Solvent-regulated coupling of 2-alkynylbenzaldehydes with cyclic amines: Selective synthesis of fused N-heterocycles and functionalized naphthalene derivatives

Article abstract of DOI:10.1021/acs.orglett.0c03442

An efficient synthesis of 1,2,3,4-tetrahydrobenzo[g]-quinoline derivatives through PdCl₂-catalyzed, TBHP-promoted, and toluene-mediated dehydrogenation/[4+2] cycloaddition of saturated cyclic amines with 2-alkynylbenzaldehydes was developed. On the contrary, when the reaction medium was changed from toluene to DMSO/H₂O, another class of important compounds, naphthyl chain amines, formed via a dehydrogenation?intermolecular condensation? C?N bond cleavage?intramolecular condensation pathway, was obtained with good selectivity.

Full text of DOI:10.1021/acs.orglett.0c03442

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Letter
Solvent-Regulated Coupling of 2‑Alkynylbenzaldehydes with Cyclic
Amines: Selective Synthesis of Fused N‑Heterocycles and
Functionalized Naphthalene Derivatives
Yan He,* Zhi Zheng, Qimeng Liu, Xinying Zhang, and Xuesen Fan*
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ABSTRACT: An efficient synthesis of 1,2,3,4-tetrahydrobenzo[g]-
quinoline derivatives through PdCl2-catalyzed, TBHP-promoted, and
toluene-mediated dehydrogenation/[4+2] cycloaddition of saturated
cyclic amines with 2-alkynylbenzaldehydes was developed. On the
contrary, when the reaction medium was changed from toluene to
DMSO/H2O, another class of important compounds, naphthyl chain
amines, formed via a dehydrogenation−intermolecular condensation−
C−N bond cleavage−intramolecular condensation pathway, was
obtained with good selectivity.
used N-heterocycles are attracting more attention because
to undergo cycloadditions with π-bond units to synthesize
polycyclic frameworks.6−8 For example, Asao, Yamamoto, and
co-workers initially discovered efficient methods toward
naphthyl ketones or debenzoylated naphthalenes through the
AuCl3/Cu(OTf)2-catalyzed benzannulation between 2-alkynyl-
benzaldehydes and alkynes.7b,c Then, the benzannulation of 2-
alkynylbenzaldehydes with alkenes, enols, or benzynes to
compose different polycyclic compounds was performed in
succession.7d−g Meanwhile, the groups of Dyker and Patil tested
the other olefins/electron-rich heteroarenes and epoxide as
partners to react with 2-alkynylbenzaldehydes.8
F
of their crucial roles in materials1 and pharmaceuticals.2
Due to their unique photochemical or electrochemical proper-
ties, some of them have been used as luminescent or
semiconductor materials.1 In addition, fused N-heterocycles
are essential building blocks of various bioactive derivatives,
which display in vivo potent analgesic activity2a or have a
significant effect on the treatment of Alzheimer’s disease,2b SiHa
human tumor,2c etc. (Figure 1). The direct C(sp3)−H bond
Recently, Liu’s group disclosed novel methods for accessing
distinct α-carbonylnaphthalenes by Cu(OAc)2-catalyzed cyclo-
addition of 2-alkynylbenzaldehydes with isoxazoles.9 Until now,
while benzannulation of 2-alkynylbenzaldehydes with various
unsaturated hydrocarbons was reported, the cycloaddition
between 2-alkynylbenzaldehydes and inactivated cyclic amines
with saturated chemical bonds to form fused N-heterocyclic
compounds is still unknown. Thus, inspired by the elegant
pioneering studies mentioned above and as a continuation of our
work on the functionalization of cyclic amines,10 we herein
report a new method for the synthesis of 1,2,3,4-
tetrahydrobenzo[g]quinoline derivatives through PdCl2-cata-
lyzed dehydrogenation/[4+2] cycloaddition of saturated cyclic
amines with 2-alkynylbenzaldehydes (Scheme 1).
Figure 1. Bioactive molecules containing the fused N-heterocyclic
moiety.
functionalization of readily available cyclic amines is an atom-
economic and attractive transformation for the synthesis of
different kinds of N-heterocyclic compounds. However, a
majority of previous discoveries were focused on the single
activation of the position α3 or β4 to the nitrogen atom. The dual
C(sp3)−H bond functionalization of saturated cyclic amines in a
single step, which was considered to be an attractive way to
synthesize fused N-heterocyclic derivatives, has rarely been
reported.5
Received: October 14, 2020
On the contrary, benzopyryliums, which were formed from
the transition metal-catalyzed intramolecular benzannulation of
2-alkynylbenzaldehydes, usually served as appealing 4-π donors
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was formed via a dehydrogenation−intermolecular condensa-
tion−C−N bond cleavage−intramolecular condensation path-
way. Among them, the DMSO/H2O solvent (19:1) was optimal
to afford 4a in a yield of 43% (for details, see Table S1). Then,
sequentially increasing the loads of PdCl2 and TBHP to 0.1 and
2 equiv, respectively, gave 4a in the highest yield of 62%
(Schemes 4a and 5).
Scheme 1. Previous Work and This Work
Scheme 4. Synthesis of 3a′ and 3b′
Considering the decomposition of saturated cyclic amines in
the oxidant circumstance,10d,e 2-(phenylethynyl)benzaldehyde
(1a, 1 equiv) was initially treated with an excess of 1-
phenylpiperidine (2a, 3 equiv) in toluene at 80 °C under air
for 8 h by using PdCl2 (0.05 equiv) as the catalyst and tert-butyl
hydroperoxide (TBHP, 1 equiv) as the oxidant, from which
phenyl(1-phenyl-1,2,3,4-tetrahydrobenzo[g]quinolin-10-yl)
methanone (3a) was isolated in a yield of 63% (Schemes 2 and
a,b
Scheme 2. Substrate Scope for the Synthesis of 3
a,b
Scheme 5. Substrate Scope for the Synthesis of 4
a
Reaction conditions: 0.2 mmol of 1, 0.6 mmol of 2, 0.02 mmol of
PdCl2, 0.4 mmol of TBHP, DMSO/H2O (19:1, 1 mL), 80 °C, air, 8
a
Reaction conditions: 0.2 mmol of 1, 0.6 mmol of 2, 0.01 mmol of
b
c
b
h. Isolated yields. The 1,2,3,4-tetrahydrobenzo[g]quinoline deriva-
PdCl2, 0.2 mmol of TBHP, toluene (1 mL), 80 °C, air, 8 h. Isolated
d
c
tive (3) was obtained as a byproduct. The 1,2,3,4-tetrahydrobenzo-
yields. Naphthyl chain amine (4) was formed in a trace amount.
e
d
e
[g]quinoline derivative (3) was formed in a trace amount. DMSO/
With 0.4 mmol of TBP instead of TBHP. Naphthyl chain amine (4)
f
f
H2O (9:1, 1 mL). [1-(4-Chlorophenyl)-1,2,3,4-tetrahydrobenzo[g]-
was obtained as a byproduct. The 2-(2-oxo-2-phenylethyl)-
benzaldehyde derivative (5) was obtained as a byproduct.
quinolin-1-yl](phenyl)methanone (3aa) as a byproduct was obtained
g
in a yield of 9%. [1-(4-Bromophenyl)-1,2,3,4-tetrahydrobenzo[g]-
quinolin-1-yl](phenyl)methanone (3bb) as a byproduct was obtained
h
in a yield of 10%. The 2-(2-oxo-2-phenylethyl)benzaldehyde
3a). After screening various catalysts and oxidants, we found the
combination of PdCl2 and TBHP was the most effective (for
details, see Table S1). Subsequently, several solvents were
tested. Accordingly, the results showed that polar solvents were
more favorable for the selective formation of phenyl{3-[3-
(phenylamino)propyl]naphthalen-1-yl}methanone (4a), which
i
derivative (5) was obtained as a byproduct. With 0.4 mmol of
TBP instead of TBHP and DMSO (1 mL).
Having the optimum reaction conditions in hand, we began to
explore the substrate scope of this dual C(sp3)−H bond
functionalization reaction for the preparation of 3. First, various
2-alkynylbenzaldehydes 1 bearing different functional groups,
such as fluoro, chloro, methyl, methoxy, and methylenedioxy
groups, on the aryl-aldehyde or aryl-terminal alkyne moiety were
tried. It showed that all of them were suitable for this
transformation and afforded the corresponding products 3a−
3k in yields of 41−81% (Scheme 2). Moreover, the alkyne-
tethered benzene rings of 2 with electron-donating groups were
Scheme 3. Synthesis of 3z
B
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more favorable than those with electron-withdrawing groups
(3g, 3j, and 3k vs 3h and 3i). Notably, alkyl-substituted alkyne 1l
took part in this reaction smoothly to give 3l in a yield of 54%.
Second, N-aryl piperidines 2 with different substituents attached
to the phenyl rings were also tested. Delightfully, functional
groups ranging from electron-deficient groups (fluoro and
bromo) to electron-rich groups (methyl and methoxy) were
suitable to this transformation, delivering target products 3m−
3s in yields of 28−82% without showing an obvious electronic
effect. However, no intended product was formed when 1-(o-
tolyl)piperidine was used as the substrate, probably due to the
steric effect. In addition, this reaction was compatible with 1-
biphenylpiperidine for the production of 3t in a yield of 80%.
Third, the suitability of different N-aryl pyrrolidines was
explored. It was found that all of them were amenable to this
cascade reaction, albeit giving corresponding products 3u−3y in
somewhat lower yields. The structure of 3g was confirmed by X-
ray single-crystal diffraction analysis (see the Supporting
Information). In addition, byproducts such as naphthyl chain
amines (4) and/or 2-(2-oxo-2-phenylethyl)benzaldehyde de-
rivatives (5) were isolated from some of the reactions for the
construction of 3. The NMR spectra and isolated yields of these
byproducts are included in the Supporting Information.
Remarkably, besides piperidines, N-phenyl pyrazine (2o) with
two nitrogen atoms could undergo this transformation to furnish
3z in a yield of 26% (Scheme 3). However, when secondary
cyclic amines, such as piperidine and pyrrolidine instead of
tertiary amines, were tried, the target 1,2,3,4-tetrahydrobenzo-
[g]quinoline derivatives were not found, and amide products 3a′
and 3b′ were obtained in yields of 31% and 22%, respectively
(Scheme 4).
14% and 18%, respectively, but pyrrolidine afforded 3b′ in a
yield of 16% (Scheme 6).
Scheme 6. Synthesis of 3a′, 3b′, and 3″
To elucidate the reaction pathway, a series of control
experiments were conducted. First, 2 equiv of radical inhibitor
butylated hydroxytoluene (BHT) was added to the standard
reaction systems for the preparation of 3a and 4a. It turned out
that the yields of 3a and 4a were not affected obviously,
excluding the radical mechanism [Scheme 7, (1) and (2)].
Scheme 7. Control Experiments
Next, we turned our attention to the substrate scope for the
synthesis of 4 (Scheme 5). First, a number of 1-arylpyridines 2
with various substituents, such as fluoro, chloro, bromo, cyano,
ester, methoxy, and methyl groups, attached at the para, meta, or
ortho position of the phenyl ring were found to be tolerated,
giving the desired products 4a−4k in yields of 21−75%. Among
them, electron-rich or halogen-substituted N-arylpyridines did
not affect the efficiency of the reaction obviously (4b−4d, 4g,
and 4h vs 4a), but 1-(4-cyanophenyl)piperidine and 1-[4-
(methoxycarbonyl)phenyl]piperidine, which were substituted
with strong electron-withdrawing group, gave the desired
products (4e and 4f) in somewhat lower yields. Due to steric
hindrance, 2 with a methyl unit at the ortho position of the
phenyl ring transformed into 4k in a low yield of 21%. Notably,
this reaction was compatible with 1-biphenylpiperidine and 1-
naphthylpiperidine, delivering 4l and 4m in yields of 46% and
28%, respectively. Second, a range of 2-alkynylbenzaldehydes 1
were studied (4n−4s). The results showed that forms of 1 with
electron-rich groups on the phenyl rings were more favorable
than those with electron-deficient groups (4o and 4p vs 4n).
Moreover, 1l, attached with an alkyl-substituted alkyne unit, was
suitable for this reaction to afford 4t in a yield of 41%. Third, 1-
aryl-substituted pyrrolidines were tested in this transformation,
affording products 4u and 4v in yields of 40% and 24%,
respectively. In addition, byproducts such as 1,2,3,4-
tetrahydrobenzo[g]quinoline derivatives (3) and/or 2-(2-oxo-
2-phenylethyl)benzaldehyde derivatives (5) were isolated from
some of the reactions for the construction of 4. The NMR
spectra and isolated yields of these byproducts are included in
the Supporting Information. Interestingly, when piperidine was
used as the substrate, fused N-heterocycle benzo[g]quinolin-10-
yl(phenyl)methanone (3″) and 3a′ were delivered in yields of
Second, 2-(2-oxo-2-phenylethyl)benzaldehyde (5a), which
could be isolated from the reaction mixture for the formation
of 4a, was treated with 1a under the standard conditions for the
construction of 3a and 4a. Consequently, 3a was not obtained
and 4a was delivered in a yield of 49%. It showed that 5 may be
the possible intermediate for 4a but not for 3a [Scheme 7, (3)
and (4)]. Third, 18O labeling experiments with H218O for the
formation of 3a and 4a were carried out [Scheme 7, (5) and
(6)], from which [16O]-3a versus [18O]-3a and [16O]-4a versus
[18O]-4a were given in a ratio of 1:0.8 and 0.2:1, respectively, as
determined by HRMS analysis. Fourth, the reactions with [18O]-
1a (0.6:1 16O:18O) were also tested. As a result, the
corresponding products [16O]-3a versus [18O]-3a and [16O]-
4a versus [18O]-4a were obtained in ratios of 0.7:1 and 8.5:1,
respectively [Scheme 7, (7) and (8)]. Fifth, when the reactions
for the synthesis of 3a and 4a were conducted under N2 instead
of air, 3a and 4a were still obtained in yields of 59% and 55%,
respectively [Scheme 7, (9) and (10)]. Given that H2O might be
C
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released from these transformations, the results presented above
suggested that the oxygen atom of the carbonyl moiety
embedded in 4a might mainly come from H2O. In addition,
both H2O and 1a might provide the oxygen source for the
formation of 3a (for details, see the Supporting Information).
On the basis of the experimental results mentioned above and
previous reports,9,10 two possible pathways for the formation of
3a are proposed in Scheme 8. Initially, 2a undergoes oxidation
I,10b which is hydrolyzed to provide intermediate J upon
cleavage of the C−N bond.10f Next, the intramolecular aldol
condensation of J occurs to produce intermediate K, which
undergoes further dehydration to deliver product 4a.10c
Notably, when the reaction for the synthesis of 4a was
conducted under the standard conditions for 4 h, intermediates
J (calcd, 424.1883; found, 424.1894) and K (calcd, 384.1958;
found, 384.1945) were detected by HRMS analysis (for details,
see the Supporting Information), which further confirms the
probability of the mechanism mentioned above for the
formation of 4a.
Scheme 8. Proposed Mechanism Accounting for the
Formation of 3a
Finally, we explored the applications of the product obtained
above. It showed that the carbonyl group in 4a could be
conveniently transformed into hydroxyl unit (6, 63%) by
subjecting it to NaBH4 in EtOH/CH3CN at 100 °C for 1 h
[Scheme 10, (1)]. Next, considering the easy conversion of
Scheme 10. Synthesis of 6 and 7 from 4a
secondary amines to N-nitroso derivatives, which is attracting
more attention due to their unique mutagenic properties,12 4a
was treated with TBN in THF at room temperature for 3 h to
deliver N-nitroso compound 7 in a yield of 72% [Scheme 10,
(2)].
In conclusion, we have developed a convenient cascade
reaction of 2-alkynylbenzaldehydes with saturated cyclic amines
to realize the selective synthesis of 1,2,3,4-tetrahydrobenzo[g]-
quinoline derivatives and naphthyl chain amines mediated by
different solvents. Various synthetically useful carbonyl-
containing naphthalene derivatives were conveniently obtained
from these transformations. Moreover, the diverse reactivity of
the carbonyl and amine moieties embedded on the product was
demonstrated by the preparation of alcohol and N-nitroso
derivatives. Further studies of the discovery of new strategies for
facile functionalization of cyclic amines are ongoing in our lab.
and subsequent dehydrogenation to produce enamine B.10a
Next, [4+2] cycloaddition between Pd-containing benzopyry-
lium C and species B occurs to deliver intermediate D. Then, D
is hydrolyzed to give intermediate E with the loss of PdCl2,
which is attached to benzopyrylium.9 Subsequently, dehydration
and aromatization of E successively take place to afford 3a.10c
Additionally, when the reaction for the formation of 3a was
conducted under the standard conditions for 4 h, intermediates
E (calcd, 384.1958; found, 384.1954) and F (calcd, 366.1852;
found, 366.1852) were detected by HRMS analysis (for details,
see the Supporting Information), which might be considered as
positive evidence in supporting the mechanism deduced above.
For another pathway, enamine B reacts with C′, which is the
resonance form of C, to deliver intermediate G.6c In the
presence of PdCl2, G undergoes a ring-opening reaction to
afford intermediate H.6c Then, a thermal electrocyclization or
Diels−Alder reaction of H occurs to give 3a.6c
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03442.
Experimental procedure, characterization data, and NMR
spectra of all products (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−3bb, 4a−4v, 5a−5c, 6, 7, and I (ZIP)
With respect to the formation of 4a, the possible pathway is
shown in Scheme 9. First, 1a is hydrolyzed to generate 5a, which
is likely to be obtained in a polar solvent.11 Then, the aldehyde
unit of 5a reacted with in situ-formed enamine B to give iminium
Accession Codes
Scheme 9. Proposed Mechanism Accounting for the
Formation of 4a
CCDC 2018736 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Yan He − Henan Key Laboratory of Organic Functional Molecules
and Drug Innovation, Key Laboratory for Yellow River and Huai
River Water Environmental Pollution Control, Ministry of
D
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Letter
N.; Nithyanandhan, J. Fused Fluorenylindolenine-Donor-Based
Unsymmetrical Squaraine Dyes for Dye-Sensitized Solar Cells. ACS
Appl. Mater. Interfaces 2018, 10, 26335.
Education, Collaborative Innovation Center of Henan Province
for Green Manufacturing of Fine Chemicals, School of
Environment, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China;
orcid.org/0000-0003-2679-2547; Email: heyan@htu.cn
Xuesen Fan − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory for Yellow River
and Huai River Water Environmental Pollution Control,
Ministry of Education, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, School of
Environment, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China;
orcid.org/0000-0002-2040-6919; Email: xuesen.fan@
htu.cn
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Zhi Zheng − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory for Yellow River
and Huai River Water Environmental Pollution Control,
Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals,
School of Environment, School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan
453007, China
Qimeng Liu − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory for Yellow River
and Huai River Water Environmental Pollution Control,
Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals,
School of Environment, School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan
453007, China
Xinying Zhang − Henan Key Laboratory of Organic Functional
Molecules and Drug Innovation, Key Laboratory for Yellow River
and Huai River Water Environmental Pollution Control,
Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals,
School of Environment, School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan
453007, China; orcid.org/0000-0002-3416-4623
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation of China (21702050), the Program for Innovative
Research Team in Science and Technology in Universities of
Henan Province (20IRTSTHN005), the Key Project of Science
and Technology of Henan Province (192102310412), and the
111 Project (D17007) for financial support.
5110. (b) Romero-Ibanez, J.; Cruz-Gregorio, S.; Sandoval-Lira, J.;
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Hernandez-Perez, J. M.; Quintero, L.; Sartillo-Piscil, F. Transition-
Metal-Free Deconstructive Lactamization of Piperidines. Angew. Chem.,
Int. Ed. 2019, 58, 8867.
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