A Four-Component Cascade C-H Functionalization/Cyclization/Nucleophilic Substitution Reaction to Construct α-Functionalized Tetrahydroquinolines by the Strategy of in Situ Directing Group Formation

Article abstract of DOI:10.1021/acs.orglett.7b00226

A four-component cascade C-H functionalization/cyclization/nucleophilic substitution reactions of anilines, carboxylic anhydrides, propenol, and alkohols have been developed by a strategy of in situ directing group formation, affording an efficient and convenient synthesis of α-alkoxyl tetrahydroquinolines from basic starting materials. A plausible mechanism involving rhodium(III) catalytic C-H functionalization and double nucleophilic attacks is proposed. The nucleophilicity order of some alcohols is also obtained for the cascade reaction.

Full text of DOI:10.1021/acs.orglett.7b00226

Letter
pubs.acs.org/OrgLett
A Four-Component Cascade C−H Functionalization/Cyclization/
Nucleophilic Substitution Reaction To Construct α‑Functionalized
Tetrahydroquinolines by the Strategy of in Situ Directing Group
Formation
†
†
,†,‡
Peng Bai, Ya-Qiong Li, and Zhi-Zhen Huang*
†
Department of Chemistry, Zhejiang University, Hangzhou, 310028, P. R. China
‡
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, 300071, P. R. China
*
S Supporting Information
ABSTRACT: A four-component cascade C−H functionalization/cyclization/nucleophilic substitution reactions of anilines,
carboxylic anhydrides, propenol, and alkohols have been developed by a strategy of in situ directing group formation, affording an
efficient and convenient synthesis of α-alkoxyl tetrahydroquinolines from basic starting materials. A plausible mechanism
involving rhodium(III) catalytic C−H functionalization and double nucleophilic attacks is proposed. The nucleophilicity order of
some alcohols is also obtained for the cascade reaction.
ost transition-metal-catalyzed C−H functionalizations
co-workers reported that N-phenyl acetamides reacted with
allylic alcohols to give indolines via C−H functionalization
M
are assisted by directing groups, which have emerged as
7
powerful methods for the formation of C−C and C−
under rhodium catalysis (Scheme 1, eq 1). Glorious et al.
1
heteroatom bonds. Recently, much attention has been paid
to the strategy of convertible directing groups for C−H
Scheme 1. Reactions Involving N-Phenyl Acetamide and
Propenol
2
−6
functionalizations.
This strategy can be classified into four
modes: (1) In situ connection of a directing group onto a
substrate followed by C−H functionalization and then in situ
disconnection of the directing group, which is fulfilled by one
2
,3
cascade reaction. (2) In situ connection of a directing group
onto a substrate followed by C−H functionalization, and then
the disconnection of the directing group, which is fulfilled by
2
,4
two reactions. (3) The connection of a directing group onto
a substrate, C−H functionalization, and then in situ
disconnection of the directing group, which is fulfilled by two
2
,5
reactions as well. (4) The connection of a directing group
onto a substrate, C−H functionalization, and then disconnec-
tion of the directing group, which is fulfilled by three
2
,6
reactions. Among these modes, the second mode avoids
the formation reaction of directing groups and is also more
atom economic and environmentally friendly. In 2014, Huang
et al. disclosed that anilines reacted with acetic anhydride to
introduce the acetyl group as a directing group in situ to form
N-phenyl acetamides followed by oxidative C−H activation/
annulation with alkynes to give N-acetyl indoles. Then,
disconnection of the acetyl group by the hydrolysis of aqueous
sodium hydroxide produced indoles. However, C(sp )−H
functionalization of anilines with allylic alcohols by the strategy
of in situ directing group formation, such as via N-phenyl
acetamide intermediates, remains unknown. In 2013, Jiang and
revealed one example of the reaction of N-phenyl acetamide
with propenol via C−H activation by rhodium catalysis and
using Cu(OAc) as an oxidant, affording a dihydroquinolinone
2
8
in a low yield. We envisioned that N-phenyl amides I formed
in situ from anilnes 1 and carboxylic anhydrides 2 could
2
4b
2
perform C(sp )−H functionalization with allylic alcohols 3
Received: January 25, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00226
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
through insertion by the direction and assistance of acyl groups,
generating propanalated N-phenyl amides II (Scheme 1, eq 2).
Then nitrogen in the amido group could perform nucleophilic
addition onto the carbonyl group in the propanal moiety to
form α-hydroxyl tetrahydroquinoline III, which should be
reactive.
Scheme 2. Scopes of Anilines 1 and Anhydrides 2 in the
Cascade Reaction
a
As we know, multicomponent reactions have become a
powerful tool to construct organic molecules from three or
9
more compounds in a single operation. A cascade reaction
combines two or more bond-forming reactions into one
process, without requiring isolation of intermediates. Both the
multicomponent reaction and the cascade reaction are atom
economic and step efficient. They reduce resource con-
sumption and environmental impact and have been widely
applied in the synthesis of natural products, pharmaceuticals,
and other bioactive molecules. Thus, we further envisioned that
if there is alcohol 4 as an additional component in the reaction
system, the reactive α-hydroxyl tetrahydroquinoline III may
continue to perform a nucleophilic substitution reaction with 4
in the presence of a Brønsted acid, producing a more stable α-
alkoxyl tetrahydroquinoline 5 (Scheme 1, eq 2). Tetrahydro-
quinoline derivatives especially α-functionalized tetrahydro-
quinolines are present in many biologically active natural
10
products and pharmacologically relevant therapeutic agents.
Thus, we embarked on the four-component cascade C−H
functionalization/cyclization/nucleophilic substitution reaction
between anilines, carboxylic anhydrides, allylic alcohols, and
alcohols by the strategy of in situ directing group formation for
the efficient construction of α-alkoxyl tetrahydroquinolines.
Initially, aniline 1a, acetic anhydride 2a, propenol 3, and
trifluoroethanol 4a were chosen as model substrates to explore
and optimize the four-component cascade C−H functionaliza-
tion/cyclization/nucleophilic substitution reaction. After vari-
ous transition-metal catalysts, oxidants, Brønsted acids,
solvents, etc. were screened, it was concluded that the
optimized reaction should be performed by the catalysis of
a
Reaction conditions: 1 (0.10 mmol), 2 (0.20 mmol), 3 (0.30 mmol),
4
(1.5 mL), [RhCp*CI ] (2.5 mol %), AgSbF (10 mol %), PivOH
2 2 6
[
RhCp*Cl ] (2.5 mol %) and AgSbF (10 mol %) using
2 2 6
(
2.0 equiv), Cu(OAc) (2.0 equiv), 50 °C, for 36 h, under N ; isolated
2 2
b c d
Cu(OAc) (2.0 equiv) and trimethylacetic acid (PivOH; 2.0
2
yields, 24 h. 60 °C. 70 °C.
equiv) as an oxidant and a Brønsted acid respectively at 50 °C
under neat conditions and a nitrogen atmosphere (see
Supporting Information (SI)). It was found that, under the
optimized conditions, various anilines bearing no group 1a,
electron-donating groups 1b−f, or electron-withdrawing groups
quinoline 5oa. Allylic alcohols bearing substituents on carbon−
carbon double bonds, such as 2-methylpropenol and (E)-but-2-
enol, did not undergo the cascade reaction. The experiment
also demonstrated that using propionic anhydride, butyric
anhydride, or valeric anhydride for in situ directing group
formation also assisted the reaction to give α-trifluoroethoxyl
tetrahydrobenzoquinolines 5pa−ra.
1
g−m on benzene rings were able to undergo the four-
component reaction smoothly with acetic anhydride 2a,
propenol 3, and trifluoroethanol 4a to give the desired α-
trifluoroethoxyl tetrahydroquinolines 5aa−ma in 50−91%
yields (Scheme 2). The structure of 5la was further confirmed
by X-ray crystallography (see SI). The trifluoroethoxyl group
has important biological activities, such as high metabolic
stability and lipophilicity, and many trifluoroethoxyl group
substituted compounds have been developed into drugs, such
Considering that many di- or monofluoroethoxyl group
containing compounds have important biological activities and
these motifs widely exist in pharmaceutically relevant
12
molecules, we successively employed difluoroethanol 4b
and monofluoroethanol 4c as nucleophiles in the four-
component reaction. The experiments demonstrated that
aniline 1b or 1c, acetic anhydride 2a, and propenol 3a were
able to undergo the cascade reaction smoothly with 4b or 4c to
give corresponding di- or monofluoroethoxyl tetrahydro-
quinolin 5bb−cc in 50−73% yields (Scheme 3). Trichlor-
oethanol 4d also performed the reaction to give α-
trichloroethoxyl tetrahydroquinoline 5cd in a 58% yield,
which was lower than that of 5ca using trifluoroethanol 4a
(Scheme 2 and Scheme 3). Various common primary alcohols
such as ethanol 4e, pentanol 4f, isobutanol 4g, neopentanol 4h,
and cyclopropanemethanol 4i also underwent the four-
12
as Silodosin, Flecainide, Lansoprazole, and Fluoroxene. The
cascade reaction is compatible to many functional groups such
as nitro, ethoxycarbonyl, fluoro, chloro, bromo, trifluorome-
thoxyl, methoxyl, and tertiary butyl groups. When naphthalene
amines 1n−o were employed, the four-component reaction was
also conducted expediently to afford the corresponding α-
trifluoroethoxyl tetrahydrobenzoquinolines 5na−oa in satisfac-
tory yields. The positions of the amino group on the α or β
position of naphthalene rings in naphthalene amines 1n−o
determines if the reaction leads to anthracene-like tetrahydro-
benzoquinoline 5na or phenanthrene-like tetrahydrobenzo-
B
DOI: 10.1021/acs.orglett.7b00226
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Organic Letters
Letter
,
a b
Scheme 3. Scope of Alcohols 4 in the Cascade Reaction
isotope effect (KIE) is 2.6. The KIE result suggests that the C−
H functionalization may be a rate-determining step in the
cascade C−H functionalization/cyclization/nucleophilic sub-
stitution reaction (Scheme 4, eq 4a and eq 4b).
13,14
Referring to the preceding literature reports,
a plausible
mechanism for the cascade C−H functionalization/cyclization/
nucleophilic substitution reaction of aniline 1a, acetyl anhydride
2a, propenol 3, and trifluoroethanol 4a is depicted in Scheme 5.
Scheme 5. Plausible Mechanism
First, aniline 1a reacts with acetyl anhydride 2a to give N-
phenylacetamide 6, forming a directing group in intermediate 6.
a
Reaction conditions: 1 (0.10 mmol), 2a (0.20 mmol), 3 (0.30 mmol),
(1.5 mL), [RhCp*Cl ] (2.5 mol %), AgSbF (10 mol %), PivOH
2+
2
Then, Cp*Rh could activate α-C(sp )−H in phenylacetamide
4
2
2
6
6
to form a six-membered rhodacycle intermediate A. Insertion
(
2.0 equiv), Cu(OAc) , (2.0 equiv), 50 °C, for 36 h, under N .
2 2
c d
b
Isolated yields, 60 °C. 3 (0.50 mmol), 4j (0.50 mmol). S = 1,4-
of propenol 3 into the rhodacycle intermediate A results in an
eight-membered rhodacycle intermediate B. β-H Elimination of
rhodacycle intermediate B gives propanalated N-phenyl
e
dioxane (1.5 mL). 4h (0.50 mmol), S = 1,4-dioxane (1.5 mL).
+
component reaction expediently to give α-alkoxyl tetrahydro-
quinolines 5be−bi in 52−86% yields. When excess allylic
alcohol (5.0 equiv) was employed as both a C−H
functionalization reagent and a nucleophile, equivalent
trifluoroethanol 4a was still needed; otherwise, no α-allyloxyl
tetrahydroquinolines 5bj was obtained. With respect to
secondary alcohols, both chain 4k−l and cyclic 4m−n alcohols
underwent the cascade reaction readily to give 5bk−mn in 40−
acetamide intermediate C and HRh Cp*. After the addition
2+
of a carboxylate anion onto HRh Cp*, loss of carboxylic acid
(HY) by reductive elimination may lead to Cp*Rh. Cp*Rh
then is oxidized into Cp*Rh2+ for catalytic recycle by
Cu(OAc) . For intermediate C, the nitrogen in the acetamido
2
group may undergo nuceophilic addition onto the carbonyl
group in the propanal moiety to form α-hydroxyl tetrahydro-
quinoline intermediate D. Finally, trifluoroethanol 4a under-
goes a nucleophilic substitution reaction with intermediate D in
the presence of a Brønsted acid, producing desired α-alkoxyl
tetrahydroquinoline 5aa.
7
8% yields (Scheme 3).
To gain insight into the mechanistic pathway of the four-
component reaction, we conducted control experiments by
using N-phenyl acetamide 6 instead of aniline 1a and acetic
anhydride 2a (Scheme 4, eq 3). As expected, N-phenyl
Acetyl and propionyl groups as directing groups in α-alkoxyl
tetrahydroquinolines 5ba and 5pa were readily removed by
treatment of BF ·Et O (Scheme 6). However, with the
3
2
Scheme 4. Primary Mechanistic Study
Scheme 6. Disconnection of Directing Group in α-Allyloxyl
Tetrahydroquinolines 5
disconnection of the acetyl or propionyl group, the
trifluoroethyl group in 5 was also removed to give dihydro-
quinolinones 7, which are core structures in a large number of
15
natural products and marketed drugs or their candidates.
To understand the nucleophilicities of different alcohols 4 in
the four-component reaction, two alcohols 4 (10 equiv) were
added together with 1b, 2a, and 3 under the standard
conditions. The competitive experiment of ethanol 4e with
isobutanol 4g indicates that the nucleophilicity of 4e is similar
and about 1.3 times as much as that of 4g in the cascade
reaction, and the chemical selectivity between 4e and 4g is poor
(Scheme 7, eq 5). The competitive experiments of ethanol 4e
acetamide 6 performed the desired cascade reaction with
propanol 3 and trifluoroethanol 4a smoothly to give 5aa in
good yields. The experimental results support that the acetyl
group could function as a directing group in the C−H
functionalization. Furthermore, parallel reactions using equi-
molar amounts of 1a and 1a-D under the optimized conditions
5
were conducted respectively, and the value of the kinetic
C
DOI: 10.1021/acs.orglett.7b00226
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Letter
Scheme 7. Nucleophilicities and Chemical Selectivities
between Two Alcohols 4 for the Cascade Reaction
ACKNOWLEDGMENTS
Financial supports from National Natural Science Foundation
of China (No. 21372195) are gratefully acknowledged.
■
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In conclusion, we have developed a new four-component
cascade C−H functionalization/cyclization/nucleophilic sub-
stitution reaction by the strategy of in situ directing group
formation, constructing α-alkoxyl tetrahydroquinolines 5 from
four basic starting materials in one reaction. By the rhodium
catalytic system, the cascade reaction of anilines 1, carboxylic
anhydrides 2, propenol 3, and alcohols 4 was able to proceed
smoothly to afford efficient and convenient synthesis of α-
alkoxyl tetrahydroquinolines 5 in moderate to excellent yields.
The plausible mechanism involving rhodium(III) catalytic C−
H functionalization and double nucleophilic attacks is also
proposed for the cascade reaction. The nucleophilicity order of
some alcohols 4 is obtained for the cascade reaction. Owing to
the advantages of simple substrates, mild reaction conditions,
moderate to excellent yields, and a highly efficient synthesis, the
novel four-component reaction may have potential applications
in the synthesis of related natural products and the production
of pharmaceuticals.
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1
ASSOCIATED CONTENT
Supporting Information
■
(
3
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00226.
(
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(13) Yi, Y. H.; Lee, H.; Jun, C. H. Chem. Commun. 2016, 52, 10171.
Experimental procedures, characterization data, and
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AUTHOR INFORMATION
Corresponding Author
■
*
(c) Uchida, R.; Imasato, R.; Shiomi, K.; Tomoda, H.; Omura, S. Org.
E-mail: huangzhizhen@zju.edu.cn.
Lett. 2005, 7, 5701.
ORCID
Zhi-Zhen Huang: 0000-0002-2225-4242
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b00226
Org. Lett. XXXX, XXX, XXX−XXX