Synthesis of Highly Fused Pyrano[2,3- b]pyridines via Rh(III)-Catalyzed C-H Activation and Intramolecular Cascade Annulation under Room Temperature

Article abstract of DOI:10.1021/acs.joc.9b03102

A facile access to the polycyclic-fused pyrano[2,3-b]pyridines has been established under room temperature via Rh(III)-catalyzed C-H bond activation and intramolecular cascade annulation. This strategy features high efficiency, unique versatility, and gen

Full text of DOI:10.1021/acs.joc.9b03102

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Article
Synthesis of Highly Fused Pyrano[2,3-b]pyridines via
Rh(III)-Catalyzed C-H Activation and Intramolecular
Cascade Annulation under Room Temperature
Xu Han, Feng Gao, Chunpu Li, Daqing Fang, Xiong Xie, Yu Zhou, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03102 • Publication Date (Web): 10 Feb 2020
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Synthesis of Highly Fused
Pyrano[2,3-b]pyridines via Rh(III)-Catalyzed
C-H Activation and Intramolecular Cascade
Annulation under Room Temperature
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Xu Hana,b, Feng Gaoa, Chunpu Lia,b, Daqing Fanga,c Xiong Xiea,b, Yu Zhoua,b,* and Hong
Liua,b,*
aState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi
Road, Shanghai, 201203, China
bUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
cKey Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education,
Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016,
China
E-mail: zhouyu@simm.ac.cn (Yu Zhou); hliu@simm.ac.cn (Hong Liu)
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Graphic Abstract
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OEt
OEt
8
OEt
N2
N
N
9
N
Ts
Rh(III) catalysis
NH
+
Ts
O
N
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H
O
HFIP, r.t, 2 h
redox-neutral
H
OH
37 examples
up to 98% yield
Good functional group tolerance and unique versatility
High efficiency and mild reaction conditions
Highly fused ring construction & moderate to excellent yields
Late-stage diversification of drugs possessing CN group
√
√
√
√
Abstract
A facile access to the polycyclic fused pyrano[2,3-b]pyridines has been established under
room temperature via Rh(III)-catalyzed C-H bond activation and intramolecular cascade
annulation. This strategy features high efficiency, unique versatility, and generality and it can
occur under mild conditions in good to excellent yields. More importantly, this strategy can
be extended to the late-stage functionalization of drugs possessing CN group.
Introduction
Fused pyrano[2,3-b]pyridines are essential privileged scaffolds in medicinal chemistry ,
exhibiting diversified biological activities including antimicrobial,1 anti-Alzheimer,2
anti-inflammatory and analgestic,3 antirhinovirus,4 and cannabinoid-1 receptor (CB1R)
inverse agonist activity5 (Figure 1). Additionally, substituted pyrano[2,3-b]pyridines have
been applied as an effective ligand for C-H bond functionalization in organometallic
chemistry.6 To date, several classical synthetic methods had been reported to build these
intriguing pyrano[2,3-b]pyridine motifs,7 and representatively, Taylor’s pioneering works on
construction of the multi-substituted pyrano[2,3-b]pyridines were developed by
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pre-preparation of a 1,2,4-triazines precursor in which electron-rich dienophiles, such as
alkynes, were incorporated followed with an intramolecular Diels-Alder reaction under high
temperature (Scheme 1a). However, these traditional strategies typically required harsh
reaction conditions and started from highly functionalized starting materials, which lead to
limited generality and low step economy. Thus, it is in high demand to develop more efficient
synthetic strategies for the preparation of these important structural motifs.
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R
H
NH2
HN
N
NH
OH
O
NH2
O
O
N
O
N
N
O
HO
Cl
antimicrobial agent
anti-Alzheimer
HN
Pranoprofen
O
anti-inflamatory drug
Cl
N
NH
Cl
Cl
N
O
N
O
Cl
Cl
CB1R Agonist
antirhinovirus activity
Figure 1. Representative biological compounds containing pyrano[2,3-b]pyridines motif
Transition-metal-catalyzed carbon-carbon and/or carbon-heteroatom bond formation
through C-H bond activation have attracted attention and been proved to be an efficient tool
for both construction of heterocyclic scaffolds and late-stage functionalization of biologically
active agents.8 Among these noble metals, Ru(II) and Rh(III) catalysts performed to be robust
catalysts in C-H bond functionalization due to their high reaction efficiency and broad
adaptability.9 For instance, in 2018, the Sahoo’s group achieved the construction of fused
pyrano[2,3-b]pyridine scaffold through one-pot dual C-H bond activation and annulation of
o-C-H bonds of arenes with cost-effective Ru(II) complex (Scheme 1b).10 Almost
simultaneously, Cheng and co-workers reported another strategy to build the similar
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pyrano[2,3-b]pyridine skeleton via a Rh(III)-catalyzed domino double annulation of C-H
bonds between sulfoxonium ylides and ethyl benzimidates (Scheme 1c).11 In Cheng’s study,
the imidate moiety in benzimidates was presented as a powerful directing group (DG) which
had been extensively exhibited in Rh(III)-catalyzed C-H bond functionalization reactions to
establish versatile heterocyclic skeletons. 12 However, it is of note that most of these imidate
assisted Rh(III)-catalyzed reactions have inevitably been carried out under high reaction
temperature, which may limited their potential application.
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Scheme 1. Pyrano[2,3-b]pyridine Construction
(a) Taylor's work
R'
R
Diels-Alder
210 oC,5 h
N
N
R'
R
N
O
N
O
(b) Sahoo's work
Ru(II) catalysis
AgSbF6 (40 mol %)
O
O
R
Ar
Me
R
R
R
R
S
N
.
+
Ph
Cu(OAc)2 H2O (1.5 equiv)
1,4-dioxane, 120 oC, 24 h
Ar
O
N
R
(c) Cheng's work
OEt
Rh(III) catalysis
AgSbF6 (20 mol %)
Cu(OAc)2 (20 mol %)
Ar
O
O
NH
+
S
Ar
Ar'
NaOAc (2.0 equiv),
DCE, N2 ,120 oC, 12 h
Ar'
O
N
Ar'
(d) this work
OEt
Rh(III) catalysis
AgOPiv (20 mol %)
N2
N
NH
Ts
+
HFIP, rt, 2 h, Ar
50-98% yield
O
H
O
N
OEt
Within our continuous research effort on rapid construction of diverse drug-like
heterocyclic skeletons via Rh(III)-catalyzed synthetic strategies,13 we serendipitously found
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that aryl imidates could smoothly couple with 4-diazoisochroman-3-imines to furnish the
polycyclic fused pyrano[2,3-b]pyridines. The biggest advantage of this methodology is that
desired products can be obtained with good to excellent yields (up to 98%) under room
temperature along with broad generality and versatility (Scheme 1d). But coincidentally,
during the period that our work has been finished and ready to submit, a similar work has
been reported by Cheng.14c However, his strategy required a rather high reaction temperature
(120 °C) and longer time (12 h) for the full conversion. On the contrary, our strategy could be
achieved under room temperature in 2 h with good to excellent yields, and it also featured
broad substrate generality, especially the strong electron-withdrawing groups, such as nitro
group or trifluoromethyl group is also independently compatible for this transformation.
Moreover, our strategy can be applied to the late-stage functionalization for different
marketed drugs possessing CN group. Herein, we report our obtained results in detail.
Results and Discussion
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Taking into account the typical conditions used in Rh(III)-catalyzed reactions, we have
chosen the following starting conditions for our studies: ethyl benzimidate (1a) and
4-diazoisochroman-3-imine (2a) were mixed in DCE in the presence of [Cp*RhCl2]2 (10
mol %), AgSbF6 (20 mol %) and CsOAc (1.0 equiv) and the resulting mixture was stirred at
80 °C for 12 h (Table 1, entry 1). The results displayed that a multiple substituted
isoquinoline scaffold 4aa was mainly attained in 75% yield, however, a product with strong
fluorescence under UV-Vis (365 nm wavelength) was isolated with a yield of 10% (Table 1,
entry 1). Further structure elucidation verified that it is a polycyclic fused
pyrano[2,3-b]pyridine motif (3aa). Intrigued by this gratifying result, we implemented a
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comprehensive screening of the reaction parameters and envisioned that 3aa could be
selectively afforded in a good yield. We first investigated the effects of AgSbF6 and CsOAc,
respectively. The results demonstrated that removal of AgSbF6 lead to sharp decrease in the
yield of 3aa (Table 1, entry 2), but omission of CsOAc could give a better yield of 3aa (Table
1, entry 3). These results indicated that AgSbF6 was of great importance for this
transformation. The reaction temperature was defined in the following explorations and we
noticed that this process could be carried out smoothly under room temperature to afford 3aa
in 36% yield (Table 1, entry 4) but 4aa was detected only in a trace yield. Solvents screening
was subsequently carried out (Table 1, entries 5-11) and HFIP was optimal for the formation
of 3aa in 66% yield (Table 1, entry 8), whereas in EtOH 4aa was predominantly afforded in
81% yield together with 11% of 3aa (Table 1, entry 6). A series of additives was successively
explored (Table 1, entries 12-19) and when displacing AgSbF6 with AgOPiv, the yield of 3aa
was dramatically increased to 83% and only trace amount of 4aa could be detected (Table 1,
entry 14). We kept exploring the optimal reaction conditions. After adjusting the equivalent of
2a to 1.5 fold and sealing the system in argon atmosphere, 3aa was detected in 94% yield and
subsequent studies revealed that it was no obvious discrepancy of the yield of 3aa when
independently ceased the reaction at 12 h and 6 h (Table 1, entries 21-22). Further study had
confirmed that this process could finish its full conversion in only 2 h with 3aa isolated in
93% yield (Table 1, entry 23). Afterwards, the amount of [Cp*RhCl2]2 was also examined and
when 5% of Rh(III) catalyst was presented, although with a slightly lower efficiency,
compound 3aa could still be detected in 86% yield (Table 1, entry 24) . However, only 50%
of 3aa was detected after altering the amount of [Cp*RhCl2]2 to 2.5% (Table 1, entry 25) and
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no more desired product was obtained under the absence of [Cp*RhCl2]2, indicating the
[Cp*RhCl2]2 catalyst is necessary for this transformation (Table 1, entry 26).
Table 1. Optimization of the Reaction Conditionsa
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OEt
OEt
OEt
NH
N2
N
N
[Cp*RhCl2]2 (10 mol %)
additive (20 mol %)
N
Ts
+
Ts
O
N
H
O
solvent, temp, time
H
OH
1a
2a
3aa
4aa
yieldb (%)
of 3aa/4aa
10 / 75
0 / 15
entry
additive
solvent
temp (°C)
1c
2
AgSbF6/CsOAc
CsOAc
DCE
80
80
80
rt
DCE
3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgBF4
DCE
39 / 32
36/trace
6/79
4
DCE
5
DMA
EtOH
TFE
rt
6
rt
11/81
7
rt
44/28
8
HFIP
Toluene
1,4-dioxane
THF
rt
66/18
9
rt
11/67
10
11
12
13
rt
19/53
rt
trace/32
27/17
HFIP
HFIP
rt
AgNTf2
rt
48/12
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AgOPiv
Ag2CO3
AgPF6
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
rt
83/trace
64/27
15
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
16
43/14
10
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17
AgOTf
AgOAc
AgTFA
AgOPiv
AgOPiv
AgOPiv
AgOPiv
AgOPiv
AgOPiv
AgOPiv
57/8
18
64/12
19
59/13
20d
86/ND
94/ND
94/ND
95(93)h/ND
86/ND
50/ND
N.R.
21 e
22e,f
23 e,g
24e,g,i
25 e,g,j
26 e,g,k
aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (10 mol %) and additive
b
1
(20 mol %) in solvent (0.1 M) for 12 h under air. Determined by H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard. c1.0 equiv of CsOAc was
d
e
supplemented. Under Argon atmosphere. 1.5 equiv of 2a was applied; the reaction was
conducted under Argon atmosphere. fThe reaction time was shorten to 6 h. gThe reaction time
was 2 h.hIsolated yield of 3aa. [Cp*RhCl2]2 (5 mol %) was presented. [Cp*RhCl2]2 (2.5
i
j
mol %) was presented. kWithout [Cp*RhCl2]2.
With the optimal reaction conditions in hand, we first verified the substrate scope of aryl
imidates (Table 2). Many aryl imidates with substituents installed on the para position of the
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benzene ring were firstly examined and these derivatives bearing an electron-withdrawing
group or electron-donating group react smoothly with 2a to afford the fused
pyrano[2,3-b]pyridine motifs (3aa-3ka) in good to excellent yields. And it is unambiguous of
the molecular structure of 3aa which was further verified by X-ray crystallography.15 The
ortho-substituted aryl imidate was additionally defined, furnishing the product in good yield
(3la, 71%). Introduction of substituents to the meta position of benzene ring was also
tolerated but without getting more products which cyclized on the less hindered site, two
regioisomeric products 3ma and 3ma’ were obtained in a total yield of 96% with an
equivalent ratio. More surprisingly, when benzodioxole derivative was applied, mono-isomer
that cyclization was occurred on the much hindered site was attained in a 98% yield (3na).
The molecular structure of 3na was subsequently confirmed with X-ray crystallography.16
These results indicated that the electrostatic effect is the predominant factor which determined
the regioselectivity of this transformation rather than the steric effect. Significantly,
heterocycles bearing indole scaffold and thiophene were independently examined and the
corresponding products 3oa and 3pa were obtained in 50% and 68% yields, respectively.
Besides these heterocycles, naphthalene imidate was also compatible under standard reaction
conditions and the desired product 3qa could be afforded in 88% yield. Moreover,
benzophenone NH imine (3ra) and other aryl imidate esters (3sa-3ta) were also tested and
they were tolerated in this reaction albeit with a slightly lower efficiency.
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Table 2. Substrate Scope with Aryl Imidates for Assymbly of 3a,b
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R2
R2
H
N2
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
N
R1
N
NH
Ts
+
O
R1
HFIP (0.1 M), rt, 2 h, Ar
O
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1a-1t
functional group tolerance
2a
3aa-3ta
:
1
3aa
R = H,
, 93%
R1 Me,
, 84%
3ca
OEt
F
OEt
=
3ba
1
R = t-Bu,
, 85%
N
N
1
3da
R = Ph,
, 84%
R1
O
O
1
3ea
R = OMe,
, 98%
1
3fa
R = N(CH3)2,
, 78%
1
3ga
R = F,
, 90%
1
3ha
R = Cl,
, 88%
, 87%
1
3ia
R = Br,
1
3ja
R = I,
, 78%
3ka
3la
, 71%
3aa
X-ray structure of
O
1
R = CF3,
, 97%
H
OEt
O
MeO
N
N
N
+
O
MeO
O
OEt
OEt
O
H
H
3ma 3ma'
3na
3na
X-ray structure of
+
, 96%
:1)
, 98%
OEt
(3ma 3ma' = 1
:
R2
N
OEt
OEt
S
N
N
N
N
O
O
O
O
Ts
2
3ra
R = Ph,
, 69%
3oa
3pa
, 68%
3qa
, 88%
, 50%
2
3sa
R = OMe,
, 76%
2
i
3ta
R = O Pr,
, 77%
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (10 mol %) and AgOPiv (20
mmol %) in HFIP (0.1 M) at ambient temperature for 2 h under Ar atmosphere; bIsolated
yield
We next evaluated the substrate scope of the diazo coupling partner (Table 3) and the
results revealed that electron-withdrawing or electron-donating groups incorporated
derivatives were fully tolerated to this process and the desired products could be obtained in
moderate to good yields. For example, when CH3 or Cl was incorporated at the para position
of benzene ring, the reaction could complete smoothly to afford 3ab and 3ac in 78% and 58%
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yield, respectively. Other substituents such as F or CF3 incorporated at the para position were
also tolerated and the desired products were obtained in good yields (3ad, 66%; 3ae, 80%). It
was worth mentioning that substrate bearing NO2 group was also compatible to furnish the
product 3af in 77% yield. Meta position incorporated starting materials were also scrutinized
and they were all tolerated to the reaction by producing the desired products in good to
excellent yields (3ag-3al). For instance, 3ai was obtained in 94% yield and 3ak, which
bearing a CF3 group, was also attained in 91% yield. Substrate with benzodioxole moiety was
also viable in this transformation albeit a slightly lower yield was detected (3al, 76%).
Table 3. Substrate Scope of 4-Diazoisochroman-3-iminesa,b
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OEt
5
6
7
8
OEt
NH
N2
N
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
N
Ts
O
+
R
HFIP (0.1 M), rt, 2 h, Ar
O
H
9
R
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1a
OEt
2b-2l
OEt
N
3ab-3al
OEt
N
OEt
N
N
O
O
O
O
Cl
F
CF3
3ae
3ab
3ac
3ad
, 78%
OEt
, 58%
, 66%
, 80%
OEt
OEt
OEt
N
N
N
N
O
O
O
O
MeO
3ah
F
NO2
, 77%
OMe
3af
3ag
3ai
, 94%
, 70%
, 79%
OEt
N
OEt
N
OEt
N
O
O
O
Cl
3aj
F3C
3ak
O
O
3al
, 76%
, 82%
, 91%
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (10 mol %) and AgOPiv (20
mmol %) in HFIP (0.1 M) at ambient temperature for 2 h under Ar atmosphere; bIsolated
yield
After established a preliminary knowledge of the optimal reaction conditions and
functional group tolerance, intrigued by the priority of directing groups, selected aryl imidates
were further explored (3ua-3wa) and the results indicated that imine as directing group
outcompeted ketone (3ua), ester (3va) and NHPiv (3wa) leading to the fused
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pyrano[2,3-b]pyridine scaffold in a very high selective manner (Scheme 2).
6
7
Scheme 2. Directing Groups Priority of Imidates
8
9
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
OEt
NH
N2
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
N
R
N
Ts
+
O
R
HFIP (0.1 M), rt, 2 h, Ar
O
H
1u-1w
2a
3ua-3wa
directing groups priority
OEt
N
OEt
OEt
N
O
N
EtO
O
O
N
O
H
O
O
3ua
, 68%
3va
3wa
, 80%
, 93%
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (10 mol %) and AgOPiv (20
b
mmol %) in HFIP (0.1 M) at ambient temperature for 2 h under Ar atmosphere; Isolated
yield
Intrigued by the highly fused heterocyclic product derived from our strategy, we have
further explored the synthetic utility of this transformation on the late-stage functionalization
for clinical drugs possessing CN group including Letrozole, Pirfenidone and Citalopram.
After first transferring the CN group in these drugs into the corresponding imidates, a
coupling reaction with 2a was independently processed under standard conditions and the
functionalized drug molecules could be obtained in moderate to good yields. These results
indicated that the strategy could be extended to the late-stage functionalization of more
clinical drugs possessing CN group for drug discovery (Scheme 3). In addition, gram-scale
reaction was subsequently conducted with a maintained reaction efficiency (91% yield, for
gram-scale reaction), which further demonstrated the potential synthetic utility of this
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strategy.
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Scheme 3. Late-stage Diversification of Drugs Possessing CN Group
8
9
N
N
N2
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
N
N
N
N
10
11
12
13
14
15
16
17
18
19
20
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N
Ts
+
O
O
HFIP (0.1 M), rt, 2 h, Ar
O
HN
NH
OEt
N
N
OEt
OEt
OEt
2a
6a
,67%
5a
, from Letrozole
O
O
N2
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
N
N
N
Ts
OEt
+
HFIP (0.1 M), rt, 2 h, Ar
O
OEt
NH
, from Pirfenidone
N
O
5b
2a
6b
,88%
OEt
OEt
N2
N
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
HN
O
O
N
Ts
O
+
O
HFIP (0.1 M), rt, 2 h, Ar
N
F
F
N
5c
2a
6c
,from Citalopram
,58%
In order to gain insight into the preliminary mechanism of this reaction, several studies
were independently performed. In the H/D exchange study, the reaction of 1a in d2-HFIP in
the absence of substrate 2a indicated that the C-H bond activation was reversible (Scheme 4,
eq 1). Furthermore, the intermolecular competition experiments were parallel conducted
between 1e and 1k or 1e and 1g under standard reaction conditions, respectively and the
results both indicated that benzimidate that bearing an electron-withdrawing group reacted
preferentially (Scheme 4, eq 2 and eq 3). Moreover, the kinetic isotope effect (KIE)
experiment was performed using substrate 1a and 1a-d5 coupled with 2a under standard
reaction conditions at a low conversion (Scheme 4, eq 4). The KIE value of 4.9 indicated that
the cleavage of C-H bond might be involved in the rate-determining step.
Scheme 4. Mechanistic Investigations
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90% D
4
5
6
[Cp*RhCl2]2 (10 mol %)
H/D NH
AgOPiv (20 mol %)
O
H
NH
d2-HFIP
O
+
(1)
(2)
7
8
9
r.t., 2 h, Ar
H
H/D
90% D
1a
OEt
OEt
N
2a
(0.3 mmol)
10
11
12
13
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N
OEt
NH
OEt
NH
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
+
O
MeO
O
F3C
+
MeO
HFIP (0.1 M), rt
2 h, Ar
F3C
3ka/3ea =
1.4 : 1
1k
, 0.2 mmol
1e
0.2 mmol
OEt
OEt
2a
(0.3 mmol)
N
N
OEt
NH
OEt
NH
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
+
O
MeO
O
F
+
(3)
HFIP (0.1 M), rt
2 h, Ar
F
MeO
1g
3ga/3ea =
1.1 : 1
, 0.2 mmol
1e
0.2 mmol
OEt
OEt
2a
, 0.3 mmol
OEt
NH
OEt
NH
N
N
[Cp*RhCl2]2 (10 mol %)
AgOPiv (20 mol %)
d4
+
O
+
O
d5
(4)
HFIP (0.1 M), rt
45 min, Ar
d5-1a
3a
1a
, 0.1 mmol
d4-3a
D = 0.83/0.17 =4.9
, 0.1 mmol
kH/k
On the basis of these results and previous reports14, 17, a plausible mechanism for the
generation of 3aa has been proposed (Scheme 5). [Cp*RhCl2]2 was first activated by ligand
exchange with AgOPiv to form Cp*Rh(OPiv)2 which coordinates with substrate 1a to
generate the rhodacyclic intermediate I via C-H bond activation following the release of
HOPiv. Meanwhile, the active catalyst is coordinated with substrate 2a following with
exclusion of N2 to yield the rhodium carbine intermediate II which subsequently undergoes
intramolecular migratory insertion to afford the intermediate III. Protonolysis of the
generated intermediate III finally triggers the formation of intermediate IV, which is
sequentially proceeded via an intramolecular nucleophilic addition and elimination of TsNH2
to eventually furnish the desired product 3aa with a release of the Rh (III) species.
Scheme 5. Proposed Catalytic Cycle
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[Cp*RhCl ]
1/2
2 2
OEt
5
6
7
8
OEt
NH
2 AgOPiv
2 AgCl
N
NHTs
O
EtO
NTs
H
NH
Cp*
OPiv
Rh
PivO
O
[Cp*Rh(OPiv)2]
9
H
1a
10
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IV
V
HOPiv
protonation
Cp*
HOPiv
C-H activation
-TsNH2
3aa
OEt
NH
OEt
NH
Rh
Cp*
Rh
TsN
O
PivO
I
III
N2
metal carbene
formation
NTs
migratory
insertion
OEt
O
NH
Rh
2a
N2
*Cp
NTs
O
II
Taking into account the strong fluorescence of compound 3aa under UV-Vis (365 nm
wavelength) and in order to verify the fluorescent properties of these compounds, UV-Vis and
fluorescence spectra were tested for chosen compounds (Scheme 6). Comparing with 3aa,
compound 3af and 3qa exhibited obvious red shift indicating a strong visible-light absorption
property (407 nm for 3af; 428 nm for 3qa) (Scheme 6a). In fluorescence spectra, 3af
exhibited strong fluorescence emission peak at 600 nm while 3qa also showed an emission
peak at 535 nm. The other compounds including 3aa, 3ah, 3ak, 3fa, 3ka and 3va had a most
similar range of the emission peak around 433-488 nm (Scheme 6b). After obtaining the
absorbance and emission data of chosen compounds, Strokes’ shift was calculated in Table 4
and it ranged from 73 nm for 3ak to 193 nm of 3af.
Scheme 6. UV-Vis and Fluorescence Spectra
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2.0
1.6
1.2
0.8
0.4
0.0
3aa
3af
3ah
3ak
3fa
3ka
3qa
3va
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250
300
350
400
450
500
Wavelength(nm)
(a) UV-Vis Spectra (5×10-5 M in DCM)
12
3aa
3af
3ah
3ak
3fa
3ka
3qa
3va
10
8
6
4
2
0
400
450
500
550
600
650
700
Wavelength(nm)
(b) Fluorescence Spectra (5×10-5 M in DCM)
Table 4. Absorption and Emission Dataa
Compound
λabs (nm)
λem (nm)
Strokes’ shift
(nm)
3aa
360
438
3af
407
600
3ah
362
443
3ak
360
433
3fa
346
448
3ka
3qa
428
535
3va
392
488
375
466
78
193
81
73
102
91
107
96
aIn DCM (5×10-5 M)
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Conclusion
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In conclusion, we have developed an efficient synthetic strategy for the rapid
establishment of highly fused heterocyclic compound via Rh(III)-catalyzed C-H bond
activation and cascade annulation under room temperature. This strategy featured broad
synthetic generality, unique versatility and high efficiency. Gram-scale reaction was also
carried out with maintained efficiency. In addition, this strategy is applicable in late-stage
diversification of drugs possessing CN group, which provided a potential tool for the
structural modification of biological active compounds.
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Experimental Section
General Information. All reagents and solvents were purchased from commercial
sources (J&K, TCI, Adamas-beta, etc.) and used as received without further purification.
Dichloro(η5‐pentamethylcyclopentadienyl)rhodium(III) dimer (99%) was purchased from
Sinocompound Technology Co., Ltd. Analytical thin layer chromatography (TLC) was HSGF
254 (0.15-0.2 mm thickness). AgOPiv was prepared as a reported literature indicated.18 1
H
13
and C nuclear magnetic resonance spectra (NMR) were acquired on a Bruker 400 MHz or
500 MHz or 600 MHz NMR spectrometer. Chemical shifts (δ) were expressed in ppm using
tetramethylsilane as an internal reference and the coupling constants (J) were indicated in Hz.
The coupling constants were described as singlet (s), doublet (d), triplet (t), quartet (q),quintet
(quint), broad (br) or multiplet (m). LRMS data was tested on a Thermo Fisher Finnigan LEQ
with Electrospray Ionization (ESI). HRMS data was obtained on an Agilent G6520 Q-TOF
with Electrospray Ionization (ESI). The UV-vis spectra were carried out on an Ocean Optics
Maya 2000 Pro spectrometer. The fluorescence spectra were measured with a HORIBA Jobin
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Yvon Fluoromax-4 fluorescence spectrometer.
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General Procedure for the Synthesis of Substrate 1 (1a-1w) and 5 (5a-5c). 1r is
commercially available and other aryl imidates were synthesized according to a reported
literature.19 Aryl nitrile (20 mmol, 1.0 equiv) was dissolved in alcohol (240 mmol, 12.0 equiv)
in a round bottom flask. To the mixture was added AcCl (160 mmol, 8.0 equiv) over 30 min
in an ice bath. After the addition, ice bath was removed and the reaction mixture was stirred at
room temperature for 4-12 h. Solvent was removed under reduced pressure and the resulting
solid was washed with EA (10 mL x 3 times). The solid was dissolved in EA (50.0 mL) and
saturated NaHCO3 solution was added dropwise until the pH of the solution is above 7. The
organic layer was collected, dried over anhydrous Na2SO4 and concentrated in vacuo to yield
the crude product which was further purified by flash chromatography to afford the desired
product. Compounds 1a19, 1b20a, 1d20b, 1e19, 1g20c, 1h19, 1k20d, 1m20e, 1p20f, 1q20b, 1r20g, 1s20h,
1t20i and d5-1a20j are known compounds and the spectroscopic and physical data were
completely matched with the characterization data from the literatures.
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1
Ethyl 4-(tert-butyl)benzimidate (1c). Colorless oil (350 mg, 78% yield); H NMR (500
MHz, DMSO-d6): δ 8.73 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 4.26 (q, J
= 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.25 (s, 10H); 13C{1H} NMR (126 MHz, DMSO-d6):
δ 165.3, 153.2, 129.5, 126.4, 125.0, 60.6, 34.3, 30.8, 14.1; LRMS (ESI): m/z 206.1 [M + H]+;
HRMS (ESI): calculated for C13H20NO+ [M + H]+: 206.1539, found: 206.1538.
Ethyl 4-(dimethylamino)benzimidate (1f).White solid (2.2 g, 57% yield); m.p.
1
58.9-59.1 °C; H NMR (600 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 6.68
13
(d, J = 9.0 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.94 (s, 6H), 1.30 (t, J = 7.2 Hz, 3H); C{1H}
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NMR (151 MHz, DMSO-d6): δ 165.5, 151.6, 127.9, 119.0, 111.0, 60.3, 39.7, 14.3; LRMS
(ESI): m/z 193.1 [M + H]+; HRMS (ESI): calculated for C11H17N2O [M + H]+: 193.2335,
found: 193.1331.
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1
Ethyl 4-bromobenzimidate (1i). Colorless oil (2.0 g, 44% yield); H NMR (600 MHz,
DMSO-d6): δ 9.00 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 4.23 (q, J = 7.2
Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, DMSO-d6): δ 164.0, 131.4, 131.2,
128.8, 124.4, 61.0, 14.2; LRMS (ESI): m/z 228.0 [M + H]+; HRMS (ESI): calculated for
C9H11NBrNO+ [M + H]+: 228.0014, found: 228.0019.
1
Ethyl 4-iodobenzimidate (1j). Colorless oil (3.6 g, 65% yield); m.p. 34.1-34.5 °C; H
NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H),
4.22 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 4H); C{1H} NMR (151 MHz, DMSO-d6): δ
13
164.3, 137.3, 131.5, 128.7, 98.2, 61.0, 14.2; LRMS (ESI): m/z 276.0 [M + H]+; HRMS (ESI):
calculated for C9H11INO+ [M + H]+: 275.9880, found: 275.9871.
1
Ethyl 2-fluorobenzimidate (1l). Colorless oil (1.6 g, 48% yield); H NMR (400 MHz,
DMSO-d6): δ 8.60 (d, J = 3.6 Hz, 1H), 77.61-7.57 (m, 1H), 7.53–7.48 (m, 1H), 7.31–7.24 (m,
2H), 4.24 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2Hz, 3H); 13C{1H} NMR (126 MHz, DMSO-d6):
δ 162.1, 159.4 (d, J = 250.2 Hz), 132.2 (d, J = 8.8 Hz), 129.3 (d, J = 2.4 Hz), 124.5 (d, J = 3.5
Hz), 121.7 (d, J = 11.5 Hz), 116.2 (d, J = 22.0 Hz), 60.93, 13.99; 19F NMR (471 MHz,
DMSO-d6): δ -116.12 (d, J = 5.9 Hz); LRMS (ESI): m/z 168.1 [M + H]+; HRMS (ESI):
calculated for C9H11FNO+ [M + H]+: 168.0819, found: 168.0816.
Ethyl benzo[d][1,3]dioxole-5-carbimidate (1n). White solid (2.8 g, 72% yield); m.p.
1
42.1-42.6 °C; H NMR (600 MHz, DMSO-d6): δ 8.70 (s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.37
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(dd, J = 7.8, 1.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.08 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.29
(t, J = 7.2 Hz, 4H); 13C{1H} NMR (151 MHz, DMSO-d6): δ 164.3, 149.2, 147.5, 126.2, 121.5,
107.9, 107.0, 101.7, 60.8, 14.2; LRMS (ESI): m/z 194.0 [M + H]+; HRMS (ESI): calculated
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+
for C10H12NO3 [M + H]+: 194.0812, found: 194.0807.
Ethyl 1-tosyl-1H-indole-5-carbimidate (1o). Light yellow solid (1.1 g, 16% yield); m.p.
136.4-137.2 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.97
(d, J = 8.8 Hz, 1H), 7.88-7.86 (m, 3H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 7.38-7.36 (m, 2H),
6.92-6.90 (m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.29 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); C{1H}
13
NMR (126 MHz, DMSO-d6): δ 165.5, 146.2, 135.6, 134.5, 130.8, 128.6, 128.3, 127.2, 123.9,
120.9, 113.3, 110.3, 61.4, 21.5, 14.7; LRMS (ESI): m/z 343.0 [M + H]+; HRMS (ESI):
calculated for C18H19N2O3S+ [M + H]+: 343.1111, found: 343.1113.
1
Ethyl 4-acetylbenzimidate (1u). White solid (1.4 g, 37% yield); m.p. 42.6-43.1 °C; H
NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.02-7.99 (m, 2H), 7.95–7.93 (m, 2H), 4.26 (q, J
= 7.2 Hz, 2H), 2.60 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, DMSO-d6): δ
197.6, 164.3, 138.2, 135.8, 128.3, 128.1, 127.7, 127.1, 61.2, 26.9, 14.2; LRMS (ESI): m/z
192.2 [M + H]+; HRMS (ESI): calculated for C11H14NO2 [M + H]+: 192.1019, found:
+
192.1014.
Ethyl 4-(ethoxy(imino)methyl)benzoate (1v). White solid (1.3g, 29% yield); m.p.
1
67.4-69.3 °C; H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.94
(d, J = 8.4 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 6H);
13C{1H} NMR (151 MHz, DMSO-d6): δ 165.2, 164.2, 136.0, 131.6, 129.2, 127.1, 61.2, 61.0,
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14.1, 14.1; LRMS (ESI): m/z 222.1 [M + H]+; HRMS (ESI): calculated for C12H16NO3 [M +
+
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H]+: 222.1125, found: 222.1120.
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Ethyl 4-pivalamidobenzimidate (1w). White solid (2.4g, 48%); m.p. 122.5-123.7 °C; H
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NMR (600 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.70 (s, 1H), 7.78–7.73 (m, 4H), 4.22 (q, J = 7.2
Hz, 2H), 1.32 (d, J = 7.2 Hz, 3H), 1.23 (s, 9H); 13C{1H} NMR (151 MHz, DMSO-d6): δ 176.7,
164.8, 141.6, 127.8, 127.2, 126.5, 119.3, 60.7, 27.1, 14.3; LRMS (ESI): m/z 249.2 [M + H]+;
+
HRMS (ESI): calculated for C14H21N2O2 [M + H]+: 249.1598, found: 249.1594.
Diethyl 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzenecarboximidate (5a). White solid
1
(465 mg, 72% yield); m.p. 102.7-103.4 °C; H NMR (500 MHz, DMSO-d6): δ 8.90 (s, 2H),
8.64 (s, 1H), 8.09 (s, 1H), 7.82 (d, J = 8.0 Hz, 4H), 7.30 (d, J = 8.5 Hz, 4H), 7.23 (s, 1H), 4.24
13
(q, J = 7.1 Hz, 4H), 1.30 (t, J = 6.0 Hz, 7H); C{1H} NMR (126 MHz, DMSO-d6): δ 164.7,
152.1, 144.6, 141.3, 131.9, 128.1, 127.1, 64.6, 60.9, 14.1; LRMS (ESI): m/z 378.2 [M + H]+;
+
HRMS (ESI): calculated for C21H24N5O2 [M + H]+: 378.1925, found: 378.1927.
Ethyl 4-(5-methyl-2-oxopyridin-1(2H)-yl)benzimidate (5b). White solid (178 mg, 82%
yield); m.p. 129.5-131.0 °C; 1H NMR (500 MHz, DMSO-d6): δ 9.03 (s, 1H), 7.94 (d, J = 8.0
Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.45-7.44 (m, 1H), 7.39 (dd, J = 9.0, 2.5 Hz, 1H), 6.44 (d, J
= 9.5 Hz, 1H), 4.36-4.26 (m, 2H), 2.05 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126
MHz, DMSO-d6): δ 164.3, 160.3, 143.2, 142.7, 135.6, 131.5, 127.5, 126.7, 120.2, 114.2, 61.0,
+
16.3, 14.1; LRMS (ESI): m/z 257.1 [M + H]+; HRMS (ESI): calculated for C15H17N2O2 [M +
H]+: 257.1285, found: 257.1284.
Ethyl
1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-
carbimidate (5c). Light yellow oil (220 mg, 24%); 1H NMR (500 MHz, CDCl3): δ 7.66 (d, J =
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8.0 Hz, 1H), 7.58 (s, 1H), 7.44-7.42 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 6.99-6.95 (m, 2H),
5.15 (dd, J = 23.0, 12.5 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 2.26–2.23 (m, 2H), 2.20–2.16 (m,
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2H), 2.14 (s, 6H), 1.52-1.43 (m, 1H), 1.40 (t, J = 7.5 Hz, 3H), 1.36-1.27 (m, 1H); C{1H}
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NMR (126 MHz, CDCl3): δ 166.9, 162.0 (d, J = 246.1 Hz), 147.0, 140.6 (d, J = 3.4 Hz),
139.7, 133.0, 126.9 (d, J = 7.9 Hz), 126.6, 121.9, 119.9, 115.2 (d, J = 21.3 Hz), 90.9 , 71.8,
61.9, 59.6, 45.3, 39.2, 22.2, 14.3; 19F NMR (471 MHz, CDCl3): δ -116.04; LRMS (ESI): m/z
+
371.1 [M + H]+; HRMS (ESI): calculated for C22H28FN2O2 [M + H]+: 371.2129, found:
371.2136.
General Procedure for the Preparation of Substrate 2 (2a-2l). Compound 2 was
synthesized starting from (2-ethynylphenyl)methanols21 according to a reported literature.22
To a two-neck round bottom flask was successively added (2-ethynylphenyl)methanols (5.0
mmol, 1.0 equiv), CuBr (0.5 mmol, 0.1 equiv) and NEt3 (10.0 mmol, 2.0 equiv) in anhydrous
MeCN (50 mL, 0.1 M). The mixture was evacuated and refilled with Ar for 3 times. To the
resulting mixture was slowly added p-toluenesulfonyl azide (75% in EA solution, 11.0 mmol,
2.2 equiv) over 10 min under Ar and the reaction was processed under room temperature for
4-6 h. Then the mixture was filtered through a pad of celite which was subsequently washed
wish CH2Cl2 (30 mL x 3). The combined organic layer was washed wish saturated NaHCO3
solution, dried over anhydrous Na2SO4 and removed under reduced pressure. The crude
residue was purified by flash chromatography eluting with Hexane/EA/CH2Cl2 = 5:1:2 to get
the desired product as a yellow solid. Compounds 2a, 2c-2e, 2g-2j, and 2l are known
compounds whose spectroscopic and physical data were completely matched with the
characterization data from the literature.22
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N-(4-diazo-7-methylisochroman-3-ylidene)-4-methylbenzenesulfonamide (2b). Yellow
solid (460 mg, 28% yield); m.p. 138.6-139.4 °C; 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J =
8.4 Hz, 2H), 7.28-7.26 (m, 2H), 7.19-7.16 (m, 1H), 6.96 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H),
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5.26 (s, 2H), 2.41 (s, 3H), 2.33 (s, 3H); C{1H} NMR (151 MHz, CDCl3): δ 164.1, 143.6,
143.1, 139.4, 136.6, 130.4, 129.8, 129.3, 127.4, 126.6, 125.6, 124.6, 118.9, 117.4, 71.4, 21.7,
21.2; LRMS (ESI): m/z 342.1 [M + H]+; HRMS (ESI): calculated for C17H16N3O3S+ [M + H]+:
342.0907, found: 342.0909.
N-(4-diazo-7-nitroisochroman-3-ylidene)-4-methylbenzenesulfonamide (2f). Yellow
solid (370 mg, 32% yield); m.p. 172.0-173.2 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.24 (dd,
J = 8.4, 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz,
1H), 7.38 (d, J = 8.0 Hz, 2H), 5.49 (s, 2H), 2.38 (s, 3H); C{1H} (151 MHz, DMSO-d6): δ
13
162.9, 144.7, 142.9, 139.0, 129.4, 129.3, 129.2, 126.8, 125.6, 125.4, 124.2, 120.9, 120.4, 70.3,
67.1, 21.0; LRMS (ESI): m/z 373.0 [M + H]+; HRMS (ESI): calculated for C16H13N4O5S+ [M
+ H]+: 373.0601, found: 373.0597.
N-(4-Diazo-6-(trifluoromethyl)isochroman-3-ylidene)-4-methylbenzenesulfonamide (2k).
Yellow solid (300 mg, 56% yield); m.p. 151.8-154.3 oC; 1H NMR (500 MHz, CDCl3): δ 7.98
(d, J = 8.5 Hz, 2H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.42-7.37 (m, 3H), 7.37 (s, 1H), 5.46 (s,
2H), 2.53 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 162.3, 143.4, 139.1, 132.3 (q, J = 8.1
Hz), 130.4, 129.4, 128.1, 127.4, 125.7, 125.6 (q, J = 273.4 Hz), 123.1 (q. J = 3.8 Hz), 122.7,
19
115.8 (q, J = 4.0 Hz), 70.7, 21.7; F NMR (471 MHz, CDCl3): δ -63.0; LRMS (ESI): m/z
396.0 [M + H]+; HRMS (ESI): calculated for C17H13F3N3O3S+ [M + H]+: 396.0624, found:
396.0623.
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General Procedure for the Preparation of Compound 3. Substrate 2 (0.3 mmol, 1.5
equiv), [Cp*RhCl2]2 (0.02 mmol, 12.4 mg, 0.1 equiv), AgOPiv (0.04 mmol, 8.4 mg, 0.2
equiv) were mixed in a Shlenk tube and to this mixture was added 1 (0.2 mmol, 1.0 equiv) in
HFIP (2.0 mL, 0.1 M). The resulting mixture was filled with Ar and stirred at ambient
temperature for 2 h. Upon completion of the reaction, the mixture was filtered through a pad
of celite and washed with CH2Cl2 (10 mL x 3). The combined organic layer was concentrated
under reduced pressure and the crude residue was purified by silica gel chromatography to
give the desired product 3.
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8-Ethoxy-5H-isochromeno[3,4-c]isoquinoline (3aa). White solid (51.6 mg, 93% yield);
1
m.p. 94.8-96.2 °C; H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 8.4 Hz, 1H), 8.21 (d, J =
8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.81-7.78 (m, 1H), 7.52-7.48 (m, 1H), 7.46-7.41 (m,
2H), 7.33 (t, J = 7.6 Hz, 1H), 5.16 (s, 2H), 4.51 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H); 13C{1H}
NMR (126 MHz, DMSO-d6): δ 159.9, 157.2, 135.5, 131.9, 131.4, 129.7, 128.3, 126.5, 125.4,
124.6, 124.5, 124.4, 123.2, 116.6, 102.0, 68.7, 62.4, 14.3; LRMS (ESI): m/z 278.2 [M + H]+;
+
HRMS (ESI): calculated for C18H16NO2 [M + H]+: 278.1176, found: 278.1177.
8-Ethoxy-11-methyl-5H-isochromeno[3,4-c]isoquinoline (3ba).White solid (49.0mg,
84% yield); m.p. 82.8-84.1 °C; 1H NMR (500 MHz, CDCl3): δ 8.20-8.18 (m, 2H), 7.92 (d, J =
7.5 Hz, 1H), 7.45-7.40 (m, 1H), 7.29-7.28 (m, 2H), 7.25(dd, J = 8.5, 1.5 Hz, 1H), 5.17 (s,
2H), 4.60 (q, J = 7.0 Hz, 2H), 2.55 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz,
CDCl3): δ 160.9, 157.8, 141.8, 136.7, 131.5, 130.9, 128.3, 126.3, 126.1, 125.3, 125.2, 124.8,
122.9, 115.9, 102.2, 69.8, 62.8, 22.5, 14.7; LRMS (ESI): m/z 292.2 [M + H]+; HRMS (ESI):
+
calculated for C19H18NO2 [M + H]+: 292.1332, found: 292.1328.
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11-Tert-butyl-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3ca). Colorless oil (56.7
mg, 85% yield); 1H NMR (500 MHz, CDCl3): δ 8.39 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 9.0 Hz,
1H), 7.92 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.30-7.29 (m,
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2H), 5.18 (s, 2H), 4.61 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H), 1.44 (s, 9H); C{1H}
NMR (126 MHz, CDCl3): δ 160.9, 157.8, 154.6, 136.5, 131.6, 131.1, 128.4, 126.3, 125.4,
125.0, 124.7, 122.8, 119.1, 115.8, 102.8, 69.9, 62.8, 35.6, 31.3, 14.7; LRMS (ESI): m/z 334.3
[M + H]+; HRMS (ESI): calculated for C22H24NO2 [M + H]+: 334.1802, found: 334.1804.
+
8-Ethoxy-11-phenyl-5H-isochromeno[3,4-c]isoquinoline (3da): White solid (59.4 mg,
84% yield); m.p. 133.0-134.2 °C; 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H), 8.37 (d, J = 8.5
Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.51 (t, J
= 7.5 Hz, 2H), 7.43 (t, J = 8.5 Hz, 2H), 7.31-7.28 (m, 2H), 5.21 (s, 2H), 4.64 (q, J = 7.0 Hz,
2H), 1.54 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 160.9, 157.9, 144.0, 140.8,
136.7, 131.4, 130.7, 129.0, 128.4, 128.1, 127.6, 126.3, 125.8, 125.3, 124.8, 123.7, 121.6,
116.6, 102.7, 69.8, 62.9, 14.6; LRMS (ESI): m/z 354.2 [M + H]+; HRMS (ESI): calculated for
+
C24H20NO2 [M + H]+: 354.1489, found: 354.1495.
8-Ethoxy-11-methoxy-5H-isochromeno[3,4-c]isoquinoline (3ea). White solid (60.2 mg,
1
98% yield); m.p. 161.2-161.6 °C; H NMR (500 MHz, CDCl3): δ 8.20 (d, J = 9.0 Hz, 1H),
7.95 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.31 – 7.28 (m, 2H),
7.04 (dd, J = 9.0, 2.0 Hz, 1H), 5.17 (s, 2H), 4.58 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 1.49 (t, J =
7.0 Hz, 3H); C{1H} NMR (126 MHz, CDCl3): δ 162.3, 160.9, 158.4, 138.4, 131.5, 131.1,
13
128.4, 127.1, 126.2, 125.4, 124.1, 115.4, 112.5, 103.5, 102.2, 69.8, 62.7, 55.5, 14.7; LRMS
(ESI): m/z 308.2 [M + H]+; HRMS (ESI): calculated for C19H18NO3 [M + H]+: 308.1281,
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found: 308.1274.
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8-Ethoxy-N, N-dimethyl-5H-isochromeno[3,4-c]isoquinolin-11-amine (3fa). White solid
8
9
1
(50.0 mg, 78% yield); m.p. 116.1-118.2 °C; H NMR (600 MHz, CDCl3): δ 8.15 (d, J = 9.0
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Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.42-7.40 (m, 1H), 7.31-7.27 (m, 2H), 6.97
(dd, J = 9.6, 2.4 Hz, 1H), 5.17 (s, 2H), 4.59 (q, J = 7.2 Hz, 2H), 3.14 (s, 6H), 1.51 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 161.0, 158.3, 152.3, 138.2, 131.6, 131.4, 128.1,
126.4, 125.7, 125.2, 123.8, 112.4, 109.4, 102.1, 101.3, 69.7, 62.4, 40.5, 14.8; LRMS (ESI):
m/z 321.2 [M + H]+; HRMS (ESI): calculated for C20H21N2O2 [M + H]+: 321.1598, found:
+
321.1611.
8-Ethoxy-11-fluoro-5H-isochromeno[3,4-c]isoquinoline (3ga). White solid (53.2 mg,
1
90% yield); m.p. 131.2-132.6 °C; H NMR (500 MHz, CDCl3): δ 8.31 (dd, J = 9.0, 6.0 Hz,
1H), 8.02 (dd, J = 11.5, 2.5 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.44-7.41 (m, 1H), 7.32-7.28
(m, 2H), 7.17-7.13 (m, 1H), 5.18 (s, 2H), 4.60 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3): δ 165 (d, J = 251.1 Hz ), 160.9, 158.6, 138.2 (d, J = 10.6
Hz), 131.3, 130.4, 128.6, 128.4 (d, J = 10.2 Hz ), 126.7, 125.4, 124.3, 114.7, 113.8 (d, J =
19
24.8 Hz), 108.0 (d, J = 23.3 Hz ), 102.5 (d, J = 4.3 Hz ), 69.9, 63.1, 14.6; F NMR (471
MHz, CDCl3): δ -106.9; LRMS (ESI): m/z 296.2 [M + H]+; HRMS (ESI): calculated for
+
C18H15FNO2 [M + H]+: 296.1081, found: 296.1080.
11-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3ha). White solid (54.8 mg,
1
88% yield); m.p. 146.2-147.3 °C; H NMR (500 MHz, CDCl3): δ 8.37 (d, J = 2.0 Hz, 1H),
8.22 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.35 (dd, J = 8.5, 2.0
Hz, 1H), 7.32-7.28 (m, 2H), 5.18 (s, 2H), 4.60 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H);
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13C{1H} NMR (126 MHz, CDCl3): δ 160.9, 158.5, 138.2, 137.3, 131.4, 130.2, 128.6, 127.1,
126.7, 125.4, 124.9, 124.6, 122.8, 116.0, 102.1, 69.9, 63.2, 14.6; LRMS (ESI): m/z 312.2 [M
7
8
9
+ H]+; HRMS (ESI): calculated for C18H15ClNO2 [M + H]+: 312.0786, found: 312.0781.
+
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11-bromo-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3ia). White solid (62 mg, 87%
yield); m.p. 137.9-139.2 °C; 1H NMR (500 MHz, CDCl3): δ 8.55 (d, J = 1.5 Hz, 1H), 8.15 (d,
J = 9.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.49 (dd, J = 9.0, 2.0 Hz, 1H), 7.46-7.43 (m, 1H),
13
7.33-7.28 (m, 2H), 5.18 (s, 2H), 4.59 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H); C{1H}
NMR (126 MHz, CDCl3): δ 161.0, 158.4, 137.6, 131.4, 130.2, 128.7, 127.5, 127.0, 126.9,
126.8, 126.0, 125.4, 124.6, 116.2, 102.0, 69.9, 63.2, 14.6; LRMS (ESI): m/z 356.2 [M + H]+;
+
HRMS (ESI): calculated for C18H15BrNO2 [M + H]+: 356.0281, found: 356.0280.
8-Ethoxy-11-iodo-5H-isochromeno[3,4-c]isoquinoline (3ja). White solid (62.8 mg, 78%
yield); m.p. 121.4-122.3 °C; 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 7.98 (d, J = 8.5 Hz,
1H), 7.82 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.33-7.28 (m, 2H),
13
5.17 (s, 2H), 4.59 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H); C{1H} NMR (126 MHz,
CDCl3): δ 161.1, 158.1, 137.7, 132.9, 132.5, 131.4, 130.1, 128.7, 126.7, 125.4, 124.7, 116.5,
101.6, 99.6, 69.9, 63.2, 14.6; LRMS (ESI): m/z 404.1 [M + H]+; HRMS (ESI): calculated for
+
C18H15INO2 [M + H]+: 404.0142, found: 404.0150.
8-Ethoxy-11-(trifluoromethyl)-5H-isochromeno[3,4-c]isoquinoline (3ka). White solid
(67.0 mg, 97% yield); m.p. 161.4-161.9 °C; 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H), 8.41
(d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 9.0, 2.0 Hz, 1H), 7.48-7.45 (m,
1H), 7.35-7.30 (m, 2H), 5.21 (s, 2H), 4.63 (q, J = 7.0 Hz, 2H), 1.53 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3): δ 160.6, 158.4, 135.6, 132.8 (q, J = 32.1 Hz), 131.3,
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129.8, 128.7, 126.9, 126.5, 125.4, 124.5, 124.1 (q, J = 273.4 Hz), 121.0 (q, J = 4.7 Hz),
119.70 (q, J = 3.3 Hz), 118.9, 103.0, 69.8, 63.2, 14.4; 19F NMR (471 MHz, CDCl3): δ -62.89;
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LRMS (ESI): m/z 346.2 [M + H]+; HRMS (ESI): calculated for C19H15F3NO2 [M + H]+:
+
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346.1049, found: 346.1046.
8-Ethoxy-9-fluoro-5H-isochromeno[3,4-c]isoquinoline (3la). White solid (42.0 mg, 71%
yield); m.p. 153.3-154.2 °C; 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J = 8.0 Hz, 1H), 7.86 (d,
J = 8.0 Hz, 1H), 7.58 (td, J = 8.0, 5.5 Hz, 1H), 7.43-7.39 (m, 1H), 7.32-7.28 (m, 2H), 7.05
(ddd, J = 11.6, 8.0, 1.0 Hz, 1H), 5.18 (s, 2H), 4.61 (q, J = 7.0 Hz, 2H), 1.51 (t, J = 7.0 Hz,
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3H); C{1H} NMR (126 MHz, CDCl3): δ 161.6, 160.2 (d, J = 5.7 Hz), 158.7 (d, J = 209.4
Hz) , 139.1, 131.7 (d, J = 9.6 Hz), 131.5, 130.5, 128.4, 126.7, 125.4, 124.9, 119.4 (d, J = 4.5
Hz), 110.2 (d, J = 21.9 Hz), 108.2 (d, J = 11.7 Hz), 102.2 (d, J = 2.9 Hz), 69.9, 63.3, 14.6; 19F
NMR (471 MHz, CDCl3): δ -107.2 (d, J = 5.7 Hz); LRMS (ESI): m/z 296.2 [M + H]+; HRMS
(ESI): calculated for C18H15FNO2 [M + H]+: 296.1081, found: 296.1080.
+
8-Ethoxy-10-methoxy-5H-isochromeno[3,4-c]isoquinoline(3ma) and 8-ethoxy-12-metho-
1
xy-5H-isochromeno[3,4-c]isoquinoline (3ma’). Colorless oil (59.0 mg, 96% yield); H NMR
(500 MHz, CDCl3) selected signals for 3ma: δ 8.33 (d, J = 9.5 Hz, 1H), 7.86 (d, J = 7.5 Hz,
1H), 7.59 (d, J = 2.5 Hz, 1H), 7.30-7.28 (m, 3H), 7.12 (d, J = 7.5 Hz, 1H), 5.19 (s, 2H), 4.62
(q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H); selected signals for 3ma’: δ 7.93 (d,
J = 8.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.22-7.20 (m, 3H), 5.17 (s, 2H), 4.59 (q, J = 7.0 Hz, 2H),
3.96 (s, 3H), 1.52 (t, J = 7.0 Hz, 3H); C{1H} NMR (126 MHz, CDCl3) for the mixtures: δ
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161.7, 159.8, 158.7, 156.4, 156.2, 154.9, 131.9, 131.7, 131.5, 130.8, 129.3, 128.3, 128.2,
127.8, 126.9, 126.4, 125.4, 125.3, 125.2, 124.9, 124.6, 124.0, 123.4, 119.6, 118.7, 117.3,
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