, L.; Zhang, M.;
Notes
The authors declare no competing financial interest.
Jiang, H. F. Angew. Chem., Int. Ed. 2015, 54, 3084−3087. (b) Xiong,
W. F.; Qi, C. R.; Peng, Y. B.; Guo, T. Z.; Zhang, M.; Jiang, H. F. Chem.
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ACKNOWLEDGMENTS
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We thank the “1000 Youth Talents Plan”, Science Foundation
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of China (21472052), and the Fundamental Research Funds
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