Microwave-Assisted Palladium-Catalyzed Reductive Cyclization/Ring-Opening/Aromatization Cascade of Oxazolidines to Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.1c02416

An efficient palladium-catalyzed reaction of N-propargyl oxazolidines for the construction of 4-substituted isoquinolines under microwave irradiation is developed. This transformation proceeds through a sequential palladium-catalyzed reductive cyclization/ring-opening/aromatization cascade via C-O and C-N bond cleavages of the oxazolidine ring. The practical value of this method has also been explored by conducting a millimole-scale reaction, as well as by transforming the isoquinoline into a key intermediate for the synthesis of a lamellarin analogue.

Full text of DOI:10.1021/acs.orglett.1c02416

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Letter
Microwave-Assisted Palladium-Catalyzed Reductive Cyclization/
Ring-Opening/Aromatization Cascade of Oxazolidines to
Isoquinolines
Xianjun Xu, Huangdi Feng,* and Erik V. Van der Eycken*
Cite This: Org. Lett. 2021, 23, 6578−6582
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ABSTRACT: An efficient palladium-catalyzed reaction of N-
propargyl oxazolidines for the construction of 4-substituted
isoquinolines under microwave irradiation is developed. This
transformation proceeds through a sequential palladium-catalyzed
reductive cyclization/ring-opening/aromatization cascade via C−O
and C−N bond cleavages of the oxazolidine ring. The practical
value of this method has also been explored by conducting a
millimole-scale reaction, as well as by transforming the isoquinoline into a key intermediate for the synthesis of a lamellarin analogue.
Scheme 1. Transition-Metal-Catalyzed Strategies to Access
Isoquinolines
soquinolines, an important class of nitrogen-containing
Iheterocycles, are frequently found in numerous natural
products and medicinally active compounds,1 such as
inhibitors of 11β-HSD12 and anti-HIV compounds,3 and as
precursors of dopamine agonists and antagonists.4 They are
also widely employed as chiral ligands in asymmetric catalysis5
and serve as phosphorescent OLED emitters.6 In the past few
decades, a huge number of synthetic methods have been
developed for the construction of the isoquinoline framework.7
Among them, transition-metal-catalyzed annulation of alkynes
has emerged as one of the most efficient tools for the synthesis
of the isoquinoline motif.8 For example, o-alkynyl benzaldi-
mines,9 which can be formed from an o-alkynyl benzaldehyde
and an amine,10 have been explored to produce 3-substituted
isoquinolines in the presence of metal-based catalysts such as
gold, platinum, copper, and silver (Scheme 1a). Strategies for
isoquinoline construction via the intermolecular [3 + 2]
annulation of 2-halobenzaldimines with alkynes have been well
developed (Scheme 1b).11 In addition, transition-metal-
catalyzed C−H functionalization has been demonstrated as
an atom- and step-economical process to construct 3,4-
disubstituted or 3-substituted isoquinolines (Scheme 1c).12
However, a general protocol for the introduction of a 4-
substituent on the isoquinoline is lacking.13 Although 4-
substituted isoquinolines can be produced by the cross-
coupling of 4-bromoisoquinolines with organometallic re-
agents14 or dehydrogenation of N-heterocycles,15 both
strategies suffer from a rather limited substrate scope.
Therefore, the development of practical and flexible
approaches for the synthesis of 4-substituted isoquinolines is
still highly desirable.
Received: July 20, 2021
Published: August 11, 2021
Recently, elegant examples of Pd-catalyzed reductive Heck
cyclization of propargylamines for the formation of hydro-
isoquinolines have emerged (Scheme 1d).16 On the basis of
https://doi.org/10.1021/acs.orglett.1c02416
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6578−6582
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our interest in the conversion of oxazolidines,17 we
hypothesized that the N-propargyl oxazolidine, readily
generated via A3 coupling,18 might be transformed into a 4-
substituted isoquinoline through a Pd-catalyzed intramolecular
reductive cyclization/ring-opening/aromatization process of an
oxazolidine under microwave irradiation (Scheme 1e). If
successful, the reaction would not only develop a new type of
aromatization strategy but also open a complementary
protocol for isoquinoline synthesis.
Our studies commenced by investigating the Pd-catalyzed
reaction of the 1,3-oxazolidine 1a in the presence of
HCOONa. Screening of various solvents showed that the
combination of DMF and H2O as the solvent is the best choice
for this reaction, giving the desired product 2a in 83% yield
(Table 1, entries 1−6). When H2O was replaced by methanol,
reaction temperature to 120 °C resulted in a decreased yield of
2a (entry 16). To our delight, when the reaction time was
shortened to 12 h, the yield of 2a was improved to 93% (87%
isolated yield, entry 17). Shortening the reaction time to 10 h
afforded a slightly decreased yield of the desired product (entry
18). Satisfactorily, when this reaction was conducted under
microwave irradiation for 30 min, the desired product was
delivered in an 85% isolated yield (entry 19).
With the optimal conditions in hand (Table 1, entry 19), we
started to explore the substrate scope of this reaction by
investigating the series of N-propargyl oxazolidines 1 (Scheme
2). We first examined the effect of the R1 substituent of the N-
Scheme 2. Scope of the Palladium-Catalyzed Reductive
a
Cyclization/Ring-Opening/Aromatization Cascade
a
Table 1. Optimization of the Reaction Conditions for 1a
entry [Pd] (mol %)
solvent (mL)
time (h) yield (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DMA/H2O (1.5/0.5)
THF/H2O (1.5/0.5)
CH3CN/H2O (1.5/0.5)
DMSO/H2O (1.5/0.5)
NMP/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/MeOH (1.5/0.5)
DMF
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
12
10
55
0
24
21
36
83
55
0
61
75
29
17
77
80
0
9
DMF/H2O (0.75/0.25)
DMF/H2O (3/1)
10
11
12
13
14
15
16
17
18
19
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
DMF/H2O (1.5/0.5)
c
d
e
f
a
Standard conditions: all reactions were performed on a 0.15 mmol
scale, Pd(PPh3)4 (5 mol %), HCOONa (2 equiv), DMF/H2O (3/1, 2
mL), 100 °C, microwave irradiation with 150 W maximum power for
30 min.
71
b
93 (87 )
81
g
b
0.5
85
a
propargyl oxazolidine 1. A phenyl group with various electron-
donating groups, such as methyl, methoxy, ethyl, and tert-butyl,
on the para position afforded the corresponding products 2b−
e in good yields. However, relatively low yields were obtained
when electron-withdrawing groups such as fluoro, trifluor-
omethyl, and chloro were introduced at different positions of
the phenyl ring, providing the desired products 2f−j in 65−
75% yield. In addition, the target product 2k was obtained in
89% yield when the phenyl group was switched to a naphthyl
group. A substrate bearing a thiophenyl group also afforded the
desired product 2l in moderate yield. However, no desired
product 2m was detected using the pyridyl-substituted starting
material. Subsequently, a series of substrates bearing an alkyl
group such as propyl, butyl, and tert-butyl were investigated
under the standard conditions. To our delight, they all
delivered the corresponding products 2n−p in excellent yields.
We then investigated the influence of the R2 substituent of the
o-bromophenyl moiety tethered on the oxazolidine ring.
Substrates bearing electron-donating groups (methyl and
methoxy) gave the targeted products 2q−t in good to excellent
yields. However, when a chloro-containing substrate was used,
Reaction conditions unless specified otherwise: 1a (0.15 mmol),
HCOONa (2.0 equiv), Pd(PPh3)4 (5 mol %), solvent, 100 °C, 12−18
h. Yields were determined by H NMR using 2,4,6-trimethoxyben-
zaldehyde as an internal standard. Isolated yield. Pd(PPh3)4 (3 mol
%) was used. Pd(PPh3)4 (10 mol %) was used. The reaction was
performed at 80 °C. The reaction was performed at 120 °C. The
reaction was performed under microwave irradiation with 150 W
maximum power.
1
b
c
d
e
f
g
the yield of 2a decreased to 55% (entry 7). It should be noted
that the desired product could not be observed without H2O
addition (entry 8). These results revealed that H2O plays a
vital role in the formation of 2a. However, changing the
amount of DMF and H2O did not improve the yield of 2a
(entries 9 and 10). Other Pd sources, such as Pd(dba)2 and
Pd2(dba)3, provided the desired product 2a in only 29% and
17% yields, respectively (entries 11 and 12). In addition, we
tried to change the catalytic loading of Pd(PPh3)4, but no
increased yield was observed (entries 13 and 14). Importantly,
when the reaction temperature was reduced to 80 °C, the
desired product was not formed (entry 15). Increasing the
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compound 2a was formed in 63% yield due to dechlorination.
Satisfactorily, when the substrates 1v,w were employed, the
desired products 2v,w were obtained in 47% and 65% yields,
respectively.
To demonstrate the practical applicability of this strategy, we
performed a millimole-scale reaction of 1a (Scheme 3). The
deuteration experiment with substrate 1a. This was reacted
under the standard conditions in the presence of deuterated
water, providing product 8 with deuterium atoms incorporated
at three positions as indicated (Scheme 4b). This result
suggests the existence of intermediate 15 in the mechanism,
and it can easily undergo a proton exchange with H2O during
the process of the ring-opening/aromatization cascade to
deliver product 2 (vide infra). Finally, the use of compound 9
or 10 as substrate did not result in the formation of 2a
(Scheme 4c), implying that our strategy has a new reaction
mechanism in comparison to the well-known process of
intramolecular reductive cyclization and oxidative aromatiza-
tion.20
a
Scheme 3. Transformations of Product 2a
On the basis of the above results and previous reports,16 we
propose the following mechanism (Scheme 5). Initially, the
Scheme 5. Plausible Mechanism
a
Standard conditions: (a) Pd(PPh3)4 (5 mol %), HCOONa (2
equiv), DMF/H2O (3/1, 4 mL), 100 °C, microwave irradiation with
150 W maximum power for 2 h; (b) BrCH2COOCH3 (1.1 equiv),
THF (2 mL), 70 °C, 4 h; (c) 1,2-diphenylethyne (1.0 equiv),
(Cp*RhCl2)2 (5 mol %), Cu(OAc)2 (1.0 equiv), KOAc (2 equiv),
DCE (1.5 mL), 120 °C, 12 h; (d) 1 M NaOH in H2O, EtOH (2 mL),
85 °C, overnight.
microwave irradiation time was extended to 2 h, resulting in
the formation of 2a in 61% yield. This was followed by a
reaction with methyl 2-bromoacetate to afford product 3 in
81% yield. Subsequently, the rhodium-catalyzed cyclization of
3 with 1,2-diphenylethyne was performed to give the pyrrole
derivative 4 in 76% yield. Compound 4 underwent ha ydrolysis
reaction to deliver the corresponding acid 5, which is an
intermediate for the synthesis of a lamellarin analogue.19
To get more insight into the mechanism, we performed the
reaction of substrate 6 under the standard conditions; the
desired product 2a was isolated in 54% yield together with
ethylene oxide 7 in 21% yield (Scheme 4a). We performed a
oxidative addition of Pd(0) to the aryl bromide of 1 gives the
Pd species 11. This is followed by a syn insertion into the
carbon−carbon triple bond, affording the cyclized intermediate
12. This undergoes ligand exchange with HCOONa, leading to
intermediate 13, which loses carbon dioxide to generate
intermediate 14. Next, the reductive elimination of inter-
mediate 14 gives intermediate 15 with regeneration of the Pd0
catalyst. C−O bond cleavage of the oxazole ring of the
intermediate 15 results in the formation of the intermediate
16, which undergoes C−N bond cleavage to form intermediate
17 and epoxide 7′. Finally, spontaneous aromatization
delivered the desired product 2.
Scheme 4. Control Experiments
In summary, we have successfully developed a microwave-
assisted palladium-catalyzed domino reaction of N-propargyl
oxazolidines for the construction of a series of 4-substituted
isoquinolines bearing different substituents. This reaction is
performed through a palladium-catalyzed reductive cycliza-
tion/ring-opening/aromatization process of oxazolidines. The
results reveal that the key for its success is the introduction of
an oxazolidine unit to the substrates, which promotes the
process of hydroisoquinoline aromatization. In addition, we
have demonstrated the utility of this process by the synthesis of
a lamellarin analogue.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02416.
■
sı
Experimental procedures and spectral data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−w, 2a−l,n−t,v,w, 3−7, 9, and 10 (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Huangdi Feng − College of Chemistry and Chemical
Engineering, Shanghai University of Engineering Science,
Shanghai 201620, People’s Republic of China; orcid.org/
0000-0002-5500-8283; Email: hdfeng@sues.edu.cn
Erik V. Van der Eycken − Laboratory for Organic &
Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, KU Leuven, Leuven B-3001, Belgium; Peoples’
Friendship University of Russia (RUDN University), Moscow
117198, Russia; orcid.org/0000-0001-5172-7208;
Email: erik.vandereycken@kuleuven.be
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Author
Xianjun Xu − Laboratory for Organic & Microwave-Assisted
Chemistry (LOMAC), Department of Chemistry, KU
Leuven, Leuven B-3001, Belgium
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02416
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (nos: 22078192, 81973453), the Fund
for Scientific Research-Flanders-FWO (Belgium), and the
RUDN University Strategic Academic Leadership Program. X.
Xu appreciates the financial support from the China Scholar-
ship Council (CSC).
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