PIFA-Mediated Cross-Dehydrogenative Coupling of N-Heteroarenes with Cyclic Ethers: Ethanol as an Efficient Promoter

Article abstract of DOI:10.1002/ejoc.202001354

Ethanol is typically used in organic synthesis as an environmentally benign solvent. Herein, we report a mild and efficient cross-dehydrogenative coupling (CDC) reaction of N-heteroarenes with cyclic ethers by uncovering the new reactivity of ethanol as an efficient promoter in PIFA-mediated radical process. The reaction proceeds smoothly under the irradiation of visible light and features excellent functional group compatibility, which allows the expedite synthesis of a variety of medicinally valuable Cα-heteroarylated cyclic ethers in moderate to high yields.

Full text of DOI:10.1002/ejoc.202001354

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: PIFA-Mediated Cross-Dehydrogenative Coupling of N-
Heteroarenes with Cyclic Ethers: Ethanol as an Efficient
Promoter
Authors: Xiang Li, Chaoyang Liu, Shixun Guo, Wei Wang, and
Yongqiang Zhang
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001354
Link to VoR: https://doi.org/10.1002/ejoc.202001354
01/2020

10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
PIFA-Mediated
Cross-Dehydrogenative
Coupling
of
N-
Heteroarenes with Cyclic Ethers: Ethanol as an Efficient Promoter
Xiang Li,§a Chaoyang Liu,§a Shixun Guo,a Wei Wang,*ab Yongqiang Zhang*a
[a]
X. Li, C.-Y. Liu, S.-X. Guo, Prof. W. Wang, Prof. Y.-Q. Zhang
State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, P. R. China
E-mail: yongqiangzhang@ecust.edu.cn, https://pharmacy.ecust.edu.cn/2018/0302/c9472a73646/page.htm
Prof. W. Wang
[b]
Department of Pharmacology and Toxicology and BIO5 Institute, University of Arizona, Tucson AZ 85721-0207, USA
E-mail: wwang@pharmacy.arizona.edu, https://weiwanggroup.wixsite.com/wwang
These two authors contributed equally to this paper
[§]
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Ethanol is typically used in organic synthesis as an
environmentally benign solvent. Herein, we wish to report a mild and
efficient cross-dehydrogenative coupling (CDC) reaction of N-
heteroarenes with cyclic ethers by uncovering the new reactivity of
ethanol as an efficient promoter in PIFA-mediated radical process.
The reaction proceeds smoothly under the irradiation of visible light
and features excellent functional group compatibility, which allows
the expedite synthesis of a variety of medicinally valuable Cα-
heteroarylated cyclic ethers in moderate to high yields.
CDC with iridium photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 at
room temperature was introduced by MacMillan group, where
persulphate was employed as the oxidant to initiate the radical
process via photoredox catalysis.[4] Alternatively, some cheap
and easily accessible photocatalysts, including benzaldehyde,
rose bengal, Eosin Y and decatungstate (TBADT), could be
used in the process.[5] Seminal efforts have also been made in
the recent procedures using selectfluor as the oxidant in the
presence of transition-metal catalysts or visible light.[6] Notably,
photoexcited diacetyl could serve as the sole promoter of the
reaction.[7] Besides, a green heterogeneous photocatalytic CDC
protocol using a modified graphitic carbon nitride and a rather
unorthodox electrophotocatalytic CDC protocol catalyzed by
trisaminocyclopropenium (TAC) ion have also been reported
without the use of stoichiometric amount of oxidants.[8]
Nonetheless, these methods are far from being ideal. One of the
most important challenges is the requirement of a large excess
amount of cyclic ethers (often used as solvent or co-solvent) in
the reaction to achieve effective transformations. This drawback
restricts the reaction to the use of simple and easily accessible
cyclic ethers, which creates a great application challenge in the
synthesis of medicinally valuable targets.
Introduction
Cross-dehydrogenative coupling (CDC), which is able to
generate C-C bond from two inert C-H bonds under oxidative
conditions, represents the state-of-art in C-C bond forming
reactions.[1] Such
a coupling allows the use of simple
unfunctionalized substrates, thus making syntheses more
economical and convenient. Remarkably, it has become a viable
strategy in directly linking cyclic ethers with electron-deficient N-
heteroarenes. The reaction occurs selectively at the Cα-position
of cyclic ethers and the electrophilic site of N-heteroarenes via
radical mechanism, allowing the facile synthesis of Cα-
heteroarylated cyclic ethers as a class of medicinally valuable
structural motifs with a broad spectrum of biological properties
(see the representative examples shown in Figure 1).[2]
Scheme 1. The CDC reactions of N-heteroarenes with cyclic ethers
developed by our group.
The efforts of our group to address this issue have furnished a
novel ammonium persulfate (APS)-mediated protocol, in which
N-hydroxysuccinimide (NHS) was identified as the optimal
additive to initiate the radical process under mild conditions
(Scheme 1a).[9] The reaction is highly efficient and allows the
decrease of the dosage of cyclic ethers to 5 - 10 equivalents.
Hence, a number of functionalized cyclic ethers could be
engaged. Nevertheless, the use of strong oxidant APS as well
as the in-situ generated strong sulfuric acid have partly impeded
further application. For example, the reaction was not
compatible with the highly electron-rich benzene-fused cyclic
Figure 1. Selected bioactive compounds that contain Cα-heteroarylated cyclic
ether functionality.
However, the classic procedures rely heavily on the use of
explosive peroxides at high temperatures.[3] Such reaction
conditions cause significant safety concerns and limit the
reaction scale. Numerous CDC reactions enabling the coupling
of N-heteroarenes with cyclic ethers under mild conditions have
been developed. For example, in 2015, a visible light-mediated
1
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
n.d c, i
21% j
ethers as well as the complex and biologically active cyclic
ethers (Table 2), which triggered us to explore new CDC
reaction.
16
17
24 W blue LEDs
24 W blue LEDs
EtOH
EtOH
[a] Reaction conditions: 24 W blue LEDs, 1a (2.0 mmol, 10 equiv.), 2a (0.2
mmol, 1 equiv.), PIFA (0.6 mmol, 3.0 equiv.), additive (0.8 mmol, 4 equiv.),
DMSO : DCE = 1:1 (1 mL), N2, rt, 12 h, unless otherwise noted. [b] Yields
were determined by 1H NMR using mesitylene as internal standard. [c] Not
detected. [d] Performed at 80 oC. [e] 2.0 equiv. of glycol was employed. [f] 1
equiv. of TsOH was employed. g) 1 equiv. of Sc(OTf)3 was employed. [h] 5
equiv. of THF was employed. [i] Performed in the absence of PIFA. [j] Under
O2.
Herein we wish to report a mild and efficient PIFA-mediated
CDC reaction of N-heteroarenes with cyclic ethers, where the
cheap, simple and environmentally benign ethanol has been
identified as an efficient promoter in the presence of visible light
(Scheme 1b). The reaction features excellent functional group
compatibility and is comparable to our previous NHS/APS-
mediated protocol in efficiency. Hence, various highly
functionalized and complex cyclic ethers, including benzene-
fused cyclic ethers and a number of complex and biologically
active cyclic ethers, are well tolerated, allowing the facile
synthesis of diverse medicinally valuable targets in moderate to
high yields.
Initially, three additives used in our previous work, including N-
hydroxysuccinimide (NHS), acetamide and quinuclidine, were
evaluated in the coupling of tetrahydrofuran (THF, 2a, 10 equiv)
with isoquinoline 1a under the atmosphere of nitrogen at room
temperature. However, these additives failed to promote the
reaction (entries 1-3, Table 1). Alcohol has been reported to
initiate PIFA-mediated radical process.[11] Methanol was then
surveyed in the reaction. To our delight, the product 3a was
obtained in a tractable yield and excellent regioselectivity (31%
yield, entry 4, Table 1). The increase of reaction temperature
had little effect on the reaction outcome (39% yield, entry 5,
Table 1), while the irradiation of visible light led to a significant
yield improvement (72% yield, entry 6, Table 1). This outcome
inspired us to investigate various alcohol additives in the
presence of visible light. As demonstrated, ethanol, isopropanol
and n-butanol also served as efficient promoter (72% - 86%
yields, entries 7 - 9, Table 1) and ethanol was proved to be
optimal. However, the using of tert-butanol and glycol as the
additive led to a dramatic decrease of the reaction efficiency
(42% - 48% yields, entries 10 - 11, Table 1). The alkoxyl radicals
generated from the redox reaction of these two alcohols with
PIFA tend to undergo β-scission rather than mediating hydrogen
atom transfer (HAT), which might help to explain the result
(Scheme S2).[11a] The addition of strong acids, such as TsOH
and Sc(OTf)3, which were reported to facilitate the reaction via
the activation of N-heteroarenes,[12] was detrimental to the
reaction outcome (38% - 44% yields, entries 12 – 13, Table 1).
Results and Discussion
Bis(trifluoroacetoxy)iodo)benzene (PIFA), a readily available and
easily handled hypervalent iodine (III) reagent with tractable
oxidative capacity, has been extensively used in CDC
reactions.[10] Notably, the potential of this reagent in promoting
the CDC reaction of N-heteroarenes with cyclic ethers has also
been demonstrated (only one example was provided, see
Scheme S1 in supporting information for details).[10a] Regrettably,
potentially explosive reagent NaN3 was employed as the additive
accompanied with low reaction efficiency. Inspired by our
previous work,[9] we envisioned that a careful screening of the
additives would enable the development of a mild, efficient and
broadly applicable approach.
Table 1. The optimization and validation of the reaction conditions. a
Significantly, the reduction of the amount of THF to
5
equivalents also resulted in the formation of 3a in a reasonable
yield (53% yield, entry 14, Table 1). Further extensive screening
of the visible light source and the amount of PIFA and ethanol
(Table S1), as well as the reaction solvent and reaction time
(Table S2), identified the optimal conditions as follow: in the
presence of 24W blue LEDs, 3 equiv. of PIFA, 4 equiv. of
ethanol, the reaction of 1a with 10 equiv. of 2a is conducted in a
solvent mixture (DMSO : DCE = 1 : 1) for 12 h at room
temperature under N2. Under this reaction conditions, 3a was
produced in excellent yield and regioselectivity (86% yield, entry
7, Table 1). Control experiments established the importance of
both PIFA and ethanol, as low yields were achieved in the
absence of these two reaction promoters (entries 15 - 16, Table
1). Furthermore, the inhibition of the reactivity was observed by
the presence of molecular oxygen (entry 17, Table 1), again
suggesting the radical nature of the reaction.
Having identified the optimal reaction conditions (entry 7,
Table 1), we next focused on examining the scope of cyclic
ether components, especially those highly functionalized and
complex cyclic ethers by employing isoquinoline 1a as the
coupling partner (Table 2). It should be noted that 3.5 equiv. of
PIFA and 5 equiv. of ethanol were typically employed for the
cyclic ether substrates with relatively low reactivity. In some
cases, methanol was used as the promoter. Notably, besides-
entry
1
light source
—
additive
NHS
yield b
n.d c
n.d c
2
—
CH3CONH2
Quinuclidine
MeOH
MeOH
MeOH
EtOH
nBuOH
iPrOH
tBuOH
3
—
trace
4
—
31%
5
—
39% d
72%
6
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
24 W blue LEDs
7
86%
8
72%
9
83%
10
11
12
13
48%
42% e
44% f
38% g
Glycol
EtOH
EtOH
14
15
24 W blue LEDs
24 W blue LEDs
EtOH
53% h
19%
—
2
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
Table 2. The scope of cyclic ethers. a
[a] See general procedure for the experimental details and isolated yields were reported, unless otherwise noted. [b] C-2 product : C-4 product = 2.4 : 1 (r.r.); the
regiomeric ratio (r.r.) was determined by 1H NMR spectroscopy. [c] MeOH was employed as the additive. [d] Performed under the standard reaction conditions of
NHS/APS-mediated CDC. [e] Diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy. [f] 5 equiv. of alcohol and 3.5 equiv. of PIFA were employed.
-tetrahydrofuran (THF), other simple cyclic ethers, such as 1, 3-
dioxolane, tetrahydropyran (THP), 1, 4-dioxane and 12-crown-4,
were also well tolerated (3a – 3f, 53% - 86% yields). The C-2
heteroarylated product was mainly detected in the reaction of 1,
3-dioxolane (3b, C-2 : C-4 = 2.4 : 1), enabling the facile
installation of aldehyde group at N-heteroarenes via the
following acid-catalyzed hydrolysis.[13] 2, 2-Dimethyl-1, 3-
dioxolane readily undergoes decomposition under strong acid
conditions to release glycol and acetone. Not surprisingly, the
using of this special cyclic ether as the substrate in our previous
work mainly resulted in the formation of Cα-heteroarylated glycol
product owing to the in-situ generation of stoichiometric amount
of sulfuric acid.[9] However, the new protocol was well compatible
with this substrate, mainly giving Cα-heteroarylated cyclic ether
3c as the major product (53% yield). The benzene-fused cyclic
ethers, which are not amenable to the NHS/APS-mediated
protocol, were then tested. Gratifyingly, this class of highly
electron-rich substrates, including 2, 3-dihydrobenzofuran, 1, 3-
benzodioxole and 1, 4-benzodioxane, were also proved effective
reactants, albeit with inferior reaction efficiency (3g – 3l, 21% -
3
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10.1002/ejoc.202001354
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63% yields), further highlighting the benign nature of the reaction. and pyrazine substrates using slightly modified reaction
conditions (4q – 4s, 27% - 46% yields). In particular, the
pesticide cloquintocet-mexyl, highly functionalized N-
Interestingly, the reaction of 2, 3-dihydrobenzofuran exclusively
gave the C-2 heteroarylated product (3l, 21% yield), providing
an alternative and green approach for the synthesis of 2-
heteroaryl-benzofuran pharmacophore in combination with the
following aromatization (Scheme S3).[14] Remarkably, the
protocol was also suitable for the cyclic ethers with various
functional groups, such as acetoxy, benzoyloxy, cyno and ester
group, affording the products in moderate yields and moderate
to excellent diastereoselectivity (3m – 3q, 33% - 60% yields).
These highly reactive function groups are well tolerated,
providing the handles for rapid derivatization. It is noted that,
different from our previous work,[9] hydroxyl-substituted cyclic
ethers are not tolerated (data not shown here). As a class of
special alcohol, these substrates tend to be oxidized to ketones
rather than undergoing the CDC with N-heteroarenes, which
might be the explanation of this result. To further demonstrate
the utility of our methods in the synthesis of medicinally valuable
targets, five naturally occurring or pharmaceutically relevant
cyclic ethers or their derivatives, inclucing sesamin (2r),
isosorbide derivative (2s), ambroxane (2t), topiramate derivative
(2u) and tegafur derivative (2v), were investigated. The
reactions proceeded smoothly, providing the coupling products
3r – 3v in 22 - 53% yields and moderate to excellent
diastereoselectivity. Interestingly, the benzene-fused cyclic ether
substructure is more favored in the reaction of sesamin (2r). The
excellent Cα selectivity of cyclic ethers was observed for
isosorbide derivative (2s) and topiramate derivative (2u), where
the Cα-H of methoxy and sulfamide groups also can participate
the CDC reaction with N-heteroarenes. Significantly, the anti-
cancer drug tegafur (N-nucleoside), which is vulnerable to acid-
catalyzed hydrolysis, also reacted well (3v, 28% yield), offering a
powerful tool for late-stage modification. In addition to cyclic
ethers, acyclic diethyl ether could also be utilized in 63% yield in
spite of its high volatility (3w, Scheme 2).
a
heteroarene, was also well tolerated (4t, 28% yield).
Interestingly, the reaction occurred selectively at C-2 position to
give only one regioisomer. It is noted that the protocol was not
compatible with some pharmaceutical relevant N-heteroarenes,
such as benzothiazole, benzimidazole, benzoxazole, quinazoline
and imidazole (data not shown here). Finally, various N-
heteroarenes were investigated in the coupling with complex
cyclic ether ambroxane 2t. The reactions proceeded smoothly
albeit with inferior reaction efficiency (5a – 5d, 19% - 47%
yields), further highlighting the potential in the synthesis of
pharmaceutically relevant Cα-heteroarylated cyclic ethers.
Table 3. Scope of N-heteroarenes. a
Scheme 2. The reaction of acyclic ether. See general procedure for the
experimental details and isolated yield was reported, unless otherwise noted.
Having demonstrated the capacity of a variety of cyclic ethers
capable of engaging in the process, we next probed the scope of
N-heteroarenes (Table 3). It is noted that 20 equiv. of THF was
employed accompanied with the extension of reaction time to
22h in some cases to further facilitate the reaction. Pleasingly, a
variety of N-heteroarenes reacted smoothly at the most
electrophilic position, mainly providing the monosubstituted
products. The isoquinoline substrates bearing both electron-
withdrawing and -donating groups readily coupled with THF at
C-1 position (4a – 4f, 66% - 83% yields). As expected, the
reactions of quinolines typically proceeded at C-2 or C-4 position
[a] See general procedure for the experimental details and isolated yields were
reported, unless otherwise noted. [b] 20 equiv. of THF was employed and the
reaction time was extended to 22h. [c] d.r. > 20 : 1, the diastereomeric ratio
(d.r.) was determined by 1H NMR spectroscopy.
in comparable yields (4g
Unsubstituted quinoline mainly gave the bis-substituted product
(4m, 61% yield). Other fused N-heteroarenes, including
phenanthridine, imidazo[1,2-a]pyrimidine and carboline, were
also selectively functionalized in moderate to good yields (4n –
4p, 38% - 76% yields). The acceptable yields and excellent
regioselectivity could also be achieved for less reactive pyridine
– 4m, 57% - 77% yields).
Having established the scope of the method, we performed a
study on the reaction mechanism. The formation of product 3a
was suppressed in the presence of TEMPO, a radical quencher
(Scheme S4), again suggesting that the reaction goes through a
radical pathway. Mixing PIFA with EtOH in d-chloroform
immediately led to
a
metastable hypervalent iodine (III)
1
intermediate, which was speculated by crude H NMR analysis
4
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
(Figure 2). The UV−visible spectra of this intermediate shows an
obvious red shift compared with that of PIFA. Hence, an
improved absorption from 420 to 450 nm is observed,
product 3a. However, considering the fact that the reaction
proceeded to give product 3a in 31% yield at room temperature
without LED irradiation (entry 4, Table 1), the background
reaction mechanism is also proposed (Scheme S6). The I-O
suggesting the enhanced possibility of energy transfer from blue
15]
LEDs to this intermediate (Figure 3).[11c,
Furthermore, a
bond of intermediate I might be weaker compared with that of
[19]
significant kinetic isotopic effect (KIE = 7.0, intermolecular
competition reaction) was observed (Scheme S5).
PIFA,
which could undergo thermal homolytic cleavage to
produce ethoxy radical and iodanyl radical in the process.
Further validation of the mechanism is still ongoing in our
laboratory.
Scheme 3. Proposed reaction mechanism.
Figure 2. The study of the reaction of PIFA with EtOH.
Conclusion
In conclusion, we have developed a mild and efficient PIFA-
mediated cross-dehydrogenative coupling (CDC) reaction for the
coupling of various N-heteroarenes with highly functionalized
and complex cyclic ethers. The protocol utilizes the simple
ethanol as the promoter in the presence of visible light to initiate
the radical process, enabling the facile synthesis of diverse
pharmaceutically relevant Cα-heteroarylated cyclic ethers in
moderate to high yields.
Experimental Section
General procedure: To an oven dried Schlenk tube equipped
with a stir bar, was added N-heteroarenes 1 (0.4 mmol), cyclic
ethers 2 (4.0 mmol), PIFA (1.2 mmol), ethanol (1.6 mmol) and 2
mL of solvent mixture (DMSO : DCE = 1 : 1). The resulting
solution was degassed for 15 min by bubbling N2 stream, then
stirred at room temperature under the irradiation of 24 W blue
LED strip for 12 h. After completion of the reaction, the solution
was diluted with 2.5 mL of aqueous NaOH (1 M) and extracted
with EtOAc (20 mL × 3). The combined organic extracts were
washed with brine (20 mL × 2), dried over Na2SO4 and
concentrated in vacuum. The residue was purified by flash
chromatography on silica gel (EtOAc : petroleum ether = 20:1) to
give product 3, 4 or 5.
Figure 3. Absorption spectra of PIFA and PIFA-EtOH complex
Based on these observations and the fact that ethanol plays
an essential role in the reaction (entry 15, Table 1), as well as
the established mechanism of PIFA-mediated racial
processes,[11, 16] especially those with alcohol as the initiator, a
plausible reaction mechanism is proposed (Scheme 3). The
reaction of PIFA with EtOH provides a hypervalent iodine (III)
intermediate I. The irradiation with visible light enables the
homolysis of the I-O bond of this intermediate and the
generation of ethoxy radical and iodanyl radical. The ethoxy
radical serves as the HAT mediator towards the Cα-H of
tetrahydrofuran owing to the polar effect (path a), [17] which is the
rate-limiting step. However, the HAT mediated by iodanyl radical
cannot be completely excluded (path b).[18] The resulting α-oxy
radical II undergoes a nucleophilic addition with the protonated
isoquinoline (by the in situ formed TFA) at the C-1 position,
followed by deprotonation and oxidation to provide the final
1-(Tetrahydrofuran-2-yl)isoquinoline (3a): Pale yellow liquid,
1
81% yield (66 mg); H NMR (400 MHz, CDCl3): δ = 8.48 (d, J =
5.7 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H),
7.66 – 7.62 (m, 1H), 7.59 – 7.54 (m, 2H), 5.70 (t, J = 7.1 Hz, 1H),
4.20 – 4.14 (m, 1H), 4.05 – 3.99 (m, 1H), 2.55 – 2.46 (m, 1H),
2.41 – 2.34 (m, 1H), 2.28 – 1.89 (m, 2H); 13C NMR (100 MHz,
5
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
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CDCl3): δ = 159.61, 141.60, 136.50, 129.82, 127.32, 127.12,
126.58, 125.25, 120.51, 79.09, 69.01, 30.79, 26.16; Spectral
data match those previously reported.[9]
J = 5.6 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H),
7.76 (d, J = 5.6 Hz, 1H), 7.73 – 7.70 (m, 1H), 7.63 – 7.55 (m,
1H), 7.44 (s, 1H), 7.03 – 6.88 (m, 4H). 13C NMR (150 MHz,
CDCl3): δ = 152.44, 147.35, 141.56, 137.01, 130.40, 128.06,
127.54, 126.30, 124.61, 123.08, 122.19, 111.04, 109.18; HRMS
(EI) Calcd. for C16H11NO2 (M) 249.0790, found 249.0788.
2-(2-(Isoquinolin-1-yl)benzo[d][1,3]dioxol-5-yl)acetonitrile
(3h): Pale yellow liquid, 54% yield (63 mg); IR (neat) cm–1 : ṽ =
3348, 2911, 2848, 2240, 1625, 1480, 1316, 1230, 1088, 987,
932, 798, 719, 637; 1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J =
5.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H),
7.79 – 7.69 (m, 2H), 7.65 – 7.58 (m, 1H), 7.50 (s, 1H), 6.88 –
6.95 (m, 3H), 3.71 (s, 2H); 13C NMR (150 MHz, CDCl3): δ =
151.97, 148.20, 147.40, 141.59, 136.99, 130.50, 128.18, 127.62,
126.20, 124.34, 123.85, 123.21, 121.82, 117.97, 111.44, 109.21,
108.90, 23.44; HRMS (ESI) Calcd. for C18H13N2O2 [(M+H)+]
289.0977, found 289.0976.
1-(1,3-Dioxolan-2-yl)isoquinoline
(3b
major
product):
1
Colorless liquid, 51% yield (41 mg); H NMR (400 MHz, CDCl3):
δ = 8.54 (d, J = 5.7 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.85 (d, J =
8.2 Hz, 1H), 7.74 – 7.59 (m, 3H), 6.48 (s, 1H), 4.37 – 4.27 (m,
2H), 4.25 – 4.14 (m, 2H); 13C NMR (150 MHz, CDCl3): δ =
154.63, 141.53, 136.77, 130.10, 127.40, 127.26, 126.37, 125.22,
121.99, 103.50, 65.54; Spectral data match those previously
reported.[9]
1-(1,3-Dioxolan-4-yl)isoquinoline
(3b
minor
product):
Colorless liquid, 21% yield (17 mg); 1H NMR (400 MHz, CDCl3):
δ = 8.50 (d, J = 5.7 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.86 (d, J =
8.1 Hz, 1H), 7.76 – 7.68 (m, 1H), 7.66 – 7.63 (m, 2H), 5.80 (t, J
= 6.7 Hz, 1H), 5.29 (s, 1H), 5.20 (s, 1H), 4.60 – 4.56 (m, 1H),
4.47 – 4.38 (m, 1H); 13C NMR (150 MHz, CDCl3): δ = 156.32,
141.51, 136.63, 130.16, 127.56, 127.46, 126.90, 124.97, 121.24,
96.04, 76.20, 68.46; Spectral data match those previously
reported.[9]
2-(Isoquinolin-1-yl)benzo[d][1,3]dioxole-5-carbonitrile
(3i):
Brown liquid, 43% yield (47 mg); IR (neat) cm–1 : ṽ = 3048, 2933,
2914, 2847, 2214, 1729, 1487, 1245, 1070, 991, 816, 738, 615;
1H NMR (400 MHz, CDCl3): δ = 8.59 (d, J = 5.6 Hz, 1H), 8.12 (d,
J = 8.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.82 – 7.72 (m, 2H),
7.68 – 7.61 (m, 2H), 7.31 (dd, J = 8.1, 1.5 Hz, 1H), 7.18 (d, J =
1.4 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H); 13C NMR (150 MHz,
1-(2,2-Dimethyl-1,3-dioxolan-4-yl)isoquinoline
(3c): Pale
yellow liquid, 53% yield (49 mg); IR (neat) cm–1 : ṽ = 2952, 2914,
2847, 1733, 1457, 1360, 1185, 1256, 1081, 965, 846, 697; 1H
NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 5.7 Hz, 1H), 8.43 (d, J
= 8.1 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.68 m, 1H), 7.61 (m, 2H), CDCl3): δ = 151.40, 151.12, 147.96, 141.70, 136.96, 130.64,
5.80 (t, J = 6.9 Hz, 1H), 4.68 (dd, J = 8.2, 7.4 Hz, 1H), 4.47 (dd,
J = 8.3, 6.6 Hz, 1H), 1.56 (s, 3H), 1.50 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 156.55, 141.50, 136.61, 130.04, 127.39,
127.32, 127.11, 125.46, 121.16, 110.25, 76.87, 67.89, 26.51,
25.77; HRMS (ESI) Calcd. for C14H16NO2 [(M+H)+] 230.1181,
found 230.1179.
128.63, 128.39, 127.76, 126.04, 123.85, 123.42, 118.89, 111.90,
111.37, 109.59, 105.47; HRMS (ESI) Calcd. for C17H11N2O2
[(M+H)+] 275.0821, found 275.0822.
1-(5-Bromobenzo[d][1,3]dioxol-2-yl)isoquinoline (3j): Brown
liquid, 36% yield (47 mg); IR (neat) cm–1 : ṽ = 3034, 2963, 2896,
2214, 1617, 1476, 1226, 1084, 1047, 987, 816, 738, 615; 1H
NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 5.6 Hz, 1H), 8.15 (m,
1H), 7.95 – 7.87 (m, 1H), 7.80 – 7.67 (m, 2H), 7.66 – 7.56 (m,
1H), 7.49 (s, 1H), 7.12 – 7.08 (m, 1H), 7.07 – 7.02 (m, 1H), 6.83
(d, J = 8.2 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ = 151.81,
148.46, 146.92, 141.58, 136.99, 130.49, 128.19, 127.62, 126.19,
124.87, 124.31, 123.25, 113.61, 112.74, 111.74, 110.10; HRMS
(ESI) Calcd. for C16H11BrNO2 [(M+H)+] 327.9973, found
327.9971.
1-(Tetrahydro-2H-pyran-2-yl)isoquinoline
(3d): Colorless
1
liquid, 76% yield (65 mg); H NMR (400 MHz, CDCl3): δ = 8.52
(d, J = 5.7 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.0 Hz,
1H), 7.71 – 7.62 (m, 1H), 7.58 (m, 2H), 5.19 (dd, J = 11.0, 2.2
Hz, 1H), 4.33 – 4.20 (m, 1H), 3.82 – 3.75 (m, 1H), 2.18 – 1.95
(m, 3H), 1.92 – 1.77 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 159.69, 141.80, 136.65, 129.76, 127.39,
126.99, 126.05, 125.24, 120.53, 79.30, 69.45, 31.10, 25.91,
23.91. Spectral data match those previously reported.[9]
1-(2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)isoquinoline
(3k):
1-(1,4-Dioxan-2-yl)isoquinoline (3e): Pale yellow solid, 75%
Pale yellow liquid, 49% yield (52 mg); IR (neat) cm–1 : ṽ = 3040,
1
1
yield (64 mg); mp 91 - 94 °C ; H NMR (400 MHz, CDCl3): δ =
2937, 2914, 2847, 1457, 1256, 1073, 1014, 794, 742; H NMR
8.53 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0
Hz, 1H), 7.75 – 7.67 (m, 1H), 7.66 – 7.54 (m, 2H), 5.48 (dd, J =
9.7, 2.9 Hz, 1H), 4.20 – 4.16 (m, 1H), 4.13 – 4.06 (m, 3H), 3.93
– 3.87 (m, 2H); 13C NMR (150 MHz, CDCl3): δ = 155.96, 141.85,
136.48, 130.05, 127.50, 126.48, 124.67, 121.08, 75.84, 70.31,
67.59, 66.52; Spectral data match those previously reported.[9]
(400 MHz, CDCl3): δ = 8.55 (d, J = 5.7 Hz, 1H), 8.38 (d, J = 8.4
Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.79 – 7.57 (m, 3H), 7.09 –
6.97 (m, 2H), 6.98 – 6.81 (m, 2H), 5.93 (dd, J = 7.8, 3.2 Hz, 1H),
4.81 – 4.68 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 154.29,
143.71, 143.48, 141.82, 136.68, 130.30, 127.88, 127.55, 126.98,
124.88, 121.90, 121.82, 121.43, 117.68, 117.28, 73.30, 67.29;
HRMS (ESI) Calcd. for C17H14NO2 [(M+H)+] 264.1025, found
264.1024.
1-(2,3-Dihydrobenzofuran-2-yl)isoquinoline (3l): Pale yellow
liquid, 21% yield (21 mg); IR (neat) cm–1 : ṽ = 3045, 2940, 2911,
1584, 1476, 1215, 1013, 920, 820, 734; 1H NMR (400 MHz,
CDCl3): δ = 8.52 (d, J = 5.6 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H),
7.88 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.67 – 7.57 (m,
2H), 7.30 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.93 (t, J =
7.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.52 (t, J = 9.3 Hz, 1H),
4.19 – 4.04 (m, 1H), 3.71 – 3.52 (m, 1H); 13C NMR (150 MHz,
1-(1,4,7,10-Tetraoxacyclododecan-2-yl)isoquinoline
(3f):
Colorless liquid, 86% yield (105 mg); 1H NMR (400 MHz, CDCl3):
δ = 8.57 (d, J = 8.5 Hz, 1H), 8.50 (d, J = 5.7 Hz, 1H), 7.82 (d, J =
8.1 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.61 – 7.57 (m, 2H), 5.66 (dd,
J = 9.4, 2.2 Hz, 1H), 4.16 – 4.10 (m, 1H), 3.94 – 3.71 (m, 12H),
3.58 – 3.46 (m, 1H); 13C NMR (150 MHz, CDCl3): δ = 157.89,
141.89, 136.62, 130.06, 127.40, 127.36, 126.94, 125.25, 120.75,
82.03, 73.73, 70.97, 70.50, 70.38, 70.20, 69.23; HRMS (ESI)
Calcd. for C17H22NO4 [(M+H)+] 304.1549, found 304.1540;
Spectral data match those previously reported.[9]
1-(Benzo[d][1,3]dioxol-2-yl)isoquinoline (3g): Brown liquid, 63% CDCl3): δ = 159.18, 157.15, 141.54, 136.82, 130.09, 128.15,
yield (63 mg); IR (neat) cm–1 :ṽ = 3045, 2911, 1475, 1476, 1360,
1226, 1070, 930, 816, 723; 1H NMR (400 MHz, CDCl3) δ 8.58 (d,
127.57, 127.50, 126.87, 126.77, 125.15, 124.99, 121.40, 120.88,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
109.70, 83.34, 34.16; HRMS (ESI) Calcd. for C17H14NO
[(M+H)+] 248.1075, found 248.1074.
129.64(129.63), 128.55(128.36), 127.52(27.47), 127.43(127.34),
126.28(126.24),
124.90,
121.09(120.97),
76.64(73.54),
1-(Benzofuran-2-yl)isoquinoline (3l′): pale yellow liquid, 83%
(16.3 mg); H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 8.4 Hz,
71.20(68.16), 66.81(64.16), 36.26(34.79), 32.00(30.23); HRMS
(EI) Calcd. for C21H20NO3 [M] 334.1443, found 334.1378.
1
1H), 8.67 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.81 –
7.63 (m, 5H), 7.54 (s, 1H), 7.43 – 7.37 (m, 1H), 7.36 – 7.28 (m,
1H); 13C NMR (150 MHz, CDCl3): δ = 155.47, 155.04, 149.11,
142.36, 137.16, 130.26, 128.35, 128.02, 127.31, 126.70, 126.22,
125.41, 123.31, 121.75, 121.06, 111.80, 109.04; HRMS (ESI)
Calcd. for C17H12NO [(M+H)+] 246.0919, found 246.0918.
Spectral data match those previously reported.[18]
2-(2-(Isoquinolin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile
(3q): Colorless liquid, 54% yield (55 mg); IR (neat) cm–1 : ṽ =
3048, 2914, 2240, 1589, 1498, 1419, 1260, 1084, 890, 831, 742.
1H NMR (400 MHz, CDCl3): δ = 8.35 – 8.39 (m, 2H), 7.83 (d, J =
8.1 Hz, 1H), 7.72 – 7.65 (m, 1H), 7.64 – 7.56 (m, 1H), 5.62 (t, J
= 4.9 Hz, 1H), 3.82 – 3.72 (m, 1H), 3.56 – 3.44 (m, 1H), 2.98 –
2.80 (m, 1H), 2.70 – 2.63 (m, 1H), 2.63 – 2.47 (m, 2H), 1.98 –
(5-(Isoquinolin-1-yl)tetrahydrofuran-2-yl)methyl acetate (3m): 1.86 (m, 2H), 1.69 – 1.57 (m, 1H). 13C NMR (150 MHz, CDCl3): δ
1
Colorless liquid, 62% yield (65 mg); H NMR (400 MHz, CDCl3):
δ = 8.49(8.47) (d, J = 5.6 Hz, 1H), 8.32(8.42) (d, J = 8.4 Hz, 1H),
7.83 (d, J = 7.8 Hz, 1H), 7.72 – 7.64 (m, 1H), 7.64 – 7.53 (m,
2H), 5.88(5.75) (t, J = 6.9 Hz, 1H), 4.63 – 4.57(4.44 – 4.38) (m,
1H), 4.30 – 4.23(4.18 – 4.14) (m, 2H), 2.61 – 2.53(2.71 – 2.66)
(m, 1H), 2.51 – 2.37 (m, 1H), 2.36 – 2.17 (m, 1H), 2.11(2.00) (s,
3H), 1.95 – 1.86 (m, 1H); 13C NMR (150 MHz, CDCl3): δ =
= 158.38, 140.95, 136.60, 129.97, 127.34, 127.29, 126.98,
125.82, 120.95, 118.66, 72.92, 62.45, 32.71, 30.61, 28.02, 23.15;
HRMS (ESI) Calcd. for C16H17N2O [(M+H)+] 253.1341, found
253.1340.
1-(5-((1S,4S)-4-(Benzo[d][1,3]dioxol-5-yl)tetrahydro-1H,3H-
furo[3,4-c]furan-1-yl)benzo[d][1,3]dioxol-2-yl)isoquinoline
(3r): Brown liquid, 51% yield (98 mg); IR (neat) cm–1 : ṽ = 3037,
2896, 2847, 1621, 1487, 1439, 1234, 1036, 928, 824, 741, 671,
555, 466; 1H NMR (600 MHz, d6-DMSO): δ = 8.55 (d, J = 5.6 Hz,
1H), 8.24 (dd, J = 8.4, 1.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.01
171.21(171.06),
136.59(136.51),
127.21(127.09),
159.06(158.69),
129.89(129.84),
126.83(126.53),
141.58(141.48),
127.34(127.26),
125.57(125.16),
120.78(120.66), 80.37(79.16), 78.03(77.34), 66.59, 30.89(29.88), (d, J = 5.6 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.77 – 7.70 (m, 2H),
28.30(28.15), 21.04(20.90); Spectral data match those
previously reported.[9]
7.03 (s, 1H), 6.99 – 6.98 (6.97 – 6.96) (d, J = 1.4 Hz, 1H), 6.95 –
6.93 (6.93 – 6.92) (m, 2H), 6.87 – 6.82 (m, 2H), 5.99 (s, 2H),
4.69 (d, J = 4.9 Hz, 1H), 4.65 (d, J = 4.9 Hz, 1H), 4.17 – 4.09 (m,
2H), 3.81 – 3.74 (m, 2H), 3.10 – 2.97 (m, 2H); 13C NMR (150
MHz, CDCl3): δ = 152.24, 147.96, 147.88(147.83), 147.10,
147.03(146.99), 141.53(141.48), 136.99(136.97), 135.56,
135.01, 130.42, 128.09(128.07), 127.53, 126.25, 124.58(124.52),
123.15(123.10), 119.99(119.88), 119.37, 111.60, 111.28,
108.72(108.66), 108.19, 107.03(106.94), 106.50, 101.07,
85.92(85.88), 85.76, 71.81(71.80), 71.71(71.67), 54.37(54.32);
HRMS (ESI) Calcd. for C29H24NO6 [(M+H)+] 482.1604, found
482.1605.
5-(Isoquinolin-1-yl)tetrahydrofuran-3-yl benzoate (3n): pale
yellow liquid, 33% yield (42 mg); IR (neat) cm–1 : ṽ = 3045, 2914,
2847, 1711, 1267, 1111, 1058, 961, 824, 708, 671, 462; 1H NMR
(400 MHz, CDCl3): δ = 8.51 (d, J = 5.7 Hz, 1H), 8.40 (d, J = 8.3
Hz, 1H), 8.18 – 8.08 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.78 –
7.68 (m, 1H), 7.66 – 7.57 (m, 3H), 7.49 (t, J = 7.6 Hz, 2H), 6.06
(dd, J = 8.9, 6.2 Hz, 1H), 5.90 – 5.70 (m, 1H), 4.44 (dd, J = 10.6,
4.6 Hz, 1H), 4.24 – 4.18 (m, 1H), 3.18 – 3.05 (m, 1H), 2.70 –
2.58 (m, 1H); 13C NMR (150 MHz, CDCl3): δ = 166.34, 157.69,
141.49, 136.60, 133.22, 130.07, 129.73, 128.45, 127.44, 127.37,
126.95, 125.18, 121.09, 78.14, 76.21, 73.75, 36.93; HRMS (ESI)
Calcd. for C20H18NO3 [(M+H)+] 320.1287, found 320.1288.
1-((3R,3aS,6S,6aS)-3,6-Dimethoxyhexahydrofuro[3,2-
b]furan-2-yl)isoquinoline (3s): Colorless liquid, 22% yield(27
mg); IR (neat) cm–1 : ṽ = 2922, 2870, 2821, 1457, 1371, 1215,
Methyl
5-(isoquinolin-1-yl)tetrahydrofuran-3-carboxylate
(3o): Colourless liquid, 41% yield (42 mg); IR (neat) cm–1 : ṽ =
3045, 2925, 2843, 1729, 1435, 1196, 1055, 991, 824, 745, 671;
1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 5.7 Hz, 1H), 8.36 (d,
J = 8.3 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.73 – 7.66 (m, 1H),
7.65 – 7.57 (m, 2H), 5.72 (dd, J = 8.8, 6.5 Hz, 1H), 4.37 (dd, J =
8.7, 7.0 Hz, 1H), 4.25 (t, J = 8.5 Hz, 1H), 3.73 (s, 3H), 3.53 –
3.34 (m, 1H), 3.03 – 2.86 (m, 1H), 2.80 – 2.58 (m, 1H); 13C NMR
(150 MHz, CDCl3): δ = 173.56, 157.86, 141.39, 136.60, 129.98,
127.35, 127.30, 126.64, 125.30, 120.99, 80.27, 70.25, 52.13,
44.35, 34.30; HRMS (ESI) Calcd. for C15H16NO3 [(M+H)+]
258.1130, found 258.1131.
1092, 986, 827, 730, 611. H NMR (400 MHz, CDCl3): δ = 8.56
1
(8.53) (d, J = 5.7 Hz, 1H), 8.30 (8.42) (d, J = 8.4 Hz, 1H), 7.91 –
7.80 (m, 1H), 7.74 – 7.66 (m, 1H), 7.66 – 7.57 (m, 2H), 5.68 –
5.66 (5.54 – 5.52) (d, J = 7.7 Hz, 1H), 4.94 – 4.92 (4.87 – 4.85)
(m, 1H), 4.90 – 4.89 (4.79 – 4.75) (m, 1H), 4.61 (dd, J = 7.7, 4.3
Hz, 1H), 4.30 – 4.24 (m, 1H), 4.08 – 4.01 (m, 1H), 4.07 – 4.02
(m, 1H), 3.43 (s, 3H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 156.56, 141.92, 136.55, 130.15, 127.50, 127.41, 127.27,
124.97, 121.17, 86.13, 85.68, 85.63, 80.68, 79.31, 73.44, 58.36,
57.40; HRMS (ESI) Calcd. for C17H20NO4 [(M+H)+] 302.1392,
found 302.1391.
2-(Isoquinolin-1-yl)tetrahydro-2H-pyran-4-yl benzoate (3p):
Colorless liquid, 49% yield (66 mg); IR (neat) cm–1 : ṽ = 3026,
2932, 2914, 2843, 1703, 1446, 1345, 1248, 1055, 831, 749, 711,
1-((3aR,5aS,9aS,9bR)-3a,6,6,9a-
tetramethyldodecahydronaphtho[2,1-b]furan-2-
yl)isoquinoline (3t): White solid, 53% yield (77 mg); mp 110 –
112 °C ; IR (neat) cm–1 :ṽ = 2989, 2914, 2851, 2847, 1558, 1450,
1375, 1304, 1122, 958, 831, 753, 656; 1H NMR (400 MHz,
CDCl3): δ = 8.51 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H),
7.79 (d, J = 7.9 Hz, 1H), 7.68 – 7.56 (m, 2H), 7.54 (d, J = 5.7 Hz,
1H), 5.92 (dd, J = 9.5, 3.1 Hz, 1H), 2.52 – 2.42 (m, 1H), 2.32 –
1
670, 537; H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 5.7 Hz,
1H), 8.32 (d, J = 8.5 Hz, 1H), 8.23 – 8.12 (m, 1H), 8.09 – 8.00
(m, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.74 – 7.47 (m, 5H), 7.43 (t, J
= 7.7 Hz, 1H), 5.74(5.36) (dd, J = 11.3, 2.2 Hz, 1H), 5.71 –
5.62(5.52 – 5.43) (m, 1H), 4.44 – 4.32(4.20 – 4.11) (m, 1H), 4.32
– 4.21 (4.00 – 3.87) (m, 1H), 2.68 – 2.49 (m, 1H), 2.48 – 2.30 (m, 2.19 (m, 1H), 2.04 (dt, J = 11.8, 3.1 Hz, 1H), 1.90 – 1.73 (m, 2H),
1H), 2.29 – 2.16 (m, 1H), 2.14 – 1.96 (m, 1H); 13C NMR (150
MHz, CDCl3): δ = 166.01(165.75), 158.36(157.61), 141.73,
136.67, 133.15(133.01), 130.59(130.34), 130.00(129.94),
1.71 – 1.58 (m, 2H), 1.51 – 1.34 (m, 7H), 1.23 – 1.05 (m, 3H),
0.93 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H); 13C NMR (150 MHz,
CDCl3): δ = 160.10, 141.75, 136.50, 129.69, 127.23, 127.06,
7
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
126.64, 125.43, 120.19, 82.55, 75.32, 59.46, 56.95, 42.43, 39.77, (d, J = 5.7 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.46 (d,
39.75, 36.45, 33.59, 33.11, 28.00, 21.74, 21.19, 20.72, 18.42,
15.08; HRMS (ESI) Calcd. for C25H34NO [(M+H)+] 364.2640,
found 364.2639.
J = 5.7 Hz, 1H), 7.41 (dd, J = 8.7, 1.5 Hz, 1H), 5.67 (t, J = 7.1 Hz,
1H), 4.21 – 4.13 (m, 1H), 4.05 – 3.97 (m, 1H), 2.51 (s, 3H), 2.49
– 2.32 (m, 2H), 2.20 – 2.04 (m, 2H); 13C NMR (150 MHz, CDCl3):
δ = 159.31, 141.70, 140.04, 136.86, 129.32, 126.20, 125.05,
124.96, 120.03, 79.11, 68.96, 30.83, 26.16, 21.84; Spectral data
match those previously reported.[9]
((3aS,5aR,8aR,8bS)-5-(Isoquinolin-1-yl)-2,2,7,7-
tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-
d]pyran-3a-yl)methyl diethylsulfamate (3u): Colorless liquid,
33% yield(69 mg); IR (neat) cm–1 : ṽ = 2914, 2847, 1643, 1466,
1360, 1201, 1163, 1062, 794, 753, 637; 1H NMR (400 MHz,
CDCl3): δ = 8.93 (d, J = 8.7 Hz, 1H), 8.58 (d, J = 5.5 Hz, 1H),
7.84 (d, J = 8.2 Hz, 1H), 7.72 – 7.53 (m, 3H), 6.04 (d, J = 2.2 Hz,
1H), 4.64 (d, J = 2.2 Hz, 1H), 4.36 – 4.23 (m, 3H), 3.80 (d, J =
12.6 Hz, 1H), 3.44 – 3.28 (m, 4H), 1.59 (s, 3H), 1.48 (s, 3H),
1.42 (s, 3H), 1.30 – 1.21 (m, 6H), 0.95 (s, 3H). 13C NMR (150
MHz, CDCl3): δ = 158.74, 141.12, 137.24, 129.86, 127.43,
127.41, 127.12, 127.02, 120.96, 109.45, 109.08, 100.99, 83.44,
73.74, 71.06, 68.99, 65.42, 42.94, 26.58, 26.18, 25.22, 24.88,
13.71; HRMS (ESI) Calcd. for C25H35N2O8S [(M+H)+] 523.2114,
found 523.2113.
6-Methoxy-1-(tetrahydrofuran-2-yl)isoquinoline
(4d):
1
Colorless liquid, 78% yield (72 mg); H NMR (400 MHz, CDCl3):
δ = 8.41 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.47 (d, J =
5.7 Hz, 1H), 7.21 (dd, J = 9.3, 2.5 Hz, 1H), 7.06 (d, J = 2.5 Hz,
1H), 5.63 (t, J = 7.2 Hz, 1H), 4.23 – 4.15 (m, 1H), 4.05 – 3.97 (m,
1H), 3.92 (s, 3H), 2.51 – 2.33 (m, 2H), 2.24 – 2.02 (m, 2H); 13C
NMR (150MHz, CDCl3): δ = 160.49, 158.99, 141.87, 138.79,
127.16, 122.19, 120.01, 119.98, 104.84, 79.13, 69.02, 55.45,
30.99, 26.16; Spectral data match those previously reported.[9]
3-Methyl-1-(tetrahydrofuran-2-yl)isoquinoline (4e): Colorless
1
liquid, 79% yield (68 mg); H NMR (400 MHz, CDCl3): δ = 8.30
(d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.65 – 7.55 (m, 1H),
7.54 – 7.43 (m, 1H), 7.39 (s, 1H), 5.65 (t, J = 7.2 Hz, 1H), 4.25 –
5-Fluoro-1-(5-(isoquinolin-1-yl)tetrahydrofuran-2-yl)-3-
methylpyrimidine-2,4(1H,3H)-dione (3v): Pale yellow liquid, 28% 4.15 (m, 1H), 4.07 – 3.99 (m, 1H), 2.68 (s, 3H), 2.59 – 2.48 (m,
yield (39 mg); IR (neat) cm–1 : ṽ = 2918, 2847, 1711,1647, 1457,
1286, 1047, 947, 749, 671; 1H NMR (400 MHz, CDCl3): δ = 8.50
(d, J = 5.7 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.1 Hz,
1H), 7.72 (t, J = 7.2 Hz, 1H), 7.68 – 7.62 (m, 3H), 6.35 (t, J = 4.4
Hz, 1H), 6.30 – 6.24 (m, 1H), 3.39 (s, 3H), 2.83 – 2.70 (m, 2H),
2.53 – 2.40 (m, 1H), 2.27 – 2.17 (m, 1H); 13C NMR (150 MHz,
CDCl3): δ = 157.30 (d, J = 26.1 Hz), 157.11, 149.24, 141.55,
140.86, 139.31, 136.61, 130.18, 127.65, 126.87 (d, J = 269.0
1H), 2.41 – 2.31 (m, 1H), 2.23 – 2.04 (m, 2H); 13C NMR (150
MHz, CDCl3): δ = 158.84, 150.17, 137.41, 129.63, 126.71,
125.99, 125.30, 124.72, 118.43, 79.80, 68.92, 30.71, 26.09,
24.39; Spectral data match those previously reported.[9]
Ethyl
1-(tetrahydrofuran-2-yl)isoquinoline-63-carboxylate
(4f): Pale yellow liquid, 66% yield (72 mg); IR (neat) cm–1 : ṽ =
2933, 2911, 2847, 1711, 1312, 1237, 1051, 958, 901, 783, 749,
678; 1H NMR (400 MHz, CDCl3): δ = 8.51 – 8.43 (m, 2H), 7.98 –
Hz), 124.45, 121.92 (d, J = 33.5Hz), 121.27, 88.98, 80.64, 32.64, 7.89 (m, 1H), 7.74 – 7.63 (m, 2H), 5.67 (t, J = 7.2 Hz, 1H), 4.47
28.62, 28.19; HRMS (ESI) Calcd. for C18H17FN3O3 [(M+H)+]
342.1254, found 342.1255.
1-(1-ethoxyethyl)isoquinoline (3w): Pale yellow liquid, 63%
(q, J = 7.1 Hz, 2H), 4.19 – 4.08 (m, 1H), 4.04 – 3.96 (m, 1H),
2.73 (m, 1H), 2.47 – 2.30 (m, 1H), 2.20 (m, 1H), 2.09 (m, 1H),
1.45 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ = 165.93,
yield (51 mg); 1H NMR (400 MHz, CDCl3): δ = 8.69 (d, J = 8.5 Hz, 159.93, 140.27, 136.38, 130.44, 129.23, 128.72, 128.16, 126.01,
1H), 8.46 (d, J = 5.7 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.74 –
7.64 (m, 1H), 7.61 – 7.49 (m, 2H), 5.17 (q, J = 6.7 Hz, 1H), 3.54
– 3.46 (m, 1H), 3.44 – 3.32 (m, 1H), 1.70 (d, J = 6.7 Hz, 3H),
1.19 (t, J = 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ = 161.81,
141.55, 136.84, 129.90, 127.43, 126.88, 126.07, 125.60, 120.53,
80.11, 64.50, 21.66, 15.48; Spectral data match those previously
reported.[9]
123.91, 80.24, 68.98, 61.55, 30.03, 26.08, 14.38. HRMS (ESI)
Calcd. for C16H18NO3 [(M+H)+] 272.1287, found 272.1288.
2-Methyl-4-(tetrahydrofuran-2-yl)quinolone (4g): Pale yellow
1
liquid, 77% yield (66 mg); H NMR (400 MHz, CDCl3): δ = 8.03
(d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.70 – 7.58 (m, 1H),
7.46 (d, J = 7.9 Hz, 1H), 7.44 – 7.37 (m, 1H), 5.55 (t, J = 7.1 Hz,
1H), 4.27 – 4.16 (m, 1H), 4.06 – 3.96 (m, 1H), 2.72 (s, 3H), 2.65
– 2.51 (m, 1H), 2.11 – 1.91 (m, 2H), 1.85 – 1.76 (m, 1H). 13C
NMR (150 MHz, CDCl3)：δ = 159.08, 149.29, 147.90, 129.39,
128.93, 125.47, 123.86, 123.00, 117.18, 76.77, 68.97, 33.88,
25.98, 25.55; Spectral data match those previously reported.[9]
6-Chloro-1-(tetrahydrofuran-2-yl)isoquinoline
(4a):
Pale
yellow liquid, 83% yield (78 mg); 1H NMR (400 MHz, CDCl3): δ =
8.47 (d, J = 5.7 Hz, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 2.0
Hz, 1H), 7.50 (dd, J = 9.1, 2.0 Hz, 1H), 7.46 (d, J = 5.7 Hz, 1H),
5.62 (t, J = 7.1 Hz, 1H), 4.18 – 4.08 (m, 1H), 4.04 – 3.95 (m, 1H), 2,6-Dimethyl-4-(tetrahydrofuran-2-yl)quinolone
2.57 – 2.46 (m, 1H), 2.42 – 2.29 (m, 1H), 2.25 – 1.98 (m, 2H);
Colorless liquid, 68% yield (62 mg); IR (neat) cm–1 : ṽ = 2911,
13C NMR (150 MHz, CDCl3): δ = 159.74, 142.61, 137.40, 136.03, 2851, 1599, 1561, 1439, 1338, 1073, 880, 824, 730, 604, 496;
(4h):
128.04, 127.33, 125.98, 124.89, 119.63, 79.26, 69.01, 30.56,
26.11; Spectral data match those previously reported.[9]
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.6 Hz, 1H), 7.56 (s,
1H), 7.47 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 5.53 (t, J = 7.1 Hz,
1H), 4.25 – 4.15 (m, 1H), 4.08 – 3.95 (m, 1H), 2.70 (s, 3H), 2.63
– 2.53 (m, 1H), 2.51 (s, 3H), 2.12 – 1.92 (m, 2H), 1.86 – 1.73 (m,
1H); 13C NMR (150 MHz, CDCl3): δ = 158.03, 148.59, 146.41,
135.16, 131.08, 129.05, 123.81, 122.00, 117.11, 76.73, 68.94,
6-Bromo-1-(tetrahydrofuran-2-yl)isoquinoline
(4b):
Pale
1
yellow liquid, 79% yield (88 mg); H NMR (400 MHz, CDCl3): δ
= 8.48 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.97 (d, J =
1.7 Hz, 1H), 7.65 (dd, J = 9.0, 1.7 Hz, 1H), 7.46 (d, J = 5.7 Hz,
1H), 5.62 (t, J = 7.1 Hz, 1H), 4.18 – 4.09 (m, 1H), 4.05 – 3.96 (m, 33.84, 25.98, 25.40, 21.89; HRMS (EI) Calcd. for C15H17NO (M)
1H), 2.57 – 2.46 (m, 1H), 2.43 – 2.28 (m, 1H), 2.22 – 2.04 (m,
2H). 13C NMR (150 MHz, CDCl3): δ = 159.88, 142.61, 137.72,
130.59, 129.36, 127.29, 125.09, 124.61, 119.47, 79.23, 69.02,
30.56, 26.11; Spectral data match those previously reported.[9]
6-Methyl-1-(tetrahydrofuran-2-yl)isoquinoline (4c): Colorless
227.1310, found 227.1311.
6-Fluoro-2-methyl-4-(tetrahydrofuran-2-yl)quinolone
pale yellow liquid, 73% yield (68 mg); 1H NMR (400 MHz, CDCl3):
δ = 8.02 (dd, J = 9.0, 5.6 Hz, 1H), 7.47 – 7.38 (m, 3H), 5.43 (t, J
= 7.2 Hz, 1H), 4.25 – 4.18 (m, 1H), 4.07 – 3.98 (m, 1H), 2.71 (s,
3H), 2.63 – 2.53 (m, 1H), 2.23 – 1.92 (m, 3H), 1.87 – 1.76 (m,
(4i):
1
liquid, 81% yield (69 mg); H NMR (400 MHz, CDCl3): δ = 8.43
8
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
1H); 13C NMR (150 MHz, CDCl3): δ = 159.47 (d, J = 300 Hz),
158.66 (d, J = 84.8 Hz), 148.69 (d, J = 4.5 Hz), 145.06, 131.75
(d, J = 9 Hz), 124.46 (d, J = 10.5 Hz), 118.85 (d, J = 25.5 Hz),
117.98, 106.88 (d, J = 22.5 Hz), 76.80, 68.99, 33.62, 25.96,
25.39; Spectral data match those previously reported.[9]
1H), 8.12 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.60 –
7.47 (m, 2H), 7.30 – 7.26 (m, 1H), 5.46 (t, J = 7.2 Hz, 1H), 4.22
– 4.02 (m, 2H), 2.66 – 2.52 (m, 1H), 2.45 – 2.33 (m, 1H), 2.15 –
1.98 (m, 2H); 13C NMR (150 MHz, CDCl3): δ = 145.43, 140.13,
138.02, 133.38, 129.55, 128.32, 121.61, 121.20, 119.67, 113.43,
111.56, 82.81, 69.02, 32.03, 25.56; HRMS (ESI) Calcd. for
C15H15N2O [(M+H)+] 239.1184, found 239.1185.
6-Bromo-2-methyl-4-(tetrahydrofuran-2-yl)quinolone
(4j):
Pale yellow liquid, 76% yield (89 mg); 1H NMR (400 MHz,
CDCl3): δ = 7.96 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H),
7.70 (dd, J = 9.0, 2.1 Hz, 1H), 7.43 (s, 1H), 5.45 (t, J = 7.2 Hz,
1H), 4.25 – 4.16 (m, 1H), 4.07 – 3.96 (m, 1H), 2.70 (s, 3H), 2.66
– 2.51 (m, 1H), 2.14 – 1.94 (m, 2H), 1.88 – 1.72 (m, 1H); 13C
NMR (150 MHz, CDCl3): δ = 159.63, 148.44, 146.55, 132.32,
131.15, 125.49, 125.18, 119.42, 118.07, 76.56, 69.00, 33.87,
26.01, 25.55; Spectral data match those previously reported.[9]
7-(Tetrahydrofuran-2-yl)imidazo[1,2-a]pyrimidine
(4p):
Colorless liquid, 40% yield (30 mg); IR (neat) cm–1 : ṽ = 2955,
1
2918, 2862, 1722, 1614, 1513, 1248, 1144, 1040, 693; H NMR
(400 MHz, CDCl3): δ = 8.56 (d, J = 4.2 Hz, 1H), 7.85 (d, J = 1.0
Hz, 1H), 7.47 (d, J = 1.o Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H), 5.24 –
5.14 (m, 1H), 4.23 – 4.13 (m, 1H), 4.09 – 3.95 (m, 1H), 2.59 –
2.47 (m, 1H), 2.18 – 2.08 (m, 1H), 2.05 – 1.99 (m, 2H); 13C NMR
(150 MHz, CDCl3): δ = 149.98, 149.42, 148.37, 135.61, 108.06,
104.17, 75.30, 69.42, 30.09, 25.63; HRMS (ESI) Calcd. for
C10H12N3O [(M+H)+] 190.0980, found 190.0981.
7-Chloro-2-methyl-4-(tetrahydrofuran-2-yl)quinolone
(4k):
Colorless liquid, 74% yield (73 mg); IR (neat) cm–1 : ṽ = 3048,
2970, 2915, 2873, 1598, 1494, 1344, 1166, 1070, 868, 816, 763,
1
644, 552. H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 2.0 Hz,
4-Phenyl-2-(tetrahydrofuran-2-yl)pyridine (4q): colorless liquid,
31% yield (28 mg); IR (neat) cm–1 :ṽ = 2914, 2847, 1599, 1554,
1H), 7.76 (d, J = 9.2 Hz, 1H), 7.54 – 7.35 (m, 2H), 5.49 (t, J =
7.2 Hz, 1H), 4.28 – 4.14 (m, 1H), 4.07 – 3.98 (m, 1H), 2.71 (s,
3H), 2.63 – 2.50 (m, 1H), 2.12 – 1.96 (m, 2H), 1.86 – 1.73 (m,
1H); 13C NMR (150 MHz, CDCl3): δ = 160.42, 149.30, 148.56,
134.75, 128.45, 126.36, 124.38, 122.32, 117.49, 76.68, 69.01,
33.90, 25.99, 25.57; HRMS (EI) Calcd. for C14H16ClO [M]
248.0842, found 248.0841.
1
1398, 1260, 1058, 775, 693, 634; H NMR (400 MHz, CDCl3): δ
= 8.63 (d, J = 5.0 Hz, 1H), 8.06 – 7.94 (m, 2H), 7.70 (s, 1H),
7.51 – 7.45 (m, 2H), 7.44 – 7.38 (m, 1H), 7.18 (d, J = 4.3 Hz,
1H), 4.97 (t, J = 7.1 Hz, 1H), 4.18 – 4.08 (m, 1H), 4.02 – 3.93 (m,
1H), 2.47 – 2.35 (m, 1H), 2.06 – 1.97 (m, 2H), 1.87 – 1.79 (m,
1H); 13C NMR (150 MHz, CDCl3): δ = 156.58, 152.55, 148.59,
138.50, 127.88, 127.67, 125.99, 118.00, 116.29, 78.28, 67.97,
33.35, 24.84; HRMS (ESI) Calcd. for C15H16NO [(M+H)+]
226.1232, found 226.1231.
4-Methyl-2-(tetrahydrofuran-2-yl)quinolone (4l): Pale yellow
1
liquid, 57% yield (49 mg); H NMR (400 MHz, CDCl3): δ = 8.05
(d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.73 – 7.63 (m, 1H),
7.60 – 7.48 (m, 1H), 7.44 (s, 1H), 5.16 – 5.08 (m, 1H), 4.22 –
4.13 (m, 1H), 4.10 – 3.96 (m, 1H), 2.70 (s, 3H), 2.56 – 2.43 (m,
1H), 2.07 – 1.98 (m, 3H); 13C NMR (150 MHz, CDCl3): δ =
163.11, 147.34, 144.96, 129.56, 129.15, 127.48, 125.83, 123.71,
118.61, 82.10, 69.28, 33.34, 25.99, 18.91; Spectral data match
those previously reported.[9]
2-(Tetrahydrofuran-2-yl)isonicotinonitrile (4r): Colorless liquid,
27% yield (19 mg); IR (neat) cm–1 : ṽ = 2933, 2914, 2851, 2236,
1
1591, 1550, 1465, 1398, 1256, 1062, 1017, 786; H NMR (400
MHz, CDCl3): δ = 8.70 (dd, J = 5.0, 0.6 Hz, 1H), 7.73 – 7.68 (m,
1H), 7.38 (dd, J = 5.0, 1.2 Hz, 1H), 5.10 – 4.95 (m, 1H), 4.15 –
4.04 (m, 1H), 4.03 – 3.85 (m, 1H), 2.56 – 2.36 (m, 1H), 2.10 –
1.85 (m, 3H); 13C NMR (150 MHz, CDCl3): δ = 165.25, 149.94,
123.40, 121.62, 120.90, 116.75, 80.65, 69.30, 33.05, 25.68;
HRMS (ESI) Calcd. for C10H11NO [(M+Na)+] 197.0691, found
197.0682.
2,4-bis(tetrahydrofuran-2-yl)quinolone (4m): Colorless liquid,
1
61% yield (66 mg); H NMR (600 MHz, CDCl3): δ = 8.16 – 8.04
(m), 7.92 – 7.83 (m, 1H), 7.77 – 7.61 (m, 2H), 7.54 – 7.46 (m,
1H), 5.78 – 5.50 (m, 1H), 5.20 – 5.11 (m, 1H), 4.32 – 4.12 (m,
2H), 4.10 – 3,96 (m, 2H), 2.70 – 2.55 (m, 1H), 2.52 – 2.44 (m,
1H), 2.25 – 1.96 (m, 5H), 1.90 – 1.71 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 163.67, 163.18, 150.05, 149.77, 147.69, 147.53,
129.83, 128.97, 125.87, 124.80, 123.22, 123.12, 113.84, 113.09,
82.35, 82.08, 77.21, 77.00, 69.36, 69.19, 69.01, 68.93, 33.92,
33.81, 33.58, 33.04, 26.00, 25.96; Spectral data match those
previously reported.[9]
6-(Tetrahydrofuran-2-yl)phenanthridine (4n): Pale yellow
liquid, 76% yield (76 mg); IR (neat) cm–1 : ṽ = 3056, 2944, 2916,
2843, 1573, 1442, 1297, 1055, 950, 727, 723, 660, 634; 1H NMR
(400 MHz, CDCl3): δ = 8.63 (d, J = 8.2 Hz, 1H), 8.58 – 8.49 (m,
1H), 8.44 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.1, 1.0 Hz, 1H), 7.88
– 7.77 (m, 1H), 7.75 – 7.67 (m, 2H), 7.67 – 7.60 (m, 1H), 5.77 (t,
J = 6.9 Hz, 1H), 4.26 – 4.17 (m, 1H), 4.13 – 4.03 (m, 1H), 2.81 –
2.67 (m, 1H), 2.48 – 2.36 (m, 1H), 2.27 – 2.07 (m, 2H); 13C NMR
(150 MHz, CDCl3): δ = 159.30, 143.27, 133.26, 130.47, 130.29,
128.49, 127.21, 126.89, 126.48, 124.79, 124.09, 122.37, 121.88,
79.62, 69.03, 30.04, 26.00; HRMS (ESI) Calcd. for C17H16NO
[(M+H)+] 250.1232, found 250.1231.
3-(Tetrahydrofuran-2-yl)pyrazine-2-carbonitrile
(4s):
Colorless liquid, 46% yield (33 mg); IR (neat) cm–1 : ṽ = 2989,
2877, 2232, 1520, 1472, 1323, 1166, 1073, 1017, 961, 742, 645;
1H NMR (400 MHz, CDCl3): δ = 8.99 – 8.65 (m, 2H), 5.07 – 5.00
(m, 1H), 4.27 – 3.89 (m, 2H), 2.61 – 2.37 (m, 1H), 2.10 – 1.84
(m, 3H). 13C NMR (150 MHz, CDCl3): δ = 161.85, 146.98, 143.23,
129.05, 115.62, 79.51, 69.56, 32.89, 25.76; HRMS (ESI) Calcd.
for C9H10N3O [(M+H)+] 176.0824, found 176.0823.
Heptan-2-yl2-((5-chloro-2-(tetrahydrofuran-2-yl)quinolin-8-
yl)oxy)acetate (4t): Pale yellow liquid, 30% yield (46 mg); IR
(neat) cm–1 : ṽ = 2925, 2851, 1725, 1696, 1591, 1461, 1368,
1264, 1107, 906, 835, 727, 645; 1H NMR (400 MHz, CDCl3): δ =
8.51 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.3
Hz, 1H), 6.91 (dd, J = 8.3, 1.3 Hz, 1H), 5.27 (t, J = 6.3 Hz, 1H),
5.07 – 4.99 (m, 1H), 4.93 (s, 2H), 4.21 – 4.11 (m, 1H), 4.08 –
3.98 (m, 1H), 2.60 – 2.48 (m, 1H), 2.08 – 1.94 (m, 3H), 1.29 –
1.16 (m, 11H), 0.89 – 0.77 (m, 1H). 13C NMR (150 MHz, CDCl3):
δ = 168.47, 163.74(163.72), 152.77, 140.05, 133.77, 126.43,
125.50, 123.76, 119.40, 110.84(110.77), 81.95, 72.64, 69.33,
67.00(66.97), 35.74, 33.66, 31.53, 25.97, 24.94, 22.50, 19.91,
13.97; HRMS (ESI) Calcd. for C22H29ClNO4 [(M+H)+] 406.1785,
found 406.1778.
1-(Tetrahydrofuran-2-yl)-9H-pyrido[3,4-b]indole
(4o):
Colorless liquid, 38% yield (37 mg); IR (neat) cm–1 : ṽ = 3048,
2914, 2843, 1621, 1561, 1419, 1315, 1226, 1054, 820, 745, 630;
1H NMR (400 MHz, CDCl3): δ = 9.38 (s, 1H), 8.37 (d, J = 5.3 Hz,
9
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10.1002/ejoc.202001354
European Journal of Organic Chemistry
FULL PAPER
6-Chloro-1-((3aR,5aS,9aS,9bR)-3a,6,6,9a-
tetramethyldodecahydronaphtho[2,1-b]furan-2-
yl)isoquinoline (5a): white solid, 31% yield (77 mg); mp 144 -
146 °C ; IR (neat) cm–1 : ṽ = 2918, 2862, 1766, 1617, 1450, 1375,
1301, 1077, 961, 876, 812, 778, 611; 1H NMR (400 MHz, CDCl3): 15.15; HRMS (ESI) Calcd. for C29H36NO [(M+H)+] 414.2797,
J = 6Hz, 6H); 13C NMR (150 MHz, CDCl3): δ = 159.63, 133.31,
130.49, 130.29, 129.90, 128.42, 127.28, 126.78, 126.73, 124.95,
124.07, 122.28, 121.80, 82.74, 75.87, 59.30, 57.01, 42.44, 39.78,
36.47, 33.57, 33.12, 29.71, 27.22, 21.91, 21.18, 20.76, 18.44,
δ = 8.51 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 9.1 Hz, 1H), 7.78 (d, J =
2.0 Hz, 1H), 7.52 (dd, J = 9.1, 2.1 Hz, 1H), 7.46 (d, J = 5.7 Hz,
1H), 5.84 (dd, J = 9.5, 3.0 Hz, 1H), 2.56 – 2.47 (m, 1H), 2.28 –
2.14 (m, 1H), 2.07 – 1.97 (m, 1H), 1.84 – 1.73 (m, 3H), 1.72 –
1.56 (m, 3H), 1.37 (s, 3H), 1.34 – 1.32 (m, 1H), 1.22 – 1.03 (m,
4H), 0.92 (s, 3H), 0.88 – 0.83 (m, 6H); 13C NMR (150 MHz,
CDCl3): δ = 160.20, 142.75, 137.42, 135.95, 128.02, 127.55,
125.88, 125.00, 119.35, 82.76, 75.50, 59.51, 56.99, 42.41, 39.78,
39.72, 36.44, 33.56, 33.10, 27.60, 21.72, 21.16, 20.70, 18.39,
15.05; HRMS (ESI) Calcd. for C25H33ClNO [(M+H)+] 398.2251,
found 398.2250.
found 414.2798.
Conflict of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the program of the National Natural
Science Foundation of China (21871086, Y.-Q. Z.; 21738002, W.
W.) is gratefully acknowledged.
6-Methoxy-1-((3aR,5aS,9aS,9bR)-3a,6,6,9a-
tetramethyldodecahydronaphtho[2,1-b]furan-2-
yl)isoquinoline (5b): Pale yellow solid, 47% yield (74 mg); mp
140 - 142 °C ; IR (neat) cm–1 : ṽ = 2921, 2851, 1621, 1453, 1375,
1
1263, 1204, 1081, 961, 861, 827, 689, 637; H NMR (400 MHz,
Keywords: PIFA • Cross-Dehydrogenative Coupling • Ethanol •
Visible Light • Cα-Heteroarylated Cyclic Ethers
CDCl3): δ = 8.43 (d, J = 5.7 Hz, 1H), 8.27 (d, J = 9.3 Hz, 1H),
7.45 (d, J = 5.7 Hz, 1H), 7.21 (dd, J = 9.3, 2.6 Hz, 1H), 7.05 (d, J
= 2.5 Hz, 1H), 5.85 (dd, J = 9.5, 3.1 Hz, 1H), 3.93 (s, 3H), 2.48 –
2.38 (m, 1H), 2.28 – 2.16 (m, 1H), 2.06 – 1.98 (m, 1H), 1.87 –
1.76 (m, 2H), 1.71 – 1.65 (m, 2H), 1.44 – 1.35 (m, 6H), 1.24 –
1.03 (m, 4H), 0.92 (s, 3H), 0.88 – 0.81 (m, 6H); 13C NMR (150
MHz, CDCl3): δ = 160.28, 159.54, 142.32, 138.64, 127.32,
122.32, 119.80, 119.61, 104.74, 82.52, 75.43, 59.50, 56.93,
55.42, 42.41, 39.73, 39.70, 36.44, 33.57, 33.10, 28.02, 21.68,
21.17, 20.69, 18.40, 15.04; HRMS (ESI) Calcd. for C26H36NO2
[(M+H)+] 394.2746, found 394.2745.
[1] a) S. A. Girard, T. Kuauber, C. J. Li, Angew. Chem. Int. Ed. 2014, 53, 74-100; b)
H. Wang, X. Gao, Z. Lv, T. Abdelilah, A. Lei, Chem. Rev. 2019, 119, 6769-6787.
[2] a) D. Barr, E. Szennyes, E. Bokor, Z. H. Al-Oanzi, C. Moffatt, S. Kun, T. Docsa,
A. Sipos, M. P. Davies, R. T. Mathomes, T. J. Snape, L. Agius, L. Somsꢀk, J. M.
Hayes, ACS Chem. Biol. 2019, 14, 1460-1470; b) S. D. Roughley, A. M. Jordan,
J. Med. Chem. 2011, 54, 3451-3479; c) R. D. Taylor, M. MacCoss, A. D. G.
Lawson, J. Med. Chem. 2014, 57, 5845-5859; d) E. J. Kang, E. Lee, Chem. Rev.
2005, 105, 4348-4378.
[3] a) Z. Y. Wu, C. Pi, X. L. Cup, J. Bai, Y. J. Wu, Adv. Synth. Catal. 2013, 355, 1971-
1976; b) S. Ambala, T. Thatikonda, S. Sharma, G. Munagala, K. R. Yempalla,
R. A. Vishwakarma, P. P. Singh, Org. Biomol. Chem. 2015, 13, 11341-11350; c) S.
Devariab, B. A. Shah, Chem. Commun. 2016, 52, 1490-1493; d) W. Sun, Z. Xie,
J. Liu, L. Wang, Org. Biomol. Chem. 2015, 13, 4596-4604. e) Y. H. Wu, N. X.
Wang, B. C. Xu, Y. Xing, Y. Org. Lett. 2019, 21, 7450-7454.
[4] J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2015, 54, 1565-1569;
[5] a) A. K. Bagdi, M. Rahman, D. Bhattacherjee, G. V. Zyryanov, S. Ghosh, O. N.
Chupakhin, A. Hajra, Green Chem, 2020, 22, 6632-6681; b) Y. Q. Zhang, K. B.
Teuscher, H. T. Jin, Chem. Sci. 2016, 7, 2111-2118; c)W. Wei, L. Wang, H. Yue, P.
Bao, W. Liu, C. Hu, D. Yang, H. Wang, ACS Sustainable Chem. Eng. 2018, 6,
17252-17257; d) A. K. Bagdi, A. Hajra, Org. Biomol. Chem. 2020, 18, 2611-2631;
e) K. D. Mane, R. B. Kamble, G. Suryavanshi, New J. Chem. 2019, 43, 7403-
7408; f) H. Cao, Y. L. Kuang, X. C. Shi, K. L. W, B. B. Tan, J. M. C. Kwan, X. G.
Liu, J. Wu, Nat. Commun. 2020, 11, 1956-1963.
6-Fluoro-2-methyl-4-((3aR,5aS,9aS,9bR)-3a,6,6,9a-
tetramethyldodecahydronaphtho[2,1-b]furan-2-yl)quinolone
(5c): Pale yellow solid, 34% yield (54 mg); mp 143 - 146 °C ; IR
(neat) cm–1 : ṽ = 2918, 2862, 1599, 1465, 1338, 1222, 1166,
1077, 1002, 902, 827, 697, 443; 1H NMR (400 MHz, CDCl3): δ =
8.08 – 7.99 (m, 1H), 7.50 (s, 1H), 7.46 – 7.36 (m, 2H), 5.61 (dd,
J = 9.8, 2.2 Hz, 1H), 2.74 (s, 3H), 2.59 – 2.44 (m, 1H), 2.19 –
2.11 (m, 1H), 1.93 – 1.83 (m, 2H), 1.78 – 1.55 (m, 4H), 1.53 –
1.46 (m, 1H), 1.39 – 1.33 (m, 6H), 1.18 – 1.09 (m, 1H), 1.05 –
0.99 (m, 1H), 0.91 (d, J = 4.1 Hz, 6H), 0.85 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ = 159.45 (d, J = 324 Hz), 158.64 (d, J =
76.5 Hz), 149.82(d, J = 5.4 Hz), 144.84, 131.68(d, J = 9.3Hz),
124.33(d, J = 9.6 Hz), 118.75(d, J = 28.1 Hz), 118.20, 106.78(d,
J = 22.4 Hz), 82.16, 73.19, 58.48, 57.14, 42.30, 39.75(d, J =
11.4 Hz), 36.22, 33.53, 33.10, 31.51, 25.46, 21.76, 21.12, 20.61,
18.24, 15.16; HRMS (ESI) Calcd. for C26H35FNO [(M+H)+]
396.2703, found 396.2704.
[6] a) X. A. Liang, L. b. Niu, S. C. Wang, J. M. Liu, A. W. Lei, Org. Lett. 2019, 21,
2441-2444; b) J. D. Zhou, Y. W. Zou, P. Zhou, Z. W. Chen, J. J. Li, Org. Chem.
Front. 2019, 10, 1594-1598.
[7] C. Y. Huang, J. B. Li, W. B. Liu, C. J. Li, Chem. Sci. 2019, 10, 5018-5024.
[8] a) A. Vijeta, E. Reisner, Chem. Commun. 2019, 55, 14007-14010; b) H. Huang,
Z. M. Strater, T. H. Lambert, J. Am. Chem. Soc. 2020, 142, 1698-1703.
[9] S. H. Liu, A. X. Liu, Y. Q. Zhang, W. Wang, Chem. Sci. 2017, 8, 4044-4050.
6-((3aR,5aS,9aS,9bR)-3a,6,6,9a-
Tetramethyldodecahydronaphtho[2,1-b]furan-2-
[10] a) A. P. Antonchick, L. Burgmann, Angew. Chem. Int. Ed. 2013, 52, 3267-
3271; b) K. Matcha, A. P. Antonchick, Angew. Chem. Int. Ed. 2013, 52, 2082-
2084.
yl)phenanthridine (5d): White solid, 19% yield (31 mg); mp
114 - 116 °C ; IR (neat) cm–1 : ṽ = 3060. 2911, 2843, 1580, 1457,
1375, 1289, 1122, 954, 753, 719, 611; 1H NMR (400 MHz,
CDCl3): δ = 8.64 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 7.7 Hz, 1H),
8.47 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.83 (t, J = 7.3
Hz, 1H), 7.74 – 7.66 (m, 2H), 7.65 – 7.58 (m, 1H), 5.96 (dd, J =
9.4, 2.6 Hz, 1H), 2.77 – 2.65 (m, 1H), 2.34 – 2.17 (m, 1H), 2.06
(dt, J = 11.8, 3.1 Hz, 1H), 1.92 – 1.83 (m, 1H), 1.82 – 1.76 (m,
1H), 1.73 – 1.59 (m, 4H), 1.57 – 1.50 (m, 1H), 1.41 (s, 3H), 1.23
– 1.12 (m, 2H), 1.09 – 1.03 (m, 1H), 0.95 (s, 3H), 0.88 – 0.84 (d,
[11] a) Y. X. Wang, L. Yang, S. Liu, L. X. Huang, Z. Q. Liu, Adv. Synth. Catal. 2019,
361, 4568-4574; b) Q. M. Yang, X. L. Han, J. Q. Zhao, H. Y. Zhang, Y. C.
Zhang, J. Org. Chem. 2019, 84, 11417-11424; c) X. X. Wu, H. Zhang, N. Tang,
C. Zhu, Nat. Commun. 2018, 9, 3343-3350.
[12] a) L. Zhou, K. Okugawa, H. Togo, Eur. J. Org. Chem. 2017, 6239-6245; b) Y.
Q. Zhang, K. B. Teuscher, H. T. Ji, Chem. Sci. 2016, 7, 2111-2118; c) M.
Salman, X. F. Huang, Z. Z. Huang, Synlett. 2015, 26, 1391-1394.
10
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FULL PAPER
[13] a) B. Vacher, B. Bonnaud, P. Funes, N. Jubault, W. Koek, M. B. Assiè, C. Cosi,
M. Kleven, J. Med. Chem. 1999, 42, 1648-1660; b) C. Giordano, F. Minisci, E.
Vismara, S. Levi, J. Org. Chem. 1986, 51, 536-537.
[16] a) X. Y. Zhang, W. Z. Weng, H. Liang, H. Yang, B. Zhang, Org. Lett. 2018, 20,
4686-4690; b) N. N.Tang, X. X. Wu, C. Zhu, C. Chem. Sci. 2019, 10, 6915-
6919; c) X. Shao, X. Wu, S. Wu, C. Zhu, Org. Lett. 2020, 22, 7450-7454.
[17] B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25-35.
[14] a) F. Baharloo, M. H. Moslemin, H. Nadri, A. Asadipour, M. Mahdavi, S.
Emami, L. Firoozpour, R. Mohebat, A. Shafiee, A. Foroumadi, Eur. J. Med.
Chem. 2015, 93, 196-201; (b) S. Santoshkumar, N. D. Satyanarayan, R.
Aanatacharya, P. Sameer, Int. J. Pharm. Pharm. Sci. 2017, 9, 260-267.
[15] a) T. Ueda, M. Ishida, S. Tamura, Y. Fujimoto, M. Yuri, T. Saito, D. Ueda, Phys.
Stat. Sol. 2003, 7, 2219–2222. b) S. Nakamura, J. Crystal Growth. 1999, 201,
290-295.
[17] a) R. Breslow, R. J. Corcoran, B. B. Snider, J. Am. Chem. Soc. 1974, 96, 6791-
6972. b) S. A. Moteki, A. Usui, S. Selvakumar, T. Zhang, K. Maruoka, Angew.
Chem. Int. Ed. 2014, 53, 11060-11064.
[18] S. Ikawa, S. Yagi, T. Maeda, H. Nakazumi, H. Fujiwara, S. Koseki, Y. Sakurai ,
Inorg. Chem. Commun. 2013, 38, 14-19.
[19] M. Ochiai, T. Sueda, K. Miyamoto, P. Kiprof, V. V. Zhdankin, Angew. Chem.
Int. Ed. 2006, 45, 8203-8206.
11
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FULL PAPER
PIFA-Mediated Cross-Dehydrogenative Coupling of
N-Heteroarenes with Cyclic Ethers: Ethanol as an
Efficient Promoter
Eur. J. Org. Chem. Year, Volume, Page – Page
Xiang Li,# Chaoyang Liu, # Shixun Guo, Wei Wang,*
Yongqiang Zhang*
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