Diversity-Oriented Synthesis of Highly Fluorescent Fused Isoquinolines for Specific Subcellular Localization

Article abstract of DOI:10.1021/acs.joc.9b02712

A multicomponent diversity-oriented synthesis of new highly emissive tetracyclic isoquinolines that target specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi four-component reaction, followed by either an intramolecular alkyne hydroarylation and subsequent alkene isomerization or through a Pomeranz-Fritsch-type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of these compounds using green channel confocal microscopy revealed remarkable and distinctive distribution patterns in live cells, showing an unprecedented high selectivity and imaging contrast. The differentiated organelle visualization - including localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum, and plasma membrane - was achieved by varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting Ugi reaction.

Full text of DOI:10.1021/acs.joc.9b02712

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Article
Diversity-Oriented Synthesis of Highly Fluorescent Fused-
isoquinolines for Specific Subcellular Localization.
Yoarhy A. Amador-Sánchez, Andres Aguilar-Granda, Ricardo Flores-Cruz, Davir González-
Calderón, Cynthia Orta, Braulio Rodríguez-Molina, Arturo Jiménez-Sánchez, and Luis D. Miranda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02712 • Publication Date (Web): 12 Dec 2019
Downloaded from pubs.acs.org on December 13, 2019
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Page 1 of 21
The Journal of Organic Chemistry
Diversity-Oriented Synthesis of Highly Fluorescent Fused-isoquinolines
for Specific Subcellular Localization.
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Yoarhy A. Amador-Sánchez, Andrés Aguilar-Granda, Ricardo Flores-Cruz, Davir González-
Calderón, Cynthia Orta, Braulio Rodríguez-Molina, Arturo Jiménez-Sánchez* and Luis D. Miranda*.
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Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán,
Ciudad de México. 04510, México
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ABSTRACT: A multicomponent Diversity-Oriented Synthesis of new highly emissive tetracyclic isoquinolines that target
specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi four-
component reaction, followed by either an intramolecular alkyne hydro-arylation and subsequent alkene isomerization, or
through a Pomeranz–Fritsch type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of
these compounds using green-channel confocal microscopy revealed remarkable and distinctive distribution patterns in live
cells, showing an unprecedent high selectivity and imaging contrast. The differentiated organelle visualization including
localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum and plasma membrane was achieved by
varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting
Ugi reaction.
INTRODUCTION.
organelle localizations requires innovative synthetic
approaches. In this regard, the Diversity-Oriented Synthesis
(DOS)7 has emerged as a powerful approach for the
construction of compound libraries with diverse molecular
architectures.
Small-molecule fluorescent probes with different organelle
localization abilities have remarkable interest in biological
applications.1 Numerous biological assays and new
experimental techniques have been developed to monitor
the output profiles of these fluorescent probes. They span
from single-channel fluorescence intensity recordings to
single-molecule localization methods.2 Ideally, those
molecular probes should be of low molecular weight, high
photostability and high brightness, so that good signal-to-
noise ratios and short acquisition times can be achieved.
Importantly, the probes should lack of fluorescence
intensity fluctuations due to spectral diffusion or triplet and
rotational jumps.3 These properties acquire significant
relevance in the rational design of subcellular fluorescent
probes where highly heterogeneous environments can
influence the probe response profile, as well as its spatial
distribution within the cell. Although some strategies to
achieve specific subcellular localizations have been
demonstrated,4 the synthetic methods to obtain single
organelle-targeted probes are still very scarce. Diversified
fluorogenic probes with distinctive molecular structures
are highly needed to monitor different subcellular
membranes and the dynamics of local biomolecular events
thus understanding the cell status in health and disease.
Most of the recent molecular fluorescent probes are based
on the same relatively small set of sometimes expensive
fluorophores such as Mitotracker® dyes (cyanines)
Lysotracker® dyes (BODIPY’s), AlexaFluorTM dyes
(xanthenes) and Atto® dyes (carbopyronines) (Figure 1).5
Thanks to the new technologies to study the different
subcellular organelles based on optical microscopy
techniques, the synthesis of novel fluorescent markers
suitable for site-specific intracellular labeling remains an
unmet need.6 Considering that the structure and function of
the cell organelles is highly diverse in nature, developing a
single synthetic route that can afford structurally fine-tuned
probes with distinct optical responses, cytotoxicity and
lifetimes is a very challenging task. Designing such a family
of subcellular probes that share a skeleton and at the same
time are able to show structural variations for different
Rylene Dyes
Cyanine Dyes
O
R
O
Bodipy Dyes
R
O
R
N
O
N
R
N
R
R
I
Cy3
N
O
R
B
N
F
F
O
N
N
N
R
O
R
Cy5
COOH
R
Bodipy R6G
I
O
1
2
Peryline-dimide
3
Xanthene Dyes
O
Carbopyronine Dyes
R
R
Oxazine dyes
O
N
N
N
N
COOH
N
R
O
N
R
MR 121
4
Fluorescein
Rhodamine
Atto 647N
6
5
Figure 1. Different fluorophore families (top labels) with
commercially available fluorescent probes (bottom labels)
used in optical microscopy techniques.
Using this strategy, the molecular structure can be
significantly modified, either by varying the peripheral
functional groups or by producing large skeletal changes,
and is
a very promising platform for the efficient
exploration of the chemical space.8 Indeed, these
approaches produce a range of compounds that allow to
investigate their influence in different biological systems,
mainly for the discovery of new medicinal leads.9 However,
DOS-strategies for the discovery of novel molecular
materials for other applications have been explored to a
much lesser extent. Recently, as a part of our ongoing
program in the Diversity-Oriented Synthesis of different
heterocyclic scaffolds,10 we envisioned that the modular
nature of the Ugi four component reaction (Ugi-4CR) might
offer the unique opportunity to design novel and expedient
methods for the synthesis of complex fluorescent scaffolds.
In principle by the judicious choice of the starting four-
component input set, the photophysical properties of the
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The Journal of Organic Chemistry
Page 2 of 21
final structure might be rapidly fine-tuned for different one of the two key amines (9a or 9b), an electron rich
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7
8
applications. It is important to note that the chemical
complexity increased when the Ugi-4CR adducts engage in
further bond forming processes.11 Based on this, we became
interested in the synthesis of a small library of the
conjugated tetracyclic fused isoquinolines 13 (Scheme 1).
benzaldehyde (10a-b) and isocyanides with various
electronic and steric demands (8a-k) reacted in methanol
at room temperature in an open flask to give the
Scheme 2. Synthesis of isoquinolines 12a-y through
hydroarylation/isomerization protocol (path a), or
Pomeranz-Fritsch type cyclization (path b).
Scheme 1. General synthetic approach for the scaffold
diversity generation of highly fluorescent fused-
isoquinolines.
R2
R2
R3
O
NH
R3
path b
O
O
N
NH
Het
X
O
p-TsOH 0.5 equiv.
acetone, 50 °C, 5 h
Het
X
OMe
R1
R3
N
OMe
R1
9
R2
O
n= 0,1
R2
R4
11a-z
n= 0,1
R4= CH(OMe)2
Het
N
10
11
12
13
14
15
16
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60
Ugi-4CR R3
O
N
NH
C
OH
8a-k
OMe
C
7a-h
O
n= 0,1
R5 OMe
Het
X
X
Methanol
48 h. r. t.
36-90%
OMe
R1
12a-y
X = I, Br
Aryl or heteroaryl
R1 = OMe, H
n= 0,1
X= I, Br
OMe
R1
R4
11a-z
R1 = OMe, H
R5= Me, H
Pivotal
O
R4= -CH(OMe)2 or
CH
NH2
NH2
9a
OMe
OMe
or
OMe
2) p-TsOH 0.5 equiv.
MeOH, 40 °C, overnight
X = I, Br
path a
9b
dihydroisoquinolines
MeO
R1 = OMe, H
10a-c
R4= -CH(OMe)2 or
1) JohnPhosAu(MeCN)SbF6
5%mol
C
CH
C
CH
CHCl3. r.t. 2.5 h.
n= 0,1 Cyclization
Au
P
N
C
CH3
R2
t-Bu
t-Bu
R2
R3
SbF6
R2
O
NH
O
R3
O
NH
Het
O
N
NH
O
OMe
R1
O
Het
X
N
OMe
R1
JohnPhosAu(MeCN)SbF6
OMe
R1
n= 0,1
(H2C)
N
X
n
Pd
n= 0,1
n= 0,1
OMe
Het
R5 OMe
R5 OMe
exo-12a
Not isolated
R3
13
12
X= I, Br
R1 = OMe, H
R5= Me, H
R1= OMe, H
R5= Me, H.
corresponding Ugi propargylic or acetamido adducts 11a-z
(36-90%, Scheme 2). Several diversification vectors were
secured in the protocol. In principle, not only the peripheric
functional groups can be varied, the nature and size of the
(hetero)aromatic systems, might be modulated in the final
scaffolds by the simple variation of the carboxylic acid,
isocyanide and aldehyde. Once the propargyl- and
dimethylacetamido-adducts 11a-z were obtained, the
intramolecular alkyne hydro-arylation/isomerization or
Pomeranz–Fritsch condensation were conducted. In the
case of the propargyl-Ugi adducts 11a-r, we found that the
catalytic use of the JohnPhosAu(MeCN)SbF6 (5 mol%) in
chloroform resulted in the complete transformation to the
corresponding tetrahydroisoquinoline exo-12a. It is worth
mentioning that the use of an electron rich benzaldehyde is
mandatory for the cycloisomerization to have an acceptable
reaction rate. We found that the reaction of the crude exo-
12a-r products with 0.5 equiv. of p-toluenesulfonic acid in
methanol completely equilibrated the product to the endo
isomers; which gave the targeted isoquinolines (endo-12a-
r) (yields 33-96%, Scheme 2, path a). In the case of the
dimethylacetamido-Ugi adducts 11s-z, the treatment with
0.5 equiv. of p-TsOH in acetone enabled the cyclization to
the desired isoquinolines 12s-y in good reaction yields
ranging from 70% to 80% (Scheme 2, path b). Interestingly,
we observed that the compound 11z (from 2,5-
dimethoxybenzaldehyde as the starting aldehyde)
exclusively afforded the ketopirazinone 14 which was
formed by the acetal deprotection reaction of 11z in acid
media followed by the intramolecular nucleophilic attack of
the primary amide moiety. At this point, the
dihydroisoquinolines 12a-y were directly submitted to
Heck ring closing conditions,13 to afford the densely
functionalized fused-isoquinoline fluorophores 13 in good
yields (Table 1). Starting from 2-iodophenylacetic acid (7b)
in this approach, it was possible to obtain fused
isoquinolinone-isoquinolines (13a-c, 13t and 13x)
Consequently, a three-step protocol was devised starting
with an Ugi-4CR (component input set: 2-halobenzoic or
phenylacetic acids, substituted benzaldehydes, different
isocyanides and 9a or 9b as amine input). With these
frameworks in hand, either an intramolecular alkyne hydro-
arylation followed by an alkene isomerization (exo→endo),
or a Pomeranz–Fritsch type cyclization were carried out to
assemble isoquinolines 12. The final event relied on the
intramolecular Heck reaction to afford the fused-
isoquinolines 13 (Scheme 1). Gratifyingly, we discovered
that the all final compounds were highly fluorescent and
decide to investigate further. Thus, a wide array of
molecular candidates was rapidly obtained to ascertain
their fluorescent properties and their potential as selective
biological localizers for the various cell organelles. As the
ultimate success of any molecule library is determined by
the biological relevance of the compounds,12 it is crucial that
the implemented synthetic sequence warrants an optimal
functionalization strategy. In this regard, our synthetic
protocol subsequently provided access to molecules with
chemical vectors to target a desired cellular organelle,
therefore combining the goals of DOS with the advantages
of organelle-targeting functionalization, which aims to
access a precise structural unit for a specific organelle. The
fluorescence response efficiency, partition coefficient and
subcellular localization for each compound was also
correlated, finding excellent fluorescent localizers for
mitochondria, lysosomes, Golgi apparatus, endoplasmic
reticulum and plasma membrane.
RESULTS AND DISCUSSION
Diversity-Oriented Synthesis of highly emissive
fluorophores. The synthesis of the multicomponent Ugi-
adducts 11 was carried out through an equimolar mixture
of the corresponding carboxylic halo-(hetero)arene (7a-h),
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The Journal of Organic Chemistry
Table 1. Multicomponent sequence and Pd-catalyzed ring closing for the Diversity-Oriented Synthesis of isoquinolines 13a-
y. Inset: obtained tricyclic compound 15 via Heck reaction of compound 14.
1
2
3
4
5
6
7
R2
R2
R3
R2
R3
R2
O
O
N
NH
O
NH
Pd(OAc)2 20 mol%
Cy3P.HBF4 40 mol%
Cs2CO3 (2.5 equiv.)
R3
O
N
NH
O
O
n
Het
N
Het
X
O
C
OH
n= 0,1
Hydroarylation/isomerization
protocol (path a)
Het
X
OMe
R1
OMe
R1
8a-k
Ugi-4CR
7a-h
OMe
R1
N
(H2C)
X
Methanol
n= 0,1
n= 0,1
toluene MW, 2.5 h, 135 ºC
Pomeranz-Fritsch type cyclization
(path b)
Aryl or heteroaryl
R4
Het
48 h. r. t.
R5 OMe
R5 OMe
OMe
R1
O
OMe
NH2
11a-z
X = I, Br
R1 = OMe, H
R4= -CH(OMe)2 or
NH2
12a-y
R3
13a-y
OMe
X= I, Br
or
R1= OMe, H
R5= Me, H
9a
OMe
10a-c
9b
R1 = OMe, H
R5= Me, H
MeO
C
CH
8
9
O
N
NH
O
N
NH
O
N
NH
O
O
NH
O
O
O
N
NH
O
O
N
NH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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60
OMe
O
OMe
OMe
O
OMe
OMe
OMe
OMe
OMe
OMe
N
OMe
13a 62%a
OMe
13b 56%a
OMe
13c 53%a
OMe
13f 59%a
OMe
13d 54%a
OMe
13e 51%a
From: 7a = 2-iodophenylacetic acid,
8a = R2 = t-Bu, 9a, 10a = R1 = H
From: 7a = 2-iodophenylacetic acid,
8a = R2 = t-Bu, 9a, 10b = R1 = OMe
From: 7a = 2-iodophenylacetic acid,
8b = R2 = Cp, 9a, 10b = R1 = OMe
From: 7b = 2-iodobenzoic acid,
From: 7b = 2-iodobenzoic acid,
8d = R2 = Bn, 9a, 10a = R1 = H
[11e 52%b, 12e 87%c
From: 7b = 2-iodobenzoic acid,
8a = R2 = t-Bu, 9a, 10a = R1 = H
[11f 58%b, 12f 90%c
]
CCDC Number: 1922627
8c = R2 = Cy, 9a, 10b = R1 = OMe
(X-ray)d
[11a 60%b, 12a 83%c
]
[11b 63%b, 12b 93%c
]
[11c 57%b, 12c 91%c
]
[11d 90%b,12d 84%c
]
]
O
O
NH
O
N
NH
O
N
NH
O
O
O
N
NH
OMe
OMe
OMe
OMe
O
N
OMe
OMe
OMe
OMe
13h 53%a
OMe
13i 65%a
Cl
F
OMe
13g 47%a
13j 69%a
CCDC Number: 1922628
From: 7b = 2-iodophenilacetic acid,
8a = R2 = t-Bu, 9a, 10b = R1 = OMe
CCDC Number: 1583874
From: 7c = 4-chloro-2-iodo-benzoic acid, From: 7d = 4-fluoro-2-iodo-benzoic acid
From: 7b = 2-iodobenzoic acid,
8e = R2 = Naph, 9a, 10a = R1 = H
8f = R2 = Ph, 9a, 10a = R1 = H
[11i 83%b,12i 96%c
8d = R2 = Bn, 9a, 10b = R1 = OMe
(X-ray)d
(X-ray)d
[11h 65%b,12h 90%c
]
]
[11j 50%b, 12j 90%c
]
[11g 33%b, 12g 66%c
]
O
Bn
O
O
N
NH
O
N
NH
O
N
NH
O
N
NH
O
NH
O
N
NH
O
O
O
N
NH
O
N
O
O
O
OMe
O
OMe

OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
N
OMe
OMe
OMe
OMe
Cl
OMe
S
OMe
O
O
OMe
OMe
13m 28%a
OMe
13o 51%a
7e = 2-bromofuran-3-carboxylic
OMe
13l 45%a
a
a
a
13q
84%
13k 42%a
13n
54%
13p
59%
From: 7b = 2-iodobenzoic acid,
7b
7e
From:
7f
From: 7g = 2-bromo-5-chloronicotinic
From:
= 2-iodobenzoic acid,
8i = R2 = L-alanine ethyl ester,
= R1 = OMe
[11m 43%b, 12m 41%c
From:
= 2-bromofuran-3-carboxylic
acid 8c = R2 = Cy, 9a, 10b = R1 = OMe
From: = 2-bromo-3-thiophenecarboxylic
acid 8a = R2 = t-Bu, 9a, 10b = R1 = OMe
From: 7b = 2-iodobenzoic acid,
8g = R2 = Docecyl, 9a, 10b = R1
OMe
8h = R2 = Octyl, 9a, 10b = R1 = OMe
acid 8c = R2 = Cy, 9a, 10a = R1 = H
8c
9a 10b
= R1 = OMe
2
acid
= R = Cy,
,
=
[11l 36%b, 12l 63%c
]
9a 10b
11n
12n
[
11o 59%b, 12o 93%c
]
11p
12p
[11q 70%b, 12q 75%c
]
b
c
b
c
76% ]
,
[
90%
,
23%
]
[
89%
,
[11k 43%b,12k 67%c
]
]
OMe
O
N
NH
O
N
NH
O
N
NH
O
N
NH
O
N
NH
O
O
N
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
O
OMe
OMe
13t 88%a
From: 7a = 2-iodophenylacetic acid,
8j = R2 = p-OMePh, 9b, 10b = R1 = OMe acid 8a = R2 = t-Bu, 9b, 10b = R1 = OMe
[11t 50%b, 12t 70%c [11u 54%b, 12u 70%c
S
OMe
a
OMe
13u 50%a
From: 7e = 2-bromofuran-3-carboxylic
OMe
13v 25%a
a
13r 42%
13s
90%
From: 7h= 2-bromonicotinic acid
8a = R2 = t-Bu, 9a, 10b = R1 = OMe
CCDC Number: 1922629
From: 7b = 2-iodobenzoic acid,
8a = R2 = t-Bu, 9b, 10b = R1 = OMe
CCDC Number: 1922630
From: 7f = 2-bromo-3-thiophenecarboxylic
acid 8a = R2 = t-Bu, 9b, 10b = R1 = OMe
(X-ray)d
(X-ray)d
[11r 79%b, 12r 60%
]
[11s 78%b, 12s 80%
]
c
c
]
]
[11v 87%b, 12v 87%c
]
MeO
O
MeO
N
O
N
NH
I
O
N
NH
O
O
NH
O
Pd(OAc)2 20 mol%
Cy3P.HBF4 40 mol%
Cs2CO3 (2.5 equiv.)
O
N
O
O
N
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
N
N
O
O
toluene MW, 2.5 h, 135 ºC
N
N
OMe
OMe
OMe
N
N
a
a
a
13w 19%
13x 88%
13y 19%
From: 7b = 2-iodobenzoic acid,
8k = R2 = -CH2CH2-Morph, 9b,
10c = 2,5-dimethoxybenzaldehyde
O
O
CCDC Number: 1922631
15e 88 %
From: 7h = 2-bromonicotinic acid
8a = R2 = t-Bu, 9b, 10b = R1 = OMe
From: 7a = 2-iodophenylacetic acid,
8h = R2 = Octyl, 9b, 10b = R1 = OMe
From: 7b = 2-iodobenzoic acid,
14
[11y 37%b, 12y 65%
(X-ray)d
8k = R2 = -CH2CH2-Morph, 9b, 10b = R1 = OMe
c
]
[11w 64%b, 12w 74%
]
[11x 37%b, 12x 65%
]
[11y 37%b, 12y 65%
]
c
c
c
a Isolated yield of the Heck ring closing event. b Isolated yield of the Ugi-4CR, c Isolated yield of the cyclization reactions,
d
Thermal ellipsoids are drawn at 50% probability, all hydrogen atoms are omitted for clarity purposes.15e The tricyclic
compound 15 was obtained from the ketopirazinone 14. All Heck reactions were carried out by microwave assistance.
in isolated yields ranging from 53 % to 88 %. Fused
isoindolone-isoquinolines (13d-m, 13s, 13y) were also
obtained in comparable isolated yields (28 - 90 %) using 2-
iodobenzoic acids (7a, c and d). The use of 2-bromofuran-
3-carboxylic acid 7e afforded the corresponding furo-
pyrrolone-isoquinolines 13n, 13o and 13u in good isolated
yields (50
bromothiophene-3-carboxylic
corresponding thieno-pyrrolone-isoquinolines 13p and
13v in moderate isolated yields (59 and 25% respectively).
Finally, when 2-bromonicotinic acids (7g-h) were used, we
found that the pyrido-pyrrolone-isoquinolines 13q, 13r
and 13w were obtained in moderate to excellent isolated
yields. Importantly, that halogens such as chloride (13i) and
fluoride (13j) were well tolerated under the Heck
conditions. A range of isocyanides with different electronic
and steric demands such as tert-butyl 8a, cyclopentyl 8b,
cyclohexyl 8c, benzyl 8d, naphthyl 8e and the lipidic
isocyanides 8g-h were also successfully implemented in the
protocol. Finally, the Heck cyclization of ketopirazinone 14
gave the pyrido-pyrrolo-pyperazinone fused tricycle 15 in
excellent yield.
-
54%). Additionally, the use of 2-
acid 7f gave the
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Fluorescence and partition coefficient studies. As were found to be specific for two organelles while 13y,
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mentioned before, the relevance of a molecular library
obtained by DOS is dictated by the visualized application,
which implies that most of the molecules could be
unsuccessful no matter how structurally diverse they are or
how efficiently this diversity has been achieved. Here we
present a new fluorophore architecture having a different
chemical composition. To verify the optical performance of
the molecules, their photophysical properties were
evaluated by spectrophotometric means. Notably, all the
compounds exhibited moderate to high fluorescence
quantum yields (Φfl), ranging from 0.19 to 0.99 (see
supporting information). This indicates that the compounds
can be considered as an efficient fluorophore library,
avoiding auto-fluorescence problems under cell conditions
as demonstrated by spectrally resolved confocal
microscopy experiments (Figure S33). Real-time spectrally
resolved confocal images provided structural information
through the emission spectra of the fluorophore and blank
hydrophilic as well, were derivatized to target lysosomes
using a morpholine-derived group, thus finding a highly
lysosomal distribution (Pearson’s correlation coefficient,
PCC = 0.91). In addition to the log P values, the high
fluorescence quantum yields (Φfl) together with the high
absorption cross-section of the fluorophores indicates
excellent photostability (Figure S34). As shown in Figure 2
(red points) most of the fluorophores presented a highly
efficient radiative deactivation in terms of Φfl thus avoiding
photobleaching. This is an excellent photophysical feature
that provides high signal-to-noise ratio images for large
time-course experiments useful for high-resolution
confocal microscopy techniques.
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Confocal fluorescence imaging studies for organelle
distribution. These experiments were performed in HeLa
cells using the fluorescence profile of the synthetized
fluorophore library. Gratifyingly, compounds 13a-y showed
specific organelle distribution. Among the most interesting
results, fluorophores 13i and 13t were highly specific for
mitochondria, an unexpected finding since both
fluorophores are not cationic (non-Nernstian lipophilic
cations),14 compared to the well-known MitoTrackers,
TMRM, JC-1 or oxonols in general. Although non-cationic
mitochondrial localizers have rarely been described,15 it is
interesting to note that 13i and 13t presented the larger log
P values, and it is possible that such lipophilicity can assist
the mitochondrial targeting, Figure 3 (see Fig. S35) for the
co-localization study). Thus, 13i and 13t fluorophores can
be used for large time-course experiments of mitochondria
when membrane polarization variations can affect the
fluorescence profiles of common Nernstian probes such as
samples
under
subcellular
environments.
MitoTrackers.
Mitochondrial
membrane
potential
depolarization experiments using the common CCCP
uncoupler were carried out to confirm that 13i and 13t are
not of the Nernstian features (Fig. S36).
A
Figure 2. Representation of the experimental partition
coefficients (log P, grey bars) and fluorescence quantum
yields (Φfl, red points) for the fluorophore library. L:
lysosome; PM: plasma membrane; mt: mitochondria; ER:
endoplasmic reticulum; GA: Golgi apparatus and ns: non-
specific localization.
However, to evaluate the performance of these
fluorophores as subcellular fluorescent labels for
bioimaging applications, the partition coefficient in terms of
log P were obtained (Table S2). Due to the structural
diversity presented in this collection, highly diverse
partition coefficients were found, as shown in Figure 2.
Nevertheless, interesting correlations between the degree
of lipophilicity and the membrane localization were
observed. The measured log P values suggest that while
most of the molecules are highly lipophilic, important
differences in their localization pattern can be found, for
example, the most lipophilic fluorophores with log P > 0.8
exhibited a high membrane distribution (13b, 13e, 13i,
13k, 13l, 13p and 13t), and molecules with less lipophilic
character were found to be equilibrated between the lipid
membranes and cytosol as non-organelle specific.
Moreover, the more hydrophilic fluorophores 13d and 13j
B
Figure 3. Intracellular localization redistribution of 5 µM
13t probe in live HeLa cells. Panel (A) shows 30 minutes 13t
incubation observed in the confocal green channel (λexc
405 nm, λem = 450 nm), indicating a clean mitochondrial
localization, while panel (B) shows the distribution in the
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red channel ( λ exc = 561 nm, λ em = 613 nm). Scale bars localization for PM indicated a PCC of 0.87 for 13l and 0.81
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represent 20 µm.
for 13x, Figure S37. Importantly, no significant crosstalk of
the green emission of these fluorophores with the red
channel was observed by using CellMask with excitation
wavelength above 560 nm. Then, the nucleoli distribution
present in the 13x fluorescence profile can be explained not
only by its lower lipophilicity compared to 13l or 13k, but
by structural differences. Although 13x also contains a
hydrocarbon chain and similar polyaromatic composition,
the 6-membered heteroaromatic ring seems to promote
intercalation in the nucleoli probably through RNA grove
interactions. Importantly, no significant crosstalk of the
green emission of these fluorophores with the red channel
was observed by using CellMask with excitation wavelength
above 560 nm. Considering these results, the nucleoli
distribution present in the 13x fluorescence profile can be
explained not only by its lower lipophilicity compared to
13l or 13k, but also by important structural differences.17
Although 13x also contains a hydrocarbon chain and similar
The low-dose experiments confirmed this hypothesis as no
fluorophore release was observed under in vitro imaging
analysis, however, large exposure to CCCP promoted cell
death and thus fluorophore release, indicating that the
mitochondrial distribution of 13i and 13t is not governed
by the membrane potential but a specific interaction
possibly with lipid domains is taking place.16 Further
screening of the library evidenced the localization breadth
of the synthesized fluorescent dyes. Fluorophores 13k, and
13l underwent plasma membrane targeting with PCC of
0.83 and 0.91, respectively (Figure 4). Conversely, Golgi
apparatus (GA) targeting was only observed for 13e. This is
relevant because GA labels are scarcely reported in
literature since it has been considered a “ low-concern ”
organelle,4 thus such commercially available fluorophores
are very uncommon. On the other hand, lysosome targeting
was observed for 13m, 13n, 13o and 13y where a varied
degree of co-localization was found for these compounds.
Endoplasmic reticulum (ER) was efficiently localized by
13v and 13w, while 13d and 13j equilibrate mitochondria
and cytosol having low specificity for one of them.
Fluorophores localizing two organelles were found to be
13a, 13q, 13u and 13x. Finally, co-localization studies for
the rest of the fluorophores indicated non-specific organelle
localization, although membrane distribution was observed
for all of them. Figure 2 summarizes the in vivo subcellular
distribution of the fluorophore library. Two representative
examples of plasma
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polyaromatic
composition,
the
6-membered
heteroaromatic ring seems to promote intercalation in the
nucleoli probably through RNA grove interactions.
Refining the structures by organelle-targeting
functionalization. Given the interesting results obtained
with the DOS strategy, the organelle-targeting
functionalization approach was subsequently employed to
develop fluorophores 13y and 15 as presented in Figure 6.
A
B
Figure 4. Intracellular localization redistribution of 5 µM
13e probe in live HeLa cells under 30 minutes incubation
indicating a high Golgi Apparatus (GA) distribution when
observed in the confocal green (λexc = 405 nm, λem = 450 nm)
red (λexc = 561 nm, λem = 613 nm) channels. The high degree
of overlap in yellow when using CellLight® Golgi-RFP co-
localizer indicates that 13e is GA specific. Scale bars
represent 20 µm.
Figure 5. Intracellular localization redistribution in live
HeLa cells. Panel (A) shows 30 minutes 5 µM 13l incubation
membrane (PM) localizers are shown in Figure 5. Panel A
shows 30 minutes 5 µM 13l incubation observed in the
green channel indicating a clean PM localization, while 13x
(panel B) equilibrates PM and nucleoli. CellMask co-
observed in the confocal green channel (λexc = 405 nm, λem
=
450 nm, indicating a clean plasma membrane (PM)
localization; while panel (B) shows equilibration between
PM and nucleolar distribution observed by 5 µM 13x. Scale
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bars represent 20 µm. CellMask co-localization for PM is 450 nm), indicating a clean lysosome localization, while
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presented in Figure S37.
panel (B) shows 5 µM 15 distribution giving low signal-to-
noise ratio imaging. Scale bars represent 20 µm. Co-
localization imaging is shown in Figure S37
This strategy, helped us tune the localization properties of
those fluorophores by functionalization with a lipophilic
morpholine derivative, which has been used as targeting
group for lysosomes.4 It is important to note the difference
in the fluorophore structure, while 13y is highly fluorescent
(Φfl = 0.57), the low fluorescence response of 15 gives only
EXPERIMENTAL SECTION
Experimental Methods
All reagents and solvents including the compounds 7a-h
and 10a-c were obtained from Aldrich and Fluka. Toluene
was freshly distilled from sodium/benzophenone,
methanol was dried over magnesium/iodide and stored
over 4 Å molecular sieves. The reaction progress was
monitored by TLC using silica gel 60 (ALUGRAM® SIL
G/UV); the spots were visualized under UV light (254 nm),
or with phosphomolybdic acid, p-isoaldehyde and vanillin.
Melting points were determined on a Fisher apparatus and
are uncorrected. All reactions were performed under a dry
argon atmosphere unless otherwise specified. 1H and 13C
NMR spectra were recorded on Bruker AV400 MHz, JEOL
Eclipse-300 MHz and Varian Unity Inova-500 MHz model
spectrometers using CDCl3 and DMSO-d6 as solvents.
Chemical shifts (δ) are reported in ppm relative to Si(CH3)4
for 1H and 13C NMR experiments were carried out in CDCl3.
Coupling constants (J) are reported in hertz (Hz), peak
multiplicity is indicated as follows: s= singlet, d= doublet, t=
triplet, m= multiplet, bs: broad signal for proton spectra.
Microwave-assisted reactions were performed using a
Biotage® microwave reactor. IR spectra were obtained
with a Bruker Tensor 27 FT-IR spectrometer. High-
resolution mass spectra were recorded with an AccuTOFLC
equipped with an ionSense DART controller ionization
source. X-Ray diffraction: X-ray diffraction studies were
realized on a Bruker Smart APEX II CCD diffractometer with
graphite-monochromatic Mo Kα irradiation. Solution and
refinement have been carried out by Simon Hernández-
Ortega and Ruben A. Toscano.
low-contrast with poor signal-to-noise ratio images (Φfl
0.01). Interestingly, the organelle-targeting
functionalization approach could be applied to all the
fluorophore library if deemed necessary, not only targeting
lysosome but also other organelles could be visualized
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using
the
appropriate
targeting
group,
i.e.
tetraphenylphosphonium ion for mitochondria or specific
cell-penetrating peptides for other organelles.
CONCLUSIONS
We have successfully implemented a diversity-oriented
synthesis for the efficient development of twenty-six small-
molecule fluorophores as specific subcellular localizers.
Starting with DOS, we obtained not only new fluorescent
structures with high fluorescent quantum yields but also
new specific organelle-targeted molecules. Through a
complementary
organelle-targeting
functionalization
strategy, the library was further refined to increase the
specificity for cell organelles. The readily access to tailored
fluorophore libraries makes the reported strategy far
superior over classical synthesis of fluorescent molecules
and commercial co-localizers.
A
Protocol for octanol/water partitioning (log P)
measurements
The log P values were measured by octanol partitioning
using the shake-flask method.18 An aliquot of each
fluorophore (100 mL, 50–300 mm) in Tris buffer (10 mm,
pH 7.4) and 1-octanol (100 mL; Aldrich) were added to a
microtube (0.5 mL). The tubes were vortexed for 2 min and
centrifuged for 2 min; 25 mL of each layer was removed and
diluted either in 100 mL 3:1 methanol/Tris or
B
methanol/octanol for
a final composition of 3:1:1
methanol/octanol/Tris. The aqueous layer was diluted an
additional fourfold. Three dilutions were prepared per
layer, each dilution (100 mL) was pipetted into a 384-well
plate, and the absorbance was read at 500 nm with a
reference wavelength at 625 nm. The mean A500 of three
dilutions was calculated for each layer. The log (A500 of the
organic layer/A500 of the aqueous layer) yielded log P. This
procedure was repeated a minimum of four times per
fluorophore to calculate the mean log P and standard error.
All absorbance measurements used were within the linear
range of the instrument.
Protocol for the synthesis of lipidic isocyanides 8g-h
Figure 6. Intracellular localization redistribution in live
HeLa cells. Panel (A) shows 30 minutes 5 µM 13y incubation
lipidic isocyanides (8g-h) were prepared according to the
described procedure in the literature:19 The corresponding
observed in the confocal green channel (λexc = 405 nm, λem
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lipidic amine (Octyl or Dodecylamine, 1 mmol) was microwave cavity. The reaction was irradiated for 2.5 h at
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dissolved in ethylformate (10 mL). the resulting solution
was stirred at reflux for 20 h, After that, the volatiles were
removed under reduced pressure furnishing the
corresponding formamide in quantitative yield. Finally, the
formamides were dehydrated using Et3N (2 mL) and
phosphorus oxychloride (1 mmol) in dry dichloromethane
(0.5 mL). The lipidic compounds was yielded 8g-h in
excellent yields after two steps. All spectroscopic data agree
directly with the data reported in the literature.
85 °C (the temperature was monitored using an internal IR
probe) under microwave irradiation (100 W) using a sealed
vessel. After the vial was cooled to room temperature, the
solvent was evaporated under reduced pressure and the
residue was dissolved in ethyl acetate (20 mL), washed with
10% aqueous NaHCO3 (2 × 10 mL portions), dried with
Na2SO4, and evaporated. The crude product was purified by
flash chromatography (SiO2).
N-(tert-butyl)-2-(3,5-dimethoxyphenyl)-2-(2-(2-
iodophenyl)-N-(prop-2-yn-1-yl)acetamido)acetamide
(11a)
9
Protocol for the synthesis of the isocyanoacetate 8i.
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The isocyanoacetate (8i) was prepared using a slightly
modified procedure found in the literature.20 Therefore,
compound 8i was synthesized from the L-phenylalanine
ethyl ester hydrochloride (634 mg, 2.76 mmol). In a first
step, the ethyl ester was formylated using formic acid
(0.136 mL, 3.58 mmol), dicyclohexylcarbodiimide (DCC 738
mg, 3.58 mmol) and dimethylaminopyridine (DMAP 67 mg,
0.552 mmol) at 0° C in dichloromethane (12 mL), after 16
hours, the ethyl formyl-L-phenylalaninate was yielded in
98% yield (600 mg). With the formamide in hand,
dehydration was carried out using triphosgene (916 mg, 1
mmol) in dichloromethane (12 mL) at -78 ° C, obtaining the
desired compound 8i as a yellow oil in 86% yield. 1H NMR
(CDCl3, 300 MHz) δ: 7.41 – 7.17 (m, 5H), 4.44 (dd, J = 8.3, 5.0
Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.35 – 3.04 (m, 2H), 1.27 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 166.2, 160.8,
134.5, 129.4, 128.9, 127.9, 62.8, 58.2, 39.0, 14.0. HRMS
(DART, [M+H]+) m/z calcd for C12H14N1O2 204.1024, found
204.1026.
Using the general procedure, this compound was obtained
as a pale-yellow solid in 60% (591 mg) yield after
purification by flash column chromatography (4/6 EtOAc–
1
hexanes) Rf. 0.6 (4/6 EtOAc–hexanes). m. p. 94-97 °C. H
NMR (CDCl3, 300 MHz) δ: 7.85 (d, J = 8.2 Hz, 1H), 7.43–7.17
(m, 2H), 7.06–6.86 (m, 1H), 6.58 (s, 2H), 6.44 (s, 1H), 6.08 (s,
1H), 5.75 (s, 1H), 4.21 (s, 2H), 4.06 (s, 2H), 3.78 (s, 6H), 2.18
(s, 1H), 1.37 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 171.4,
168.5, 161.1, 139.5, 138.9, 137.1, 130.8, 128.8, 128.6, 107.4,
101.4, 101.0, 79.8, 72.5, 61.4, 55.6, 52.0, 46.2, 35.8, 28.8. IR
(ν=max/cm-1): 3331, 3292, 2962, 1644, 1594, 747. HRMS
(DART, [M+H]+) m/z calcd for C25H30I1N2O4 549.1250,
found 549.1235.
N-(tert-butyl)-2-(2-(2-iodophenyl)-N-(prop-2-yn-1-
yl)acetamido)-2-(3,4,5-trimethoxyphenyl)acetamide (11b)
Using the general procedure, this compound was obtained
as a white solid in 63% (656 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes), Rf.
Ugi-4CR/alkyne hydro-arylation/isomerization/ Heck
cyclization process experimental methods
1
0.72 (4/6 EtOAc–hexanes), m. p. 62-65 °C. H NMR (CDCl3,
300 MHz) δ: 7.81 (d, J = 7.8 Hz, 1H), 7.39–7.17 (m, 2H), 7.01–
6.87 (m, 1H), 6.65 (s, 2H), 6.14 (d, J = 5.5 Hz, 2H), 4.20 (s,
2H), 4.04 (d, J = 3.7 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 6H), 2.20
(s, 1H), 1.34 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 171.2,
168.6, 153.2, 139.2, 138.7, 137.9, 130.6, 130.2, 128.6, 128.3,
106.5, 101.2, 79.7, 72.2, 61.0, 60.8, 56.1, 51.6, 46.0, 35.5,
28.5. IR (ν=max/cm-1): 3328, 3247, 2963, 2934, 1643, 1179,
1123, 1007, 746, 531. HRMS (DART, [M+H]+) m/z calcd for
C26H31I1N2O5 579.1355, found 579.1334.
General procedure for the synthesis of the Ugi adducts 11a-
11z
Method A. To a 25 mL round bottom flask equipped with a
magnetic stirring bar were added propargylamine
(Compounds 11a-r), or aminoacetaldehyde dimethyl acetal
(Compounds 11s-z) (1.8 mmol, 1.0 eq) and the
corresponding aldehyde (1.8 mmol, 1.0 eq.) in methanol (10
mL). The mixture was stirred for 30 min at room
temperature under argon atmosphere. Then the
corresponding carboxylic acid (1.8 mmol, 1.0 eq.) was
added. After stirring the mixture for further 5 min at room
temperature, the corresponding isocyanide (1.8 mmol, 1.0
eq.) was added. The reaction was stirred at room
temperature for 48 h. After that, the solvent was evaporated
under reduced pressure, and the residue was dissolved in
ethyl acetate (20 mL), washed with 10% aqueous NaHCO3
(2 × 10 mL portions), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash column
chromatography on silica gel (SiO2).
N-cyclopentyl-2-(2-(2-iodophenyl)-N-(prop-2-yn-1-
yl)acetamido)-2-(3,4,5-trimethoxyphenyl)acetamide (11c)
Using the general procedure, this compound was obtained
as a white solid in 57% (605 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.4
(4/6 EtOAc–hexanes), m. p. 151-154 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.82 (d, J = 7.9 Hz, 1H), 7.37–7.22 (m, 2H), 7.02–6.89
(m, 1H), 6.63 (s, 2H), 6.16 (s, 1H), 6.08 (d, J = 7.2 Hz, 1H),
4.29–4.12 (m, 2H), 4.03 (d, J = 4.5 Hz, 2H), 3.84 (s, 3H), 3.82
(s, 6H), 2.18 (t, J = 1.9 Hz, 1H), 2.05–1.91 (m, 2H), 1.80 (s,
1H), 1.63–1.55 (m, 4H), 1.45–1.18 (m, 2H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 171.4, 168.7, 153.4, 139.4, 138.7, 138.2,
130.7, 130.1, 128.9, 128.6, 106.6, 101.3, 79.6, 72.5, 61.0,
60.8, 56.3, 51.5, 46.2, 35.7, 33.0, 32.8, 23.8, 23.8. IR
(ν=max/cm-1): 3253, 2952, 2867, 1636, 1589, 730. HRMS
(DART, [M+H]+) m/z calcd for C27H32I1N2O5 591.1355, found
591.1364.
Method B. To a 10 mL vial equipped with a magnetic
stirring bar were added propargylamine (Compounds 11a-
r) or aminoacetaldehyde dimethyl acetal (Compounds 11s-
z) (1.8 mmol, 1.0 eq.), the corresponding aldehyde (1.8
mmol, 1.0 eq.) in anhydrous methanol (10 mL). The mixture
was stirred for 30 min at room temperature under argon
atmosphere. The carboxylic acid (1.8 mmol, 1.0 eq.) was
added; and after 15 min, the isocyanide (1.8 mmol, 1.0 eq.)
was added. The vial was capped and placed in the
N-(2-(cyclohexylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-2-iodo-N-(prop-2-yn-1-
yl)benzamide (11d)
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Using the general procedure, this compound was obtained
as a white solid in 90% (956 mg) yield after purification by
1627, 766. HRMS (DART, [M+H]+) m/z calcd for
C30H26I1N2O4 605.0937, found 605.0913.
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flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.4
(4/6 EtOAc–hexanes), m. p. 79-82 °C. H NMR (CDCl3, 300
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-2-iodo-N-(prop-2-yn-1-
yl)benzamide (11h)
1
MHz) δ: 7.85 (dd, J = 8.0, 1.0 Hz, 1H), 7.43 – 7.34 (m, 2H),
7.15 – 7.08 (m, 1H), 6.82 (s, 2H), 6.70 (s, 1H), 6.17 – 5.96 (m,
1H), 3.86 (s, 8H), 3.84 (s, 4H), 2.04 (d, J = 0.9 Hz, 1H), 1.96
(s, 2H), 1.73 – 1.57 (m, 4H), 1.36 – 1.16 (m, 4H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: (major rotamer) 171.3, 167.9, 153.4,
141.2, 139.7, 139.3, 138.4, 130.8, 128.3, 127.8, 127.4,
107.4, 78.9, 72.5, 67.1, 61.0, 56.3, 48.8, 33.1, 33.0, 32.9,
25.6, 24.9. IR (ν=max/cm-1): 3293, 2930, 2851, 1637, 1589,
1328, 1246, 1125, 1007, 771. HRMS (DART, [M+H]+) m/z
calcd C27H32I1N2O5 591.1359, found 591.1355.
Using the general procedure, this compound was obtained
as an orange solid in 65% (367 mg) yield after purification
by flash column chromatography (5/5 EtOAc–hexanes) Rf.
0.5 (5/5 EtOAc–hexanes), m. p. 202-205 °C. 1H NMR (CDCl3,
300 MHz) δ: (mixture of rotamers) 7.92 – 7.78 (m, 2H), 7.40
(dt, J = 12.4, 6.6 Hz, 3H), 7.18 – 7.05 (m, 2H), 6.82 (s, 2H),
6.73 (s, 1H), 3.86 (s, 9H), 3.84 (s, 6H), 2.10 (s, 1H), 2.04 (s,
1H), 1.42 (s, 9H), 1.38 (s, 4H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: (mixture of rotamers) 171.4, 170.4, 153.4, 141.3, 139.7,
139.4, 138.4, 130.9, 130.7, 129.8, 128.7, 128.2, 127.8, 127.6,
107.4, 107.2, 92.5, 79.9, 79.1, 72.3, 71.1, 67.1, 61.0, 56.3,
52.2, 51.9, 37.3, 33.5, 28.8, 28.7. IR (ν=max/cm-1): 3296, 2962,
2929, 2832, 2120, 1665, 1592, 761. HRMS
(DART+) m/z calcd for C25H30I1N2O5 [M + H]+ 565.1199,
found 565.1203.
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N-(2-(benzylamino)-1-(3,5-dimethoxyphenyl)-2-
oxoethyl)-2-iodo-N-(prop-2-yn-1-yl)benzamide (11e)
Using the general procedure, this compound was obtained
as a pale yellow solid in 52% (532 mg) yield after
purification by flash column chromatography (4/6 EtOAc–
1
hexanes) Rf. 0.5 (4/6 EtOAc–hexanes), m. p. 60-63 °C. H
NMR (CDCl3, 300 MHz) δ: (major rotamer) 7.93 – 7.74 (m,
1H), 7.49 – 7.28 (m, 7H), 7.10 (t, J = 6.6 Hz, 1H), 6.72 (s, 2H),
6.61 (s, 1H), 6.45 (s, 2H), 4.54 (s, 2H), 4.48 – 3.93 (m, 2H),
3.76 (s, 7H), 2.00 (s, 1H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
(major rotamer) 171.4, 168.8, 161.2, 141.2, 139.4, 138.0,
136.0, 130.8, 128.8, 128.5, 128.2, 127.9, 127.7, 127.5, 108.1,
101.3, 92.7, 78.7, 73.0, 62.5, 55.6, 44.0, 37.6. IR (ν=max/cm-
1): 3288, 2932, 2837, 1637, 2598, 1153, 748. HRMS (DART,
[M+H]+) m/z calcd for C27H26I1N2O4 569.0937, found
569.0909.
4-chloro-N-(1-(3,5-dimethoxyphenyl)-2-oxo-2-
(phenylamino)ethyl)-2-iodo-N-(prop-2-yn-1-yl)benzamide
(11i)
Using the general procedure, this compound was obtained
as a pale yellow solid in 83% (878mg) yield after
purification by flash column chromatography (3/7 EtOAc–
hexanes) Rf. 0.3 (3/7 EtOAc–hexanes), m.p. 79-82 °C. 1H
NMR (CDCl3, 400 MHz) δ: 7.84 (d, J = 1.9 Hz, 1H), 7.48 (d, J =
7.6 Hz, 2H), 7.44 – 7.22 (m, 4H), 7.20 – 6.99 (m, 2H), 6.76 (s,
2H), 6.47 (t, J = 1.9 Hz, 1H), 6.28 (s, 1H), 4.14 – 3.80 (m, 2H),
3.78 (s, 6H), 2.05 (d, J = 16.2 Hz, 1H). 13C{1H} NMR (CDCl3,
100 MHz) δ: 171.0, 161.3, 139.5, 138.9, 137.7, 135.9, 135.7,
129.0, 128.6, 128.3, 124.6, 120.3, 108.5, 108.0, 101.1, 78.5,
73.0, 55.6, 55.5, 37.7. IR (ν=max/cm-1): 3329, 3063, 2835,
1631, 1598, 1153, 1099, 829, 747. HRMS (DART,
[M+H]+) m/z calcd for C26H23Cl1I1N2O4 589.0391, found
589.0383.
N-(2-(tert-butylamino)-1-(3,5-dimethoxyphenyl)-2-
oxoethyl)-2-iodo-N-(prop-2-yn-1-yl)benzamide (11f)
Using the general procedure, this compound was obtained
as a white solid in 58% (557 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.6
1
(4/6 EtOAc–hexanes). H NMR (CDCl3, 300 MHz) δ: 7.91 –
7.81 (m, 1H), 7.43 – 7.35 (m, 2H), 7.16 – 7.06 (m, 1H), 6.73
(d, J = 1.8 Hz, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.46 (q, J = 2.1 Hz,
1H), 5.95 (s, 1H), 3.79 (d, J = 4.2 Hz, 8H), 2.12 (t, J = 2.3 Hz,
1H), 1.39 (d, J = 10.2 Hz, 9H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: 171.39, 161.09, 141.39, 139.40, 130.95, 130.74, 128.36,
128.25, 127.92, 127.65, 108.25, 101.06, 79.00, 71.35, 55.58,
51.99, 37.53, 33.49, 28.82. IR (ν=max/cm-1): 3300, 2964,
2837, 1677, 1635, 1597, 1152, 1050, 769. HRMS (DART,
[M+H]+) m/z calcd for C24H28I1N2O4 535.1093, found
535.1085.
N-(2-(benzylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-4-fluoro-2-iodo-N-(prop-2-yn-1-
yl)benzamide (11j)
Using the general procedure, this compound was obtained
as a white solid in 50% (554 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.2
(3/7 EtOAc–hexanes), m. p. 175-178 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.56 (dd, J = 8.0, 2.3 Hz, 1H), 7.36 – 7.27 (m, 7H),
7.16 – 7.06 (m, 1H), 6.77 (s, 2H), 6.62 (s, 1H), 6.09 (s, 1H),
4.63 – 4.41 (m, 3H), 3.84 (s, 3H), 3.79 (s, 8H), 1.99 (s, 1H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 170.7, 168.6, 168.3, 162.05
(d, J = 255.6 Hz), 153.4, 138.6, 137.9, 137.38 (d, J = 3.4 Hz),
129.1, 128.7, 128.0, 127.6, 126.49 (d, J = 23.8 Hz), 115.63
(d, J = 20.9 Hz), 107.3, 78.6, 72.6, 62.0, 60.9, 56.3, 43.8, 37.4.
IR (ν=max/cm-1): 3116, 2922, 2833, 1671, 1638, 1591, 1123,
997, 752. HRMS (DART, [M+H]+) m/z calcd for
C28H27F1I1N2O5 617.0948, found 617.0972.
N-(1-(3,5-dimethoxyphenyl)-2-(naphthalen-2-ylamino)-2-
oxoethyl)-2-iodo-N-(prop-2-yn-1-yl)benzamide (11g)
Using the general procedure, this compound was obtained
as a white solid in 33% (359 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.5
1
(3/7 EtOAc–hexanes), m. p. 92-95 °C. H NMR (CDCl3, 300
MHz) δ: 8.20 (s, 1H), 7.82 (s, 1H), 7.72 – 7.65 (m, 4H), 7.40
(dd, J = 8.9, 2.2 Hz, 5H), 7.13 – 7.08 (m, 1H), 6.82 (s, 2H), 6.46
(s, 1H), 4.14 – 4.00 (m, 2H), 3.80 (s, 1H), 3.72 (s, 6H), 2.09
(s, 1H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 171.9, 161.2, 141.0,
139.4, 136.0, 133.8, 130.9, 130.8, 128.6, 128.3, 127.8, 127.7,
127.6, 126.4, 125.0, 120.2, 116.9, 101.0, 78.7, 72.9, 55.6,
37.8. IR (ν=max/cm-1): 3289, 3247, 3956, 2956, 2926, 1691,
N-(2-(dodecylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-2-iodo-N-(prop-2-yn-1-
yl)benzamide (11k)
Using the general procedure, this compound was obtained
as a pale yellow oil in 43% (350 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
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The Journal of Organic Chemistry
0.2 (3/7 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.87 2H), 1.71 – 1.55 (m, 3H), 1.36 – 1.12 (m, 5H). 13C{1H} NMR
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– 7.76 (m, 1H), 7.42 – 7.31 (m, 2H), 7.09 (td, J = 7.9, 2.0 Hz,
2H), 6.79 (s, 2H), 6.64 (s, 1H), 3.82 (s, 9H), 3.80 (d, J = 3.5 Hz,
2H), 3.26 (ddd, J = 22.6, 12.2, 5.6 Hz, 2H), 1.53 – 1.43 (m,
2H), 1.22 (s, 18H), 0.83 (d, J = 6.9 Hz, 3H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: (mixture of rotamers) 171.4, 170.6,
168.8, 153.4, 141.2, 139.7, 139.3, 131.0, 130.8, 129.7, 128.5,
128.3, 127.8, 127.4, 107.5, 107.2, 92.5, 79.7, 78.8, 72.4, 71.2,
67.1, 61.7, 60.9, 56.4, 56.3, 39.9, 37.2, 31.9, 29.7, 29.7, 29.6,
29.5, 29.4, 27.1, 22.7, 14.2. IR (ν=max/cm-1): 3309, 2925,
2853, 1678, 1642, 1463, 1127, 771, 727. HRMS (DART,
[M+H]+) m/z calcd for C33H46I1N2O5 677.2451, found
677.2448.
(CDCl3, 75 MHz) δ: 167.8, 165.0, 153.5, 144.6, 138.4, 129.6,
120.0, 111.9, 106.8, 79.6, 72.4, 60.9, 56.3, 48.8, 32.9, 25.5,
24.9. IR (ν=max/cm-1): 3259, 3090, 2998, 2932, 2853, 2117,
1741, 1641, 1590, 1497, 1451, 1423, 1330, 1249, 1176,
1129, 1007, 943, 845, 757. HRMS (DART, [M+H]+) m/z calcd
for C25H3079Br1N2O6 533.1287, found 533.1287.
2-bromo-N-(2-(cyclohexylamino)-1-(3,5-
dimethoxyphenyl)-2-oxoethyl)-N-(prop-2-yn-1-yl)furan-3-
carboxamide (11o)
9
Using the general procedure, this compound was obtained
as a beige solid in 59% (533 mg) yield after purification by
flash column chromatography (3/7 EtOAc–Hexanes) Rf. 0.2
(3/7 EtOAc–Hexanes). m. p. 140-143 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.43 (d, J = 2.1 Hz, 1H), 6.68 (s, 1H), 6.54 (s, 2H),
6.40 (t, J = 2.2 Hz, 1H), 6.16 (s, 1H), 5.85 (s, 1H), 4.28 – 3.96
(m, 2H), 3.82 (ddt, J = 14.4, 7.7, 3.8 Hz, 1H), 3.74 (s, 6H), 2.11
(s, 1H), 1.91 (d, J = 12.2 Hz, 2H), 1.62 (ddd, J = 29.0, 8.6, 3.3
Hz, 3H), 1.38 – 1.06 (m, 5H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: 167.7, 165.0, 161.1, 144.5, 136.4, 120.0, 111.9, 107.5,
100.8, 79.6, 72.4, 55.5, 48.8, 32.9, 25.5, 24.9, 24.8. HRMS
(DART, [M+H]+) m/z calcd for C24H2879Br1N2O5 503.1181,
found 503.1171.
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2-iodo-N-(2-(octylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(prop-2-yn-1-yl)benzamide
(11l)
Using the general procedure, this compound was obtained
as a pale yellow oil in 36% (401 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
0.3 (3/7 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.82
(d, J = 8.0 Hz, 1H), 7.44 – 7.33 (m, 2H), 7.14 – 7.08 (m, 1H),
6.79 (s, 2H), 6.19 (s, 1H), 3.85 – 3.83 (m, 6H), 3.81 (d, J = 2.7
Hz, 5H), 3.28 (ddq, J = 18.9, 12.9, 6.1 Hz, 2H), 2.01 (s, 1H),
1.49 (d, J = 6.5 Hz, 2H), 1.23 (s, 10H), 0.92 – 0.82 (m, 3H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 171.4, 168.9, 153.4, 141.2,
139.8, 139.4, 131.0, 130.8, 128.5, 128.3, 127.8, 127.4, 107.5,
107.1, 78.8, 72.5, 67.1, 61.8, 61.0, 56.4, 39.9, 33.4, 29.6, 29.3,
27.1, 22.7, 14.2. IR (ν=max/cm-1): 3307, 2928, 2854, 1640,
1540, 1463, 1128, 773, 747. HRMS (DART, [M+H]+) m/z
calcd for C29H38I1N2O5 621.1825, found 621.1825.
2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(prop-2-yn-1-yl)thiophene-3-
carboxamide (11p)
Using the general procedure, this compound was obtained
as a white solid in 89% (835 mg) yield after purification by
flash column chromatography (4/6 EtOAc–Hexanes) Rf. 0.2
(4/6 EtOAc–Hexanes). m. p. 204-206 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.30 (d, J = 5.6 Hz, 1H), 7.05 (s, 1H), 6.73 (s, 1H),
6.53 (s, 1H), 5.99 (d, J = 22.7 Hz, 1H), 4.18 – 3.93 (m, 2H),
3.82 (s, 9H), 2.03 (s, 1H), 1.38 (s, 9H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 168.0, 153.5, 138.4, 136.5, 129.9, 127.6, 126.8,
112.3, 106.8, 79.4, 72.2, 62.4, 61.0, 56.2, 52.0, 37.1, 28.7. IR
(ν=max/cm-1): 3302, 3113, 3067, 3008, 2966, 2932, 2834,
1677, 1658, 1595, 1545, 1438, 1330, 1236, 1174, 1130,
1045, 998, 917, 849, 743. HRMS (DART, [M+H]+) m/z calcd
for C23H2879Br1N2O5S1 523.0902, found 523.0888.
Ethyl (2-(2-iodo-N-(prop-2-yn-1-yl)benzamido)-2-(3,4,5-
trimethoxyphenyl)acetyl)-L-phenylalaninate (11m)
Using the general procedure, this compound was obtained
as a pale yellow oil in 43% (264 mg) yield after purification
by flash column chromatography (4/6 EtOAc–hexanes) Rf.
0.3 (4/6 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ:
(diasteromeric mixture) 7.90 – 7.76 (m, 3H), 7.37 (dd, J =
16.5, 6.9 Hz, 8H), 7.21 – 6.97 (m, 13H), 6.82 (s, 1H), 6.80 (s,
1H), 6.77 (s, 3H), 6.66 (s, 1H), 4.31 – 4.07 (m, 7H), 3.86 (s,
3H), 3.85 (s, 9H), 3.83 (s, 10H), 3.80 (s, 4H), 3.28 – 3.08 (m,
6H), 2.33 (dd, J = 5.0, 2.5 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.92
(t, J = 2.2 Hz, 1H), 1.70 (s, 2H), 1.25 (dt, J = 14.1, 6.9 Hz, 10H).
13C{1H} NMR (CDCl3, 75 MHz) δ: (diasteromeric mixture)
171.3, 171.2, 153.6, 153.5, 144.2, 141.2, 139.3, 135.8, 130.9,
129.4, 129.2, 128.7, 128.4, 128.0, 127.3, 107.6, 107.4, 78.7,
61.9, 61.6, 61.0, 56.4, 53.8, 53.5, 37.9, 37.6, 14.2. IR
(ν=max/cm-1): 3293, 3260, 2935, 2835, 1737, 1677, 1643,
1589, 1505, 1183, 1122, 1008, 771, 744, 699, 636. HRMS
(DART, [M+H]+) m/z calcd for C32H34I1N2O7 685.1410, found
685.1410.
2-bromo-5-chloro-N-(2-(cyclohexylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(prop-2-yn-1-yl)nicotinamide
(11q)
Using the general procedure, this compound was obtained
as a beige solid in 70% (726 mg) yield after purification by
flash column chromatography (3/7 EtOAc–Hexanes) Rf. 0.1
3/7 EtOAc–Hexanes). m. p. 149-152 °C. 1H NMR (CDCl3, 300
MHz) δ: 8.37 (d, J = 2.6 Hz, 1H), 7.73 (s, 1H), 6.71 (s, 2H),
6.62 (s, 1H), 3.84 (s, 9H), 3.81 (d, J = 3.3 Hz, 3H), 2.11 (s, 1H),
1.94 (t, J = 14.4 Hz, 2H), 1.73 – 1.57 (m, 3H), 1.34 (t, J = 11.0
Hz, 2H), 1.13 (q, J = 10.7, 9.9 Hz, 3H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 167.4, 166.9, 153.6, 149.5, 138.7, 136.8, 135.9,
135.1, 131.7, 106.8, 78.6, 72.8, 71.4, 66.7, 61.0, 56.3, 49.0,
32.9, 25.4, 24.8. IR (ν=max/cm-1): 3228, 3282, 3079, 2931,
2853, 1678, 1634, 1592, 1509, 1451, 1404, 1330, 1245,
1125, 1007, 904, 754. HRMS (DART, [M+H]+) m/z calcd for
C26H3079Br1Cl1N3O5 578.1057, found 578.1055.
2-bromo-N-(2-(cyclohexylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(prop-2-yn-1-yl)furan-3-
carboxamide (11n)
Using the general procedure, this compound was obtained
as a white solid in 90% (861 mg) yield after purification by
flash column chromatography (5/5 EtOAc–Hexanes) Rf. 0.2
(5/5 EtOAc–Hexanes). m. p. 166-168 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.45 (d, J = 2.1 Hz, 1H), 6.65 (s, 3H), 6.07 (d, J = 8.0
Hz, 1H), 5.87 (s, 1H), 4.25 – 3.94 (m, 2H), 3.86 – 3.84 (m, 1H),
3.82 (s, 3H), 3.81 (s, 6H), 2.10 (s, 1H), 1.93 (d, J = 11.5 Hz,
2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(prop-2-yn-1-yl)nicotinamide
(11r)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
Using the general procedure, this compound was obtained flash column chromatography (6/4 EtOAc–Hexanes) Rf. 0.4
(6/4 EtOAc–Hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.49 (d,
J = 2.1 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.59 (s, 2H), 6.09 (s,
1H), 6.00 (d, J = 6.0 Hz, 1H), 3.92 – 3.83 (m, 6H), 3.81 (s, 9H),
1.54 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 167.7, 153.5,
153.2, 144.9, 137.9, 130.6, 130.0, 112.2, 111.6, 106.6, 106.3,
106.1, 105.8, 102.6, 65.8, 60.8, 56.1, 53.5, 51.7, 28.5, 28.5. IR
(ν=max/cm-1): 3330, 3118, 2966, 2938, 2837, 1732, 1681,
1641, 1591, 1458, 1237, 1127, 1006, 743. HRMS (DART,
[M+H]+) m/z calcd for C24H3479Br1N2O8 557.1498, found
557.1498.
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7
8
as a white solid in 79% (736 mg) yield after purification by
flash column chromatography (5/5 EtOAc–Hexanes) Rf. 0.2
1
(5/5 EtOAc–Hexanes). m. p. 83-85 °C. H NMR (CDCl3, 300
MHz) δ: (major rotamer) 8.40 (dd, J = 4.8, 2.0 Hz, 1H), 7.69
(d, J = 25.0 Hz, 1H), 7.32 (dtd, J = 8.9, 6.5, 5.7, 3.0 Hz, 2H),
6.74 (s, 2H), 6.66 (s, 1H), 3.83 (s, 9H), 3.81 (s, 2H), 2.01 (s,
1H), 1.38 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: (mixture
of rotamers) 168.24, 167.86, 153.54, 150.92, 150.78,
138.70, 138.52, 136.94, 134.52, 129.43, 128.02, 122.92,
122.68, 107.30, 106.92, 78.76, 72.48, 71.24, 66.96, 61.91,
61.00, 56.22, 52.06, 36.85, 33.35, 28.71. IR (ν=max/cm-1):
3404, 3110, 2966, 2936, 2936, 1682, 1646, 1592, 1550,
1508, 1457, 1391, 1330, 1243, 1127, 1004, 813, 510, 534.
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2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(2,2-
dimethoxyethyl)thiophene-3-carboxamide (11v)
HRMS
(DART,
[M+H]+) m/z
calcd
for
Using the general procedure, this compound was obtained
as a yellow oil in 87% (895 mg) yield after purification by
flash column chromatography (6/4 EtOAc–Hexanes) Rf. 0.4
(6/4 EtOAc–Hexanes). 1H NMR (CDCl3, 300 MHz) δ:
(mixture of rotamers) 7.50 (s, 1H), 7.30 (d, J = 4.3 Hz, 1H),
7.21 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 16.9 Hz, 2H), 6.71 (s,
2H), 6.31 (s, 3H), 5.61 (s, 1H), 5.19 (s, 1H), 4.95 (s, 1H),
3.74 (d, J = 9.4 Hz, 16H), 3.44 – 3.33 (m, 6H), 3.05 (d, J =
6.6 Hz, 6H), 1.37 (s, 9H), 1.31 (s, 9H). 13C{1H} NMR (CDCl3,
75 MHz) δ: (mixture of rotamers) 167.7, 153.5, 153.2, 144.9,
137.9, 130.6, 130.0, 112.2, 111.6, 106.6, 106.3, 106.1, 105.8,
102.6, 65.8, 60.8, 56.1, 53.5, 51.7, 28.5. IR (ν=max/cm-1):
3334, 3082, 2964, 2937, 2835, 1682, 1638, 1591, 1507,
1456, 1237, 1127, 1076, 727. HRMS (FAB+, [M+H]+) m/z
calcd for C24H3479Br1N2O7S1 573.1270, found 573.1288.
C24H2979Br1N3O5 518.1290, found 518.1291.
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(2,2-dimethoxyethyl)-2-
iodobenzamide (11s)
Using the general procedure, this compound was obtained
as a pale yellow oil in 78% (861 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
0.4 (3/7 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ:
(major rotamer) 7.91 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz,
1H), 7.44 – 7.24 (m, 5H), 7.17 – 7.02 (m, 2H), 6.93 (s, 1H),
6.86 (s, 1H), 6.62 (s, 2H), 3.86 (s, 6H), 3.83 (s, 12H), 3.50 (s,
3H), 3.40 (s, 3H), 1.45 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: (mixture of rotamers) 168.2, 168.0, 153.2, 139.9, 139.0,
131.0, 130.2, 128.7, 128.5, 128.3, 128.0, 127.2, 107.3, 103.6,
103.1, 102.5, 68.1, 65.2, 63.9, 60.8, 56.2, 55.8, 55.5, 54.8,
54.6, 51.7, 51.4, 50.8, 49.1, 47.2, 28.6. IR (ν=max/cm-1): 3325,
2963, 2937, 2834, 1681, 1646, 1589, 1506, 1459, 1387,
1234, 1127, 1074, 1009, 751, 565, 525. HRMS (DART,
[M+H]+) m/z calcd for C26H36I1N2O7 615.1567, found
615.1578.
2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(2,2-
dimethoxyethyl)nicotinamide (11w)
Using the general procedure, this compound was obtained
as a colorless oil in 64% (683 mg) yield after purification by
flash column chromatography (7/3 EtOAc–Hexanes) Rf. 0.4
(7/3 EtOAc–Hexanes). 1H NMR (CDCl3, 300 MHz) δ: (major
rotamer) 8.35 (d, J = 4.5 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.36 –
7.30 (m, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 4.79 (dd,
J = 6.5, 3.8 Hz, 1H), 3.85 (d, J = 3.9 Hz, 6H), 3.80 (s, 3H), 3.38
(d, J = 23.7 Hz, 4H), 3.21 (s, 2H), 3.07 (s, 3H), 1.36 (s, 9H).
13C{1H} NMR (CDCl3, 75 MHz) δ: (mixture of rotamers)
169.1, 168.1, 167.8, 167.4, 153.5, 150.9, 150.3, 150.2, 138.2,
138.0, 136.5, 135.1, 130.7, 129.5, 129.0, 122.9, 122.6, 107.6,
107.1, 107.0, 103.4, 102.7, 67.9, 64.1, 63.4, 61.0, 56.2, 56.1,
55.5, 55.3, 55.1, 55.0, 51.9, 51.7, 50.5, 48.8, 46.6, 28.7. IR
(ν=max/cm-1): 3341, 3062, 2964, 2937, 1683, 1642, 1591,
1507, 1458, 1237, 1126, 1082, 751, 710. HRMS (DART,
[M+H]+) m/z calcd for C25H3579Br1N3O7 568.1658, found
568.1655.
N-(2,2-dimethoxyethyl)-2-(2-iodophenyl)-N-(2-((4-
methoxyphenyl)amino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)acetamide (11t)
Using the general procedure, this compound was obtained
as a pale yellow solid in 50% (610 mg) yield after
purification by flash column chromatography (5/5 EtOAc–
hexanes) Rf. 0.3 (5/5 EtOAc–hexanes). m. p.76-79 °C 1H
NMR (CDCl3, 300 MHz) δ: 8.35 (s, 1H), 7.79 (d, J = 8.4 Hz,
1H), 7.54 (d, J = 11.1 Hz, 1H), 7.38 – 7.25 (m, 4H), 6.95 – 6.88
(m, 2H), 6.79 (s, 2H), 6.48 (s, 1H), 6.06 (s, 1H), 4.06 (s, 2H),
3.86 (s, 3H), 3.82 (s, 6H), 3.79 (s, 1H), 3.76 (s, 3H), 3.49 (s,
2H), 3.31 (s, 3H), 3.29 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: (mixture of rotamers) 172.8, 167.7, 167.4, 156.4, 153.4,
139.5, 139.3, 139.2, 138.3, 130.9, 130.7, 130.6, 130.3, 129.7,
129.0, 128.8, 128.6, 128.5, 128.4, 122.3, 122.0, 114.3, 114.0,
107.1, 106.6, 104.2, 102.5, 101.3, 67.2, 63.3, 60.9, 56.3, 55.9,
55.9, 55.5, 49.0, 47.6, 46.7, 45.9. IR (ν=max/cm-1): 3313, 3062,
2936, 2834, 1686, 1650, 1591, 1461, 1126, 1008, 830, 749.
HRMS (FAB+, [M+H]+) m/z calcd for C30H36I1N2O8 679.1516,
found 679.1517.
N-(2,2-dimethoxyethyl)-2-(2-iodophenyl)-N-(2-
(octylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)acetamide (11x)
Using the general procedure, this compound was obtained
as a white solid in 48% (590 mg) yield after purification by
flash column chromatography (3/7 EtOAc–Hexanes) Rf. 0.2
(3/7 EtOAc–Hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.80 (d,
J = 7.7 Hz, 1H), 7.37 – 7.19 (m, 2H), 6.99 – 6.88 (m, 1H), 6.73
(s, 2H), 6.38 (s, 1H), 6.18 (t, J = 5.6 Hz, 1H), 5.85 (s, 1H), 4.02
(s, 2H), 3.83 (s, 3H), 3.81 (s, 5H), 3.77 (s, 2H), 3.27 (d, J = 1.2
Hz, 6H), 1.43 (q, J = 7.0 Hz, 2H), 1.22 (s, 10H), 0.84 (t, J = 6.4
2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)ethyl)-N-(2,2-dimethoxyethyl)furan-3-
carboxamide (11u)
Using the general procedure, this compound was obtained
as a colorless oil in 54% (540 mg) yield after purification by
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: (mixture of
with ethyl acetate (sat. NaCl), washed with sodium
1
2
3
4
5
6
7
8
rotamers) 172.4, 169.4, 153.5, 139.5, 139.3, 138.3, 130.7,
128.6, 128.4, 107.1, 106.6, 104.3, 102.6, 101.3, 66.9, 62.5,
60.9, 56.3, 55.9, 55.7, 49.0, 45.9, 39.8, 31.8, 29.5, 29.3, 29.2,
27.0, 22.7, 14.1. IR (ν=max/cm-1): 3297, 3092, 2928, 2855,
1650, 1587, 1466, 1425, 1458, 1328, 1243, 1185, 1125,
1076, 1010, 821, 747, 727, 599, 532. HRMS (FAB+,
[M+H]+) m/z calcd for C31H46I1N2O7 685.2350, found
685.2343.
bicarbonate (sat. solution) and the organic phase was dried
(Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography
(SiO2).
N-(tert-butyl)-2-(2-(2-iodophenyl)acetyl)-5,7-dimethoxy-
4-methyl-1,2-dihydroisoquinoline-1-carboxamide (12a)
Using the general procedure, this compound was obtained
as a brown solid in 83% (90 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes), Rf. 0.4
N-(2,2-dimethoxyethyl)-2-iodo-N-(2-((2-
morpholinoethyl)amino)-2-oxo-1-(3,4,5-
trimethoxyphenyl)-ethyl)benzamide (11y)
9
1
(4/6 EtOAc–hexanes), m. p. 70-73 °C. H NMR (CDCl3, 300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz) δ: 7.87 (d, J = 7.5 Hz, 1H), 7.35 – 7.29 (m, 2H), 6.99
(ddd, J = 7.9, 6.2, 2.8 Hz, 1H), 6.44 – 6.40 (m, 2H), 6.35 (s,
1H), 6.00 (s, 1H), 5.95 (s, 1H), 4.06 (d, J = 16.3 Hz, 2H), 3.82
(s, 3H), 3.80 (s, 3H), 2.24 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 168.6, 167.8, 160.0, 157.8, 139.5, 138.0,
133.6, 130.3, 129.0, 128.7, 121.1, 118.7, 114.3, 105.0, 101.3,
99.3, 58.2, 55.5, 51.5, 45.5, 28.8, 28.6, 20.1. IR (ν=max/cm-1):
3395, 3332, 2963, 2837, 1686, 1652, 742. HRMS (DART,
[M+H]+) m/z calcd for C25H30I1N2O4 549.1244, found
549.1250.
Using the general procedure, this compound was obtained
as a colorless solid in 37% (456 mg) yield after purification
by flash column chromatography (9/1 EtOAc–MeOH) Rf. 0.2
(9/1 EtOAc–MeOH). m. p. 62-63°C. 1H NMR (CDCl3, 300
MHz) δ: 7.81 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.0 Hz, 1H), 7.39
(d, J = 5.9 Hz, 2H), 7.14 – 7.05 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H),
6.80 (s, 2H), 3.91 – 3.74 (m, 14H), 3.67 (d, J = 14.6 Hz, 5H),
3.57 – 3.42 (m, 3H), 2.69 – 2.41 (m, 9H).13C{1H} NMR (CDCl3,
75 MHz) δ: 171.3, 169.1, 153.4, 141.2, 140.1, 139.3, 138.5,
130.8, 128.3, 127.9, 127.7, 107.5, 72.5, 66.2, 61.0, 56.9, 56.4,
53.3, 35.8. IR (ν=max/cm-1): 3410, 3296, 2937, 2836, 1676,
1642, 1590, 1508, 1461, 1424, 1330, 1246, 1125, 1010, 914,
749, 638. HRMS (DART, [M+H]+) m/z calcd for
C28H39I1N3O8 672.1781, found 672.1800.
N-(tert-butyl)-2-(2-(2-iodophenyl)acetyl)-5,6,7-
trimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12b)
Using the general procedure, this compound was obtained
as a pale yellow solid in 93% (107 mg) yield after
purification by flash column chromatography (4/6 EtOAc–
N-(2,2-dimethoxyethyl)-N-(1-(2,5-dimethoxyphenyl)-2-
((2-morpholinoethyl)amino)-2-oxoethyl)-2-
iodobenzamide (11z)
1
hexanes), Rf. 0.5, (4/6 EtOAc–hexanes) m. p. 66-69 °C. H
NMR (CDCl3, 300 MHz) δ: 7.88 (d, J = 7.8 Hz, 1H), 7.38 – 7.27
(m, 2H), 7.05 – 6.95 (m, 1H), 6.57 (s, 1H), 6.40 (s, 1H), 6.04
(s, 1H), 5.92 (s, 1H), 4.12 – 3.92 (m, 2H), 3.88 (s, 3H), 3.86
(s, 6H), 2.24 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR (CDCl3, 75
MHz) δ: 168.8, 168.1, 153.0, 151.3, 142.8, 139.6, 138.0,
130.4, 129.2, 128.8, 127.0, 120.9, 119.6, 118.8, 107.8, 101.4,
61.3, 60.9, 58.0, 56.2, 51.7, 45.7, 29.0, 19.4. IR (ν=max/cm-1):
3325, 3059, 2962, 2839, 1737, 1663, 739. HRMS (DART,
[M+H]+) m/z calcd for C26H32I1N2O5 579.1355, found
579.1337.
Using the general procedure, this compound was obtained
as a colorless oil in 65% (749 mg) yield after purification by
flash column chromatography (2/8 EtOAc–hexanes) Rf. 0.5
(2/8 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ: (mixture
of rotamers) 7.75 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.39 – 7.25
(m, 6H), 7.07 – 6.96 (m, 3H), 6.83 (d, J = 1.8 Hz, 4H), 6.76 (s,
3H), 6.06 (s, 1H), 5.78 (s, 1H), 4.20 (t, J = 5.0 Hz, 2H), 3.77 (s,
5H), 3.74 (s, 4H), 3.68 (s, 4H), 3.45 (s, 6H), 3.02 (s, 3H), 2.97
(s, 3H), 2.58 – 2.35 (m, 17H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: (mixture of rotamers) 171.5, 169.8, 168.8, 153.7, 153.4,
152.2, 151.8, 141.8, 140.4, 140.0, 139.7, 139.1, 130.8, 130.6,
130.3, 130.1, 128.9, 128.4, 128.0, 127.9, 127.8, 124.7, 123.4,
118.2, 117.7, 117.0, 114.7, 114.3, 111.4, 111.3, 103.7, 103.5,
102.7, 102.2, 92.6, 66.7, 63.2, 60.0, 59.5, 57.4, 57.1, 56.8,
56.2, 55.9, 55.7, 54.9, 54.8, 54.7, 54.5, 53.5, 53.3, 53.2, 51.9,
49.8, 49.3, 46.9, 36.4, 36.2, 36.1. IR (ν=max/cm-1): 3333, 3070,
2953, 2832, 1676, 1647, 1501, 1461, 1118, 1073, 772, 749.
N-cyclopentyl-2-(2-(2-iodophenyl)acetyl)-5,6,7-
trimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12c)
Using the general procedure, this compound was obtained
as a brown solid in 91% (107 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.4
(4/6 EtOAc–hexanes), m. p. 164-167 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.81 (d, J = 7.9 Hz, 1H), 7.25 (qd, J = 7.7, 1.7 Hz, 2H),
6.93 (td, J = 7.5, 2.2 Hz, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 6.03
(d, J = 7.1 Hz, 1H), 5.91 (s, 1H), 4.13 – 3.91 (m, 2H), 3.81 (s,
3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (s, 1H), 2.17 (s, 3H), 1.96
– 1.74 (m, 2H), 1.54 – 1.48 (m, 4H), 1.24 (dd, J = 11.2, 6.2 Hz,
1H), 0.92 – 0.71 (m, 1H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
168.8, 168.4, 153.0, 151.2, 142.8, 139.6, 137.9, 130.3, 129.1,
128.8, 126.7, 120.6, 119.6, 118.7, 107.7, 101.3, 61.3, 60.8,
57.3, 56.2, 51.5, 45.6, 33.3, 33.2, 23.9, 19.4. IR (ν=max/cm-1):
3327, 2921, 2853, 1649, 1099, 727. HRMS (DART,
[M+H]+) m/z calcd for C27H32I1N2O5 591.1355, found
591.1346.
HRMS
C27H37I1N3O7 642.1676, found 642.1688.
General procedure for the
dihydroisoquinolines 12a-12r
(DART,
[M+H]+) m/z
calcd
for
synthesis
of
In a round-bottom flask equipped with a magnetic stirring
bar, the corresponding Ugi adduct 11a-r (0.2 mmol, 1
equiv.) was added to a solution of JohnPhosAu(MeCN)SbF6
(5 mol%, 0.05 equiv) and CHCl3 (1 mL/0.1 mmol of Ugi
adduct 11a-r). The mixture was stirred for 2.5 h at room
temperature under argon atmosphere. After that, the crude
of the hydro-arylation reaction was treated with p-
toluenesulfonic acid (0.1 mmol, 0.5 equiv.) in MeOH (0.1 M
for the Ugi adduct) for 12 hours at 40 °C in an oil bath.
Finally, after removal of volatiles the crude was extracted
N-cyclohexyl-2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-
methyl-1,2-dihydroisoquinoline-1-carboxamide (12d)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Using the general procedure, this compound was obtained
Page 12 of 21
2837, 1694, 1629, 1595, 1142, 830, 754. HRMS (DART,
[M+H]+) m/z calcd for C30H26I1N2O4 605.0937, found
1
2
3
4
5
6
7
8
as a beige solid in 84% (99 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes), Rf. 0.5
(3/7 EtOAc–hexanes), m. p. 152-155 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.89 (d, J = 9.3 Hz, 1H), 7.41 (t, J = 7.1 Hz, 2H), 7.15
(td, J = 7.9, 1.7 Hz, 2H), 6.70 (s, 1H), 6.08 (s, 1H), 5.85 – 5.78
(m, 1H), 3.90 (s, 3H), 3.87 (s, 4H), 3.83 (s, 4H), 3.77 – 3.68
(m, 1H), 2.06 (s, 3H), 1.96 – 1.81 (m, 2H), 1.64 (d, J = 6.5 Hz,
2H), 1.36 – 1.13 (m, 6H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
168.6, 167.5, 152.9, 151.1, 142.8, 140.4, 139.5, 131.1, 128.7,
128.4, 126.1, 120.4, 119.6, 107.9, 92.9, 61.1, 60.7, 57.6, 56.1,
48.9, 33.1, 33.0, 25.5, 24.7, 19.1. IR (cm-1): 3319, 2926, 2851,
1635, 1596, 1101, 772. HRMS (DART, [M+H]+) m/z calcd for
C27H32I1N2O5 591.1355, found 591.1369.
605.0963.
N-(tert-butyl)-2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-
methyl-1,2 dihydroisoquinoline-1-carboxamide (12h)
Using the general procedure, this compound was obtained
as a pale yellow solid in 90% (101 mg) yield after
purification by flash column chromatography (4/6 EtOAc–
1
hexanes), Rf. 0.4 (4/6 EtOAc–hexanes), m. p. 79-82 °C. H
9
NMR (CDCl3, 300 MHz) δ: 7.88 (d, J = 7.9 Hz, 1H), 7.46 – 7.34
(m, 2H), 7.14 (td, J = 7.9, 1.7 Hz, 2H), 6.64 (s, 1H), 6.01 (s,
1H), 5.84 – 5.77 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.83 (s,
3H), 2.07 (s, 3H), 1.33 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: 168.0, 166.8, 153.4, 152.9, 143.2, 135.8, 132.2, 129.5,
129.1, 128.3, 126.2, 123.9, 123.8, 120.5, 117.2, 107.5, 61.4,
61.0, 58.1, 56.3, 51.8, 29.8, 28.8, 17.0. IR (ν=max/cm-1): 3405,
2924, 2853, 1692, 1653, 1385, 1102, 1015, 813, 766. HRMS
(DART, [M+H]+) m/z calcd for C25H30I1N2O5 565.1199, found
565.1188.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-benzyl-2-(2-iodobenzoyl)-5,7-dimethoxy-4-methyl-1,2-
dihydroisoquinoline-1-carboxamide (12e)
Using the general procedure, this compound was obtained
as a pale yellow solid in 87% (99 mg) yield after purification
by flash column chromatography (4/6 EtOAc–hexanes) Rf.
0.4 (4/6 EtOAc–hexanes), m. p. 171-174 °C. 1H NMR (CDCl3,
300 MHz) δ: 7.82 (d, J = 7.9 Hz, 1H), 7.44 – 7.20 (m, 7H), 7.18
– 6.98 (m, 2H), 6.55 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.21 (s,
1H), 5.76 (s, 1H), 4.45 (d, J = 5.5 Hz, 2H), 3.84 (s, 3H), 3.79
(s, 3H), 2.07 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.8,
168.5, 160.2, 157.9, 140.6, 139.5, 138.0, 132.5, 131.2, 128.8,
128.7, 128.4, 128.1, 127.6, 127.1, 119.5, 114.4, 105.3, 99.8,
92.9, 57.9, 55.6, 55.6, 44.0, 20.1. IR (ν=max/cm-1): 3223, 2924,
2847, 1652, 1631, 1577, 1206, 1096, 745, 696. HRMS
(DART, [M+H]+) m/z calcd for C27H26I1N2O4 569.0937, found
569.0915.
2-(4-chloro-2-iodobenzoyl)-5,7-dimethoxy-4-methyl-N-
phenyl-1,2dihydroisoquinoline-1 carboxamide (12i)
Using the general procedure, this compound was obtained
as a beige solid in 96% (113 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes), Rf. 0.4
1
(3/7 EtOAc–hexanes), m. p. 70-73 °C. H NMR (CDCl3, 300
MHz) δ: 8.47 (s, 1H), 7.90 (s, 1H), 7.52 (d, J = 7.9 Hz, 2H),
7.40 (dd, J = 8.2, 1.7 Hz, 1H), 7.32 – 7.20 (m, 3H), 7.12 – 7.00
(m, 1H), 6.52 (d, J = 2.2 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.29
(s, 1H), 5.80 – 5.74 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.09
(s, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.5, 166.5, 160.3,
158.1, 139.2, 137.8, 136.5, 131.7, 129.6, 129.0, 128.8, 124.4,
119.9, 118.9, 114.5, 105.0, 99.8, 93.4, 58.7, 55.6, 55.5, 20.2.
IR (ν=max/cm-1): 3331, 2965, 2931, 2832, 1667, 1631, 1599,
1089, 830, 748. HRMS (DART, [M+H]+) m/z calcd for
C26H23Cl1I1N2O4 589.0391, found 589.0381.
N-(tert-butyl)-2-(2-iodobenzoyl)-5,7-dimethoxy-4-methyl-
1,2-dihydroisoquinoline-1-carboxamide (12f)
Using the general procedure, this compound was obtained
as a pale yellow solid in 90% (96 mg) yield after purification
by flash column chromatography (4/6 EtOAc–hexanes), Rf.
1
0.4 (4/6 EtOAc–hexanes), m. p. 79-82 °C. H NMR (CDCl3,
N-benzyl-2-(4-fluoro-2-iodobenzoyl)-5,6,7-trimethoxy-4-
methyl-1,2-dihydroisoquinoline-1-carboxamide (12j)
300 MHz) δ: 7.88 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H),
7.14 (t, J = 7.7 Hz, 2H), 6.45 (d, J = 7.1 Hz, 3H), 6.04 (s, 1H),
5.76 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.06 (s, 3H), 1.33 (s,
9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.7, 167.5, 160.0,
157.9, 139.6, 133.0, 131.2, 128.9, 128.4, 119.4, 114.4, 105.2,
99.5, 93.2, 58.5, 55.6, 55.5, 51.8, 29.0, 20.1. IR (ν=max/cm-1):
3393, 2966, 2927, 2837, 1686, 1626, 747. HRMS (DART,
[M+H]+) m/z calcd for C24H28I1N2O4 535.1093, found
535.1086.
Using the general procedure, this compound was obtained
as a white solid in 90% (111 mg) yield after purification by
flash column chromatography (5/5 EtOAc–hexanes) Rf. 0.5
(5/5 EtOAc–hexanes), m. p. 187-190 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.56 (d, J = 7.8 Hz, 2H), 7.30 – 7.21 (m, 5H), 7.12 (d,
J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.18 (s, 1H), 5.80 (s, 1H), 4.45
(dq, J = 16.0, 9.1, 7.4 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.85
(s, 3H), 2.10 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.3,
168.0, 162.35 (d, J = 255.6 Hz), 153.1, 151.2, 143.0, 137.8,
129.94 (d, J = 8.2 Hz), 128.7, 127.9, 127.6, 126.8, 126.5,
125.7, 120.10 (d, J = 27.6 Hz), 118.5, 115.85 (d, J = 21.6 Hz),
107.9, 92.9, 61.2, 60.7, 57.7, 56.1, 43.9, 19.2. IR (ν=max/cm-
1): 3322, 3075, 2922, 2834, 1652, 1629, 1404, 1013, 758.
2-(2-iodobenzoyl)-5,7-dimethoxy-4-methyl-N-
(naphthalen-2-yl)-1,2-dihydroisoquinoline-1-carboxamide
(12g)
Using the general procedure, this compound was obtained
as a brown solid in 66% (80 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes), Rf. 0.5
(3/7 EtOAc–hexanes), m. p. 100-103 °C. 1H NMR (CDCl3, 300
MHz) δ: 8.81 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H),
7.73 (t, J = 8.1 Hz, 3H), 7.42 (tt, J = 15.2, 8.6 Hz, 5H), 7.17 (t,
J = 7.7 Hz, 1H), 6.52 (d, J = 11.8 Hz, 2H), 6.39 (s, 1H), 5.81 (s,
1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 169.4, 167.0, 160.2, 158.0, 139.6, 135.3,
133.8, 131.3, 130.6, 128.7, 128.6, 128.4, 127.7, 127.5, 126.4,
124.9, 120.6, 120.0, 118.9, 116.7, 114.6, 104.9, 100.0, 99.8,
93.0, 58.6, 55.5, 55.4, 20.2. IR (ν=max/cm-1): 3289, 2933,
HRMS
(DART,
[M+H]+) m/z calcd
for
C28H27F1I1N2O5 617.0948, found 617.0945.
N-dodecyl-2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-methyl-
1,2-dihydroisoquinoline-1-carboxamide (12k)
Using the general procedure, this compound was obtained
as a pale yellow solid in 67% (90 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
0.4 (3/7 EtOAc–hexanes) m. p. 177-181 °C. 1H NMR (CDCl3,
300 MHz) δ: 7.88 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H),
7.24 – 7.06 (m, 2H), 6.72 (s, 1H), 6.11 (s, 1H), 5.82 (s, 1H),
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The Journal of Organic Chemistry
3.88 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.22 (q, J = 6.5 Hz, 2H),
(ν=max/cm-1): 3312, 2930, 2854, 1648, 1597, 1494, 1457,
1409, 1329, 1253, 1161, 1110, 1026, 942, 887, 754. HRMS
(DART, [M+H]+) m/z calcd for C25H3079Br1N2O6 533.1287,
found 533.1305.
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4
5
6
7
8
2.05 (s, 3H), 1.51 – 1.41 (m, 2H), 1.22 (s, 16H), 0.85 (d, J =
6.9 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.7, 168.4,
152.9, 151.2, 142.8, 140.4, 139.6, 131.3, 129.8, 128.7, 128.5,
126.0, 120.4, 119.7, 118.6, 107.9, 92.9, 61.2, 60.8, 57.5, 56.1,
39.9, 31.9, 29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 26.9, 22.7,
19.2, 14.2. IR (ν=max/cm-1): 3330, 3067, 2926, 2853, 1652,
1596, 1462, 1108, 768, 749. HRMS (DART, [M+H]+) m/z
calcd for C33H46I1N2O5 677.2451, found 677.2438.
2-(2-bromofuran-3-carbonyl)-N-cyclohexyl-5,7-
dimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12o)
Using the general procedure, this compound was obtained
as a beige solid in 93% (94 mg) yield after purification by
flash column chromatography (4/6 EtOAc–Hexanes) Rf. 0.5
(4/6 EtOAc–Hexanes). m. p. 208-209 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.46 (d, J = 2.1 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.44
(s, 2H), 6.29 (d, J = 7.8 Hz, 1H), 6.14 (s, 1H), 5.94 (s, 1H), 3.81
(s, 3H), 3.79 (s, 3H), 2.14 (s, 3H), 1.79 (t, J = 10.8 Hz, 2H),
1.70 – 1.46 (m, 3H), 1.35 – 1.11 (m, 5H).13C{1H} NMR (CDCl3,
75 MHz) δ: 167.7, 161.9, 160.1, 157.9, 144.3, 132.9, 126.3,
120.2, 120.0, 119.3, 114.7, 113.1, 104.7, 99.4, 60.5, 58.4,
55.6, 55.5, 48.3, 32.8, 25.6, 24.5, 19.9, 14.3. IR (ν=max/cm-1):
3293, 3089, 2924, 2853, 1648, 1604, 1574, 1493, 1464,
1402, 1334, 1210, 1166, 1103, 1040, 889, 810, 735. HRMS
(DART, [M+H]+) m/z calcd for C24H2879Br1N2O5 503.1181,
found 503.1181.
2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-methyl-N-octyl-1,2-
dihydroisoquinoline-1-carboxamide (12l)
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Using the general procedure, this compound was obtained
as a yellow solid in 63% (78 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.3
1
(3/7 EtOAc–hexanes). m. p. 78-81 °C. H NMR (CDCl3, 300
MHz) δ: 7.88 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.23
– 7.11 (m, 1H), 6.71 (s, 1H), 6.10 (s, 1H), 5.82 (s, 1H), 3.89
(s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.23 (q, J = 6.5 Hz, 2H), 2.05
(s, 3H), 1.47 (dq, J = 10.8, 6.4, 4.9 Hz, 2H), 1.23 (s, 10H), 0.88
– 0.81 (m, 3H).13C{1H} NMR (CDCl3, 75 MHz) δ: 168.8, 168.5,
153.0, 151.2, 142.9, 139.6, 131.3, 128.7, 126.0, 120.4, 119.8,
108.0, 92.9, 61.3, 60.8, 57.5, 56.2, 39.9, 31.9, 29.6, 29.3, 27.0,
22.7, 19.3, 14.2. IR (ν=max/cm-1): 3330, 2926, 2853, 1652,
1596, 1462, 1108, 768, 749. HRMS (DART, [M+H]+) m/z
calcd for C29H38I1N2O5 621.1825, found 621.1802.
2-(2-bromothiophene-3-carbonyl)-N-(tert-butyl)-5,6,7-
trimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12p)
ethyl (2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-methyl-1,2-
dihydroisoquinoline-1-carbonyl)-L-phenylalaninate (12m)
Using the general procedure, this compound was obtained
as a white solid solid in 76% (80 mg) yield after purification
by flash column chromatography (3/7 EtOAc–Hexanes) Rf.
0.2 (3/7 EtOAc–Hexanes). m. p. 152-154 °C. 1H NMR (CDCl3,
300 MHz) δ: 7.31 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 5.7 Hz, 1H),
6.62 (s, 1H), 6.35 (s, 1H), 6.02 (s, 1H), 5.95 (s, 1H), 3.88 (s,
3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.13 (s, 3H), 1.31 (s, 9H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 167.9, 163.6, 152.9, 151.2,
142.8, 135.1, 128.0, 127.3, 126.4, 120.4, 119.9, 118.9, 114.8,
107.7, 61.3, 60.8, 58.4, 56.1, 51.7, 28.8, 19.2. IR (ν=max/cm-
1): 3378, 3077, 2966, 2937, 2849, 1689, 1652, 1627, 1522,
1491, 1417, 1327, 1268, 1184, 1108, 1024, 877, 825, 707.
Using the general procedure, this compound was obtained
as a pale yellow oil in 41% (68 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
0.3 (3/7 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ:
(diastereomeric mixture) 7.83 (d, J = 7.6 Hz, 2H), 7.39 (t, J
= 6.9 Hz, 2H), 7.26 – 7.10 (m, 11H), 7.05 – 6.91 (m, 4H),
6.67 (d, J = 9.8 Hz, 3H), 6.14 (d, J = 13.9 Hz, 1H), 5.82 (d, J
= 29.3 Hz, 1H), 4.80 (t, J = 6.1 Hz, 2H), 4.14 (q, J = 5.6, 4.5
Hz, 4H), 3.86 (s, 12H), 3.81 (s, 7H), 3.10 (dd, J = 12.7, 5.2
Hz, 4H), 2.04 (d, J = 6.4 Hz, 6H), 1.29 – 1.18 (m, 8H).
13C{1H} NMR (CDCl3, 75 MHz) δ: (diastereomeric mixture)
170.9, 168.7, 168.4, 167.9, 152.9, 151.2, 143.0, 140.5, 139.4,
135.8, 131.2, 129.5, 128.8, 128.7, 128.6, 128.5, 127.1, 125.4,
121.2, 120.6, 119.1, 118.5, 107.8, 93.0, 61.6, 61.3, 60.8, 57.6,
57.2, 56.1, 53.5, 37.8, 37.5, 29.7, 19.2, 19.1, 14.2. IR
(ν=max/cm-1): 3329, 3061, 2933, 2851, 1737, 1622, 1633,
1598, 1492, 1405, 1375, 1328, 1196, 1106, 1022, 772, 740,
HRMS
(DART,
[M+H]+) m/z
calcd
for
C23H2879Br1N2O5S1 523.0902, found 523.0893.
2-(2-bromo-5-chloronicotinoyl)-N-cyclohexyl-5,6,7-
trimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12q)
Using the general procedure, this compound was obtained
as a pale yellow solid in 75% (87 mg) yield after purification
by flash column chromatography (3/7 EtOAc–Hexanes) Rf.
0.2 (3/7 EtOAc–Hexanes). m. p. 238-239 °C. 1H NMR (CDCl3,
300 MHz) δ: (major rotamer) 8.44 (d, J = 2.6 Hz, 1H), 7.54
(s, 1H), 6.70 (s, 1H), 6.05 (s, 1H), 5.86 (s, 1H), 3.91 (s, 3H),
3.87 (s, 3H), 3.84 (s, 3H), 3.78 – 3.65 (m, 1H), 2.10 (s, 3H),
1.73 – 1.50 (m, 5H), 1.22 – 0.85 (m, 5H). 13C{1H} NMR (CDCl3,
75 MHz) δ: (mixture of rotamers) 167.4, 166.9, 153.3, 153.1,
151.5, 150.0, 149.6, 139.7, 137.0, 136.2, 135.1, 132.2, 120.6,
120.3, 107.1, 61.3, 60.9, 57.7, 56.3, 49.1, 33.1, 32.6, 29.8,
25.5, 25.3, 24.8, 24.3, 19.3. IR (ν=max/cm-1): 3305, 3078,
2924, 2851, 1645, 1597, 1550, 1495, 1454, 1401, 1332,
1278, 1112, 1024, 898, 772. HRMS (DART, [M+H]+) m/z
calcd for C26H3079Br1Cl1N3O5 578.1057, found 578.1055.
702.
HRMS
(DART,
[M+H]+) m/z
calcd
for
C32H34I1N2O7 685.1410, found 685.1386.
2-(2-bromofuran-3-carbonyl)-N-cyclohexyl-5,6,7-
trimethoxy-4-methyl-1,2-dihydroisoquinoline-1-
carboxamide (12n)
Using the general procedure, this compound was obtained
as a pale yellow solid in 23% (26 mg) yield after purification
by flash column chromatography (4/6 EtOAc–Hexanes) Rf.
0.2 (4/6 EtOAc–Hexanes). m. p. 148-149 °C. 1H NMR (CDCl3,
300 MHz) δ: 7.48 (d, J = 2.1 Hz, 1H), 6.64 (s, 1H), 6.60 (s,
1H), 6.37 (d, J = 7.1 Hz, 1H), 6.20 (s, 1H), 5.93 (s, 1H), 3.86
(s, 6H), 3.85 (s, 3H), 3.76 – 3.60 (m, 1H), 2.17 (s, 3H), 1.86
– 1.73 (m, 2H), 1.65 – 1.50 (m, 3H), 1.34 – 1.14 (m, 5H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 167.8, 162.0, 153.0, 151.3,
144.5, 142.9, 126.4, 121.1, 119.5, 119.2, 119.1, 113.1, 107.5,
61.3, 60.9, 58.1, 56.2, 48.4, 32.8, 25.6, 24.5, 19.2. IR
2-(2-bromonicotinoyl)-N-(tert-butyl)-5,6,7-trimethoxy-4-
methyl-1,2-dihydroisoquinoline-1-carboxamide (12r)
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The Journal of Organic Chemistry
Page 14 of 21
Using the general procedure, this compound was obtained
as a white solid in 60% (558 mg) yield after purification by
[M+H]+) m/z calcd for C28H28I1N2O6 615.0992, found
615.0992.
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2
3
4
5
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7
8
9
flash column chromatography (5/5 EtOAc–Hexanes) Rf. 0.3
(5/5 EtOAc–Hexanes). m. p. 74-77 °C. H NMR (CDCl3, 300
2-(2-bromofuran-3-carbonyl)-N-(tert-butyl)-5,6,7-
trimethoxy-1,2-dihydroisoquinoline-1-carboxamide (12u)
1
MHz) δ: 8.48 (dd, J = 4.8, 2.0 Hz, 1H), 7.57 (s, 1H), 7.37 (dd,
J = 7.4, 4.9 Hz, 1H), 6.66 (s, 1H), 6.02 (s, 1H), 5.88 – 5.79 (m,
1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.08 (s, 3H), 1.32
(s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 167.2, 165.5, 153.2,
151.3, 142.9, 138.9, 137.6, 133.9, 126.2, 123.1, 120.9, 119.3,
107.8, 61.3, 60.8, 58.1, 56.2, 51.9, 28.9, 19.2. IR (ν=max/cm-
1): 3444, 2924, 2856, 1684, 1631, 1600, 1458, 1405, 1326,
1276, 1110, 1023, 846, 812, 756, 525. HRMS (DART,
[M+H]+) m/z calcd for C24H2979Br1N3O5 518.1290, found
518.1287.
Using the general procedure, this compound was obtained
as a pale brown solid in 70% (172 mg) yield after
purification by flash column chromatography (5/5 EtOAc–
Hexanes) Rf. 0.4 (5/5 EtOAc–Hexanes). 1H NMR (CDCl3, 300
MHz) δ 7.49 (d, J = 2.1 Hz, 1H), 6.60 (s, 2H), 6.49 (d, J = 10.9
Hz, 1H), 6.35 (s, 1H), 6.25 (d, J = 9.6 Hz, 1H), 5.93 (s, 1H),
3.91 (s, 3H), 3.87 (s, 6H), 1.29 (s, 9H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 182.5, 179.3, 167.7, 162.6, 153.3, 144.5, 124.4,
122.8, 119.0, 112.9, 106.9, 106.8, 61.5, 60.9, 58.2, 56.2, 56.3,
51.6, 28.7. IR (ν=max/cm-1): 3368, 3113, 2967, 2937, 1690,
1654, 1625, 1569, 1461, 1259, 1121, 1038, 745. HRMS
(DART, [M+H]+) m/z calcd for C22H2679Br1N2O6 493.0974,
found 493.0984.
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General
procedure
for
the
synthesis
of
dihydroisoquinolines 12s-y and 14
In a round-bottom flask equipped with a magnetic stirring
bar the corresponding Ugi adduct 11s-z (0.5 mmol) was
added to a solution of p-toluenesulfonic acid (0.5 equiv; in
the case of morpholine derivates 1.5 equiv) and acetone
(100 mg of the Ugi Adduct/1 mL of Acetone). The mixture
was stirred for 5 h at 50°C (for 12 h at 50°C in the case of the
morpholine derivates) in an oil bath. After that, the volatiles
were removed under reduced pressure and the crude was
extracted with ethyl acetate and sodium bicarbonate (sat.
solution) and the organic phase was dried (Na2SO4) and
concentrated under reduced pressure. The residue was
purified by flash column chromatography (SiO2).
2-(2-bromothiophene-3-carbonyl)-N-(tert-butyl)-5,6,7-
trimethoxy-1,2-dihydroisoquinoline-1-carboxamide (12v)
Using the general procedure, this compound was obtained
as a yellow solid in 87% (221 mg) yield after purification by
flash column chromatography (6/4 EtOAc–Hexanes) Rf. 0.4
1
(6/4 EtOAc–Hexanes). m. p. 73-76 °C. H NMR (CDCl3, 300
MHz) 7.33 (d, J = 5.7 Hz, 1H), 6.98 (d, J = 5.6 Hz, 1H), 6.63 (s,
1H), 6.32 (d, J = 7.6 Hz, 2H), 6.20 (d, J = 7.8 Hz, 1H), 6.02 (s,
1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 1.32 (s, 9H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 167.3, 164.0, 152.9, 148.5,
141.6, 134.6, 127.4, 127.2, 123.9, 122.2, 117.0, 114.1, 106.8,
106.5, 61.2, 60.6, 57.8, 55.8, 51.3, 28.4. IR (ν=max/cm-1):
3334, 3082, 2964, 2937, 2835, 1682, 1638, 1591, 1507,
1456, 1237, 1127, 1076, 727. HRMS (DART, [M+H]+) m/z
calcd for C22H2679Br1N2O5S1 509.0746, found 509.0744
N-(tert-butyl)-2-(2-iodobenzoyl)-5,6,7-trimethoxy-1,2-
dihydroisoquinoline-1-carboxamide (12s)
Using the general procedure, this compound was obtained
as a pale yellow solid in 80% (220 mg) yield after
purification by flash column chromatography (5/5 EtOAc–
hexanes) Rf. 0.5 (5/5 EtOAc–hexanes). m. p. 136-139 °C 1H
NMR (CDCl3, 300 MHz) δ: 7.86 (s, 1H), 7.39 (s, 2H), 7.13 (t, J
= 8.4 Hz, 2H), 6.64 (s, 1H), 6.09 (s, 2H), 6.06 (s, 1H), 3.84 (s,
9H), 1.32 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 169.3,
167.5, 153.2, 148.8, 141.9, 139.6, 131.3, 128.4, 122.5, 107.1,
106.8, 92.9, 61.5, 60.9, 57.9, 56.2, 28.9, 28.5. IR (ν=max/cm-
1): 3400, 3054, 2969, 2937, 1687, 1652, 1463, 1366, 1119,
1092, 769, 742. HRMS (DART, [M+H]+) m/z calcd for
C24H28I1N2O5 551.1042, found 551.1049.
2-(2-bromonicotinoyl)-N-(tert-butyl)-5,6,7-trimethoxy-
1,2-dihydroisoquinoline-1-carboxamide (12w)
Using the general procedure, this compound was obtained
as a yellow solid in 74% (186 mg) yield after purification by
flash column chromatography (7/3 EtOAc–Hexanes) Rf. 0.5
(7/3 EtOAc–Hexanes). m. p.152-155 °C. 1H NMR (CDCl3, 300
MHz) δ: 8.46 (dd, J = 4.8, 2.0 Hz, 1H), 7.53 (s, 1H), 7.44 – 7.27
(m, 2H), 6.66 (s, 1H), 6.17 (s, 1H), 6.12 (s, 1H), 6.07 (s, 1H),
3.86 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 1.30 (s, 9H). 13C{1H}
NMR (CDCl3, 75 MHz) δ: 167.0, 166.2, 153.4, 151.3, 150.8,
139.9, 138.7, 137.4, 123.0, 122.2, 121.4, 108.1, 107.3, 106.9,
106.6, 61.4, 60.9, 57.9, 56.2, 51.8, 28.8. IR (ν=max/cm-1):
3403, 3365, 3065, 2968, 2937, 2842, 1688, 1631, 1575,
1496, 1462, 1395, 1363, 1249, 1120, 1092, 889, 813, 753,
677, 631, 469. HRMS (DART, [M+H]+) m/z calcd for
C23H2779Br1N3O5 504.1134, found 504.1134.
2-(2-(2-iodophenyl)acetyl)-5,6,7-trimethoxy-N-(4-
methoxyphenyl)-1,2-dihydroisoquinoline-1-carboxamide
(12t)
Using the general procedure, this compound was obtained
as a pale yellow solid in 70% (214 mg) yield after
purification by flash column chromatography (5/5 EtOAc–
1
hexanes) Rf. 0.6 (5/5 EtOAc–hexanes). m. p. 99-102 °C H
2-(2-(2-iodophenyl)acetyl)-5,6,7-trimethoxy-N-octyl-1,2-
dihydroisoquinoline-1-carboxamide (12x)
NMR (CDCl3, 300 MHz) (mixture of rotamers) δ: 7.86 (d, J =
7.8 Hz, 1H), 7.39 – 7.13 (m, 5H), 7.05 – 6.89 (m, 3H), 6.80 –
6.72 (m, 1H), 6.67 (s, 1H), 6.35 (s, 1H), 5.92 (d, J = 5.6 Hz,
1H), 3.92 (s, 1H), 3.88 (s, 1H), 3.86 – 3.74 (m, 12H). 13C{1H}
NMR (75 MHz, CDCl3) (mixture of rotamers) δ: 169.7, 168.3,
163.6, 158.9, 156.3, 153.7, 153.4, 148.9, 139.6, 137.5, 137.4,
130.3, 130.2, 129.2, 128.7, 128.5, 127.0, 121.5, 121.3, 116.3,
115.1, 114.6, 114.5, 114.0, 107.1, 107.1, 104.0, 103.2, 62.7,
61.5, 60.9, 60.8, 58.6, 57.7, 56.3, 56.2, 55.6, 55.5, 45.6, 45.5,
45.1. IR (ν=max/cm-1): 3297, 3056, 2936, 2834, 1682, 1661,
1590, 1462, 1125, 1011, 832, 746. HRMS (DART,
Using the general procedure, this compound was obtained
as a pale yellow oil in 92% (285 mg) yield after purification
by flash column chromatography (3/7 EtOAc–Hexanes) Rf.
0.3 (3/7 EtOAc–Hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.89
– 7.74 (m, 1H), 7.34 – 7.11 (m, 2H), 7.04 – 6.89 (m, 1H), 6.55
(s, 1H), 6.25 (dd, J = 5.8, 1.4 Hz, 1H), 6.18 (s, 1H), 5.71 – 5.64
(m, 1H), 3.97 – 3.87 (m, 2H), 3.84 – 3.74 (m, 9H), 3.55 (q, J =
7.0 Hz, 2H), 1.65 – 1.50 (m, 2H), 1.34 – 1.16 (m, 10H), 0.86
(t, J = 6.5 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: (major
rotamer) 168.2, 163.9, 153.4, 139.6, 137.5, 131.8, 130.2,
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The Journal of Organic Chemistry
129.2, 128.8, 128.5, 115.0, 113.7, 108.5, 104.1, 103.2, 101.1, Using the general procedure, this compound was obtained
1
2
3
4
5
6
7
8
60.9, 58.4, 56.2, 46.7, 46.4, 45.6, 45.2, 31.8, 29.2, 28.5, 26.7,
22.7, 14.2. IR (ν=max/cm-1): 3450, 2928, 2854, 1675, 1589,
1505, 1459, 1420, 1367, 1327, 1240, 1127, 1010, 845, 746,
593, 490. HRMS (DART, [M+H]+) m/z calcd for
C29H38I1N2O5 621.1825, found 621.1810.
as an pale brown solid in 62% (39 mg) yield after
purification by flash column chromatography (2/8 EtOAc–
hexanes) Rf. 0.3 (2/8 EtOAc–hexanes), m. p. 199-201 °C. 1H
NMR (CDCl3, 300 MHz) δ: 7.64 (dd, J = 6.3, 2.1 Hz, 1H), 7.38–
7.27 (m, 3H), 6.59 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H),
5.95 (s, 1H), 5.32 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.65 (s,
2H), 2.62 (s, 3H), 1.04 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: 168.7, 167.6, 160.3, 158.6, 135.7, 133.1, 132.2, 128.0,
127.8, 127.2, 126.9, 126.4, 121.7, 114.4, 105.9, 100.2, 56.5,
55.7, 55.6, 51.4, 40.0, 28.4, 16.6. IR (ν=max/cm-1): 3321, 2970,
2923, 1691, 1641, 1600, 1324, 1161, 761. HRMS (DART,
[M+H]+) m/z calcd for C25H29N2O4 421.2127, found
421.2129.
2-(2-iodobenzoyl)-5,6,7-trimethoxy-N-(2-
morpholinoethyl)-1,2-dihydroisoquinoline-1-carboxamide
(12y)
9
Using the general procedure, this compound was obtained
as a white solid in 65% (197 mg) yield after purification by
flash column chromatography (9/1 EtOAc–MeOH) Rf. 0.3
(9/1 EtOAc–MeOH). m. p. 95-98 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.79 (dd, J = 28.8, 7.9 Hz, 2H), 7.46 – 7.33 (m, 2H),
7.20 – 6.98 (m, 2H), 6.74 (s, 1H), 6.47 – 6.33 (m, 1H), 6.22 –
6.03 (m, 1H), 3.84 – 3.77 (m, 9H), 3.67 – 3.64 (m, 2H), 3.40
– 3.20 (m, 2H), 2.68 – 2.34 (m, 8H). 13C{1H} NMR (CDCl3, 75
MHz) δ: (mixture of rotamers) 169.5, 166.2, 166.0, 153.3,
153.2, 140.3, 139.1, 131.6, 131.3, 131.2, 130.7, 130.6,
129.2, 128.6, 128.5, 128.4, 128.2, 106.8, 86.7, 67.0, 66.3,
61.5, 61.0, 57.8, 57.3, 57.2, 56.6, 56.3, 55.9, 54.0, 53.3,
42.1, 41.8. IR (ν=max/cm-1): 3432, 3292, 2939, 2855, 1678,
1643, 1591, 1461, 1332, 1187, 1125, 1035, 1010, 815, 774,
749, 683, 568. HRMS (DART, [M+H]+) m/z calcd for
C26H31I1N3O6 608.1257, found 608.1245.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(tert-butyl)-10,11,12-trimethoxy-13-methyl-6-oxo-5,8-
dihydro-6H-isoquinolino[3,2-a]isoquinoline-8-
carboxamide (13b)
Using the general procedure, this compound was obtained
as an orange solid in 56% (38 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.4
1
(3/7 EtOAc–hexanes), m. p. 79-82 °C. H NMR (CDCl3, 300
MHz) δ: 7.72 – 7.57 (m, 1H), 7.33 (dq, J = 11.1, 6.3, 4.8 Hz,
4H), 6.77 (s, 1H), 5.93 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.84
(s, 3H), 3.62 (d, J = 27.7 Hz, 2H), 2.65 (s, 3H), 1.04 (s, 9H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 168.6, 167.7, 153.3, 152.4,
143.0, 132.9, 132.3, 129.1, 128.3, 127.9, 127.6, 127.3, 126.5,
121.2, 118.5, 108.7, 61.3, 60.9, 56.2, 51.5, 40.0, 29.8, 28.4,
15.9. IR (ν=max/cm-1): 3420, 3345, 2923, 2852, 1735, 1674,
2-(2-iodobenzoyl)-5,8-dimethoxy-N-(2-morpholinoethyl)-
1,2-dihydroisoquinoline-1-carboxamide (14)
[M+H]+) m/z calcd
for
Using the general procedure, this compound was obtained
as a white solid in 67% (193 mg) yield after purification by
flash column chromatography (9/1 EtOAc–MeOH) Rf. 0.6
(9/1 EtOAc–MeOH). m. p. 71-74 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.81 (d, J = 7.8 Hz, 1H), 7.46 – 7.34 (m, 1H), 7.16 –
6.99 (m, 3H), 6.89 – 6.71 (m, 2H), 6.58 (s, 1H), 5.91 (d, J =
6.4 Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H), 5.59 (s, 1H), 3.87 (s, 2H),
3.73 (s, 3H), 3.65 – 3.57 (m, 4H), 3.30 (s, 1H), 2.58 – 2.48 (m,
2H), 2.47 – 2.39 (m, 4H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
168.9, 164.0, 153.6, 151.6, 139.4, 138.7, 130.9, 130.5, 128.4,
127.7, 115.1, 113.9, 112.8, 111.2, 66.9, 66.3, 56.9, 56.5, 55.9,
55.7, 54.2, 53.7, 43.2. IR (ν=max/cm-1): 3463, 2953, 2832,
2810, 1656, 1585, 1500, 1459, 1246, 1115, 1017, 771, 763.
1100.
HRMS
(DART,
C26H31N2O5 451.2233, found 451.2233.
N-cyclopentyl-10,11,12-trimethoxy-13-methyl-6-oxo-5,8-
dihydro-6H-isoquinolino[3,2-a]isoquinoline-8-
carboxamide (13c)
Using the general procedure, this compound was obtained
as an orange solid in 53% (37 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.4
1
(4/6 EtOAc–hexanes), m. p. 72-75 °C. H NMR (CDCl3, 300
MHz) δ: 7.67 – 7.59 (m, 1H), 7.39 – 7.28 (m, 3H), 6.80 (s, 1H),
6.00 (s, 1H), 5.41 (d, J = 7.1 Hz, 1H), 4.08 – 3.96 (m, 1H), 3.93
(s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.67 (s, 2H), 2.64 (s, 3H),
1.79 – 1.67 (m, 2H), 1.42 – 1.34 (m, 2H), 1.06 – 0.84 (m, 4H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 168.7, 167.9, 153.3, 152.4,
143.1, 132.7, 132.3, 128.8, 128.3, 127.9, 127.5, 127.3, 126.5,
121.0, 118.5, 108.7, 61.3, 60.9, 56.2, 55.6, 51.5, 40.0, 33.1,
32.8, 29.8, 23.6, 23.5, 16.0. IR (ν=max/cm-1): 3411, 3327,
2921, 2853, 1649, 1596, 1099. 761. HRMS (DART,
[M+H]+) m/z calcd for C27H31N2O5 463.2233, found
463.2217.
HRMS
(DART,
[M+H]+) m/z
calcd
for
C25H29I1N3O5 578.1151, found 578.1153.
General Procedure for the synthesis of fused-isoquinolines
13a-y and 15
A deoxygenated solution (Argon-1 h) of the corresponding
dihydroisoquinoline 12a–y (0.15 mmol, 1.0 equiv.),
palladium(II) acetate (20 mol%), tricyclohexylphosphine
tetrafluoroborate (40 mol %), and cesium carbonate (2.5
equiv.) in anhydrous toluene (0.1 M) was heated at 135 °C
(the temperature was monitored using an internal IR
probe) under microwave irradiation (100 W) for 2.5 hours
using a sealed vessel. After removal of volatiles the crude
was partitioned between ethyl acetate and sat. NaCl, and the
organic phase was dried (Na2SO4) and concentrated under
reduced pressure. The resulting crude was purified by flash
column chromatography (SiO2).
N-cyclohexyl-1,2,3-trimethoxy-12-methyl-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13d)
Using the general procedure, this compound was obtained
as an yellow solid in 54% (37 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.4
(3/7 EtOAc–hexanes), m. p. 232-235 °C. 1H NMR (CDCl3, 300
MHz) δ: 8.03 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.65
(t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H), 6.78
(d, J = 7.8 Hz, 1H), 5.98 (s, 1H), 3.95 (s, 3H), 3.89 (s, 6H), 3.63
(tt, J = 13.7, 6.7 Hz, 1H), 2.79 (s, 3H), 1.83 – 1.68 (m, 2H),
1.54 (d, J = 15.3 Hz, 2H), 1.27 – 1.03 (m, 5H), 0.92 – 0.78 (m,
1H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.1, 166.9, 153.4,
N-(tert-butyl)-10,12-dimethoxy-13-methyl-6-oxo-5,8-
dihydro-6H-isoquinolino[3,2-a]isoquinoline-8-
carboxamide (13a)
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152.8, 143.1, 135.8, 132.2, 129.8, 129.1, 128.2, 126.3, 124.0, MHz) δ: 8.01 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.67–
1
2
3
4
5
6
7
8
123.6, 120.3, 117.2, 107.6, 61.4, 60.9, 57.6, 56.2, 48.7, 32.6,
32.6, 25.5, 24.6, 17.0. IR (ν=max/cm-1): 3301, 2928, 2852,
1705, 1651, 1102, 1019, 726. HRMS (DART,
[M+H]+) m/z calcd for C27H31N2O5 463.2233, found
463.2240.
7.60 (m, 1H), 7.53–7.46 (m, 1H), 6.77 (s, 1H), 6.27 (s, 1H),
5.79 (s, 1H), 3.93 (s, 3H), 3.90 (s, 6H), 2.78 (s, 3H), 1.23 (s,
9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 168.0, 166.8, 153.4,
152.9, 143.2, 135.8, 132.2, 129.5, 129.1, 128.3, 126.2, 123.9,
123.8, 120.5, 117.2, 107.5, 61.5, 61.0, 58.1, 56.3, 51.8, 28.8,
17.0. IR (ν=max/cm-1): 3326, 3063, 3031, 2924, 2852, 1738,
N-benzyl-1,3-dimethoxy-12-methyl-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13e)
1644,
1111.
HRMS
(DART+) m/z calcd
for
C25H29N2O5 [M+H]+ 437.2076, found 437.2069.
Using the general procedure, this compound was obtained
as an yellow solid in 46% (30 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.3
(4/6 EtOAc–hexanes), m. p. 237-240 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.96 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.61
(t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 2.6 Hz,
1H), 7.17 (dq, J = 5.2, 2.7 Hz, 3H), 7.08 (dt, J = 4.8, 2.6 Hz,
2H), 6.65 (s, 1H), 6.48 (s, 1H), 5.93 (s, 1H), 4.40 – 4.30 (m,
2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.73 (s, 3H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 168.9, 166.8, 160.6, 159.3, 132.1, 128.6,
128.0, 127.3, 123.9, 123.6, 105.2, 99.9, 57.7, 43.7, 29.8, 18.0.
IR (ν=max/cm-1): 3296, 2920, 2850, 1720, 1690, 1652, 1455,
1396, 1158, 1028, 753, 694. HRMS (DART,
[M+H]+) m/z calcd for C27H25N2O4 441.1814, found
441.1801.
10-chloro-1,3-dimethoxy-12-methyl-7-oxo-N-phenyl-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13i)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Using the general procedure, this compound was obtained
as an yellow solid in 65% (45 mg) yield after purification by
flash column chromatography (5/5 EtOAc–hexanes) Rf. 0.4
(5/5 EtOAc–hexanes), m. p. 280-283 °C. 1H NMR (CDCl3, 400
MHz) δ: 8.66 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.2
Hz, 1H), 7.44 (dd, J = 8.1, 1.7 Hz, 2H), 7.42–7.36 (m, 2H),
7.23–7.13 (m, 1H), 7.07–6.95 (m, 1H), 6.71 (d, J = 2.5 Hz,
1H), 6.50 (d, J = 2.5 Hz, 1H), 6.14 (s, 1H), 3.89 (s, 3H), 3.88
(s, 3H), 2.74 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ: 166.7,
166.4, 161.1, 159.7, 138.6, 137.8, 137.2, 132.0, 128.9, 128.3,
127.7, 127.2, 125.0, 124.4, 123.8, 120.3, 119.9, 116.0, 105.5,
99.9, 58.4, 55.7, 29.9, 18.2. IR (ν=max/cm-1): 3284, 3079,
2924, 2839, 1693, 1662, 1598, 1201, 946, 751. HRMS
(DART, [M+H]+) m/z calcd for C26H22Cl1N2O4 461.1268,
found 461.1258.
N-(tert-butyl)-1,3-dimethoxy-12-methyl-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13f)
Using the general procedure, this compound was obtained
as an yellow solid in 59% (36 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.4
(3/7 EtOAc–hexanes), m. p. 245-248 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.96 (d, J = 8.0 Hz, 1H), 7.90 (dt, J = 7.5, 0.9 Hz, 1H),
7.75 – 7.39 (m, 3H), 6.65 (d, J = 2.5 Hz, 1H), 6.45 (d, J = 2.4
Hz, 1H), 6.37 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.73 (s, 3H),
1.20 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 167.9, 166.8,
160.4, 159.3, 135.9, 134.1, 132.9, 132.0, 129.1, 128.9, 128.6,
127.8, 123.7, 118.0, 105.1, 99.6, 60.5, 58.4, 55.7, 51.7, 28.7,
18.0. IR (ν=max/cm-1): 3293, 3054, 2967, 2930, 2838, 1660,
1602, 1207, 1157. HRMS (DART, [M+H]+) m/z calcd for
C24H27N2O4 407. 1970, found 407.1966.
N-benzyl-10-fluoro-1,2,3-trimethoxy-12-methyl-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13j)
Using the general procedure, this compound was obtained
as an yellow pale solid in 49% (36 mg) yield after
purification by flash column chromatography (3/7 EtOAc–
hexanes) Rf. 0.3 (3/7 EtOAc–hexanes), m. p. 254-257 °C. 1H
NMR (CDCl3, 400 MHz) δ: 7.86 (dd, J = 8.4, 5.3 Hz, 1H), 7.65
(dd, J = 9.6, 1.9 Hz, 1H), 7.23 – 7.14 (m, 4H), 7.07 (dd, J = 6.8,
2.5 Hz, 2H), 6.86 (s, 1H), 6.62 (t, J = 5.4 Hz, 1H), 5.88 (s, 1H),
4.41 – 4.28 (m, 2H), 3.91 (s, 6H), 3.90 (s, 3H), 2.73 (s, 3H).
13C{1H} NMR (CDCl3, 100 MHz) δ: 168.9, 166.7, 165.06 (d, J
= 178.8 Hz), 153.8, 153.1, 143.4, 137.9, 128.7, 127.5, 127.4,
125.89 (d, J = 8.1 Hz), 120.1, 118.4, 116.11 (d, J = 24.2 Hz),
111.01 (d, J = 26.4 Hz), 107.6, 61.5, 61.0, 57.6, 56.3, 43.8,
29.9, 16.9. HRMS (DART, [M+H]+) m/z calcd for
C28H26F1N2O5 489. 1825, found 489.1851.
1,3-dimethoxy-12-methyl-N-(naphthalen-2-yl)-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13g)
Using the general procedure, this compound was obtained
as an yellow solid in 47% (34 mg) yield after purification by
flash column chromatography (2/8 EtOAc–hexanes) Rf. 0.3
N-dodecyl-2-(2-iodobenzoyl)-5,6,7-trimethoxy-4-methyl-
1,2-dihydroisoquinoline-1-carboxamide (13k).
1
(2/8 EtOAc–hexanes), m. p. decomposition at > 200 °C. H
NMR (DMSO-d6, 300 MHz) δ: 10.76 (s, 1H), 8.21 (s, 1H), 8.12
(d, J = 7.9 Hz, 1H), 7.88 – 7.73 (m, 4H), 7.58 (t, J = 7.5 Hz, 2H),
7.41 (dt, J = 14.8, 6.8 Hz, 2H), 7.18 (d, J = 1.9 Hz, 1H), 6.65 (d,
J = 2.0 Hz, 1H), 6.02 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.68 (s,
3H). 13C{1H} NMR (DMSO-d6, 75 MHz) δ: 167.6, 165.7, 160.2,
159.0, 135.96, 135.4, 133.3, 132.3, 132.2, 129.9, 129.4,
128.7, 128.5, 128.1, 127.4, 127.3, 126.5, 124.8, 123.8, 123.0,
119.6, 115.5, 115.1, 114.8, 105.8, 99.2, 57.4, 56.0, 55.5, 17.6.
HRMS (DART, [M+H]+) m/z calcd for C30H25N2O4 477. 1814,
found 477.1820.
Using the general procedure, this compound was obtained
as a pale yellow solid in 67% (90 mg) yield after purification
by flash column chromatography (3/7 EtOAc–hexanes) Rf.
0.4 (3/7 EtOAc–hexanes) m. p. 177-181 °C. 1H NMR (CDCl3,
300 MHz) δ (mixture of rotamers) 7.61 (d, J = 8.3 Hz, 2H),
7.45 (d, J = 7.4 Hz, 3H), 6.71 (s, 1H), 6.53 (t, J = 5.5 Hz, 1H),
6.19 (s, 1H), 6.02 (s, 1H), 3.87 (d, J = 2.9 Hz, 9H), 3.19 (q, J =
6.6 Hz, 2H), 2.12 (s, 3H), 1.44 (s, 2H), 1.24 (s, 32H), 0.87 (t, J
= 6.7 Hz, 6H). 13C{1H} NMR (CDCl3, 75 MHz) δ 169.2, 169.1,
152.9, 151.2, 142.9, 133.7, 131.5, 129.4, 128.5, 126.4, 123.8,
122.6, 120.3, 119.2, 117.8, 107.4, 61.3, 60.8, 58.4, 56.2, 39.7,
32.0, 29.7, 29.4, 29.3, 26.9, 22.8, 19.1, 14.2. IR (ν=max/cm-1):
3330, 3067, 2926, 2853, 1652, 1596, 1462, 1108, 768, 749.
HRMS (DART, [M+H]+) m/z calcd for C33H45N2O5 549.3328,
found 549.3327.
N-(tert-butyl)-1,2,3-trimethoxy-12-methyl-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13h)
Using the general procedure, this compound was obtained
as a yellow solid in 53% (34 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.4
1
(3/7 EtOAc–hexanes), m. p. 89-92 °C. H NMR (CDCl3, 300
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The Journal of Organic Chemistry
1,2,3-trimethoxy-12-methyl-N-octyl-7-oxo-5,7- flash column chromatography (4/6 EtOAc–Hexanes) Rf. 0.2
(4/6 EtOAc–Hexanes). m. p. 270-272 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.55 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.61
(d, J = 2.2 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 8.0 Hz,
1H), 5.66 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.71 – 3.51 (m,
1H), 2.63 (s, 3H), 1.74 (d, J = 12.9 Hz, 4H), 1.55 (d, J = 10.0
Hz, 2H), 1.05 (d, J = 11.8 Hz, 2H), 0.83 (d, J = 7.5 Hz, 2H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 168.3, 161.6, 160.9, 160.1,
148.5, 133.8, 121.0, 119.8, 117.0, 113.9, 106.1, 105.5, 99.3,
58.0, 55.6, 48.6, 32.8, 29.8, 27.8, 26.7, 25.5, 24.6, 18.4. IR
(ν=max/cm-1): 3299, 2924, 2855, 1695, 1648, 1602, 1548,
1455, 1360, 1323, 1204, 1162, 1093, 1047, 892, 846, 727.
HRMS (DART, [M+H]+) m/z calcd for C24H27N2O5 423.1920,
found 423.1910.
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dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13l)
Using the general procedure, this compound was obtained
as a yellow solid in 45% (33 mg) yield after purification by
flash column chromatography (3/7 EtOAc–hexanes) Rf. 0.3
(3/7 EtOAc–hexanes). m. p. 184-187 °C. 1H NMR (CDCl3, 300
MHz) δ: 8.02 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.64
(td, J = 7.7, 1.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H),
6.87 (t, J = 5.5 Hz, 1H), 5.99 (s, 1H), 3.95 (s, 3H), 3.88 (s, 3H),
3.88 (s, 3H), 3.11 (dtq, J = 27.3, 14.0, 7.1 Hz, 2H), 2.78 (s, 3H),
1.34 – 1.11 (m, 10H), 0.83 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 169.0, 166.9, 153.4, 152.7, 143.1, 135.8,
132.2, 129.7, 129.1, 128.2, 126.2, 123.9, 123.6, 120.2, 117.3,
107.6, 61.4, 60.9, 57.4, 56.2, 39.8, 31.8, 29.3, 29.2, 29.2, 26.8,
22.7, 16.9, 14.1. IR (ν=max/cm-1): 3307, 2926, 2853, 1706,
1654, 1464, 1106, 759, 720. HRMS (DART, [M+H]+) m/z
calcd for C29H37N2O5 493.2702, found 493.2696.
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N-(tert-butyl)-8,9,10-trimethoxy-11-methyl-4-oxo-4,6-
dihydrothieno[2',3':3,4]pyrrolo[1,2-b]isoquinoline-6-
carboxamide (13p)
ethyl (2S)-2-phenyl-2-(1,2,3-trimethoxy-12-methyl-7-oxo-
5,7-dihydroisoindolo[2,1-b]isoquinoline-5-
carboxamido)acetate (13m)
Using the general procedure, this compound was obtained
as a pale yellow solid in 16% (11 mg) yield after purification
by flash column chromatography (4/6 EtOAc–Hexanes) Rf.
0.1 (4/6 EtOAc–Hexanes). m. p. 222-225 °C. 1H NMR (CDCl3,
300 MHz) δ: 7.42 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 5.7 Hz, 1H),
6.90 (s, 1H), 6.61 (s, 1H), 5.74 (s, 1H), 3.91 (s, 3H), 3.89 (s,
3H), 3.86 (s, 3H), 2.56 (s, 3H), 1.24 (s, 9H). 13C{1H} NMR
(CDCl3, 75 MHz) δ: 168.4, 163.2, 153.6, 153.1, 143.5, 142.9,
136.6, 130.9, 127.8, 127.0, 120.1, 118.9, 115.9, 107.6, 61.4,
60.9, 58.6, 56.2, 51.8, 28.7, 18.1. IR (ν=max/cm-1): 3409, 3305,
3077, 2967, 2856, 1662, 1594, 1550, 1457, 1363, 1325,
1250, 1152, 1102, 1018, 1018, 981, 883, 732, 518. HRMS
(DART, [M+H]+) m/z calcd for C23H27N2O5S1 443.1640,
found 443.1629.
Using the general procedure, this compound was obtained
as a yellow solid in 28% (23 mg) yield after purification by
flash column chromatography (4/6 EtOAc–hexanes) Rf. 0.3
(4/6 EtOAc–hexanes). 1H NMR (CDCl3, 300 MHz) δ: 7.95 (dd,
J = 13.7, 7.7 Hz, 2H), 7.71 – 7.59 (m, 1H), 7.50 (t, J = 7.5 Hz,
1H), 7.11 – 6.99 (m, 3H), 6.86 – 6.79 (m, 2H), 6.75 (s, 1H),
6.54 (d, J = 7.6 Hz, 1H), 5.85 (s, 1H), 4.70 (dt, J = 7.5, 5.5 Hz,
1H), 4.06 (q, J = 7.1 Hz, 2H), 3.93 (d, J = 8.8 Hz, 1H), 3.90 –
3.89 (m, 5H), 3.88 (s, 3H), 3.14 – 2.89 (m, 2H), 2.71 (s, 3H),
1.12 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
170.4, 168.2, 166.2, 153.4, 153.0, 152.4, 142.9, 135.2, 135.2,
131.8, 128.9, 128.7, 128.0, 127.9, 126.5, 124.9, 123.7, 123.5,
119.8, 116.1, 107.2, 101.5, 61.2, 60.6, 56.9, 55.9, 53.0, 37.1,
29.4, 16.4, 13.7. IR (ν=max/cm-1): 3299, 2927, 2852, 1691,
1658, 1597, 1457, 1329, 1199, 1104, 1026, 744, 699. HRMS
(DART, [M+H]+) m/z calcd for C32H33N2O7 557.2287, found
557.2287.
3-chloro-N-cyclohexyl-9,10,11-trimethoxy-12-methyl-5-
oxo-5,7-dihydropyrido[2',3':3,4]pyrrolo[1,2-
b]isoquinoline-7-carboxamide (13q)
Using the general procedure, this compound was obtained
as a pale yellow solid in 84% (62 mg) yield after purification
by flash column chromatography (3/7 EtOAc–Hexanes) Rf.
0.2 (3/7 EtOAc–Hexanes). m. p. 258-260 °C. 1H NMR (CDCl3,
300 MHz) δ: 8.76 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H),
6.80 (s, 1H), 6.11 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 3.92 (s, 3H),
3.91 (s, 3H), 3.88 (s, 3H), 3.67 – 3.56 (m, 1H), 3.06 (s, 3H),
1.74 (dd, J = 13.9, 3.7 Hz, 4H), 1.61 – 1.56 (m, 2H), 1.05 (dd,
J = 10.4, 2.3 Hz, 2H), 0.90 – 0.79 (m, 2H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 167.5, 165.0, 162.7, 154.2, 153.6, 151.8, 143.4,
130.8, 126.1, 123.8, 122.2, 119.3, 109.5, 107.2, 61.4, 60.9,
57.6, 56.3, 48.9, 32.8, 32.7, 29.8, 25.4, 24.6, 15.9. IR
(ν=max/cm-1): 3311, 3292, 2928, 2854, 1704, 1646, 1593,
1461, 1329, 1112, 1034, 799. HRMS (DART, [M+H]+) m/z
calcd for C26H29ClN3O5 498.1795, found 498.1788.
N-cyclohexyl-8,9,10-trimethoxy-11-methyl-4-oxo-4,6-
dihydrofuro[2',3':3,4]pyrrolo[1,2-b]isoquinoline-6-
carboxamide (13n)
Using the general procedure, this compound was obtained
as a beige solid in 51% (35 mg) yield after purification by
flash column chromatography (4/6 EtOAc–Hexanes) Rf. 0.2
(4/6 EtOAc–Hexanes). m. p. 167-170 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.59 (d, J = 1.9 Hz, 1H), 6.82 (s, 1H), 6.68 (d, J = 1.9
Hz, 1H), 6.04 (d, J = 8.4 Hz, 1H), 5.66 (s, 1H), 3.91 (s, 3H),
3.89 (s, 3H), 3.87 (s, 3H), 3.71 – 3.57 (m, 1H), 2.66 (s, 3H),
1.84 – 1.72 (m, 3H), 1.57 – 1.45 (m, 3H), 1.13 – 1.03 (m, 3H),
0.84 (dd, J = 10.6, 5.3 Hz, 1H). 13C{1H} NMR (CDCl3, 75 MHz)
δ: 168.5, 161.5, 153.8, 153.5, 148.9, 143.0, 127.1, 122.0,
120.2, 118.3, 116.1, 107.8, 106.2, 61.5, 60.9, 57.8, 56.3, 48.7,
32.8, 29.8, 25.5, 24.6, 17.3. IR (ν=max/cm-1): 3294, 2928,
2853, 1677, 1649, 1596, 1554, 1465, 1106, 1027, 988 HRMS
(DART, [M+H]+) m/z calcd for C25H29N2O6 453.2025, found
453.2032.
N-(tert-butyl)-9,10,11-trimethoxy-12-methyl-5-oxo-5,7-
dihydropyrido[2',3':3,4]pyrrolo[1,2-b]isoquinoline-7-
carboxamide (13r)
Using the general procedure, this compound was obtained
as a yellow solid in 42% (33 mg) yield after purification by
flash column chromatography (5/5 EtOAc–Hexanes) Rf. 0.2
(5/5 EtOAc–Hexanes). m. p. decomposition at > 205 °C. 1H
NMR (CDCl3, 300 MHz) δ: 8.84 (dd, J = 4.8, 1.7 Hz, 1H), 8.12
(dd, J = 7.7, 1.7 Hz, 1H), 7.35 (ddd, J = 7.7, 4.9, 2.4 Hz, 1H),
6.91 (s, 1H), 6.49 (s, 1H), 5.88 (s, 1H), 3.93 (s, 3H), 3.90 (s,
3H), 3.87 (s, 3H), 3.11 (s, 3H), 1.22 (s, 9H). 13C{1H} NMR
N-cyclohexyl-8,10-dimethoxy-11-methyl-4-oxo-4,6-
dihydrofuro[2',3':3,4]pyrrolo[1,2-b]isoquinoline-6-
carboxamide (13o)
Using the general procedure, this compound was obtained
as a yellow solid in 74% (47 mg) yield after purification by
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The Journal of Organic Chemistry
Page 18 of 21
(CDCl3, 75 MHz) δ: 167.9, 164.2, 156.1, 154.0, 152.8, 143.2,
(6/4 EtOAc–Hexanes). m. p. 100-103 °C:1H NMR (CDCl3, 300
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131.1, 127.2, 126.5, 123.1, 122.2, 121.5, 119.6, 107.2, 61.4,
60.9, 58.1, 56.2, 51.8, 28.7, 15.9. IR (ν=max/cm-1): 3310, 2966,
2931, 2851, 1699, 1667, 1592, 1546, 1456, 1403, 1368,
1322, 1194, 1108, 1022, 1194, 1108, 1022, 950, 787, 553,
MHz) δ: 7.42 (d, J = 4.9 Hz, 1H), 7.30 (d, J = 2.9 Hz, 2H), 6.80
(s, 1H), 6.71 (s, 1H), 6.08 (s, 1H), 5.64 (s, 1H), 3.99 (s, 3H),
3.91 (s, 3H), 3.90 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 168.2, 153.9, 137.7, 130.5, 128.5, 127.6, 126.1,
125.1, 120.3, 106.9, 105.9, 101.0, 70.3, 60.9, 58.6, 57.2, 56.2,
45.6, 28.6. IR (ν=max/cm-1): 3311, 3068, 1665, 1600, 1458,
1359, 1232, 1119, 1086, 1029, 730, 618, 482. HRMS (DART,
[M+H]+) m/z calcd for C22H25N2O5S1 429.1484, found
429.1487.
512.
HRMS
(DART,
[M+H]+) m/z
calcd
for
C24H28N3O5 438.2029, found 438.2033.
N-(tert-butyl)-1,2,3-trimethoxy-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13s)
9
Using the general procedure, this compound was obtained
as a brown solid in 62% (40 mg) yield after purification by
flash column chromatography (5/5 EtOAc–hexanes) Rf. 0.4
(5/5 EtOAc–hexanes). m. p. 185-188 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.76 (t, J = 6.8 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.42
(t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 5.84
(s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 1.19 (s, 9H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 168.2, 166.8, 153.6, 150.0,
141.9, 135.2, 132.0, 131.6, 128.9, 128.4, 125.0, 123.1, 120.5,
117.6, 106.9, 99.2, 61.7, 60.9, 58.1, 56.2, 51.7, 28.6. IR
(ν=max/cm-1): 3306, 3062, 2966, 2843, 1671, 1599, 1494,
1464, 1120, 1090, 761, 727. HRMS (DART, [M+H]+) m/z
calcd for C24H27N2O5 423.1920, found 423.1915.
N-(tert-butyl)-9,10,11-trimethoxy-5-oxo-5,7-
dihydropyrido[2',3':3,4]pyrrolo[1,2-b]isoquinoline-7-
carboxamide (13w)
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Using the general procedure, this compound was obtained
as a yellow solid in 19% (15 mg) yield after purification by
flash column chromatography (7/3 EtOAc–Hexanes) Rf. 0.4
(7/3 EtOAc–Hexanes). m. p. 182-185 °C. 1H NMR (CDCl3, 300
MHz) δ: (major rotamer) 8.75 (dd, J = 4.9, 1.5 Hz, 1H), 8.06
(dd, J = 7.8, 1.6 Hz, 1H), 7.34 (dd, J = 7.8, 4.9 Hz, 2H), 6.87 (s,
1H), 6.59 (s, 1H), 5.82 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.82
(s, 3H), 1.20 (s, 9H). 13C{1H} NMR (CDCl3, 75 MHz) δ:
(mixture of rotamers) 169.3, 167.9, 164.4, 154.3, 153.4,
152.8, 142.0, 140.9, 131.8, 131.7, 131.3, 125.4, 124.5, 123.3,
122.7, 117.2, 106.6, 105.4, 101.5, 61.7, 60.9, 58.2, 55.9, 55.9,
55.2, 51.8, 28.7, 28.6. IR (ν=max/cm-1): 3312, 3064, 2970,
2939, 1672, 1594, 1549, 1462, 1366, 1324, 1226, 1179,
1119, 1083, 1028, 991, 781. HRMS (DART, [M+H]+) m/z
calcd for C23H26N3O5 424.1872, found 424.1882.
10,11,12-trimethoxy-N-(4-methoxyphenyl)-6-oxo-5,8-
dihydro-6H-isoquinolino[3,2-a]isoquinoline-8-
carboxamide (13t)
Using the general procedure, this compound was obtained
as a pale brown solid in 35% (26 mg) yield after purification
by flash column chromatography (5/5 EtOAc–hexanes) Rf.
1
10,11,12-trimethoxy-N-octyl-6-oxo-5,8-dihydro-6H-
isoquinolino[3,2-a]isoquinoline-8-carboxamide (13x)
0.4 (5/5 EtOAc–hexanes). m. p. 95-98 °C. H NMR (CDCl3,
300 MHz) δ: 7.41 (d, J = 6.3 Hz, 1H), 7.33 – 7.21 (m, 5H), 6.99
– 6.92 (m, 2H), 6.56 (s, 2H), 6.47 (s, 1H), 6.42 (s, 1H), 3.90
(d, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66 (s, 6H).
13C{1H} NMR (75 MHz, CDCl3) δ: 167.1, 163.2, 159.0, 153.5,
132.0, 130.2, 129.3, 128.6, 128.1, 127.4, 127.2, 122.0, 120.6,
114.6, 111.9, 103.1, 60.8, 57.8, 55.9, 55.6, 38.0. IR (ν=max/cm-
1): 3351, 3072, 2936, 2836, 1687, 1590, 1509, 1245, 1125,
1001, 833, 760. HRMS (DART, [M+H]+) m/z calcd for
C28H27N2O6 487.1869, found 487.1878.
Using the general procedure, this compound was obtained
as a brown oil in 48% (35 mg) yield after purification by
flash column chromatography (4/6 EtOAc–Hexanes) Rf. 0.3
(4/6 EtOAc–Hexanes). m. p. 182-185 °C. 1H NMR (CDCl3, 300
MHz) δ:7.45 – 7.38 (m, 1H), 7.30 – 7.25 (m, 2H), 7.23 – 7.17
(m, 1H), 6.45 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 3.82 (s, 2H),
3.74 (s, 3H), 3.62 (s, 6H), 1.67 – 1.59 (m, 2H), 1.26 (dd, J =
9.3, 4.5 Hz, 12H), 0.84 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 167.1, 163.5, 153.4, 130.6, 129.3, 128.5, 128.1,
127.9, 127.5, 122.0, 120.5, 110.7, 103.2, 60.8, 57.5, 55.9,
47.0, 38.0, 31.8, 29.2, 28.6, 26.7, 22.7, 14.1. IR (ν=max/cm-1):
3431, 2928, 2855, 1677, 1591, 1461, 1418, 1327, 1127,
1007, 760, 525. HRMS (DART, [M+H]+) m/z calcd for
C29H37N2O5 493.2702, found 493.2684.
N-(tert-butyl)-8,9,10-trimethoxy-4-oxo-4,6-
dihydrofuro[2',3':3,4]pyrrolo[1,2-b]isoquinoline-6-
carboxamide (13u)
Using the general procedure, this compound was obtained
as a brown solid in 50% (31 mg) yield after purification by
flash column chromatography (5/5 EtOAc–Hexanes) Rf. 0.5
(5/5 EtOAc–Hexanes). m. p. 191-194 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.56 (d, J = 1.9 Hz, 1H), 6.94 (s, 1H), 6.74 (s, 1H),
6.64 (d, J = 1.9 Hz, 1H), 6.57 (s, 1H), 5.71 (s, 1H), 3.94 (s, 3H),
3.89 (s, 3H), 3.86 (s, 3H), 1.26 (s, 9H). 13C{1H} NMR (CDCl3,
75 MHz) δ: 168.6, 161.9, 160.3, 154.1, 150.5, 149.0, 141.8,
125.7, 123.6, 120.3, 116.7, 106.9, 106.0, 103.5, 100.2, 61.7,
60.9, 58.0, 56.2, 51.7, 28.6. IR (ν=max/cm-1): 3431, 3314,
2970, 2940, 1694, 1667, 1596, 1548, 1495, 1468, 1330,
1302, 1128, 987, 737, 565. HRMS (DART, [M+H]+) m/z calcd
for C22H25N2O6 413.1712, found 413.1728.
1,2,3-trimethoxy-N-(2-morpholinoethyl)-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (13y)
Using the general procedure, this compound was obtained
as a yellow solid in 72% (51 mg) yield after purification by
flash column chromatography (9/1 EtOAc–MeOH) Rf. 0.3
(9/1 EtOAc–MeOH). m. p. 79-82 °C. 1H NMR (CDCl3, 300
MHz) δ: (major rotamer) 7.87 – 7.79 (m, 2H), 7.68 – 7.61 (m,
1H), 7.52 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 6.90 (s, 1H), 6.69
(d, J = 7.1 Hz, 1H), 6.04 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.87
(s, 4H), 3.84 (s, 2H), 3.73 (s, 2H), 2.95 – 2.84 (m, 4H), 2.76 –
2.68 (m, 2H), 2.64 – 2.56 (m, 2H). 13C{1H} NMR (CDCl3, 75
MHz) δ: (major rotamer) 169.9, 166.9, 154.2, 153.6, 150.2,
142.1, 135.2, 132.3, 131.0, 129.2, 128.3, 123.3, 120.7, 116.9,
107.3, 105.4, 99.6, 65.0, 61.8, 61.0, 57.7, 56.9, 56.5, 53.2,
34.4. IR (ν=max/cm-1): 3386, 2929, 2852, 2246, 1652, 1592,
1506, 1460, 1422, 1329, 1237, 1188, 1126, 1012, 915, 814,
N-(tert-butyl)-8,9,10-trimethoxy-4-oxo-4,6-
dihydrothieno[2',3':3,4]pyrrolo[1,2-b]isoquinoline-6-
carboxamide (13v)
Using the general procedure, this compound was obtained
as a yellow solid in 34% (21 mg) yield after purification by
flash column chromatography (6/4 EtOAc–Hexanes) Rf. 0.5
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The Journal of Organic Chemistry
731, 694, 567. HRMS (DART, [M+H]+) m/z calcd for
C26H30N3O6 480.2134, found 480.2138.
4. Zhu, H.; Fan, j.; Du, j.; Peng, X. Fluorescent probes for
sensing and imaging within specific cellular organelles. Acc.
Chem. Res. 2016, 49, 2115-2126.
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1,4-dimethoxy-N-(2-morpholinoethyl)-7-oxo-5,7-
dihydroisoindolo[2,1-b]isoquinoline-5-carboxamide (15)
5. a) Dorh, N.; Zhu, S.; Dhungana, K. B.; Pati, R.; Luo, F.; Liu, H.;
Tiwari, A. BODIPY-Based fluorescent probes for sensing
protein surface-hydrophobicity. Scientific Reports. 2015, 5,
18337. b) Shabir, G.; Saeed, A.; Channar, P. A. A. Review on
the recent trends in synthetic strategies and applications of
xanthene dyes. Mini-Reviews in Organic Chemistry 2018, 15,
3, 166-197. c) Kolmakov, K.; Belov, V. N.; Wurm, C. A.; Harke,
B.; Leutenegger, M.; Eggeling, C.; Hell, S. W. A Versatile route
to red-emitting carbopyronine dyes for optical microscopy
and nanoscopy. Eur. J. Org. Chem, 2010, 3593–361.
Using the general procedure, this compound was obtained
as a brown solid in 88% (60 mg) yield after purification by
flash column chromatography (9/1 EtOAc–MeOH) Rf. 0.5
(9/1 EtOAc–MeOH). m. p. 75-78 °C. 1H NMR (CDCl3, 300
MHz) δ: 7.74 (d, J = 7.7 Hz, 1H), 7.62 – 7.48 (m, 2H), 7.41 –
7.34 (m, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.78 (s, 1H), 6.75 (d, J
= 2.8 Hz, 1H), 6.51 (s, 1H), 6.12 (s, 1H), 3.74 (s, 3H), 3.68 (s,
3H), 3.66 – 3.53 (m, 2H), 2.60 (t, J = 6.5 Hz, 1H), 2.52 – 2.45
(m, 3H), 1.92 – 1.78 (m, 3H), 1.46 – 1.36 (m, 1H), 1.28 – 1.18
(m, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 165.1, 164.7, 153.6,
151.3, 133.7, 131.7, 128.8, 128.1, 123.7, 118.9, 116.2, 113.9,
112.9, 107.9, 67.0, 56.7, 55.2, 53.7, 44.6, 35.7, 34.9, 27.0,
26.9, 26.3, 26.2. IR (ν=max/cm-1): 3388, 3080, 2930, 2852,
1676, 1616, 1502, 1449, 1248, 1115, 1045, 759, 718. HRMS
(DART, [M+H]+) m/z calcd for C25H28N3O5 450.2029, found
450.2030.
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6. Kozma, E.
& Kele, P. Fluorogenic probes for super-
resolution microscopy. Org. Biomol. Chem. 2019, 17, 215–
233.
7. Burke, M.D. & Schreiber, S. L. A planning strategy for
diversity-oriented synthesis. Angew. Chem. Int. Ed. 2004,
43, 46–58.
8. Isidro-Llobet, A.; Murillo, T.; Bello, P.; Cilibrizzi, A.;
Hodgkinson, J. T.; Galloway, W. R. J. D.; Bender, A.; Welch,
M.; Spring, D.R. Diversity-oriented synthesis of macrocyclic
peptidomimetics. PNAS 2011, 108 (17), 6793-6798.
9. A. Roy. Early probe and drug discovery in academia: a
minireview. High-Throughput 2018, 7, 4.
10. a) Mijangos, M. V.; Miranda L. D. Multicomponent access to
indolo[3,3a-c]isoquinolin-3,6-diones: formal synthesis of
(±)-plicamine. Org. Biomol. Chem. 2016, 14, 3677-3680. (b)
Supporting Information. Spectroscopic 1H and 13C NMR
data, UV-Vis emission spectrophotometry, confocal
microscopy figures, X-ray crystallography data and CIF files
are provided in the supporting information file. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Miranda,
L.
D.
Hernández-Vázquez,
E.
Multicomponent/palladium-catalyzed cascade entry to
benzopyrrolizidine derivatives: synthesis and antioxidant
evaluation. J. Org. Chem. 2015, 80, 10611-10623. (c)
Chavez-Acevedo, L, Miranda, L. D. Synthesis of novel
tryptamine-based macrocycles using an Ugi 4-
CR/microwave assisted click-cycloaddition reaction
protocol. Org. Biomol. Chem. 2015, 13, 4408-4412. (d) For
a selected review in post-Ugi transformations, see: Sharma,
U. K.; Sharma, N.; Vachhani, D. D.; Van der Eycken, E. V.
Metal-mediated post-Ugi transformations for the
construction of diverse heterocyclic scaffolds. Chem. Soc.
Rev. 2015, 44, 1836-1860.
AUTHOR INFORMATION
Corresponding Author
lmiranda@unam.mx
arturo.jimenez@iquimica.unam.mx
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final
version of the manuscript.
11. (a) Contreras-Cruz, D. A.; Sánchez-Carmona, M. A.;
Vengoechea-Gómez, F. A.; Peña-Ortíz, D.; Miranda, L. D.
Diversity-oriented synthesis of cyclopropyl peptides from
Ugi-derived dehydroalanines. Tetrahedron 2017, 73, 6146-
6156. (b) Pérez-Labrada, K.; Cruz-Mendoza, M. A.; Chávez-
Riveros, A.; Hernández-Vázquez, E.; Torroba, T.; Miranda, L.
D. Diversity-oriented synthesis and cytotoxic activity
evaluation of biaryl-containing macrocycles. Org. Biomol.
Chem. 2017, 15, 2450-2458. (c) García-González, M. C.;
Hernández-Vázquez, E.; Gordillo-Cruz, R. E.; Miranda, L. D.
Ugi-derived dehydroalanines as a pivotal template in the
diversity oriented synthesis of aza-polyheterocycles.
Chem.Commun. 2015, 51, 11669-11672. For previous
reports of fluorescent heterocycles synthetized by Ugi-4CR,
see: (a) Burchak, O. N.; Mugherli, L.; Ostuni, M.; Lacapère, J.
J.; Balakirev, M. Y. Combinatorial Discovery of Fluorescent
Pharmacophores by Multicomponent Reactions in Droplet
Arrays. J. Am. Chem. Soc. 2011, 133, 10058–10061. (b)
Vázquez-Romero, A.; Kielland, N.; Arévalo, M. J. Preciado, S.;
Mellanby, R. J.; Feng, Y.; Lavilla, R.; Vendrell, M.
Multicomponent Reactions for de Novo Synthesis of
BODIPY Probes: In Vivo Imaging of Phagocytic
Macrophages. J. Am. Chem. Soc. 2013, 135, 16018−16021.
(c) Bay, S.; Villnow, T.; Ryseck, G.; Rai-Constapel, V.; Gilch,
P.; Müller, T. J. J. The Ugi Four-Component Reaction Route
ACKNOWLEDGMENTS
Financial support from CONACYT (284976) is gratefully
acknowledged. Y. A. A.-S. thanks to CONACYT (scholarship
308263). R. F.-C. thanks to CONACYT (scholarship 576635).
We appreciate the technical assistance from Francisco
Javier Pérez Flores, Luis Velasco Ibarra, Ma. Carmen García
González, María de los Ángeles Peña González, Elizabeth
Huerta Salazar, Simón Hernández Ortega, Rubén A. Toscano
(MS, NMR, X-ray) and Ruth Rincón Heredia (PhD., Unidad de
Imagenología del IFC-UNAM, confocal microscopy).
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Table of Contents
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4
R3
X
R2
Het
N
CO2
H
C
5
6
7
8
OMe
O
NH2
Mitochondria
R4
R1
if R4
=
OMe
1) Au(I)/p-TsOH
2) Pd(0)
Lysosome
MeOH Ugi-4CR
if R4
1) p-TsOH
2) Pd(0)
=
CH(OMe)2
R2
O
N
NH
O
X
9
OMe
R1
Fused-Isoquinoline
Plasma
Membrane
Het
10
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-25 examples
-up to 85% yield
-fluorescent probes
R3
R4
OMe
Ugi 4-
Golgi
Apparatus
CR/Propargyl(Dimethylacet
amido) adduct
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