Iron-catalyzed, chelation-induced remote C-H allylation of quinolines via 8-amido assistance

Article abstract of DOI:10.1021/ol501534z

An iron-catalyzed, 8-amido-enabled regiodivergent C-H allylation of quinolines is described. This reaction represents a rare example of chelation-induced geometrically inaccessible C-H functionalization, allowing for the highly regio- and stereoselective preparation of either the C5- or the C4-allylated quinoline scaffolds regiocontrolled by the catalytic systems.

Full text of DOI:10.1021/ol501534z

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed, Chelation-Induced Remote C−H Allylation of
Quinolines via 8‑Amido Assistance
Xuefeng Cong and Xiaoming Zeng*
Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054,
P. R. China
S
* Supporting Information
ABSTRACT: An iron-catalyzed, 8-amido-enabled regiodiver-
gent C−H allylation of quinolines is described. This reaction
represents a rare example of chelation-induced geometrically
inaccessible C−H functionalization, allowing for the highly
regio- and stereoselective preparation of either the C5- or the
C4-allylated quinoline scaffolds regiocontrolled by the catalytic
systems.
he broad distribution of quinoline scaffolds in bioactive
molecules and natural products has spurred considerable
Scheme 1. Models for Chelation-Assisted C−H
T
Functionalization
efforts toward the development of efficient strategies to the
functionalization of these appealing structural motifs.1 However,
because of the difficulty in the control of the regioselectivity, the
C−H functionalization of quinolines poses a significant challenge
but is a step-economic approach for the buildup of diversely
functionalized derivatives.2 Successful examples in the field
typically focus on the transformation of C−H bonds at the C2,
C3, and C8 positions of quinolines.3 In contrast, efficient
approaches to the C5- and C4-functionalization of quinolines are
still rare.4 Among the various methods for C−H transformation,
the allylation of unactivated C−H bonds attracts immense
attention due to its ability to incorporate valuable allyl structural
motifs5 by greatly increasing the complexity of the resulting
compounds,6−10 notably disclosed by Glorius,9 Ma,7a Cramer,7b
and Nakamura10 via chelation-assisted C−H transformation. In
view of the obvious synthetic utility for the functionalization of
quinolines, the development of a C−H allylation protocol to
selectively buildup the 5- or the 4-allylquinoline motifs is
particularly interesting.
synthesis.14,15 Current studies in the field typically focus on the
C−H functionalization on the carboxamide scaffolds.13−15 In
contrast, the C−H transformations on the quinoline frameworks
are less studied, a known C−H chlorination by a single-electron-
transfer (SET) mechanism reported by Stahl.16 We hypothesized
that, after the formation of the chelation complex B, the amido
group can undergo a property reversal from the X-type to the L-
type ligand (Scheme 2). This variation may adjust the
distribution of electron density on the quinoline and leads the
carbon at the 5- or the 4-position to nucleophilic attack of the π-
allyl species with the formation of the related imino complex C or
D, which can convert into the C5- or the C4-allylated quinoline
through a deprotonation and aromatization process.17
To achieve high regioselectivity, a general strategy is to take
advantage of the chelation assistance of the auxiliary, rendering a
coordinative transition metal to proximity adjacent C−H bonds,
resulting in selective cleavage of a regiospecific C−H bond with
the formation of a cyclometalated species A (Scheme 1a). In
contrast, a strategy for the transformation of a geometrically
inaccessible C−H bond that is located far from the coordinative
metal center remains largely undeveloped, despite its unique
capability in the preparation of structural motifs that are currently
challenging to access by conventional means.11 In this paper, we
disclose an iron-catalyzed, chelation-induced, and site-control-
lable C−H allylation of quinolines via 8-amido assistance,
allowing the preparation of uneasily accessible 5-allylquinoline
frameworks in a highly selective manner (Scheme 1b).12
We started our study by examining the effect of catalysts on the
reaction of 8-aminoquinoline-bearing carboxamide 1a with
commercially available cinnamyl alcohol (Table 1). In the
presence of a mixture of Ru salt and AgSbF6, we were pleased to
Since the pioneering investigation by Daugulis,13 the bidentate
chelation-assisted C−H functionalization using 8-aminoquino-
line as auxiliary provides a powerful tool toward diverse molecule
Received: May 28, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
electrophiles to probe the substrate scope. Interestingly, when
the reaction was conducted with a low-valent iron catalytic
system, the C4-allylation product 4a was generated in
combination with trace amount of ortho-selective α-compound
5a (eq 1). This result is distinctive for the iron-catalyzed ortho-
C−H allylation for the synthesis of γ-allylarenes that was
disclosed by Nakamura’s group.10
Scheme 2. Proposed Mechanism for the Chelation-Induced
C5- and C4-Allylation of 8-Aminoquinolines
Next, we probed the influence of 8-amido scaffolds on the C−
H allylation of quinolines (Scheme 3). Replacement of the aryl
Scheme 3. Influence of 8-Amido Groups on C−H
Table 1. Evaluation the Influence of Catalysts and Allyl
Sources for the C5-Allylation of 8-Aminoquinolines
ab
,
Allylation
ab
,
yield of 3a recovery of 1a
entry
LG
catalyst
(%)
(%)
c
1
OH (2a)
[Ru(p-cymene)Cl2]2
AgSbF6
53
35
2
OH
AgSbF6
Cu(OTf)2
Ni(OTf)2
Fe(OTf)2
FeCl3
50
53
36
40
47
49
28
90
91
30
26
28
38
3
OH
4
OH
40
5
OH
40
6
OH
62
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), FeCl3 (0.02
7
OH
Fe(acac)3
FeCl2
trace
trace
57
b
mmol), DCE (1 mL), 140 °C, 30 h. Isolated yield. The number in
parentheses is the yield of the recovered starting carboxamide.
8
OH
9
OMe
OAc
OCO2-t-Bu
FeCl3
10
11
12
FeCl3
65
with the thienyl and furanyl groups has only a negligible effect on
the transformation (3b−d). A functional alkenyl moiety can be
successfully incorporated into the structural motifs of the
resulting allylquinolines (3e and 3f). Interestingly, as compared
with the related aromatic substituent-containing carboxamides,
the use of alkyl-substituted substrates gives the better perform-
ance in the conversion (3g and 3h).
Further exploration of the scope of quinolines revealed that
the employment of N-methyl-protected carboxamide 6 fails to
afford the allylated product, implying that the proton on the
amido scaffold is indispensable for the improvement of the
conversion (Figure 1). In particular, we found that N-(1-
naphthyl)carboxamide and quinoline cannot give rise to the
desired allylquinolines. This result indicates that a chelation of
iron with N,N′-bidentate 8-aminoquinoline plays a predominant
role in ensuring the allylation to occur effectively. Moreover, the
FeCl3
65
OPO(OEt)2 FeCl3
40
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), catalyst (0.02
b
c
mmol), DCE (1.0 mL), 140 °C, 30 h. Isolated yield. [Ru(p-
cymene)Cl2]2 (2.5 mol %) and AgSbF6 (10 mol %) were used.
find that a C5-position allylated quinoline 3a was formed as a
single product (entry 1). Interestingly, without the Ru salt, the
transformation also takes place smoothly (entry 2). At this stage,
we assumed that AgSbF6 could serve as a Lewis acid in promoting
the transformation. Indeed, It was found that other Lewis acids
such as Cu(OTf)2, Ni(OTf)2, and Fe(OTf)2 enable improve-
ment of the conversion (entries 3−5). Note that the use of a
stronger Lewis acid of FeCl3 gives a better result, providing 5-
allylquinoline 3a in good yield with complete regio- and
stereoselectivity (entry 6). However, the formation of 3a in
trace amounts was observed using Fe(acac)3 and FeCl2 (entries 7
and 8).
Further screening showed that allyl acetate, carbonate and
phosphate are suitable partners in the reaction (entries 10−13).
Because of the easily accessible advantage and yielding water as a
side product in the conversion, allyl alcohols were chosen as allyl
Figure 1. Ineffective substrates in the Fe-catalyzed C5-allylation.
B
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Organic Letters
Letter
installation of electron-rich substituents such as amino and
dimethylamino groups at the C8 position of quinolines hampers
the conversion (9 and 10), suggesting that a traditional Friedel−
Crafts reaction pathway by the formation of an aromatic cation
may be excluded in the mechanism.
The variation of substituents on the allyl alcohols was then
investigated (Scheme 4). As expected, electron-rich p-methyl-
Encouraged by these results, we turned our attention to
probing the postsynthetic functionalization of the amido scaffold
on the resulting allylated quinolines (Scheme 5). The C−H
Scheme 5. Gram-Scale C−H Allylation of 1b and Synthetic
Applications
a b
,
Scheme 4. Iron-Catalyzed C5-Allylation of Quinolines
allylation reaction was successfully conducted on gram scale,
giving quantities of the desired 5-allylquinoline 3h in 73% yield.
Importantly, the amido scaffold on the allylated product enables
facile undergoing a hydrolysis leading to the corresponding
amino moiety, which was successfully converted to the
synthetically useful iodo substituent via a consecutive diazotiza-
tion and iodination.
As shown in Scheme 6a, the C5-allylation still carries out
smoothly when the addition of 2,4-di-tert-butyl-4-methylphenol
Scheme 6. Mechanistic Insights
a
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), FeCl3 (0.02
b
mmol), DCE (1 mL), 140 °C, 30 h. Isolated yield. The number in
parentheses is the yield of the recovered starting carboxamide.
substituted cinnamyl alcohol can be employed in the allylation
(3i). Notably, substitution of the methyl group with the electron-
withdrawing fluoride remarkable accelerates the conversion,
leading to the desired allylquinoline 3j in excellent yield (90%).
This result indicates that the transformation is sensitive to the
substituents on the allyl scaffolds, while electron-withdrawing
groups may favor the conversion due to the facilely generation of
an π-allyl species with iron. Functional groups such as chloride,
bromide, and trifluoromethyl are well tolerated by the reaction
system (3k−m). 2,3-Disubstituted allyl alcohols have been
shown to be suitable partners in the allylation (3n−p). However,
simple allyl alcohol is inefficient in the reaction (3q). Meanwhile,
the use of other simple allylic oxygens such as allyl phenyl ether,
acetate, carbonates and phosphate also give the C5-allylated
quinoline 3q in trace amounts (see the Supporting Information
for details). Interestingly, 3-octen-2-ol furnishes mixed α- and γ-
selective coupling products 3r and 3s, which are thought to be
generated from two different SE2 and SE2′ pathways toward the
nucleophilic attack.18 In particular, the installation of sterically
hindered methyl and methoxy group at the C6-site of quinolines
has no obvious influence on reactivity and regioselectivity, giving
rise to the 5-allylquinolines in good yields (3t−w). It is worth
mentioning that the C−H allylation proceeds with complete
stereoselectivity, and no relevant isomerization of the double
bond to vinylquinoline derivatives was observed in these cases.
(BHT) into the catalytic system, implying that a SET pathway is
less feasible in the transformation. Because no deuterium was
detected by the treatment of 1a with FeCl3 and CD3CO2D, an
irreversible C−H cleavage can be considered for the allylation
(Scheme 6b). In particular, the formation of E-products was
observed starting from Z-allyl alcohols, suggesting that an (π-
allyl)iron species can be involved in the reaction via an
isomerization to form E-products (Scheme 6c). In contrast
with giving α-products from primary alcohols, secondary allyl
alcohols 2b lead to γ-selective linear allylquinolines, showing a
sterically controlled site selectivity for the nucleophilic attack to
C
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Organic Letters
Letter
(4) For selected examples on the C−H functionalization at the C4
position of quinolines, see: (a) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li,
C.-Y.; Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887.
(b) Chen, Q.; du Jourdin, X. M.; Knochel, P. J. Am. Chem. Soc. 2013, 135,
4958.
(5) The allyl scaffold allows facile divergent transformations, such as
epoxidation, olefin metathesis, cycloaddition, dihydroxylation, hydro-
boration, etc. See: Carreira, E. M.; Kvaerno, L. Classics in Stereoselective
Synthesis; Wiley-VCH: Weinheim, 2009; pp 153−185.
(6) For examples on the C−H allylation of electron-deficient arenes
and heteroarenes, see: (a) Yao, T.; Hirano, K.; Satoh, T.; Miura, M.
Angew. Chem., Int. Ed. 2011, 50, 2990. (b) Makida, Y.; Ohmiya, H.;
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see: (a) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597.
(b) Ye, B.; Cramer, N. J. Am. Chem. Soc. 2013, 135, 636. (c) Zhang, Y. J.;
Skucas, E.; Krische, M. J. Org. Lett. 2009, 11, 4248.
the allyl alcohols (Scheme 6d). As to the low-valent Fe-catalyzed
C4-allylation of quinolines, it was found that the ligands heavily
influence the transformation (see the Supporting Information for
more details). Unlike the Fe-catalyzed o-C−H allylation
described by Nakamura,10 the employment of 1,2-bis-
(diphenylphosphino)ethane (dppe) gives a better performance,
and a zinc reagent, TMEDA·ZnCl2, is not required for improving
the conversion. These two factors may be responsible for the
achieving a distinct C4-site-selectivity of quinolines. Meanwhile,
Fe(acac)3 is superior to Fe(acac)2 and Fe(OTf)2 in the
transformation, whereas no allylated product was detected by
use of FeCl2.
In summary, chelation-induced reaction design has extended
C−H allylation to quinoline frameworks. This iron-catalyzed, 8-
amido-enabled procedure allows regiospecific C−H bonds on
the quinolines to site selectively couple with allyl alcohols. It
provides a controllable route for the C−H functionalization at
the C5 or the C4-position of quinoline scaffolds that has rarely
been explored and enables highly selectivity and scalable access
to allylated quinoline derivatives using low-cost, readily available
iron catalyst. Further efforts will be focused on the isolation of
active intermediates and expanding the application in target-
oriented molecule synthesis.
(8) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308.
(b) Oi, S.; Tanaka, Y.; Inoue, Y. Organometallics 2006, 25, 4773.
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̈
5386.
(10) Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135,
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(11) For selected examples, see: (a) Tang, R.; Li, G.; Yu, J.-Q. Nature
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ASSOCIATED CONTENT
* Supporting Information
■
S
(12) For selected examples on the synthesis of 5-allylquinolines, see:
(a) Bromidge, S. M.; Arban, R.; Bertani, B.; Borriello, M.; Capelli, A.-M.;
Di-Fabio, R.; Faedo, S.; Gianotti, M.; Gordon, L. J.; Granci, E.;
Pasquarello, A.; Spada, S. K.; Worby, A.; Zonzini, L.; Zucchelli, V. Bioorg.
Med. Chem. Lett. 2010, 20, 7092. (b) Kopp, F.; Krasovskiy, A.; Knochel,
P. Chem. Commun. 2004, 2288.
(13) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154.
(14) For selected reviews on the use of 8-aminoquinolinyl as auxiliary
in C−H transformations, see: (a) Rouquet, G.; Chatani, N. Angew.
Chem., Int. Ed. 2013, 52, 11726. (b) Corbet, M.; De Campo, F. Angew.
Chem., Int. Ed. 2013, 52, 9896.
Detailed optimization data; experimental procedures; character-
ization data of all new compounds; ORTEP drawing of 3g and
4a; and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
(15) For selected recent examples on the use of 8-aminoquinolinyl as
auxiliary in C−H transformations, see: (a) Aihara, Y.; Chatani, N. Chem.
Sci. 2013, 4, 664. (b) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014,
136, 1789. (c) Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem., Int. Ed.
2014, 53, 3706. (d) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. J.
Am. Chem. Soc. 2014, 136, 646. (e) Tran, L. D.; Roane, J.; Daugulis, O.
Angew. Chem., Int. Ed. 2013, 52, 6043. (f) Song, M. S. W.; Lackner, M. S.
S.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53, 2477. (g) Pan, F.;
Shen, P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758.
(h) Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng, X. Org. Lett.
2014, 16, 2248.
(16) (a) Suess, A. M.; Ertem, M. Z.; Cramer, C. J.; Stahl, S. S. J. Am.
Chem. Soc. 2013, 135, 9797. (b) The formation of 5-methoxy-
substituted compound as side product was previously observed, see:
Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-
F. Chem. Sci. 2013, 4, 4187.
ACKNOWLEDGMENTS
■
Support for this work by the National Natural Science
Foundation of China [Nos. 21202128 (X.Z.)] and XJTU is
gratefully acknowledged. We are grateful to Y.-Z. Zheng (XJTU)
for X-ray crystallographic analysis.
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