Synthesis of 1,2-Dihydroquinolines via Hydrazine-Catalyzed Ring-Closing Carbonyl-Olefin Metathesis

Article abstract of DOI:10.1021/acs.orglett.0c02116

The synthesis of 1,2-dihydroquinolines by the hydrazine-catalyzed ring-closing carbonyl-olefin metathesis (RCCOM) of N-prenylated 2-aminobenzaldehydes is reported. Substrates with a variety of substitution patterns are shown. With an acid-labile protecting group on the nitrogen atom, in situ deprotection and autoxidation furnish quinoline. In comparison with related oxygen-containing substrates, the cycloaddition step of the catalytic cycle is shown to be slower, but the cycloreversion is found to be more facile.

Full text of DOI:10.1021/acs.orglett.0c02116

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Letter
Synthesis of 1,2-Dihydroquinolines via Hydrazine-Catalyzed Ring-
Closing Carbonyl-Olefin Metathesis
Yunfei Zhang, Jae Hun Sim, Samantha N. MacMillan, and Tristan H. Lambert*
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ABSTRACT: The synthesis of 1,2-dihydroquinolines by the
hydrazine-catalyzed ring-closing carbonyl-olefin metathesis
(RCCOM) of N-prenylated 2-aminobenzaldehydes is reported.
Substrates with a variety of substitution patterns are shown. With
an acid-labile protecting group on the nitrogen atom, in situ
deprotection and autoxidation furnish quinoline. In comparison
with related oxygen-containing substrates, the cycloaddition step of
the catalytic cycle is shown to be slower, but the cycloreversion is found to be more facile.
named reactions (e.g., Skraup,3 Friedlaender,4 and Combes5),
have long proven valuable for the construction of quinoline
structures, although these methods often necessitate conditions
(e.g., strong acid) that are incompatible with many complex
molecules. In more recent times, a number of transition-metal-
catalyzed reactions have been reported that enable the
construction of quinolino-moieties under mild and selective
conditions.6 Nevertheless, one of the goals of organic synthetic
chemistry is to invent technologies that enable the creation of a
given molecular target from an ever-growing set of precursor
substrates, thereby expanding the flexibility of the chemist to
devise optimal synthetic campaigns. In this regard, a missing
capability in the quinoline synthesis repertoire is the ability to
convert readily available N-allyl 2-aminobenzaldehydes 4
(anthranilaldehydes7) to 1,2-dihydroquinolines 5 via ring-
closing carbonyl-olefin metathesis (RCCOM) (Figure 1B).
Here we show that this goal can be achieved with high
efficiency via hydrazine catalysis.8
uinolines and their partially saturated derivatives are
Q heterocyclic ring systems that commonly occur in
molecules with a broad spectrum of biological activities
(Figure 1A).1 As such, the development of novel synthetic
strategies to construct these motifs has remained a perennial
interest for synthetic chemists.2 Traditional methods, including
Despite a long history of stoichiometric variants, carbonyl-
olefin metathesis (COM) reactions have only recently
succumbed to catalysis.9,10 Our group’s contribution to this
area has been through the introduction of a hydrazine-
catalyzed strategy that involved [3 + 2] cycloadditions and
cycloreversions.11 Recently, we reported that this strategy
enabled the synthesis of 2H-chromenes via the RCCOM of O-
allyl salicylaldehyde derivatives.10c Given the obvious analogies
between those substrates and the corresponding nitrogen
analogues, we expected that similar success might be found
Received: June 26, 2020
Figure 1. (A) Quinoline, its saturated derivatives 1,2-dihydroquino-
line and 1,2,3,4-tetrahydroquinoline, and some natural products
containing these ring systems. (B) Hydrazine-catalyzed RCCOM
strategy to form 1,2-dihydroquinolines.
https://dx.doi.org/10.1021/acs.orglett.0c02116
© XXXX American Chemical Society
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Letter
here as well (Figure 1B). On the contrary, the greater donating
power of the nitrogen atom made it unclear to what degree the
rate of the cycloaddition step might be inhibited, or the
intermediate cycloadduct 7 shunted down a different
mechanistic pathway by premature rupture of the benzylic
C−N bond. Despite these concerns, we have found that the
RCCOM reaction operates efficiently and with even greater
facility than the oxygen congener.
To determine if it would be possible to achieve such a
transformation, we followed our previous strategy10c by
conducting the cycloaddition and cycloreversion steps
independently to determine their efficiency (Scheme 1).
Scheme 1. Investigation of RCCOM to Form
Dihydroquinoline 11 by Stepwise Cycloaddition and
a
Cycloreversion Reactions
a
Structure 10 is depicted with 50% ellipsoid contour probability
levels.
Thus aldehyde 8 was treated with a stoichiometric quantity
of hydrazine 9 as the bis-trifluoroacetate (TFA) salt in
isopropanol at 80 °C. Although the rate for this reaction was
slower than that of the corresponding ether 12 (Figure 2A),
the cycloadduct 10 was isolated in 75% yield. The structure of
10 was confirmed by single-crystal X-ray analysis. Next, we
found that the cycloreversion of 10 to furnish dihydroquino-
line 11 occurred efficiently in 93% yield by heating to 140 °C
for 10 min (Scheme 1). In this case, the rate of cycloreversion
was significantly faster than that with the corresponding ether
13 (Figure 2B). Clearly, the greater donating power of the
nitrogen atom retards the rate of bond formation in the
cycloaddition but assists bond breaking in the cycloreversion.
The success of the two reactions shown in Scheme 1 gave us
optimism that catalysis might be an effective strategy for this
transformation.
In our previous work for the RCCOM of O-allylsalicylalde-
hydes, we found that the use of a 3,3-diethylallyl or a similar
group was necessary to achieve a reasonable reaction rate and
to discourage deallylation side reactions. In the current case,
given the facility and efficiency of the cycloreversion step, we
speculated that simpler allyl groups might suffice. We thus
conducted a brief study of the impact of varying this structural
component under unoptimized catalytic conditions (Table 1).
As previously seen, neither an allyl (15a, entry 1) nor a
cinnamyl group (15b, entry 2) was an effective participant for
this reaction, but sterically demanding groups such as
adamantylidene (15c, entry 3) and diethylidene (15d, entry
4) provided excellent yields of adduct 11. In contrast with our
previous study, however, an N-prenyl group led to a reasonable
yield of the RCCOM product (15e, entry 5). Although less
efficient than the diethylallyl group, prenyl bromide, from
which substrate 15e is derived, is an inexpensive, commercially
available building block. We thus selected this group for further
optimization (Table 2).
Figure 2. Comparison of conversion rates of O (blue dots) and NT
(orange dots) derivatives for (A) cycloaddition and (B) cyclo-
reversion. Studies were performed at lower temperatures (i.e., 60 and
120 °C) than the optimal conditions to aid comparison. CD3CN was
1
used as the solvent to aid in yield determination by H NMR.
solvent instead of acetonitrile (entry 1), nearly full conversion
but no increase in yield was observed. The analysis of the crude
reaction mixture revealed that dimethyl acetal formation had
consumed significant amounts of the starting material.
Changing the alcohol solvent to ethanol (entry 3), which we
reasoned would have a slower rate of acetalization, improved
the yield to 80%. On the contrary, 10% of the diethyl acetal
derivative was still observed in the reaction. Switching to
isopropanol proved to be most effective (entry 4), leading to
essentially full conversion and an 86% yield, as determined by
1H NMR (82% isolated yield). We found that good conversion
and yield could also be obtained at a reaction temperature of
The solvent was found to be an important parameter for this
transformation. When methanol (entry 2) was used as the
B
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Table 1. Evaluation of the Effect of Alkene Substituents
a
Conversions and yields were determined by 1H NMR using CH2Br2
as an internal standard.
Table 2. Optimization of Reaction Conditions
a
Figure 3. Hydrazine-catalyzed synthesis of dihydroquinoline.
Diethylidene compound was used instead of prenylated moiety for
entry 7.
entry
R
catalyst (mol %)
solvent
conv. (%) 11 yield (%)
1
2
3
4
Ts
Ts
Ts
Ts
Ts
Ts
Bz
Boc
Ms
Ac
Me
9
9
9
9
9
CH3CN
MeOH
EtOH
71
96
97
97
88
15
98
97
96
92
100
47
49
80
86 (82)
75
0
72
64
86
59
0
b
the eight-position led to a very poor yield of 20 (entry 5),
likely due to severe steric conflict between the methyl
substituent and the tosyl group during the cycloaddition. On
the contrary, methyl substitution on the two- and three-
positions was well-tolerated (entries 6 and 7), furnishing
adducts 21 and 22 in 75 and 71% yields, respectively. Halogen
substitution in various positions was also feasible (entries 8−
11), including for the production of the 7-fluoro adduct 26
(entry 11). Electron-donating methoxy (entry 12) and
trifluoromethoxy (entry 13) products 27 and 28 were
generated in high yield, whereas an electron-withdrawing
trifluoromethyl-bearing product 29 was also accessible (entry
14). Lastly, the tricyclic adduct 30 was furnished in high yield
from a naphthalene substrate (entry 15).
The conditions for this chemistry are compatible with a
broad range of functionality. To demonstrate this fact, we
conducted a functional group tolerance screen by adding
various compounds to the standard reaction (see the
Supporting Information).12 We found that additives like
electron-rich terminal alkyne, alkene, ketone, pyridine, indole,
benzofuran, benzothiophene, alkyl alcohol, alkyl carboxylic
acid, and amide all had no adverse effect on the product yield,
and the additives were largely recovered intact. Additives that
did diminish yields included an aniline and an alkyl halide,
presumably due to the competitive reaction with either the
aldehyde or the catalyst.
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
c
5
d
6
7
8
9
10
11
TFA
b
9
9
9
9
9
be
,
f
a
Conversions and yields were determined by 1H NMR using CH2Br2
as an internal standard. Isolated yield. At 120 °C. 20% of TFA.
b
c
d
e
f
15% of quinoline was observed. 7% of quinoline was observed.
120 °C (entry 5), although the conversion and yield were
somewhat diminished for the same 12 h time frame.
Importantly, no reaction occurred when 20% of TFA was
used as the catalyst (entry 6), demonstrating the crucial role of
the hydrazine catalyst 9. Other N-protecting groups like
benzoyl (Bz), t-butyloxycarbonyl (Boc), methanesulfonyl
(Ms), and acetyl (Ac) were also tested, and product yields
of 59−86% were obtained (entries 7−10). In the case of Boc
and Ac, some amount of quinoline was also formed. On the
contrary, an N-methyl substrate was fully decomposed under
the reaction conditions and delivered no product (entry 9).
The optimized reaction conditions proved to be efficient for
accessing a range of 1,2-dihydroquinolines (Figure 3). In
addition to 11 (entry 1), we explored the impact of methyl
substitution around the ring structure. In terms of the aryl ring,
five-, six-, and seven-methyl substituted products 17−19 were
formed in high yield (entries 2−4). In contrast, substitution at
As previously mentioned, the reaction of an N-Boc-
protected substrate led to a 64% yield of 1,2-dihydroquinoline
11 (see Table 2, entry 8); however, we observed the formation
of 15% of quinoline 1 as well. Recognizing the importance of
C
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the quinoline motif, we developed a procedure to increase the
yield of this product (Figure 4A). Thus following the RCCOM
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02116.
Experimental procedures and characterization data
including NMR spectra; crystallographic data for 10
(PDF)
Accession Codes
CCDC 1952207 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Tristan H. Lambert − Department of Chemistry and Chemical
Biology, Cornell University, Ithaca, New York 14853, United
States; orcid.org/0000-0002-7720-3290; Email: thl36@
cornell.edu
Authors
Yunfei Zhang − Department of Chemistry and Chemical
Biology, Cornell University, Ithaca, New York 14853, United
States
Jae Hun Sim − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States
Samantha N. MacMillan − Department of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York 14853,
United States; orcid.org/0000-0001-6516-1823
Figure 4. (A) Synthesis of quinoline (1) via RCCOM. (B) SNAr and
hydrazine-catalyzed RCCOM. (C) Telescoped RCCOM/cycloaddi-
tion for the synthesis of azapterocarpan analogue 36.
reaction of 31 under standard conditions, treatment of the
reaction mixture with a 1 M solution of HCl for 5 min led to
the removal of the Boc group and autoxidation to furnish
quinoline (1) in 61% isolated yield.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02116
Notes
To further illustrate some of the synthetic possibilities of this
RCCOM reaction, we conducted the transformations shown in
Figure 4B,C. First, we found that the reaction of 2-
fluorobenzaldehyde (32) with N-tosyl prenylamine (33)
under classic SNAr conditions,13 followed by 9-catalyzed
RCCOM, led to the formation of adduct 11 in 59% yield
over two steps. Second, we found that the RCCOM of
substrate 34 under standard conditions followed by solvent
exchange to CH2Cl2 and subjection to Lewis-acid-mediated
cycloaddition with quinone 35 according to the literature
procedure14 furnished the azapterocarpan analogue 3615 in
52% yield over the two telescoped steps.
In conclusion, we have developed a novel approach to the
synthesis of dihydroquinolines via the hydrazine-catalyzed
ring-closing carbonyl-olefin metathesis of N-prenyl-2-amino-
benzaldehydes. In comparison with the analogous ether
substrates, the anilides underwent the rate-determining
cycloreversion at a more facile rate, which enabled the use of
commercially available prenyl bromide as the ultimate alkene
source. The simple conditions of alcohol solvent and heat
along with the mild nature of the buffered hydrazine catalyst
render a wide variety of functionalities compatible with this
chemistry. This work thus offers a new tool for the
construction of a privileged heterocyclic motif and expands
the scope of catalytic carbonyl-olefin metathesis chemistry.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by the National
Institutes of Health (R35GM127135).
■
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